EA045626B1 - COMPLEMENT INHIBITORS BASED ON SUBSTITUTED BENZOFURAN, BENZOPYRROLE, BENZOTHIOPHENE AND THEIR STRUCTURAL DERIVATIVES - Google Patents

Description

Related applications

This patent application claims priority to U.S. Provisional Patent Application No. 62/654,108, filed April 6, 2018.

BACKGROUND OF THE INVENTION

The complement system is a branch of the body's immune system that enhances the ability of antibodies and phagocytic cells to destroy and remove foreign particles (such as pathogens) from the body. The complement system includes a set of plasma proteins that work together to attack extracellular forms of pathogens and induce a range of inflammatory responses that help fight infection. Complement activation can occur in several ways. For example, complement activation can occur spontaneously in response to certain pathogens or by antibody binding to the pathogen. When complement proteins are activated, a cascade is initiated, as a result of which one complement protein induces the activation of the next protein in the sequence. Activation of a small number of complement proteins early in the pathway is greatly enhanced by each subsequent enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response (Marrides, S. Pharmacological Reviews 1998, Vol. 50, pages 59-88). In healthy organisms, regulatory mechanisms exist to prevent uncontrolled complement activation.

When activated, complement proteins can bind to pathogens, opsonizing them for engulfment by phagocytes bearing complement receptors. Small fragments of certain complement proteins then act as chemoattractants to recruit more phagocytes to the site of complement activation and also to activate those phagocytes. Next, complement proteins create holes or pores in penetrating microorganisms, leading to their destruction. Although complement plays an important role in protecting the body from foreign organisms, it can also destroy healthy cells and tissues. Disproportionate activation of complement has been suggested in a long list of disease pathologies (Morgan, B. Eur J Clin Invest 1994, Vol. 24, pages 219-228) affecting the immune, renal, cardiovascular and neurological systems. Accordingly, there is a need to develop additional complement inhibitors that have therapeutic potential in the treatment of numerous disorders.

The essence of the invention

In certain aspects, the invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts and prodrugs thereof:

ί A) where ring O is (C ₆ -C ₁₀ )aryl, heteroaryl, (C ₃ -C ₁₂ )cycloalkyl or heterocycloalkyl;

_ (c)___________,___ ring is furyl;

D?) ring O is (C ₆ -C ₁₀ )aryl or heteroaryl;

R ^a , independently for each case, is selected from the group consisting of halogen, cyano, hydroxy, -NH ₂ , -NHC(O)CH ₃ , -C(O)NH ₂ , (C ₃ -C ₁₂ )cycloalkyl, ( C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl and aminoalkyl;

R ^{b is} , independently for each case, selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C 1 -C ₆ )alkyl, hydroxy(C 1 -C ₆ )alkyl, (C 1 -C ₆ )alkoxy(C 1 -C ₆ )alkyl, (hydroxy)halogen(C 1 -C ₆ )alkyl, hydroxy((C ₃ -C ₁₂ )cycloalkyl)(C ₁ -C ₆ )alkyl, (heterocycloalkyl)(C ₁ -C ₆ )alkylα, heteroaryl(C ₁ -C ₆ )alkyl, (C ₃ -C ₁₂ )cycloalkyl, C(O)((C1-C ₆ )alkyl), and -(C ₁ -C ₆ )alkylene -NR'R ^k ;

R ^{c is} , independently for each case, selected from the group consisting of halogen, -OH and (C ₁ -C ₆ )alkyl;

R ¹ is selected from the group consisting of -NH ₂ , -CH2COOH, -CH(NH(CO)((C ₁ -C ₆ )alkyl))COOH, -CH(NH(CO)((C ₁ -C ₆ ) aryl(C ₁ -C ₆ )alkyl))COOH, -CH(NHC(O)((C ₃ -C ₁₂ )cycloalkyl))COOH,

-CH(NH(CO)((C ₁ -C ₆ )aryl-substituted (C ₃ -C ₁₂ )cycloalkyl)COOH and -CONH(CH ₂ (optionally substituted (C ₆ -C ₁₀ )aryl));

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

J represents -C(O)-, -NH- or -CH2-;

K represents -C(O)-, -NH- or -O-;

where at least one of J and K represents -C(O)- or -CH ₂ -;

L is selected from the group consisting of bonds, -CH ₂ -, -CH ₂ CH ₂ -, -CHR ² -, -C(O)- and -C(=NRL)-;

where RL represents H or alkyl;

- 1 045626 or where R ^l and the present R ^c together with the intermediate atoms form a substituted or unsubstituted heteroaryl ring containing in total from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R ² is (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or halogen(C ₁ -C ₆ )alkyl;

Rj and ^Rk are each independently selected from the group consisting of H, (C ₁ -C ₆ )alkyl, amino(C ₁ -C ₆ )alkyl, (heterocycloalkyl)(C ₁ -C ₆ )alkyl and optionally substituted heterocycloalkyl;

U represents N or CR ³ ;

R ³ represents H, halogen or (C ₁ -C ₆ )alkoxy;

V represents N or CH; And

V represents N or CH;

d heteroaryl refers to a monocyclic, bicyclic or polycyclic aromatic group containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

heterocycloalkyl refers to a monocyclic, bicyclic or polycyclic non-aromatic ring system containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and when the group is substituted, said one or more substituents are independently selected from the group consisting of halogen and (C ₁ -C ₆ )alkyl.

In some aspects, the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

In some aspects, the invention provides methods for treating a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranous proliferative glomerulonephritis, dense sediment disease, cold weather disease agglutinins, catastrophic antiphospholipid syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), IgA nephropathy, age-related macular degeneration (AMD), systemic lupus erythematosus, autoimmune hemolytic anemia with warm agglutinin syndrome, and focal segmental glomerulosclerosis.

Detailed description of the invention

Complement inhibitors are useful in therapeutic methods and compositions suitable for treating disorders of the immune, renal, cardiovascular and neurological systems. Provided herein are compounds of formulas (I) and (II), as well as pharmaceutically acceptable salts and prodrugs thereof, that are useful in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.

Definitions.

In the context of this document, the singular form is used to denote one or more than one (ie, at least one) grammatical object of the description. By way of example, an element means one element or more than one element.

The term heteroatom is recognized in the art and means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

The term alkyl as used herein refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In some embodiments, the straight or branched chain alkyl has 30 or less carbon atoms in its backbone (e.g., C1-C30 for straight chain, _C3 - _C30 for branched chain) and, alternatively, about 20 or less, or 10 or less. In some embodiments, the term alkyl refers to a C ₁ -C ₁₀ alkyl group. In some embodiments, the term alkyl refers to a C1-C6 alkyl group, such as a straight chain C1-C6 alkyl group. In some embodiments, the term alkyl refers to a C3-C12 branched chain alkyl group. In some embodiments, the term alkyl refers to a branched chain C ₃ -C ₈ alkyl group. Typical examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each containing from 3 to 12 carbon atoms. Some cycloalkyls have from 5 to 12

- 2,045,626 carbon atoms in its ring structure and more preferably from 6 to 10 carbon atoms in its ring structure. Preferably, the cycloalkyl is (C ₃ -C ₇ )cycloalkyl, which is a monocyclic saturated carbocyclic ring containing from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexenyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge between one and three additional carbon atoms (i.e., a bridging group of the form -(CH ₂ ) _w -, where w is 1, 2 or 3 ). Representative examples of bicyclic ring systems include bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2. 1]nonane, but not limited to them. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to or phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclyl or monocyclic heteroaryl. A bridged or fused bicyclic cycloalkyl is connected to the parent molecular moiety via any carbon atom within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted. In some embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to or a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocycle, or 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

The term (cycloalkyl)alkyl as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a cycloalkyl is the cyclohexylmethyl group.

The term heterocycloalkyl as used herein refers to a radical of a non-aromatic ring system, including but not limited to monocyclic, bicyclic and tricyclic rings, which may be fully saturated or which may contain one or more units of unsaturation, for the avoidance of doubt the degree of unsaturation does not result in producing an aromatic ring system and contains from 3 to 12 atoms, including at least one heteroatom such as nitrogen, oxygen or sulfur. For purposes of explanation, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1, 3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thiethanyl, thiethyl, diazetidinyl, dioxetanil, dioxetenyl, dithiethanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl , triazinyl, isothiazolyl, isoxazolyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, those trahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolidinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopranil, trithianyl and 2-azobicycl[3.1.0]hexane. The heterocycloalkyl group is optionally substituted with one or more substituents, as described below.

The term (heterocycloalkyl)alkyl as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

The term alkenyl as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl . The unsaturated bond(s) of the alkenyl group may be located anywhere on this moiety and may have either the (Z) configuration or the (E) configuration relative to the double bond(s). .

The term alkynyl as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term alkylene is recognized in the art and, as used herein, refers to a diradical obtained by removing two hydrogen atoms of an alkyl group as defined above. In one embodiment of the invention, alkylene refers to a disubstituted alkane, i.e. an alkane substituted in two positions with such substituents as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amino, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (eg, trifluoromethyl), cyano or the like. Namely, in one embodiment of the invention, the substituted alkyl is alkylene.

The term amino is a term in the art and, as used herein, refers to both unsubstituted and substituted amines, for example a moiety that can be represented by the general formulas:

where Ra, Rb, and Rc each independently represent hydrogen, alkyl, alkenyl, -(CH ₂ ) _x -R _d , or Ra and Rb, taken together with the N atom to which they are attached, complete a heterocycle containing from 4 to 8 atoms in a ring structure; Rd is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclyl; and x is zero or an integer ranging from 1 to 8. In some embodiments, only one of Ra or Rb may be a carbonyl, eg, Ra, Rb, and nitrogen together do not form an imide. In other embodiments, R _a and R _b (and optionally R _c ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) _x -Rd. In some embodiments, the term amino refers to -NH2.

In some embodiments, the term alkylamino refers to -NH(alkyl).

In some embodiments, the term dialkylamino refers to -N(alkyl) ₂ .

The term amido as used herein means -NHC(=O)-, where the amido group is linked to the parent molecular moiety via a nitrogen. Examples of the amido group include alkylamido such as CH3C(=O)N(H)- and CH3CH2C(=O)N(H)-.

The term acyl is a term in the art and, as used herein, refers to any group or radical of the form RCO-, where R is an organic group, such as alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl and malonyl.

The term aminoalkyl as used herein refers to an alkyl group substituted with one or more amino groups. In one embodiment of the invention, the term aminoalkyl refers to an aminomethyl group, i.e. -CH2NH2.

The term aminoacyl is a term in the art and, as used herein, refers to an acyl group substituted by one or more amino groups.

The term aminothionyl as used herein refers to an aminoacyl in which the O from RC(O)- has been replaced by sulfur, thereby forming the RC(S)- form.

The term phosphoryl is a term in the art and is used herein, and in general it can be represented by the formula:

Q5O

OR59 where Q50 is S or O, and R59 is hydrogen, lower alkyl or aryl; for example P(O)(OMe)- or -P(O)(OH) ₂ . When used to substitute, for example, alkyl, the phosphoryl group of phosphorylalkyl can be represented by the general formulas:

Q50 Q50

--Q51—[I--o--- --Q51J-OR59

OR59 OR59 wherein Q50 and R59 are each independently defined above, and Q51 is O, S or N; for example -O-P(O)(OH)OMe or -NH-P(O)(OH) ₂ . When Q50 is S, the phosphoryl moiety is phosphorothioate.

The term aminophosphoryl as used herein refers to a phosphoryl group substituted with at least one amino group as defined herein; for example -P(O)(OH)NMe2.

The term azide or azido as used herein means the group -N ₃ .

The term carbonyl as used herein refers to -C(=O)-.

The term thiocarbonyl as used herein refers to -C(=S)-.

The term alkylphosphoryl as used herein refers to a phosphoryl group substituted with at least one alkyl group as defined herein; for example -P(O)(OH)Me.

The term alkylthio as used herein refers to alkyl-S-. The term (alkyl- 4 045626 thio)alkyl refers to an alkyl group substituted with an alkylthio group.

The term carboxy as used herein means a -CO2H group.

The term aryl is a term in the art and, as used herein, is used to include monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene and pyrene. Typically, an aryl group contains 6-10 carbon ring atoms (ie (C ₆ -C ₁₀ )aryl). The aromatic ring may be substituted at one or more positions on the ring with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl , carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (eg, trifluoromethyl), cyano, and the like. The term aryl also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are fused rings), wherein at least one of the rings is an aromatic hydrocarbon, for example the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls. In some embodiments, the term aryl refers to a phenyl group.

The term heteroaryl is a term in the art and, as used herein, refers to a monocyclic, bicyclic and polycyclic aromatic group having from 3 to 12 common atoms, including in the ring structure one or more heteroatoms such as nitrogen, oxygen or sulfur. Examples of heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadi azolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanil and the like. Heteroaryl may be substituted at one or more positions on the ring with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (eg, trifluoromethyl), cyano, and the like. The term heteroaryl also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are fused rings), wherein at least one of the rings is an aromatic group containing one or more heteroatoms in a ring structure, for example, other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls.

The term aralkyl or arylakyl is a term in the art and, as used herein, refers to an alkyl group substituted by an aryl group, which moiety is attached to the parent molecule via the alkyl group.

The term heteroaralkyl or heteroarylakyl is a term in the art and, as used herein, refers to an alkyl group substituted by a heteroaryl group attached to the parent molecular moiety via an alkyl group.

The term alkoxy as used herein means an alkyl group, as defined herein, attached to the parent molecular moiety via an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy.

The term alkoxyalkyl refers to an alkyl group substituted with an alkoxy group.

The term alkoxycarbonyl means an alkoxy group, as defined herein, attached to the parent molecular moiety via a carbonyl group represented by C(=O)-, as defined herein.

Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

The term alkylcarbonyl as used herein means an alkyl group, as defined herein, attached to the parent molecular moiety via a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

The term arylcarbonyl as used herein means an aryl group, as defined herein, attached to the parent molecular moiety via a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

- 5 045626

The terms alkylcarbonyloxy and arylcarbonyloxy as used herein mean an alkylcarbonyl or arylcarbonyl group, as defined herein, attached to the parent molecular moiety via an oxygen atom. Representative examples of the alkylcarbonyloxy group include, but are not limited to, acetoxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of the arylcarbonyloxy group include, but are not limited to, phenylcarbonyloxy.

The term alkenoxy or alkenoxyl as used herein means an alkenyl group, as defined herein, attached to the parent molecular moiety via an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propen-1-oxyl (ie, CH ₂ =CH-CH ₂ -O-) and vinyloxy (ie, CH ₂ =CH-O-).

The term aryloxy as used herein means an aryl group, as defined herein, attached to the parent molecular moiety via an oxygen atom.

The term heteroaryloxy as used herein means a heteroaryl group, as defined herein, attached to the parent molecular moiety via an oxygen atom.

The term carbocyclyl as used herein means a monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is fully saturated or contains one or more unsaturated bonds, and for the avoidance of doubt the degree of unsaturation does not lead to the formation of an aromatic ring system (for example, phenyl). Examples of carbocyclyl groups are 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.

The term cyano is a term in the art and, as used herein, refers to -CN.

The term halogen is a term in the art and, as used herein, refers to -F, -Cl, -Br or -I.

The term haloalkyl, as used herein, refers to an alkyl group, as defined herein, in which some or all of the hydrogens are replaced by halogen atoms.

The term hydroxy is a term in the art and, as used herein, refers to -OH.

The term hydroxyalkyl, as used herein, means at least one hydroxyl group, as defined herein, attached to the parent molecular moiety by an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3dihydroxypentyl and 2-ethyl-4-hydroxyheptyl.

The term silyl as used herein includes hydrocarbyl derivatives of a silyl (H ₃ Si-) group (i.e. (hydrocarbyl) ₃ Si-), wherein hydrocarbyl groups are monovalent groups formed by the removal of a hydrogen atom from a hydrocarbon, such as ethyl, phenyl The hydrocarbon groups can be combinations of different groups, which can be varied to provide a range of silyl groups such as trimethylsilyl (TMS), t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS) and [2(trimethylsilyl) ethoxy]methyl (SEM).

The term silyloxy as used herein means a silyl group, as defined herein, attached to the parent molecule via an oxygen atom.

Some compounds contained in the compositions of this invention may exist in certain geometric or stereoisomeric forms. In addition, the compounds of this invention may be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (d)-isomers, (l)isomers, racemic mixtures thereof, and other mixtures thereof falling within scope of this invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for example, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved off to obtain the pure desired enantiomers. Alternatively, when the molecule contains a basic functional group such as an amino or an acidic functional group such as carboxyl, diastereomeric salts are formed with a suitable optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of pure enantiomers.

It will be understood that the terms substitution or substituted include the implied

- 6 045626 a disclaimer that such substitution corresponds to the permitted valence of the substituted atom and substituent, and that the substitution results in a stable compound, for example a compound that does not spontaneously undergo a transformation such as rearrangement, fragmentation, decomposition, cyclization, elimination or other reaction .

The term substituted is also intended to include all acceptable substituents for organic compounds. In broad terms, acceptable substituents include acyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above herein. Acceptable substituents may be one or more and may be the same or different for the respective organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and/or any permissible substituents of the organic compounds described herein that satisfy the valency of the heteroatoms. The present invention is not intended to be limited in any way by the permissible organic substituents.

As used herein, the term substituted or unsubstituted when preceding a list of chemical moieties means that in the list of chemical moieties that follows, each element is substituted or unsubstituted. For example, substituted or unsubstituted aryl, heteroaryl and cycloalkyl means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted cycloalkyl.

The phrase protecting group as used herein refers to temporary substitutes that protect a potentially reactive functional group from undesired chemical changes. Examples of such protecting groups are esters of carboxylic acids, silyl esters of alcohols, acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, ^2nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

For the purposes of the invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Other chemical terms in this document are used in accordance with common usage in the art, as shown in The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by links). Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates.

The term pharmaceutically acceptable salt as used herein includes salts derived from inorganic or organic acids, including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2sulfonic and other acids. Pharmaceutically acceptable forms of salts may include forms in which the ratio of the molecules comprising the salt is not 1:1. For example, a salt may contain more than one molecule of inorganic or organic acid per molecule of base, such as two molecules of hydrochloric acid per molecule of a compound of Formula I. In another example, a salt may contain less than one molecule of inorganic or organic acid per molecule of base, such as two molecules of a compound of Formula I per tartaric acid molecule.

The term prodrug as used herein refers to a compound that can be metabolized in vivo to provide a compound of formula I or II. Thus, prodrugs include compounds that can be prepared by modifying one or more functional groups in a compound of formula I or II to provide a corresponding compound that can be metabolized in vivo to provide a compound of formula I or II. Such modifications are known in the art. For example, one or more hydroxyl groups or amine groups in a compound of Formula I or II may be acylated with alkyl-C(=O) groups or amino acid residues to provide a prodrug.

Prodrug forms of a compound bearing various nitrogen-containing functional groups (amino, hydroxyamino, amide, etc.) may include the following types of derivatives, where each R _p group individually can be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, arylalkyl, aralkenyl, aralkynyl, cycloalkyl or cycloalkenyl.

(a) Carboxamides, represented as -NHC(O)R _p .

(b) Carbamates, represented as -NHC(O)OR _p .

(c) (Acyloxy)alkylcarbamates, represented as NHC(O)OROC(O)R _p .

- 7 045626 (d) Enamines, represented as -NHCR(=CHCO2Rp) or -NHCR(=CHCONRpRp).

(e) Schiff bases, represented by -N=CRpRp.

(f) Mannich bases (from carboximide compounds) are represented as RCONHCH2NRpRp.

The preparation of such derivatives of prodrugs is discussed in various literature sources (examples are given: Alexander et al., J. Med. Chem. 1988, 31,318; Aligas-Martin et al., PCT WO 0041531, p. 30).

Prodrugs of carbonyl-bearing compounds include esters (-CO2R _m ), where the R _m group corresponds to any alcohol that will be released in the body by enzymatic or hydrolytic processes at pharmaceutically acceptable levels. Another prodrug derived from the carboxylic acid form herein may be a type of quaternary salt of the structure described by Bodor et al., J. Med. Chem. 1980, 23, 469.

The terms carrier and pharmaceutically acceptable carrier as used herein refer to the diluent, adjuvant, excipient or vehicle by which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline solutions and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring and coloring agents can be used. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, incorporated by reference in its entirety.

The term treat as used herein means to prevent, stop, slow, or eliminate the progression of a disease or condition in a subject. In one embodiment of the invention, to treat means to stop, slow, or eliminate the progression of a disease or condition in a subject. In one embodiment of the invention, to treat means to reduce at least one objective manifestation in a subject of a disease or condition.

The term effective amount as used herein refers to an amount sufficient to achieve the desired biological effect.

The term therapeutically effective amount as used herein refers to an amount sufficient to achieve the desired therapeutic effect.

The term inhibit as used herein means a decrease by an objectively measurable amount or degree. In various embodiments of the invention, inhibit means a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95 percent compared to the corresponding control. In one embodiment of the invention, inhibit means reduce by 100 percent, i.e. stop or eliminate.

The term subject as used herein refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment of the invention, the subject is a human.

Connections.

The present invention provides compounds having the structure of formula (I), and their pharmaceutically acceptable salts or prodrugs:

wherein ring VV is (C ₆ -C ₁₀ )aryl, heteroaryl, (C ₃ -C ₁₂ )cycloalkyl or heterocycloalkyl;

the ring is furyl;

the ring is (C ₆ -C ₁₀ )aryl or heteroaryl;

R ^a , independently for each case, is selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NHC(O)CH ₃ , -C(O)NH ₂ , (C ₃ -C ₁₂ )cycloalkyl, (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl and aminoalkyl;

R ^{b is} , independently for each case, selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkylα, (hydroxy)halogen(C ₁ -C ₆ )alkyl, hydroxy((C ₃ -C ₁₂ )cycloalkyl)(C ₁ -C ₆ )alkyl, (heterocycloalkyl)(C ₁ -C ₆ )alkyl, heteroaryl(C ₁ -C ₆ )alkyl, (C ₃ -C ₁₂ )cycloalkyl, C(O)((C1-C ₆ )alkyl), and -(C ₁ -C ₆ )alkylene -NR ^j R ^k ;

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R ^{c is} , independently for each case, selected from the group consisting of halogen, -OH and (C1- _C6 )alkyl;

R1 is selected from the group consisting of -NH2, -CH2COOH, -CH(NH(CO)((C ₁ -C ₆ )alkyl))COOH,

-CH(NH(CO)((C1-C6)aryl(C1-C6)alkyl))COOH, -CH(NHC(O)((C3-C12)cycloalkyl))COOH,

-CH(NH(CO)((C ₁ -C ₆ )aryl-substituted (C ₃ -C ₁₂ )cycloalkyl)COOH and -CONH(CH ₂ (optionally substituted (C6-C ₁₀ )aryl));

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

J represents -C(O)-, -NH- or -CH2-;

K represents -C(O)-, -NH- or -O-;

where at least one of J and K is -C(O)- or -CH2-;

L is selected from the group consisting of bonds, -CH2-, -CH2CH2-, -CHR ² -, -C(O)- and -C(=NR ^L )-;

where RL represents H;

or wherein RL and the present R ^c together with intermediate atoms form a substituted or unsubstituted heteroaryl ring containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R ² is (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or halogen(C ₁ -C ₆ )alkyl;

Rj and ^Rk are each independently selected from the group consisting of H, (C ₁ -C ₆ )alkyl, amino(C ₁ -C ₆ )alkyl, (heterocycloalkyl)(C ₁ -C ₆ )alkyl and optionally substituted heterocycloalkyl;

U represents N or CR ³ ;

R ³ represents H, halogen or (C ₁ -C ₆ )alkoxy; And

V represents N or CH;

where heteroaryl refers to a monocyclic, bicyclic or polycyclic aromatic group containing in total from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

heterocycloalkyl refers to a monocyclic, bicyclic or polycyclic non-aromatic ring system containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and when the group is substituted, said one or more substituents are independently selected from the group consisting of halogen and (C ₁ -C ₆ )alkyl.

In some embodiments, a compound of formula (I) has the structure of formula (Ia):

R' J—К ,Α ^(R ^“®OT ^(Ra>₽

W^z Λ 'Y^L-NH _{2 (Ia);} where W represents N, CH or CR ^c ;

X represents N, CH or CR ^c ;

Y is N, CH or CR ^c ; And

Z represents N, CH or CR ^c , wherein ring A, ring B, ring C, R ^a , R ^b , R ^c , R ¹ , U, V, J, K, L, p and m are as defined higher.

In some embodiments, ring CE) is naphthyl, indenyl, cyclopentyl, pyrrolidinyl, phenyl, benzofuranyl, thiophenyl, or pyridinyl.

In some embodiments, ring W is phenyl, thiophenyl, or pyridinyl, preferably phenyl.

In some embodiments, a compound of formula (I) has the structure of formula (Ib):

in this case, the ring B, R ^a , R ^b , R ¹ , U, V, J, K, L, W, X, Y, Z, p and m are as defined above.

In some embodiments, p is equal to 1.

- 9 045626

In some such embodiments, R ^a is halogen, cyano, hydroxy, -NHC(O)CH3, -C(O)NH ₂ , (C ₃ -C ₁₂ )cycloalkyl, (C ₁ -C ₆ )alkyl, hydroxy (C ₁ -C ₆ )alkyl or aminoalkyl.

In other such embodiments, R ^a is halogen, cyano, -NH ₂ , -NH(Ac), -C(O)CH ₃ , -C(O)NH2, hydroxymethyl, or substituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy, alkyl or aminoalkyl.

In other such embodiments, R ^a is halogen, -NH(Ac), -C(O)CH ₃ or substituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy, alkyl or aminoalkyl. In additional such embodiments, R ^a is alkyl, cycloalkyl, or halogen.

Alternatively, in some embodiments of the invention, p is 0.

In some embodiments, R ¹ is -CH2COOH.

Alternatively, in some embodiments, R ¹ is -CO(NH)CH ₂ (substituted or unsubstituted (C ₆ -C ₁₀ )aryl).

In some embodiments:

J represents -C(O)-, -NH-, -CH ₂ -; And

K represents -C(O)-, -NH-, -O-.

In some embodiments, -J-K- is selected from the group consisting of -C(O)NH-, -NH-C(O)- and -CH2O-, preferably -CH2O-.

In some embodiments, U is N or CR ³ and R ³ is H, halogen or (C ₁ -C ₆ )alkoxy.

In some embodiments, U is CH. In additional embodiments, V is CH.

Alternatively, in some embodiments, U is CR ³ and R ³ is H, halogen, alkyl, alkoxy, or haloalkyl.

In some embodiments, a compound of formula (I) has the structure of formula (Ic):

Alternatively, in some embodiments, a compound of formula (I) has a structure of formula (Id):

It has

In still additional structure of formula (Ie):

In embodiments of the invention, the compound of formula (I) has

In other further embodiments, the compound of formula (I) has the structure of formula (If):

It has

- 10 045626 (V)

In any of the above embodiments, the '—' ring is furyl.

In some embodiments, m is 0.

In some embodiments, m is 1. In some embodiments, R ^b is, in each case, halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, hydroxy(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (hydroxy)halogen(C ₁ -C ₆ )alkyl, hydroxy((C ₃ -C ₁₂ )cycloalkyl)(C ₁ - C ₆ )alkyl, (heterocycloalkyl)(C1-C ₆ )alkyl, heteroaryl(C1-C ₆ )alkyl, (C ₃ C ₁₂ )cycloalkyl, -C(O)((C1-C ₆ )alkyl) or -( C ₁ -C ₆ )alkylene-NR'R ^k .

In other such embodiments, R ^b is selected from the group consisting of substituted or unsubstituted (C ₁ -C ₆ )alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and (cycloalkyl)alkyl. In alternative embodiments, R ^b is -alkylene-NR'R ^k .

In other embodiments, m is 2. In some such embodiments, each R ^b is (C ₁ -C ₆ )alkyl.

In some such embodiments, W, X, Y, and Z are each CH.

In some such embodiments, at least one of W, X, Y and Z is CR ^c . For example, Z may be CR ^c and/or Y may be CR ^c . In some such embodiments, R ^c is selected from the group consisting of halogen, -OH, -NRjR ^k , alkoxy, and alkyl. In some preferred embodiments of the invention, R ^c is a halogen, such as fluoride.

Alternatively, at least W, X, Y, and Z are N. For example, Z may be N. Alternatively, Y may be N.

In some embodiments, L is selected from the group consisting of the bond, -CH2-, -CH2CH2-, -CHR ² -, -C(O)-, and -C(=NR ^l )-.

In some embodiments, L is -CH2-.

In some embodiments of compounds of formula (I):

vO 5 ~ (С С Ί (С С Ί ring BC is (Cb-Ciu)aryl, heteroaryl, (C3-C12)cycloalkyl or heterocycloalkyl;

the hU ring is furyl;

ring W is (C6-C ₁₀ )aryl or heteroaryl;

R ^a , independently for each case, is selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NHC(O)CH ₃ , -C(O)NH ₂ , (C ₃ -C ₁₂ )cycloalkyl, (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl and aminoalkyl;

R ^{b is} , independently for each case, selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (hydroxy)halogen(C ₁ -C ₆ )alkyl, hydroxy((C ₃ -C ₁₂ )cycloalkyl)(C 1 -C6)alkyl, (heterocycloalkyl)(C 1 -C6)alkyl, heteroaryl(C 1 -C6)alkyl, (C ₃ -C ₁₂ )cycloalkyl, C(O)((C ₁ -C6)alkyl), and -(C ₁ -C ₆ )alkylene-NR'^Rk;

R ^{c is} , independently for each case, selected from the group consisting of halogen, -OH and (C1- _C6 )alkyl;

R ¹ is selected from the group consisting of -NH2, -CH2COOH, -CH(NH(CO)((C ₁ -C ₆ )alkyl))COOH, -CH(NH(CO)((C1-C6)aryl(C1 -C6)alkyl))COOH, -CH(NHC(O)((C3-C12)cycloalkyl))COOH,

-CH(NH(CO)((C ₁ -C ₆ )aryl-substituted (C ₃ -C ₁₂ )cycloalkyl)COOH and -CONH(CH ₂ (optionally substituted (C ₆ -C ₁₀ )aryl));

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

J represents -C(O)-, -NH- or -CH2-;

K represents -C(O)-, -NH- or -O-;

where at least one of J and K is -C(O)- or -CH2-;

L is selected from the group consisting of bonds, -CH2-, -CH2CH2-, -CHR ² -, -C(O)- and -C(=NR ^L )-;

where R ^l represents H;

or wherein R ^L and the present R ^c , together with intermediate atoms, form a substituted or unsubstituted heteroaryl ring containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R ² is (C1-C ₆ )alkyl, hydroxy(C1-C ₆ )alkyl or halogen(C1-C ₆ )alkyl;

Rj and ^Rk are each independently selected from the group consisting of H, (C1- _C6 )alkyl, amino(C1- _C6 )alkyl, (heterocycloalkyl)(C1- _C6 )alkyl, and optionally substituted heterocycloalkyl;

U represents N or CR ³ ;

R ³ represents H, halogen or (C1-C ₆ )alkoxy; And

- 11 045626

V represents N or CH;

where heteroaryl refers to a monocyclic, bicyclic or polycyclic aromatic group containing in total from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

heterocycloalkyl refers to a monocyclic, bicyclic or polycyclic non-aromatic ring system containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and when the group is substituted, said one or more substituents are independently selected from the group consisting of halogen and (C ₁ -C ₆ )alkyl.

In some embodiments, a compound of formula (I) is selected from the following table of compounds and pharmaceutically acceptable salts and prodrugs thereof:

- 12 045626

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zA ν% θ dd νη ₂ νη ₂ ΟΛΧΓ ^οΧ ζ" »τςτ°Α .,% ⁰ ,10 I M Z z=/ cA Ξ\\__/ ΟΌ o o z Ά -:5......V ^h 2 ⁿ JXj х°А n^А%% _з ^cr°A .,% °

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nh ₂

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Xr-χ χχ« MX* ¹ ! tex." δ/τΧ X °Χ%. X? χχ ^Η 2 ^Ν Χ^ ^: ΧΧ· Χ°Χ H?X _N J χΧ« α»Χ° <χ ⁷ -.-ΑγΧ» X ° χχ" ^Η ! ^Ν Χ

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In some embodiments, p is equal to 0.

In some embodiments, R ¹ is -CH2COOH.

In some embodiments, -J-K- is selected from the group consisting of -C(O)NH-, -NH-C(O)- and -CH2O-, preferably -CH2O-.

In some embodiments, U is CH. In additional embodiments, V is CH.

In some such embodiments, W, X, Y, and Z are each CH.

In some such embodiments, at least one of W, X, Y and Z is CR ^c . For example, Z may be CR ^c and/or Y may be CR ^c . In some such embodiments, R ^c is a halogen, such as fluoride.

Alternatively, at least W, X, Y, and Z are N. For example, Z may be N. Alternatively, Y may be N.

In some embodiments, L is -CH2-.

In some embodiments, a compound of the present invention is selected from the following table of compounds and pharmaceutically acceptable salts and prodrugs thereof:

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OD .0H .0H CoX r H2JU X 41? X ) ΝγΝ ^H T Ή ^F X> ⁿ G <w % OUL ί H ₂ N,4x4 CH ₃ n/X νΛ^ο \ N<4 0 ,ΟΗ h ₂ nXX _f ch ₃ J cux..^ VHO j F./L o ji i n ₂ m^A^

'7 uQ V _x nh ₂ X ^NH ₂ ~„.o ^NyJ n ₂ ^m EO V α Ν^Ν w V iii 0 ^η ₂ Ν^Λ^ ίΧ "ιΤ X X О £ЛХ^° zx θ=< n ₂ nEM U AA 4 ABOUT ^F \zA ^H 2 ^N ^JU Yes U ^soon nh ₂ 7 Phil UL _χ νη ₂

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Pharmaceutical compositions.

The invention provides pharmaceutical compositions, each of which contains one or more compounds of this invention or pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition contains a compound of this invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition contains a plurality of compounds of this invention, which may include pharmaceutically acceptable salts and/or prodrugs thereof, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition of this invention further includes at least one additional pharmaceutically active agent other than a compound of this invention. At least one additional pharmaceutically active agent may be useful in treating a disease or condition characterized by aberrant complement system activity.

The pharmaceutical compositions of this invention can be prepared by combining one or more compounds of this invention with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutically active agents.

Methods of application.

The present invention provides compounds and their pharmaceutically acceptable salts and prodrugs that are useful for treating or preventing a disease or condition characterized by aberrant activity of the complement system.

In some aspects, the invention provides a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, for use as a drug.

In some aspects, the invention provides methods for treating or preventing a disease or condition characterized by aberrant complement system activity. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of this invention or a pharmaceutically acceptable salt or prodrug thereof, thereby treating or preventing a disease or condition characterized by aberrant activity of the complement system. By reducing the activity of the complement system in a subject, a disease or condition characterized by aberrant complement system activity is cured.

Alternatively, in some aspects, the invention provides a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, for treating a disease or condition characterized by aberrant complement system activity.

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Alternatively, in some aspects, the invention provides the use of a compound of this invention, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for use in treating a disease or condition characterized by aberrant complement system activity.

As used herein, the phrase disease or condition characterized by aberrant activity of the complement system refers to any disease or condition in which it is desirable to reduce the activity of the complement system. For example, it may be desirable to reduce the activity of the complement system in conditions of inappropriate activation or hyperactivation of the complement system.

In some embodiments, the disease or condition characterized by aberrant complement system activity is an immunological disorder.

In some embodiments, the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system.

In some embodiments, the disease or condition characterized by aberrant activity of the complement system is a kidney disease.

In some embodiments, the disease or condition characterized by aberrant complement system activity is a cardiovascular disease.

In some embodiments, the disease or condition characterized by aberrant complement system activity is a neurodegenerative disease or neurological disease.

In some embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranous proliferative glomerulonephritis, dense sediment disease, cold weather disease agglutinins and catastrophic antiphospholipid syndrome.

In some embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

In some embodiments, the disease or condition is atypical hemolytic uremic syndrome.

In some embodiments, the disease or condition is organ transplant rejection.

In some embodiments, the disease or condition is myasthenia gravis.

In some embodiments, the disease or condition is neuromyelitis optica.

In some embodiments, the disease or condition is membrane proliferative glomerulonephritis.

In some embodiments of the invention, the disease or condition is a dense sediment disease.

In some embodiments, the disease or condition is a cold agglutinin disease.

In some embodiments, the disease or condition is catastrophic antiphospholipid syndrome.

In other embodiments, the disease or condition characterized by aberrant complement system activity is adult airway distress syndrome, myocardial infarction, pneumonia, hyperactive rejection (transplant rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis , multiple organ dysfunction syndrome, Guillain-Barré syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, organ rejection (transplantation), myasthenia gravis, multiple sclerosis, platelet storage or hemodialysis.

In other embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

In some embodiments, the disease or condition characterized by aberrant activity of the complement system is a hematological disorder.

In other embodiments of the invention, a disease or condition characterized by

- 64 045626 aberrant activity of the complement system, constitutes an ocular disorder or ocular disorder.

In some embodiments, the disease or condition characterized by aberrant complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behçet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization disease, post-transplant corneal rejection, corneal degeneration disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjögren's syndrome, environmentally induced dry eye disease, Fuchs' endothelial dystrophy, retinal vein occlusion or postoperative inflammation.

Formulations, routes of administration and dosage.

The compounds of this invention and their pharmaceutically acceptable salts or prodrugs can be formulated into pharmaceutical compositions and administered to a mammalian host, for example a human patient, in various forms adapted to the chosen route of administration, for example, orally or parenterally, intravenous, intraperitoneal, intramuscular, topical or subcutaneous routes. This invention also contemplates additional routes of administration.

Thus, the present compounds can be administered systemically, for example orally, in combination with a pharmaceutically acceptable carrier vehicle, such as an inert diluent or digestible edible carrier. They may be enclosed in hard or soft gelatin capsules, compressed into tablets, or may be included directly in the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and administered in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations must contain at least 0.1% of the active compound. The percentage of compositions and preparations may, of course, vary and may conveniently range from 2% to 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

Tablets, lozenges, tablets, capsules and the like may also contain the following diluents and carriers: binders such as gum tragacanth, gum acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame, or a flavoring agent such as peppermint, oil of wintergreen or cherry flavor may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. A variety of other materials may be present as coatings or may otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like. The syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, coloring and a flavoring agent such as cherry or orange flavoring. Of course, any material used in the preparation of any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compound may be formulated into sustained release formulations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water or a physiologically acceptable aqueous solution, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerin, liquid polyethylene glycols, triacetin and mixtures thereof, and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions, or sterile powders, containing the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusion solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form must be sterile, liquid and stable under conditions of manufacture and storage. The liquid carrier or carrier medium may be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (eg, glycerin, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by forming liposomes, by maintaining the required particle size in the case of dispersions, or by using surfactants. Prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases it is preferable to include isotonic agents such as sugars, buffers or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using absorption delaying agents in the compositions, such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in required quantity in a suitable diluent with various other ingredients listed above as per requirement and followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, preparation methods may include vacuum drying and lyophilization techniques that yield a powder of the active ingredient plus any additional desired component present in pre-sterile-filtered solutions.

For topical application, the present compounds can be used in pure form, that is, when they are liquid. However, it is generally desirable to apply them to the skin in the form of compositions or formulations in combination with a dermatologically acceptable carrier, which may be solid or liquid.

Suitable solid carriers include fine solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Suitable liquid carriers include water, alcohols or glycols or water-alcohol/glycol mixtures in which the present compounds can be dissolved or dispersed at effective levels, optionally with the help of non-toxic surfactants. Adjuvants such as flavors and additional antimicrobial agents may be added to optimize properties for a given application. The resulting liquid compositions can be applied using absorbent wipes, used to impregnate bandages and other dressings, or, for example, sprayed onto the affected area using pump or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified celluloses or modified minerals can also be used with liquid carriers to form easily spreadable pastes, gels, ointments, soaps and the like, for direct application to the user's skin.

Examples of useful dermatological compositions that can be used to deliver the compounds of this invention to the skin are known in the art; for example see Jacquet et al. (U.S. Patent No. 4,608,392; incorporated herein by reference), Geria (U.S. Patent No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Patent No. 4,559,157; incorporated herein by reference) and Wortzman (U.S. Patent No. 4,820,508; incorporated herein by reference).

Suitable dosages of the compounds of this invention may initially be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; for example, see US Patent No. 4,938,949 (incorporated herein by reference).

The amount required for use in treatment of a compound, or a pharmaceutically acceptable salt or prodrug thereof, will depend not only on the particular compound, salt or prodrug, but also on the route of administration, the nature of the disease being treated and the age and condition of the patient, and ultimately, will depend on the judgment of the attending physician or clinician.

In general, however, a suitable dose will range from about 0.5 to about 100 mg/kg of recipient body weight per day, for example from about 3 to about 90 mg/kg body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, from about 10 to about 60 mg/kg body weight per day, or from about 15 to about 50 mg/kg body weight per day.

The compounds of this invention, or pharmaceutically acceptable salts or prodrugs thereof, may conveniently be formulated in unit dosage form, eg, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition containing a compound of this invention or pharmaceutically acceptable salts or prodrugs thereof formulated in such a unit dosage form. The desired dose may conveniently be administered in a single dose or in divided doses administered simultaneously at appropriate intervals, for example in two, three, four or more portions per day. The portion of the dose itself may be further divided, for example into a number of separate, freely spaced administrations.

The compounds of this invention, or pharmaceutically acceptable salts or prodrugs thereof, may also be administered in combination with other therapeutic agents, for example with other agents that are useful for treating or preventing ischemia, blood loss, or reperfusion injury. In some embodiments, the compounds of this invention, or pharmaceutically acceptable salts or prodrugs thereof, may also be administered in combination with one or more other therapeutic agents that are useful for treating or preventing ocular

- 66 045626 disorders or ocular disorders.

Other delivery systems may include sustained release, delayed release, or slow release delivery systems, as are well known in the art. Repeated administrations of the active compound can be avoided with such systems, increasing convenience for the subject and the physician. Many types of controlled release delivery systems are available and well known to those of ordinary skill in the art. It may be desirable to use a continuous slow release implant. Sustained release as used herein means that the delivery system or implant is designed and configured to deliver therapeutic levels of the active ingredient for at least 30 days and preferably 60 days.

In some embodiments, a compound of this invention is formulated for intraocular administration, such as direct injection or administration orally or in conjunction with an intraocular medical device. In some embodiments, the compound of this invention is formulated as an ophthalmic solution. In some embodiments, a compound of this invention may be administered via ocular delivery, such as local ocular administration, including topical, intravitreal, periocular, transscleral, retrobulbar, periscleral, suprachoroidal, or sub-Tenon's administration. A compound of this invention may be administered via ocular delivery either alone or in combination with one or more additional therapeutic agents.

The compounds of this invention may be formulated for placement in a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other device that may be placed or permanently implanted within a body lumen. As a specific example, it is desirable to have devices and methods that can deliver the compounds of this invention to an area of the body that has been prepared by invasive techniques.

In an exemplary embodiment, a compound of this invention may be placed within a medical device, such as a stent, and delivered to a treatment site to treat a part of the body.

Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are usually permanently implanted in coronary or peripheral vessels. Stent designs include those described in US Patent No. 4,733,655 (Palmaz), US Patent No. 4,800,882 (Gianturco), or US Patent No. 4,886,062 (Wiktor). These designs include both metal and polymer stents, as well as self-expanding stents and balloon-expandable stents. Stents can also be used to deliver drugs at the site of contact with the vascular system, as disclosed in US Patent No. 5,102,417 (Palmaz), US Patent No. 5,419,760 (Narciso, Jr.), US Patent No. 5,429,634 (Narciso, Jr. .) and in international patent applications No. WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), for example.

The term deposited means that the compound is applied, adsorbed, placed or otherwise incorporated into the device by methods known in the art. For example, the compound may be embedded in and released from polymeric materials (matrix type) or surrounded by and released through polymeric materials (reservoir type) that coat or surround the medical device. In the latter example, the compound may be incorporated within or bound to polymeric materials using one or more techniques for preparing such materials known in the art. In other formulations, the compound may bind to the surface of the medical device without the need for coating, such as through release bonds, and be released over time or may be removed by active mechanical or chemical processes. In other formulations, the compound may be in a permanently immobilized form that presents the compound at the site of implantation.

In some embodiments, the compound may be formulated with polymer compositions during the formation of biocompatible coatings for medical devices, such as stents. Coatings obtained from these components are generally uniform and suitable for coating a range of devices intended for implantation.

The polymer can be either biostable or bioabsorbable depending on the desired release rate or the desired degree of stability of the polymer, but often this embodiment is preferable to using a bioabsorbable polymer because, unlike a biostable polymer, it will not be present long after implantation to cause any adverse chronic local reaction. Bioabsorbable polymers that may be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA/PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), polyC-lactic acid), poly(D,L-lactic acid), poly(D, L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-trimethylene carbonate) (PGA/PTMC), polyethylene oxide (PEO), polydioxanone (PDS), complex poly

- 67 045626 phosphoester, polyurethane polyphosphoester, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ester-esters) (e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin , fibrinogen, cellulose, starch, collagen and hyaluronic acid, poly-epsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, cross-linked or amphipathic block copolymers of hydrogels and other suitable bioabsorbable poplymers known in the art. Biostable polymers with relatively low chronic tissue response may also be used, such as polyurethanes, silicones and polyesters, and other polymers may also be used if they can be dissolved and cured or polymerized on the medical device, such as polyolefins, polyisobutylene-ethylene-alpha copolymers -olefins; acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatic compounds such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins such as ethylene methyl methacrylate copolymers, acrylonitrile styrene copolymers, ABS resins and ethylene vinyl acetate copolymers; pyran copolymer; polyhydroxypropyl methacrylamide phenol; polyhydroxyethyl aspartamide phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyesters; epoxy resins, polyurethanes; viscose; viscose triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose.

Polymers and semi-permeable polymer matrices can be formed into shaped articles such as valves, stents, tubes, prostheses and the like.

In some embodiments, the compound of this invention is associated with a polymer or semi-permeable polymer matrix that is formed into a stent or stent graft.

Typically, polymers are applied to the surface of an implantable device by spin coating, dipping, or spraying. For this purpose, additional methods known in the art can also be used. Spraying methods include both traditional methods and micro-deposition methods using a jet-type dispenser. In addition, the polymer can be deposited onto the implantable device using photolithography to place the polymer only on certain parts of the device. This device coating provides a uniform layer around the device, which allows for improved diffusion of various analytes through the device coating.

In some embodiments of the invention, the compound is formulated for release from the polymer coating into the environment in which the medical device is placed. Preferably, the compound is released in a controlled manner over an extended period of time (eg, months) using at least one of several well-known methods using polymeric carriers or layers to control elution. Some of these methods are described in US patent application 2004/0243225 A1, the full disclosure of which is included herein in its entirety.

Moreover, as described, for example, in US Pat. No. 6,770,729, which is incorporated herein in its entirety, the reagents and reaction conditions of the polymer compositions can be adjusted so that the release of the compound from the polymer coating can be controlled. For example, the diffusion coefficient of one or more polymer coatings can be modulated to control the release of a compound from the polymer coating. In a variation on this topic, the diffusion coefficient of one or more polymer coatings can be controlled to modulate the ability of an analyte present in the environment in which the medical device is located (for example, an analyte that facilitates the degradation or hydrolysis of some portion of the polymer) to gain access to one or more more components within the polymer composition (and, for example, thereby modulating the release of the compound from the polymer coating). Another embodiment of the invention is a device having a plurality of polymer coatings, each of which has a plurality of diffusion coefficients. In such embodiments, the release of the compound from the polymer coating can be modulated by a plurality of polymer coatings.

In yet another embodiment of the invention, the release of a compound from the polymer coating is controlled by modulating one or more properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds, or, alternatively, the pH of the polymer composition. For example, some polymer compositions may be designed to release a compound in response to a decrease in the pH of the polymer composition.

Sets.

The invention also provides a kit containing a compound of this invention or

- 68 045626 a pharmaceutically acceptable salt or prodrug thereof, at least one other therapeutic agent, packaging material and instructions for administering a compound of this invention or a pharmaceutically acceptable salt or prodrug thereof, and other therapeutic agent or agents to a mammal for the treatment or prevention of a disease or condition , characterized by aberrant complement activity. In one embodiment, the mammal is human.

One of ordinary skill in the art will appreciate that other suitable modifications and adaptations with respect to the compositions and methods described herein are readily apparent from the description of the invention contained herein in light of information known to one of ordinary skill in the art and may be made without departing from the scope of the invention or any embodiment thereof.

Examples

Having described the present invention in detail, it will also be more clearly understood by considering the following examples, which are included herein for purposes of illustration only and are not intended to limit the present invention.

Scheme-1

Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (1h).

Stage-1. Preparation of 2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b).

To a solution of 2,4-dichloropyrrolo[2,1-1][1,2,4]triazine (1a) (3 g, 15.96 mmol, CAS No. 918538-05-3) in DMF (50 ml) in atmosphere Ar added 1-ethoxyvinyl-tri-n-butyltin (7.07 ml, 20.74 mmol, CAS No. 97674-02-7) and bis(triphenylphosphine) palladium(P) chloride (0.56 g, 0.8 mmol ). The mixture was heated with stirring at 100°C for 30 minutes, cooled to room. pace. and diluted with EtOAc (150 ml). The reaction mixture was washed with water (50 ml), brine (30 ml), dried, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in hexane] to give 2-chloro-4-(1ethoxyvinyl)pyrrolo[2,1-1][1,2 ,4]triazine (1b) (2.2 g, 62% yield) as an orange oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.23 (dd, J=2.6, 1.4 Hz, 1H), 7.34 (dd, J=4.7, 1.4 Hz, 1H ), 7.11 (dd, J=4.7, 2.6 Hz, 1H), 5.64 (d, J=2.4 Hz, 1H), 4.88 (d, J=2.4 Hz , 1H), 4.03 (k, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).

Stage-2. Preparation of ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c).

Sodium periodate (1.17 g, 5.47 mmol) was suspended in water (9 ml) and sonicated until a clear solution was obtained (pH ~4). This solution was added to a solution of 2-chloro-4-(1ethoxyvinyl)pyrrolo[2,1-1][1,2,4]triazine (1b) (612 mg, 2.74 mmol) in 1,4-dioxane (40 ml). KMnO ₄ (43 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 7-8 using saturated aqueous K ₂ CO ₃ solution. The precipitate was filtered off and washed thoroughly with DCM (4x20 ml). The combined filtrates were washed with water, brine, dried, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give ethyl 2-chloropyrrolo[2,1-1][1,2,4]triazine-4 -carboxylate (1c) (212 mg, 34% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (dd, J=2.5, 1.3 Hz, 1H), 7.45 (dd, J=4.8, 1.3 Hz, 1H ), 7.30 (dd, J=4.8, 2.5 Hz, 1H), 4.47 (k, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz , 3H).

Stage-3. Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1G][1,2,4]triazine-4-carboxylic acid (1e).

3-((tert- butoxycarbonylamino)methyl)phenylboronic acid (1d) (192 mg,

- 69 045626

0.77 mmol; CAS No. 199609-62-6), potassium triphosphate (282 mg, 1.33 mmol) in water (1 ml), tricyclohexylphosphine (56 mg, 0.2 mmol) and Pd ₂ (dba) ₃ (61 mg, 0. 07 mmol). The mixture was degassed and filled with Ar, and then heated at 125°C for 30 min. The mixture was cooled to room temperature, diluted with EtOAc, washed with water, brine, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 30%] to give 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1 -!][1,2,4]triazine-4-carboxylic acid (1e) (150 mg, 61% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.21-8.08 (m, 3H), 7.53 (dd, J=11.2, 5.0 Hz, 1H), 7.46 ( d, J=7.6 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.14-7.08 (m, 1H), 7.06-7.00 (m , 1H), 4.22 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Stage-4. Preparation of methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f] [1,2,4]triazine-4-carboxamido)phenyl)acetate (1f ).

To a solution of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxylic acid (1e) (95 mg, 0.26 mmol ) to DMF (8 ml) was added methyl 2-(2-aminophenyl) acetate (51 mg, 0.31 mmol, CAS No. 35613-44-6), DIPEA (0.14 ml, 0.77 mmol) and HATU ( 118 mg, 0.31 mmol). The resulting mixture was stirred at RT overnight, diluted with EtOAc (60 ml), washed with water (3 times), brine, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] to give methyl 2-(2-(2-( 3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1f) (98 mg, 74% yield) as white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.41-8.31 (m, 2H), 7.82-7.75 (m, 1H), 7.58-7.48 (m, 3H), 7.46-7.37 (m, 3H), 7.31-7.23 (m, 2H ), 4.27 (d, J=6.1 Hz, 2H), 3.89 (s, 2H), 3.56 (s, 3H), 1.41 (s, 9H).

Stage-5. Preparation of methyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-N1,2,4]triazine-4carboxamido)phenyl)acetate (1g).

To a solution of methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1!][1,2,4]triazine-4-carboxamido)phenyl)acetate (1f) (92 mg, 0.18 mmol) in DCM (8 ml) was added TFA (0.28 ml, 3.57 mmol). The resulting mixture was stirred at RT for 2 hours and concentrated under vacuum to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] to give compound (1g) (73 mg, 98% yield) as a yellow solid, 23 mg converted into HCl salt, and lyophilized to give methyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate ( 1g) (25 mg), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H, D ₂ O replaceable), 8.69-8.62 (m, 1H), 8.58 (d, J=7.5 , 1.6 Hz, 1H), 8.50-8.39 (m, 3H, D2O replaceable), 8.39-8.33 (m, 1H), 7.77-7.56 (m, 4H) , 7.47-7.36 (m, 2H), 7.34-7.24 (m, 2H), 4.23-4.11 (m, 2H), 3.90 (s, 2H), 3 .55 (s, 3H); MS (ESI+): 416.3 (M+1); (ESI-): 414.4 (M-1), 450.3 (M+Cl); HPLC, purity 92.70%.

Stage-6. Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-!][1,2,4]triazine-4carboxamido)phenyl)acetic acid (1h).

To a solution of methyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-N1,2,4]triazine-4carboxamido)phenyl)acetate (1g) (62 mg, 0.15 mmol) to THF (10 ml) was added lithium hydroxide monohydrate (63 mg, 1.49 mmol) in water (2 ml). The resulting mixture was stirred at room. pace. during the night. The THF was removed in vacuo, the resulting residue was acidified to pH 4 by adding HCl (2N), the resulting solid was collected by filtration, washed with water (3x2 ml) and dried in vacuo to give 2-(2-(2-(3-(aminomethyl)phenyl )pyrrolo[2,1-!][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (1h) (36 mg, 61% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H, _D2O replaceable), 9.36 (s, 1H), 9.19 (s, 3H, _D2O replaceable), 8, 43-8.33 (m, 1H), 8.33-8.21 (m, 1H), 8.00-7.84 (m, 1H), 7.72-7.61 (m, 1H), 7.60-7.48 (m, 2H), 7.34-7.22 (m, 3H), 7.19-7.05 (m, 1H), 4.13 (s, 2H), 3. 50 (s, 2H); MS (ESI+): 402.4 (M+1); (ESI-): 400.4 (M-1); purity after HPLC 90.46%.

- 70 045626

Scheme-2

2d 2e 2f

Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4carboxamido)phenyl)acetic acid (2f).

Stage-1. Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5Hcyclopenta[d]pyrimidine-4-carboxylate (2b).

Compound 2b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloro-6,7-dihydro-5H-cyclopenta[d]nirimidine-4-carboxylateα (2a) (200 mg, 0.88 mmol; CAS No. 1660116-32-4; prepared according to the procedure described by Blaquiere, Nicole et al, PCT International Application, 2015025026, February 26, 2015) in DMF (20 ml) using 3-((tert-butoxycarbonylamino)methyl) phenylboronic acid (1d) (251 mg, 0.97 mmol), potassium fluoride (169 mg, 2.91 mmol), tri-tert-butylphosphine (1.59 ml, 1.59 mmol) and Pd ₂ (dba) ₃ (162 mg, 0.18 mmol) under nitrogen when heated at 120°C for 14 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (from 1:0 to 4:1)] ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5Hcyclonent[d]pyrimidine-4-carboxylate (2b) (128 mg , 37% yield) in the form of a colorless resin;

1H NMR (300 MHz, DMSO-d6) δ 8.32-8.22 (m, 2H), 7.57-7.33 (m, 3H), 4.40 (k, J=7.1 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.22 (t, J=7.5 Hz, 2H), 3.07 (t, J=7.8 Hz, 2H) , 2.12 (p, J=7.7 Hz, 2H), 1.46-1.30 (m, 12H); MS (ESI+): 420.3 (M+Na).

Stage-2. Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5Hcyclonent[d]nirimidine-4-carboxylic acid (2c).

Compound 2c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]πpyrimidine -4carboxylate (2b) (125 mg, 0.31 mmol) in THF (10 ml) and MeOH (10 ml), using a solution of lithium hydroxide monohydrate (81 mg, 1.89 mmol) in water (10 ml). This resulted in the preparation after treatment of 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylic acid (2c), which was used as is at the next stage; MS (ESI-) 368.4 (M-1).

Stage-3. Preparation of methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro5H-cyclopenta[d]πpyrimidine-4-carboxamido)phenyl)acetate (2d).

Compound 2d was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]nirimidin- 4-carboxylic acid (2c) using methyl 2-(2-aminophenyl)acetate (104 mg, 0.63 mmol), DIPEA (0.22 ml, 1.26 mmol) and HATU (239 mg, 0.63 mmol ). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 2:1)] methyl 2-(2-(2-(3-(( (tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5Hcyclopenta[d]πpyrimidine-4-carboxamido)phenyl)acetate (2d) (127 mg) as a yellow solid, which was used as is in the following stages; MS (ESI+): 517.4 (M+1), 539.4 (M+Na); (ESI): 515.4 (M-1).

Stage-4. Preparation of methyl 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5Hcyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2e).

Compound 2e was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H -cyclopenta[d]pyrimidine-4carboxamido)phenyl)acetate (2d) (127 mg, 0.25 mmol) using TFA (0.57 mL, 7.38 mmol) in DCM (20 mL). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DCM/DMA-80 (1:0 to 4:1)] methyl 2-(2-(2-(3( aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]πpyrimidine-4-carboxamido)phenyl)α acetate (2e) (68 mg, 66% yield over three steps) as a white solid;

- 71 045626

1H NMR (300 MHz, DMSO- _d6 ) δ 10.67 (s, 1H), 8.58-8.54 (m, 1H), 8.47-8.42 (m, 1H), 7.91 -7.67 (m, 1H),

7.56-7.43 (m, 2H), 7.42-7.34 (m, 2H), 7.29-7.17 (m, 1H), 3.87 (s, 2H), 3. 84 (s, 2H), 3.55 (s, 3H), 3.09 (t, J=7.8

Hz, 2H), 2.21-2.07 (m, 2H); MS (ESI+): 417.3 (M+1); (ESI-) 415.3 (M-1).

Stage-5. Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4carboxamido)phenyl)acetic acid (2f).

Compound 2f was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4 -carboxamido)phenyl)acetate (2e) (34 mg, 0.082 mmol) in THF (5 ml) and MeOH (5 ml), using a solution of lithium hydroxide monohydrate (21 mg, 0.49 mmol) in water (5 ml). This resulted in the production after treatment of 2-(2-(2-(3(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetic acid (2f) (24 mgs , 73% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.35 (s, 1H), 9.46 (s, 1H), 9.27 (s, 3H), 8.46-8.23 (m, 1H ), 7.87-7.77 (m, 1H), 7.55-7.47 (m, 2H), 7.30-7.19 (m, 2H), 7.13-7.05 (m , 1H), 4.11 (s, 2H), 3.42 (s, 2H), 3.08 (t, J=7.8 Hz, 2H), 2.22-2.05 (m, 2H) ; MS (ESI+): 403.3 (M+1); (ESI-): 401.4 (M-1).

Scheme-3

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxamido)phenyl)acetic acid (3i).

Stage-1. Preparation of tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)benzylcarbamate (3c).

Compound 3c was prepared according to the procedure described in step-3 of Scheme-1 from 2,4dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3a) (5 g, 14.61 mmol; CAS No. 934524-10-4; prepared according to the procedure described by Su, Qibin et al.; in Journal of Medicinal Chemistry, 57(1), 144-158; 2014) in dioxane (100 ml) using tert-butyl 3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzylcarbamate (3b) (3.25 g, 9.74 mmol; CAS No: 832114-05-3), tripotassium phosphate (4 .55 g, 21.43 mmol) in water (1 ml), tricyclohexylphosphine (0.82 g, 2.92 mmol) and Pd ₂ (dba) ₃ (0.89 g, 0.97 mmol) in an argon atmosphere at heating at 120°C for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 70% EtOAc in hexane] tert-butyl 3-(2- chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate) (3c) (2.9 g, 58.0% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=4.1 Hz, 1H), 8.10-8.07 (m, 1H), 8.06-8.04 (m , 1H), 7.96-7.90 (m, 2H), 7.58-7.44 (m, 5H), 7.24 (d, J=4.1 Hz, 1H), 4.23 ( d, J=6.2 Hz, 2H), 2.39 (s, 3H), 1.40 (s, 9H); MS (ESI+): 535.3, 537.3 (M+Na); (ESI-): 511.3, 513.3 (M-1).

Stage-2. Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)benzylcarbamate (3d).

Compound 3d was prepared according to the procedure described in step-1 of Scheme-1 from tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3c) (2.5 g, 4.87 mmol) in DMF (100 ml), using 1-ethoxyvinyl-tri-n-butyltin (2.16 ml, 6.34 mmol) and Pd(Ph ₃ P) ₄ (0. 28 g, 0.24 mmol) under argon by heating at 110°C for 4 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane from 0% up to 70%] tert-butyl 3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- 72 045626 yl)benzylcarbamate (3d) (1.7 g, 64% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (d, J=8.4 Hz, 2H), 8.07 (d, J=4.0 Hz, 1H), 8.01-7 .94 (m, 2H), 7.597.50 (m, 2H), 7.50-7.40 (m, 3H), 7.18 (d, J=4.1 Hz, 1H), 5.72 ( d, J=1.7 Hz, 1H), 4.73 (d, J=1.7 Hz, 1H), 4.24 (d,

J=6.2 Hz, 2H), 4.02 (k, J=6.9 Hz, 2H), 2.38 (s, 3H), 1.52 (t, J=6.9 Hz, 3H) , 1.40 (s, 9H); MS (ESI+): 571.4 (M+Na); (ESI-): 547.4 (M-1).

Stage-3. Preparation of ethyl 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidine-2-carboxylate (3e).

Compound 3e was prepared according to the procedure described in step-2 of Scheme-1 from tert-butyl 3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) benzylcarbamate (3d) (1.5 g, 2.73 mmol) in 1,4-dioxane (50 ml), using a solution of sodium periodate (1.17 g, 5.47 mmol) in water (10 ml) and KMnO ₄ (2x86 mg, 2x0.55 mmol, second dose after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7 -tosyl-7H-pyrrolo[2,3d]pyrimidine-2-carboxylate (3e) (500 mg, 33% yield) as a yellow solid; MS (ESI+): 551.3 (M+1), 573.3 (M+Na); (ESI-): 549.4 (M-1).

Stage-4. Preparation of 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3d]pyrimidine-2-carboxylic acid (3f).

Compound 3f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 4-(3((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine- 2-carboxylate (3e) (500 mg, 0.91 mmol) in THF (10 ml), using lithium hydroxide monohydrate (76 mg, 1.82 mmol) in water (4 ml). This resulted in 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7Hpyrrolo[2,3-d]pyrimidine-2-carboxylic acid (3f) (145 mg, 43% yield) as white solid matter;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.18 (s, 1H, D ₂ O replaceable), 12.69 (d, J=21.6 Hz, 1H, D2O replaceable), 8.18- 8.05 (m, 2H), 7.97-7.88 (m, 1H), 7.62-7.53 (m, 2H), 7.48-7.40 (m, 1H), 7. 05-6.97 (m, 1H), 4.27 (d, J=6.3 Hz, 2H), 1.41 (s, 9H); MS (ESI-): 367.3 (M-1).

Stage-5. Preparation of methyl 2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3d]pyrimidine-2-carboxamido)phenyl)acetate (3g).

Compound 3g was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid ( 3f) (120 mg, 0.33 mmol) in DMF (5 ml), using methyl 2-(2-aminophenyl) acetate (161 mg, 0.98 mmol), DIPEA (0.11 ml, 0.65 mmol) and HATU (186 mg, 0.49 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] methyl 2-(2-( 4-(3-((tertbutoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3g) (42 mg, 25% yield) as a white solid; MS (ESI+) 538.3 (M+1).

Stage-6. Preparation of methyl 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxamido)phenyl)acetate (3h).

Compound 3h was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d] pyrimidine-2carboxamido)phenyl)acetate (3g) (40 mg, 0.078 mmol) in DCM (8 ml), using TFA (0.06 ml, 0.78 mmol). This gave methyl 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3d]pyrimidine-2-carboxamido)phenyl)acetate (3h) (13 mg, 40% yield) , which was used as is in the next stage.

Stage-7. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxamido)phenyl)acetic acid (3i).

To a solution of methyl 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxamido)phenyl)acetate (3h) (13 mg from the previous step) in MeOH ( 5 ml) NaOH (12 mg, 0.31 mmol) in water (1 ml) was added and stirred at RT for 2 hours. MeOH was removed in vacuo, the residue was acidified to pH 3 and purified by reverse phase chromatography [C18 (50 d), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3d]pyrimidine -2-carboxamido)phenyl)acetic acid (3i) (2 mg, 6% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.78 (s, 1H, D2O replaceable), 10.83 (s, 1H, D2O replaceable), 8,498.23 (m, 5H, partially D2O replaceable), 8.01-7.92 (m, 2H), 7.69 (d, J=4.8 Hz, 2H), 7.43-7.32 (m, 2H), 7.27-7.12 ( m, 2H), 4.28-4.14 (m, 2H), 3.77 (s, 2H); MS (ESI+): 402.3 (M+1); (ESI-): 436.3 (M+Cl); purity after HPLC 98.03%.

- 73 045626

Scheme-4

Preparation of (R)-2-(2-(2-(3-( 1 -aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (4e).

Stage-1. Preparation of (R)-2-(3 -(1 -(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxylic acid (4b).

Compound 4b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33 mmol ) in dioxane (6 ml), using (R)-tert-butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (4a) (600 mg, 1.73 mmol; CAS No. 887254-66-2, prepared in accordance with the procedure described in international application PCT, 2015009977, January 22, 2015), tripotassium phosphate solution (564 mg, 2.66 mmol) in water (1 ml), tricyclohexylphosphine (112 mg, 0.4 mmol) and Pd ₂ (dba) ₃ (122 mg, 0.13 mmol) in an argon atmosphere when heated at 125 ° C for 30 min. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM from 0-30%] (R)-2-(3-(1(tert-butoxycarbonylamino)ethyl)phenyl )pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (4b) (150 mg, 30% yield) as a yellow solid; MS (ESI-): 381.3 (M-1).

Stage-2. Preparation of (R)-methyl 2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1G][1,2,4]triazine-4-carboxamido)phenyl) acetate (4c).

Compound 4c was prepared according to the procedure described in step-4 of Scheme-1 from (R)-2-(3(1 -(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-carboxylic acid (4b) (150 mg, 0.39 mmol) in DMF (8 ml), using methyl 2-(2-aminophenyl) acetate (78 mg, 0.47 mmol), DIPEA ( 0.21 ml, 1.18 mmol) and HATU (179 mg, 0.47 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] (R)-methyl 2- (2-(2-(3-(1 -(tertbutoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (4c) (60 mg, 29% yield) as a yellow solid; MS (ESI+): 552.4 (M+1).

Stage-3. Preparation of (R)-methyl 2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4carboxamido)phenyl)acetate (4d).

Compound 4d was prepared according to the procedure described in step-5 of Scheme-1 from (R)methyl 2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1 -f][1,2,4]triazine-4carboxamido)phenyl)acetate (4c) (60 mg, 0.11 mmol) in DCM (8 ml) using TFA (0.087 ml, 1.13 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 100%] (R)-methyl 2-(2-(2-(3-(1aminoethyl )phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (4d) (12 mg, 25% yield), MS (ESI+): 452.3 (M +Na); (ESI-): 428.3 (M-1).

Stage-4. Preparation of (R)-2-(2-(2-(3-( 1 -aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (4e).

To a solution of (R)-methyl 2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (4d) (12 mg, 0.028 mmol) in MeOH (5 ml) was added a solution of NaOH (18 mg, 0.45 mmol) in water (1 ml). The resulting mixture was stirred for 2 hours at RT and concentrated in vacuo to remove MeOH. The residue was acidified to pH~3 and purified by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give (R)-2-(2-(2 -(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (4e) (7 mg, 15% yield) as yellow solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H, D2O replaceable), 10.89 (s, 1H, D2O replaceable), 8.708.46 (m, 5H, partially D2O replaceable), 8 .42-8.35 (m, 1H), 7.89-7.81 (m, 1H), 7.78-7.69 (m, 1H, D2O replaceable), 7.69-7.58 (m , 2H), 7.46-7.35 (m, 2H), 7.33-7.21 (m, 2H), 4.65-4.47 (m, 1H), 3.81 (s, 2H ), 1.60 (d, J=6.7 Hz, 3H); MS (ESI+): 438.3 (M+Na); (ESI-): 414.4 (M-1); purity after HPLC 98.78%.

- 74 045626

Scheme-5

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2carboxamido)phenyl)acetic acid (5h).

Stage-1. Preparation of tert-butyl 3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a).

Compound 5a was prepared according to the procedure described in step-3 of Scheme-1 from 2,4dichloropyrrolo[2,1-f][1,2,4]triazine (1a) (1 g, 5.32 mmol) in dioxane (50 ml) using tert-butyl 3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (1.48 g, 4.43 mmol), tripotassium phosphate (1.88 g, 8.86 mmol) in water (5 ml), tricyclohexylphosphine (373 mg, 1.33 mmol) and Pd ₂ (dba) ₃ (0.406 g, 0.44 mmol) in Ar atmosphere when heated at 75°C for 60 min. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM from 0-30%] tert-butyl 3-(2-chloropyrrolo[2,1-f][1, 2,4]triazin-4-yl)benzylcarbamate (5a) (1 g, 63% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.34-8.27 (m, 1H), 8.08-7.98 (m, 2H), 7.65-7.50 (m, 3H) , 7.40-7.30 (m, 1H), 7.24-7.14 (m, 1H), 4.27 (d, J=6.2 Hz, 2H), 1.41 (s, 9H ).

Stage-2. Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4yl)benzylcarbamate (5b).

Compound 5b was prepared according to the procedure described in step-1 of Scheme-1 from tert-butyl 3-(2-chloropyrrolo[2,1-£][1,2,4]triazin-4-yl)benzylcarbamate (5a) ( 3.2 g, 8.92 mmol) in DMF (60 ml), using 1-ethoxyvinyl-tri-n-butyltin (3.65 ml, 10.70 mmol) and Pd(PPh ₃ ) ₄ (0.515 g, 0 .45 mmol) under argon by heating at 110°C for 10 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane 0% to 70%] tert-butyl 3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5b) (3.1 g, 88% yield) as yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.28-8.21 (m, 1H), 8.11-8.00 (m, 2H), 7.64-7.47 (m, 3H) , 7.22 (dd, J=4.6, 1.4 Hz, 1H), 7.12-7.04 (m, 1H), 5.74 (d, J=1.8 Hz, 1H), 4.79 (d, J=1.8 Hz, 1H), 4.28 (d, J=6.2 Hz, 2H), 3.99 (k, J=6.9 Hz, 2H), 1, 46-1.31 (m, 12H).

Stage-3. Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f][1,2,4]triazine-2-carboxylate (5c).

Compound 5c was prepared according to the procedure described in step-2 of Scheme-1 from tert-butyl 3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl) benzylcarbamate (5b) (500 mg, 1.27 mmol) in 1,4-dioxane (50 ml), using a solution of sodium periodate (542 mg, 2.54 mmol) in water (20 ml) and KMnO ₄ (120 mg, 0.76 mmol, first portion and second portion 40 mg, 0.25 mmol after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo [2,1-f][1,2,4]triazine-2-carboxylate (5c) (255 mg, 51% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.45-8.39 (m, 1H), 8.10-8.01 (m, 2H), 7.64-7.49 (m, 3H), 7.38-7.33 (m, 1H), 7.33-7.26 (m, 1H), 4.42 (k, J=7.1 Hz, 2H), 4.27 (d, J= 6.2 Hz, 2H), 1.47-1.31 (m, 12H); MS (ESI+): 397.3 (M+1); (ESI-): 395.4 (M-1).

Stage-4. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-75 045626 ^[1,2,4]triazine-2-carboxylic acid (5d).

Compound 5d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4 ]triazine-2-carboxylate (5c) (1.6 g, 4.04 mmol) in MeOH/THF (20 ml, 1:1), using sodium hydroxide (258 mg, 6.46 mmol) in water (3 ml ). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 10%] 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[ 2,1N[1,2,4]triazine-2-carboxylic acid (5d) (960 mg, 65% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 13.71 (s, 1H), 8.43-8.33 (m, 1H), 8.11-8.02 (m, 2H), 7. 64-7.47 (m, 3H), 7.34 (dd, J=4.6, 1.4 Hz, 1H), 7.32-7.25 (m, 1H), 4.27 (d, J=6.2 Hz, 2H), 1.41 (s, 9H); MS (ESI+): 369.3 (M+1); (ESI-): 367.3 (M-1).

Stage-5. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1^[1,2,4]triazine-2-carboxamido)phenyl)acetate (5f ).

Compound 5f was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4] triazine-2-carboxylic acid (5d) (200 mg, 0.54 mmol) in DMF (10 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (117 mg, 0.65 mmol), DIPEA ( 0.142 ml, 0.81 mmol) and HATU (248 mg, 0.65 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] followed by reverse column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2, 4]triazine-2-carboxamido)phenyl)acetate (5f) (212 mg, 74% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.44 (dd, J=2.7, 1.3 Hz, 1H), 8.29-8.18 (m , 2H), 7.85-7.75 (m, 1H), 7.66-7.53 (m, 3H), 7.47-7.41 (m, 1H), 7.38 (d, J =7.5 Hz, 2H), 7.34-7.29 (m, 1H), 7.28-7.19 (m, 1H), 4.30 (d, J=6.2 Hz, 2H) , 3.98 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.40 (s, 9H), 0.99 (t, J=7.1 Hz, 3H) ; MS (ESI+): 530.4 (M+1); (ESI-): 528.5 (M-1).

Stage-6. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2carboxamido)phenyl)acetate (5g).

Compound 5g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f] [1,2,4]triazine-2carboxamido)phenyl)acetate (5f) (210 mg, 0.4 mmol) in DCM (10 ml) using TFA (0.31 ml, 3.97 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3 -(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2- carboxamido)phenyl)acetate (5g) (152 mg, 89% yield) as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.64 (s, 1H, _D2O replaceable), 8.62 (s, 3H, D2O replaceable), 8.51-8.44 (m, 2H) , 8.42-8.35 (m, 1H), 7.86-7.80 (m, 1H), 7.80-7.64 (m, 3H), 7.43-7.31 (m, 3H), 7.28-7.20 (m, 1H), 4.234.17 (m, 2H), 3.98 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 430.3 (M+1), 452.3 (M+Na); purity after HPLC, 99.46%.

Stage-7. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2carboxamido)phenyl)acetic acid (5h).

Compound 5h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine -2-carboxamido)phenyl)acetate (5g) (70 mg, 0.16 mmol) in MeOH (10 ml), using sodium hydroxide (33 mg, 0.82 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3-(aminomethyl)phenyl)pyrrolo[2,1f][1,2,4]triazine-2-carboxamido)phenyl)acetic acid (5h) (39 mg, 60% yield) as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.75 (s, 1H, D2O replaceable), 10.78 (s, 1H, D2O replaceable), 8.598.32 (m, 6H), 7.90-7 .83 (m, 1H), 7.84-7.77 (m, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.64 (dd, J=4.7, 1 .3 Hz, 1H), 7.427.31 (m, 3H), 7.27-7.18 (m, 1H), 4.22 (s, 2H), 3.75 (s, 2H); MS (ESI+): 402.3 (M+1); (ESI-): 400.4 (M-1), 436.3 (M+Cl); purity after HPLC, 99.40%.

- 76 045626

Scheme-6

Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetic acid (6e).

Stage-1. Preparation of ethyl 2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b).

Ethyl 2-(2 -aminophenyl)acetate (5e) (593 mg, 3.31 mmol; CAS No. 87-25-2) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI, 697 mg, 3.64 mmol), the resulting mixture was stirred at RT overnight and diluted with EtOAc (60 ml). The organic layer was separated, washed with water (3x), brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%], followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0 .1% HCl) from 0% to 100%] to give ethyl 2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b) (770 mg, 65% yield ) as an off-white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.05 (s, 1H), 9.15 (d, J=2.1 Hz, 1H), 8.22-8.08 (m, 2H) , 8.03 (d, J=2.0 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.40-7.32 (m, 2H), 7.17 ( td, J=7.5, 1.3 Hz, 1H), 4.02 (k, J=7.1 Hz, 2H), 3.94 (s, 2H), 1.07 (t, J=7 ,1 Hz, 3H); MS (ESI+): 358.2 (M+1), 380.2 (M+Na).

Stage-2. Preparation of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8carboxamido)phenyl)acetate (6d).

Compound 6d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b) (250 mg, 0.70 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (196 mg, 1.05 mmol; CAS No. 146285-80-5), tripotassium phosphate (1.3 M solution) (1.61 ml, 2.10 mmol), tricyclohexylphosphine (58.8 mg, 0.210 mmol) and Pd ₂ (dba) ₃ (64.0 mg, 0.07 mmol) in an Ar atmosphere when heated at 125 ° C in for 30 minutes in the microwave. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%], followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate ( 6d) (195 mg, 65% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6 with D2O) δ 9.29 (s, 1H), 8.73 (s, 1H), 8.33-8.26 (m, 1H), 7.99-7, 89 (m, 2H), 7.86 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.67-7.60 (m, 1H ), 7.60-7.52 (m, 1H), 7.43-7.33 (m, 2H), 7.337.22 (m, 1H), 4.16-4.09 (m, 2H), 3.93-3.92 (m, 2H), 3.83 (s, 2H), 0.99-0.89 (m, 3H); MS (ESI+): 429.3 (M+1); 451.3 (M+Na); (ESI-): 463.4 (M+Cl); purity after HPLC 99.56%.

Stage-3. Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8carboxamido)phenyl)acetic acid (6e).

Compound 6e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl) acetate (6d) (108 mg, 0.25 mmol) in MeOH (10 ml), using sodium hydroxide (50.4 mg, 1.26 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(6-( 3(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetic acid (6e) (90 mg, 89% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6 with D2O) δ 9.29 (d, J=1.7 Hz, 1H), 8.73 (d, J=1.7 Hz, 1H), 8.28 (d , J=1.9 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=7.7 Hz, 1H ), 7.73 (d, J=7.9 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.59-7.52 (m, 1H), 7.42 -7.31 (m, 2H), 7.31-7.21 (m, 1H), 4.12 (s, 2H), 3.77 (s, 2H); MS (ESI+): 401.3 (M+1); (ESI-): 399.4 (M-1), 435.4 (M+Cl); purity after HPLC, 100%.

- 77 045626

Scheme-7

Preparation of 2-(2-(4-(3 -(aminomethyl)phenyl)-1 H-indazole-6-carboxamido)phenyl)acetic acid (7d).

Stage-1. Preparation of ethyl 2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b).

To a solution of 4-bromo-1H-indazole-6-carboxylic acid (7a) (500 mg, 2.07 mmol; CAS No. 885523-433) in MeOH (10 ml) was added ethyl 2-(2-aminophenyl) acetate (5e ) (372 mg, 2.07 mmol) and N1((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI, 437 mg, 2.28 mmol), stirred at RT overnight and concentrated in vacuo to remove MeOH. The resulting residue was dissolved in water (5 ml) and TBME (3 ml), stirred at RT for 30 min at RT and the solid was collected by filtration to give ethyl 2-(2-(4-bromo-1H-indazol-6carboxamido)phenyl )acetate (7b) (650 mg, 78% yield) as a tan solid;

1H NMR (300 MHz, DMSO-d6) δ 13.87 (s, 1H), 10.22 (s, 1H), 8.17 (s, 2H), 7.86 (s, 1H), 7.44 -7.20 (m, 4H), 3.96 (k, J=7.1 Hz, 2H), 3.75 (s, 2H), 1.01 (t, J=7.1 Hz, 3H) .

Stage-2. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6carboxamido)phenyl)acetate (7c).

Compound 7c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) (300 mg, 0.75 mmol ) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (210 mg, 1.12 mmol), tripotassium phosphate (1.3 M solution) (1.72 ml, 2.24 mmol), tricyclohexylphosphine (63 mg, 0.22 mmol) and Pd ₂ (dba) ₃ (68 mg, 0.075 mmol) in an Ar atmosphere by heating at 125 °C for 30 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)- 1Hindazole-6-carboxamido)phenyl)acetate (7c) (210 mg, 66% yield) as a white solid; 110 mg of product was collected and further purified by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-(4 -(3(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate (7c) (57 mg), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6 with _D2O ) δ 10.28 (s, 1H, D2O replaceable), 8.56 (s, 3H, D2O replaceable), 8.47 (d, J=1, 0 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.91-7.81 (m, 2H), 7.68-7, 54 (m, 2H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 2H), 7.31-7.22 (m, 1H), 4.15 ( t, J=5.9 Hz, 3H), 3.95 (k, J=7.1 Hz, 2H), 3.79 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 429.3 (M+1); 451.3 (M+Na); (ESI-): 463.4 (M+Cl); HPLC, purity 99.41%.

Stage-3. Preparation of 2-(2-(4-(3 -(aminomethyl)phenyl)-1 H-indazole-6-carboxamido)phenyl)acetic acid (7d).

Compound 7d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate (7c) ( 95 mg, 0.22 mmol) in MeOH (10 ml), using sodium hydroxide (44 mg, 1.11 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3-(aminomethyl)phenyl)-1H-indazole-6carboxamido)phenyl)acetic acid (7d) (40 mg, 45% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.75 (br.s, 1H, D2O replaceable), 10.28 (s, 1H, D2O replaceable), 8.59-8.43 (m, 4H, partly D2O replaceable), 8.19 (s, 1H), 8.00 (s, 1H), 7.91-7.82 (m, 2H), 7.67-7.54 (m, 2H), 7 .51-7.44 (m, 1H), 7.40-7.30 (m, 2H), 7.30-7.19 (m, 1H), 4.20-4.15 (m, 2H) , 3.72 (s, 2H); MS (ESI+): 401.3 (M+1); 423.3 (M+Na); (ESI-): 399.3 (M-1), 435.3 (M+Cl); HPLC, purity, 100%.

- 78 045626

Scheme-8

_CJ NaBH ₄ ^{8a PPh3}

5d

8c 8d 8e

Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2yl)methoxy)phenyl)acetic acid (8e).

Stage-1. Preparation of tert-butyl 3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4yl)benzylcarbamate (8a).

To a stirred solution of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f][1,2,4]triazine-2-carboxylic acid (5d) (390 mg, 1.06 mmol) and N-methylmorpholine (0.13 ml, 1.17 mmol) in THF (5 ml) was added isobutyl chloroformate (0.15 ml, 1.17 mmol) at -5°C. After 10 min the mixture was filtered on Celite and the precipitate was washed with THF (3x5 ml). The filtrate was cooled to 0°C and a solution of NaBH ₄ (60 mg, 1.59 mmol) in water (0.5 ml) was carefully added dropwise. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3x). The organic layers were combined, dried, filtered and concentrated in vacuo to give tert-butyl 3-(2-(hydroxymethyl)pyrrolo[2,1-1][1,2,4]triazin4-yl)benzylcarbamate (8a) (300 mg, 80% yield) as a yellow oil;

Ή NMR (300 MHz, DMSO-06) δ 8.19-8.11 (m, 1H), 8.07-7.95 (m, 2H), 7.63-7.45 (m, 3H), 7.21-7.13 (m, 1H), 7.11-7.03 (m, 1H), 5.51 (t, J=6.3 Hz, 1H), 4.60 (d, J= 5.7 Hz, 2H), 4.26 (d, J=6.2 Hz, 2H), 1.41 (s, 9H); MS (ESI+): 355.3 (M+1); (ESI-): 353.3 (M-1).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f][1,2,4]triazin-2-yl)methoxy)phenyl) acetate (8c).

To a solution of tert-butyl 3-(2-(hydroxymethyl)pyrrolo[2,1-G][1,2,4]triazin-4-yl)benzylcarbamate (8a) (250 mg, 0.71 mmol) in THF ( 5 mL) at 0°C, DIAD (0.18 mL, 0.92 mmol), ethyl 2-(2hydroxyphenyl)acetate (23b) (165 mg, 0.917 mmol; CAS No. 41873-65-8) and triphenylphosphine (241 mg, 0.92 mmol). The resulting mixture was stirred at room. pace. during the night. The reaction mixture was quenched with water and extracted with EtOAc (3x). The organic layers were combined, washed with saturated aq. NH4Cl, water, brine, dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)pyrrolo[2,1f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8c) (300 mg, 82% yield) as a yellow oil;

^1H NMR (300 MHz, DMSO-06) δ 8.23-8.17 (m, 1H), 8.08-7.94 (m, 2H), 7.63-7.48 (m, 3H) , 7.31-7.16 (m, 4H), 7.15-7.09 (m, 1H), 6.93 (td, J=7.3, 1.3 Hz, 1H), 5.22 (s, 2H), 4.26 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.34 (s, 2H), 1.39 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 517.4 (M+1); (ESI-): 515.4 (M-1).

Stage-3. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2yl)methoxy)phenyl)acetate (8d).

Compound 8d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f ][1,2,4]triazin-2yl)methoxy)phenyl)acetate (8c) (300 mg, 0.58 mmol) in DCM (10 ml) using TFA (0.45 ml, 5.81 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine- 2-yl)methoxy)phenyl)acetate (8d) (200 mg, 83% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.75 (br.s, 1H, D2O replaceable), 10.28 (s, 1H, D2O replaceable), 8.59-8.43 (m, 4H, partly D2O replaceable), 8.19 (s, 1H), 8.00 (s, 1H), 7.91-7.82 (m, 2H), 7.67-7.54 (m, 2H), 7 .51-7.44 (m, 1H), 7.40-7.30 (m, 2H), 7.30-7.19 (m, 1H), 4.20-4.15 (m, 2H) , 3.72 (s, 2H); MS (ESI+): 417.3 (M+1); 439.3 (M+Na); purity after HPLC, 99.88%.

Stage-4. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2yl)methoxy)phenyl)acetic acid (8e).

Compound 8e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4] triαzin-2-yl)methoxy)phenyl)acetate (8d) (100 mg, 0.24

- 79 045626 mmol) in MeOH/THF (10 ml, 1:1), using sodium hydroxide (48 mg, 1.2 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetic acid (8e) (71 mg, 76% yield) as a yellow solid ;

Ή NMR (300 MHz, DMSO-d6) δ 8.57 (s, 3H, D2O replaceable), 8.30-8.20 (m, 2H), 8.19-8.11 (m, 1H), 7 .84-7.74 (m, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.43 (dd, J=4.7, 1.3 Hz, 1H), 7. 28-7.11 (m, 4H), 6.92 (t, J=7.2, 1.4 Hz, 1H), 5.26 (s, 2H), 4.22-4.14 (m, 2H), 3.61 (s, 2H); MS (ESI+): 389.4 (M+1); (ESI-): 387.4 (M-1); 423.4 (M+Cl); purity after HPLC, 100%.

Scheme-9

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (9d).

Stage-1. Preparation of ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b).

Compound 9b was prepared according to the procedure described in step-1 of Scheme-7 from 4-bromo1H-indole-6-carboxylic acid (9a) (500 mg, 2.08 mmol; CAS No. 374633-27-9) in MeOH ( 10 ml) using ethyl 2-(2-aminophenyl) acetate (5e) (411 mg, 2.29 mmol) and EDCI (479 mg, 2.5 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido )phenyl)acetate (9b) (320 mg, 38% yield) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.02 (s, 1H), 8.10-8.02 (m, 1H), 7.83 (d, J =1.3 Hz, 1H), 7.68 (t, J=2.8 Hz, 1H), 7.42-7.28 (m, 3H), 7.28-7.19 (m, 1H) , 6.54-6.44 (m, 1H), 3.96 (k, J=7.1 Hz, 2H), 3.74 (s, 2H), 1.01 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate (9c).

Compound 9c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (300 mg, 0.75 mmol ) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (210 mg, 1.12 mmol), tripotassium phosphate (1.3 M solution) (1.72 ml, 2.24 mmol), tricyclohexylphosphine (63 mg, 0.22 mmol) and Pd ₂ (dba) ₃ (69 mg, 0.075 mmol) in an Ar atmosphere by heating at 125 °C for 30 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-(4-(3(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate (9c) (133 mg, 42% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 11.74 (s, 1H), 10.03 (s, 1H), 8.38 (s, 3H, D2O replaceable), 8.08 (s, 1H) , 7.90 (s, 1H), 7.82-7.72 (m, 2H), 7.65 (t, J=2.8 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.54-7.48 (m, 1H), 7.46-7.39 (m, 1H), 7.37-7.29 (m, 2H), 7.27-7, 20 (m, 1H), 6.76 (t, J=2.4 Hz, 1H), 4.23-4.08 (m, 2H), 3.96 (k, J=7.1 Hz, 2H ), 3.77 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 428.3 (M+1); 450.3 (M+Na); (ESI-): 426.4 (M-1); purity after HPLC 97.82%.

Stage-3. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (9d).

Compound 9d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate (9c) ( 70 mg, 0.16 mmol) in MeOH (10 ml), using sodium hydroxide (66 mg, 1.61 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3-(aminomethyl)phenyl)-1H-indole-6carboxamido)phenyl)acetic acid (9d) (23 mg, 35% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.28 (s, 1H, D2O replaceable), 11.76 (t, 1H), 10.08 (s, 1H, D2O replaceable), 8 .48 (s, 3H, D2O replaceable), 8.10 (s, 1H), 7.91 (s, 1H), 7.83-7.74 (m, 2H), 7.65 (t, J= 2.8 Hz, 1H),

7.61-7.46 (m, 3H), 7.37-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.79-6.72 (m, 1H ), 4.20-4.08 (m, 2H), 3.70 (s, 2H); MS (ESI ⁺ ) 400.3 (M+1); 422.3 (M+Na); (ESI-) 398.4 (M-1); 434.4 (M+Cl); purity after HPLC, 99.02%.

Scheme-10

Yus 10d

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(oppropylmethyl ring)-1H-indazole-6carboxamido)phenyl)acetic acid (10d).

Stage-1. Preparation of ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6carboxamido)phenyl)acetate (10a) and ethyl 2-(2-(4-bromo-2-(cyclopropylmethyl)-2H- indazole-6carboxamido)phenyl)acetate (10b).

(Bromomethyl)cyclopropane (151 mg, 1.12 mmol) and potassium carbonate (206 mg, 1.49 mmol). The resulting mixture was stirred at 60°C overnight, cooled to RT, diluted with EtOAc (100 ml), washed with water (3x), brine, dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazol- 6carboxamido)phenyl)acetate (10a) (106 mg, 31% yield);

^1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.44-7.15 (m, 4H ), 4.34 (d, J=7.0 Hz, 2H), 3.96-3.89 (m, 2H), 3.71 (s, 2H), 1.37-1.23 (m, 1H), 0.94 (t, J=7.1 Hz, 3H), 0.53-0.32 (m, 4H); the first elution gave ethyl 2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6carboxamido)phenyl)acetate (10b) (86 mg, 25% yield);

1H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 7.79-7.73 (m, 1H) , 7.41 (d, J=6.9 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.21 (m, 1H), 4.37 (d, J =7.3 Hz, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.77 (s, 2H), 1.53-1.31 (m, 1H), 1.02 (t, J=7.1, 2.1 Hz, 3H), 0.68-0.41 (m, 4H).

Stage-2. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6carboxamido)phenyl)acetic acid (10d).

Compound 10d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate (10a) (95 mg, 0.21 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (59 mg, 0.31 mmol), tripotassium phosphate (1.3 M solution) (0.48 ml, 0.63 mmol), tricyclohexylphosphine (18 mg, 0.06 mmol) and Pd ₂ (dba) ₃ (19 mg, 0.021 mmol) in an Ar atmosphere when heated at 125°C for 30 min in a microwave oven. This resulted in, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6carboxamido)phenyl)acetate (10c) (26 mg, 0.054 mmol, 25.9% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.27 (s, 1H, D2O replaceable), 8.52 (s, 3H, D2O replaceable), 8.46-8.36 (m, 2H), 8 .00 (s, 1H), 7.93-7.78 (m, 2H), 7.67-7.53 (m, 2H), 7.50-7.41 (m, 1H), 7.41 -7.32 (m, 2H), 7.32-7.22 (m, 1H), 4.44 (d, J=7.0 Hz, 2H), 4.21-4.11 (m, 2H ), 3.94 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.45-1.32 (m, 1H), 0.96 (t, J=7, 1 Hz, 3H), 0.59-0.38 (m, 4H); MS (ESI+): 483.4 (M+1); (ESI-): 517.5 (M+Cl); HPLC purity, 97.36%, and 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6carboxamido)phenyl)acetic acid (10d) (7 mg, 0.015 mmol, 7.40% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H, D2O replaceable), 8.55-8.33 (m, 5H), 7.98 (d, J=1.7 Hz, 1H, partially D2O replaceable), 7.91-7.80 (m, 2H), 7.67-7.54 (m, 2H), 7.54-7.45 (m, 1H), 7.41- 7.30 (m, 2H), 7.307.18 (m, 1H), 4.44 (d, J=7.0 Hz, 2H), 4.22-4.09 (m, 2H), 3.72 (s, 2H), 1.50-1.33 (m, 1H), 0.64-0.38 (m, 4H); MS (ESI+): 455.4 (M+1); (ESI-): 453.4 (M-1), 489.4 (M+Cl); purity after HPLC, 99.31%.

- 81 045626

Scheme-11 he

Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazol-6carboxamido)phenyl)acetate (11a) and 2-(2-(4-(3-( aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole6-carboxamido)phenyl)acetic acid (11b).

Compounds 11a and 11b were prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-carboxamido)phenyl)acetate (10b ) (86 mg, 0.19 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (53 mg, 0.28 mmol), tripotassium phosphate (1.3 M solution) (0. 44 ml, 0.57 mmol), tricyclohexylphosphine (16 mg, 0.06 mmol) and Pd ₂ (dba) ₃ (17 mg, 0.02 mmol) in an Ar atmosphere when heated at 125 ° C for 30 min in the microwave ovens. This resulted in, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazol-6carboxamido)phenyl)acetate (11a) (10 mg, 11% yield) as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H, D2O replaceable), 8.94 (s, 1H), 8.55 (s, 3H, D2O replaceable), 8.33 (s , 1H), 7.96 (s, 1H), 7.87-7.72 (m, 2H), 7.68-7.52 (m, 2H), 7.48-7.41 (m, 1H ), 7.39-7.30 (m, 2H), 7.307.21 (m, 1H), 4.39 (d, J=7.2 Hz, 2H), 4.16 (k, J=6, 0 Hz, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.53-1.39 (m, 1H), 1.01 (t, J=7.1 Hz, 3H), 0.62-0.44 (m, 4H); MS (ESI+): 483.4 (M+1); 505.4 (M+Na); (ESI-): 481.4 (M1); HPLC purity, 95.20% and 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazol-6carboxamido)phenyl)acetic acid (11b) (13 mg, 15 % yield) as an off-white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.17 (s, 1H, D2O replaceable), 8.96 (s, 1H), 8.59 (s, 3H, D2O replaceable), 8.33 ( s, 1H), 7.97 (s, 1H), 7.86-7.80 (m, 1H), 7.80-7.74 (m, 1H), 7.66-7.48 (m, 3H), 7.39-7.29 (m, 2H), 7.287.19 (m, 1H), 4.38 (d, J=7.3 Hz, 2H), 4.21-4.09 (m , 2H), 3.73 (s, 2H), 1.57-1.38 (m, 1H), 0.61-0.45 (m, 4H); MS (ESI+): 455.4 (M+1); 477.4 (M+Na); (ESI-): 453.4 (M-1); purity after HPLC 98.50%.

Scheme-12

C.I.

12b 12c

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (12c).

Stage-1. Preparation of (S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-1-(methylsulfonyl)-1H-indol-6-yl) methoxy)phenyl)acetate (12a).

Compound 12a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (211a) (0.6 g, 1.17 mmol) in dioxane (5 ml), using (8)-No((4-chloro -3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (0.46 g, 1.75 mmol), bis(triphenylphosphine) palladium(P) chloride (0.12 g, 0.18 mmol) and a solution of K2CO3 (0.40 g, 2.92 mmol) in water (0.5 ml) in an Ar atmosphere by heating at 90°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH=9:1 in DCM 0% to 70%] (S)-ethyl 2-(2-(( 4-(2-((1,1- 82 045626 dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (12a) (0, 33 g, 46% yield) as a yellow solid; MS (ESI+):

616.0 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1Nindol-6-yl)methoxy)phenyl)acetate (12b).

Compound 12b was prepared according to the procedure described in step-5 of Scheme-220 from (S)ethyl 2-(2-((4-(2-(( 1,1 -dimethylethylsulfinamido)methyl)-3-fluoropyridine-4- yl)-1-(methylsulfonyl)-1Hindol-6-yl)methoxy)phenyl)acetate (12a) (0.33 g, 0.54 mmol) in methanol (10 ml) using hydrochloric acid (4 M in 1, 4-dioxane, 0.40 ml, 1.61 mmol). This resulted in 12b (0.26 g, 95% yield) as a yellow solid upon workup. This was purified using reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((4-( 2-(aminomethyl)-3-fluoropyridin-4-yl)-1(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12b), HCl salt, as a yellow solid;

¹ H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 3H), 8.61 (d, J=4.9 Hz, 1H), 8.10 (t, J=1.0 Hz, 1H), 7.75 (d, J=3.8 Hz, 1H), 7.67 (t, J=5.3 Hz, 1H), 7.54-7.52 (m, 1H), 7, 31-7.19 (m, 2H), 7.14 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H) , 6.81-6.76 (m, 1H), 5.32 (s, 2H), 4.34 (d, J=6.0 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 3.55 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.70; MS (ESI+): 512.9 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (12c).

Compound 12c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -(methylsulfonyl)-1 N-indol-6-yl)methoxy)phenyl)acetate (12b) (0.15 g, 0.29 mmol) in MeOH/THF (4 mL each) using lithium hydroxide monohydrate (123 mg, 2.93 mmol ) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (12c) (0.06 g, 52% yield), HCl salt as yellow solid substances;

1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.57 (s, 3H), 8.56-8.54 (m, 1H), 7.69 (t, J= 5.4 Hz, 1H), 7.65 (d, J=1.1 Hz, 1H), 7.49 (t, J=2.8 Hz, 1H), 7.27 (d, J=1, 2 Hz, 1H), 7.26-7.18 (m, 2H), 7.14-7.08 (m, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H ), 6.39 (t, J=2.7 Hz, 1H), 5.26 (s, 2H), 4.44-4.30 (m, 2H), 3.57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.77; MS (ESI+): 406.0 (M+1). Purity after HPLC: 98.02%,

Scheme-13 he

Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)acetic acid (13c).

Stage-1. Preparation of ethyl 2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate (13b).

Compound 13b was prepared according to the procedure described in step-4 of Scheme-1 from 8-bromoquinoline-6-carboxylic acid (13a) (250 mg, 0.992 mmol, CAS No. 791632-21-8) using ethyl 2(2-aminophenyl )acetate (5e) (213 mg, 1.19 mmol), DIPEA (0.52 ml, 2.98 mmol) and HATU (453 mg, 1.19 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH:EtOAc (9:1) in 0 to 60% hexanes] ethyl 2-(2-(8-bromoquinoline-6-carboxamido) phenyl)acetate (13b) (315 mg, 77% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.13 (dd, J=4.2, 1.6 Hz, 1H), 8.66 (d, J=1 .9 Hz, 1H), 8.62 (td, J=4.1, 1.7 Hz, 2H), 7.75 (dd, J=8.3, 4.2 Hz, 1H), 7.45 -7.23 (m, 4H), 3.96 (k, J=7.1 Hz, 2H), 3.78 (s, 2H), 1.00 (t, J=7.1 Hz, 3H) .

Stage-2. Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)acetic acid (13c).

Compound 13c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate (13b) (150 mg, 0.36 mmol) in dioxane ( 2 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (68 mg, 0.363 mmol), tripotassium phosphate (1.3 M solution) (0.84 ml, 1.09 mmol), tricyclohexylphosphine (31 mg, 0 .11 mmol) and Pd ₂ (dba) ₃ (33 mg, 0.036 mmol) in an Ar atmosphere when heated at 125°C for 1 hour in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (40 g), eluted with ethyl acetate in hexanes (0 to 40%)] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(8-(3(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)acetic acid (13c) (18 mg, 12% output) in the form

- 83 045626 white powder;

1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H, D2O replaceable), 9.04 (dd, J=4.2, 1.7 Hz, 1H), 8.70 (s, 1H ), 8.65 (dt, J=8.5, 1.8 Hz, 1H), 8.50 (s, 3H, D2O replaceable), 8.35 (t, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.82-7.76 (m, 1H), 7.76-7.69 (m, 1H), 7.60-7.55 (m, 2H), 7. 48 (d, J=7.6 Hz, 1H), 7.40-7.30 (m, 2H), 7.30-7.21 (m, 1H), 4.14 (k, J=5, 9 Hz, 2H), 3.73 (s, 2H); MS (ESI+): 412.3 (M+1); MS (ESI-): 410.4 (M-1); purity after HPLC: 93.59%.

Scheme-14 he %n

6s

1 ₂ NS1

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetic acid (14d).

Stage-1. Preparation of ethyl 2-(2-(4-bromo-1H-pyrrolo[2,3-b]niridine-6-carboxamido)phenyl)acetateα (14b).

Compound 14b was prepared according to the procedure described in step-1 of Scheme-7 from 4-bromo1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (14a) (300 mg, 1.25 mmol; CAS No. 1190321 -81-3) in MeOH (10 ml) using ethyl 2-(2-aminophenyl)acetate (5e) (268 mg, 1.49 mmol) and EDCI (286 mg, 1.49 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(4-bromo-Spyrrolo[2,3-b ]pyridine-6-carboxamido)phenyl)acetate (14b) (356 mg, 71% yield) as an off-white solid; MS (ESI+): 424.2, 426.2 (M+Na), (ESI-): 400.2, 402.3 (M-1).

Stage-2. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6carboxamido)phenyl)acetate (14c).

Compound 14c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate (14b) (200 mg, 0.55 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (154 mg, 0.82 mmol), tripotassium phosphate (1.3 M solution) (0.72 ml, 0.93 mmol), tricyclohexylphosphine (46 mg, 0.16 mmol) and Pd ₂ (dba) ₃ (50 mg, 0.055 mmol) in an Ar atmosphere when heated at 125°C for 1 hour in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl) acetate (14c) (108 mg, 46% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H, D2O replaceable), 10.31 (s, 1H, D2O replaceable), 8.55 (s, 3H, D2O replaceable), 8, 06 (s, 1H), 7.98 (s, 1H), 7.89-7.76 (m, 3H), 7.64 (d, J=4.5 Hz, 2H), 7.42-7 .29 (m, 2H), 7.27-7.14 (m, 1H), 6.93-6.82 (m, 1H), 4.23-4.12 (m, 2H), 4.08 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 1.06 (t, J=7.1 Hz, 3H); MS (ESI+): 429.4 (M+1); (ESI-): 427.4 (M-1), 463.4 (M+Cl); purity after HPLC, 99.45%.

Stage-3. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6carboxamido)phenyl)acetic acid (14d).

Compound 14d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6- carboxamido)phenyl)acetate (14c) (16 mg, 0.038 mmol) in MeOH/THF (3 ml), using lithium hydroxide monohydrate (7.98 mg, 0.19 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetic acid (14d) (12 mg, 79% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H, D2O replaceable), 10.35 (s, 1H, D2O replaceable), 8.39 (s, 3H, D2O replaceable), 8.07 (s, 1H), 7.98 (s, 1H), 7.90-7.78 (m, 3H), 7.70-7.57 (m, 2H), 7.43-7.30 (m , 2H), 7.267.13 (m, 1H), 6.90-6.80 (m, 1H), 4.18 (k, J=5.9 Hz, 2H), 3.73 (s, 2H) ; MS (ESI+): 401.3 (M+1); (ESI-): 399.3

- 84 045626 (M-1), 435.4 (M+Cl); purity after HPLC, 96.09%.

Scheme-15

15c ^15d

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetic acid (15d).

Stage-1. Preparation of ethyl 2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b).

Compound 15b was prepared according to the procedure described in step-1 of Scheme-7 from 7bromobenzofuran-5-carboxylic acid (15a) (100 mg, 0.42 mmol; CAS No. 286836-25-7) in MeOH (10 ml) using ethyl 2-(2-aminophenyl)acetate (5e) (89 mg, 0.5 mmol) and EDCI (95 mg, 0.5 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(7-bromobenzofuran-5carboxamido)phenyl)acetate (15b ) (80 mg, 48% yield) as a pink semi-solid; MS (ESI+): 424.2, 426.2 (M+Na), (ESI-): 400.2, 402.2 (M-1).

Stage-2. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetic acid (15d).

Compound 15d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b) (80 mg, 0.2 mmol) in dioxane ( 3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (56 mg, 0.3 mmol), tripotassium phosphate (1.3 M solution) (0.26 ml, 0.34 mmol), tricyclohexylphosphine (17 mg , 0.06 mmol) and Pd ₂ (dba) ₃ (18 mg, 0.02 mmol) in an Ar atmosphere when heated at 125°C for 1 hour in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-(7-(3(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetate (15c) (21 mg, 25% yield ) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H, D2O replaceable), 8.43 (s, 3H, D2O replaceable), 8.33-8.27 (m, 1H), 8 .22 (d, J=2.2 Hz, 1H), 8.21-8.18 (m, 1H), 8.08 (s, 1H), 8.03-7.94 (m, 1H), 7.67-7.54 (m, 2H), 7.45-7.39 (m, 1H), 7.38-7.30 (m, 2H), 7.30-7.18 (m, 2H ), 4.16 (s, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.79 (s, 2H), 0.98 (t, J=7.1 Hz, 3H ); MS (ESI+): 429.3 (M+1); 451.3 (M+Na); (ESI-): 463.3 (M+Cl); HPLC purity, 99.50% and 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetic acid (15d) (25 mg, 31% yield) as a white solid substances;

1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H, D2O replaceable), 10.20 (s, 1H, D2O replaceable), 8.41 (s, 3H, D2O replaceable), 8.34 -8.29 (m, 1H), 8.24-8.20 (m, 1H), 8.20-8.16 (m, 1H), 8.09-8.04 (m, 1H), 8 .02-7.96 (m, 1H), 7.66-7.55 (m, 2H), 7.51-7.44 (m, 1H), 7.38-7.28 (m, 2H) , 7.27-7.19 (m, 2H), 4.21-4.09 (m, 2H), 3.71 (s, 2H); MS (ESI+): 401.3 (M+1); 423.3 (M+Na); (ESI-): 399.3 (M-1), 435.3 (M+Cl); purity after HPLC, 92.60%.

- 85 045626

Scheme-16

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3^]pyrimidine-2carboxamido)phenyl)acetic acid (16i).

Stage-1. Preparation of 2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b).

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (16a) (1 g, 5.32 mmol; CAS No. 90213-66-4) in acetonitrile (35 ml) at 0°C was added portionwise sodium hydride (319 mg, 7.98 mmol). The reaction mixture was stirred at room temperature for 30 min until gas evolution ceased. (Bromomethyl)cyclopropane (1.62 g, 11.97 mmol) was then added and the resulting mixture was stirred at

CT scan overnight. The reaction mixture was poured into water and extracted with EtOAc (3x). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] to give 2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d ]pyrimidine (16b) (998 mg, 78% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.88 (d, J=3.6 Hz, 1H), 6.71 (d, J=3.6 Hz, 1H), 4.09 (d , J=7.2 Hz, 2H), 1.34-1.17 (m, 1H), 0.58-0.48 (m, 2H), 0.48-0.37 (m, 2H); MS (ESI+): 265.3 (M+Na).

Stage-2. Preparation of tert-butyl 3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)benzylcarbamate (16c).

Compound 16c was prepared according to the procedure described in step-3 of Scheme-1 from 2,4dichloro-7-(cyclopropylmethyl)-7H-nirrolo[2,3-d]pyrimidine (16b) (4.5 g, 18. 59 mmol) in dioxane (100 ml) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (4.42 g, 13 .28 mmol), tripotassium phosphate (22.47 ml, 29.2 mmol, 1.3 M solution in water), tricyclohexylphosphine (1.12 g, 3.98 mmol) and Pd ₂ (dba) ₃ (1.22 g , 1.33 mmol) in an Ar atmosphere when heated at 120°C for 60 min in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 70% EtOAc in hexane] tert-butyl 3(2-chloro-7-(cyclopropylmethyl)-7H-nirrolo[2 ,3-d]pyrimidin-4-yl)benzylcarbamate (16c) (3.2 g, 58% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10-7.97 (m, 2H), 7.87 (d, J=3.7 Hz, 1H), 7.61-7.50 (m , 2H), 7.49-7.41 (m, 1H), 6.99 (d, J=3.7 Hz, 1H), 4.25 (d, J=6.2 Hz, 2H), 4 .11 (d, J=7.2 Hz, 2H), 1.41 (s, 9H), 1.35-1.31 (m, 1H), 0.58-0.49 (m, 2H), 0.49-0.40 (m, 2H); MS (ESI+): 413.4 (M+1); 435.3 (M+Na); (ESI-): 411.4 (M-1).

Stage-3. Preparation of tert-butyl 3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)benzylcarbamate (16d).

Compound 16d was prepared according to the procedure described in step-1 of Scheme-1 from tert-butyl 3-(2-chloro-7-(cyclopropylmethyl)-7H-nirrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate ( 16c) (3.2 g, 7.75 mmol) in DMF (35 ml), using 1-ethoxyvinyl-tri-n-butyltin (3.17 ml, 9.30 mmol) and Pd(PPh ₃ ) ₄ (0.448 g, 0.39 mmol) under argon by heating at 110°C for 12 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0 to 60 EtOAc in hexane %] tert-butyl 3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16d) (2.5 g, 72% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14-8.02 (m, 2H), 7.83 (d, J=3.6 Hz, 1H), 7.55 (k, J=7 ,8, 7.0 Hz, 2H), 7.45-7.36 (m, 1H), 6.92 (d, J=3.6 Hz, 1H), 5.63 (d, J=1, 4 Hz, 1H), 4.61 (d, J=1.5 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H),

- 86 045626

4.16 (d, J=7.2 Hz, 2H), 3.98 (k, J=7.0 Hz, 2H), 1.45-1.25 (m, 13H), 0.57-0 .46 (m, 4H); MS (ESI+) 449.4 (M+1); (ESI-) 447.4 (M-1).

Stage-4. Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (16e).

Compound 16e was prepared according to the procedure described in step-2 of Scheme-1 from tert-butyl 3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidine-4- yl)benzylcarbamate (16d) (2.5 g, 5.57 mmol) in 1,4-dioxane (50 ml), using a solution of sodium periodate (2.384 g, 11.15 mmol) in water (20 ml) and KMnO ₄ (0.881 g, 5.57 mmol in 4 ml water as first portion and second portion 528 mg, 3.34 mmol after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) -7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxylate (16e) (1.06 g, 42% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.12-8.03 (m, 3H), 7.62-7.52 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.04 (d, J=3.5 Hz, 1H), 4.42 (k, J=7.1 Hz, 2H), 4.27 (d, J=6.2 Hz, 2H), 4.22 (d, J=7.2 Hz, 2H), 1.45-1.30 (m, 13H), 0.570.45 (m, 4H).

Stage-5. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7Hpyrrolo[2,3-d]pyrimidine-2-carboxylic acid (16f).

Compound 16f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3 -d]pyrimidine-2carboxylate (16e) (1.06 g, 2.353 mmol) in MeOH/THF (15 ml, 1:1), using sodium hydroxide (235 mg, 5.88 mmol) in water (3 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 20% MeOH in DCM] 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-( cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxylic acid (16f) (650 mg, 65% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11-8.00 (m, 2H), 7.89 (d, J=3.6 Hz, 1H), 7.60-7.48 (m , 2H), 7.46-7.38 (m, 1H), 6.94 (d, J=3.5 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H), 4 .18 (d, J=7.2 Hz, 2H), 1.41 (s, 9H), 1.34-1.30 (m, 1H), 0.56-0.43 (m, 4H); MS (ESI+) 423.3 (M+1); 445.3 (M+Na); (ESI-), 421.4 (M-1), 457.4 (M+Cl).

Stage-6. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl) acetate (16g).

Compound 16g was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3- d]pyrimidine-2carboxylic acid (16f) (150 mg, 0.536 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (95 mg, 0.533 mmol), DIPEA (0.12 ml , 0.71 mmol) and HATU (203 mg, 0.533 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-(4-(3 -(((tertbutoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2carboxamido)phenyl)acetate (16g) (152 mg, 73% yield) as white solid matter; MS (ESI+) 584.5 (M+1).

Stage-7. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3d]pyrimidine-2-carboxamido)phenyl)acetate (16h).

Compound 16h was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H -pyrrolo[2,3d]pyrimidine-2-carboxamido)phenyl)acetate (16g) (150 mg, 0.26 mmol) in DCM (10 ml) using TFA (0.4 ml, 5.14 mmol). This resulted in, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine2- carboxamido)phenyl)acetate (16h) (88 mg, 71% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.79 (s, 1H, D ₂ O replaceable), 8.68 (s, 3H, D2O replaceable), 8.46 (d, J=1.7 Hz , 1H), 8.43-8.35 (m, 1H), 8.11 (d, J=3.6 Hz, 1H), 7.93-7.87 (m, 1H), 7.79- 7.73 (m, 1H), 7.73-7.61 (m, 1H), 7.44-7.36 (m, 2H), 7.34 (d, J=3.6 Hz, 1H) , 7.27-7.15 (m, 1H), 4.37-4.25 (m, 2H), 4.17 (s, 2H), 4.00 (k, J=7.1 Hz, 2H ), 3.88 (s, 2H), 1.46-1.32 (m, 1H), 1.00 (t, J=7.1 Hz, 3H), 0.60-0.45 (m, 4H); MS (ESI+): 484.5 (M+1); (ESI-): 482.5 (M-1); 518.5 (M+Cl); purity after HPLC, 99.46%.

Stage-8. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3d]pyrimidine-2-carboxamido)phenyl)acetic acid (16i).

Compound 16i was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d ]pyrimidine-2carboxamido)phenyl)acetate (16h) (50 mg, 0.10 mmol) in MeOH (10 ml), using sodium hydroxide (21 mg, 0.52 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2- 87 045626 carboxamido)phenyl)acetic acid (16i) (24 mg, 51% yield) as yellow solid matter;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.85 (s, 1H, D2O replaceable), 8.56 (s, 3H, D2O replaceable), 8.46-8.40 (m, 1H), 8 ,40-8.32 (m, 1H), 8.11 (d, J=3.6 Hz, 1H), 7.98 (dd, J=8.4, 1.3 Hz, 1H), 7. 78-7.63 (m, 2H), 7.44-7.33 (m, 2H), 7.31 (d, J=3.6 Hz, 1H), 7.27-7.13 (m, 1H), 4.29 (d, J=7.2 Hz, 2H), 4.23-4.18 (m, 2H), 3.78 (s, 2H), 1.441.31 (m, 1H), 0.59-0.47 (m, 4H); MS (ESI+): 456.3 (M+1); 478.3 (M+Na); (ESI-): 454.3 (M-1); 490.3 (M+Cl); HPLC, purity, 99.60%.

Scheme-17

17s

Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6carboxamido)phenyl)acetic acid (17c).

Stage-1. Preparation of ethyl 2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6carboxamido)phenyl)acetate (17b).

Compound 17b was prepared according to the procedure described in step-4 of Scheme-1 from 8-bromo[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (17a) (500 mg, 2 .07 mmol, CAS No. 1216475-30-7), using ethyl 2-(2-aminophenyl) acetate (5e) (648 mg, 3.62 mmol), DIPEA (1.08 ml, 6.2 mmol) and HATU (1375 mg, 3.62 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH:EtOAc (9:1) in 0 to 100% hexanes], ethyl 2-(2-(8-bromo-[1,2 ,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate (17b) (200 mg, 24% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.27 (s, 1H), 9.56 (s, 1H), 9.25 (s, 1H), 8.20 (s, 1H), 7 ,41-7.23 (m, 4H), 3.98 (k, J=7.1 Hz, 2H), 3.74 (s, 2H), 1.05 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6carboxamido)phenyl)acetic acid (17c).

Compound 17c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl )acetate (17b) (200 mg, 0.5 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (139 mg, 0.74 mmol), tripotassium phosphate (1.3 M solution ) (1.145 ml, 1.49 mmol), tricyclohexylphosphine (42 mg, 0.15 mmol) and Pd ₂ (dba) ₃ (45 mg, 0.05 mmol) in an Ar atmosphere when heated at 120°C for 1 hour in the microwave. This resulted in, after work-up, purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(8-( 3(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetic acid (17c) (41 mg, 21% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.52 (s, 1H, D2O replaceable), 9.66-9.54 (m, 1H), 9.39-9.28 (m, 1H), 8.56 (s, 3H, D2O replaceable), 8.41 (s, 1H), 8.39-8.30 (m, 2H), 7.64 (d, J=4.4 Hz, 2H), 7.48-7.38 (m, 1H), 7.427.31 (m, 2H), 7.33-7.23 (m, 1H), 4.32-4.02 (m, 2H), 3. 72 (d, J=2.3 Hz, 2H); MS (ESI+): 402.3 (M+1); MS (ESI-): 400.4 (M-1); purity after HPLC: 93.65%.

Scheme-18 he

18e 18"

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphtamido)phenyl)acetic acid (18f).

Stage-1. Preparation of methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphtholate (18b).

- 88 045626

Compound 18b was prepared according to the procedure described in step-3 of Scheme-1 from methyl 4-bromo-2-naphtholate (18a) (250 mg, 0.94 mmol; CAS No. 1013-80-5) in DMF (3 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (355 mg, 1.42 mmol), tripotassium phosphate (1.3 M solution, 1.45 ml, 1.89 mmol), tricyclohexylphosphine (79 mg , 0.28 mmol) and Pd ₂ (dba) ₃ (86 mg, 0.09 mmol) under nitrogen when heated at 120°C for 14 hours. This resulted in, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with hexanes/ethyl acetate 0% to 100%] methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphtholate (18b) (257 mg, 70% yield ) in the form of oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.69 (s, 1H), 8.32-8.19 (m, 1H), 7.95-7.81 (m, 2H), 7. 72-7.61 (m, 2H), 7.57-7.47 (m, 2H), 7.44-7.27 (m, 3H), 4.27-4.16 (m, 2H), 3.93 (s, 3H), 1.38 (s, 9H).

Stage-2. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c).

Compound 18c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphtholate (18b) (240 mg, 0.613 mmol ) in THF (10 ml), using a solution of lithium hydroxide monohydrate (29 mg, 1.23 mmol) in water (2 ml) This gave, upon workup, 4-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)-2-naphthoic acid (18c) (150 mgs, 65%), which was used as is in the next step;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.61 (s, 1H), 8.24-8.11 (m, 1H), 7.89-7.77 (m, 2H), 7.67 -7.56 (m, 2H), 7.48 (m, 2H), 7.35 (m, 3H), 4.22 (d, J=6.1 Hz, 2H), 1.35 (s, 9H).

Stage-3. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2naphtamido)phenyl)acetate (18d).

Compound 18d was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c) (150 mg, 0.397 mmol) in DMF (8 ml) using ethyl 2-(2-aminophenyl) acetate (5e) (125 mg, 0.695 mmol), DIPEA (0.21 ml, 1.2 mmol) and HATU (264 mg, 0.695 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-(4- (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphtamido)phenyl)acetate (18d) (169 mg, 79% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 8.59 (s, 1H), 8.13 (dd, J=20.3, 7.9 Hz, 1H), 7.97-7.83 (m, 2H), 7.64 (p, J=7.0 Hz, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.46-7 .29 (m, 7H), 7.30-7.08 (m, 1H), 4.25 (d, J=6.2 Hz, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.77 (s, 2H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphtamido)phenyl)acetate (18e).

Compound 18e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphtamido)phenyl)acetate (18d) (150 mg, 0.28 mmol) using TFA (0.22 mL, 2.78 mmol) in DCM (10 mL). This gave, upon work-up, ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphtamido)phenyl)acetate (18e) (84 mg, 69%), which was used as is in the next step; MS (ESI+): 439.4 (M+1).

Stage-5. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphtamido)phenyl)acetic acid (18f).

Compound 18f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-2-naphtamido)phenyl)acetate (18e) (70 mg, 0 .16 mmol) in THF (5 ml), using a solution of lithium hydroxide monohydrate (19 mg, 0.8 mmol) in water (2 ml) This gave, after work-up and purification by reverse phase column chromatography, [C18 (50 d), eluted with ACN in water (with 0.1% HCl) from 0-100%] 2-(2-(4-(3-(aminomethyl)phenyl)-2naphtamido)phenyl)acetic acid (18f) (43 mg , 66% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.39 (s, 1H, D2O replaceable), 10.41 (s, 1H, D2O replaceable), 8.64 (s, 1H), 8.34 (s , 3H, D2O replaceable), 8.17 (d, J=7.7 Hz, 1H), 7.99 (d, J=1.9 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.747.56 (m, 6H), 7.50 (d, J=7.7 Hz, 1H), 7.39-7.28 (m, 2H), 7.28-7.20 (m, 1H), 4.16 (s, 2H), 3.70 (s, 2H); MS (ESI+): 411.3 (M+1), 433.3 (M+Na), (ESI-): 409.4 (M-1, 445.4 (M+Cl); HPLC purity: 93.35%.

Scheme-19

Preparation of 2-(2-(4-(3 -(aminomethyl)-5-fluorophenyl)-1 H-indole-6-carboxamido)phenyl)acetic acid (19c).

Stage-1. Preparation of 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6

- 89 045626 carboxamido)phenyl)acetic acid (19b).

Compound 19b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (320 mg, 0.80 mmol ) in dioxane (3 ml), using tert-butyl 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (19a) (420 mg, 1 .2 mmol; CAS No. 1421773-36-5), tripotassium phosphate (1.3 M solution) (1.23 ml, 1.60 mmol), tricyclohexylphosphine (67 mg, 0.24 mmol) and Pd ₂ (dba) ₃ (73 mg, 0.08 mmol) under Ar atmosphere by heating at 120°C for 60 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 90%] 2(2-(4-(3-(((tert-butoxycarbonyl)amino )methyl)-5-fluorophenyl)-1H-indole-6carboxamido)phenyl)acetic acid (19b) (175 mg, 42% yield) as a yellow solid; MS (ESI+): 518.4 (M+1); (ESI-): 516.4 (M-1).

Stage-2. Preparation of 2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6carboxamido)phenyl)acetic acid (19c).

Compound 19c was prepared according to the procedure described in step-5 of Scheme-1 from 2-(2-(4(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6 -carboxamido)phenyl)acetic acid (19b) (170 mg, 0.33 mmol) in DCM (10 ml) using TFA (0.25 ml, 3.28 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-(3-(aminomethyl)-5fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19c) ( 69 mg, 50% yield) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H, D2O replaceable), 11.80 (t, J=2.2 Hz, 1H), 10.08 (s, 1H, D2O replaceable ), 8.52 (s, 3H, D2O replaceable), 8.12 (s, 1H), 7.86-7.81 (m, 1H), 7.80-7.75 (m, 1H), 7 .68 (t, J=2.8 Hz, 1H), 7.64-7.56 (m, 1H), 7.53-7.39 (m, 2H), 7.38-7.28 (m , 2H), 7.27-7.18 (m, 1H), 6.84-6.76 (m, 1H), 4.17 (s, 2H), 3.70 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.22; MS (ESI+): 418.4 (M+1); (ESI-): 416.4 (M-1); 452.4 (M+Cl); HPLC purity; 98.96%.

Scheme-20

Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8carboxamido)phenyl)acetic acid (20e).

Stage-1. Preparation of 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5a]pyridine-8-carboxylic acid (20b).

Compound 20b was prepared according to the procedure described in step-3 of Scheme-1 from methyl 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (20a) (500 mg, 1.953 mmol; CAS No. 1801262-20-3) in dioxane (3 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (735 mg, 2.93 mmol), tripotassium phosphate (1.3 M solution, 3.0 ml, 3.91 mmol), tricyclohexylphosphine (164 mg, 0.59 mmol) and Pd ₂ (dba) ₃ (179 mg, 0.2 mmol) under nitrogen atmosphere when heated at 120°C for 1 hour in the microwave. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with ethyl acetate in 0% to 100% hexanes] 6-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1 ,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (20b) (200 mg, 28%) as oil; MS (ESI-) 367.3 (M-1).

Stage-2. Preparation of ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20s).

Compound 20c was prepared according to the procedure described in step-4 of Scheme-1 from 6-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a ]pyridine-8-carboxylic acid (20b) (200 mg, 0.54 mmol) in DMF (8 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (170 mg, 0.95 mmol), DI - 90 045626

PEA (0.28 ml, 1.63 mmol) and HATU (361 mg, 0.95 mmol). This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted 0-60%

EtOAc/MeOH (9:1) in hexane from 0% to 100%] ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[ 1,5-a]pyridine-8-carboxamido)phenyl)acetate (20c) (153 mg, 53% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.63 (d, J=1.8 Hz, 1H), 8.78 (s, 1H), 8.70 ( d, J=1.8 Hz, 1H), 8.19-8.09 (m, 1H), 7.77 (m, 2H), 7.51 (m, 2H), 7.38 (m, 3H ), 7.23 (m, 1H), 4.26 (d, J=6.1 Hz, 2H), 4.06 (k, J=7.1 Hz, 2H), 3.96 (s, 2H ), 1.40 (s, 9H), 1.09 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8carboxamido)phenyl)acetate (20d).

Compound 20d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4] triazolo[1,5-a]pyridine-8carboxamido)phenyl)acetate (20c) (140 mg, 0.264 mmol) using TFA (0.41 mL, 5.29 mmol) in DCM (2 mL). This resulted in the preparation after treatment of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20d) (65 mg, 57%), which was used as is in the next step;

1H NMR (300 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.64 (d, J=1.8 Hz, 1H), 8.77 (s, 1H), 8.71 (d , J=1.8 Hz, 1H), 8.13 (dd, J=7.3, 2.0 Hz, 1H), 7.87 (s, 1H), 7.76-7.68 (m, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.40-7.35 (m, 2H), 7.26-7 .16 (m, 1H), 4.06 (k, J=7.1 Hz, 2H), 3.95 (s, 2H), 3.82 (s, 2H), 2.11 (s, 2H) , 1.09 (t, J=7.1 Hz, 3H); MS (ESI+): 430.4 (M+1).

Stage-4. Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8carboxamido)phenyl)acetic acid (20e).

Compound 20e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a] pyridine-8-carboxamido)phenyl)acetate (20d) (60 mg, 0.14 mmol) in THF (5 ml), using a solution of lithium hydroxide monohydrate (17 mg, 0.7 mmol) in water (1 ml) This resulted obtained after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(6-(3( aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetic acid (20e) (53 mg, 95% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 9.69 (d, J=1.8 Hz, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.76 (s, 1H), 8.48 (s, 3H, D2O replaceable), 8.21-8.13 (m, 1H), 8.09 (s, 1H), 7.95 ( dt, J=6.5, 2.3 Hz, 1H), 7.66-7.55 (m, 2H), 7.43-7.31 (m, 2H), 7.25-7.16 ( m, 1H), 4.16 (d, J=5.8 Hz, 2H), 3.89 (s, 2H); MS (ESI+) 402.3 (M+1), (ESI-) 400.4 (M-1), 436.4 (M+Cl); purity after HPLC: 98.75%.

Scheme-21

21s ^21d

Preparation of 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (21d).

Stage-1. Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxylic acid (21a).

Compound 21a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (200 mg, 0.89 mmol ;) in dioxane (3 ml), using tert-butyl 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (19a) (467 mg, 1.33 mmol), tripotassium phosphate (1.3 M solution, 1.36 ml, 0.089 mmol), tricyclohexylphosphine (75 mg, 0.27 mmol) and Pd ₂ (dba) ₃ (81 mg, 0.089 mmol) under nitrogen atmosphere when heated at 120°C for 1 hour in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 90%] 2-(3-(((tert-butoxycarbonyl)amino)methyl)-5 -fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (21 a) (118 mg, 35% yield) as a yellow solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.04 (s, 1H), 8.01 (t, J=2.0 Hz, 1H), 7.90-7.83 (m, 1H), 7.58 (t, J=6.2 Hz, 1H), 7.17 (dt, J=9.8, 2.0 Hz, 1H), 6.99-6.93 (m, 2H), 4 .23 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Stage-2. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5fluorophenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)phenyl) acetate (21b).

Compound 21b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1 -f][1,2 ,4]triazine-4-carboxylic acid (21a) (110 mg, 0.29 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (77 mg, 0.43 mmol) , DIPEA (0.1 ml, 0.57 mmol) and HATU (162 mg, 0.43 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0 to 100% hexane] ethyl 2-(2-(2 -(3-(((tert-butoxycarbonyl)amino)methyl)-5fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21b) (125 mg, 80 % yield) as a yellow solid; MS (ESI-): 546.5 (M-1).

Stage-3. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (21c).

Compound 21c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1 -f][1,2,4]triazine-4carboxamido)phenyl)acetate (21b) (42 mg, 0.08 mmol) using TFA (0.06 mL, 0.77 mmol) in DCM (10 mL). This resulted in, after workup followed by purification by flash chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] then reverse phase chromatography on a column [C18 (50 g), eluted with ACN in water (with 0.1 % HCl) from 0% to 100%] ethyl 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido )phenyl)acetate (21c) (33 mg, 96% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.92 (s, 1H), 8.58-8.49 (m, 1H), 8.45-8.36 (m, 2H), 8. 26 (s, 3H), 7.71 (d, J=7.9 Hz, 1H), 7.65-7.60 (m, 1H), 7.60-7.53 (m, 1H), 7 ,46-7.38 (m, 2H), 7.35-7.25 (m, 2H), 4.20 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.86 (s, 2H), 1.00 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (21d).

Compound 21d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)phenyl)acetate (21c) (19 mg, 0.042 mmol) in MeOH (10 ml), using sodium hydroxide (17 mg, 0.43 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(2-( 3-(aminomethyl)-5fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (21d) (15 mg, 84% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H, D2O replaceable), 10.94 (s, 1H, D2O replaceable), 8.52 (s, 3H, D2O replaceable), 8, 48-8.45 (m, 1H), 8.45-8.35 (m, 2H), 7.81-7.74 (m, 1H), 7.65-7.57 (m, 2H), 7.45-7.35 (m, 2H), 7.34-7.24 (m, 2H), 4.27-4.13 (m, 2H), 3.78 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.09; MS (ESI+) 420.3 (M+1); (ESI-) 418.4 (M-1); purity after HPLC, 98.34%.

Scheme-22

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -(methylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (22a).

Compound 22a was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H -indol-6-yl)methoxy)phenyl)acetate (12b) (0.1 g, 0.20 mmol) in MeOH/THF (4 ml each), using lithium hydroxide monohydrate (8 mg, 0.2 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(2- (aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (22a) (0.03 g, 36% yield), HCl salt, as yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.60 (d, J=4.9 Hz, 1H), 8.53 (s, 3H), 8.12 (s, 1H), 7.75 (d, J=3.8 Hz, 1H),

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7.71-7.64 (m, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.29-7.18 (m, 2H), 7.16-7.07 ( m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H),

6.76 (t, J=3.3 Hz, 1H), 5.34 (s, 2H), 4.37 (d, J=6.0 Hz, 2H), 3.59 (s, 2H), 3.55 (s, 3H); ¹⁹ F NMR (282 MHz,

DMSO-d ₆ ) δ -128.61; MS (ESI+): 484.9 (M+1); MS (ESI-): 482.9 (M-1). Purity after HPLC: 93.84%.

Scheme-23

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23e).

Stage-1. Preparation of (7-bromobenzofuran-5-yl)methanol (23a).

To a stirred solution of 7-bromobenzofuran-5-carboxylic acid (15a) (10 g, 41.5 mmol) and N-methylmorpholine (5.47 ml, 49.8 mmol) in THF (200 ml) at -5°C was added isobutyl chloroformate (6.54 ml, 49.8 mmol). The reaction mixture was stirred for 15 min, filtered through a pad of celite, and the precipitate was washed with THF (3x20 ml). The filtrate was cooled to 0°C and a solution of NaBH ₄ (4.71 g, 124 mmol) in water (10 ml) was carefully added (gases were quickly released). The reaction mixture was stirred for 30 min, diluted with water (20 ml), washed with ethyl acetate (3x). The organic layers were combined, dried, filtered and concentrated in vacuo to give (7-bromobenzofuran-5yl)methanol (23 a) (9 g, 96% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.49 (d , J=1.4 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.34 (t, J=5.8 Hz, 1H), 4.57 (d, J =5.8 Hz, 2H).

Stage-2. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c).

To a solution of (7-bromobenzofuran-5-yl)ethanol (23a) (9 g, 39.6 mmol), triphenylphosphine (11.44 g, 43.6 mmol) and ethyl 2-(2-hydroxyphenyl) acetate (23b) (7.86 g, 43.6 mmol; CAS No. 41873-65-8) in DCM (180 ml) at 0°C was added dropwise a solution of bis(4-chlorobenzyl) azodicarboxylate (DCAD, 16.01 g, 43, 6 mmol; CAS No: 916320-82-6) in DCM (40 ml). The resulting mixture was stirred at RT for 30 min and filtered to remove solids. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with 0% to 50% EtOAc in hexane] to give ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy )phenyl)acetate (23c) (11.5 g, 75% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.30- 7.19 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.91 (td, J=7 ,4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.07 (t , J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23d).

Compound 23d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (300 mg, 0.77 mmol) in dioxane (6 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (217 mg, 1.16 mmol), tripotassium phosphate (1.3 M solution) (0.77 ml, 2.31 mmol), tricyclohexylphosphine (65 mg, 0.23 mmol) and Pd ₂ (dba) ₃ (71 mg, 0.077 mmol) in an Ar atmosphere when heated at 125 °C for 45 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by purification by reverse phase chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23d) (107 mg, 33% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.20 (s, 3H, _D2O replaceable), 8.14-8.09 (m, 1H), 7.98 (s, 1H), 7, 91 (d, J=7.3 Hz, 1H), 7.81-7.71 (m, 1H), 7.67-7.47 (m, 3H), 7.34-7.19 (m, 2H), 7.17-7.06 (m, 2H), 6.92 (t, J=7.5 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 4.01-3.86 (m, 2H), 3.63 (s, 2H), 1.04-0.93 (m, 3H); MS (ESI+): 416.3 (M+1); 831.5 (2M+1); MS (ESI-): 450.4 (M+Cl); purity after HPLC: 96.49%

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Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23e).

Compound 23e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23d) ( 2.25 g, 5.42 mmol) in MeOH/THF (30 ml), using a solution of lithium hydroxide monohydrate (682 mg, 16.25 mmol) in water (5 ml) This resulted after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0-100%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl )methoxy)phenyl)acetic acid (23e) (1.5 g, 72% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (s, 1H, D2O replaceable), 8.53 (s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 8.04-7.99 (m, 1H), 7.97-7.89 (m, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d , J=1.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.23 (d, J=7.4 Hz, 2H), 7.13-7.04 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H); MS (ESI+): 388.3 (M+1); (ESI-): 386.3 (M-1); 422.3 (M+Cl); purity after HPLC: 99.44%.

Scheme-24 he I

225f 24a

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6yl)methoxy)phenyl)acetic acid (24b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6yl)methoxy)phenyl)acetate (24a).

Compound 24a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl) acetate (225f) (191 mg, 0.388 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117 mg, 0.692 mmol), K2CO3 solution (186 mg, 1.346 mmol) in water (0.5 ml), Pd(PPh ₃ ) ₂ Cl ₂ (55 mg, 0.078 mmol) and heating in an Ar atmosphere at 100°C for 3 hours. This resulted in the following treatment and purification by flash column chromatography (silica gel 12 g, eluted with DMA80 in DCM from 0-50%) ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6yl)methoxy) phenyl)acetate (24a) (181 mg, 100% yield) as a pale yellow oil. MS (ESI+): 467.9 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6yl)methoxy)phenyl)acetic acid (24b).

Compound 24b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl )acetate (24a) (205 mg, 0.438 mmol) in MeOH/THF (6 ml), using a solution of lithium hydroxide (132 mg, 3.15 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((4-(3-( aminomethyl)-2-fluorophenyl)-2chlorobenzofuran-6-yl)methoxy)phenyl)acetic acid (24b) (60 mg, 31% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 2H), 7.70 (s, 1H), 7.62 (t, J=7.1 Hz, 1H), 7.54 (t , J=7.4 Hz, 1H), 7.42 (s, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.16 (d, J=7.4 Hz, 2H ), 7.02 (dd, J=13.9, 5.9 Hz, 2H), 6.84 (t, J=7.3 Hz, 1H), 5.23 (s, 2H), 4.09 (s, 2H), 3.53 (s, 2H). MS (ESI+): 439.9 (M+1); MS (ESI-): 437.9 (M-1).

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Scheme-25

Preparation of 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazin-4yl)methoxy)phenyl)acetic acid (25d).

Stage-1. Preparation of tert-butyl 3-(4-(hydroxymethyl)pyrrolo[2,1-1][1,2,4]triazin-2yl)benzylcarbamate (25a).

Compound 25a was prepared according to the procedure described in step-1 of Scheme-23 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4 ]triazine-4-carboxylic acid (1e) (570 mg, 1.55 mmol) in THF (30 ml), using N-methylmorpholine (0.2 ml, 1.86 mmol), isobutyl chloroformate (0.24 ml, 1 .86 mmol) and NaBH4 (176 mg, 4.64 mmol) in water (0.8 ml). This resulted in tert-butyl 3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate (25a) (100 mg, 18% yield) after treatment. as a yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.23-8.17 (m, 2H), 8.12 (s, 1H), 7.57-7.43 (m, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.20 (d, J=4.5 Hz, 1H), 7.02 (dd, J=4.5, 2.5 Hz, 1H), 5 .77 (d, J=5.7 Hz, 1H), 4.87 (d, J=6.1 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 1.42 (s, 9H); MS (ESI+): 355.3 (M+1), 377.3 (M+Na), (ESI-): 353.4 (M-1).

Stage-2. Preparation of ethyl 2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,11][1,2,4]triazin-4-yl)methoxy)phenyl) acetate (25b).

Compound 25b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate ( 25a) (95 mg, 0.27 mmol) in THF (5 ml), using triphenylphosphine (91 mg, 0.35 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (63 mg, 0.35 mmol ) and diisopropyl azodicarboxylate (DIAD, 71 mg, 0.35 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((2-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25b) (42 mg, 30% yield) as a solid; MS (ESI+): 539.4, 540.5 (M+Na), (ESI-): 515.4, 516.5 (M-1).

Stage-3. Preparation of ethyl 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4yl)methoxy)phenyl)acetate (25c).

Compound 25c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f ][1,2,4]triazin-4yl)methoxy)phenyl)acetate (25b) (140 mg, 0.27 mmol) using TFA (0.21 mL, 2.71 mmol) in DCM (5 mL). This gave, after workup followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((2-( 3(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25c) (26 mg, 23% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.45-8.40 (m, 1H), 8.40-8.27 (m, 4H, partly D2O replaceable), 8.228.16 (m, 1H), 7.68-7.54 (m, 2H), 7.30-7.20 (m, 2H), 7.20-7.14 (m, 2H), 7.12-7.07 (m, 1H ), 7.00-6.91 (m, 1H), 5.54 (s, 2H), 4.21-4.08 (m, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.04 (t, J=7.1 Hz, 3H); MS (ESI+): 417.3 (M+1); 439.3 (M+Na); purity after HPLC: 97.50%.

Stage-4. Preparation of 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4yl)methoxy)phenyl)acetic acid (25d).

Compound 25d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4] triazin-4-yl)methoxy)phenyl)acetate (25c) (38 mg, 0.09 mmol) in MeOH (5 ml), using sodium hydroxide (15.49 mg, 0.39 mmol) in water (0.5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((2- (3(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetic acid (25d) (3.6 mg, 12% yield) as yellow solid matter;

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1H NMR (300 MHz, methanol^) δ 8.50 (s, 1H), 8.44-8.36 (m, 1H), 8.08-8.03 (m, 1H), 7.63-7 .56 (m, 2H),

7.31-7.19 (m, 3H), 7.11-7.02 (m, 2H), 7.01-6.92 (m, 1H), 5.58 (s, 2H), 4. 23 (s, 2H), 3.75 (s, 2H); MS (ESI+):

389.3 (M+1); 411.3 (M+Na); (ESI-): 387.2 (M-1); 423.4 (M+Cl); HPLC, purity, 87.71%.

Scheme-26

DIAD, PPh ₃

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2yl)methoxy)phenyl)acetic acid (26d).

Stage-1. Preparation of tert-butyl 3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)benzylcarbamate (26a).

Compound 26a was prepared according to the procedure described in step-1 of Scheme-23 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3- d]pyrimidine-2carboxylic acid (16f) (500 mg, 1.18 mmol) in THF (30 ml), using N-methylmorpholine (0.14 ml, 1.3 mmol), isobutyl chloroformate (0.17 ml, 1. 3 mmol) and NaBH4 (90 mg, 2.37 mmol) in water (0.8 ml). This resulted in the preparation after treatment of tert-butyl 3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (26a) (330 mg, 68% yield) as a yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10-8.03 (m, 2H), 7.78 (d, J=3.6 Hz, 1H), 7.61-7.48 (m , 2H), 7.41 (d, J=7.6 Hz, 1H), 6.89 (d, J=3.6 Hz, 1H), 5.17 (t, J=6.1 Hz, 1H ), 4.71 (d, J=6.1 Hz, 2H), 4.25 (d, J=6.3 Hz, 2H), 4.16 (d, J=7.2 Hz, 2H), 1.41 (s, 9H), 1.34-1.21 (m, 1H), 0.58-0.40 (m, 4H);

1H NMR (300 MHz, DMSO-d6/D2O) δ 8.05-7.96 (m, 2H), 7.70 (d, J=3.6 Hz, 1H), 7.57-7.43 ( m, 1H), 7.39 (d, J=7.6 Hz, 1H), 6.85 (d, J=3.6 Hz, 1H), 4.69 (s, 2H), 4.23 ( d, J=4.8 Hz, 2H), 4.13 (d, J=7.2 Hz, 2H), 1.37 (s, 9H), 1.31-1.17 (m, 1H), 0.54-0.36 (m, 4H).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy )phenyl)acetate (26b).

Compound 26b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) benzylcarbamate (26a) (327 mg, 0.8 mmol) in THF (8 ml), using triphenylphosphine (273 mg, 1.04 mmol), ethyl 2-(2hydroxyphenyl) acetate (23b) (188 mg, 1.04 mmol ) and (E)-diisopropyldiazene-1,2-dicarboxylate (DIAD, 210 mg, 1.04 mmol). This gave, upon workup and by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2yl)methoxy)phenyl)acetate (26b) (352 mg, 77% yield) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.90 (s, 2H), 8.08-7.98 (m, 2H), 7.82 (d, J=3.6 Hz, 1H), 7.58-7.48 (m, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.24-7.13 (m, 3H), 6.96-6.83 ( m, 2H), 5.35 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 4.13 (d, J=7.2 Hz, 2H), 3.96 ( k, J=7.1 Hz, 2H), 1.40 (s, 9H), 1.34-1.19 (m, 1H), 1.01 (t, J=7.1 Hz, 3H), 0.51-0.34 (m, 4H).

Stage-3. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3d]pyrimidin-2-yl)methoxy)phenyl)acetate (26c).

Compound 26c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)- 7H-pyrrolo[2,3d]pyrimidin-2-yl)methoxy)phenyl)acetate (26b) (350 mg, 0.61 mmol) using TFA (0.47 mL, 6.13 mmol) in DCM (25 mL ). This resulted in the following workup followed by purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM from 0% to 100%] followed by reverse phase chromatography on a [C18 (50 g) column. eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2, 3d]pyrimidin-2-yl)methoxy)phenyl)acetate (26c) (256 mg, 89% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.54 (s, 3H, D2O replaceable), 8.27 (s, 1H), 8.18 (dt, J=7.4, 1.6 Hz, 1H), 7.88 (d, J=3.6 Hz, 1H), 7.75-7.59 (m, 2H), 7.27-7.10 (m, 4H), 6.90 (td , J=7.2, 1.3 Hz, 1H), 5.38 (s, 2H), 4.16 (t,

- 96 045626

J=7.1 Hz, 4H), 3.97 (k, J=7.1 Hz, 2H), 3.70 (s, 2H), 1.36-1.19 (m, 1H), 1, 02 (t, J=7.1 Hz, 3H), 0.55-0.34 (m, 4H);

MS (ESI+): 471.4 (M+1); 493.4 (M+Na); (ESI-): 505.4 (M+Cl); purity after HPLC: 99.60%.

Stage-4. Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3d]pyrimidin-2-yl)methoxy)phenyl)acetic acid (26d).

Compound 26d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3- d]pyrimidin-2yl)methoxy)phenyl)acetate (26c) (105 mg, 0.22 mmol) in MeOH (10 ml), using sodium hydroxide (44.6 mg, 1.12 mmol) in water (2 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2yl)methoxy)phenyl)acetic acid (26d) (23 mg, 23% yield) as a white solid substances;

^1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 3H, D2O replaceable), 8.26 (d, J=2.1 Hz, 1H), 8.18 (dd, J=7, 6, 1.6 Hz, 1H), 7.87 (d, J=3.6 Hz, 1H), 7.73-7.58 (m, 2H), 7.25-7.09 (m, 4H ), 6.92-6.84 (m, 1H), 5.40 (s, 2H), 4.224.09 (m, 4H), 3.67 (s, 2H), 1.32-1.21 ( m, 1H), 0.52-0.31 (m, 4H); MS (ESI+): 443.4 (M+1); 465.4 (M+Na); (ESI-): 441.5 (M-1); 477.4 (M+Cl); purity after HPLC: 99.44%.

Scheme-27

Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetic acid (27f).

Stage-1. Preparation of 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid (27c).

Compound 27c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 6chlorimidazo[1,2-b]pyridazine-8-carboxylate (27a) (500 mg, 2.22 mmol; CAS No. 1161847-33- 1) in dioxane (6 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (835 mg, 3.32 mmol), tripotassium phosphate (1.5 ml, 4.43 mmol, 1.3 M aqueous solution), tricyclohexylphosphine (186 mg, 0.67 mmol) and Pd ₂ (dba) ₃ (203 mg, 0.22 mmol) under nitrogen atmosphere when heated at 120°C for 1 hour in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with hexanes in ethyl acetate 0-100%] ethyl 6-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1, 2-b]pyridazine-8-carboxylate (27b) (123 mg, 14% yield) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (d, J=1.2 Hz, 1H), 8.09 (s, 1H), 7.99-7.94 (m, 2H), 7.92 (d, J=1.2 Hz, 1H), 7.58-7.39 (m, 3H), 4.47 (k, J=7.1 Hz, 2H), 4.24 (d , J=6.2 Hz, 2H), 1.43-1.30 (m, 12H); MS (ESI+): 397.3 (M+1), first elution gave 6-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]niridazine-8-carboxylic acid (27c) (60 mg, 7% yield) as an oil;

1H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.05 (s, 1H), 8.00-7.94 (m, 2H), 7.91 (d, J= 1.3 Hz, 1H), 7.59-7.38 (m, 3H), 4.24 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Stage-2. Preparation of ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2b]pyridazine-8-carboxamido)phenyl)acetate (27d).

Compound 27d was prepared according to the procedure described in step-4 of Scheme-1 from 6-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid ( 27s) (180

- 97 045626 mg, 0.489 mmol), using ethyl 2-(2-aminophenyl) acetate (5e) (153 mg, 0.86 mmol), DIPEA (0.26 ml, 1.47 mmol) and HATU (325 mg, 0.87 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-(6-(3 -(((tert-butoxycarbonyl)amino)methyl)phenyl)imudazo[1,2-b]pyridazine-8carboxamido)phenyl)acetate (27d) (140 mg, 54% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.20-8.13 (m, 1H ), 8.05-7.97 (m, 2H), 7.93 (s, 1H), 7.62-7.52 (m, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.22 (t, J=7.5 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H), 4.06 (k, J=7.1 Hz, 2H), 3.98 (s, 2H), 1.41 (s, 9H), 1.10 (t, J=7.1 Hz, 3H); MS (ESI+): 530.4 (M+1).

Stage-3. Preparation of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8carboxamido)phenyl)acetate (27e).

Compound 27e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b] pyridazine-8carboxamido)phenyl)acetate (27d) (125 mg, 0.24 mmol) using TFA (0.18 mL, 2.36 mmol) in DCM (5 mL). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0% to 100%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazin-8-carboxamido)phenyl)acetate (27e ) (100 mg, 99% yield) as a pale yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 11.78 (s, 1H, D2O replaceable), 8.61 (d, J=1.4 Hz, 1H), 8.51-8.35 (m, 4H , 3H D2O replaceable), 8.31 (s, 1H), 8.18 (dd, J=7.9, 4.2 Hz, 2H), 7.97 (d, J=1.4 Hz, 1H) , 7.75-7.61 (m, 2H), 7.477.37 (m, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.20 (k, J=5.9 Hz, 2H), 4.06 (k, J=7.1 Hz, 2H), 3.99 (s, 2H), 1.10 (t, J=7.1 Hz, 3H); MS (ESI+:) 430.5 (M+1), 452.4 (M+Na), (ESI-): 464.5 (M+Cl); purity after HPLC: 97.66%.

Stage-4. Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8carboxamido)phenyl)acetic acid (27f).

Compound 27f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(6-(3-(aminomethyl)phenyl)umidazo[1,2-b]pyridazin-8-carboxamido)phenyl) acetate (27e) (61 mg, 0.142 mmol) in THF (5 ml), using a solution of lithium hydroxide monohydrate (10 mg, 0.43 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(6-( 3(aminomethyl)phenyl)imidazo[1,2-b]pyridazin-8-carboxamido)phenyl)acetic acid (27f) (65 mg, 100% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H, D2O replaceable), 8.61 (d, J=1.4 Hz, 1H), 8.58-8.43 (m, 4H , 3H D2O replaceable), 8.32 (d, J=1.9 Hz, 1H), 8.22-8.10 (m, 2H), 8.00 (d, J=1.4 Hz, 1H) , 7.75-7.62 (m, 2H), 7.39 (m, 2H), 7.22 (td, J=7.5, 1.3 Hz, 1H), 4.18 (k, J =5.5 Hz, 2H), 3.90 (s, 2H); MS (ESI+): 402.4 (M+1), 424.4 (M+Na); (ESI-): 400.5 (M-1); purity after HPLC: 97.80%.

Scheme-28

^28c 28d

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetic acid (28d).

Stage-1. Preparation of ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b).

Compound 28b was prepared according to the procedure described in step-4 of Scheme-1 from 7chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a) (500 mg, 2.53 mmol; CAS No. 478148-53- 7) in DMF (4 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (794 mg, 4.43 mmol), DIPEA (1.33 ml, 7.59 mmol) and HATU (1684 mg, 4.43 mmol). This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in hexane 0% to 60%]

- 98 045626 ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b) (500 mg, 55% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.53 (s, 1H), 8.49 (d, J=2.1 Hz, 1H), 7.79- 7.72 (m, 1H), 7.39-7.32 (m, 3H), 7.25-7.15 (m, 1H), 4.08 (k, J=7.1 Hz, 2H) , 3.79 (s, 2H), 1.11 (t, J=7.1 Hz, 3H); MS (ESI+): 359.2 (M+1); (ESI-) 357.3 (M-1).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5carboxamido)phenyl)acetate (28c).

Compound 28c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b) (500 mg, 1.394 mmol) in dioxane (11 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (261 mg, 1.394 mmol), tripotassium phosphate (1.3 M solution) (1.394 ml, 4.18 mmol), tricyclohexylphosphine ( 117 mg, 0.418 mmol) and Pd ₂ (dba) ₃ (128 mg, 0.139 mmol) in an Ar atmosphere when heated at 125°C for 1 hour in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with ethyl acetate in 0% to 100% hexanes] ethyl 2-(2-(7-(3(aminomethyl)phenyl)furo[ 2,3-c]pyridine-5-carboxamido)phenyl)acetate (28c) (0.304 g, 51% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.60 (s, 1H), 8.69 (s, 1H), 8.61-8.56 (m, 1H), 8.54 (d, J =1.2 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.69 (d, J=4 .6 Hz, 2H), 7.44-7.33 (m, 3H), 7.27-7.18 (m, 1H), 4.20 (s, 2H), 3.93 (k, J= 7.2 Hz, 2H), 3.86 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); MS (ESI+): 430.3 (M+1); MS (ESI-): 428.3 (M-1), 474.4 (M+Cl); purity after HPLC: 96.63%,

Stage-3. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5carboxamido)phenyl)acetic acid (28d).

Compound 28d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl) acetate (28c) (61 mg, 0.142 mmol) in THF (8 ml), using a solution of lithium hydroxide monohydrate (41 mg, 1.71 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetic acid (28d) (140 mgc, 61% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.75 (s, 1H), 8.69 (s, 1H), 8.59-8.56 (m, 1H) , 8.55 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.43 (s, 3H), 7.96 (d, J=7.6 Hz, 1H) , 7.71-7.66 (m, 2H), 7.41-7.34 (m, 3H), 7.247.17 (m, 1H), 4.21 (d, J=5.7 Hz, 2H ), 3.78 (s, 2H); MS (ESI+): 402.3 (M+1); 424.3 (M+Na), (ESI-): 400.3 (M-1); purity after HPLC 98.75.

Scheme-29

Preparation of (S)-2-(2-(2-(3-( 1 -aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (29d ).

Stage-1. Preparation of (S)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1G][1,2,4]triazine-4-carboxylic acid (29a).

Compound 29a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloropyrrolo[2,1-G][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33 mmol ) in dioxane (6 ml) using (S)-tert-butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (29e) (693 mg, 1.99 mmol; CAS No. 887254-65-1, prepared in accordance with the procedure described in PCT International Application, 2015009977, January 22, 2015), tripotassium phosphate (0.753 ml, 2.26 mmol, 3 M aqueous solution) tricyclohexylphosphine (112 mg, 0.4 mmol) and Pd ₂ (dba) ₃ (122 mg, 0.13 mmol) under argon while heating at 125°C for 1 hour in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 30% MeOH in DCM] (S)-2-(3-(1-(tert-butoxycarbonylamino)ethyl )phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic

- 99 045626 acid (29a) (110 mg, 15% yield) in the form of a solid; MS (ESI-): 381.4, 382.4 (M-1).

Stage-2. Preparation of (S)-ethyl 2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1f] [1,2,4]triazine-4-carboxamido )phenyl)acetate (29b).

Compound 29b was prepared according to the procedure described in step-4 of Scheme-1 from (S)-2(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][ 1,2,4]triazine-4-carboxylic acid (29a) (110 mg, 0.29 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (77 mg, 0. 43 mmol), DIPEA (0.1 ml, 0.575 mmol) and HATU (164 mg, 0.431 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] (S)-ethyl 2- (2-(2-(3-(1 -((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (29b) ( 103 mg, 66% yield) as a white solid; MS (ESI+): 566.4 (M+Na); (ESI-) 542.5, 543.5 (M-1).

Stage-3. Preparation of (S)-ethyl 2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (29c).

Compound 29c was prepared according to the procedure described in step-5 of Scheme-1 from (S)-ethyl 2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo [2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (29b) (103 mg, 0.19 mmol) in DCM (5 ml) using TFA (0.15 ml, 1. 90 mmol). This resulted in the production after treatment of (S)-ethyl 2-(2-(2-(3-(1aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl) acetate (29c) (29 mg, 35% yield) as a yellow solid, MS (ESI+): 444.4 (M+1).

Stage-4. Preparation of (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (29d).

Compound 29d was prepared according to the procedure described in step-4 of Scheme-4 from (S)-ethyl 2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][ 1,2,4]triazine-4-carboxamido)phenyl)acetate (29c) (29 mg, 0.065 mmol) in MeOH (5 ml), using a solution of NaOH (38 mg, 0.95 mmol) in water (0.5 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- (2-(3-(laminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (29d) (28 mg, 35% yield) as yellow solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H, D2O replaceable), 10.91 (s, 1H), 8.66 (s, 1H), 8.60 (s, 3H, D2O replaceable), 8.55-8.50 (m, 1H), 8.39 (dd, J=2.5, 1.4 Hz, 1H), 7.90-7.80 (m, 1H), 7.77-7.71 (m, 1H), 7.707.57 (m, 2H), 7.48-7.35 (m, 2H), 7.34-7.21 (m, 2H), 4. 67-4.45 (m, 1H), 3.81 (s, 2H), 1.61 (d, J=6.7 Hz, 3H); MS (ESI+): 416.3 (M+1); (ESI-): 414.4 (M-1); 450.4 (M+Cl); HPLC purity; 99.56%.

Scheme-30

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5carboxamido)phenyl)acetic acid (30d).

Stage-1. Preparation of ethyl 2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5carboxamido)phenyl)acetate (30b).

Compound 30b was prepared according to the procedure described in step-1 of Scheme-7 from 7-bromo1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid (30a) (500 mg, 2.53 mmol; CAS No. 1420800-254) in MeOH (10 ml) using ethyl 2-(2-aminophenyl)acetate (5e) (549 mg, 3.07 mmol) and EDCI (641 mg, 3.34 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(7-bromo-1,2-dimethyl1H-benzo [d]imidazole-5-carboxamido)phenyl)acetate (30b) (300 mg, 28% yield) as an off-white solid. MS (ESI+): 432.3 (M+1); (ESI-) 464.3, 466.3 (M+Cl).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5carboxamido)phenyl)acetate (30c).

- 100 045626

Compound 30c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazol-5-carboxamido)phenyl)acetate ( 30b) (300 mg, 0.697 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (196 mg, 1.046 mmol), tripotassium phosphate (1.3 M solution) (0.697 ml, 2.092 mmol ), tricyclohexylphosphine (59 mg, 0.209 mmol) and Pd ₂ (dba) ₃ (64 mg, 0.07 mmol) in an Ar atmosphere when heated at 125 °C for 45 min in a microwave oven. This resulted in, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazol-5carboxamido)phenyl) acetate (30c) (220 mg, 69% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 8.70 (s, 3H), 8.43 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.72-7.51 (m, 3H), 7.41-7.21 ( m, 4H), 4.13 (d, J=5.8 Hz, 3H), 3.93 (k, J=7.1 Hz, 2H), 2.84 (s, 3H), 3.45 ( s, 3H), 0.97 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5carboxamido)phenyl)acetic acid (30d).

Compound 30d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5 -carboxamido)phenyl)acetate (30c) (125 mg, 0.27 mmol) in MeOH (10 ml), using a solution of sodium hydroxide (110 mg, 2.74 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetic acid (30d) (81 mg, 69% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H, D2O replaceable), 8.71 (s, 3H, D2O replaceable), 8.45 (d, J=1.6 Hz, 1H ), 7.99 (d, J=1.6 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.74-7.68 (m, 1H), 7.67 -7.54 (m, 2H), 7.43-7.20 (m, 4H), 4.13 (k, J=5.9 Hz, 2H), 3.68 (s, 2H), 3, 46 (s, 3H), 2.85 (s, 3H); MS (ESI+): 429.4 (M+1); (ESI-): 427.4 (M-1); 463.4 (M+Cl); purity after HPLC: 100%.

Scheme-31 i^A^NHBoc Pd ₂ (dba) ₃

NH ₂ 5e

K ₃ RO ₄

R(Su) ₃

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (31f).

Stage-1. Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2d]pyrimidine-2-carboxylate (31b).

Compound 31b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 4chlorothieno[3,2-d]pyrimidine-2-carboxylate (31a) (350 mg, 1.44 mmol; CAS No. 319442-18- 7) in dioxane (3 ml), using (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1d) (543 mg, 2.16 mmol), tripotassium phosphate (0.82 ml, 2.452 mmol , 3 M aqueous solution), tricyclohexylphosphine (81 mg, 0.288 mmol) and Pd ₂ (dba) ₃ (73 mg, 0.079 mmol) under argon while heating at 125 °C for 30 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 70% EtOAc in hexane] ethyl 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[ 3,2-d]pyrimidine-2-carboxylate (31b) (400 mg, 67% yield) as a yellow solid.

Stage-2. Preparation of 4-(3-(((tert-butokCicarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2carboxylic acid (31c).

Compound 31c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate ( 31b) (400 mg, 0.97 mmol) in MeOH (10 ml), using a solution of NaOH (193 mg, 4.84 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 4-(3-(((tert-butoxycarbonyl )amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylic acid (31c) (365 mg, 98%

- 101 045626 yield) in the form of a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.46 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 8.19-7.99 (m, 2H), 7.86 (d, J=5.6 Hz, 1H), 7.69-7.47 (m, 3H), 4.28 (d, J=6.2 Hz, 2H), 1.41 (s , 9H).

Stage-3. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2d]pyrimidine-2-carboxamido)phenyl)acetate (31d).

Compound 31d was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylic acid ( 31c) (365 mg, 0.95 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (204 mg, 1.14 mmol), DIPEA (0.331 ml, 1.894 mmol) and HATU (432 mg, 1.14 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31 d) (425 mg, 82% yield) as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 8.77 (d, J=5.5 Hz, 1H), 8.27-8.19 (m, 2H), 7.90 (d, J=5.5 Hz, 1H), 7.86-7.81 (m, 1H), 7.70-7.61 (m, 1H), 7.60-7.51 ( m, 2H), 7.44-7.34 (m, 2H), 7.28-7.19 (m, 1H), 4.30 (d, J=6.2 Hz, 2H), 3.98 (k, J=7.1 Hz, 2H), 3.86 (s, 2H), 1.40 (s, 9H), 0.98 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2carboxamido)phenyl)acetate (31e).

Compound 31e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d] pyrimidine-2carboxamido)phenyl)acetate (31d) (400 mg, 0.73 mmol) in DCM (5 ml) using TFA (0.56 ml, 7.32 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4- (3(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31e) (308 mg, 94% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H, D2O replaceable), 8.80 (d, J=5.4 Hz, 1H), 8.60 (s, 3H, D2O replaceable) , 8.51 (s, 1H), 8.39-8.31 (m, 1H), 7.93 (d, J=5.5 Hz, 1H), 7.89-7.72 (m, 3H ), 7.45-7.35 (m, 2H), 7.327.21 (m, 1H), 4.22 (s, 2H), 3.98 (k, J=7.1 Hz, 2H), 3 .87 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 447.3 (M+1); (ESI-): 481.3 (M+Cl); purity after HPLC, 99.72%.

Stage-5. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2carboxamido)phenyl)acetic acid (31f).

Compound 31f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl) acetate (31e) (256 mg, 0.57 mmol) in MeOH/THF (10 ml, 1:1), using a solution of NaOH (92 mg, 2.29 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (31f) (112 mg, 47% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H, D2O replaceable), 8.80 (d, J=5.5 Hz, 1H), 8.60-8.42 (m, 4H, partially D2O replaceable), 8.39-8.30 (m, 1H), 7.95-7.70 (m, 4H), 7.45-7.33 (m, 2H), 7.23 ( t, J=7.4 Hz, 1H), 4.27-4.20 (m, 2H), 3.79 (s, 2H); MS (ESI+) 419.3 (M+1); 441.3 (M+Na); (ESI-) 417.3 (M-1), 453.3 (M+Cl); HPLC, 0.395 min, 98.46%.

Scheme-32

32a 32b 32c

32d 32e

32f 32g 32h

- 102 045626

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (32h).

Stage-1. Preparation of tert-butium 3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b).

Compound 32b was prepared according to the procedure described in step-3 of Scheme-1 from 2,4dichlorothieno[2,3-d]pyrimidine (32a) (4.5 g, 21.94 mmol; CAS No. 18740-39-1 ) in dioxane (100 ml), using tert-butium 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (5.63 g, 16.88 mmol), tripotassium phosphate (22.07 ml, 28.7 mmol) in water (1 ml), tricyclohexylphosphine (0.95 g, 3.38 mmol) and Pd ₂ (dba) ₃ (0.85 g, 0.93 mmol) under argon and heating in an oil bath at 120°C for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexane from 0% to 70% ] tert-butyl 3-(2-chlorothieno[2,3d]pyrimidin-4-yl)benzylcarbamate (32b) (4.5 g, 71% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (d, J=6.0 Hz, 1H), 7.89-7.83 (m, 2H), 7.74 (d, J= 6.1 Hz, 1H), 7.627.47 (m, 3H), 4.25 (d, J=6.2 Hz, 2H), 1.40 (s, 9H).

Stage-2. Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c).

Compound 32c was prepared according to the procedure described in step-1 of Scheme-1 from tert-butium 3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b) (4.5 g, 11. 97 mmol) in DMF (60 ml) using 1-ethoxyvinyl-tri-n-butyltin (4.89 ml, 14.37 mmol) and Pd(PPh ₃ ) ₄ (0.692 g, 0.599 mmol) under argon with heating at 110°C for 10 hours. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 70% EtOAc in hexane] tert-butyl 3-(2-( 1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c) (4.4 g, 89% yield) as a yellow solid; MS (ESI+): 412.2 (M+1).

Stage-3. Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3d]pyrimidine-2-carboxylate (32d).

Compound 32d was prepared according to the procedure described in step-2 of Scheme-1 from tert-butyl 3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c) (4, 4 g, 10.69 mmol) in 1,4dioxane (50 ml), using a solution of sodium periodate (4.57 g, 21.38 mmol) in water (20 ml) and KMnO ₄ (0.676 g, 4.28 mmol, and a second portion of 0.338 g, 2.138 mmol after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno [2,3-d]pyrimidine-2-carboxylate (32d) (1.6 g, 36% yield) as a yellow solid; MS (ESI+): 414.2 (M+1), 436.1 (M+Na).

Stage-4. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2carboxylic acid (32e).

Compound 32e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate ( 32d) (1.6 g, 3.87 mmol) in THF/MeOH (30 ml, 1:1), using lithium hydroxide monohydrate (0.812 g, 19.35 mmol) in water (5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 4-(3-(((tert-butoxycarbonyl )amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylic acid (32e) (0.55 g, 37% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.93-7.87 (m, 2H), 7 .82 (d, J=6.1 Hz, 1H), 7.64-7.44 (m, 3H), 4.26 (d, J=6.2 Hz, 2H), 1.40 (s, 9H).

Stage-5. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3d]pyrimidine-2-carboxamido)phenyl)acetate (32f).

Compound 32f was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylic acid ( 32e) (547 mg, 1.42 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (305 mg, 1.703 mmol), DIPEA (0.5 ml, 2.84 mmol ) and HATU (648 mg, 1.703 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3d]pyrimidine-2-carboxamido)phenyl)acetate (32f) (620 mg, 1.134 mmol, 80% yield) as white solid matter;

1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.29 (d, J=6.1 Hz, 1H), 8.12-7.99 (m, 2H), 7 .89 (d, J=6.1 Hz, 1H), 7.86-7.78 (m, 1H), 7.65-7.48 (m, 3H), 7.38 (d, J=7 .5 Hz, 2H), 7.29-7.18 (m, 1H), 4.29 (d, J=6.1 Hz, 2H), 3.96 (k, J=7.1 Hz, 2H ), 3.85 (s, 2H), 1.40 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 569.4 (M+Na); (ESI-): 545.5 (M-1).

Stage-6. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2carboxamido)phenyl)acetate (32g).

Compound 32g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d] pyrimidine-2-103 045626 carboxamido)phenyl)acetate (32f) (600 mg, 1.10 mmol) in DCM (10 ml) using TFA (0.85 ml, 10.98 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32g ) (385 mg, 79% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H, _D2O replaceable), 8.58 (s, 3H, D2O replaceable), 8.35-8.27 (m, 2H) , 8.24 (d, J=7.6 Hz, 1H), 8.10 (d, J=6.1 Hz, 1H), 7.84-7.75 (m, 2H), 7.75- 7.68 (m, 1H), 7.42-7.34 (m, 2H), 7.29-7.20 (m, 1H), 4.30-4.14 (m, 2H), 3. 98 (k, J=7.2 Hz, 2H), 3.85 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 447.3 (M+1); (ESI-): 481.3 (M+Cl); purity after HPLC, 99.41%.

Stage-7. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2carboxamido)phenyl)acetic acid (32h).

Compound 32h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl) acetate (32g) (200 mg, 0.448 mmol) in MeOH/THF (10 ml, 1:1), using a solution of NaOH (72 mg, 1.79 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (32h) (150 mg, 80% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.79 (s, 1H, D2O replaceable), 10.81 (s, 1H, D2O replaceable), 8.60 (s, 3H, D2O replaceable), 8, 35-8.27 (m, 2H), 8.27-8.20 (m, 1H), 8.17-8.07 (m, 1H), 7.95-7.84 (m, 1H), 7.83-7.77 (m, 1H), 7.77-7.67 (m, 1H), 7.44-7.33 (m, 2H), 7.29-7.17 (m, 1H ), 4.26-4.17 (m, 2H), 3.78 (s, 2H); MS (ESI+): 419.3 (M+1); 441.3 (M+Na); (ESI-): 417.3 (M-1), 453.3 (M+Cl); HPLC, 0.406 min, 100%.

Scheme-33

Preparation of (R)-2-(2-(2-(3-( 1 -aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid ( 33f).

Stage-1. Preparation of (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (33b) .

Compound 33b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (450 mg, 1.99 mmol ) in dioxane (15 ml), using (R)-tert-butyl (1-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )ethyl)carbamate (33a) (1.093 g, 2.99 mmol; CAS No. 1645556-74-2, prepared according to the procedure described in PCT International Application, 2015009977, January 22, 2015), 3 M aqueous solution tripotassium phosphate (1.33 ml, 3.99 mmol), tricyclohexylphosphine (112 mg, 0.4 mmol) and Pd ₂ (dba) ₃ (183 mg, 0.2 mmol) under argon while heating at 125°C for 45 minutes in the microwave. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in DCM] (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl )amino)ethyl)-2-fluorophenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxylate (33b) (0.73 g, 85% yield) as an orange solid;

1H NMR (300 MHz, DMSO-d6) δ 8.44-8.37 (m, 1H), 7.88-7.79 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.41-7.32 (m, 2H), 7.29 (dd, J=4.6, 2.6 Hz, 1H), 5 .07-4.91 (m, 1H), 4.50 (k, J=7.1 Hz, 2H), 1.45-1.27 (m, 15H); MS (ESI+): 429.3 (M+1); (ESI-): 427.3 (M-1).

Stage-2. Preparation of (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1G][1,2,4]triazine-4-carboxylic acid (33c) .

Compound 33c was prepared according to the procedure described in step-6 of Scheme-1 from (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2, 1-f][1,2,4]triazine-4-carboxylate (33b) (0.73 g, 1.704 mmol) in THF (15 ml), using lithium hydroxide monohydrate (0.107 g, 2.56 mmol) in

- 104 045626 water (3 ml). This led to the preparation after treatment of A)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-0[1,2,4]triazine-4-carboxylic acid (33c) (0.67 g, 98% yield) as a pale orange foam;

1H NMR (300 MHz, DMSO-d6) δ 14.37 (s, 1H), 8.39-8.34 (m, 1H), 7.87 (t, J=7.2 Hz, 1H), 7 .63 (d, J=8.0 Hz, 1H), 7.59-7.51 (m, 1H), 7.40-7.31 (m, 2H), 7.25 (dd, J=4 ,6, 2.6 Hz, 1H), 4.99 (t, J=7.4 Hz, 1H), 1.46-1.24 (m, 12H); MS (ESI+): 423.3 (M+Na); (ESI-): 399.4 (M-1).

Stage-3. Preparation of (R)-ethyl 2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2fluorophenyl)pyrrolo[2,1-0[1,2,4]triazine-4 -carboxamido)phenyl)acetate (33d).

Compound 33d was prepared according to the procedure described in step-4 of Scheme-1 from (R)-2(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazine-4-carboxylic acid (33c) (200 mg, 0.499 mmol) in DMF (3 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (134 mg, 0 .75 mmol), DIPEA (0.174 ml, 1.00 mmol) and HATU (228 mg, 0.6 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 100% EtOAc in hexane] (R)-ethyl 2-(2-(2-(3-(1 -((tert-butoxycarbonyl)amino)ethyl)-2fluorophenyl)pyrrolo[2,1-0[1,2,4]triazine-4-carboxamido)phenyl)acetate (33d) (0.22 g, 78% yield) as an orange solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.16 (t, J=7.4 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.61-7.51 (m, 2H), 7, 44-7.32 (m, 3H), 7.32-7.20 (m, 2H), 5.09-4.93 (m, 1H), 3.95 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 1.43-1.19 (m, 12H), 1.02-0.90 (m, 3H); MS (ESI+): 584.4 (M+Na); (ESI-): 560.5 (M-1).

Stage-4. Preparation of (R)-ethyl 2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-0[1,2,4]triazine4-carboxamido)phenyl)acetate (33e ).

Compound 33e was prepared according to the procedure described in step-5 of Scheme-1 from (R)-ethyl 2-(2-(2-(3 -(1 -((tert-butoxycarbonyl)amino)ethyl)-2- fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (33d) (200 mg, 0.356 mmol) in DCM (2 mL), using TFA (0.274 mL, 3.56 mmol). This gave, after work-up and purification by reverse column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] (R)-ethyl 2-(2-( 2-(3-(1aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33e) (0.164 g, 100% yield), salt HCl, as an orange solid.

1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.48-8.35 (m, 5H), 7.83-7.72 (m, 2H), 7.64- 7.57 (m, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.46-7.36 (m, 2H), 7.36-7.23 (m, 2H) , 4.85-4.69 (m, 1H), 3.97 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.58 (d, J=6.7 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO46) δ -118.34; MS (ESI+): 462.3 (M+1), 484.3 (M+Na); purity after HPLC 99.38%.

Stage-5. Preparation of (R)-2-(2-(2-(3 -(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid ( 33f).

Compound 33f was prepared according to the procedure described in step-4 of Scheme-4 from (R)-ethyl 2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazine-4-carboxamido)phenyl)acetate (3 3 e) (120 mg, 0.26 mmol) in THF (4 ml) using 2 M aqueous NaOH (0.52 ml , 1.04 mmol). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (R)-2-(2- (2-(3-(1-αmunoethyl)-2fluorophenyl)pyrrolo[2,1-0[1,2,4]triazine-4-carboxamido)phenyl)acetic acid (33f) (0.06 g, 53% yield ), HCl salt, as an orange solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.73 (s, 1H), 10.74 (s, 1H), 8.62 (s, 3H), 8.46-8.32 (m, 2H ), 7.92-7.78 (m, 2H), 7.66-7.58 (m, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.44-7, 35 (m, 2H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 4.84-4.70 (m, 1H), 3.76 (s, 2H), 1.60 (d, J=6.7 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.36; MS (ESI+): 434.3 (M+1), MS (ESI-): 432.4 (M-1); purity after HPLC 99.62%.

- 105 045626

Scheme-34

34d 34e 34f

Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (34f).

Stage-1. Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxylate (34b).

Compound 34b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (400 mg, 1.77 mmol ) in dioxane (15 ml) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (1.093 g, 2 .99 mmol; CAS No. 1360819-53-9), 3 M aqueous tripotassium phosphate (1.18 ml, 3.55 mmol), tricyclohexylphosphine (99 mg, 0.36 mmol) and Pd ₂ (dba) ₃ (162 mg , 0.18 mmol) under argon and heating at 125°C for 45 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)- 2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxylate (34b) (0.61 g, 83% yield) as an orange solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (dd, J=2.6, 1.4 Hz, 1H), 7.91-7.83 (m, 1H), 7.57- 7.42 (m, 2H), 7.417.31 (m, 2H), 7.29 (dd, J=4.6, 2.5 Hz, 1H), 4.50 (k, J=7.1 Hz , 2H), 4.26 (d, J=6.0 Hz, 2H), 1.47-1.30 (m, 12H); MS (ESI+): 415.3 (M+1); (ESI-): 413.4 (M-1).

Stage-2. Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,11][1,2,4]triazine-4-carboxylic acid (34c).

Compound 34c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1, 2,4]triazine-4-carboxylate (34b) (0.6 g, 1.448 mmol) in THF (15 ml), using lithium hydroxide monohydrate (0.122 g, 2.90 mmol) in water (1 ml). This resulted in the production after treatment of 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (34c) ( 0.54 g, 97% yield) as a pale orange foam;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 14.37 (s, 1H), 8.36 (dd, J=2.6, 1.4 Hz, 1H), 7.95-7.87 ( m, 1H), 7.57-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.25 (dd, J=4.6, 2.5 Hz, 1H) , 4.26 (d, J=6.1 Hz, 2H), 1.40 (s, 9H); MS (ESI-): 385.3 (M-1).

Stage-3. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl) acetate (34d).

Compound 34d was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2 ,4]triazine-4-carboxylic acid (34c) (250 mg, 0.647 mmol) in DMF (4 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (125 mg, 0.7 mmol), DIPEA (0.23 ml, 1.29 mmol) and HATU (295 mg, 0.776 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 100% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl )amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34d) (0.31 g, 87% yield) as an orange solid .

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.40 (dd, J=2.7, 1.4 Hz, 1H), 8.22 (t, J=7 .5 Hz, 1H), 7.817.75 (m, 1H), 7.61-7.55 (m, 2H), 7.50 (dt, J=13.5, 6.3 Hz, 1H), 7 .44-7.32 (m, 3H), 7.32-7.21 (m, 2H), 4.28 (d, J=6.1 Hz, 2H), 3.96 (k, J=7 .0 Hz, 2H), 3.83 (s, 2H), 1.41 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 570.4 (M+Na); (ESI-): 546.5 (M-1).

Stage-4. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (34e).

Compound 34e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2,4]triazine-4- 106 045626 carboxamido)phenyl)acetate (34d) (200 mg, 0.365 mmol) in DCM (5 ml) using TFA (0.281 ml, 3.65 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(2- (3(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34e) (0.16 g,

98% yield) as HCl salt;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.72 (s, 1H), 8.53-8.36 (m, 5H), 7.81-7.71 (m, 2H), 7.60 (dd, J=4.6, 1.4 Hz, 1H), 7.52-7.36 (m, 3H), 7.34-7.23 (m, 2H), 4.20 (s, 2H ), 3.97 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -116.67; MS (ESI+): 448.3 (M+1), MS (ESI-): 482.4 (M+Cl); purity after HPLC 98.75%

Stage-5. Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4carboxamido)phenyl)acetic acid (34f).

Compound 34f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)phenyl)acetate (34e) (110 mg, 0.246 mmol) in THF (4 ml) using 2 M aqueous NaOH (0.62 ml, 1.23 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 40%] 2-(2-(2-( 3-(aminomethyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (34f) (0.072 g, 70% yield) as HCl salt;

1H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.76 (s, 1H), 8.57-8.34 (m, 5H), 7.86 (d, J= 8.1 Hz, 1H), 7.76 (t, J=7.1 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 7.47 (t, J=7, 8 Hz, 1H), 7.45-7.33 (m, 2H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 7.25 (t, J=7.4 Hz, 1H), 4.20 (s, 2H), 3.76 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -116.66; MS (ESI+): 420.3 (M+1), MS (ESI-): 418.3 (M-1); purity after HPLC 99.49%.

Scheme-35

Preparation of 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetic acid (35f).

Stage-1. Preparation of ethyl 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3carboxylate (35b).

Compound 35b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 1chloro-2,7-naphthyridine-3-carboxylate (35a) (1000 mg, 4.23 mmol; CAS No. 263881-19-2) in DMF (11 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (1.59 g, 6.34 mmol), tripotassium phosphate (1.3 M solution, 2.82 ml, 8. 45 mmol), tricyclohexylphosphine (355 mg, 1.27 mmol) and Pd ₂ (dba) ₃ (387 mg, 0.42 mmol) under nitrogen when heated at 120°C for 1 hour in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with hexanes/ethyl acetate 0% to 100%] ethyl 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2 ,7-naphthyridine-3-carboxylate (35b) (1.32 g, 77% yield) as an oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.88 (d, J=5.7 Hz, 1H), 8.67 (s, 1H), 8.21 ( dd, J=5.7, 1.0 Hz, 1H), 7.68-7.45 (m, 5H), 4.43 (k, J=7.1 Hz, 2H), 4.27 (d , J=6.2 Hz, 2H), 1.40-1.28 (m, 12H).

Stage-2. Preparation of 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3carboxylic acid (35c).

Compound 35c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 1(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate (35b) ( 1250 mg, 3.07 mmol) in THF (20 ml), using a solution of lithium hydroxide monohydrate (220 mg, 9.2 mmol) in water (4 ml) This resulted in 1-(3-(((tert) -butoxycarbonyl)amino)methyl)phenyl)-2,7naphthyridine-3-carboxylic acid (35c) (300 mgc, 26%), which was used as is in the next step;

1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.86 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.17 (d , J=5.8 Hz, 1H),

- 107 045626

7.72-7.41 (m, 5H), 4.27 (d, J=6.2 Hz, 2H), 1.38 (s, 9H).

Stage-3. Preparation of ethyl 2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine3-carboxamido)phenyl)acetate (35d).

Compound 35d was prepared according to the procedure described in step-4 of Scheme-1 from 1-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylic acid (35c) ( 300 mg, 0.79 mmol) in DMF (4 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (248 mg, 1.38 mmol), DIPEA (0.41 ml, 2.37 mmol) and HATU (526 mg, 1.38 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3carboxamido)phenyl)acetate (35d) (300 mg, 70% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 9.55 (s, 1H), 8.90 (d, J=5.7 Hz, 1H), 8.74 ( s, 1H), 8.26 (d, J=5.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.57-7.46 (m, 2H), 7.44-7.32 (m , 2H), 7.21 (t, J=7.4 Hz, 1H), 4.29 (d, J=6.2 Hz, 2H), 3.87-3.73 (m, 4H), 1 .37 (s, 9H), 0.88 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35e).

Compound 35e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2-(2(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3 -carboxamido)phenyl)acetate (35d) (300 mg, 0.56 mmol) using TFA (0.43 mL, 5.55 mmol) in DCM (5 mL). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3carboxamido)phenyl)acetate (35e) (0 .21 g, 86% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.74 (s, 1H), 8.94 (d, J=5.6 Hz, 1H), 8.81 (s , 1H), 8.64 (s, 2H), 8.39 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J=7.5 Hz , 1H), 7.89 (d, J=8.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H ), 7.39 (t, J=8.3 Hz, 2H), 7.23 (td, J=7.3, 1.3 Hz, 1H), 4.19 (k, J=5.8 Hz , 2H), 3.96-3.69 (m, 4H), 0.92 (t, J=7.1 Hz, 3H); MS (ESI+): 441.3 (M+1), 463.3 (M+Na); (ESI-): 475.3 (M+Cl); purity after HPLC: 98.24%,

Stage-5. Preparation of 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetic acid (35f).

Compound 35f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35e ) (150 mg, 0.34 mmol) in MeOH/THF (10 ml, 1:1), using a solution of sodium hydroxide (54 mg, 1.36 mmol) in water (2 ml) This resulted after workup and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0 to 100%] 2-(2-(1-(3-(aminomethyl)phenyl)-2 ,7naphthyridine-3-carboxamido)phenyl)acetic acid (35f) (0.12 g, 85% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.81 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.71 (d, J=6.4 Hz, 3H), 8.47 (d, J=5.5 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J=7.6 Hz , 1H), 8.02-7.92 (m, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7 .44-7.32 (m, 2H), 7.28-7.13 (m, 1H), 4.20 (k, J=5.9 Hz, 2H), 3.74 (s, 2H); MS (ESI+): 413.3 (M+1), 435.3 (M+Na); (ESI-): 411.4 (M-1), 447.3 (M+Cl); purity after HPLC: 94.81%.

Scheme-36

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid

- 108 045626 acid (36h).

Stage-1. Preparation of tert-butyl 3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b).

Compound 36b was prepared according to the procedure described in step-3 of Scheme-1 from 2,4dichlorofuro[3,2-d]pyrimidine (36a) (3 g, 15.87 mmol; CAS No. 956034-07-4) in dioxane (100 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (3.78 g, 11.34 mmol) , tripotassium phosphate (8.31 ml, 24.94 mmol, 3 M aqueous solution) in water (1 ml), tricyclohexylphosphine (0.95 g, 3.38 mmol) and Pd ₂ (dba) ₃ (1.04 g, 1.13 mmol) under argon and heating in an oil bath at 120°C for 1.5 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane from 0 to 70%] tert-butyl 3-(2chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) (2.65 g, 65% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.74 (d, J=2.3 Hz, 1H), 8.29 (d, J=7.5 Hz, 2H), 7.66-7 .47 (m, 3H), 7.33 (d, J=2.3 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H), 1.42 (s, 9H); MS (ESI-): 358.3 and 360.3 (M-1).

Stage-2. Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c).

Compound 36c was prepared according to the procedure described in step-1 of Scheme-1 from tert-butyl 3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) (2 g, 5.56 mmol ) in DMF (30 ml) using 1-ethoxyvinyl-tri-n-butyltin (2.46 ml, 7.23 mmol) and Pd(PPh ₃ ) ₄ (0.64 g, 0.56 mmol) under argon when heated at 110°C for 4 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0 to 50% EtOAc in hexane] tert-butyl 3-(2- (1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c) (1.80 g, 82% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=2.2 Hz, 1H), 8.36 (d, J=7.4 Hz, 2H), 7.66-7, 46 (m, 3H), 7.35 (d, J=2.2 Hz, 1H), 5.68 (d, J=1.7 Hz, 1H), 4.68 (d, J=1.7 Hz, 1H), 4.27 (d, J=6.2 Hz, 2H), 3.99 (p, J=7.0 Hz, 2H), 1.55-1.24 (m, 12H); MS (ESI+): 396.3 (M+1); MS (ESI-): 430.4 (M+Cl).

Stage-3. Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2d]pyrimidine-2-carboxylate (36d).

Compound 36d was prepared according to the procedure described in step-2 of Scheme-1 from tert-butyl 3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c) (1, 7 g, 4.30 mmol) in 1,4dioxane (100 ml), using a solution of sodium periodate (1.839 g, 8.60 mmol) in water (10 ml) and KMnO ₄ (0.41 g, 2.58 mmol, and a second portion of 0.41 g, 2.58 mmol after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo [3,2-d]pyrimidine-2-carboxylate (36d) (0.55 g, 32% yield) as a yellow solid; MS (ESI ^- ) 396.4 (M-1).

Stage-4. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2carboxylic acid (36e).

Compound 36e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate ( 36d) (0.35 g, 0.88 mmol) in THF/MeOH (10 ml, 1:1), using sodium hydroxide (0.14 g, 3.52 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 4-(3-(((tert-butoxycarbonyl )amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylic acid (36e) (0.22 g, 68% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=2.3 Hz, 1H), 8.36-8.24 (m, 2H), 7.57 (dd, J=9, 4, 6.6 Hz, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 4.25 (d, J= 6.2 Hz, 2H), 1.40 (s, 9H); MS (ESI-): 368.3 (M-1).

Stage-5. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2d]pyrimidine-2-carboxamido)phenyl)acetate (36f).

Compound 36f was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylic acid ( 36e) (0.2 g, 0.54 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (120 mg, 0.65 mmol), DIPEA (0.19 ml, 1.08 mmol) and HATU (250 mg, 0.65 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2d]pyrimidine-2-carboxamido)phenyl)acetate (36f) (0.17 g, 59% yield) as a white solid substances; MS (ESI+): 553.5 (M+Na).

Stage-6. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2carboxamido)phenyl)acetate (36g).

Compound 36g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d] pyrimidine-2carboxamido)phenyl)acetate (36f) (170 mg, 0.32 mmol) in DCM (5 ml), using TFA (0.25 ml, 3.2

- 109 045626 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36g ) (0.12 g,

87% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.88-8.77 (m, 2H), 8.69 (s, 2H), 8.66-8.61 ( m, 1H), 7.85 (m, 1H), 7.80-7.69 (m, 2H), 7.53-7.46 (m, 1H), 7.43-7.35 (m, 2H), 7.30-7.21 (m, 1H), 4.20 (k, J=5.8 Hz, 2H), 3.99 (k, J=7.1 Hz, 2H), 3, 87 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 431.3 (M+1); purity after HPLC: 97.05%.

Stage-7. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (36h).

Compound 36h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl) acetate (36g) (600 mg, 0.14 mmol) in MeOH/THF (10 ml, 1:1), using a solution of NaOH (20 mg, 0.56 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (36h) (0.03 g, 57% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.75 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.52 (s, 2H), 7.94-7.70 (m, 3H), 7.50 (d, J=2.3 Hz, 1H) , 7.38 (t, J=7.0 Hz, 2H), 7.23 (t, J=7.3 Hz, 1H), 4.22 (d, J=5.8 Hz, 2H), 3 .79 (s, 2H); MS (ESI+): 403.3 (M+1), 425.3 (M+Na); MS (ESI-): 401.3 (M-1), 437.3 (M+Cl).

Scheme-37

Preparation of 2-(2-(4-(3 -(aminomethyl)-2-fluorophenyl)-1 H-indole-6-carboxamido)phenyl)acetic acid (37c).

Stage-1. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H indole-6-carboxamido)phenyl)acetate (37a).

Compound 37a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (0.23 g, 0. 57 mmol) in dioxane (30 ml) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (200 mg , 0.57 mmol), tripotassium phosphate (0.42 ml, 1.25 mmol, 3 M aqueous solution) in water (1 ml), tricyclohexylphosphine (0.05 g, 0.06 mmol) and Pd ₂ (dba) ₃ (0.05 g, 0.06 mmol) under argon and heating in an oil bath at 120°C for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted EtOAc in hexane from 0 to 70%] ethyl 2-(2(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37a ) (0.21 g, 68% yield) as a white solid. MS (ESI-): 544.5 (M-1).

Stage-2. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6carboxamido)phenyl)acetate (37b).

Compound 37b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indol- 6-Carboxamido)phenyl)acetate (37a) (150 mg, 0.28 mmol) in DCM (5 ml) using TFA (0.21 ml, 2.75 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)-2fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37b) ( 0.09 g, 74% yield) as a yellow solid;

- 110 045626

1H NMR (300 MHz, DMSO- _d6 ) δ 11.74 (s, 1H), 10.01 (s, 1H), 8.50 (s, 3H), 8.17-8.07 (m, 1H ), 7.74-7.58 (m, 4H), 7.49-7.38 (m, 1H), 7.32 (m, 2H), 7.29-7.18 (m, 1H), 6.50-6.36 (m, 1H), 4.18 (d, J=6.0 Hz, 2H), 4.02-3.90 (m, 2H), 3.75 (s, 2H) , 1.14-0.86 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.67; MS (ESI+): 446.3 (M+1),

448.3 (M+Na); MS (ESI-): 480.4 (M+Cl). Purity after HPLC: 93.30%.

Stage-3. Preparation of 2-(2-(4-(3 -(aminomethyl)-2-fluorophenyl)-1 H-indole-6carboxamido)phenyl)acetic acid (37c).

Compound 37c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate ( 37b) (80 mg, 0.17 mmol) in MeOH/THF (5 ml, 1:1), using a solution of NaOH (30 mg, 0.67 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3-(aminomethyl)-2-fluorophenyl)-1Hindol-6-carboxamido)phenyl)acetic acid (37c) (0.04 g, 54% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.74 (s, 1H), 10.05 (s, 1H), 8.50 (s, 3H), 8.15 (s, 1H), 7.71 (s, 1H), 7.69-7.59 (m, 2H), 7.54-7.38 (m, 2H), 7.32 (m, 2H), 7.26-7.17 (m, 1H), 6.45 (d, J=2.8 Hz, 1H), 4.18 (d, J=5.9 Hz, 2H), 3.68 (s , 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.51; MS (ESI+): 418.3 (M+1); MS (ESI-): 416.4 (M-1), 452.3 (M+Cl). Purity after HPLC: 97.67%.

Scheme-38

Preparation of 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (38f).

Stage-1. Preparation of (S)-N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropan-2-sulfinamide (38b).

Compound 38b was prepared according to the procedure described in step-1 of scheme-220 from 7bromobenzofuran-3-carbaldehyde (38a) (110 mg, 0.489 mmol; CAS No. 1368142-94-2) in DCM (20 ml) using Cs ₂ CO ₃ (381 mg, 1.169 mmol) and (S)-2-methylpropane-2-sulfinamide (119 mg, 0.982 mmol). This resulted in (S)-N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2sulfinamide (38b) (160 mg, 100% yield) after treatment, which was used as is in the next step without additional cleaning. MS (ESI+): 328.0 (M+1).

Stage-2. Preparation of (S)-N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropan-2-sulfinamide (38c).

Compound 38c was prepared according to the procedure described in step-2 of Scheme-220 from (S)N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropan-2-sulfinamide (38b) (160 mg, 0.487 mmol) in DCM (12 ml) and methanol (4 ml) using NaBH ₄ (83 mg, 2.194 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 30-100% ethyl acetate in hexanes) (S)-N-((7-bromobenzofuran-3-yl)methyl)-2- methylpropane-2-sulfinamide (38c) (120 mg, 75% yield) as a colorless oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=1.1 Hz, 1H), 7.72 (dd, J=7.8, 1.1 Hz, 1H), 7, 56 (dd, J=7.8, 1.0 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 5.77 (t, J=5.5 Hz, 1H), 4.28 (dt, J=5.6, 1.1 Hz, 2H), 1.11 (s, 9H).

Stage-3. Preparation of (S)-ethyl 2-(2-((3'-((1,1-dimethylethylsulfinamido)methyl)-[7,7'-bibenzofuran]5-yl)methoxy)phenyl)acetate (38d).

Compound 38d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (178 mg, 0.408 mmol) in dioxane (5 ml) using (S)-N-((7-bromobenzofuran-3-yl)methyl)-2- methylpropane-2sulfinamide (38c) (120 mg, 0.363 mmol), bis(triphenylphosphine) palladium(I) chloride (45 mg, 0.064 mmol) and a solution of K ₂ CO ₃ (158 mg, 1.143 mmol) in water (0.5 ml ) in an Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with 30-100% hexanes in ethyl acetate) (S)-ethyl 2-(2((3'-((1,1- dimethylethylsulfinamido)methyl)-[7,7'-dibenzofuran]-5-yl)methoxy)phenyl)acetate (38d) (189 mg, 83% yield) as a pale yellow oil. MS (ESI+): 560.0 (M+1).

Stage-4. Preparation of ethyl 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (38e).

Compound 38e was prepared according to the procedure described in step-5 of Scheme-220 from (S)ethyl 2-(2-((3'-((1,1-dimethylethylsulfinamido)methyl)-[7,7'-dibenzofuran ]-5-yl)methoxy)phenyl)acetate (38d) (182 mg, 0.325 mmol) in methanol (8 ml) using hydrochloric acid (4 M in 1,4dioxane, 0.35 ml, 1,400 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with DMA80/DCM, 0% to 80%), ethyl 2-(2((3'-(aminomethyl)-[7,7' -dibenzofuran]-5-yl)methoxy)phenyl)acetate (38e) (96 mg, 45% yield) as a yellow foam. (ESI+): 456.0 (M+1).

Stage-5. Preparation of 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (38f).

Compound 38f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((3'-(aminomethyl)-[7,7'-dibenzofuran]-5-yl)methoxy)phenyl)acetate (38e) (94 mg, 0.206 mmol) in THF/methanol (6 mL each), using lithium hydroxide monohydrate (84 mg, 2.0 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((3' -(aminomethyl)-[7,7'dibenzofuran]-5-yl)methoxy)phenyl)acetic acid (38f) (61 mg, 69% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (s, 2H), 8.12 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.93 ( dd, J=7.9, 1.2 Hz, 1H), 7.76 (d, J=1.7 Hz, 1H), 7.66 (dd, J=4.7, 3.0 Hz, 2H ), 7.42 (t, J=7.7 Hz, 1H), 7.17 (dd, J=9.4, 6.7 Hz, 2H), 7.05 (d, J=8.0 Hz , 1H), 7.00 (d, J=2.2 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 5.22 (s, 2H), 4.18 (s , 2H), 3.53 (s, 2H). MS (ESI+): 427.9 (M+1); MS (ESI-): 425.9 (M-1). HPLC: purity 99.10%.

Scheme-39

39c 39d

Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-C[1,2,4]triazine-4-carboxamido)-4methylphenyl)acetic acid (39d).

Stage-1. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f] [1,2,4]triazine-4-carboxamido)-4-methylphenyl) acetate (3 9b).

Compound 39b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4] triazine-4-carboxylic acid (1e) (0.15 g, 0.41 mmol) in DMF (3 ml), using ethyl 2-(2-amino-4-methylphenyl) acetate (39a) (118 mg, 0.611 mmol , CAS No. 1261742-93-1), DIPEA (0.213 ml, 1.22 mmol) and HATU (186 mg, 0.489 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4methylphenyl)acetate (39b) (0.18 g, 81% yield) as an orange foam;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.44 (d, J=7.9 Hz, 1H), 8.40-8.32 (m, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.60-7.47 (m, 3H), 7.43 (d, J=7.6 Hz, 1H), 7.33-7 .22 (m, 2H), 7.12-7.03 (m, 1H), 4.26 (d, J=6.1 Hz, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 2.36 (s, 3H), 1.41 (s, 9H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 544.5 (M+1).

Stage-2. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetate (39c).

- 112 045626

Compound 39c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-G] [1,2,4]triazine-4-carboxamido)-4methylphenyl)acetate (39b) (180 mg, 0.33 mmol) in DCM (5 ml) using TFA (0.255 ml, 3.31 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(2- (3(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39c) (0.055 g, 38% yield), HCl salt, in form of a solid.

^1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.66-8.55 (m, 2H), 8.43-8.27 (m, 4H), 7.74 -7.54 (m, 4H), 7.33-7.25 (m, 2H), 7.15-7.06 (m, 1H), 4.18 (s, 2H), 4.00 (k , J=7.1 Hz, 2H), 3.82 (s, 2H), 2.36 (s, 3H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+) 444.4 (M+1), MS (ESI-) 478.4 (M+Cl); purity after HPLC: 94.27%.

Stage-3. Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)4-methylphenyl)acetic acid (39d).

Compound 39d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine -4-carboxamido)-4-methylphenyl)acetate (39c) (0.11 g, 0.248 mmol) in THF (30 ml) using sodium hydroxide (0.62 ml, 1.24 mmol, 2 M aq). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(2-( 3(aminomethyl)phenyl)n-yrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetic acid (39d) (0.05 g, 48.5% yield), HCl salt, as a solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.76 (s, 1H), 10.85 (s, 1H), 8.61 (s, 1H), 8.54 (dt, J=7.1 , 1.8 Hz, 1H), 8.44-8.30 (m, 4H), 7.73-7.59 (m, 4H), 7.32-7.25 (m, 2H), 7, 08 (dd, J=7.6, 1.7 Hz, 1H), 4.24-4.12 (m, 2H), 3.74 (s, 2H), 2.36 (s, 3H). MS (ESI+) 416.3 (M+1), MS (ESI-) 414.4 (M-1), 829.7 (2M-1); purity after HPLC: 97.48%.

Scheme-40

40d 40e

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (40e).

Stage-1. Preparation of 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a).

To a solution of 4-bromo-1H-indole-6-carboxylic acid (9a) (1.5 g, 6.25 mmol) in DMF (9.5 ml) at 0°C was added NaH (60% in mineral oil, 0.625 g, 15.62 mmol). After 15 min of stirring at 0°C, tosyl-Cl (1.43 g, 7.50 mmol) was added in 1 g portions at 0°C every 15 min, and the reaction mixture was slowly warmed in an ice bath to 10°C. Then it was stirred for 2 hours, the mixture was poured into H2O and acidified with 5 M HCl. The precipitate was collected by filtration, washed with water and dried to give 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) (1.85 g, 4.69 mmol, 75% yield) as a tan solid, which was used in the next step without further purification;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.42 (s, 1H), 8.54-8.48 (m, 1H), 8.19 (d, J=3.8 Hz, 1H), 8.01-7.94 (m, 1H), 7.93-7.84 (m, 2H), 7.44 (d, J=8.1 Hz, 2H), 6.92-6.84 ( m, 1H), 2.33 (s, 3H).

Stage-2. Preparation of (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b).

Compound 40b was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) (1.5 g, 3.8 mmol) using N- methylmorpholine (0.5 ml, 4.57 mmol) in THF (30 ml), isobutyl chloroformate (0.6 ml, 4.57 mmol) and NaBH ₄ (0.43 g, 11.41 mmol) in water (0. 8 ml). This resulted in (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b) (1.2 g, 82% yield) as a clear oil, which was used as is in the next step without additional cleaning; MS (ESI+) 402.1, 404.1 (M+Na), (ESI-) 378.2, 380.2 (M-1).

- 113 045626

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c).

Compound 40c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-tosyl-1H-indol-6-yl)methanol (40b) (1.2 g, 3.16 mmol) in THF (15 ml) using triphenylphosphine (1.07 g, 4.1 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.739 g, 4.1 mmol) and DIAD (0.83 g, 4. 1 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-((4-bromo-1-tosyl-Shindol- 6-yl)methoxy)phenyl)acetate (40c) (0.4 g, 23% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.04 (s, 1H), 7.94 (d, J=3.7 Hz, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 6.94 (t, J=7.4 Hz, 1H), 6 ,81-6.69 (m, 4H), 5.26 (s, 2H), 4.07-4.01 (m, 2H), 3.66 (s, 2H), 2.31 (s, 3H ), 1.03 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6yl)methoxy)phenyl)acetate (40d).

Compound 40d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) ( 400 mg, 0.74 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (207 mg, 1.11 mmol), tripotassium phosphate (1.3 M solution, 0.42 ml, 1.25 mmol), tricyclohexylphosphine (62 mg, 0.22 mmol) and Pd ₂ (dba) ₃ (68 mg, 0.074 mmol) in an Ar atmosphere when heated at 125 °C for 20 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40d) (48 mg, 11% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.37 (s, 3H, D2O replaceable), 8.07 (s, 1H), 7.94-7.85 (m, 3H), 7.70 ( s, 1H), 7.61-7.48 (m, 3H), 7.41 (s, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.28-7.19 (m, 2H), 7.12-7.04 (m, 1H), 7.00 (d, J=3.8 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H) , 5.32 (s, 2H), 4.15-4.04 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 2, 32 (s, 3H), 0.94 (t, J=7.1 Hz, 3H); MS (ESI+): 569.4 (M+1); 591.4 (M+Na); (ESI-): 603.4 (M+Cl); purity after HPLC: 95.30%.

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6yl)methoxy)phenyl)acetic acid (40e).

Compound 40e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy) phenyl)acetate (40d) (150 mg, 0.26 mmol) in MeOH/THF (10 ml, 1:1), using a solution of lithium hydroxide monohydrate (11 mg, 0.26 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (40e) (50 mg, 35% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.24 (s, 1H, D2O replaceable), 8.35 (s, 3H, D2O replaceable), 8.08 (s, 1H), 7.94-7 .89 (m, 2H), 7.88 (s, 1H), 7.70 (s, 1H), 7.61-7.48 (m, 3H), 7.45 (d, J=1.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.29-7.18 (m, 2H), 7.09-7.02 (m, 1H), 6.99 (d, J=3.8 Hz, 1H), 6.96-6.90 (m, 1H), 5.34 (s, 2H), 4.10 (s, 2H), 3.64 (s, 2H), 2.32 (s, 3H); MS (ESI+): 541.4 (M+1); 563.3 (M+Na); (ESI-): 539.4 (M-1), 575.4 (M+Cl).

Scheme-41

Preparation of 2-(2-(7-(3 -(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3yl)acetic acid (41d).

Stage-1. Preparation of ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (41b).

Compound 41b was prepared according to the procedure described in step-1 of Scheme-6, from 7-114 045626 chlorfuro[2,3-c]pyridine-5-carboxylic acid (28a) (200 mg, 1.01 mmol) in MeOH (10 ml) using ethyl 2-(2-aminothiophen-3-yl) acetate (41a) (225 mg, 1.22 mmol, CAS No. 387390-67-2, prepared according to the procedure described by Adrian Liam and Harris , William in PCT International Application, 2002002567, January 10, 2002) and EDCI (233 mg, 1.22 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine -5-carboxamido)thiophen-3-yl)acetate (41b) (320 mg, 0.877 mmol, 87% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.84 (s, 1H), 8.58-8.45 (m, 2H), 7.42-7.33 (m, 1H), 7. 16 (d, J=5.5 Hz, 1H), 6.91 (d, J=5.5 Hz, 1H), 4.15 (k, J=7.1 Hz, 2H), 3.79 ( s, 2H), 1.21 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of 2-(2-(7-(3 -(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3yl)acetic acid (41d).

Compound 41d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-chlorofuro[2,3-c]pyridin-5-carboxamido)thiophen-3-yl)acetate (41b) (140 mg, 0.38 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (108 mg, 0.58 mmol), tripotassium phosphate (1.3 M solution, 0.22 ml , 0.65 mmol), tricyclohexylphosphine (32 mg, 0.12 mmol) and Pd ₂ (dba) ₃ (35 mg, 0.038 mmol) in an Ar atmosphere when heated at 125°C for 1 hour in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 70% DCM] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophene-3- yl)acetate (41c) (37 mg, 22% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 11.18 (s, 1H, D2O replaceable), 8.73 (s, 1H), 8.64-8.57 (m, 1H), 8.578.43 (m , 5H, partially D2O replaceable), 7.75-7.66 (m, 2H), 7.38 (d, J=2.2 Hz, 1H), 7.17 (d, J=5.5 Hz, 1H), 6.94 (d, J=5.5 Hz, 1H), 6.55 (s, 1H), 4.19 (s, 2H), 4.08 (k, J=7.1 Hz, 2H), 3.86 (s, 2H), 1.10 (t, J=7.1 Hz, 3H); MS (ESI+): 436.3 (M+1); (ESI-): 470.3 (M+Cl); purity after HPLC: 98.86%. Followed by 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetic acid (41d) (19 mg, 12% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H, D2O replaceable), 11.28 (s, 1H, D2O replaceable), 8.73 (s, 1H), 8.65-8, 57 (m, 1H), 8.56-8.37 (m, 5H, partially D2O replaceable), 7.75-7.65 (m, 2H), 7.38 (d, J=2.2 Hz, 1H), 7.15 (d, J=5.5 Hz, 1H), 6.93 (d, J=5.5 Hz, 1H), 4.20 (k, J=5.7 Hz, 2H) , 3.79 (s, 2H); MS (ESI+) 408.3 (M+1); (ESI-) 406.3 (M-1), 442.3 (M+Cl); purity after HPLC: 99.41%.

Scheme-42

42c 42d

Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4methoxyphenyl)acetic acid (42d).

Stage-1. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,11][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl) acetate (42b).

Compound 42b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4] triazine-4-carboxylic acid (1e) (0.18 g, 0.49 mmol) in DMF (4 ml), using ethyl 2-(2-amino-4-methoxyphenyl) acetate (42a) (123 mg, 0.586 mmol , CAS No. 138344-20-4), DIPEA (0.26 ml, 1.47 mmol) and HATU (223 mg, 0.59 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-100% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4methoxyphenyl)acetate (42b) (0.19 g, 70% yield) as an orange solid;

- 115 045626

1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.36 (d, J=2.3 Hz, 2H ), 7.61-7.39 (m, 5H), 7.32 (d, J=8.5 Hz, 1H), 7.25 (dd, J=4.6, 2.5 Hz, 1H) , 6.86 (dd, J=8.5, 2.7 Hz, 1H), 4.26 (d, J=6.1 Hz,

2H), 4.01 (k, J=7.1 Hz, 2H), 3.87-3.71 (m, 5H), 1.41 (s, 9H), 1.00 (t, J=7 ,1 Hz, 3H); MS (ESI+): 560.4 (M+1),

582.4 (M+Na); (ESI-): 558.5 (M-1).

Stage-2. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-4-methoxyphenyl)acetate (42c).

Compound 42c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f] [1,2,4]triazine-4-carboxamido)-4methoxyphenyl)acetate (42b) (190 mg, 0.34 mmol) in DCM (5 ml) using TFA (0.26 ml, 3.4 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) 0% to 60%] ethyl 2-(2-(2- (3(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42c) (0.05 g, 32.0% yield) in as HCl salt;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.79 (s, 1H), 8.66-8.55 (m, 2H), 8.45-8.32 (m, 4H), 7.73 -7.56 (m, 3H), 7.41 (d, J=2.7 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.29 (dd, J= 4.6, 2.5 Hz, 1H), 6.88 (dd, J=8.5, 2.7 Hz, 1H), 4.18 (s, 2H), 4.00 (k, J=7 ,1 Hz, 2H), 3.86-3.75 (m, 5H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 460.3 (M+1), MS (ESI-): 494.3 (M+Cl); purity after HPLC: 96.26%.

Stage-3. Preparation of 2-(2-(2-(3-(αminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)4-methoxyphenyl)acetic acid (42d).

Compound 42d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine -4-carboxamido)-4-methoxyphenyl)acetate (42c) (0.11 g, 0.239 mmol) in THF (2 ml) using sodium hydroxide (0.24 ml, 0.48 mmol, 2 M aq). This gave, after work-up and purification by reverse phase chromatography on a [C18 (30 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 40%] 2-(2-(2-( 3(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetic acid (42d) (0.045 g, 44% yield) as HCl salt;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.77 (s, 1H), 10.88 (s, 1H), 8.62 (s, 1H), 8.57-8.34 (m, 5H ), 7.74-7.59 (m, 3H), 7.52 (d, J=2.7 Hz, 1H), 7.36-7.25 (m, 2H), 6.85 (dd, J=8.5, 2.7 Hz, 1H), 4.23-4.12 (m, 2H), 3.80 (s, 3H), 3.73 (s, 2H); MS (ESI+): 432.3 (M+1); MS (ESI-): 430.4 (M-1); purity after HPLC: 98.05%.

Scheme-43 he I

THF

43c 43d

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (43d).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b).

Compound 43b was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2,3-dihydrobenzofuran-5-yl)methanol (43a) (200 mg, 0.87 mmol; CAS No. 501430-83- 7) in THF (15 ml), using triphenylphosphine (0.30 g, 1.135 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (205 mg, 1.14 mmol) and DIAD (0.23 g, 1 .14 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2(2-((7-bromo-2,3-dihydrobenzofuran-5 -yl)methoxy)phenyl)acetate (43b) (0.27 g, 78% yield) as a colorless oil; MS (ESI-): 389.3, 391.3 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5yl)methoxy)phenyl)acetate (43c).

Compound 43c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b) (0. 52 g, 1.33 mmol) in dioxane (6 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.37 g, 2.0 mmol), potassium carbonate solution (0.55 g, 4. 0 mmol) in water (2 ml), and PdCl ₂ (PPh ₃ ) ₂ (0.140 g, 0.2 mmol) in an Ar atmosphere at

- 116 045626 heating at 100°C for 2 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM from

0% to 20%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7-( 3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5yl)methoxy)phenyl)acetate (43c) (0.23 g, 42% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.26 (s, 3H), 7.79 (s, 1H), 7.75-7.70 (m, 1H), 7.54-7, 40 (m, 2H), 7.38 (s, 1H), 7.31-7.18 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.90 (td , J=7.4, 1.1 Hz, 1H), 5.05 (s, 2H), 4.60 (t, J=8.7 Hz, 2H), 4.08 (s, 2H), 3 .95 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 3.25 (t, J=8.7 Hz, 2H), 1.04 (t, J=7, 1 Hz, 3H); MS (ESI+) 418.4 (M+1); (ESI-) 416.4 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5yl)methoxy)phenyl)acetic acid (43d).

Compound 43d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl) acetate (43c) (0.12 g, 0.29 mmol) in THF/MeOH (4 ml), using lithium hydroxide monohydrate (60 mg, 1.44 mmol) in water (0.8 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (43d) (40 mgg, 31% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 8.38 (s, 3H), 7.80 (s, 1H), 7.74 (dt, J=7, 2, 1.8 Hz, 1H), 7.52-7.41 (m, 3H), 7.32 (d, J=1.6 Hz, 1H), 7.27-7.18 (m, 2H ), 7.06 (dd, J=8.2, 1.1 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 5.07 (s, 2H) , 4.60 (t, J=8.7 Hz, 2H), 4.07 (d, J=5.3 Hz, 2H), 3.56 (s, 2H), 3.25 (t, J= 8.7 Hz, 2H); MS (ESI+): 390.4 (M+1); MS (ESI-): 388.5 (M-1), 424.4 (M+Cl). Purity after HPLC: 91.28%.

Scheme-44

HE

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6carboxamido)phenyl)acetic acid (44c).

Stage-1. Preparation of ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6carboxamido)phenyl)acetate (44a).

To a solution of ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (0.2 g, 0.50 mmol) in DMF was added (bromomethyl)cyclopropane (0.07 ml , 0.75 mmol) and potassium carbonate (0.14 g, 1.0 mmol) and stirred at 60°C overnight. The reaction mixture was diluted with EtOAc (100 ml), washed with water (3x), brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole- 6carboxamido)phenyl)acetate (44a) (0.15 g, 64% yield);

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.78 (d, J=3, 1 Hz, 1H), 7.477.19 (m, 4H), 6.50 (d, J=3.1 Hz, 1H), 4.15 (d, J=7.1 Hz, 2H), 3.96 (m, 2H), 3.75 (s, 2H), 1.32 (m, 1H), 1.00 (t, J=7.1 Hz, 3H), 0.58-0.31 (m, 4H). MS (ESI+): 455.3 and 457.3 (M+1).

Stage-2. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6carboxamido)phenyl)acetic acid (44c).

Compound 44c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate (44a) (140 mg, 0.31 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (90 mg, 0.46 mmol), tripotassium phosphate (1.3 M solution) (0.71 ml, 0.92 mmol), tricyclohexylphosphine (30 mg, 0.09 mmol) and Pd ₂ (dba) ₃ (30 mg, 0.03 mmol) in an Ar atmosphere when heated at 125 ° C for 45 min in a micro- 117 045626 rowave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclononylmethyl)-1H-indole-6carboxamido)phenyl)acetate (44b) ( 0.06 g, 37% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.04 (s, 1H), 8.32 (s, 2H), 8.25 (s, 1H), 7.88 (s, 1H), 7 .80 (d, J=1.3 Hz, 1H), 7.77 (s, 1H), 7.75 (d, J=3.0 Hz, 2H), 7.59 (t, J=7, 6 Hz, 1H), 7.55-7.40 (m, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.25 (td, J=7.2, 1.5 Hz, 1H), 6.74 (d, J=3.2 Hz, 1H), 4.18 (m, 2H), 4.15 (s, 2H), 3.95 (m, 2H), 3, 78 (s, 2H), 1.37 (m, 1H), 0.98 (t, J=7.1 Hz, 3H), 0.62-0.39 (m, 4H); MS (ESI+): 482.4 (M+1); MS (ESI-): 516.5 (M+Cl). Purity after HPLC: 96.64%; followed by 2-(2-(4-(3-(aminomethyl)phenyl)-1(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetic acid (44c) (0.01 g, 7% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ): δ 8.37 (s, 2H), 8.24 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7 .79 (d, J=7.7 Hz, 1H), 7.75 (d, J=3.2 Hz, 1H), 7.58 (t, J=7.7 Hz, 2H), 7.49 (d, J=7.7 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 6.74 (d , J=3.2 Hz, 1H), 6.56 (s, 1H), 4.25-4.09 (m, 4H), 3.69 (s, 2H), 1.48-1.29 ( m, 1H), 0.60-0.37 (m, 4H); MS (ESI+): 454.4 (M+1); MS (ESI-): 452.4 (M-1), 488.4 (M+Cl). Purity after HPLC: 97.36%.

Scheme-45

He

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1 -methyl-1 H-indole-6-carboxamido)phenyl)acetic acid (45e).

Stage-1. Preparation of methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole6-carboxylate (45a).

Compound 45a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (45f) (500 mg, 1.87 mmol; CAS No: 1246867 -53-7) in dioxane (11 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (702 mg, 2.80 mmol), tripotassium phosphate (1.3 M solution, 1.1 ml , 3.17 mmol), tricyclohexylphosphine (157 mg, 0.56 mmol) and Pd ₂ (dba) ₃ (171 mg, 0.19 mmol) under nitrogen when heated at 120°C for 45 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 100% hexanes/ethyl acetate] methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)- 1-methyl-1H-indole-6-carboxylate (45 a) (620 mg, 84% yield) as a yellow solid; MS (ESI+): 417.3 (M+Na).

Stage-2. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6carboxylic acid (45b).

Compound 45b was prepared according to the procedure described in step-6 of Scheme-1 from methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate ( 45a) (600 mg, 1.52 mmol) in THF/MeOH (15 ml), using a solution of lithium hydroxide monohydrate (383 mg, 9.13 mmol) in water (1 ml). This resulted in 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylic acid (45b) (500 mg, 86% yield) as dirty a white solid, which was used in the next step without further purification.

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.73 (s, 1H, D2O replaceable), 8.09 (s, 1H), 7.73 (d, J=1.3 Hz, 1H), 7 .63 (d, J=3.1 Hz, 1H), 7.60-7.42 (m, 4H), 7.27 (d, J=7.6 Hz, 1H), 6.63 (d, J=3.2 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.91 (s, 3H), 1.40 (s, 9H).

Stage-3. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1Nindol-6-carboxamido)phenyl)acetate (45c).

Compound 45c was prepared according to the procedure described in step-4 of Scheme-1, from 4-(3

- 118 045626 (((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylic acid (45b) (300 mg,

0.79 mmol) in DMF (10 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (184 mg, 1.03 mmol), DIPEA (0.28 ml, 1.58 mmol) and HATU ( 360 mg, 0.79 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)-1-methyl-1H-indole-6carboxamido)phenyl)acetate (45c) (211 mg, 49% yield) as a pink semi-solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H, D2O replaceable), 8.11 (s, 1H), 7.77 (d, J=1.4 Hz, 1H), 7 .65 (s, 1H), 7.63-7.57 (m, 2H), 7.54-7.40 (m, 3H), 7.37-7.31 (m, 2H), 7.30 -7.22 (m, 2H), 6.64 (d, J=3.1 Hz, 1H), 4.23 (d, J=6.2 Hz, 2H), 3.98-3.88 ( m, 5H), 3.77 (s, 2H), 1.40 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 564.5 (M+Na); (ESI-): 540.5 (M-1).

Stage-4. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6carboxamido)phenyl)acetate (45d).

Compound 45d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole -6-carboxamido)phenyl)acetate (45c) (210 mg, 0.39 mmol) using TFA (0.3 mL, 3.88 mmol) in DCM (5 mL). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1methyl-1H-indole-6-carboxamido)phenyl)acetate (45d) (114 mg, 67% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H, D2O replaceable), 8.45 (s, 3H, D2O replaceable), 8.18 (s, 1H), 7.90 (d, J=1.7 Hz, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.80-7.72 (m, 1H), 7.65 (d, J=3.1 Hz, 1H), 7.62-7.49 (m, 2H), 7.44 (dd, J=7.6, 1.7 Hz, 1H), 7.38-7.29 (m, 2H) , 7.25 (td, J=7.1, 1.5 Hz, 1H), 6.75 (d, J=3.1 Hz, 1H), 4.14 (s, 2H), 4.04- 3.89 (m, 5H), 3.79 (s, 2H), 0.99 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of 2-(2-(4-(3-(αminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (45e).

Compound 45e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45d) (65 mg, 0.15 mmol) in MeOH/THF (10 ml, 1:1), using a solution of sodium hydroxide (35 mg, 0.88 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (45e) (29 mg, 48% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H, D2O replaceable), 10.10 (s, 1H, D2O replaceable), 8.43 (s, 3H, D2O replaceable), 8, 18 (s, 1H), 7.92-7.87 (m, 1H), 7.86-7.80 (m, 1H), 7.80-7.73 (m, 1H), 7.65 ( d, J=3.1 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.39-7.29 (m , 2H), 7.22 (td, J=7.4, 1.4 Hz, 1H), 6.74 (d, J=3.1 Hz, 1H), 4.14 (s, 2H), 3 .93 (s, 3H), 3.71 (s, 2H); MS (ESI+): 414.3 (M+1); 436.3 (M+Na); (ESI-): 412.4 (M1), 448.4 (M+Cl).

Scheme-46

fl X N |f θ DMF С N^N Р0С1 ₃ ^ CI 1с J г \ N ———► N NaBH(OAc) ₃ a Х7 ' χ °' ¹ XA^NHBoc 46e OH S Ajt AE ί! chNVos CH U ⁰ NY _pd2(dba)3 ^ V ^α Ρ%), C%NHB«e 46a 46b e 9 A Π ! J Yo^\ ^γοΗ Y%A<o> _K ft NaOH^ hx N NH ₂ 5e X Д ^hatu ' EA^NHBoe <Д.^ННБос DIPEA 46c 46d X) X) TFA N _V N ^H NaOH M ^H X/ OH X θ ^Ί Λ θ ΧΧ^ΝΗ ₂ Χλ^ ^ΝΗ 2 46f 46g

- 119 045626

Preparation of 2-(2-(2-(3 -(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine4-carboxamido)phenyl)acetic acid (46g).

Stage-1. Preparation of ethyl 2-chloro-7-formylpyrrolo[2,1-G][1,2,4]triazine-4-carboxylate (46a).

To POCl ₃ (1.239 mL, 13.30 mmol) in a sealed tube cooled with ice water, add DMF (0.515 mL, 6.65 mmol) and stir until the reaction mixture is homogeneous. The reaction mixture was warmed to room temperature and ethyl 2-chloropyrrolo[2,1£][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33 mmol) was added and heated at 95°C in a sealed test tube for 5 hours. The reaction mixture was cooled to room temperature and poured into ice-cold saturated solution. aq. NaHCO ₃ (60 ml), extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 9:1)] to give ethyl 2-chloro-7formylpyrrolo[2,1-1,2,4]triazine-4-carboxylate (46a) (224 mg, 66% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 7.78 (d, J=5.1 Hz, 1H), 7.51 (d, J=5.1 Hz , 1H), 4.50 (k, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46b).

Compound 46b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloro-7-formylpyrrolo[2,1-A1,2,4]triazine-4-carboxylate (46a) (250 mg, 0.99 mmol) in DMF (10 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (371 mg, 1.48 mmol), potassium fluoride (189 mg, 3.25 mmol), tri-tert -butylphosphine (1.281 ml, 1.28 mmol) and Pd ₂ (dba) ₃ (90 mg, 0.099 mmol) under argon while heating at 120°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate 0% to 50%] ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) -7formylpyrrolo[2,1-A1,2,4]triazine-4-carboxylate (46b) (339 mg, 81% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.34-8.27 (m, 2H), 7.73 (d, J=5.0 Hz, 1H), 7.61-7.51 (m, 2H), 7.51-7.44 (m, 1H), 7.41 (d, J=5.0 Hz, 1H), 4.54 (k, J= 7.1 Hz, 2H), 4.26 (d, J=6.2 Hz, 2H), 1.49-1.39 (m, 12H); MS (ESI+): 447.3 (M+1).

Stage-3. Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46c ).

To a solution of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1£][1,2,4]triazine-4-carboxylate (46b) (150 mg, 0.35 mmol) to DCE (10 ml) pyrrolidine (27.6 mg, 0.39 mmol) and acetic acid (0.020 ml, 0.35 mmol) were added. The resulting mixture was stirred at RT for 2 hours followed by the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The resulting mixture was stirred at RT for 2 hours, diluted with EtOAc, washed with water, dried, filtered and concentrated in vacuo. The resulting residue was purified by chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl )pyrrolo[2,1-£][1,2,4]triazine-4carboxylate (46c) (140 mg, 83% yield) as a yellow semi-solid;

1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, J=6.2 Hz, 2H), 7.59-7.47 (m, 2H), 7.41 (d, J=7, 7 Hz, 1H), 7.35 (d, J=4.6 Hz, 1H), 7.20 (d, J=4.6 Hz, 1H), 4.51 (k, J=7.1 Hz , 2H), 4.25 (d, J=6.2 Hz, 2H), 4.18 (s, 2H), 2.64-2.55 (m, 4H), 1.75-1.63 ( m, 4H), 1.50-1.29 (m, 12H); MS (ESI+): 480.4 (M+1); 502.4 (M+Na); (ESI-): 478.5 (M1).

Stage-4. Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (46d ).

Compound 46d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2. 1-£][1,2,4]triazine4-carboxylate (46c) (140 mg, 1.52 mmol) in THF/MeOH (10 ml), using a solution of sodium hydroxide (70 mg, 1.75 mmol) in water (2 ml). This gave, after workup followed by purification by flash column chromatography [silica gel (4 g), eluted with MeOH in DCM 0% to 100%] 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl )-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1£][1,2,4]triazine-4-carboxylic acid (46d) (60 mg, 46% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.40-8.27 (m, 2H), 7.60-7.49 (m, 2H), 7.46-7.30 (m, 3H), 4.95 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.57-3.36 (m, 4H), 2.08-1.83 (m, 4H) , 1.41 (s, 9H); MS (ESI+): 452.4 (M+1); 474.4 (M+Na); (ESI-): 450.4 (M-1); 486.4 (M+Cl).

Stage-5. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin1 -ylmethyl)pyrrolo[2,1-f][1,2,4]triazine -4-carboxamido)phenyl)acetate (46e).

Compound 46e was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1 -f][1,2,4]triazine-4- 120 045626 carboxylic acid (46d) (56 mg, 0.12 mmol) in DMF (10 ml) using ethyl 2-(2-aminophenyl) acetate (5e) (29 mg, 0.16 mmol), DIPEA (0.043 ml, 0.25 mmol) and HATU (57 mg, 0.15 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)-7(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46e) (53 mg, 70% yield) in as a pink semi-solid; MS (ESI+): 613.4 (M+1); 635.4 (M+Na); (ESI-): 611.5 (M-1).

Stage-6. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46f).

Compound 46f was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidine-1- ylmethyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46e) (53 mg, 0.086 mmol) using TFA (0.067 mL, 0.87 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 50% DCM] ethyl 2-(2-(2-(3(aminomethyl)phenyl)-7-( pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (46f) (27 mg, 61% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H, D2O replaceable), 9.00 (s, 1H, D2O replaceable), 8.71 (d, J=7.6 Hz, 3H), 7.72 (t, J=7.9 Hz, 2H), 7.68-7.61 (m, 2H), 7.53 (d, J=4.7 Hz, 1H), 7, 42 (t, J=7.3 Hz, 2H), 7.31 (td, J=7.5, 7.1, 1.4 Hz, 1H), 5.07 (s, 2H), 4.19 (d, J=5.1 Hz, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.88 (s, 2H), 3.58-3.43 (m, 2H) , 3.33-3.25 (m, 2H), 2.14-1.97 (m, 2H), 1.95-1.80 (m, 2H), 1.02 (t, J=7, 1 Hz, 3H); MS (ESI+): 513.4 (M+1); 535.4 (M+Na).

Stage-7. Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (46g).

Compound 46g was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1- f][1,2,4]triazine-4carboxamido)phenyl)acetate (46f) (25 mg, 0.049 mmol) in MeOH/THF (10 ml, 1:1) using sodium hydroxide solution (12 mg, 0.29 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(2-( 3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (46g) (11 mg, 47% yield ) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H, D2O replaceable), 11.09 (s, 1H, D2O replaceable), 10.94 (s, 1H), 8.97 (d, J=1.7 Hz, 1H), 8.80-8.60 (m, 4H, partially D2O replaceable), 7.83 (d, J=8.1 Hz, 1H), 7.73-7.60 (m, 3H), 7.55 (d, J=4.7 Hz, 1H), 7.47-7.37 (m, 2H), 7.28 (td, J=7.4, 1.3 Hz, 1H), 5.08 (d, J=4.5 Hz, 2H), 4.26-4.12 (m, 2H), 3.81 (s, 2H), 3.59-3.41 (m, 4H), 2.16-1.97 (m, 2H), 1.95-1.78 (m, 2H); MS (ESI+) 485.4 (M+1); (ESI-) 483.4 (M-1); purity after HPLC, 93.69%.

Scheme-47

Preparation of 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (47f).

Stage-1. Preparation of ethyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxylate (47b).

To a solution of ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (400 mg, 1.77 mmol) in dioxane (12 ml) was added hydrochloride (5-(aminomethyl )-2-fluorophenyl)boronic acid (47a) (546 mg, 2.66 mmol; CAS No. 1072946-46-3), 3 M aq. potassium triphosphate (1.182 ml, 3.55 mmol), tricyclohexylphosphine (99 mg, 0.355 mmol) and Pd ₂ (dba) ₃ (162 mg, 0.177 mmol). The mixture was degassed and filled with Ar, then heated at 125°C for 30 min in a microwave oven. The mixture was cooled to room temperature, diluted with water (60 ml) and EtOAc (60 ml). BOC anhydride (580 mg,

- 121 045626

2.66 mmol) and stirred at room temperature for 3 hours. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml). The organic layers were combined, washed with water, brine, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in 0 to 60% hexanes] to give ethyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo [2,11][1,2,4]triazine-4-carboxylate (47b) (0.32 g, 0.772 mmol, 43.6% yield) as an orange foam;

^1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (d, J=7.3 Hz, 1H), 7.53 (t, J=6.1 Hz, 1H), 7.49-7.24 (m, 4H), 4.50 (k, J=7.1 Hz, 2H), 4.19 (d, J=6.2 Hz, 2H), 1, 44-1.33 (m, 12H); MS (ESI+): 437.3 (M+Na).

Stage-2. Preparation of 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1C[1,2,4]triazine-4-carboxylic acid (47c).

Compound 47c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-C[1,2 ,4]triazine-4-carboxylate (47b) (0.32 g, 0.772 mmol) in THF (10 ml) using sodium hydroxide (0.772 ml, 1.544 mmol, 2 M aqueous solution). This resulted in the preparation after treatment of 2-(5-(((tert-butoxycarbonyl)amino)methyl)2-fluorophenyl)pyrrolo[2,1-C[1,2,4]triazine-4-carboxylic acid (47c) ( 0.29 g, 97% yield) as a light orange foam.

^1H NMR (300 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.36 (dd, J=2.6, 1.4 Hz, 1H), 7.92 (dd, J=7 ,5, 2.2 Hz, 1H), 7.53 (t, J=6.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.32 (m, 2H), 7.24 (dd, J=4.6, 2.5 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.39 (s, 9H); MS (ESI-): 385.3 (M-1).

Stage-3. Preparation of ethyl 2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-C[1,2,4]triazine-4-carboxamido)phenyl)acetate (47d).

Compound 47d was prepared according to the procedure described in step-4 of Scheme-1 from 2-(5(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-carboxylic acid (47c) (180 mg, 0.47 mmol) in DMF (3 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (125 mg, 0.7 mmol) , DIPEA (0.24 ml, 1.4 mmol) and HATU (213 mg, 0.56 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(2-(5-(((tert-butoxycarbonyl )amino)methyl)-2-fluorophenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47d) (0.19 g, 75% yield) as an orange foam;

^1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.41 (dd, J=2.6, 1.4 Hz, 1H), 8.18 (dd, J=7 .6, 2.2 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.59 (dd, J=4.6, 1.4 Hz, 1H), 7.55 -7.33 (m, 5H), 7.37-7.20 (m, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 548.3 (M+1), 570.3 (M+Na); (ESI-): 582.4 (M+Cl).

Stage-4. Preparation of ethyl 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (47e).

Compound 47e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2,4]triazine-4carboxamido)phenyl)acetate (47d) (180 mg, 0.329 mmol) in DCM (5 ml) using TFA (0.025 ml, 0.329 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(2- (5(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47e) (0.045 g, 31% yield) as HCl salt;

^1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.53 (d, J=7.1 Hz, 1H), 8.49-8.32 (m, 4H), 7.81-7.70 (m, 2H), 7.61 (dd, J=4.6, 1.3 Hz, 1H), 7.51 (dd, J=11.1, 8.5 Hz, 1H), 7.45-7.37 (m, 2H), 7.35-7.24 (m, 2H), 4.21-4.10 (m, 2H), 3.94 (k, J= 7.1 Hz, 2H), 3.84 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -113.01; MS (ESI+): 448.3 (M+1), MS (ESI-): 482.3 (M+Cl); purity after HPLC 94.88%.

Stage-5. Preparation of 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (47f).

Compound 47f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)phenyl)acetate (47e) (110 mg, 0.246 mmol) in THF (4 ml) using 2 M aqueous NaOH (0.246 ml, 0.492 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (30 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 40%] 2-(2-(2-( 5-(aminomethyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (47f) (0.045 g, 44% yield) as HCl salt;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.70 (s, 1H), 11.12-10.76 (m, 1H), 8.66-8.55 (m, 1H), 8. 51-8.33 (m, 4H), 7.90-7.82 (m, 1H), 7.75-7.65 (m, 1H), 7.63 (dd, J=4.6, 1 ,3 Hz, 1H), 7.49 (dd, J=11.1, 8.5 Hz, 1H), 7.43-7.34 (m, 2H), 7.31 (dd, J=4, 6, 2.6 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 4.23-4.08 (m, 2H), 3.74 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.49; MS (ESI+) 420.3 (M+1), MS (ESI-) 418.3 (M-1); purity after HPLC: 97.95%.

- 122 045626

Scheme-48

2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4^]pyrimidine-2 Preparation of carboxamido)phenyl)acetic acid (48h).

Stage-1. Preparation of tert-butyl 3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4yl)benzylcarbamate (48b).

Compound 48b was prepared according to the procedure described in step-3 of Scheme-1 from 2,4dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (48a) (2 g, 10.47 mmol; CAS No. 848398 -41-4) in dioxane (100 ml), using tert-butium 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (2.49 g , 7.48 mmol), tripotassium phosphate (5.48 ml, 16.45 mmol, 3 M aqueous solution), tricyclohexylphosphine (0.63 g, 2.24 mmol) and Pd ₂ (dba) ₃ (0.69 g, 0.75 mmol) under argon and heating in an oil bath at 120°C for 1.5 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane from 0 to 70%] tert-butyl 3-(2chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b) (0.72 g, 27% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J=2.0 Hz, 1H), 7.74-7.68 (m, 1H), 7.59-7.44 (m, 3H), 5.40 (t, J=1.8 Hz, 2H), 5.02 (d, J=1.8 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H) , 1.41 (s, 9H). MS (ESI-): 360.4 and 362.3 (M-1).

Stage-2. Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4yl)benzylcarbamate (48c).

Compound 48c was prepared according to the procedure described in step-1 of Scheme-1 from tert-butyl 3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b) (0 .7 g, 1.94 mmol) in DMF (20 ml), using 1-ethoxyvinyl-tri-n-butyltin (0.86 ml, 2.52 mmol) and Pd(PPh ₃ ) ₄ (0.22 g, 0.19 mmol) under argon when heated at 110°C for 4 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane 0 to 50%] tert-butyl 3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4yl)benzylcarbamate (48c) (0.51 g, 66% yield) as a white solid; MS (ESI+): 398.4 (M+1), 420.3 (M+Na); MS (ESI-): 396.4 (M-1), 432.4 (M+Cl).

Stage-3. Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4d]pyrimidine-2-carboxylate (48d).

Compound 48d was prepared according to the procedure described in step-2 of Scheme-1 from tert-butyl 3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamateα ( 48c) (0.5 g, 1.258 mmol) in 1,4-dioxane (100 ml), using a solution of sodium periodate (0.54 g, 2.52 mmol) in water (10 ml) and KMnO ₄ (0.12 g, 0.76 mmol, and a second portion of 0.12 g, 0.76 mmol after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)- 5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (48d) (0.28 g, 56% yield) as a yellow solid; MS (ESI+): 400.3 (M+1), 422.3 (M+Na); MS (ESI-): 398.4 (M-1).

Stage-4. Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4

- 123 045626

d]pyrimidine-2-carboxylic acid (48e).

Compound 48e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 4(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine -2-carboxylate (48d) (0.28 g, 0.70 mmol) in THF/MeOH (5 ml, 1:1), using sodium hydroxide (0.11 g, 2.80 mmol) in water (2 ml ). This gave, upon treatment, 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (48e) (0.16 g , 62% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 2H), 7.45 (d, J=7.7 Hz, 1H), 5.47 (s, 2H), 5.08 (d, J=1.8 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 1.41 (s, 9H); MS (ESI-): 370.3 (M1).

Stage-5. Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate (48f).

Compound 48f was prepared according to the procedure described in step-4 of Scheme-1 from 4-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidin- 2-carboxylic acid (48e) (0.16 g, 0.43 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (0.09 g, 0.52 mmol), DIPEA (0.15 ml, 0.86 mmol) and HATU (0.20 g, 0.52 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 4-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2carboxamido)phenyl)acetate (48f) (0.17 g, 72% yield) in as a white solid; MS (ESI+): 555.3 (M+Na); MC (ESI-): 531.6 (M-1).

Stage-6. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2carboxamido)phenyl)acetate (48g).

Compound 48g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3 ,4-d]pyrimidine-2carboxamido)phenyl)acetate (48f) (160 mg, 0.30 mmol) in DCM (5 ml) using TFA (0.23 ml, 3.0 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido) phenyl)acetate (48g) (0.11 g, 85% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.62 (s, 3H), 8.19 (m, 2H), 7.79-7.71 (m, 2H) , 7.66 (t, J=7.6 Hz, 1H), 7.38 (m, 2H), 7.24 (t, J=7.2 Hz, 1H), 5.61 (s, 2H) , 5.14 (s, 2H), 4.17 (d, J=5.8 Hz, 2H), 3.98 (k, J=7.0 Hz, 2H), 3.84 (s, 2H) , 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 433.3 (M+1), 455.3 (M+Na). Purity after HPLC: 94.03%.

Stage-7. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2carboxamido)phenyl)acetic acid (48h).

Compound 48h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2 -carboxamido)phenyl)acetate (48g) (50 mg, 0.116 mmol) in MeOH/THF (5 ml, 1:1), using a solution of NaOH (18 mg, 0.462 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetic acid (48h) (0.016 g, 34% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.51 (s, 3H), 8.20 (s, 1H), 8.14 (d, J=7.5, Hz, 1H), 7.82 (d, J=7.5, Hz, 1H), 7.78-7.72 (m, 1H), 7.67 (t, J=7.6 Hz, 1H) , 7.38 (m, 2H), 7.27-7.18 (m, 1H), 5.60 (s, 2H), 5.15 (s, 2H), 4.18 (k, J=5 .8 Hz, 2H), 3.76 (s, 2H); MS (ESI+): 405.3 (M+1), 427.3 (M+Na); MS (ESI-): 403.3 (M-1), 439.3 (M+Cl). Purity after HPLC: 96.60%.

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Scheme-49

49b ^NaBH « 49c

49e 49f

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6yl)methoxy)phenyl)acetic acid (49f).

Stage-1. Preparation of 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (49b).

Compound 49b was prepared according to the procedure described in step-1 of Scheme-40 from 4bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (49a) (0.7 g, 2.90 mmol; CAS No: 1190321-81-3) in DMF (9.5 ml), using NaH (60% in mineral oil, 0.29 g, 7.26 mmol) and tosyl-Cl (0.66 g, 3.48 mmol). This resulted in 4-6rom-1-tosyl-1H-pyrrolo[2,3-b]pyridine-6carboxylic acid (49b) (0.79 g, 69% yield) as a tan solid upon treatment. used in the next step without further purification. MS (ESI-): 393.2 and 395.1 (M-1).

Stage-2. Preparation of (4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methanol (49c).

Compound 49c was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (49b) (0.6 g, 1 .52 mmol) using Nmethylmorpholine (0.20 ml, 1.82 mmol) in THF (30 ml), isobutyl chloroformate (0.24 ml, 1.82 mmol) and NaBH ₄ (0.17 g, 4.55 mmol ) in water (0.8 ml). This resulted in (4-bromo-1tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methanol (49c) (0.27 g, 49% yield) as a clear oil after treatment; MS (ESI+): 382.5 (M+1); MS (ESI-): 415.2 and 417.2 (M+Cl).

Stage-3. Preparation of ethyl 2-(2-((4-6rom-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6yl)methoxy)phenyl)acetate (49d).

Compound 49d was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methanol (49c) (0.28 g , 0.73 mmol) in THF (15 ml), using triphenylphosphine (0.25 g, 0.96 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.17 g, 0.96 mmol) and DIAD (0.19 ml, 0.96 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-((4bromo-1-tosyl-1H-pyrrolo[2, 3-b]pyridin-6-yl)methoxy)phenyl)acetate (49d) (0.31 g, 78% yield) as a colorless oil; MS (ESI+): 543.1 and 545.2 (M+1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6 yl)methoxy)phenyl)acetate (49e).

Compound 49e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy )phenyl)acetate (49d) (0.2 g, 0.368 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.103 g, 0.552 mmol), tripotassium phosphate (1.3 M solution , 0.849 ml, 1.104 mmol), tricyclohexylphosphine (0.031 g, 0.11 mmol) and Pd ₂ (dba) ₃ (0.034 g, 0.037 mmol) under Ar and heating at 125 °C for 30 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-nirrolo[2,3-b]pyridin-6yl) methoxy)phenyl)acetate (49e) (0.152 g, 73% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (s, 3H), 8.16-8.05 (m, 2H), 8.00 (d, J=4.1 Hz, 1H) , 7.84 (s, 1H), 7.73-7.65 (m, 1H), 7.61 (m, 2H), 7.54 (s, 1H), 7.42 (d, J=8 .0 Hz, 2H), 7.29-7.14 (m, 2H), 7.11 (d, J=4.1 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H ), 6.92 (t, J=7.4 Hz, 1H), 5.35 (s, 2H), 4.11 (k, J=5.9 Hz, 2H), 3.88 (k, J =7.1 Hz, 2H), 3.69 (s, 2H), 2.36 (s, 3H), 0.91 (t, J=7.1 Hz, 3H); MS (ESI+): 570.4 (M+1), 592.3 (M+Na); MS (ESI-): 604.4 (M+Cl). Purity after HPLC: 90.90%.

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6yl)methoxy)phenyl)acetic acid (49f).

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Compound 49f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b] pyridin-6-yl)methoxy)phenyl)acetate (49e) (0.05 g, 0.088 mmol) in MeOH/THF (5 ml, 1:1), using a solution of sodium hydroxide (4 mg, 0.088 mmol) in water ( 1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetic acid (49f) (0.01 g, 21% yield) as white solid matter;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.29 (s, 1H), 8.47 (s, 3H), 8.09 (d, J=8.0 Hz, 2H), 8.00 (d, J=4.1 Hz, 1H), 7.83 (s, 1H), 7.70 (d, J=6.5 Hz, 1H), 7.59 (m, 3H), 7.43 (d, J=8.1 Hz, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.10 (d , J=4.1 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.36 (s, 2H ), 4.10 (d, J=5.9 Hz, 2H), 3.64 (s, 2H), 2.35 (s, 3H); MS (ESI+): 542.3 (M+1), 564.3 (M+Na); MS (ESI-): 576.4 (M+Cl). Purity after HPLC: 88.38%.

Scheme-50

Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-1 -methyl-1 H-indol-6-yl)methoxy)phenyl)acetic acid (50e).

Stage-1. Preparation of 4-bromo-1-methyl-1H-indole-6-carboxylic acid (50a).

Compound 50a was prepared according to the procedure described in step-6 of Scheme-1 from methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (45f) (3 g, 11.19 mmol) in THF/MeOH (30 ml) using a solution of lithium hydroxide monohydrate (2.82 g, 67.1 mmol) in water (3 ml). This resulted in 4-bromo-1-methyl-1H-indole-6-carboxylic acid (50a) (2.2 g, 77% yield) as a white solid upon treatment;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 7.69 (d, J=3, 1 Hz, 1H), 6.526.42 (m, 1H), 3.89 (s, 3H). MS (ESI-): 252.1 (M-1).

Stage-2. Preparation of (4-bromo-1-methyl-1H-indol-6-yl)methanol (50b).

Compound 50b was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-methyl-1H-indole-6-carboxylic acid (50a) (3.7 g, 14.56 mmol) using N- methylmorpholine (1.92 ml, 17.47 mmol) in THF (100 ml), isobutyl chloroformate (2.30 ml, 17.47 mmol) and NaBH ₄ (1.65 g, 43.7 mmol) in water. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH=9:1 in hexane from 0% to 100%] (4-bromo-1-methyl-1H-indole-6 -yl)methanol (50b) (2.1 g, 60% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 7.41 (d, J=3.2 Hz, 2H), 7.22 (s, 1H), 6.34 (dd, J=3.1, 0, 9 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 3.79 (s, 3H).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c).

Compound 50c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-methyl-1H-indol-6-yl)methanol (50b) (1 g, 4.16 mmol) in DCM (50 ml), using triphenylphosphine (1.42 g, 5.41 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.98 g, 5.41 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 1.99 g, 5.41 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in 0% to 60% hexane] ethyl 2-(2-((4-bromo -1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) (0.66 g, 39% yield) as a colorless oil; MS (ESI+): 424.2 and 426.1 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetate (50d).

Compound 50d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) ( 0.65 g, 1.62 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.45 g, 2.42 mmol), K ₂ CO ₃ (0.67 g ,

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4.85 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.17 g, 0.24 mmol) in an Ar atmosphere and heating at 100 °C for 2 h in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from

0% to 50%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50d) (0.16 g , 23% yield) as a white solid; MS (ESI+): 429.3 (M+1).

Stage-5. Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-1 -methyl-1 H-indol-6-yl)methoxy)phenyl)acetic acid (50e).

Compound 50e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy) phenyl)acetate (50d) (0.16 g, 0.373 mmol) in THF/MeOH (8 ml), using a solution of lithium hydroxide monohydrate (0.078 g, 1.867 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (50e) (0.045 g, 30% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.34 (s, 3H), 7.81 (s, 1H), 7.72-7.65 (m, 1H), 7.59 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.51-7.46 (m, 1H), 7.45 (d, J=3.1 Hz, 1H), 7, 27-7.22 (m, 2H), 7.21 (s, 1H), 7.11 (d, J=8.1 Hz, 1H), 6.936.86 (m, 1H), 6.64 (d , J=3.2 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.84 (s, 3H), 3.60 (s, 2H); MS (ESI+): 401.3 (M+1), 423.3 (M+Na); MS (ESI-): 399.3 (M-1), 435.3 (M+Cl). Purity after HPLC: 98.50%.

Scheme-51

51b ^51c

Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4methylphenyl)acetic acid (51c).

Stage-1. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4 -methylphenyl)acetate (51a).

Compound 51a was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2 ,4]triazine-4-carboxylic acid (34c) (0.1 g, 0.259 mmol) in DMF (3 ml), using ethyl 2-(2-amino-4-methylphenyl) acetate (39a) (118 mg, 0.611 mmol), DIPEA (0.136 ml, 0.776 mmol) and HATU (118 mg, 0.311 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino )Methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (51a) (0.1 g, 69% yield) as orange foam ; 1H NMR (300 MHz, DMSO4) δ 10.63 (s, 1H), 8.40 (d, J=2.6 Hz, 1H), 8.26-8.17 (m, 1H), 7.65 -7.61 (m, 1H), 7.59 (d, J=4.6 Hz, 1H), 7.56-7.43 (m, 2H), 7.36 (t, J=7.7 Hz, 1H), 7.31-7.23 (m, 2H), 7.07 (dd, J=7.8, 1.8 Hz, 1H), 4.28 (d, J=6.1 Hz , 2H), 3.95 (k, J=7.1 Hz, 2H), 3.77 (s, 2H), 2.35 (s, 3H), 1.40 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetate (51b).

Compound 51b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetate (51a) (0.1 g, 0.178 mmol) in DCM (3 mL), using TFA (0.137 mL, 1.78 mmol) . This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2(2-( 3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (51b) (0.028 g, 34% yield) as HCl salts;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.52-8.32 (m, 5H), 7.75 (t, J=7.1 Hz, 1H), 7.63-7.58 (m,

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2H), 7.47 (t, J=7.8 Hz, 1H), 7.32 (dd, J=4.6, 2.5 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 4.20 (s,

2H), 3.96 (k, J=7.1 Hz, 2H), 3.78 (s, 2H), 2.35 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ

-116.69; MS (ESI+): 462.3 (M+1), 484.3 (M+Na); MS (ESI-): 460.4 (M-1), 496.4 (M+Cl); cleanliness after

HPLC 99.65%

Stage-3. Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetic acid (51c).

Compound 51c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)-4-methylphenyl)acetate (51b) (0.07 g, 0.152 mmol) in THF (4 ml) using sodium hydroxide (0.152 ml, 0.303 mmol, 2 M aq). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(2-( 3(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetic acid (51c) (0.025 g, 38.0% yield) as HCl salt;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.71 (s, 1H), 10.74 (s, 1H), 8.52-8.31 (m, 4H), 7.81-7.67 (m, 3H), 7.63 (dd, J=4.7, 1.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.32 (dd, J= 4.6, 2.5 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.06 (dd, J=7.8, 1.7 Hz, 1H), 4, 20 (s, 2H), 3.69 (s, 2H), 2.35 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -116.59; MS (ESI+): 434.3 (M+1), MS (ESI-): 432.3 (M+Cl); purity after HPLC 97.76%.

Scheme-52

2-(2-((4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6 Preparation of yl)methoxy)phenyl)acetic acid (52a).

Compound 52a was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b] pyridin-6-yl)methoxy)phenyl)acetate (49e) (0.04 g, 0.070 mmol) in THF (5 ml), using a solution of sodium hydroxide (0.028 g, 0.702 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetic acid (52a) (0.012 g, 44% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.91 (s, 1H), 8.36 (s, 3H), 7.92 (s, 1H), 7.79 (dt, J=6.9 , 1.9 Hz, 1H), 7.59 (m, 3H), 7.42 (s, 1H), 7.22 (m, 2H), 7.08 (m, 1H), 6.90 (t , J=7.3 Hz, 1H), 6.76 (m, 1H), 5.28 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.63 (s , 2H); MS (ESI+): 388.3 (M+1); MS (ESI-): 386.4 (M-1), 422.3 (M+Cl). Purity after HPLC: 91.49%.

Scheme-53

2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3 Preparation of methylphenyl)acetic acid (53 d).

Stage-1. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f][1,2,4]triazine-4-carboxamido)-3-methylphenyl) acetate (53b).

- 128 045626

Compound 53b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4] triazine-4-carboxylic acid (1e) (0.18 g, 0.489 mmol) in DMF (3 ml), using ethyl 2-(2-amino-3-methylphenyl) acetate (53a) (113 mg, 0.586 mmol, CAS No. 1261751-05-6), DIPEA (0.256 ml, 1.466 mmol) and HATU (223 mg, 0.586 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3methylphenyl)acetate (53b) (0.21 g, 79% yield) as an orange foam;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.40 (s, 1H), 8.37 -8.32 (m, 1H), 7.56-7.47 (m, 3H), 7.43 (d, J=7.6 Hz, 1H), 7.32-7.20 (m, 4H ), 4.26 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.74 (s, 2H), 2.29 (s, 3H ), 1.41 (s, 9H), 0.89 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4carboxamido)-3-methylphenyl)acetate (53c).

Compound 53c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-1] [1,2,4]triazine-4-carboxamido)-3methylphenyl)acetate (53b) (200 mg, 0.368 mmol) in DCM (5 ml) using TFA (0.283 ml, 3.68 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(2- (3(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate (53c) (0.035 g, 22% yield) as HCl salt;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.67-8.60 (m, 1H), 8.47 (s, 4H), 8.36 (dt, J=2.9, 1.5 Hz, 1H), 7.73-7.58 (m, 2H), 7.54 (dd, J= 4.6, 1.4 Hz, 1H), 7.32-7.22 (m, 3H), 4.23-4.10 (m, 2H), 3.95-3.84 (m, 2H) , 3.74 (s, 2H), 2.29 (s, 3H), 0.93-0.84 (m, 3H).

Stage-3. Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-G][1,2,4]triazine-4-carboxamido)3-methylphenyl)acetic acid (53 d).

Compound 53d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine -4-carboxamido)-3-methylphenyl)acetate (53c) (0.12 g, 0.271 mmol) in THF (4 ml) using sodium hydroxide (0.135 ml, 0.271 mmol, 2 M aq). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(2-( 3(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetic acid (53d) (0.07 g, 0.168 mmol, 62.3% output) in the form of HCl salt;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.42 (s, 1H), 10.64 (s, 1H), 8.67-8.56 (m, 2H), 8.44-8.28 (m, 4H), 7.717.58 (m, 2H), 7.55 (dd, J=4.6, 1.4 Hz, 1H), 7.31-7.23 (m, 4H), 4, 23-4.13 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H). MS (ESI+) 416.3 (M+1), MS (ESI-) 414.4 (M-1); purity after HPLC 98.00%.

Scheme-54

54c 54d

Preparation of 2-(5-(2-(3 -(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3 methyl-1H-pyrazol-1 -yl)acetic acid (54d).

Stage-1. Preparation of ethyl 2-(5-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3 -methyl-1H-pyrazol-1-yl)acetate (54b).

Compound 54b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2 ,4]triazine-4-carboxylic acid (34c) (150 mg, 0.388 mmol) in DMF (10 ml), using ethyl 2-(5-amino-3-methyl-1H-pyrazol-1-yl) acetate (54a ) (75 mg, 0.388 mmol; CAS No. 956440-82-7), DIPEA (0.203 ml, 1.165 mmol) and HATU (221 mg, 0.582 mmol). This resulted in, after work-up and purification by flash chromatography,

- 129 045626 column [silica gel (12 g), eluted with DCM/methanol (1:0 to 19:1)] ethyl 2-(5-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2- fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1Hpyrazol-1-yl)acetate (54b) (0.19 g, 89% yield) as brown solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.40 (s, 1H), 8.26-8.15 (m, 1H), 7.57-7.42 (m, 3H), 7.36 (t, J=7.7 Hz, 1H), 7.32-7.24 (m, 1H), 6.29 (s, 1H), 5.01 (s, 2H), 4.28 (d, J=6.3 Hz, 2H), 4.08 (k, J=7.1 Hz, 2H), 2.17 (s, 3H), 1.40 (s, 9H), 1.11 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -119.39; MS (ESI+) 552.3 (M+1); (ESI-) 550.4 (M-1).

Stage-2. Preparation of ethyl 2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-3-methyl-1H-pyrazole-1 -yl)acetate (54c).

Compound 54c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(5-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -G][1,2,4]triazin-4carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate (54b) (0.18 g, 0.326 mmol) in DCM (15 ml) using TFA ( 1.01 ml, 13.05 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DCM/methanol (1:0 to 9:1)] ethyl 2-(5-(2(3-(aminomethyl)-2 -fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1yl)acetate (54c) (0.14 g, 95% yield) in as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.87 (s, 1H), 8.52-8.42 (m, 1H), 8.38 (d, J=2.6 Hz, 1H) , 8.29 (s, 3H), 7.77-7.67 (m, 1H), 7.52-7.44 (m, 2H), 7.32 (dd, J=4.6, 2, 6 Hz, 1H), 6.29 (s, 1H), 5.01 (s, 2H), 4.22 (s, 2H), 4.09 (k, J=7.0 Hz, 2H), 2 .18 (s, 3H), 1.11 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -116.54; MS (ESI+): 452.3 (M+1), 474.3 (M+Na); MS (ESI-): 450.4 (M-1).

Stage-3. Preparation of 2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-3-methyl-1H-pyrazol-1- yl)acetic acid (54d).

Compound 54d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)-3-methyl-1H-pyrazol1-yl)acetate (54c) (0.129 g, 0.286 mmol) in THF/MeOH (20 ml, 1:1) using lithium hydroxide monohydrate (73, 4 mg, 1.714 mmol) in water (10 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(5-(2-( 3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-3-methyl-1H-pyrazol-1-yl)acetic acid (54d) (47 mg , 39% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 11.63 (s, 1H), 8.80 (s, 3H), 8.49-8.39 (m, 1H), 8.16 (t, J =7.3 Hz, 1H), 7.71 (t, J=7.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.43 (t, J=7.7 Hz , 1H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 6.30 (s, 1H), 4.66 (s, 2H), 4.14 (s, 2H) , 2.15 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -115.10; MS (ESI-): 422.4 (M-1).

Scheme-55 o

55d

55f 55g

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5yl)methoxy)phenyl)acetic acid (55 g).

Stage-1. Preparation of methyl 2-cyclopropyl-7-iodobenzofuran-5-carboxylate (55b).

To a solution of methyl 4-hydroxy-3,5-diiodobenzoate (55a) (3 g, 7.43 mmol, CAS No. 3337-66-4) in pyridine (10 ml) was added ethynylcyclopropane (0.49 g, 7.43 mmol , CAS No. 6746-94-7) and copper(I) oxide (0.53 g, 3.71 mmol). The mixture was degassed, filled with Ar, stirred for 10 min at room temperature and heated at 125°C for 3 h in a sealed flask. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with 1N aq. HCl (4x100 ml), water and saline solution. The organic layer was dried, filtered and concentrated in vacuo. Received

- 130 045626 the residue was purified by flash column chromatography [silica gel (24 g), eluted with 0% to 70% EtOAc in hexane] to give methyl 2-cyclopropyl-7-iodobenzofuran-5-carboxylate (55b) (1.6 g, 63% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 2H), 6.85 (s, 1H), 2.24-2.14 (m, 1H), 1.11-1.03 (m, 2H), 0.970.90 (m, 2H); MS (ESI+): 365.1 (M+Na); (ESI-): 341.1 (M-1).

Stage-2. Preparation of 2-cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c).

Compound 55c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-cyclopropyl-7-iodobenzofuran-5-carboxylate (55b) (1.3 g, 3.80 mmol) in MeOH/THF (10 ml) using a solution of lithium hydroxide monohydrate (0.32 g, 7.60 mmol) in water (2 ml) This gave after treatment 2-cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c) (1.19 g, 95% yield) as a white solid;

% NMR (300 MHz, DMSO- _d6 ) δ 13.06 (s, 1H), 8.14-8.05 (m, 2H), 6.83 (s, 1H), 2.18 (m, 1H ), 1.06 (dt, J=8.3, 3.1 Hz, 2H), 0.97-0.87 (m, 2H).

Stage-3. Preparation of (2-cyclopropyl-7-iodobenzofuran-5-yl)methanol (55d).

Compound 55d was prepared according to the procedure described in step-1 of Scheme-23 from 2cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c) (1.16 g, 3.54 mmol) using Nmethylmorpholine (0.47 ml , 4.2 mmol) in THF (50 ml), isobutyl chloroformate (0.56 ml, 4.24 mmol) and NaBH ₄ (0.40 g, 10.61 mmol) in water (2.0 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in hexane] (2cyclopropyl-7-iodobenzofuran-5-yl)methanol (55d) (1. 02 g, 92% yield) as a clear oil;

% NMR (300 MHz, DMSO-d6) δ 7.52 (d, J=1.5 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 6.68 (s, 1H ), 5.25 (t, J=5.8 Hz, 1H, D ₂ O replaceable), 4.51 (d, J=5.8 Hz, 2H), 2.19-2.07 (m, 1H ), 1.09-0.98 (m, 2H), 0.93-0.85 (m, 2H); MS (ESI+): 337.3 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e).

Compound 55e was prepared according to the procedure described in step-2 of Scheme-23 from (2cyclopropyl-7-iodobenzofuran-5-yl)methanol (55d) (850 mg, 2.71 mmol) in DCM (10 ml) using triphenylphosphine (781 mg, 2.98 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (536 mg, 2.98 mmol) and di(4-chlorobenzyl) azodicarboxylate (DCAD, 1093 mg, 2.98 mmol ). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((2-cyclopropyl-7-iodobenzofuran-5- yl)methoxy)phenyl)acetate (55e) (800 mg, 62% yield) as a clear oil;

% NMR (300 MHz, DMSO-d6) δ 7.62 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.29-7.18 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H), 6.72 (s, 1H) , 5.11 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 2.23-2.05 (m, 1H), 1, 14-0.98 (m, 5H), 0.96-0.83 (m, 3H); MS (ESI+): 499.1 (M+Na); (ESI-): 475.3 (M-1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5yl)methoxy)phenyl)acetate (55f).

Compound 55f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e) (250 mg, 0 .53 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (148 mg, 0.787 mmol), tripotassium phosphate (3 M aqueous solution, 0.30 ml, 0.89 mmol), tricyclohexylphosphine (44.2 mg, 0.16 mmol) and Pd ₂ (dba) ₃ (48 mg, 0.052 mmol) under Ar and heating at 125°C for 45 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1, v/v) in 0% to 70% hexane] ethyl 2-(2 -((7-(3(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate (55f) (120 mg, 32% yield) as the free base. 70 mg of the free base was purified by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((7- (3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate (55f) (25 mg, 30% yield), HCl salt, as a white solid;

% NMR (300 MHz, DMSO- _d6 ) δ 8.44 (s, 3H, D2O replaceable), 7.95 (s, 1H), 7.92-7.83 (m, 1H), 7.66- 7.45 (m, 5H), 7.32-7.17 (m, 2H), 7.15-7.06 (m, 1H), 6.97-6.86 (m, 1H), 6. 67 (s, 1H), 5.20 (s, 2H), 4.12 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.22-2.09 (m, 1H), 1.07-0.96 (m, 5H), 0.96-0.90 (m, 2H); MS (ESI+): 456.3 (M+1); (ESI-): 490.3 (M+Cl).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5yl)methoxy)phenyl)acetic acid (55g).

Compound 55g was prepared according to the procedure described in step-4 of scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate ( 55f) (50 mg, 0.11 mmol) in MeOH/THF (3 ml), using a solution of sodium hydroxide (21.9 mg, 0.55 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%]2-(2-((7- (3(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetic acid (55g) (21 mg,

- 131 045626

45% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H, D ₂ O replaceable), 8.43 (s, 2H, D ₂ O replaceable), 7.95 (d, J=1, 6 Hz, 1H), 7.90 (dt, J=7.5, 1.6 Hz, 1H), 7.63-7.49 (m, 4H), 7.29-7.17 (m, 2H ), 7.08 (d, J=8.1 Hz, 1H), 6.946.85 (m, 1H), 6.66 (s, 1H), 5.23 (s, 2H), 4.13 (s , 2H), 3.59 (s, 2H), 2.22-2.12 (m, 1H), 1.10-0.97 (m, 2H), 0.970.88 (m, 2H); MS (ESI+): 428.3 (M+1); 450.4 (M+Na); (ESI-): 426.4 (M-1), 462.3 (M+Cl).

Scheme-56

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (56c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (56b).

Compound 56b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (250 mg, 0.64 mmol) in dioxane (3 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (198 mg, 0.96 mmol; CAS No. 1072946-44-1), tetrakis(triphenylphosphine)palladium(0 ) (148 mg, 0.128 mmol), potassium carbonate (266 mg, 1.93 mmol) in water (1 ml) under Ar atmosphere and heating at 150°C for 55 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1, v/v) in hexane from 0% to 100%] followed by reverse phase Column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl) benzofuran-5-yl)methoxy)phenyl)acetate (56b) (125 mg, 45% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (s, 3H, D2O replaceable), 8.06 (d, J=2.2 Hz, 1H), 7.79 (d, J=1, 6 Hz, 1H), 7.74-7.62 (m, 2H), 7.46-7.39 (m, 2H), 7.30-7.19 (m, 2H), 7.11 (d , J=8.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H), 5.24 (s, 2H), 4.17 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 0.99 (t, J=7, 1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.52; MS (ESI+): 434.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (56c).

Compound 56c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 56b) (65 mg, 0.15 mmol) in MeOH/THF (3 ml), using a solution of lithium hydroxide monohydrate (25.2 mg, 0.60 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (56c) (26 mg, 43% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.13-8.08 (m, 1H, D2O replaceable), 8.06 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.73-7.61 (m, 2H), 7.50-7.39 (m, 2H), 7.28-7.18 (m, 2H), 7 ,12-7.02 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.18 (s, 2H), 3.58 ( s, 2H); MS (ESI+): 406.3 (M+1); 428.3 (M+Na); (ESI-): 404.4 (M-1), 440.3 (M+Cl).

- 132 045626

Scheme-57

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (57c).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl1H-indol-6-yl)methoxy)phenyl)acetate (57a).

Compound 57a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) ( 500 mg, 0.92 mmol) in dioxane (5 ml) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate ( 34a) (0.49 g, 1.38 mmol), 3 M aqueous solution of tripotassium phosphate (0.52 ml, 1.57 mmol), tricyclohexylphosphine (78 mg, 0.277 mmol) and Pd ₂ (dba) ₃ (80 mg, 0.09 mmol) under argon and heating at 125°C for 60 min in a microwave oven. This resulted in, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane 0% to 70%] followed by reverse phase chromatography on a column of [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H- indol-6yl)methoxy)phenyl)acetate (57a) (0.36 g, 57% yield) as a white solid; MS (ESI+): 709.4 (M+Na), MS (ESI-): 685.4 (M-1), 721.5 (M+Cl).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6yl)methoxy)phenyl)acetate (57b).

Compound 57b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1 -tosyl-1H-indol-6yl)methoxy)phenyl)acetate (57a) (0.35 g, 0.51 mmol) in DCM (5 ml) using TFA (0.39 ml, 5.1 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy )phenyl)acetate (57b) (0.15 g, 50% yield) as a yellow solid; MS (ESI+): 587.3 (M+1), MS (ESI-): 621.4 (M+Cl).

Stage-3. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6yl)methoxy)phenyl)acetic acid (57c).

Compound 57c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl )methoxy)phenyl)acetate (57b) (100 mg, 0.17 mmol) in MeOH/THF (10 ml, 1:1), using a solution of lithium hydroxide monohydrate (40 mg, 1.02 mmol) in water (2 ml ). This resulted in the production after treatment of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (57c) (0.02 g, 16% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 3H), 8.13 (m, 2H), 8.00-7.86 (m, 3H), 7.71-7.62 (m, 1H), 7.52 (m, 1H), 7.45-7.33 (m, 4H), 7.23 (m, 1H), 7.07 (m, 1H), 6.93 ( t, J=7.4 Hz, 1H), 6.82-6.68 (m, 1H), 5.34 (s, 2H), 4.11 (k, J=5.9 Hz, 2H), 3.63 (s, 2H), 2.32 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.79; MS (ESI+): 559.2 (M+1), 581.3 (M+Na); MS (ESI-): 557.4 (M-1).

- 133 045626

Scheme-58

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (58b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6yl)methoxy)phenyl)acetate (58a).

To a solution of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6yl)methoxy)phenyl)acetate (57b) (0.31 g, 0. 53 mmol) in THF (5 ml) was added tetra-butylammonium fluoride (1.38 g, 5.28 mmol). The mixture was heated at 90°C in THF for 6 hours, cooled to room temperature, diluted with EtOAc (60 ml), washed with water (3x), brine, dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] followed by reverse phase chromatography [C18 (50 g ), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (58a) (0.12 g, 53% yield) as a purple solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.52 (br. s, 3H), 7.61 (m, 2H), 7.53 (s, 1H), 7.42 (m, 1H), 7.37 (m, 1H), 7.30-7.17 (m, 2H), 7.13 (m, 2H), 6.90 (t, J=7, 3 Hz, 1H), 6.36 (t, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.15 (d, J=5.5 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.80; MS (ESI+): 433.3 (M+1), 455.3 (M+Na); MS (ESI-): 467.3 (M+Cl). Purity after HPLC: 92.85%.

Stage-2. Preparation Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (58b).

Compound 58b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl )acetate (58a) (30 mg, 0.07 mmol) in MeOH/THF (5 ml, 1:1), using a solution of sodium hydroxide (10 mg, 0.28 mmol) in water (2 ml). This gave, after work-up and purification by flash column chromatography [silica gel (4 g), eluted with DMA80 in DCM 0% to 100%] 2-(2-((4-(3-(aminomethyl)-2- fluorophenyl)-1H-indol6-yl)methoxy)phenyl)acetic acid (58b) (0.01 g, 43% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.1082 (br. s, 1H); 11.31 (s, 1H), 8.34 (s, 3H), 7.65-7.57 (m, 2H), 7.56 (s, 1H), 7.50-7.33 (m, 2H), 7.21 (m, 2H), 7.18-7.07 (m, 2H), 6.89 (t, J=7.3 Hz, 1H), 6.35 (s, 1H), 5.24 (s, 2H), 4.17 (s, 2H), 3.57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.65; MS (ESI+) 405.3 (M+1), 427.2 (M+Na); MS (ESI-): 439.3 (M+Cl). Purity after HPLC: 94.55%.

Scheme-59

Preparation of (S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (59d).

Stage-1. Preparation of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (59a).

To a degassed solution of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (8.9 g, 22.87 mmol), bis(pinacolato)diboron (8.71 g, 34.3 mmol, CAS No.: 73183-34-3) and potassium acetate (6.73 g, 68.6 mmol) in anhydrous dioxane (150 ml) was added Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (1, 87 g, 2.29 mmol). The resulting mixture was degassed, filled with Ar and stirred at 90°C overnight. Then reactionary

- 134 045626 the mixture was diluted with EtOAc (400 ml) and washed with water (100 ml). The aqueous layer was re-extracted with EtOAc (100 ml x 2). The organic layers were combined, washed with water (100 ml), brine (100 ml), dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with 0% to 40% EtOAc in hexane] to give ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (59a) (9 g, 90% yield) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.65 (d , J=1.8 Hz, 1H), 7.34-7.17 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.98-6.87 (m, 2H), 5.17 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.34 (s, 12H), 1.05 ( t, J=7.1 Hz, 3H).

Stage-2. Preparation of (S)-ethyl 2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (59c).

Compound 59c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (450 mg, 1.03 mmol) in dioxane (6 ml), using (S)-2-amino-2-(3-chlorophenyl)ethanol (59b) (301 mg, 1.75 mmol; CAS No. 663611-73-2), tripotassium phosphate (3 M aq, 0.58 ml, 1.75 mmol), tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd ₂ ( dba) ₃ (94 mg, 0.10 mmol) under Ar and heating at 125°C for 60 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), DMA80 in DCM 0% to 70%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (0. 1% HCl) 0% to 100%] (S)-ethyl 2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (59c) (253 mg, 55% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.74 (s, 3H, D2O replaceable), 8.13 (d, J=2.2 Hz, 1H), 8.03 (d, J=2 .0 Hz, 1H), 7.93 (dt, J=6.9, 1.8 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.70-7.54 (m, 3H), 7.34-7.19 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H) , 6.97-6.87 (m, 1H), 5.66 (t, J=5.0 Hz, 1H, D2O replaceable), 5.26 (s, 2H), 4.38 (t, J= 6.0 Hz, 1H), 3.94 (k, J=7.1 Hz, 2H), 3.83 (t, J=5.6 Hz, 2H), 3.64 (s, 2H), 0 .99 (t, J=7.1 Hz, 3H); MS (ESI+): 446.3 (M+1); 468.4 (M+Na); (ESI-): 480.3 (M+Cl).

Stage-3. Preparation of (S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (59d).

Compound 59d was prepared according to the procedure described in step-6 of Scheme-1 from (S)-ethyl 2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5- yl)methoxy)phenyl)acetate (59c) (96 mg, 0.22 mmol) in MeOH/THF (5 ml), using a solution of lithium hydroxide monohydrate (36 mg, 0.86 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- ((7-(3-(1amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (59d) (65 mg, 72% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (s, 1H, D2O replaceable), 8.59 (s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.97-7.87 (m, 1H), 7.77 (d, J=1.5 Hz, 1H), 7, 66 (d, J=1.6 Hz, 1H), 7.647.54 (m, 2H), 7.28-7.20 (m, 2H), 7.14-7.03 (m, 2H), 6 .97-6.78 (m, 1H), 5.62 (br. s, 1H, D2O replaceable), 5.28 (s, 2H), 4.46-4.33 (m, 1H), 3. 86-3.73 (m, 2H), 3.60 (s, 2H); MS (ESI+): 418.3 (M+1); 440.3 (M+Na); (ESI-): 416.4 (M-1), 452.3 (M+Cl).

Scheme-60

Preparation of 2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (60c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (60b).

Compound 60b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (300 mg, 0.69 mmol) in dioxane (3 ml), using (5-bromo-2-fluorophenyl)methanamine hydrochloride (60a) (248 mg, 1 .03 mmol, CAS No. 202865-69-8), tripotassium phosphate (3 M aq, 0.85 ml, 2.54 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd ₂ (dba) ₃ (63 mg, 0.069 mmol) under Ar atmosphere and heating at 125°C for 90 min in a microwave oven. This resulted in the following work-up and purification by flash column chromatography [silica gel (12 g), EtOAc in hexane 0% to 70%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (60b)

- 135 045626 (165 mg, 55% yield) in the form of a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 3H, D2O replaceable), 8.16-8.07 (m, 2H), 8.03-7.92 (m, 1H), 7 .76-7.70 (m, 1H), 7.65-7.58 (m, 1H), 7.52-7.41 (m, 1H), 7.30-7.19 (m, 2H) , 7.15-7.05 (m, 2H), 6.96-6.87 (m, 1H), 5.24 (s, 2H), 4.16 (s, 2H), 3.94 (k , J=7.1 Hz, 2H), 3.63 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -117.93; MS (ESI+): 434.3 (M+1); 476.4 (M+Na); (ESI-): 468.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (60c).

Compound 60c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 60b) (65 mg, 0.15 mmol) in MeOH/THF (3 ml), using a solution of sodium hydroxide (24 mg, 0.6 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-4fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (60c) (36 mg, 59% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 3H, D2O replaceable), 8.18-8.10 (m, 2H), 8.05-7.96 (m, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.52-7.41 (m, 1H), 7.29-7 .19 (m, 2H), 7.14-7.05 (m, 2H), 6.96-6.87 (m, 1H), 5.27 (s, 2H), 4.17 (s, 2H ), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.03; MS (ESI+): 406.3 (M+1); (ESI-): 404.3 (M-1); 440.3 (M+Cl).

Scheme-61

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5carboxamido)phenyl)acetic acid (61f).

Stage-1. Preparation of methyl 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylate (61b).

To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (61a) (0.2 g, 0.81 mmol; CAS No. 260249-10-3) in DCM (10 ml) was added N-(dichloromethylene)-chloride N-methylmethanaminium (0.26 g, 1.63 mmol) and triethylamine (0.34 ml, 2.44 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with water, dried and concentrated. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give methyl 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylate (61b ) (0.22 g, 90% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.72 (d, J=1.5 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 3.85 (s, 3H), 3.15 (s, 6H); MS (ESI+): 299.1 and 301.1 (M+1).

Stage-2. Preparation of 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylic acid (61c).

Compound 61c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylate (61b) (220 mg, 0.735 mmol) in MeOH ( 10 ml) using a solution of lithium hydroxide monohydrate (0.185 g, 4.41 mmol) in water (2 ml). This resulted in 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylic acid (61c) (0.18 g, 86% yield) as a white solid upon treatment;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.14 (s, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 3.16 (s, 6H); MS (ESI-): 283.1 (M-1).

Stage-3. Preparation of ethyl 2-(2-(7-bromo-2-(dimethylamino)benzo[d]oxazole-5carboxamido)phenyl)acetate (61d).

Compound 61d was prepared according to the procedure described in step-4 of Scheme-1 from 7-bromo2-(dimethylamino)benzo[d]oxazole-5-carboxylic acid (61c) (180 mg, 0.76 mmol) in DMF ( 5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (0.14 g, 0.76 mmol), HATU (0.29 g, 0.76 mmol) and DIPEA (0.22 ml, 1 .26 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(7bromo-2-(dimethylamino)benzo[ d]oxazole-5-carboxamido)phenyl)acetate (61d) (0.17 g, 60% yield) as a white solid; MS (ESI ^- ): 444.3 and 446.2 (M-1), 482.2 and 484.1 (M+Cl).

Stage-4. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5carboxamido)phenyl)acetate (61e).

Compound 61e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate (61d) ( 90 mg, 0.2 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (60 mg, 0.3 mmol), tripotassium phosphate (3 M aq, 0.2 ml, 0 .61 mmol), tricyclohexylphosphine (20 mg, 0.06 mmol) and Pd ₂ (dba) ₃ (20 mg, 0.06 mmol) under Ar and heating at 125°C for 90 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-(7-(3(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl) acetate (61e) (0.03 g, 30% yield) as a white solid; MS (ESI+): 473.3 (M+1), MS (ESI-): 471.4 (M-1).

Stage-5. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5carboxamido)phenyl)acetic acid (61f).

Compound 61f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido) phenyl)acetate (61 e) (20 mg, 0.04 mmol) in MeOH (5 ml), using a solution of sodium hydroxide (7 mg, 0.17 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetic acid (61f) (0.01 g, 59% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 8.60 (s, 3H), 8.08 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.94 (dd, J=5.3, 2.8 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.60 (m, 2H), 7.49 (d, J=7.7 Hz, 1H), 7.38-7.28 (m, 2H), 7.22 (m, 1H), 4.14 (k, J=5.8 Hz , 2H), 3.71 (s, 2H), 3.21 (s, 6H); MS (ESI+): 445.3 (M+1), 467.3 (M+Na); MS (ESI-): 443.3 (M-1), 439.3 (M+Cl). Purity after HPLC: 98.13%.

Scheme-62

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5carboxamido)phenyl)acetic acid (62c).

Stage-1. Preparation of ethyl 2-(2-(2-cyclopropyl-7-iodobenzofuran-5-carboxamido)phenyl)acetate (62a).

Compound 62a was prepared according to the procedure described in step-4 of Scheme-1 from 2-cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c) (185 mg, 0.56 mmol) in DMF (10 ml) using ethyl 2 -(2-aminophenyl)acetate (5e) (121 mg, 0.68 mmol), HATU (257 mg, 0.68 mmol) and DIPEA (0.20 ml, 1.13 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(2cyclopropyl-7-iodobenzofuran-5-carboxamido)phenyl)acetate (62a) (145 mg, 53% yield) as a semi-solid; MS (ESI+): 490.2 (M+1); 512.2 (M+Na); (ESI-): 488.2 (M-1).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5carboxamido)phenyl)acetate (62b).

Compound 62b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(2-cyclopropyl-7-iodobenzofuran-5-carboxamido)phenyl)acetate (62a) (160 mg, 0.33 mmol ) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (92 mg, 0.49 mmol), tripotassium phosphate (3 M aq, 0.40 ml, 1.21 mmol), tricyclohexylphosphine ( 28 mg, 0.098 mmol) and

- 137 045626

Pd ₂ (dba) ₃ (30 mg, 0.033 mmol) under Ar and heating at 125°C for 60 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 70% DCM] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)acetate (62b) (86 mg , 56% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.12 (s, 1H, D2O replaceable), 8.44 (s, 3H, D2O replaceable), 8.15-8.11 (m, 1H), 8.11-8.07 (m, 1H), 8.04 (s, 1H), 7.99-7.92 (m, 1H), 7.68-7.52 (m, 2H), 7. 44-7.38 (m, 1H), 7.38-7.30 (m, 2H), 7.29-7.21 (m, 1H), 6.82 (s, 1H), 4.15 ( s, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.78 (s, 2H), 2.28-2.16 (m, 1H), 1.121.03 (m, 2H ), 1.03-0.93 (m, 5H); MS (ESI+): 469.3 (M+1); (ESI-): 503.4 (M+Cl).

Stage-3. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5carboxamido)phenyl)acetic acid (62c).

Compound 62c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)acetate (62b) ( 53 mg, 0.11 mmol) in MeOH/THF (3 ml), using a solution of sodium hydroxide (18 mg, 0.45 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)acetic acid (62c) (15 mg, 31% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.37 (s, 1H, D2O replaceable), 10.17 (s, 1H, D2O replaceable), 8.41 (s, 3H, D2O replaceable), 8 .14 (d, J=1.7 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.05-8.00 (m, 1H), 8.00-7, 92 (m, 1H), 7.677.52 (m, 2H), 7.51-7.44 (m, 1H), 7.37-7.28 (m, 2H), 7.22 (td, J= 7.4, 1.4 Hz, 1H), 6.81 (s, 1H), 4.15 (s, 2H), 3.69 (s, 2H), 2.28-2.13 (m, 1H ), 1.11-1.01 (m, 2H), 1.01-0.92 (m, 2H); MS (ESI+): 441.3 (M+1); 463.3 (M+Na); (ESI-): 439.4 (M-1); purity after HPLC: 98.99%.

Scheme-63

Preparation of 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4methylphenyl)acetic acid (63c).

Stage-1. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4 -methylphenyl)acetate (63 a).

Compound 63a was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-1][1, 2,4]triazine-4-carboxylic acid (21a) (0.15 g, 0.388 mmol) in DMF (3 ml), using ethyl 2-(2-amino-4-methylphenyl) acetate (39a) (90 mg, 0.466 mmol), DIPEA (0.20 ml, 1.165 mmol) and HATU (0.177 g, 0.466 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino )Methyl)-5fluorophenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (63a) (0.17 g, 78% yield) as orange foam ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.33 (d, J=10.3 Hz , 1H), 8.19 (s, 1H), 7.62-7.54 (m, 3H), 7.33-7.19 (m, 3H), 7.13-7.06 (m, 1H ), 4.27 (d, J=6.2 Hz, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 2.36 (s, 3H ), 1.42 (s, 9H), 1.00 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d6) δ -113.24; MS (ESI+): 562.4 (M+1), 584.3 (M+Na), (ESI-): 560.5 (M-1).

Stage-2. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-1][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetate (63b).

Compound 63b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1 -1][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetate (63a) (0.17 g, 0.303 mmol) in DCM (3 mL), using TFA (0.02 mL, 0.30 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2(2-( 3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-1][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (63b) (0.036 g, 26% yield) as HCl salts;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.87 (s, 1H), 8.58-8.47 (m, 1H), 8.45-8.34 (m, 2H), 8. 27 (s, 3H), 7.63 (dd, J=4.6, 1.4 Hz, 1H), 7.60-7.52 (m, 2H), 7.34-7.27 (m, 2H), 7.11 (d, J=7.7 Hz, 1H), 4.20 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 2.36 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.48; MS

- 138 045626 (ESI+): 462.3 (M+1); MS (ESI-): 496.3 (M+Cl).

Stage-3. Preparation of 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)-4-methylphenyl)acetic acid (63 sec) .

Compound 63c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)-4-methylphenyl)acetate (63b) (0.08 g, 0.173 mmol) in THF (2 ml) using sodium hydroxide (0.173 ml, 0.347 mmol, 2 M aq). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(2-( 3(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetic acid (63c) (0.026 g, 35% yield) as HCl salts;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.64 (s, 1H), 10.93 (s, 1H), 8.51-8.35 (m, 6H), 7.66-7.60 (m, 2H), 7.607.54 (m, 1H), 7.34-7.25 (m, 2H), 7.09 (dd, J=7.8, 1.8 Hz, 1H), 4, 26-4.15 (m, 2H), 3.72 (s, 2H), 2.36 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.08; MS (ESI+) 434.3 (M+1); MS (ESI-) 432.4 (M-1); purity after HPLC: 94.02%.

Scheme-64

64d 64e 64f

Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetic acid (64f).

Stage-1. Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4carboxylate (64b).

Compound 64b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2chloroquinazoline-4-carboxylate (64a) (0.4 g, 1.69 mmol; CAS No. 1092352-52-7) in dioxane (5 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (0.64 g, 2.54 mmol), tripotassium phosphate (3 M aq, 0.96 ml, 2.87 mmol), tricyclohexylphosphine 100 mg, 0.34 mmol) and Pd ₂ (dba) ₃ (90 mg, 0.09 mmol) under Ar and heating at 125°C for 60 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 70% EtOAc in hexane] ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline -4-carboxylate (64b) (0.6 g, 87% yield) as a yellow solid; MS (ESI+): 430.3 (M+Na), MS (ESI-): 406.4 (M-1).

Stage-2. Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylic acid (64c).

Compound 64c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylate (64b) (0.6 g, 1.47 mmol) in THF/MeOH (5 ml), using lithium hydroxide (0.35 g, 14.73 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(3-(((tert-butoxycarbonyl )amino)methyl)phenyl)quinazoline-4-carboxylic acid (64c) (0.44 g, 79% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 14.56 (s, 1H), 8.44 (d, J=8.0 Hz, 2H), 8.37 (d, J=8.4 Hz, 1H), 8.11 (d, J=7.0 Hz, 2H), 7.80 (t, J=7.3 Hz, 1H), 7.55 (m, 2H), 7.44 (d, J=7.5 Hz, 1H), 4.26 (d, J=6.0 Hz, 2H), 1.43 (s, 9H); MS (ESI-): 378.4 (M-1).

Stage-3. Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4carboxamido)phenyl)acetate (64d).

Compound 64d was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylic acid (64c) (0.2 g, 0.53 mmol) in DMF (5 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (0.11 g, 0.63 mmol), DIPEA (0.18 ml, 1.05

- 139 045626 mmol) and HATU (0.24 g, 0.63 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4carboxamido)phenyl)acetate (64d) (0.26 g, 91% yield) as a white solid; MS (ESI+):

541.4 (M-1); MS (ESI-): 539.5 (M-1).

Stage-4. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate (64e).

Compound 64e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxamido)phenyl) acetate (64d) (0.13 g, 0.24 mmol) in DCM (5 ml) using TFA (0.19 ml, 2.41 mmol). This gave, after work-up and purification by reverse column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-(2-(3 -(aminomethyl)phenyl)quinazoline-4carboxamido)phenyl)acetate (64e) (0.1 g, 94% yield) as a yellow solid; MS (ESI+): 441.4 (M+1).

Stage-5. Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetic acid (64f).

Compound 64f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate (64e) (100 mg, 0.227 mmol) in MeOH/THF (5 ml) using a solution of NaOH ((0.036 g, 0.908 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography, [C18 (30 g ), eluted with ACN in water (with 0.1% HCl) 0% to 40%] 2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4carboxamido)phenyl)acetic acid (64f) (0.042 g, 45% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.85 (d, J=2.9 Hz, 1H), 9.07-8.94 (m, 1H), 8.82 (t, J=1 .8 Hz, 1H), 8.73 (d, J=7.7 Hz, 1H), 8.54 (s, 3H), 8.24-8.08 (m, 2H), 7.84 (m , 2H), 7.74 (m, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.41 (m, 2H), 7.28 (t, J=7.5 Hz , 1H), 4.20 (k, J=5.8 Hz, 2H), 3.83 (s, 2H); MS (ESI+): 413.2 (M+1); MS (ESI-): 411.3 (M-1). Purity after HPLC: 96.86%.

Scheme-65

Preparation of (R)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (65c).

Stage-1. Preparation of (R)-ethyl 2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (65b).

Compound 65b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (300 mg, 0.69 mmol) in dioxane (5 ml), using (R)-1-(3-chloro-2-fluorophenyl)ethanamine hydrochloride (65a) (289 mg, 1.38 mmol, CAS No. 1253792-97-0), tripotassium phosphate (3 M aq, 0.92 ml, 2.75 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd ₂ ( dba) ₃ (63 mg, 0.069 mmol) under Ar and heating at 130°C for 30 min in a microwave oven. This resulted in the following work-up and purification by flash column chromatography [silica gel (12 g), EtOAc in hexane 0% to 70%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] (R)-ethyl 2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy) phenyl)acetate (65b) (256 mg, 83% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (s, 3H, D2O replaceable), 8.07 (d, J=2.2 Hz, 1H), 7.84-7.74 (m, 2H), 7.66 (td, J=7.4, 1.7 Hz, 1H), 7.51-7.41 (m, 2H), 7.31-7.20 (m, 2H), 7 ,16-7.09 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5, 24 (s, 2H), 4.79-4.62 (m, 1H), 3.92 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.59 (d , J=6.8 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 448.3 (M+1); (ESI-): 482.4 (M+Cl).

Stage-2. Preparation of (R)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (65c).

Compound 65c was prepared according to the procedure described in step-6 of Scheme-1 from (R)-ethyl 2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl )methoxy)phenyl)acetate (65b) (58 mg, 0.13 mmol) in MeOH/THF (3 ml), using a solution of lithium hydroxide monohydrate (21.76 mg, 0.52 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (R)-2-(2- ((7-(3-(1aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (65c) (17 mg, 31% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.22 (s, 1H, D2O replaceable), 8.68 (s, 3H, D2O replaceable), 8.06 (d,

- 140 045626

J=2.2 Hz, 1H), 7.85-7.73 (m, 2H), 7.71-7.61 (m, 1H), 7.51-7.41 (m, 2H), 7 ,27-7.18 (m, 2H), 7.13-7.02 (m, 2H),

6.90 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.71 (d, J=7.2 Hz, 1H), 3.58 (s, 2H), 1.59 (d, J=6.8 Hz, 3H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -119.76; MS (ESI+): 420.3 (M+1); (ESI-): 418.3 (M-1); 454.3 (M+Cl).

Scheme-66

C.I.

Preparation of ^)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (66c).

Stage-1. Preparation of (S)-ethyl 2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (66b).

Compound 66b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (300 mg, 0.69 mmol) in dioxane (5 ml), using (S)-1-(3-chloro-2-fluorophenyl)ethanamine hydrochloride (66a) (253 mg, 1.20 mmol, CAS No. 1313593-59-7), tripotassium phosphate (3 M aq, 0.92 ml, 2.75 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd ₂ ( dba) ₃ (63 mg, 0.069 mmol) under Ar and heating at 130°C for 60 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), DMA80 in DCM 0% to 70%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] (S)-ethyl 2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy) phenyl)acetate (66b) (130 mg, 42% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 3H, D2O replaceable), 8.07 (d, J=2.2 Hz, 1H), 7.88-7.75 (m, 2H), 7.69-7.59 (m, 1H), 7.51-7.39 (m, 2H), 7.30-7.19 (m, 2H), 7.16-7.03 ( m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.24 (s, 2H), 4.70 (k, J=6.5 Hz, 1H), 3.91 ( k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.59 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.02; MS (ESI+): 448.3 (M+1); (ESI-): 482.3 (M+Cl); purity after HPLC: 98.77%.

Stage-2. Preparation of (S)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (66c).

Compound 66c was prepared according to the procedure described in step-6 of Scheme-1 from (S)-ethyl 2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl )methoxy)phenyl)acetate (66b) (72 mg, 0.16 mmol) in MeOH/THF (3 ml), using a solution of lithium hydroxide monohydrate (27 mg, 0.64 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- ((7-(3-(1aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (66c) (26 mg, 39% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (s, 2H, D2O replaceable), 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1 .6 Hz, 1H), 7.77 (t, J=7.2 Hz, 1H), 7.66 (t, J=7.4 Hz, 1H), 7.51-7.38 (m, 2H ), 7.30-7.16 (m, 2H), 7.14-7.02 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.72 (k, J=6.8 Hz, 1H), 3.58 (s, 2H), 1.59 (d, J=6.7 Hz, 3H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -119.75; MS (ESI+): 420.3 (M+1); (ESI-): 418.3 (M-1), 454.3 (M+Cl); purity after HPLC: 99.82%.

Scheme-67

Preparation of (S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (67c).

Stage-1. Preparation of (S)-ethyl 2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (67b).

Compound 67b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (316 mg, 0.72 mmol) in dioxane (5 ml) using (S)-2-amino-2-(3-chloro-2-fluorophenyl) ethanol hydrochloride (67a) (327 mg, 1.45 mmol, CAS No. 1391506-22-1), tripotassium phosphate (3 M aq, 0.41 ml, 1.23 mmol), tricyclohexylphosphine (61 mg, 0.22 mmol ) and Pd2(dba)3 (66 mg, 0.072 mmol) under Ar and heating at 125°C for 60 min in a microwave oven. This resulted in obtaining after processing and purification

- 141 045626 by flash column chromatography [silica gel (12 g), DMA80 in DCM from 0% to 70%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1 %

HCl) from 0% to 100%] (S)-ethyl 2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate ( 67b) (142 mg, 42% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 3H, D ₂ O replaceable), 8.07 (d, J=2.1 Hz, 1H), 7.83-7.72 ( m, 2H), 7.67 (td, J=7.4, 1.6 Hz, 1H), 7.52-7.41 (m, 2H), 7.31-7.18 (m, 2H) , 7.12 (dd, J=8.3, 1.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td, J=7.4, 1 ,1 Hz, 1H), 5.68 (t, J=5.2 Hz, 1H, D ₂ O replaceable), 5.24 (s, 2H), 4.60 (t, J=5.9 Hz, 1H), 3.92 (k, J=7.1 Hz, 2H), 3.85-3.72 (m, 2H), 3.62 (s, 2H), 0.99 (t, J=7 ,1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -119.52; MS (ESI+): 464.3 (M+1); 486.3 (M+Na); (ESI-): 498.3 (M+Cl); purity after HPLC: 98.65%,

Stage-2. Preparation of (S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (67c).

Compound 67c was prepared according to the procedure described in step-6 of Scheme-1 from (S)-ethyl 2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl) benzofuran-5-yl)methoxy)phenyl)acetate (67b) (65 mg, 0.14 mmol) in MeOH/THF (5 ml), using a solution of lithium hydroxide monohydrate (24 mg, 0.56 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- ((7(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (67c) (31 mg, 51% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (s, 2H, D2O replaceable), 8.07 (d, J=2.2 Hz, 1H), 7.85-7.80 (m, 1H), 7.76 (t, J=7.3 Hz, 1H), 7.67 (t, J=7.3 Hz, 1H), 7.50-7.42 (m, 2H), 7, 27-7.17 (m, 2H), 7.13-7.04 (m, 2H), 6.956.86 (m, 1H), 5.67 (s, 1H, D ₂ O replaceable), 5.27 (s, 2H), 4.60 (t, J=5.7 Hz, 1H), 3.87-3.71 (m, 2H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -119.34; MS (ESI+) 436.3 (M+1); (ESI-), 434.3 (M-1); 470.3 (M+Cl); purity after HPLC: 99.26%.

Scheme-68

Preparation of 2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (68c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5yl)methoxy)phenyl)acetate (68b).

Compound 68b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (315 mg, 0.72 mmol) in dioxane (5 ml), using (3-chloro-2-methylphenyl)methanamine (68a) (225 mg, 1. 44 mmol, CAS No. 226565-61-3), tripotassium phosphate (3 M aq, 0.41 ml, 1.23 mmol), tricyclohexylphosphine (61 mg, 0.22 mmol) and Pd ₂ (dba) ₃ (66 mg , 0.072 mmol) in an Ar atmosphere and heating at 130°C for 60 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), DMA80 in DCM 0% to 70%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (0. 1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate (68b) (188 mg, 61% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.49 (s, 3H, D2O replaceable), 7.99 (d, J=2.2 Hz, 1H), 7.74 (d, J=1, 6 Hz, 1H), 7.52 (dd, J=7.4, 1.7 Hz, 1H), 7.42-7.31 (m, 2H), 7.31-7.17 (m, 3H ), 7.12 (d, J=8.0 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.97-6.86 (m, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.11 (s, 3H), 0 .99 (t, J=7.1 Hz, 3H); MS (ESI+): 430.4 (M+1); 452.3 (M+Na).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (68c).

Compound 68c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 68b) (55 mg, 0.13 mmol) in MeOH/THF (5 ml), using a solution of lithium hydroxide monohydrate (22 mg, 0.51 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (68c) (23 mg, 45% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H, D2O replaceable), 7.98 (d, J=2.2 Hz, 1H), 7.78 (d, J=1, 6 Hz, 1H), 7.51 (dd, J=7.0, 1.9 Hz, 1H), 7.42-7.29 (m, 2H), 7.27-7.18 (m, 3H ), 7.09 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.2

- 142 045626

Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.12 (s, 2H), 3.57 (s, 2H), 2, 11 (s, 3H); MS (ESI+): 402.3 (M+1); 424.3 (M+Na); (ESI-): 400.4 (M-1), 436.4 (M+Cl).

Scheme-69

9a NaBH ₄ ^69a

Preparation of 2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-III-indol-6-yl)methoxy)phenyl)acetic acid (69e).

Stage-1. Preparation of (4-bromo-1H-indol-6-yl)methanol (69a).

Compound 69a was prepared according to the procedure described in step-1 of Scheme-23 from 4-bromo1H-indole-6-carboxylic acid (9a) (10 g, 41.7 mmol) in THF (100 ml) using N-methylmorpholine (5.50 ml, 50.0 mmol), isobutyl chloroformate (6.56 ml, 50.0 mmol) and NaBH ₄ (4.73 g, 125 mmol) in water (0.8 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with ethyl acetate/MeOH (9:1) in hexane 0% to 100%] (4-bromo-Shindol-6-yl) methanol (69a) (6.1 g, 65% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 7.42 (t, J=2.8 Hz, 1H), 7.36 (t, J=1.1 Hz , 1H), 7.18 (d, J=1.2 Hz, 1H), 6.35 (m, 1H), 5.22 (t, J=5.9 Hz, 1H), 4.56 (d , J=5.6 Hz, 2H).

Stage-2. Preparation of ethyl 2-(2-((4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (69b).

Compound 69b was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1H-indol-6-yl)methanol (69a) (3 g, 13.27 mmol) in toluene (50 ml) using triphenylphosphine (4.52 g, 17.25 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (3.11 g, 17.25 mmol) and a solution of (E)-diazen1,2-diylbis(piperidine- 1-ylmethanone) (ADD, 4.35 g, 17.25 mmol) in toluene (50 ml). This resulted in, after workup and purification by flash column chromatography [silica gel (48 g), eluted with EtOAc/MeOH (9:1) in hexane from 0% to 10% for 40 min, then 10% to 50%] ethyl 2-(2-((4bromo-1H-indol-6-yl)methoxy)phenyl)acetate (69b) (1.3 g, 25% yield) as a yellow oil;

1H NMR (300 MHz, DMSO-de) δ 11.54 (s, 1H), 7.51-7.44 (m, 2H), 7.27 (d, J=1.2 Hz, 1H), 7 .26-7.18 (m, 2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H ), 6.39 (m, 1H), 5.16 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.07 (t , J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (69c).

Compound 69c was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2(2-((4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (69b) (1.3 g , 3.35 mmol) in anhydrous dioxane (20 ml), using bis(pinacolato)diboron (1.28 g, 5.02 mmol), potassium acetate (0.986 g, 10.04 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.41 g, 0.50 mmol) and heating under argon at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(2-((4-(4 ,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (69c) (0.98 g, 67% yield) as a yellow oil ; MS (ESI+) 458.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6yl)methoxy)phenyl)acetate (69d).

Compound 69d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indol-6-yl)methoxy)phenyl)acetate (69c) (0.98 g, 2.25 mmol) in dioxane (7 ml) using (3-bromo-5-fluorophenyl)methanamine (73a) ( 0.20 ml, 1.50 mmol), solution of potassium carbonate (0.52 g, 3.75 mmol) in water (0.7 ml), bis(triphenylphosphine) palladium(P) chloride (0.16 g, 0 .23 mmol) in an Ar atmosphere and heating at 100°C for 2 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate ( 69d) (0.19 g, 29% yield) as a yellow solid;

- 143 045626

1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.34 (s, 3H), 7.68 (d, J=1.5 Hz, 1H), 7.54-7 .45 (m, 3H),

7.37 (d, J=9.7 Hz, 1H), 7.28-7.18 (m, 3H), 7.12 (d, J=8.1 Hz, 1H), 6.91 (dd , J=7.4, 1.1 Hz, 1H), 6.68 (d, J=2.9

Hz, 1H), 5.23 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.61 ( s, 2H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F

NMR (282 MHz, DMSO-06) δ -112.87; MS (ESI+) 433.2 (M+1); MS (ESI-) 431.3 (M-1). HPLC: 97.87%.

Stage-5. Preparation of 2-(2-((4-(3 -(aminomethyl)-5-fluorophenyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (69e).

Compound 69e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl )acetate (69d) (0.15 g, 0.35 mmol) in MeOH/THF (4 ml), using a solution of lithium hydroxide monohydrate (73 mg, 1.73 mmol) in water (0.8 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (69e) (0.02 g, 15% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.14 (s, 1H), 11.41 (s, 1H), 8.41 (s, 3H), 7.68 (s, 1H), 7. 57-7.43 (m, 3H), 7.37 (d, J=9.4 Hz, 1H), 7.26 (d, J=1.3 Hz, 1H), 7.22 (s, 1H ), 7.20 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.67 (d, J =2.6 Hz, 1H), 5.25 (s, 2H), 4.15 (s, 2H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.73; MS (ESI+) 405.1 (M+1). Purity after HPLC: 95.81%.

Scheme-70

40d 70a

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (70a).

Compound 70a was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy) phenyl)acetate (40d) (0.08 g, 0.141 mmol) in MeOH/THF (5 ml, 1:1), using a solution of sodium hydroxide (56 mg, 1.41 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (70a) (0.021 g, 39% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 11.37 (s, 1H), 8.34 (s, 4H), 7.82 (t, J=1.7 Hz , 1H), 7.70 (dt, J=7.7, 1.5 Hz, 1H), 7.56 (m, 1H), 7.51 (m, 1H), 7.48-7.43 ( m, 1H), 7.27-7.17 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.89 (td, J=7.4, 1.2 Hz , 1H), 6.66 (d, J=2.7 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 3.58 (s, 2H); MS (ESI+): 387.3 (M+1); MS (ESI-): 421.4 (M+Cl).

Scheme-71

NaBH ₄ 7!b 71с

(Su) ₃ R, K ₃ RO ₄ 71d 71e

Preparation of 2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetic acid (71e).

Stage-1. Preparation of (6-chloroimidazo[1,2-a]pyridin-8-yl)methanol (71b).

Compound 71b was prepared according to the procedure described in step-1 of Scheme-23 from 6chloroimidazo[1,2-a]pyridine-8-carboxylic acid (71a) (1.0 g, 5.09 mmol; CAS No. 155735- 02-7) using N-methylmorpholine (0.615 ml, 5.60 mmol) in THF (20 ml), isobutyl chloroformate (0.735 ml, 5.60

- 144 045626 mmol) and NaBH4 (0.289 g, 7.63 mmol) in water. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with ethyl acetate in hexane from

0% to 100%] (6-chloroimidazo[1,2-a]pyridin-8-yl)methanol (71b) (0.401 g, 43% yield) as a pale yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.76-8.73 (m, 1H), 7.99-7.91 (m, 1H), 7.60-7.54 (m, 1H ), 7.28-7.13 (m, 1H), 5.54 (s, 1H, D2O replaceable), 4.84 (s, 2H).

Stage-2. Preparation of ethyl 2-(2-((6-chloroimidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate (71c).

Compound 71c was prepared according to the procedure described in step-2 of Scheme-23 from (6chloroimidazo[1,2-a]pyridin-8-yl)methanol (71b) (0.4 g, 2.19 mmol) in THF (25 mL) using triphenylphosphine (0.747 g, 2.85 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.513 g, 2.85 mmol) and DIAD (0.554 mL, 2.85 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 100% EtOAc in hexane] ethyl 2-(2-((6chloroimidazo[1,2-a]pyridine-8- yl)methoxy)phenyl)acetate (71c) (0.66 g, 87% yield) as a yellow solid.

MS (ESI+): 367.2 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8yl)methoxy)phenyl)acetate (71d).

Compound 71d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((6-chloroimidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate (71c) ( 0.65 g, 1.89 mmol) in dioxane (6 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.530 g, 2.83 mmol), tripotassium phosphate (1.3 M, 1.885 ml, 5 .66 mmol), tricyclohexylphosphine (0.159 g, 0.566 mmol) and Pd ₂ (dba) ₃ (0.173 g, 0.189 mmol) under Ar and heating at 125°C for 45 min in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%], ethyl 2-(2-((6-(3-(aminomethyl)phenyl) imidazo[1,2a]pyridin-8-yl)methoxy)phenyl)acetate (71d) (0.151 g, 19% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.39-9.35 (m, 1H), 8.64 (s, 3H, D ₂ O replaceable), 8.42 (d, J=2.0 Hz, 1H), 8.40-8.26 (m, 2H), 8.05 (s, 1H), 7.90-7.76 (m, 1H), 7.69-7.58 (m, 2H), 7.38-7.18 (m, 3H), 7.05-6.93 (m, 1H), 5.58 (s, 2H), 4.21-4.03 (m, 2H) , 3.86 (k, J=7.1 Hz, 2H), 3.69 (s, 2H), 0.91 (t, J=7.1 Hz, 3H); MS (ESI+): 416.3 (M+1); MS (ESI-): 450.4 (M+Cl); purity after HPLC: 97.21%. Analysis calculation for: C25H25N ₃ O ₃ -3H ₂ O-2HCl: C, 55.35; N, 6.13; Cl, 13.07; N, 7.75; observed: C, 55.41; N, 5.96; Cl, 13.01; N, 7.79.

Stage-4. Preparation of 2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8yl)methoxy)phenyl)acetic acid (71e).

Compound 71e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy )phenyl)acetate (71d) (0.040 g, 0.096 mmol) in THF (4 ml) and methanol (8 ml), using 2 M aqueous sodium hydroxide (0.193 ml, 0.385 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((6- (3(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetic acid (71e) (0.026 g, 70% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 9.35 (s, 1H), 8.62 (s, 3H, _D2O exchangeable, 2H), 8.45-8.39 (m, 1H), 8.33 (d, J=12.0 Hz, 2H), 8.05 (s, 1H), 7.88-7.76 (m, 1H), 7.64 (d, J=4.7 Hz , 2H), 7.40-7.16 (m, 3H,), 7.04-6.94 (m, 1H), 5.58 (s, 2H), 4.20-4.02 (m, 2H), 3.72 (s, 2H); MS (ESI+): 388.3 (M+1); MS (ESI-): 386.4 (M-1); 422.3 (M+Cl); analysis calculation for: C2 ₃ H2 ₁ N ₃ 0 ₃ -2,OH ₂ 0-2,OHCI: C, 55.65; N, 5.48; N, 8.47; observed: C, 55.53; N, 5.71; N, 8.15.

Scheme-72

Preparation of (S)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofurαn-5-yl)methoxy)phenyl)acetic acid (72c).

Stage-1. Preparation of (S)-ethyl 2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (72b).

Compound 72b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (450 mg, 1.03 mmol) in dioxane (6 ml), using (S)-1-(3-bromophenyl)ethanamine (72a) (351 mg, 1.75 mmol;

- 145 045626

CAS No. 139305-96-7), tripotassium phosphate (3 M aq, 0.58 ml, 1.75 mmol), tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd ₂ (dba) ₃ (94 mg, 0. 10 mmol) under Ar atmosphere and heating at 120°C for 90 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), DMA80 in DCM 0% to 70%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (0. 1% HCl) 0% to 100%] (S)-ethyl 2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (72b) ( 312 mg, 70% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (s, 3H, D2O replaceable), 8.12 (d, J=2.2 Hz, 1H), 8.02 (d, J=2 .0 Hz, 1H), 7.96-7.85 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.67-7.58 (m, 3H), 7 .31-7.19 (m, 2H), 7.17-7.10 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td, J=7 ,4, 1.0 Hz, 1H), 5.25 (s, 2H), 4.50 (k, J=6.7 Hz, 1H), 3.93 (k, J=7.1 Hz, 2H ), 3.64 (s, 2H), 1.60 (d, J=6.7 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 430.3 (M+1); (ESI-): 464.3 (M+Cl).

Stage-2. Preparation of (S)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (72c).

Compound 72c was prepared according to the procedure described in step-6 of Scheme-1 from (S)-ethyl 2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy) phenyl)acetate (72b) (145 mg, 0.34 mmol) in MeOH/THF (5 ml), using a solution of lithium hydroxide monohydrate (57 mg, 1.35 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- ((7-(3-(1aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (72c) (114 mg, 84% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H, D2O replaceable), 8.66 (s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H ), 8.02 (s, 1H), 7.96-7.86 (m, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.68 (d, J=1, 6 Hz, 1H), 7.65-7.54 (m, 2H), 7.30-7.16 (m, 2H), 7.15-7.03 (m, 2H), 6.90 (t , J=7.3 Hz, 1H), 5.27 (s, 2H), 4.57-4.41 (m, 1H), 3.60 (s, 2H), 1.60 (d, J= 6.7 Hz, 3H); MS (ESI+): 402.3 (M+1); 424.3 (M+Na); (ESI-): 400.4 (M-1), 436.3 (M+Cl).

Scheme-73

Vg

Preparation of 2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (73c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (73b).

Compound 73b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (400 mg, 0.92 mmol) in dioxane (5 ml), using (3-bromo-5-fluorophenyl)methanamine (73a) (374 mg, 1. 83 mmol; CAS No. 1094555-68-6), tripotassium phosphate (3 M aq, 0.52 ml, 1.56 mmol), tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd ₂ (dba) ₃ (84 mg , 0.092 mmol) under Ar atmosphere and heating at 120°C for 90 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3(aminomethyl)-5-fluorophenyl)benzofuran -5-yl)methoxy)phenyl)acetate (73b) (223 mg, 56% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.62 (s, 3H, D2O replaceable), 8.14 (d, J=2.2 Hz, 1H), 7.91 (d, J=1, 7 Hz, 1H), 7.80-7.72 (m, 2H), 7.68 (d, J=1.6 Hz, 1H), 7.54-7.46 (m, 1H), 7, 30-7.19 (m, 2H), 7.14-7.06 (m, 2H), 6.956.87 (m, 1H), 5.25 (s, 2H), 4.15 (s, 2H) , 3.95 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 434.3 (M+1); (ESI-): 468.3 (M+Cl);

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (73c).

Compound 73c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 73b) (89 mg, 0.21 mmol) in MeOH/THF (5 ml), using a solution of lithium hydroxide monohydrate (35 mg, 0.82 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (73c) (64 mg, 77% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H, D2O replaceable), 8.59 (s, 3H, D2O replaceable), 8.13 (d, J=2.1 Hz, 1H ), 7.90 (d, J=1.8 Hz, 1H), 7.83-7.74 (m, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.54 -7.45 (m, 1H), 7.28-7.18 (m, 2H), 7.13-7.04 (m, 2H), 6.90 (t, J=7.3 Hz, 1H ), 5.27 (s, 2H), 4.16 (s, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz,

- 146 045626

DMSO-d6) δ -112.57; MS (ESI+): 406.3 (M+1); (ESI-): 404.4 (M-1), 440.3 (M+Cl).

Scheme-74

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (74c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (74b).

Compound 74b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (300 mg, 0.69 mmol) in dioxane (3 ml), using (4-chloropyridin-2-yl)methanamine (74a) (196 mg, 1. 38 mmol; CAS No. 180748-30-5), tripotassium phosphate (3 M aq, 0.39 ml, 1.169 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd ₂ (dba) ₃ (63 mg, 0.069 mmol) in an Ar atmosphere and heating at 120°C for 90 min in a microwave oven. This resulted in, after workup and purification by flash column chromatography, [silica gel (12 g), DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (0 .1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (74b) (98 mg, 34% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J=5.4 Hz, 1H), 8.74 (s, 3H, D2O exchangeable), 8.25 (s, 1H), 8, 19 (d, J=2.2 Hz, 1H), 8.08 (dd, J=5.5, 1.8 Hz, 1H), 7.89-7.81 (m, 2H), 7.31 -7.18 (m, 2H), 7.17-7.07 (m, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.27 (s, 2H), 4, 34 (k, J=5.8 Hz, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 417.3 (M+1); 439.3 (M+Na); (ESI-): 451.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (74c).

Compound 74c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (74b) (66 mg, 0.16 mmol) in MeOH/THF (5 mL), using a solution of lithium hydroxide monohydrate (27 mg, 0.63 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (74c) (36 mg, 59% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.89-8.70 (m, 4H, D2O replaceable), 8.33 (d, J=1.6 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 8.15 (dd, J=5.6, 1.7 Hz, 1H), 7.91 (s, 2H), 7.22 (d, J=7.4 Hz, 2H), 7.16-7.04 (m, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.29 (s, 2H), 4.38 (d, J =5.4 Hz, 2H), 3.61 (s, 2H); MS (ESI+): 489.3 (M+1); 411.3 (M+Na); (ESI-): 387.3 (M-1), 423.3 (M+Cl).

Scheme-75

C.I.

Preparation of 2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (75c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (75b).

Compound 75b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (400 mg, 0.917 mmol) in dioxane (6 ml), using (3-chloro-2,6-difluorophenyl)methanamine (75a) (244 mg, 1. 38 mmol; CAS No. 261762-46-3), tripotassium phosphate (3 M aq, 0.52 ml, 1.56 mmol), tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd ₂ (dba) ₃ (84 mg , 0.092 mmol) under Ar atmosphere and heating at 120°C for 90 min in a microwave oven. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexane 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (75b) (96.8 mg) as a white solid;

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1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (s, 3H, D2O replaceable), 8.08 (d, J=2.2 Hz, 1H), 7.84-7.73 (m, 2H),

7.46-7.37 (m, 2H), 7.32-7.19 (m, 2H), 7.17-7.06 (m, 2H), 6.97-6.88 (m, 1H ), 5.24 (s, 2H), 4.16 (s, 2H), 3.94 (k,

J=7.1 Hz, 2H), 3.63 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.50, -113.05; MS (ESI+): 452.3 (M+1); (ESI-): 486.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(3 -(aminomethyl)-2,4-difluorophenyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (75 sec).

Compound 75c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl) acetate (75b) (130 mg, 0.29 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (36 mg, 0.86 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (75c) (79 mg, 65% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 2H, D2O replaceable), 8.07 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.82-7.73 (m, 1H), 7.47 (s, 1H), 7.44-7.34 (m, 1H), 7.27-7.18 (m, 2H), 7.13-7.04 (m, 2H), 6.95-6.86 (m, 1H), 5.27 (s, 2H), 4.16 (s, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.64, -112.92; MS (ESI+): 424.3 (M+1); 446.3 (M+Na); (ESI-): 422.3 (M-1), 458.3 (M+Cl).

Scheme-76 o

55a 76a 76b

76d 76e 76f

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (76f).

Stage-1. Preparation of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5carboxylate (76a).

Compound 76a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (5 g, 12.38 mmol) in pyridine (10 ml) using tert-butyldimethyl( prop-2-ynyloxy)silane (2.11 g, 12.38 mmol; CAS No. 76782-82-6) and copper(I) oxide (0.89 g, 6.19 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 70% EtOAc in hexane] methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5 -carboxylate (76a) (3.2 g, 58% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (d, J=1.6 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 6.95 (s, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 0.76 (s, 9H), -0.00 (s, 6H); MS (ESI+): 469.1 (M+Na).

Stage-2. Preparation of (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (76b).

LiBH ₄ was added to a solution of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (76a) (12 g, 26.9 mmol) in THF (150 ml) at -78°C (26.9 ml, 53.8 mmol, 2 M solution in THF) and MeOH (2.2 ml, 53.8 mmol). The reaction mixture was stirred at RT for 24 hours, quenched with saturated aq. NH ₄ Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with 0% to 60% EtOAc in hexane] to give (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5- yl)methanol (76b) (10.4 g, 92% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.4 Hz, 1H), 6.92 (d, J=1.2 Hz, 1H), 5.25 (t, J=5.8, 1.2 Hz, 1H, D2O replaceable), 4.81 (s, 2H), 4.53 (d, J= 5.8 Hz, 2H), 0.89 (s, 9H), 0.12 (s, 6H); MS (ESI+): 441.2 (M+Na); (ESI-): 417.2 (M-1).

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Stage-3. Preparation of ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5yl)methoxy)phenyl)acetate (76c).

Compound 76c was prepared according to the procedure described in step-2 of Scheme-23 from (2(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (76b) (2.6 g, 6.22 mmol) in DCM (50 ml) using triphenylphosphine (1.79 g, 6.84 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.23 g, 6.84 mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 2.51 g, 6.84 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl )-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (76c) (2.86 g, 79% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (d, J=1.5 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.28-7 .18 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.96 (s, 1H), 6.95-6.87 (m, 1H), 5.13 ( s, 2H), 4.82 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.12 (s, 6H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (76d).

Compound 76d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl )acetate (76c) (1.2 g, 2.07 mmol) in dioxane (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.58 g, 3.10 mmol), K ₂ solution CO ₃ (0.86 g, 6.20 mmol) in water (4 ml), bis(triphenylphosphine) palladium(11) chloride (0.218 g, 0.310 mmol) by heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1, v/v) in hexane from 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7(3-(aminomethyl)phenyl)-2-(((tert -butyldimethylsilyl)oxy)methyl)benzofuran-5yl)methoxy)phenyl)acetate (76d) (1.01 g, 87% yield) as a white solid; MS (ESI+): 560.4 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (76e).

To a solution of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (76d) (175 mg, 0.31 mmol) in THF (20 ml) at 0°C was added TBAF (102 mg, 0.39 mmol). The reaction mixture was left to warm to RT for 1 hour and quenched with saturated aq. NH ₄ Cl solution. The reaction mixture was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification using reverse phase column chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] to obtain ethyl 2-(2-((7-(3(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 76e) (70 mg, 50% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 3H, D2O replaceable), 7.98 (s, 1H), 7.92 (dt, J=7.5, 1.7 Hz, 1H ), 7.66 (d, J=1.6 Hz, 1H), 7.64-7.51 (m, 3H), 7.31-7.18 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.96-6.87 (m, 1H), 6.85 (s, 1H), 5.55 (t, J=5.9 Hz, 1H, D2O replaceable) , 5.23 (s, 2H), 4.61 (d, J=5.9 Hz, 2H), 4.13 (s, 2H), 3.94 (k, J=7.1 Hz, 2H) , 3.63 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 446.3 (M+1); 468.3 (M+Na); (ESI-): 480.4 (M+Cl).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (76f).

Compound 76f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl )acetate (76e) (700 mg, 1.57 mmol) in MeOH/THF (30 ml), using a solution of lithium hydroxide monohydrate (165 mg, 3.93 mmol) in water (3.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (76f) (455 mg, 69% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.21 (s, 1H, D2O replaceable), 8.61 (s, 3H, D2O replaceable), 8.02 (s, 1H), 7.96-7 .89 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.60-7.54 (m, 2H), 7.28-7.18 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6, 84 (s, 1H), 5.66-5.49 (m, 1H, D2O replaceable), 5.25 (s, 2H), 4.62 (d, J=4.2 Hz, 2H), 4, 13 (s, 2H), 3.60 (s, 2H); MS (ESI+): 418.3 (M+1); (ESI-): 416.3 (M-1), 452.3 (M+Cl).

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Scheme-77 ci

Preparation of (S)-2-(2-((7-(2-(1-amino-2-hydroxyethyl)niridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (77 s).

Stage-1. Preparation of (S)-ethyl 2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (77b).

Compound 77b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (400 mg, 0.917 mmol) in dioxane (6 ml) using (S)-2-amino-2-(4-chloropyridin-2-yl)ethanol hydrochloride (77a) (288 mg, 1.38 mmol; CAS No. 1213411-99-4), tripotassium phosphate (3 M aq, 1.13 mL, 3.39 mmol), tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd ₂ (dba) ₃ (84 mg, 0.092 mmol) under Ar and heating at 120°C for 90 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-ethyl 2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5yl )methoxy)phenyl)acetate (77b) (215 mg, 53% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.3 Hz, 1H), 8.64 (d, J=5.4 Hz, 3H, D2O replaceable), 8, 19 (d, J=2.2 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.03 (dd, J=5.3, 1.6 Hz, 1H), 7.88-7.80 (m, 2H), 7.32-7.19 (m, 2H), 7.167.09 (m, 2H), 6.92 (t, J=7.4 Hz, 1H) , 5.27 (s, 2H), 4.61-4.49 (m, 1H), 3.99-3.82 (m, 4H), 3.65 (s, 2H), 0.99 (t , J=7.1 Hz, 3H); MS (ESI+): 447.3 (M+1); 469.3 (M+Na); (ESI-): 481.3 (M+Cl).

Stage-2. Preparation of (S)-2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (77c).

Compound 77c was prepared according to the procedure described in step-6 of Scheme-1 from (S)-ethyl 2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl) benzofuran-5-yl)methoxy)phenyl)acetate (77b) (88 mg, 0.20 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (25 mg, 0.59 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- ((7(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (77c) (31 mg, 38% yield), HCl salt, as white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.77 (d, J=5.3 Hz, 1H), 8.63-8.41 (m, 3H, D2O replaceable), 8.17 (d , J=2.1 Hz, 1H), 8.10 (s, 1H), 8.00 (dd, J=5.3, 1.6 Hz, 1H), 7.88 (s, 1H), 7 .83 (d, J=1.6 Hz, 1H), 7.28-7.19 (m, 2H), 7.14-7.05 (m, 2H), 6.91 (t, J=7 .3 Hz, 1H), 5.29 (s, 2H), 4.60-4.51 (m, 1H), 3.91-3.85 (m, 2H), 3.60 (s, 2H) ; MS (ESI+): 419.3 (M+1); 441.3 (M+Na); (ESI-): 417.3 (M-1), 453.3 (M+Cl).

Scheme-78

Preparation of (R)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (78c).

Stage-1. Preparation of (R)-ethyl 2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (78b).

Compound 78b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (450 mg, 1.03 mmol) in dioxane (6 ml), using (R)-1-(3-bromophenyl)ethanamine (78a) (351 mg, 1.75 mmol; CAS No. 176707-77-0), tripotassium phosphate (3 M aq, 0.58 ml, 1.75 mmol), tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd ₂ (dba) ₃ ( 94 mg, 0.10 mmol) under Ar and heating at 120°C for 90 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) 0% to 100%] (R)-ethyl 2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (78b ) (300 mg,

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68% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.60 (s, 3H, D ₂ O replaceable), 8.12 (d, J=2.2 Hz, 1H), 8.01 (s, 1H) , 7.947.87 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.67-7.55 (m, 3H), 7.31-7.20 (m, 2H ), 7.16-7.10 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H) , 5.25 (s, 2H), 4.57-4.43 (m, 1H), 3.93 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1, 59 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 430.3 (M+1); 452.3 (M+Na); (ESI-): 464.4 (M+Cl).

Stage-2. Preparation of (R)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (78c).

Compound 78c was prepared according to the procedure described in step-6 of Scheme-1 from (R)-ethyl 2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy) phenyl)acetate (78b) (156 mg, 0.36 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (46 mg, 1.09 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (R)-2-(2- ((7-(3-(1aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (78c) (108 mg, 74% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.24 (s, 1H, D ₂ O replaceable), 8.62 (s, 3H, D ₂ O replaceable), 8.11 (d, J=2, 2 Hz, 1H), 8.02 (s, 1H), 7.95-7.88 (m, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.64-7.56 (m, 2H), 7.28-7.18 (m, 2H), 7.10 (d, J=8.1 Hz, 1H ), 7.06 (d, J=2.2 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.50 (k, J =5.9 Hz, 1H), 3.60 (s, 2H), 1.60 (d, J=6.7 Hz, 3H); MS (ESI+): 402.3 (M+1); (ESI-): 400.4 (M-1), 436.3 (M+Cl).

Scheme-79

Preparation of 2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (79c).

Stage-1. Preparation of ethyl 2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (79b).

Compound 79b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (450 mg, 1.03 mmol) in dioxane (6 ml), using (6-bromopyridin-2-yl)methanamine (79a) (289 mg, 1. 55 mmol; CAS No. 188637-63-0), tripotassium phosphate (3 M aq, 0.58 ml, 1.75 mmol), tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd ₂ (dba) ₃ (94 mg , 0.10 mmol) in an Ar atmosphere and heating at 120°C for 45 min in a microwave oven. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexane 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (79b) ( 146 mg, 34% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (s, 3H, D2O replaceable), 8.50 (d, J=1.6 Hz, 1H), 8.39-8.31 (m, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.06 (t, J=7.8 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H) , 7.55 (d, J=7.7 Hz, 1H), 7.32-7.19 (m, 2H), 7.17-7.06 (m, 2H), 6.92 (t, J =7.4 Hz, 1H), 5.28 (s, 2H), 4.30 (k, J=5.9 Hz, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 417.3 (M+1); 439.3 (M+Na).

Stage-2. Preparation of 2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (79c).

Compound 79c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (79b) (66 mg, 0.16 mmol) in MeOH/THF (10 mL), using a solution of lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (6(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (79c) (36 mg, 59% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.56 (s, 3H, D2O replaceable), 8.48 (d, J=1.7 Hz, 1H), 8.35 (d, J=7, 9 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.05 (t, J=7.8 Hz, 1H), 7.86 (d, J=1.7 Hz , 1H), 7.53 (d, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 7.14-7.05 (m, 2H), 6.91 ( t, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.35-4.28 (m, 2H), 3.61 (s, 2H); MS (ESI+): 389.3 (M+1); (ESI-): 387.3.3 (M-1); 423.3 (M+Cl).

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Scheme-80

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (80e).

Stage-1. Preparation of tert-butyl ((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (80b).

To a solution of 4-chloro-3-fluoropicolinonitrile (80a) (0.26 g, 1.661 mmol; CAS No. 1155847-43-0) in methanol (15 ml) was added BOC anhydride (0.54 g, 2.49 mmol) , nickel(N) chloride hydrate (0.025 g, 0.17 mmol). Sodium borohydride (0.19 g, 4.98 mmol) was added to the reaction mixture over 2 hours. The reaction mixture was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.9 mL, 8.30 mmol). and stirring was continued at RT for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (60 ml) and EtOAc (60 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (40 ml). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel 12 g, eluted with EtOAc in 0 to 60% hexanes] to give tert-butyl ((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (80b) (0. 26 g, 60% yield) as a crystalline solid.

Stage-2. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)phenyl)acetate (80c).

Compound 80c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (243 mg, 0.56 mmol) in dioxane (6 ml) using tert-butyl ((4-chloro-3-fluoropyridin-2-yl)methyl) carbamate (80b) (145 mg, 0.56 mmol), tripotassium phosphate (3 M aq, 0.32 ml, 0.95 mmol), tricyclohexylphosphine (47 mg, 0.17 mmol) and Pd ₂ (dba) ₃ ( 51 mg, 0.056 mmol) under Ar and heating at 120°C for 90 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 70% EtOAc in hexane] ethyl 2-(2-((7(2-(((tert-butoxycarbonyl)amino )Methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (80c) (185 mg, 62% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (d, J=5.0 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.85 (d , J=1.5 Hz, 1H), 7.63 (t, J=5.3 Hz, 1H), 7.53 (s, 1H), 7.34-7.28 (m, 1H), 7 .28-7.19 (m, 2H), 7.15-7.08 (m, 2H), 6.91 (td, J=7.3, 1.3 Hz, 1H), 5.25 (s , 2H), 3.95-3.86 (m, 2H), 3.62 (s, 2H), 3.34 (s, 2H), 1.39 (s, 9H), 1.00-0, 92 (m, 3H); MS (ESI+): 535.4 (M+1); 557.4 (M+Na); (ESI-): 534.3 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (80d).

Compound 80d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl) benzofuran-5yl)methoxy)phenyl)acetate (80c) (182 mg, 0.34 mmol) in DCM (5 ml) using TFA (0.26 ml, 3.40 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy )phenyl)acetate (80d) (136 mg, 92% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=5.0 Hz, 4H, partially D2O replaceable), 8.12 (d, J=2.2 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.31-7.19 (m, 2H) , 7.16-7.09 (m, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.36 (s, 2H ), 3.94 (k, J=7.1, 1.3 Hz, 2H), 3.63 (s, 2H), 1.00 (t, J=7.1, 1.3 Hz,

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3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.52; MS (ESI+): 435.3 (M+1); (ESI-): 469.3 (M+Cl).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (80e).

Compound 80e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (80d) (61 mg, 0.14 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (18 mg, 0.42 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (80e) (32 mg, 56% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.73-8.58 (m, 4H, partly D2O replaceable), 8.11 (d, J=2.1 Hz, 1H), 7.92 (d , J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.61 (s, 1H), 7.28-7.19 (m, 2H), 7 ,14-7.06 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.29 (s, 2H), 4.39-4.33 (m, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.34; MS (ESI+): 407.2 (M+1); 429.2 (M+Na); (ESI-): 405.3 (M-1); 441.3 (M+Cl).

Scheme-81

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (81d).

Stage-1. Preparation of ethyl 2-(2-(4-bromo-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81b).

Compound 81b was prepared according to the procedure described in step-4 of Scheme-1 from 4-bromo3-methyl-1H-indole-6-carboxylic acid (81a) (0.3 g, 1.18 mmol; CAS No. 1360890- 98-7) in methanol (10 ml) using ethyl 2-(2-aminophenyl)acetate (5e) (233 mg, 1.30 mmol) and EDCI.HCl (272 mg, 1.42 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-( 4-bromo-3methyl-1H-indole-6-carboxamido)phenyl)acetate (81b) (0.11 g, 22% yield) as an off-white solid; MS (ESI+): 437.1 and 439.1 (M+Na), MS (ESI-): 449.2 and 451.1 (M+Cl).

Stage-2. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6carboxamido)phenyl)acetate (81c).

Compound 81c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-bromo-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81b) (60 mg, 0.14 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (41 mg, 0.22 mmol), tripotassium phosphate (1.3 M, 0.33 ml, 0.43 mmol ), tricyclohexylphosphine (12 mg, 0.04 mmol) and Pd ₂ (dba) ₃ (13 mg, 0.01 mmol) under Ar and heating at 125°C for 90 min in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-(4-(3(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81c) (0.03 g, 39% yield), HCl salt, as a white solid; MS (ESI+): 442.3 (M+1), MS (ESI-): 440.4 (M-1).

Stage-3. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6carboxamido)phenyl)acetic acid (81d).

Compound 81d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81c) (0.02 g, 0.05 mmol) in THF/MeOH (5 ml), using a solution of sodium hydroxide (0.02 g, 0.45 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3-(aminomethyl)phenyl)3-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (81d) (0.01 g, 43% yield), HCl salt, as a white solid;

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1H NMR (300 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.38 (s, 1H), 9.98 (s, 1H), 8.25 (br.s, 3H), 8.06 (s, 1H),

7.57 (m, 1H), 7.54-7.44 (m, 4H), 7.39-7.24 (m, 3H), 7.21 (m, 1H), 4.13 (d, J=5.5 Hz, 2H), 3.66 (s, 2H), 1.85 (s,

3H); MS (ESI+): 414.3 (M+1), 436.3 (M+Na); MS (ESI-): 412.4 (M-1), 448.3 (M+Cl). Cleanliness after

HPLC: 97.98%.

Scheme-82

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5yl)methoxy)phenyl)acetic acid (82f).

Stage-1. Preparation of methyl 2-cyclopentyl-7-iodobenzofuran-5-carboxylate (82b).

Compound 82b was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (6 g, 14.85 mmol) in pyridine (20 ml) using ethynylcyclopentane ( 82a) (1.4 g, 14.85 mmol; CAS No. 930-51-8) and copper(I) oxide (1.063 g, 7.43 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (120 g), eluted with 0% to 15% EtOAc in hexane] methyl 2-cyclopentyl-7-iodobenzofuran-5-carboxylate (82b) (5, 1 g, 93% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.16 (d, J=1.5 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 6.90 (d, J=1.0 Hz, 1H), 3.86 (s, 3H), 3.33-3.24 (m, 1H), 2.19-1.56 (m, 8H).

Stage-2. Preparation of (2-cyclopentyl-7-iodobenzofuran-5-yl)methanol (82c).

Compound 82c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 2-cyclopentyl-7-iodobenzofuran-5-carboxylate (82b) (4.48 g, 12.10 mmol) in THF (30 ml), using LiBH ₄ (18.15 ml, 36.3 mmol, 2 M solution in THF) and MeOH (1.47 ml, 36.3 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] (2-cyclopentyl-7-iodobenzofuran-5-yl)methanol (82c) ( 3.4 g, 82% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d6) δ 7.55 (d, J=1.5 Hz, 1H), 7.44 (d, J=1.4 Hz, 1H), 6.72 (d, J =1.0 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H, D2O replaceable), 4.52 (d, J=5.8 Hz, 2H), 3.31-3, 18 (m, 1H), 2.11-2.00 (m, 2H), 1.79-1.64 (m, 6H).

Stage-3. Preparation of ethyl 2-(2-((2-cyclopentyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (82d).

Compound 82d was prepared according to the procedure described in step-2 of Scheme-23 from (2cyclopentyl-7-iodobenzofuran-5-yl)methanol (82c) (3.4 g, 9.94 mmol) in DCM (15 ml) using triphenylphosphine (2.87 g, 10.93 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.970 g, 10.93 mmol) and di-(4-chlorobenzyl) azodicarboxylate di-(4-chlorobenzyl) azodicarboxylate (DCAD, 4.01 g, 10.93 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((2-cyclopentyl-7iodobenzofuran-5-yl) methoxy)phenyl)acetate (82d) (3.2 g, 64% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (d, J=1.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.28-7, 19 (m, 2H), 7.06 (d, J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H), 6.76 (d, J =1.0 Hz, 1H), 5.12 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 3.31-3.20 (m, 1H), 2.12-1.98 (m, 2H), 1.80-1.64 (m, 6H), 1.09 (t, J=7.1 Hz, 3H); MS (ESI+): 527.2 (M+Na); (ESI-): 503.3 (M-1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5yl)methoxy)phenyl)acetate (82e).

Compound 82e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-cyclopentyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (82d) (500 mg, 0 .99 mmol) in dioxane (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (279 mg, 1.49 mmol), 3 M solution of tripotassium phosphate (1.223 ml, 3.67 mmol) in water (1 ml), tricyclohexylphosphine (83 mg, 0.30 mmol) and Pd ₂ (dba) ₃ (91 mg, 0.1 mmol) when heated at 125°C for 60 min in a microwave oven.

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This resulted in, after workup and purification by flash column chromatography,

[silica gel (12 g), eluted with DMA80 in DCM from 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)acetate (82e) (223 mg, 47% yield), HCl salt, as off-white solid matter;

1H NMR (300 MHz, DMSO-06) δ 8.47 (s, 3H, D2O replaceable), 7.99-7.95 (m, 1H), 7.92 (dt, J=7.3, 1, 8 Hz, 1H), 7.63-7.51 (m, 4H), 7.29-7.18 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6, 91 (t, J=7.3 Hz, 1H), 6.71-6.66 (m, 1H), 5.22 (s, 2H), 4.12 (s, 2H), 3.95 (k , J=7.1 Hz, 2H), 3.62 (s, 2H), 2.13-1.98 (m, 2H), 1.85-1.59 (m, 7H), 1.01 ( t, J=7.1 Hz, 3H); MS (ESI+): 484.4 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5 yl)methoxy)phenyl)acetic acid (82f).

Compound 82f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)acetate ( 82e) (150 mg, 0.31 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (39 mg, 0.93 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)acetic acid (82f) (52 mg, 37% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.13 (s, 1H, D2O replaceable), 8.40 (s, 2H, D2O replaceable), 7.98-7.89 (m, 2H), 7 .64-7.60 (m, 1H), 7.60-7.50 (m, 3H), 7.22 (d, J=7.4 Hz, 2H), 7.08 (d, J=8 ,1 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 6.68 (s, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.59 (s, 2H), 2.50-2.49 (m, 1H), 2.13-1.98 (m, 2H), 1.83-1.61 (m, 6H); MS (ESI+): 456.3 (M+1); (ESI-): 454.3 (M-1); 490.3 (M+Cl).

Scheme-83

Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-III-pyrrolo[3,2-c]pyridine-6carboxamido)phenyl)acetic acid (83h).

Stage-1. Preparation of 4,6-dichloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83b).

Compound 83b was prepared according to the procedure described in step-1 of Scheme-40 from 4,6dichloro-III-pyrrolo[3,2-c]pyridine (83a) (4 g, 21.39 mmol; CAS No. 67139-79 -1) in DMF (30 ml) using NaH (60% in mineral oil, 2.14 g, 53.5 mmol) and tosyl-Cl (4.89 g, 25.7 mmol). This gave 4,6-dichloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83b) (6.8 g, 93% yield) as a tan solid upon treatment, which was used at the next stage without additional purification.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=3.8 Hz, 1H), 8.09-8.02 (d, J=8.4 Hz, 2H), 7, 98 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 6.96 (d, J=3.8 Hz, 1H), 2.36 (s, 3H).

Stage-2. Preparation of 4-chloro-6-(1-ethoxyvinyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83c).

Compound 83c was prepared according to the procedure described in step-1 of Scheme-1 from 4,6dichloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83b) (3 g, 8.79 mmol) in DMF (20 ml) using 1ethoxyvinyl-tri-n-butyltin (3.89 ml, 11.43 mmol) and Pd(Ph ₃ P) ₄ (1.02 g, 0.88 mmol) under argon and heating at 110°C for 2 hours. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 50% EtOAc in hexane] 4chloro-6-(1 -ethoxyvinyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83c) (1.6 g, 48% yield) as a white solid; MS (ESI+): 377.2 (M+1), 399.2 (M+Na).

Stage-3. Preparation of ethyl 4-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (83d).

Compound 83d was prepared according to the procedure described in step-2 of Scheme-1 from 4-chloro6-(1-ethoxyvinyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83c) (1 g, 2.65 mmol) in 1,4-dioxane (100 ml), using a solution of sodium periodate (1.14 g, 5.31 mmol) in water (10 ml) and KMnO ₄ (0.252 g, 1.592 mmol, and a second portion 0.25 g, 1.59 mmol after 12 hours). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 60% EtOAc in hexane] ethyl 4-chloro-1-tosyl-1H-pyrrolo[3,2-c ]pyridine-6-carboxylate (83d) (0.21 g, 21% yield) as a yellow solid; MS (ESI+): 379.1 (M+1), 401.2 (M+Na).

Stage-4. Preparation of 4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (83e).

Compound 83e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 4chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (83d) (0.2 g, 0 .53 mmol) in THF/MeOH (5 mL), using sodium hydroxide (0.13 g, 3.17 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] 4-chloro-1H-pyrrolo[3 ,2-c]pyridine-6-carboxylic acid (83e) (0.07 g, 63% yield), HCl salt, as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 11.93 (s, 1H), 7.66 (s, 2H), 6.97 (s, 1H). MS (ESI-): 195.1 (M-1), 231.1 (M+Cl).

Stage-5. Preparation of ethyl 2-(2-(4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate (83f).

Compound 83f was prepared according to the procedure described in step-4 of Scheme-1 from 4-chloro1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (83e) (0.06 g, 0.31 mmol) in MeOH (5 ml) using ethyl 2-(2-aminophenyl)acetate (5e) (0.06 g, 0.34 mmol) and EDCI.HCl (0.07 g, 0.37 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-(4-chloro-III-pyrrolo[3,2 -c]pyridine-6carboxamido)phenyl)acetate (83f) (0.02 g, 18% yield) as an off-white solid; MS (ESI+): 358.3 (M+1), 380.2 (M+Na); MS (ESI-): 356.2 (M-1), 392.3 (M+Cl).

Stage-6. Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6carboxamido)phenyl)acetate (83g).

Compound 83g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate (83f) (0.02 g, 0.06 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.02 g, 0.08 mmol), tripotassium phosphate (1.3 M, 0 .03 ml, 0.10 mmol), tricyclohexylphosphine (5 mg, 0.02 mmol) and Pd ₂ (dba) ₃ (5 mg, 5.59 μmol) in an Ar atmosphere and heating at 125 ° C for 90 min in microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with hexane in 0% to 70% ethyl acetate] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) 0% to 100%] ethyl 2-(2-(4(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate ( 83g) (0.02 g, 84% yield) as a white solid; MS (ESI+): 429.3 (M+1); MS (ESI-): 427.4 (M-1), 463.5 (M+Cl).

Stage-7. Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6carboxamido)phenyl)acetic acid (83h).

Compound 83h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido )phenyl)acetate (83g) (0.02 g, 0.05 mmol) in MeOH/THF (5 ml), using a solution of NaOH (0.15 ml, 0.37 mmol, 2.5 M) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-(4-( 3(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetic acid (83h) (0.01 g, 59% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.80 (s, 1H), 8.69 (s, 3H), 8.47 (s, 1H), 8.26 (t, J=5.0 Hz, 1H), 8.23 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.68 (t, J=2.7 Hz , 1H), 7.55 (m, 2H), 7.37 (m, 2H), 7.23 (s, 1H), 7.18 (t, J=7.3 Hz, 1H), 4.15 (d, J=5.8 Hz, 2H), 3.80 (s, 2H); MS (ESI+): 401.3 (M+1), 423.3 (M+Na); MS (ESI-): 399.4 (M-1), 435.3 (M+Cl). Purity after HPLC: 98.19%.

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Scheme-84

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (84f).

Stage-1. Preparation of methyl 7-bromo-2-methylbenzofuran-5-carboxylate (84b).

Compound 84b was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (150 g, 484 mmol; CAS No. 41727-47-3) in pyridine (500 ml ), using 1-(trimethylsilyl)-1-propyne (54.3 g, 484 mmol; CAS No. 6224-91-5) and copper(I) oxide (69.3 g, 484 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (330 g), eluted with 0% to 70% EtOAc in hexane] methyl 7-bromo-2methylbenzofuran-5-carboxylate (84b) (76 g, 58 % yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 6.85 (d, J=1.3 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H).

Stage-2. Preparation of (7-bromo-2-methylbenzofuran-5-yl)methanol (84c).

Compound 84c was prepared according to the procedure described in step-2 of scheme-76 from methyl 7-bromo-2-methylbenzofuran-5-carboxylate (84b) (67 g, 249 mmol) in THF (500 ml) using LiBH ₄ (2 M in THF, 311 ml, 622 mmol) and MeOH (25.2 ml, 622 mmol). This resulted in (7-bromo-2-methylbenzofuran-5-yl)methanol (84c) (60 g, 100% yield) as a clear oil which converted to a white solid upon standing at RT. This compound was used in the next step without further purification;

^1H NMR (300 MHz, DMSO-d6) δ 7.46 (d, J=1.4 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 6.68 (d, J=1.3 Hz, 1H), 5.31 (t, J=5.8 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 2.48 (s, 3H) .

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d).

Compound 84d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-methylbenzofuran-5-yl)methanol (84c) (2.2 g, 9.13 mmol) in DCM (15 ml) using triphenylphosphine (2.87 g, 10.93 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.81 g, 10.04 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 3, 69 g, 10.04 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-methylbenzofuran-5- yl)methoxy)phenyl)acetate (84d) (2.2 g, 60% yield) as a white solid;

1H NMR (300 MHz, chloroform-d) δ 7.50-7.43 (m, 2H), 7.31-7.19 (m, 2H), 7.03-6.91 (m, 2H), 6.49-6.41 (m, 1H), 5.12 (s, 2H), 4.15 (k, J=7.1 Hz, 2H), 3.69 (s, 2H), 2.53 (d, J=1.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (84e).

Compound 84e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d) (500 mg, 1 .24 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (302 mg, 1.61 mmol), bis(triphenylphosphine) palladium(I) chloride (131 mg, 0.186 mmol), solution of K ₂ CO ₃ (514 mg, 3.72 mmol) in water (3 ml) and heating in an argon atmosphere at 100 ° C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84e) ( 160 mg, 30% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.45 (s, 3H, D2O replaceable), 7.99-7.93 (m, 1H), 7.93-7.85 (m, 1H), 7.62-7.53 (m, 3H), 7.52-7.48 (m, 1H), 7.30-7.19 (m, 2H), 7.17-7.07 (m, 1H ), 6.97-6.86 (m, 1H), 6.67 (d, J=1.4 Hz, 1H), 5.21 (s, 2H), 4.13 (s, 2H), 3 .95 (k, J=7.1 Hz, 2H), 3.69 (s, 2H), 2.49 (s, 3H), 1.01 (t, J=7.1, 1.6 Hz, 3H);

- 157 045626

MS (ESI+): 430.3 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (84f).

Compound 84f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate ( 84e) (46 mg, 0.11 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (14 mg, 0.32 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (84f) (17 mg, 40% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.21 (s, 1H, D2O replaceable), 8.40 (s, 3H, D2O replaceable), 8.02-7.86 (m, 2H), 7 .65-7.50 (m, 4H), 7.29-7.17 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7 .4 Hz, 1H), 6.66 (s, 1H), 5.23 (s, 2H), 4.14 (s, 2H), 3.59 (s, 2H), 2.50 (s, 3H ); MS (ESI+): 402.3 (M+1); (ESI-): 400.4 (M-1), 436.3 (M+Cl).

Scheme-85

O

Preparation of 2-(2-((7-(3-carbamidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (85c) and 2-(2-((7-(3-carbamoylphenyl)benzofuran-5-yl )methoxy)phenyl)acetic acid (85d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-carbamidoylphenyl)benzofuran-5yl)methoxy)phenyl)acetate (85b).

Compound 85b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (400 mg, 0.92 mmol) in dioxane (6 ml), using 3-bromobenzimidamide hydrochloride (85a) (367 mg, 1.56 mmol; CAS No. 16796 -52-4), tripotassium phosphate (3 M aq, 0.92 ml, 2.75 mmol), tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd ₂ (dba) ₃ (84 mg, 0.092 mmol) in atmosphere Ar and heat at 120°C for 90 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 70% EtOAc in hexane] ethyl 2-(2-((7(3-carbamidoylphenyl)benzofuran-5-yl) methoxy)phenyl)acetate (85b) (120 mg, 31% yield) as a yellow solid; MS (ESI+): 429.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-carbamidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (85c) and 2-(2-((7-(3-carbamoylphenyl)benzofuran-5-yl )methoxy)phenyl)acetic acid (85d).

Compounds 85c and 85d were prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2-(2-((7-(3-carbamidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate (85b) ( 120 mg, 0.28 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (35 mg, 0.84 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3carbamidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (85c) (10 mg, 9% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H, D2O replaceable), 9.45 (s, 2H, D2O replaceable), 9.19 (s, 2H, D2O replaceable), 8, 35-8.21 (m, 2H), 8.12 (d, J=2.2 Hz, 1H), 7.92-7.83 (m, 1H), 7.83-7.74 (m, 3H), 7.29-7.17 (m, 2H), 7.16-7.03 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.29 (s , 2H), 3.60 (s, 2H); MS (ESI+): 401.3 (M+1); 423.3 (M+Na); (ESI-): 435.4 (M+Cl); and 2-(2-((7-(3-carbamoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (85d) (37 mg, 33% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H, D2O replaceable), 8.38 (t, J=1.8 Hz, 1H), 8.11 (d, J=2, 2 Hz, 1H), 8.09-8.02 (m, 2H, D2O replaceable, 1H), 7.97-7.88 (m, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.28-7, 17 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.96-6.84 (m, 1H ), 5.28 (s, 2H), 3.60 (s, 2H); MS (ESI+) 402.2 (M+1); 424.3 (M+Na); (ESI-) 400.3 (M-1), 436.3 (M+Cl).

- 158 045626

Scheme-86

86a 86b

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-nurrolo[2,3-b]pyridin-6yl)methoxy)phenyl)acetic acid (86b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3b]pyridin-6-yl)methoxy)phenyl)acetate (86a).

Compound 86a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy )phenyl)acetate (49d) (0.08 g, 0.15 mmol) in dioxane (4 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.045 g, 0.221 mmol), tripotassium phosphate ( 1.3 M solution, 0.08 ml, 0.25 mmol), tricyclohexylphosphine (0.01 g, 0.04 mmol) and Pd ₂ (dba) ₃ (0.01 g, 0.02 mmol) in an Ar atmosphere and heating at 125°C for 90 minutes in a microwave oven. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-III-nirrolo[2,3-b]pyridine -6yl)methoxy)phenyl)acetate (86a) (0.06 g, 71% yield) as a white solid, which was used as is in the next step.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-pyrrolo[2,3-b]nirudin-6yl)methoxy)phenyl)acetic acid (86b).

Compound 86b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3 -b]pyridin-6-yl)methoxy)phenyl)acetate (86a) (0.06 g, 0.10 mmol) in MeOH/THF (6 ml, 1:1) using sodium hydroxide solution (0.41 ml , 1.02 mmol, 2.5 M) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)-2-fluorophenyl)-1H-πpyrrolo[2,3-b]πyridin-6-yl)methoxy)phenyl)acetic acid (86b) (0.02 g, 44% yield), HCl salt , as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 8.55 (s, 3H), 7.67 (m, 2H), 7.56 (t, J=2, 9 Hz, 1H), 7.44 (m, 1H), 7.34 (s, 1H), 7.21 (m, 2H), 7.09 (m, 1H), 6.90 (t, J= 7.3 Hz, 1H), 6.45 (k, J=2.7 Hz, 1H), 5.29 (s, 2H), 4.16 (k, J=5.9 Hz, 2H), 3 .60 (s, 2H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -118.12; MS (ESI+): 406.3 (M+1); MS (ESI-): 404.3 (M-1), 440.3 (M+Cl). Purity after HPLC: 98.61%.

Scheme-87

Preparation of 2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (87c).

Stage-1. Preparation of ethyl 2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5yl)methoxy)phenyl)acetate (87b).

Compound 87b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (400 mg, 0.92 mmol) in dioxane (3 ml), using 7-bromoisoquinolin-1-amine (87a) (307 mg, 1.38 mmol; CAS No. 215453-53-5), tripotassium phosphate (3 M aq, 0.52 ml, 1.56 mmol), tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd ₂ (dba) ₃ (84 mg, 0.092 mmol ) in an Ar atmosphere and heating at 120°C for 60 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 70% EtOAc in hexane] ethyl 2-(2-((7(1-aminoisoquinolin-7-yl)benzofuran- 5-yl)methoxy)phenyl)acetate (87b) (154 mg, 37% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H, D2O replaceable), 9.21 (s, 2H, D2O replaceable), 9.05 (d, J=1.7 Hz, 1H ), 8.50 (dd, J=8.5, 1.6 Hz, 1H), 8.17-8.09 (m, 2H), 7.84-7.78 (m, 2H), 7, 75 (d, J=6.8 Hz, 1H), 7.31

- 159 045626 (d, J=6.8 Hz, 1H), 7.29-7.20 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.12-7 .10 (m, 1H), 6.92 (t, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 3.90 (k, J=7.1, 1 .5 Hz, 2H), 3.65 (s, 2H), 0.94 (t, J=7.1, 1.4 Hz, 3H); MS (ESI+): 453.3 (M+1); (ESI): 487.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (87c).

Compound 87c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate (87b) (114 mg, 0.25 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (1aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (87c) (32 mg, 30% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.28 (s, 1H, D2O replaceable), 12.20 (s, 1H, D2O replaceable), 9.10 (s, 2H, D2O replaceable), 9, 02 (s, 1H), 8.49 (dd, J=8.4, 1.6 Hz, 1H), 8.17-8.06 (m, 2H), 7.86-7.78 (m, 2H), 7.74 (d, J=6.9 Hz, 1H), 7.34-7.26 (m, 1H), 7.23 (d, J=7.6 Hz, 2H), 7, 17-7.06 (m, 2H), 6.91 (t, J=7.2 Hz, 1H), 5.31 (s, 2H), 3.61 (s, 2H); MS (ESI+): 425.3 (M+1); (ESI-): 423.3 (M-1), 459.3 (M+Cl).

Scheme-88 he

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5yl)methoxy)phenyl)acetic acid (88b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5yl)methoxy)phenyl)acetate (88a).

Compound 88a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e) (500 mg, 1 .05 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (345 mg, 1.68 mmol), bis(triphenylphosphine) palladium(P) chloride (111 mg, 0 .16 mmol) and a solution of K ₂ CO ₃ (435 mg, 3.15 mmol) in water (3 ml) in an Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (contains 0.1%) HCl) from 0% to 100%] ethyl 2-(2-((7-(3(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl) acetate (88a) (299 mg, 60% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.57 (s, 3H, D2O replaceable), 7.73-7.57 (m, 3H), 7.42 (t, J=7.7 Hz , 1H), 7.31 (s, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.91 (t, J= 7.4 Hz, 1H), 6.65 (s, 1H), 5.20 (s, 2H), 4.17 (s, 2H), 3.94 (k, J=7.1 Hz, 2H) , 3.61 (s, 2H), 2.15-2.03 (m, 1H), 1.07-0.93 (m, 5H), 0.89-0.81 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.85; MS (ESI+): 474.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5yl)methoxy)phenyl)acetic acid (88b).

Compound 88b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl )acetate (88a) (185 mg, 0.39 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (49 mg, 1.17 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetic acid (88b) (135 mg, 78% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.66 (s, 2H, D2O replaceable), 7.73-7.59 (m, 3H), 7.42 (t, J=7.6 Hz, 1H), 7.34 (d, J=1.4 Hz, 1H), 7.26-7.17 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 6, 89 (t, J=7.4, 1.1 Hz, 1H), 6.63 (s, 1H), 5.21 (s, 2H), 4.17 (s, 2H), 3.57 (s , 2H), 2.14-2.06 (m, 1H), 1.06-0.93 (m, 2H), 0.89-0.80 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.64; MS (ESI+): 446.3 (M+1); 468.3 (M+Na); (ESI-): 444.4 (M-1), 480.3 (M+Cl).

- 160 045626

Scheme-89

Preparation of 2-(2-((7-(3-(aminomethyl)-5-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (89c).

Compound 89c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (327 mg, 0.75 mmol) in dioxane (15 ml), using (3-bromo-5-methylphenyl)methanamine (89a) (150 mg, 0. 75 mmol; CAS No. 1177558-42-7), bis(triphenylphosphine) palladium(P) chloride (79 mg, 0.112 mmol), solution of K2CO3 (311 mg, 2.25 mmol) in water (3 ml) under Ar atmosphere and heating at 100°C for 13 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (contains 0.1%) HCl) from 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-5-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 89b) (83 mg, 26% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 3H, D2O replaceable), 8.10 (d, J=2.3 Hz, 1H), 7.80 (d, J=1, 9 Hz, 1H), 7.72 (d, J=1.7 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.39 (s, 1H), 7.29 -7.18 (m, 2H), 7.15-7.08 (m, 1H), 7.087.03 (m, 1H), 6.96-6.85 (m, 1H), 5.24 (s , 2H), 4.08 (s, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.43 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 430.3 (M+1); and 2-(2-((7-(3-(aminomethyl)-5-methylphenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (89c) (18 mg, 6% yield), HCl salt, as a white solid substances: ^1H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H, D2O replaceable), 8.25 (s, 3H, D2O replaceable), 8.11-8.07 (m, 1H) , 7.82-7.77 (m, 1H), 7.77-7.71 (m, 2H), 7.65-7.59 (m, 1H), 7.36 (s, 1H), 7 .22 (d, J=7.4 Hz, 2H), 7.14-7.07 (m, 1H), 7.07-7.02 (m, 1H), 6.95-6.85 (m , 1H), 5.26 (s, 2H), 4.09 (s, 2H), 3.60 (s, 2H), 2.43 (s, 3H); MS (ESI+): 402.3 (M+1); 425.3 (M+Na); (ESI-): 400.3 (M-1); 436.3 (M+Cl).

Receipt

Scheme-90

2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5 -yl)methoxy)-5 fluorophenyl)acetic acid (90d).

Stage-1. Preparation of ethyl 2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (90a) .

Compound 90a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a) (0.2 g, 0.49 mmol), using bis(pinacolato)diboron (0.19 g, 0.74 mmol), potassium acetate (0.10 g, 0.98 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ ( 0.06 g, 0.07 mmol) in anhydrous dioxane (5 ml) under Ar and heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(5-fluoro-2-(( 7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (90a) (0.21 g, 94% yield) as white oils;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.64 (d , J=1.8 Hz, 1H), 7.16-7.06 (m, 3H), 6.97 (d, J=2.2 Hz, 1H), 5.15 (s, 2H), 4 .01 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.34 (s, 12H), 1.081.04 (m, 3H); MS (ESI-): 453.2 (M-1).

Stage-2. Preparation of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate ( 90b).

- 161 045626

Compound 90b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (90a) (0.21 g, 0.46 mmol) in dioxane (4 ml) using (S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)-2methylpropan-2-sulfinamide (220c) (0.18 g, 0.69 mmol), bis(triphenylphosphine) palladium(P) chloride (0.05 g, 0.07 mmol) and a solution of K ₂ CO ₃ (0.16 g, 1.16 mmol) in water (0.5 ml) in an Ar atmosphere and heating at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% MeOH in DCM] (S)-ethyl 2(2-((7-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5 -yl)methoxy)-5 fluorophenyl)acetate (90b) (0.2 g, 78% yield) as a white solid; MS (ESI+): 557.2 (M+1); MS (ESI-): 555.2 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetate (90c).

Compound 90c was prepared according to the procedure described in step-5 of Scheme-220 from (S)ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridine-4 -yl)benzofuran-5-yl)methoxy)5-fluorophenyl)acetate (90b) (0.2 g, 0.36 mmol) in methanol (5 ml) using hydrochloric acid (4 M in 1,4-dioxane, 0.27 ml, 1.08 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (90c) (0. 15 g, 92% yield) as a white solid; MS (ESI+): 453.2 (M+1); MS (ESI-): 451.0 (M-1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (90d).

Compound 90d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -5-fluorophenyl)acetate (90c) (0.19 g, 0.42 mmol) in MeOH/THF (4 ml each), using lithium hydroxide monohydrate (0.14 g, 3.36 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (90d) (0.06 g, 31% yield), HCl salt, as a white solid substances;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=5.0 Hz, 1H), 8.57 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.58 (d, J=1.4 Hz, 1H) , 7.17-7.01 (m, 4H), 5.26 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.36, 124.02; MS (ESI+): 425.1 (M+1); MS (ESI-): 423.0 (M-1).

Scheme-91

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetic acid (91h).

Stage-1. Preparation of methyl 3-acetamido-5-bromo-4-hydroxybenzoate (91b) To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (91a) (0.3 g, 1.22 mmol; CAS No. 260249-10-3) Acetic anhydride (0.14 mL, 1.46 mmol) was added to THF (5 mL). The resulting mixture was stirred at RT for 3 hours, diluted with water and extracted with EtOAc. The organic layer was separated, washed with water, brine, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 70% hexane in ethyl acetate] to give methyl 3-acetamido-5-bromo-4-hydroxybenzoate (91b) (0.12 g, 34% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.32-7.19

- 162 045626 (m, 1H), 3.81 (s, 3H), 2.13 (s, 3H); MS (ESI-): 286.1 and 288.2 (M-1).

Stage-2. Preparation of methyl 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate (91c) Methyl 3-acetamido-5bromo-4-hydroxybenzoate (91b) was added to a 50 ml flask equipped with a condenser and a drying tube containing anhydrous CaCl ₂ (0.28 g, 0.97 mmol), phosphoryl trichloride (1.81 ml, 19.44 mmol) and CHC13 (5 ml). The reaction mixture was heated at 90°C for 40 h, cooled to room temperature, diluted with EtOAc (10 ml) and ice water (10 ml). The reaction mixture was basified to pH 8 with aqueous NaOH and extracted with EtOAc (3x100 ml). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in 0% to 50% hexane] to give methyl 7bromo-2-methylbenzo[d]oxazole-5-carboxylate (91c) (0.1 g, 38% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 8.09 (s, 1H), 3.89 (s, 3H), 2.69 (s, 3H); MS (ESI+): 270.0 and 272.0 (M+1).

Stage-3. Preparation of 7-bromo-2-methylbenzo[d]oxazole-5-carboxylic acid (91d).

Compound 91d was prepared according to the procedure described in step-4 of Scheme-4 from methyl 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate (91c) (0.1 g, 0.37 mmol) in MeOH /THF (5 ml) using a solution of sodium hydroxide (1.48 ml, 3.70 mmol, 2.5 M) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 7-bromo-2-methylbenzo[d ]oxazole-5-carboxylic acid (91d) (0.08 g, 79% yield) as a white solid; MS (ESI-): 254.1 (M-1).

Stage-4. Preparation of (7-bromo-2-methylbenzo[d]oxazol-5-yl)methanol (91e).

Compound 91e was prepared according to the procedure described in step-1 of Scheme-23 from 7bromo-2-methylbenzo[d]oxazole-5-carboxylic acid (91d) (0.12 g, 0.46 mmol) using Nmethylmorpholine ( 0.06 ml, 0.55 mmol) in THF (10 ml), isobutyl chloroformate (0.07 ml, 0.55 mmol) and NaBH ₄ (0.05 g, 1.37 mmol) in water (0.8 ml ). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 100% EtOAc in hexane] (7-bromo-2-methylbenzo[d]oxazol-5-yl)methanol (91e) (0.08 g, 68% yield) as a clear oil; MS (ESI+): 242.0 and 244.1 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-bromo-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91f).

Compound 91f was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-methylbenzo[d]oxazol-5-yl)methanol (91e) (0.12 g, 0.50 mmol) in DCM (10 ml) using triphenylphosphine (0.17 g, 0.64 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.12 g, 0.64 mmol) and di-(4chlorobenzyl) azodicarboxylate (DIAD , 0.24 g, 0.64 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-methylbenzo[d] oxazol-5-yl)methoxy)phenyl)acetate (91f) (0.07 g, 32% yield) as a colorless oil; MS (ESI+): 426.1 and 428.1 (M+Na).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5yl)methoxy)phenyl)acetate (91g).

Compound 91g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91f) ( 0.06 g, 0.15 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.04 g, 0.22 mmol), tripotassium phosphate (3 M aqueous solution, 0. 19 ml, 0.25 mmol), tricyclohexylphosphine (0.01 g, 0.05 mmol) and Pd ₂ (dba) ₃ (0.01 g, 0.02 mmol) under Ar and heating at 125°C for 90 minutes in the microwave. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3(aminomethyl)phenyl)- 2-Methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91g) (0.02 g, 31% yield) as a white solid; MS (ESI+): 431.2 (M+1).

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5yl)methoxy)phenyl)acetic acid (91h).

Compound 91h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy) phenyl)acetate (91g) (0.02 g, 0.05 mmol) in MeOH/THF (4 ml), using a solution of sodium hydroxide (0.15 ml, 0.37 mmol, 2.5 M) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetic acid (91h) (0.01 g, 32% yield) as a white solid;

1H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 3H), 8.00 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.75 (s , 1H), 7.72 (s, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 7.23 (m, 2H), 7.08 (d, J=8, 0 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.28 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.60 (s, 2H), 2.66 (s, 3H); MS (ESI+): 403.3 (M+1), 425.3 (M+Na); MC (ESI-): 401.3 (M1). Purity after HPLC: 87.37%.

- 163 045626

Scheme-92 he

84d _92a

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (92b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (92a).

Compound 92a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d) (500 mg, 1 .24 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (331 mg, 1.61 mmol), bis(triphenylphosphine) palladium(P) chloride (131 mg, 0.186 mmol), solution of K ₂ CO ₃ (514 mg, 3.72 mmol) in water (3 ml) and heating in an argon atmosphere at 100 ° C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (92a ) (336 mg, 61% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.74-8.30 (m, 3H, D2O replaceable), 7.76-7.57 (m, 3H), 7.42 (t, J=7, 7 Hz, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.67 (s, 1H), 5.20 (s, 2H), 4.16 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 2.43 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.71; MS (ESI+): 448.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (92b).

Compound 92b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl )acetate (92a) (256 mg, 0.57 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (72.0 mg, 1.72 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (92b) (123 mg, 51% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H, D2O replaceable), 8.58 (s, 3H, D2O replaceable), 7.76-7.58 (m, 3H), 7, 41 (t, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.27-7.18 (m, 2H), 7.09 (d, J=8.0 Hz, 1H ), 6.90 (t, J=7.4 Hz, 1H), 6.66 (t, J=1.1 Hz, 1H), 5.22 (s, 2H), 4.17 (s, 2H ), 3.57 (s, 2H), 2.43 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 118.56; MS (ESI+): 420.3 (M+1); (ESI-): 418.3 (M-1), 456.3 (M+Cl); purity after HPLC: 100%.

Scheme-93

Preparation of 2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetic acid

- 164 045626 acid (93h).

Stage-1. Preparation of ethyl 2-(1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrrol-2-yl)-2-oxoacetate (93b).

To a solution of ethyl 2-oxo-2-(1H-pyrrol-2-yl)acetate (93a) (1 g, 5.98 mmol; CAS No. 27472-43-1), 3-(2bromoacetyl)benzonitrile (1.608 g, 7.18 mmol) in acetonitrile (20 ml), potassium carbonate (1.240 g, 8.97 mmol) was added and the suspension was stirred at room temperature for 6 hours. The reaction mixture was diluted with EtOAc (30 ml), filtered through a pad of celite, the layer was washed EtOAc (2x15 ml) and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with EtOAc in 0 to 60% hexanes] to give ethyl 2-(1-(2-(3cyanophenyl)-2-oxoethyl)-1H-pyrrol-2-yl )-2-oxoacetate (93b) (900 mg, 49% yield) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.19 (t, J=1.8 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.98-7 .91 (m, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.43 (t, J=2.0 Hz, 1H), 7.25 (dd, J=4, 3, 1.6 Hz, 1H), 6.37 (dd, J=4.3, 2.4 Hz, 1H), 5.93 (s, 2H), 4.30 (k, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 3-(3-cyanophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate (93c).

To a solution of ethyl 2-(1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrrol-2-yl)-2-oxoacetate (93b) (0.7 g, 2.26 mmol) in ethanol (30 ml) ammonium acetate (1.74 g, 22.56 mmol) was added and stirred at 90°C for 16 hours. The reaction mixture was partitioned between water (100 ml) and EtOAc (80 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (60 ml) and the combined organics were washed with brine, dried, filtered, concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with EtOAc in hexane 0 to 60%] to give ethyl 3-(3-cyanophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate (93c) ( 250 mg, 38% yield) as a light orange solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.44 (d, J=1.7 Hz, 1H), 8.38 (dt, J=8.1, 1 .5 Hz, 1H), 7.95 (dd, J=2.6, 1.3 Hz, 1H), 7.87 (dt, J=7.7, 1.4 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.29 (d, J=4.2 Hz, 1H), 7.14 (dd, J=4.1, 2.6 Hz, 1H), 4 .48 (k, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); MS (ESI+): 292.2 (M+1), 314.2 (M+Na).

Stage-3. Preparation of ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2a]pyrazine-1-carboxylate (93d).

Compound 93d was prepared according to the procedure described in step-1 of scheme-80 from ethyl 3(3-cyanophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate (93c) (210 mg, 0.721 mmol) in methanol (20 ml), THF (5 ml), using BOC anhydride (0.251 ml, 1.08 mmol), Nickel(N) chloride (9 mg, 0.072 mmol), sodium borohydride (82 mg, 2.16 mmol) and N1-(2-aminoethyl)ethane-1,2-diamine (372 mg, 3.60 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in 0 to 65% hexanes] ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[ 1,2-a]pyrazine-1-carboxylate (93d) (80 mg, 28% yield) as a white solid.

Stage-4. Preparation of 3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1carboxylic acid (93e).

Compound 93e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 3(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate ( 93d) (75 mg, 0.19 mmol) in THF (5 ml) using aqueous NaOH (0.759 ml, 0.759 mmol, 1 M). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DCM-80 in DCM] 3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1. 2-a]pyrazine1-carboxylic acid (93e) (40 mg, 57% yield) as a colorless solid;

1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.04-7.84 (m, 3H), 7.44 (t, J=7.7 Hz, 2H), 7 .25 (t, J=5.8 Hz, 2H), 7.06 (dd, J=4.1, 2.6 Hz, 1H), 4.22 (d, J=6.1 Hz, 2H) , 1.40 (d, J=4.9 Hz, 9H); MS (ESI+): 390.3 (M+Na), (ESI-): 366.3 (M-1).

Stage-5. Preparation of ethyl 2-(2-(3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2a]pyrazine-1-carboxamido)phenyl)acetate (93f).

Compound 93f was prepared according to the procedure described in step-4 of Scheme-1 from 3-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylic acid ( 93e) (34 mg, 0.093 mmol) in DMF (2 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (25 mg, 0.14 mmol), DIPEA (0.05 ml, 0.278 mmol) and HATU (53 mg, 0.14 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-60% EtOAc in hexane] ethyl 2-(2-(3-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)pyrrolo[1,2-a]pyrazine-1carboxamido)phenyl)acetate (93f) (34 mg, 70% yield) as a semi-solid;

1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.18 (s, 1H), 8.06 (d, J=9.8 Hz, 2H), 7.97 (dd , J=2.6, 1.3 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.51 (d, J=4.1 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.39 (dd, J=5.5, 1.8 Hz, 3H), 7.31-7.16 (m, 2H), 7.11 ( dd, J=4.2, 2.5 Hz, 1H), 4.25 (d, J=6.1 Hz, 2H), 3.98 (k, J=7.2 Hz, 2H), 3, 87 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 551.3 (M+Na).

Stage-6. Preparation of ethyl 2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-165 045626 carboxamido)phenyl)acetate (93 g).

Compound 93g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a] pyrazine-1carboxamido)phenyl)acetate (93f (30 mg, 0.057 mmol) in DCM (2 ml) using TFA (0.044 ml, 0.568 mmol). This resulted after work-up and purification by flash column chromatography [silica gel ( 12 g), eluted with DMA80 in DCM 0% to 50%]ethyl 2-(2-(3-(3(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate (93g ) (25 mg, 103% yield), TFA salt, as brown syrup. The resulting material was used in the following reaction without further purification; MS (ESI+): 429.3 (M+1), 451.3 (M+Na ).

Stage-7. Preparation of 2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1carboxamido)phenyl)acetic acid (93h).

Compound 93h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl) acetate (93g) (25 mg, 0.057 mmol) in THF (5 ml) using aqueous NaOH (0.114 ml, 0.228 mmol, 2 M). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(3-( 3-(aminomethyl)phenyl)pyrrolo[1,2a]pyrazine-1-carboxamido)phenyl)acetic acid (93h) (14 mg, 61% yield), hydrochloride salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.67 (s, 1H, _D2O replaceable), 9.26 (s, 1H), 8.51-8.24 (m, 4H, 3H D2O replaceable), 8.16 (d, J=7.5 Hz, 1H), 8.01-7.97 (m, 1H), 7.94 (d, J=8.2 Hz, 1H), 7, 63-7.47 (m, 4H), 7.43-7.34 (m, 2H), 7.27-7.18 (m, 1H), 7.16-7.10 (m, 1H), 4.15 (k, J=5.9 Hz, 2H), 3.79 (s, 2H); MS (ESI+): 401.3 (M+1), 423.3 (M+Na), (ESI-): 399.3 (M-1); purity after HPLC: 97.62%.

Scheme-94

^76с 94а

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (94c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (94a).

Compound 94a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl )acetate (76c) (7.2 g, 12.40 mmol) in dioxane (50 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (3.82 g, 18.60 mmol), solution of K ₂ CO ₃ (5.14 g, 37.2 mmol) in water (10 ml), bis(triphenylphosphine) palladium(P) chloride (1.31 g, 1.86 mmol) when heated at 100 ° C in for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with DMA80 in 0% to 50% DCM] ethyl 2-(2-((7(3-(aminomethyl)-2-fluorophenyl) -2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5yl)methoxy)phenyl)acetate (94a) (5.4 g, 75% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (d, J=1.7 Hz, 1H), 7.58-7.49 (m, 3H), 7.41-7.35 (m , 1H), 7.33 (s, 1H), 7.27-7.13 (m, 3H), 7.06 (d, J=8.1 Hz, 1H), 6.89-6.79 ( m, 2H), 5.15 (s, 2H), 4.71 (s, 2H), 3.84 (k, J=7.1 Hz, 2H), 3.77 (s, 2H), 3, 56 (s, 2H), 0.92 (t, J=7.1, 2.3 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (94b).

To a solution of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (94a) ( 700 mg, 1.21 mmol) to THF (10 ml) was added HCl (2N aq) (1.82 ml, 3.63 mmol). The resulting mixture was stirred at RT for 12 hours and concentrated under vacuum until dry and a solid residue was obtained. After TLC indicated completion of the reaction, the organic solvent was removed and the residue was purified by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (0.1% HCl) 01 to 00%] to give ethyl 2- (2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-166 045626 yl)methoxy)phenyl)acetate (94b) (173 mg, 31% yield), salt HCl, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.62 (s, 3H, D2O replaceable), 7.75-7.69 (m, 2H), 7.69-7.61 (m, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.40-7.35 (m, 1H), 7.30-7.18 (m, 2H), 7.15-7.07 ( m, 1H), 6.91 (t, J=7.4, 1.2 Hz, 1H), 6.85 (s, 1H), 5.50 (t, J=5.8 Hz, 1H, D2O replaceable), 5.22 (s, 2H), 4.55 (d, J=4.8 Hz, 2H), 4.16 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.74; MS (ESI+): 464.3 (M+1); (ESI-): 498.3 (M+Cl).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (94c).

Compound 94c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl) methoxy)phenyl)acetate (94b) (420 mg, 0.73 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (92 mg, 2.18 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (94c) (249 mg, 79% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H, D2O replaceable), 8.63 (s, 3H, D2O replaceable), 7.75 (d, J=1.6 Hz, 1H ), 7.73-7.62 (m, 2H), 7.46-7.37 (m, 2H), 7.28-7.17 (m, 2H), 7.09 (d, J=8 ,1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.84 (s, 1H), 5.24 (s, 2H), 4.55 (s, 2H), 4.16 (d, J=5.7 Hz, 2H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.57; MS (ESI+): 436.3 (M+1); (ESI-): 470.3 (M+Cl).

Scheme-95

Preparation of 2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (95c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (95b).

Compound 95b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (450 mg, 1.03 mmol) in dioxane (6 ml), using 3-bromophenethylamine (95a) (351 mg, 1.75 mmol; CAS No. 58971- 11-2), tripotassium phosphate (3 M, 0.584 ml, 1.75 mmol), tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd ₂ (dba) ₃ (94 mg, 0.10 mmol) under Ar and heating at 120°C for 90 minutes in the microwave. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (95b) (252 mg, 57% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.27-7.92 (m, 4H, partly D2O replaceable), 7.81-7.73 (m, 2H), 7.72 (d, J= 1.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.34 (d, J=7, 6 Hz, 1H), 7.30-7.19 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.08-7.02 (m, 1H), 6, 91 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 3.183, 05 (m, 2H), 3.05-2.96 (m, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 430.3 (M+1); (ESI-): 464.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (95c).

Compound 95c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (95b ) (160 mg, 0.37 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (47 mg, 1.12 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(2aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (95c) (82 mg, 55% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H, D2O replaceable), 8.16-7.96 (m, 4H, D2O replaceable), 7.83-7.72 (m, 3H ), 7.64 (d, J=1.7 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.37-7.29 (m, 1H), 7.28 -7.20 (m, 2H), 7.137.06 (m, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.90 (t, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 3.60 (s, 2H), 3.18-3.06 (m, 2H), 3.06-2.94 (m, 2H); MS (ESI+): 402.3 (M+1); (ESI-): 400.3 (M-1), 436.3 (M+Cl).

- 167 045626

Scheme-96

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (96e).

Stage-1. Preparation of methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a).

Compound 96a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (7 g, 17.33 mmol) in pyridine (15 ml) using methyl propargyl ether (1.22 g, 17.33 mmol) and copper(I) oxide (1.24 g, 8.66 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 70% EtOAc in hexane] methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a) (3.45 g, 58% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (d, J=1.5 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 7.18 (d , J=0.8 Hz, 1H), 4.60 (s, 2H), 3.88 (s, 3H), 3.36 (s, 3H).

Stage-2. Preparation of (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b).

Compound 96b was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a) (3.45 g, 9.97 mmol) in THF ( 60 ml) using LiBH ₄ (14.95 ml, 29.9 mmol, 2 M solution in THF) and MeOH (0.96 g, 29.9 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol ( 96b) (2.94 g, 93% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.66-7.62 (m, 1H), 7.56-7.51 (m, 1H), 7.02 (t, J=0.9 Hz, 1H), 5.26 (t, J=5.8, 1.1 Hz, 1H), 4.58-4.50 (m, 4H), 3.33 (s, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (96c).

Compound 96c was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (2.94 g, 9.24 mmol) in DCM ( 180 ml), using triphenylphosphine (2.67 g, 10.17 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.83 g, 10.17 mmol) and di(4-chlorobenzyl) azodicarboxylate ( DCAD, 3.73 g, 10.17 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran -5yl)methoxy)phenyl)acetate (96c) (3.92 g, 88% yield) as a clear oil that became a white solid upon standing at RT.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (d, J=1.5 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.29-7 .18 (m, 2H), 7.107.04 (m, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.14 (s, 2H), 4.56 (s, 2H) , 4.03 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 3.34 (s, 3H), 1.09 (t, J=7.1 Hz, 3H) .

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (96d).

Compound 96d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (96c) (500 mg, 1.04 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (254 mg, 1.35 mmol), K ₂ CO ₃ solution (432 mg, 3.12 mmol) in water (3 ml), bis(triphenylphosphine) palladium(P) chloride (110 mg, 0.16 mmol) by heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 96d) (262 mg, 55% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.61 (s, 3H, D2O replaceable), 7.98 (s, 1H), 7.95-7.85 (m, 1H), 7.70 (d,

- 168 045626

J=1.6 Hz, 1H), 7.66-7.56 (m, 3H), 7.30-7.18 (m, 2H), 7.15-7.09 (m, 1H), 7 .00 (s, 1H), 6.92 (t, J=7.4, 1.1 Hz, 1H),

5.24 (s, 2H), 4.59 (s, 2H), 4.12 (s, 2H), 3.95 (k, J=7.2 Hz, 2H), 3.57 (s, 2H ), 3.33 (s, 3H), 1.00 (t, J=7.1, 1.4 Hz,

3H); MS (ESI+): 460.3 (M+1); (ESI-): 494.3 (M+Cl).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (96e).

Compound 96e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl )acetate (96d) (152 mg, 0.33 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (42 mg, 0.99 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (96e) (95 mg, 67% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.22 (s, 1H, D2O replaceable), 8.53 (s, 3H, D2O replaceable), 7.97 (s, 1H), 7.95- 7.88 (m, 1H), 7.75-7.70 (m, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.61-7.53 (m, 2H) , 7.27-7.17 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.99 (s, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.26 (s, 2H), 4.58 (s, 2H), 4.13 (s, 2H), 3.60 (s, 2H), 3.33 (s, 3H); MS (ESI+): 432.3 (M+1); (ESI-): 430.3 (M-1), 466.3 (M+Cl).

Scheme-97

97b

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetic acid (97b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetate (97a).

Compound 97a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indol-6-yl)methCi)phenyl)acetate (50c) ( 0.5 g, 1.24 mmol) in dioxane (5 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.38 g, 1.86 mmol), tripotassium phosphate (3 M aqueous solution , 0.70 ml, 2.11 mmol), tricyclohexylphosphine (0.11 g, 0.37 mmol) and Pd ₂ (dba) ₃ (0.11 g, 0.12 mmol) in an Ar atmosphere and heating at 125° C for 90 minutes in the microwave. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with hexane in 0% to 70% ethyl acetate] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy )phenyl)acetate (97a) (0.26 g, 47% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 3H), 7.68-7.54 (m, 3H), 7.44-7.34 (m, 2H), 7.29 -7.18 (m, 2H), 7.18-7.10 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 6.35 (t, J=2.9 Hz, 1H), 5.25 (s, 2H), 4.16 (s, 2H), 3.93 (k, J=7.0 Hz, 2H), 3.85 (s, 3H), 3, 63 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.88; MS (ESI+): 447.3 (M+1); MS (ESI-): 481.3 (M+Cl). Purity after HPLC: 98.44%.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetic acid (97b).

Compound 97b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl )methoxy)phenyl)acetate (97a) (0.08 g, 0.18 mmol) in MeOH/THF (4 ml), using sodium hydroxide solution (0.57 ml, 1.43 mmol, 2.5 M) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (97b) (0.02 g, 21% yield), HCl salt, as a white solid substances;

^1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.41 (s, 4H), 7.64 (s, 1H), 7.63-7.54 (m, 1H ), 7.45-7.35 (m, 2H), 7.29-7.15 (m, 3H), 7.11 (d, J=8.1 Hz, 1H), 6.95-6, 86 (m, 1H), 6.34 (t, J=3.0 Hz, 1H), 5.27 (s, 2H), 4.17 (s, 2H), 3.84 (s, 3H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.79; MS (ESI+): 419.3 (M+1); MS (ESI-): 417.4 (M-1), 453.3 (M+Cl). Purity after HPLC: 94.07%.

- 169 045626

Scheme-98

racemate 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5 Preparation of yl)methoxy)phenyl)acetic acid (98e), (+)-isomer (98f) and (-)-isomer (98g).

Stage-1. Preparation of ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98a).

Compound 98a was prepared according to the procedure described in step-5 of scheme-76 from ethyl 2(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl) acetate (76c) (4 g, 6.89 mmol) in THF (60 ml), using added TBAF (2.25 g, 8.61 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 70% EtOAc in hexane] ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran- 5yl)methoxy)phenyl)acetate (98a) (2.5 g, 78% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.29-7, 18 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.95-6.87 (m, 2H), 5.54 (t, J=5.9 Hz, 1H ), 5.14 (s, 2H), 4.60 (d, J=5.9 Hz, 2H), 4.04 (k, J=7.1 Hz, 2H), 3.61 (s, 2H ), 1.09 (t, J=7.1 Hz, 3H); MS (ESI+): 489.1 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b).

To a solution of ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98a) (500 mg, 1.07 mmol) in DCM (20 ml) was added Dessa periodinan -Martina (546 mg, 1.29 mmol). The resulting mixture was stirred at RT for 3 hours, diluted with dichloromethane, washed with saturated aq. sodium bicarbonate, dried, filtered and evaporated under vacuum. The crude product was purified by flash column chromatography [silica gel (24 g)] to give ethyl 2-(2-((2-formyl-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (410 mg, 82% yield ) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 8.12 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.31-7.18 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.93 (t, J= 7.4, 1.1 Hz, 1H), 5.20 (s, 2H), 4.03 (k, J=7.1, 1.7 Hz, 2H), 3.63 (s, 2H), 1.09 (t, J=7.1, 1.7 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98c).

To a solution of ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (410 mg, 0.88 mmol) in THF (20 ml) at -78°C methylmagnesium bromide (1.4 M in THF) (0.63 mL, 0.88 mmol) was added. The resulting mixture was stirred at -78°C for 1 hour, quenched with saturated NH ₄ Cl solution and extracted with EtOAc (3x). The combined organic layers were washed with saturated aq. sodium bicarbonate, dried, filtered and evaporated under vacuum. The crude product was purified by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] to give ethyl 2-(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl) methoxy)phenyl)acetate (98c) (290 mg, 68% yield) as a yellow semi-solid;

¹ H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.29-7, 18 (m, 2H), 7.06 (d, J=8.0 Hz, 1H), 6.91 (t, J=7.3 Hz, 2H), 6.85 (s, 1H), 5, 61-5.53 (m, 1H), 5.13 (s, 2H), 4.92-4.80 (m, 1H), 4.03 (k, J=7.1 Hz, 2H), 3 .61 (s, 2H), 1.47 (d, J=6.6 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H); MS (ESI+): 503.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetate (98d).

Compound 98d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2

- 170 045626 (2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98c) (285 mg, 0.59 mmol) in dioxane (15 ml), using hydrochloride 3-(aminomethyl)phenylboronic acid (6c) (145 mg, 0.77 mmol), solution of K2CO3 (246 mg, 1.78 mmol) in water (3 ml), bis(triphenylphosphine) palladium(P) chloride (63 mg , 0.089 mmol) when heated at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (98d) (156 mg, 57% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (s, 3H, D2O replaceable), 8.01 (d, J=2.3 Hz, 1H), 7.97-7.88 (m , 1H), 7.65 (d, J=1.7 Hz, 1H), 7.61-7.52 (m, 3H), 7.31-7.18 (m, 2H), 7.11 ( d, J=8.1 Hz, 1H), 6.96-6.85 (m, 1H), 6.79 (s, 1H), 5.58 (s, 1H, D ₂ O replaceable), 5, 23 (s, 2H), 4.88 (d, J=6.9 Hz, 1H), 4.13 (s, 2H), 3.95 (k, J=7.1 Hz, 2H), 3, 63 (s, 2H), 1.49 (d, J=6.5 Hz, 3H), 1.01 (t, J=7.1, 1.5 Hz, 3H); MS (ESI+): 460.3 (M+1); (ESI-): 494.3 (M+Cl).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid racemate (98e).

Compound 98e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy )phenyl)acetate (98d) (92 mg, 0.20 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] racemic 2-(2-((7 -(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (98e) (53 mg, 61% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H, D2O replaceable), 8.49 (s, 3H, D2O replaceable), 8.05-7.90 (m, 2H), 7 .73-7.66 (m, 1H), 7.64-7.52 (m, 3H), 7.27-7.18 (m, 2H), 7.13-7.05 (m, 1H) , 6.90 (t, J=7.4 Hz, 1H), 6.78 (s, 1H), 5.26 (s, 2H), 4.88 (k, J=6.6 Hz, 1H) , 4.13 (d, J=5.9 Hz, 2H), 3.60 (s, 2H), 1.49 (d, J=6.6 Hz, 3H); MS (ESI+): 432.3 (M+1); (ESI-): 430.4 (M-1), 466.3 (M+Cl).

Stage-6. Preparation of the (+)-isomer of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (98f) and (-)-isomer 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (98g)

Racemic compound 2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (98e) (30 mg) was subjected to chiral resolution using chiral column (CHIRALPAK IBN), eluted with hexane/ethanol/TEA (85/15/0.1) to give:

1. pica-1 (17.2 mg) as a white wax. This sample, after chiral resolution, was dissolved in acetonitrile and water and lyophilized to dryness to give (+)-2-(2-((7-(3-(aminomethyl)phenyl)-2(1-hydroxyethyl)benzofuran-5-yl) methoxy)phenyl)acetic acid (98f) (9 mg) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.35-8.28 (m, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.87 (d, J=1 .7 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.15-7.05 (m, 2H), 6.95 (d, J=8.0 Hz, 1H), 6.85-6.76 (m, 2H), 5.59 (s, 1H, D2O replaceable), 5.25 (s, 2H), 4.88 (k, J=6.5 Hz, 1H), 4.02 (s, 2H), 3.40 (s, 2H ), 1.49 (d, J=6.5 Hz, 3H); MS (ESI+): 432.2 (M+1), MS (ESI-): 430.2 (M-1); enantiomeric purity: (% ee) = 93.7%; optical rotation: [a] _D = (+) 28.0 [DMSO/CH3OH (1:1), 0.05].

2. pic-2 (71.3 mg) as a yellow wax. This sample, after chiral resolution, was dissolved in acetonitrile and water and lyophilized to dryness to give (-)-2-(2-((7-(3-(aminomethyl)phenyl)-2(1-hydroxyethyl)benzofuran-5-yl) methoxy)phenyl)acetic acid (98g) (26 mg); this substance was further purified by reverse phase chromatography on a [EZ-PREP, C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to give (-)-2-(2-((7-(3(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy) phenyl)acetic acid (98g) (2.1 mg), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H, D2O replaceable), 8.31 (br. s, 3H, D2O replaceable), 8.007.91 (m, 2H), 7.68 (d, J=1.6 Hz, 1H), 7.64-7.57 (m, 2H), 7.56-7.49 (m, 1H), 7.23 (s, 1H), 7. 21 (s, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 6.79 (d, J=0.9 Hz, 1H), 5.58 (s, 1H, D2O replaceable), 5.25 (s, 2H), 4.954.82 (m, 1H), 4.29-4.05 (m, 2H), 3, 59 (s, 2H), 1.49 (d, J=6.6 Hz, 3H); MS (ESI+): 432.3 (M+1), MS (ESI-): 430.3 (M-1); enantiomeric purity: (% ee) = 70.85; optical rotation: [a] _D = (-) 24.0 [DMSO/CH3OH (1:1), 0.05].

- 171 045626

Scheme-99

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (99b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (99a).

Compound 99a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (96c) (500 mg, 1.04 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (278 mg, 1.35 mmol), K2CO3 solution (432 mg, 3.12 mmol) in water (3 ml), bis(triphenylphosphine) palladium(P) chloride (110 mg, 0.16 mmol) by heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl )acetate (99a) (386 mg, 78% yield), HCl salt, as a white solid;

Ή NMR (300 MHz, DMSO- _d6 ) δ 8.66 (s, 3H, D2O replaceable), 7.79-7.69 (m, 2H), 7.69-7.59 (m, 1H), 7.49-7.38 (m, 2H), 7.31-7.18 (m, 2H), 7.15-7.07 (m, 1H), 7.02 (s, 1H), 6. 91 (t, J=7.4, 1.0 Hz, 1H), 5.23 (s, 2H), 4.52 (s, 2H), 4.16 (s, 2H), 3.92 (k , J=7.1 Hz, 2H), 3.62 (s, 2H), 3.28 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 478.3 (M+1); (ESI-): 512.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (99b).

Compound 99b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)phenyl)acetate (99a) (120 mg, 0.251 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (32 mg, 0.75 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (99b) (63 mg, 56% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H, D2O replaceable), 8.60 (s, 3H, D2O replaceable), 7.79 (d, J=1.6 Hz, 1H ), 7.75-7.62 (m, 2H), 7.48-7.39 (m, 2H), 7.28-7.18 (m, 2H), 7.09 (d, J=8 ,1 Hz, 1H), 7.00 (s, 1H), 6.90 (t, J=7.3, 1.0 Hz, 1H), 5.25 (s, 2H), 4.52 (s , 2H), 4.16 (s, 2H), 3.58 (s, 2H), 3.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.67; MS (ESI+): 450.3 (M+1); 472.3 (M+Na); (ESI-): 448.3 (M-1), 484.3 (M+Cl).

Scheme-100

Preparation of 2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (100c).

Stage-1. Preparation of ethyl 2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (100b).

Compound 100b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (300 mg, 0.69 mmol) in dioxane (6 ml), using 1-(6-chloropyridin-2-yl)ethanamine (100a) (108 mg, 0.69 mmol; CAS No. 1060811-97-3), potassium carbonate (190 mg, 1.38 mmol) and bis(triphenylphosphine) palladium(P) chloride (97 mg, 0.14 mmol) under Ar and heating at 100°C for 90 minutes in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(6-(1aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (100b ) (82 mg, 28% yield) as a white solid; MS (ESI+): 431.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5 yl)methoxy)phenyl)acetic acid (100c).

Compound 100c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl )acetate (100b) (82 mg, 0.19 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (24 mg, 0.57 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (6-(1aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (100c) (29 mg, 38% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 3H, D2O replaceable), 8.53 (d, J=1.6 Hz, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.07 (t, J=7.9 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.4 Hz, 2H), 7.16-7.06 (m, 2H), 6, 91 (t, J=7.4 Hz, 1H), 5.32 (s, 2H), 4.70-4.54 (m, 1H), 3.61 (s, 2H), 1.62 (d , J=6.8 Hz, 3H); MS (ESI+): 403.3 (M+1); 425.3 (M+Na); (ESI-): 401.3 (M-1), 437.3 (M+Cl).

Scheme-101

HE

23a 101a

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (101c).

Stage-1. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a).

Compound 101a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromobenzofuran-5-yl)methanol (23a) (2 g, 8.81 mmol) in DCM (30 ml) using triphenylphosphine (3, 00 g, 11.45 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl) acetate (205a) (2.27 g, 11.45 mmol) and di-(4chlorobenzyl) azodicarboxylate solution (DCAD, 4.20 g, 11.45 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH (9:1) in 0% to 50% hexanes], ethyl 2-(2-((7-bromobenzofuran -5-yl)methoxy)-5fluorophenyl)acetate (101a) (1.04 g, 29% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.20-7.02 (m, 4H), 5.16 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3, 64 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); MS (ESI-): 406.9 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetate (101b).

Compound 101b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a) (0.3 g, 0.74 mmol) in dioxane (4 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.23 g, 1.11 mmol), K ₂ CO ₃ solution (0. 20 g, 1.47 mmol) in water (0.5 ml), Pd(PPh ₃ ) ₂ Cl ₂ (0.08 g, 0.11 mmol) and heating in an Ar atmosphere at 90 ° C for 3 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 to 50% MeOH in DCM] ethyl 2-(2-((7-(3(aminomethyl)-2-fluorophenyl)benzofuran -5-yl)methoxy)-5-fluorophenyl)acetate (101b) (0.21 g, 63% yield) as a white solid; it was then purified by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0 to 100%] to give compound 101b, HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H), 7.47-7.39 (m, 2H), 7.17-7.04 (m, 4H), 5.22 (s, 2H) , 4.17 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.53, 124.00; MS (ESI+): 452.9 (M+1); MS (ESI-): 450.9 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (101c).

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Compound 101c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl )acetate (101b) (0.16 g, 0.35 mmol) in THF/methanol (6 mL each), using a solution of lithium hydroxide monohydrate (0.12 g, 2.84 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (101c) (0.08 g, 53% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.68 (td, J=7.1, 5.1 Hz, 2H), 7.48-7.38 (m, 2H), 7.12 (dd, J=7.6, 2, 2 Hz, 1H), 7.11-7.07 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 5.24 (s, 2H), 4.17 (s, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.40, 124.07; MS (ESI+): 424.9 (M+1); MS (ESI-): 422.9 (M-1).

Scheme-102

Preparation of 2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetic acid (102g).

Stage-1. Preparation of methyl 8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2a]pyridine-6-carboxylate (102b).

Compound 102b was prepared according to the procedure described in step-3 of Scheme-1 from methyl 8-bromimidazo[1,2-a]pyridine-6-carboxylate (102a) (1.00 g, 3.92 mmol; CAS no. 1234616-08-0) in dioxane (20 ml), using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (0.984 g, 3.92 mmol), tripotassium phosphate (2.222 ml, 6.66 mmol; 3 M solution) in water (1 ml), tricyclohexylphosphine (0.220 g, 0.784 mmol) and Pd ₂ (dba) ₃ (0.197 g, 0.216 mmol) under nitrogen and heating at 90°C for 12 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc/methanol (9:1) in 0% to 100% hexane] methyl 8-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylate (102b) (1.289 g, 86% yield) as a pale yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.38 (d, J=1.6 Hz, 1H), 8.24-8.21 (m, 1H), 8.05 (d, J=7 .7 Hz, 1H), 7.91 (s, 1H), 7.81-7.68 (m, 2H), 7.59-7.41 (m, 2H), 7.32 (d, J= 7.6 Hz, 1H), 4.30-4.13 (m, 2H), 3.92 (s, 3H), 1.41 (s, 9H); MS (ESI+): 382.3 (M+1).

Stage-2. Preparation of 8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6carboxylic acid (102c).

Compound 102c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylate (102b) (1.25 g, 3.28 mmol) in THF (10 mL) and methanol (20 mL), using sodium hydroxide (2 M aq) (6.55 mL, 13.11 mmol). This resulted in 8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylic acid (102c) (1.06 g, 88% yield) after treatment. as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H), 9.36 (d, J=1.6 Hz, 1H), 8.27 (s, 1H), 8.00 ( d, J=7.8 Hz, 1H), 7.93-7.77 (m, 3H), 7.57-7.43 (m, 2H), 7.34 (d, J=7.6 Hz , 1H), 4.23 (d, J=6.1 Hz, 2H), 1.40 (s, 9H).

Stage-3. Preparation of tert-butyl 3-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)benzylcarbamate (102d).

Compound 102d was prepared according to the procedure described in step-1 of Scheme-23 from 8-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylic acid ( 102c) (0.60 g, 1.633 mmol) using N-methylmorpholine (0.215 mL, 1.960 mmol) in THF (20 mL), isobutyl chloroformate (0.257 mL, 1.960 mmol) and NaBH ₄ (0.185 g, 4.90 mmol) in water (3 ml). This resulted in, after work-up and purification by flash column chromatography [silica gel (24 g), eluted

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EtOAc/MeOH (9:1) in hexanes from 0% to 40%] tert-butyl 3-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-8yl)benzylcarbamate (102d) (0.443 g, 77% yield) as a pale yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.52-8.44 (m, 1H), 8.08-7.99 (m, 2H), 7.95 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.53-7.37 (m, 3H), 7.28 (d, J=7.6 Hz, 1H), 5.40 (t, J= 5.6 Hz, 1H), 4.57 (d, J=5.6, 1.1 Hz, 2H), 4.21 (d, J=6.2 Hz, 2H), 1.40 (s, 9H); MS (ESI+): 354.3 (M+1), 376.3 (M+Na); MS (ESI-): 352.3 (M-1).

Stage-4. Preparation of ethyl 2-(2-((8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2a]pyridin-6-yl)methoxy)phenyl)acetate (102e).

Compound 102e was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)benzylcarbamate (102d) (0.300 g, 0.849 mmol) in THF (25 ml) using triphenylphosphine (0.289 g, 1.104 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.199 g, 1.104 mmol) and DIAD (0.215 ml, 1.104 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 100% EtOAc in hexane] ethyl 2-(2-((8-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridin-6yl)methoxy)phenyl)acetate (102e) (0.328 g, 75% yield) as a pale yellow solid; MS (ESI+): 516.4 (M+1), 538.3 (M+Na); MS (ESI-): 514.5 (M-1), 550.4 (M+Cl).

Stage-5. Preparation of ethyl 2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6yl)methoxy)phenyl)acetate (102f).

Compound 102f was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a ]pyridin-6yl)methoxy)phenyl)acetate (102e) (0.318 g, 0.617 mmol) in DCM (10 ml) using TFA (0.713 ml, 9.25 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((8 -(3(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate (102f) (0.172 g, 67% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.65 (s, 3H), 8.53-8.45 (m, 1H), 8.18 (s, 1H ), 8.09-7.97 (m, 2H), 7.89-7.76 (m, 1H), 7.73-7.64 (m, 2H), 7.35-7.22 (m , 2H), 7.18 (d, J=8.1 Hz, 1H), 6.97 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4 .24-4.07 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.68 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 416.3 (M+1); MS (ESI-): 450.3 (M+Cl).

Stage-6. Preparation of 2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6yl)methoxy)phenyl)acetic acid (102g).

Compound 102g was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy )phenyl)acetate (102f) (0.055 g, 0.132 mmol) in THF (4 ml) and methanol (8 ml), using sodium hydroxide (0.265 ml, 0.530 mmol, 2 M aq). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((8- (3(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetic acid (102g) (0.023 g, 45% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.30 (s, ^1H , _D2O replaceable), 9.01 (s, 1H), 8.66 (s, 3H, _D2O replaceable), 8.55-8.44 (m, 1H), 8.17 (s, 1H), 8.04 (d, J=6.1 Hz, 2H), 7.89-7.77 (m, 1H) , 7.72-7.62 (m, 2H), 7.34-7.21 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.96 (t, J =7.4 Hz, 1H), 5.34 (s, 2H), 4.15 (k, J=5.9 Hz, 2H), 3.64 (s, 2H); MS (ESI+): 388.3 (M+1); MS (ESI-): 386.3 (M-1), 422.3 (M+Cl), 773.5 (2M-1); purity after HPLC: 98.95%.

Scheme-103

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (103d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2formylbenzofuran-5-yl)methoxy)phenyl)acetate (103a).

Compound 103a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (2.2 g , 4.74 mmol) in dioxane (15

- 175 045626 ml), using (3-((tert-butoxycarbonyl)amino)methyl)phenylboronic acid (1d) (1.79 g, 7.11 mmol), K ₂ CO ₃ solution (1.965 g, 14.22 mmol ) in water (3 ml), bis(triphenylphosphine) palladium(11) chloride (0.50 g, 0.71 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)-2formylbenzofuran-5-yl)methoxy)phenyl)acetate (103a) (1.52 g, 59% yield) as a brown semi-solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.81-7.71 (m, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.49-7.39 (m, 1H), 7.35 (d , J=7.6 Hz, 1H), 7.30-7.20 (m, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.92 (t, J=7, 4 Hz, 1H), 5.28 (s, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.38 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 566.3 (M+Na); (ESI-) 542.5 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(2,2,2trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl )acetate (103b)

Trimethyl(trifluoromethyl)silane (CaS No: 81290-20-2) (283 mg, 1.99 mmol) and CsF (233 mg, 1.53 mmol) were added to the solution of ethyl 2-(2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)phenyl)-2formylbenzofuran-5-yl)methoxy)phenyl)acetate (103a) (833 mg, 1.53 mmol) in anhydrous THF (20 ml) at room temperature in atmosphere Ar, and the mixture was sonicated for 20 min to initiate the reaction. The mixture was stirred at room temp. for 12 hours, after which aq. was added. HCl (1 M, 15 ml) and the mixture was stirred for an additional 15 minutes. The mixture was extracted with EtOAc, washed with saturated NaHCO ₃ , brine, dried and evaporated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted (EtOAc/hexane 7:3)] to give ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)-2-(2,2,2trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (103b) (312 mg, 33% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.81-7.69 (m, 3H), 7.60 (d, J=1.6 Hz, 1H), 7.55-7.41 (m , 2H), 7.36-7.18 (m, 4H), 7.17-7.07 (m, 2H), 6.91 (t, J=7.4, 1.1 Hz, 1H), 5.56-5.42 (m, 1H), 5.24 (s, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.91 (k, J=7.1 Hz , 2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ 75.90; MS (ESI+): 636.3 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (103c).

Compound 103c was prepared according to the procedure described in step-2 of Scheme-94 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(2, 2,2-Trifluoro-1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetate (103b) (300 mg, 0.49 mmol) in THF (10 ml) using hydrochloric acid (2.45 ml, 4.89 mmol) when heated at 60°C for 2 hours. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0 to 60%] followed by reverse phase purification chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0 to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2, 2,2trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (103c) (109 mg, 43% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.38 (s, 3H, D2O replaceable), 7.98 (s, 1H), 7.94 (d, J=7.4 Hz, 1H), 7 .75 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.65-7.52 (m, 2H), 7.34-7, 27 (m, 1H), 7.27-7.19 (m, 2H), 7.16 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.91 (t , J=7.3 Hz, 1H), 5.53 (p, J=6.9 Hz, 1H), 5.24 (s, 2H), 4.12 (s, 2H), 3.92 (k , J=7.1 Hz, 2H), 3.63 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -75.83; MS (ESI+): 514.3 (M+1); (ESI-): 512.3 (M+1); 548.3 (M+Cl).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran5-yl)methoxy)phenyl)acetic acid (103d).

Compound 103d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl )benzofuran-5-yl)methoxy)phenyl)acetate (103c) (78 mg, 0.15 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (19 mg, 0.46 mmol) in water ( 1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (103d) (39 mg, 53% yield) as a white solid ;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.20 (s, 1H, D2O replaceable), 8.41 (s, 2H, D2O replaceable), 8.03-7.92 (m, 2H), 7 .78 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.65-7.53 (m, 2H), 7.31 (d, J=6.5 Hz, 1H), 7.28-7.19 (m, 2H), 7.15 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6, 91 (t, J=7.3 Hz, 1H), 5.60-5.47 (m, 1H), 5.27 (s, 2H), 4.13 (s, 2H), 3.60 (s , 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -75.81; MS (ESI+): 486.3 (M+1); (ESI-): 484.3 (M-1), 520.3 (M+Cl).

- 176 045626

Scheme-104

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (104e).

Stage-1. Preparation of methyl 7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (104a).

Compound 104a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (7 g, 22.59 mmol) in pyridine (20 ml) using 2 -methyl-4(trimethylsilyl)but-3-yn-2-ol (3.53 g, 22.59 mmol; CAS No.: 5272-33-3) and copper(I) oxide (3.23 g, 22. 59 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 70% EtOAc in hexane] methyl 7-bromo-2-(2hydroxypropan-2-yl)benzofuran-5- carboxylate (104a) (5 g, 71% yield) as a yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (d, J=1.6 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 6.95 (d, J=0.9 Hz, 1H), 5.56 (s, 1H, D2O replaceable), 3.89 (s, 3H), 1.55 (s, 6H).

Stage-2. Preparation of 2-(7-bromo-5-(hydroxymethyl)benzofuran-2-yl)propan-2-ol (104b).

Compound 104b was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (104a) (4 g, 12.77 mmol ) in THF (60 ml), using LiBH ₄ (19.16 ml, 38.3 mmol, 2 M solution in THF) and MeOH (1.23 g, 38.3 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] 2-(7-bromo-5-(hydroxymethyl)benzofuran-2-yl) propan-2ol (104b) (2.86 g, 79% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, J=1.2 Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 6.77 (d, J =1.1 Hz, 1H), 5.44 (s, 1H, D2O replaceable), 5.28 (t, J=5.8, 1.1 Hz, 1H, D2O replaceable), 4.55 (d, J=5.8 Hz, 2H), 1.53 (s, 6H).

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (104c).

Compound 104c was prepared according to the procedure described in step-2 of Scheme-23 from 2-(7bromo-5-(hydroxymethyl)benzofuran-2-yl)propan-2-ol (104b) (2.82 g, 9. 89 mmol) in DCM (180 ml) using triphenylphosphine (2.85 g, 10.88 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.87 g, 10.38 mmol) and di- (4-chlorobenzyl)azodicarboxylate (DCAD, 3.99 g, 10.88 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-(2-hydroxypropane -2yl)benzofuran-5-yl)methoxy)phenyl)acetate (104c) (1.8 g, 41% yield) as a clear oil which became a white solid after standing;

1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=1.4 Hz, 1H), 7.53 (d, J=1.4 Hz, 1H), 7.28-7.18 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.80 (s, 1H), 5.47 (d, J=1.1 Hz, 1H), 5.16 (s, 2H), 4.03 (k, J=7.1 Hz, 3H), 1.53 (s, 6H), 1.09 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (104d).

Compound 104d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl) acetate (104c) (700 mg, 1.57 mmol) in dioxane (25 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (381 mg, 2.03 mmol), K ₂ CO ₃ solution (649 mg , 4.69 mmol) in water (3 ml), bis(triphenylphosphine) palladium(P) chloride (165 mg, 0.24 mmol) by heating at 100°C for 3 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography

[C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(2-hydroxypropane -2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (104d) (585 mg, 79% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (s, 3H, D2O replaceable), 8.01-7.93 (m, 2H), 7.64 (d, J=1.6 Hz , 1H), 7.62-7.53 (m, 3H), 7.29-7.19 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.91 ( t, J=7.2 Hz, 1H), 6.76 (s, 1H), 5.48 (s, 1H, D2O replaceable), 5.23 (s, 2H), 4.13 (d, J= 5.7 Hz, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.55 (s, 6H), 1.00 (t, J= 7.1 Hz, 3H); MS (ESI+): 474.3 (M+1); (ESI-): 508.3 (M+Cl).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (104e).

Compound 104e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5 -yl)methoxy)phenyl)acetate (104d) (70 mg, 0.15 mmol) in MeOH/THF (5 ml), using a solution of lithium hydroxide monohydrate (12.41 mg, 0.30 mmol) in water (1, 0 ml). This gave, after work-up and purification by flash column chromatography [silica gel (4 g), eluted with DMA80 in DCM 0% to 80%] 2-(2-((7-(3(aminomethyl)phenyl)-2-( 2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (104e) (20 mg, 30% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.15-7.03 (m, 2H) , 6.93 (d, J=8.1 Hz, 1H), 6.88-6.67 (m, 2H), 5.50 (s, 1H, D2O replaceable), 5.25 (s, 2H) , 4.01 (s, 2H), 3.39 (s, 2H), 1.55 (s, 6H);

Ή NMR (300 MHz, methanol-d ₄ ) δ 8.25-8.13 (m, 2H), 7.89 (s, 1H), 7.55-7.40 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.8 Hz, 2H), 6.96 (d, J=8.1 Hz, 1H), 6.87 (t , J=7.4 Hz, 1H), 6.70 (s, 1H), 5.21 (s, 2H), 4.09 (s, 2H), 3.59 (s, 2H), 1.64 (s, 6H); MS (ESI+): 446.3 (M+1); (ESI-): 444.4 (M-1), 480.3 (M+Cl).

Scheme-105

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (105c).

Stage-1. Preparation of ethyl 2-(2-((2-(cyclopropyl(hydroxy)methyl)-7-iodobenzofuran-5yl)methoxy)phenyl)acetate (105a).

Compound 105a was prepared according to the procedure described in step-3 of Scheme-98 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (500 mg, 1.08 mmol) in THF (20 ml) using cyclopropyl magnesium bromide (1.0 M in THF, 1.185 ml, 1.185 mmol) at -78°C. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 to 60% EtOAc in hexane] ethyl 2-(2-((2-(cyclopropyl(hydroxy)methyl)-7iodobenzofuran -5-yl)methoxy)phenyl)acetate (105a) (227 mg, 42% yield) as a clear oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.69 (s, 1H), 7.63 (s, 1H), 7.29-7.16 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.97-6.80 (m, 2H), 5.64 (d, J=5.5 Hz, 1H), 5.14 (s, 2H), 4, 16 (t, J=6.6 Hz, 1H), 4.03 (k, J=7.2 Hz, 2H), 3.61 (s, 2H), 1.34-1.18 (m, 1H ), 1.09 (t, J=7.0 Hz, 3H), 0.59-0.28 (m, 4H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (105b).

Compound 105b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(cyclopropyl(hydroxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (105a ) (227 mg, 0.45 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (109 mg, 0.58 mmol), K ₂ CO ₃ solution (186 mg, 1. 35 mmol) in water (3 ml), bis(triphenylphosphine) palladium(I) chloride (47 mg, 0.067 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 50% DCM] ethyl 2-(2-((7(3-(aminomethyl)phenyl)-2- (cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (105b)

- 178 045626 (150 mg, 69% yield) in the form of a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.86 (s, 1H), 7.77 (dt, J=7.5, 1.5 Hz, 1H), 7.62 (d, J=1 .5 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.30-7.19 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.94-6.86 (m, 1H), 6.81 (s, 1H), 5.55 (s, 1H), 5.23 (s, 2H), 4.16 (d, J=7.6 Hz, 1H, D ₂ O replaceable), 3.94 (k , J=7.1 Hz, 2H), 3.82 (s, 2H), 3.63 (s, 2H), 1.32-1.16 (m, 1H), 1.00 (t, J= 7.1 Hz, 3H), 0.58-0.48 (m, 2H), 0.48-0.37 (m, 2H); MS (ESI+): 486.3 (M+1); (ESI ^- ): 484.3 (M-1), 520.4 (M+Cl).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran5-yl)methoxy)phenyl)acetic acid (105c).

Compound 105c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5- yl)methoxy)phenyl)acetate (105b) (96 mg, 0.20 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in water (1.0 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (105c) (50 mg, 55% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.13-7.05 (m, 2H) , 6.94 (d, J=8.1 Hz, 1H), 6.87-6.77 (m, 2H), 5.26 (s, 2H), 4.17 (d, J=7.6 Hz, 2H), 4.01 (s, 2H), 3.40 (s, 2H), 1.33-1.21 (m, 1H), 0.59-0.48 (m, 2H), 0 .48-0.33 (m, 2H); MS (ESI+): 458.3 (M+1); 480.3 (M+Na); (ESI-): 456.4 (M-1), 492.3 (M+Cl).

Scheme-106

Preparation of 2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (106c).

Stage-1. Preparation of ethyl 2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5yl)methoxy)phenyl)acetate (106b).

Compound 106b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (382 mg, 0.88 mmol) in dioxane (10 ml), using (5-bromopyridin-3-yl)methanamine (106a) (246 mg, 1. 31 mmol), bis(triphenylphosphine) palladium(P) chloride (92 mg, 0.13 mmol) and a solution of K ₂ CO ₃ (363 mg, 2.63 mmol) in water (1 ml) in an Ar atmosphere and heating at 95 °C for 2 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(5-(aminomethyl)pyridinium- 3yl)benzofuran-5-yl)methoxy)phenyl)acetate (106b) (112 mg, 31% yield) as a white solid; MS (ESI+): 417.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (106c).

Compound 106c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (106b) (112 mg, 0.27 mmol) in MeOH/THF (10 mL), using a solution of lithium hydroxide monohydrate (34 mg, 0.81 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (5(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (106c) (55 mg, 53% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.26 (d, J=1.8 Hz, 1H), 8.72 (s, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.15 (t, J=1.7 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.16-7, 06 (m, 3H), 6.98 (d, J=8.1 Hz, 1H), 6.86-6.77 (m, 1H), 5.29 (s, 2H), 4.07 (s , 2H), 3.43 (s, 2H); MS (ESI+): 389.3 (M+1); 411.2 (M+Na); (ESI-): 387.3 (M-1), 423.3 (M+Cl).

- 179 045626

Scheme-107

Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetic acid (107f).

Stage-1. Preparation of 5-chlorimidazo[1,2-a]pyridine-7-carboxylic acid (107b).

To a solution of 2-amino-6-chloroisonicotinic acid (107a) (0.5 g, 2.90 mmol; CAS No. 6313-55-9) in EtOH (20 ml) was added 2-chloroacetaldehyde (1.47 ml, 11. 59 mmol) and refluxed overnight. The reaction mixture was cooled to RT, diluted with EtOAc, washed with water, brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 100%] to give 5-chloroimidazo[1,2-a]pyridine-7-carboxylic acid (107b) (0 .45 g, 79% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 7.95 (s, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H); MS (ESI+): 197.0 and 199.1 (M+1); MS (ESI-): 195.1 and 197.1 (M-1).

Stage-2. Preparation of (5-chlorimidazo[1,2-a]pyridin-7-yl)methanol (107c).

Compound 107c was prepared according to the procedure described in step-1 of Scheme-23 from 5chloroimidazo[1,2-a]pyridine-7-carboxylic acid (107b) (0.6 g, 3.05 mmol) using Nmethylmorpholine ( 0.40 ml, 3.66 mmol) in THF (50 ml), isobutyl chloroformate (0.48 ml, 3.66 mmol) and NaBH ₄ (0.35 g, 9.16 mmol) in water (0.8 ml ). This resulted in, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 50% DCM] (5-chloroimidazo[1,2-a]pyridin-7-yl)methanol (107c) (0.3 g, 54% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.96 (s, 1H), 7.67 (s, 1H), 7.51 (s, 1H), 7.12 (s, 1H), 5 .51 (t, J=5.8 Hz, 1H), 4.55 (dd, J=5.8, 1.1 Hz, 2H); MS (ESI+): 183.1 (M+1).

Stage-3. Preparation of ethyl 2-(2-((5-chloroimidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate (107d).

Compound 107d was prepared according to the procedure described in step-2 of Scheme-23 from (5chloroimidazo[1,2-a]pyridin-7-yl)methanol (107c) (0.15 g, 0.82 mmol) in DCM (10 ml) using triphenylphosphine (0.28 g, 1.07 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.19 g, 1.07 mmol) and di-(4chlorobenzyl) azodicarboxylate ( DIAD, 0.39 g, 1.07 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] ethyl 2-(2-((5-chloroimidazo[1,2-a] pyridin-7-yl)methoxy)phenyl)acetate (107d) (0.2 g, 71% yield) as a colorless oil; MS (ESI-): 343.2 (M-1).

Stage-4. Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7yl)methoxy)phenyl)acetate (107e).

Compound 107e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((5-chlorimidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate (107d) ( 0.15 g, 0.44 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.12 g, 0.65 mmol), tripotassium phosphate (3 M aqueous solution, 0. 25 ml, 0.74 mmol), tricyclohexylphosphine (0.04 g, 0.13 mmol) and Pd ₂ (dba) ₃ (0.04 g, 0.04 mmol) under Ar and heating at 125°C for 120 minutes in the microwave. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%], ethyl 2-(2-((5-(3(aminomethyl)phenyl)imidazo [1,2-a]pyridin-7-yl)methoxy)phenyl)acetate (107e) (0.08 g, 44% yield) as a white solid; MS (ESI+): 416.3 (M+1).

Stage-5. Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7yl)methoxy)phenyl)acetic acid (107f).

Compound 107f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy )phenyl)acetate (107e) 0.07 g, 0.17

- 180 045626 mmol) in MeOH/THF (4 ml), using a solution of sodium hydroxide (0.61 ml, 1.52 mmol, 2.5 M) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((5- (3(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetic acid (107f) (0.01 g, 9% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 8.55 (s, 3H), 7.67 (dt, J=14.6, 6.9 Hz, 2H) , 7.56 (t, J=2.9 Hz, 1H), 7.44 (dt, J=15.3, 7.7 Hz, 1H), 7.34 (s, 1H), 7.21 ( d, J=7.3 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 6.45 (k, J=2.7 Hz, 1H), 5.29 (s, 2H), 4.16 (k, J=5.9 Hz, 2H), 3.60 (s, 2H); MS (ESI+): 388.3 (M+1); MS (ESI-): 386.3 (M-1), 422.3 (M+Cl). Purity after HPLC: 95.72%.

Scheme-108

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetic acid (108f).

Stage-1. Preparation of methyl 7-iodo-2-isopropylbenzofuran-5-carboxylate (108b).

Compound 108b was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (10 g, 24.76 mmol) in pyridine (10 ml) using 3- methylbut-1-yne (108a) (1.69 g, 24.76 mmol; CAS No.: 598-23-2) and copper(I) oxide (1.77 g, 12.38 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 70% EtOAc in hexane] methyl 7-iodo-2-isopropylbenzofuran-5-carboxylate (108b) (5, 77 g, 68% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (d, J=1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 6.86 (d, J=1.1 Hz, 1H), 3.87 (s, 3H), 3.20-3.07 (m, 1H), 1.32 (d, J=6.9 Hz, 6H).

Stage-2. Preparation of (7-iodo-2-isopropylbenzofuran-5-yl)methanol (108c).

Compound 108c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-iodo-2-isopropylbenzofuran-5-carboxylate (108b) (4.77 g, 13.86 mmol) in THF (200 ml) using LiBH ₄ (13.86 ml, 27.7 mmol, 2 M solution in THF) and MeOH (1.12 ml, 27.7 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 60% EtOAc in hexane] (7-iodo-2-isopropylbenzofuran-5-yl)methanol (108c) ( 2.7 g, 62% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.56 (d, J=1.5 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 6.69 (d, J=1.1 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.16-3.00 ( m, 1H), 1.30 (d, J=6.9 Hz, 6H).

Stage-3. Preparation of ethyl 2-(2-((7-iodo-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate (108d).

Compound 108d was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-isopropylbenzofuran-5-yl)methanol (108c) (2.7 g, 8.54 mmol) in DCM (50 ml) using triphenylphosphine (2.46 g, 9.39 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.69 g, 9.39 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 3. 45 g, 9.39 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-iodo-2-isopropylbenzofuran-5- yl)methoxy)phenyl)acetate (108d) (2.8 g, 69% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.65 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.28-7, 17 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.73 (d, J=1.0 Hz, 1H), 5.13 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 3.18-2.99 (m, 1H ), 1.29 (s, 7H), 1.09 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5yl)methoxy)phenyl)acetate (108e).

Compound 108e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate (108d) (850 mg, 1 .78 mmol) in dioxane

- 181 045626 (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (433 mg, 2.31 mmol), solution of K ₂ CO ₃ (737 mg, 5.33 mmol) in water (5 ml) , bis(triphenylphosphine) palladium(P) chloride (187 mg, 0.27 mmol) by heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2isopropylbenzofuran-5-yl)methoxy)phenyl)acetate (108e) (468 mg, 58% yield), HCl salt, as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (s, 3H, D2O replaceable), 7.97 (d, J=2.3 Hz, 1H), 7.93 (dt, J=7, 4, 1.7 Hz, 1H), 7.65-7.59 (m, 2H), 7.59-7.56 (m, 1H), 7.54 (d, J=1.7 Hz, 1H ), 7.29-7.19 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H) , 6.67 (d, J=1.0 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H), 3.94 (k, J=7.1 Hz, 2H) , 3.63 (s, 2H), 3.18-3.04 (m, 1H), 1.32 (d, J=6.9 Hz, 6H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 458.3 (M+1); (ESI-): 492.3 (M+Cl).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5yl)methoxy)phenyl)acetic acid (108f).

Compound 108f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate ( 108e) (225 mg, 0.49 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (62 mg, 1.48 mmol) in water (1.0 ml). This gave, upon treatment, 2-(2-((7-(3-(aminomethyl)phenyl)-2isopropylbenzofuran-5-yl)methoxy)phenyl)acetic acid (108f) (165 mg, 78% yield) as white solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.16 (s, 3H, D ₂ O replaceable), 8.01 (d, J=1.9 Hz, 1H), 7.96 (d, J= 7.8 Hz, 1H), 7.64-7.62 (m, 1H), 7.62-7.55 (m, 2H), 7.55-7.49 (m, 1H), 7.23 -7.16 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.66 (d, J= 1.0 Hz, 1H), 5.24 (s, 2H), 4.12 (s, 2H), 3.57 (s, 2H), 3.19-3.06 (m, 1H), 1. 33 (d, J=6.9 Hz, 6H); MS (ESI+): 430.3 (M+1); (ESI-): 428.4 (M+1); 464.4 (M+Cl).

Scheme-109

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (109g).

Stage-1. Preparation of methyl 4-bromo-1-isopropyl-1H-indole-6-carboxylate (109b) To a solution of methyl 4-bromo-1H-indole-6-carboxylate (109a) (1.5 g, 5.90 mmol; CAS No. 882679-96-1) in DMF (10 ml) was added 2-bromopropane (1.3 ml, 14.76 mmol), potassium carbonate (2.86 g, 20.66 mmol) and heated at 60°C for 3 days. The reaction mixture was diluted with EtOAc (100 ml), washed with water (3x), brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] to give methyl 4-bromo-1-isopropyl-1H-indole-6-carboxylate (109b) (0 .85 g, 49% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.90 (d, J=3.2 Hz, 1H), 7.79 (s, 1H), 6.54 (d , J=3.2 Hz, 1H), 4.92 (m Hz, 1H), 3.88 (s, 3H), 1.47 (d, J=6.6 Hz, 6H); MS (ESI+): 297.4 (M+1).

Stage-2. Preparation of 4-bromo-1-isopropyl-1H-indole-6-carboxylic acid (109c).

Compound 109c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 4-bromo-1-isopropyl-1H-indole-6-carboxylate (109b) (0.8 g, 2.70 mmol) in THF /MeOH (20 ml) using a solution of lithium hydroxide monohydrate (0.68 g, 16.21 mmol) in water (3 ml). This resulted in 4-bromo-1-isopropyl-1H-indole-6-carboxylic acid (109c) (0.7 g, 92% yield) as a white solid upon treatment;

1H NMR (300 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.17 (s, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.77 (s , 1H), 6.52 (d, J=3.2 Hz, 1H), 4.90 (m, 1H), 1.47 (d, J=6.6 Hz, 6H); MS (ESI-): 282.2 (M-1). Stage-3. Preparation of (4-bromo1-isopropyl-1H-indol-6-yl)methanol (109d).

- 182 045626

Compound 109d was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-isopropyl-1H-indole-6-carboxylic acid (109c) (0.75 g, 2.66 mmol) using Nmethylmorpholine ( 0.35 ml, 3.19 mmol) in THF (100 ml), isobutyl chloroformate (0.42 ml, 3.19 mmol) and NaBH ₄ (0.30 g, 7.97 mmol) in water (0.8 ml ). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH=9:1 in hexane from 0% to 100%] (4-bromo-1-isopropyl-1H-indole -6-yl)methanol (109d) (0.65 g, 91% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.58 (d, J=3.3 Hz, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 6.37 ( d, J=3.3 Hz, 1H), 5.24 (t, J=5.8 Hz, 1H), 4.73 (m, 1H), 4.58 (d, J=5.8 Hz, 2H), 1.45 (d, J=6.7 Hz, 6H).

Stage-4. Preparation of ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e).

Compound 109e was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-isopropyl-1H-indol-6-yl)methanol (109d) (0.65 g, 2.42 mmol) in DCM (10 ml) using triphenylphosphine (0.83 g, 3.15 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.57 g, 3.15 mmol) and di-(4chlorobenzyl) azodicarboxylate ( DCAD, 1.16 g, 3.15 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in 0-60% hexane] ethyl 2-(2-((4-bromo-1 -isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e) (0.12 g, 12% yield) as a colorless oil; MS (ESI-): 428.3 and 430.2 (M-1).

Stage-5. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetate (109f).

Compound 109f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e) ( 0.3 g, 0.70 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.2 g, 1.05 mmol), K ₂ CO ₃ (0.29 g , 2.09 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(11) chloride (0.07 g, 0.11 mmol) in an Ar atmosphere by heating at 100 °C for 4 h in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 20%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl1H-indol-6-yl)methoxy)phenyl)acetate ( 109f) (0.25 g, 79% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (s, 3H), 7.80 (d, J=1.7 Hz, 1H), 7.67 (dt, J=7.7, 1 .4 Hz, 1H), 7.64 (s, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7. 48 (d, J=7.7 Hz, 1H), 7.27-7.20 (m, 2H), 7.19 (d, J=1.2 Hz, 1H), 7.13 (d, J =8.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H), 5.25 (s , 2H), 4.81 (p, J=6.7 Hz, 1H), 4.13 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.63 (s , 2H), 1.50 (d, J=6.6 Hz, 6H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 457.5 (M+1); MS (ESI-): 491.6 (M+Cl). Purity after HPLC: 97.55%.

Stage-6. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetic acid (109g).

Compound 109g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy) phenyl)acetate (109f) (0.04 g, 0.09 mmol) in THF/MeOH (4 ml), using a solution of lithium hydroxide monohydrate (0.02 g, 0.53 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (109g) (0.02 g, 56% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.21 (s, 1H), 8.33 (s, 4H), 7.80 (s, 1H), 7.68 (m, 2H), 7. 61 (d, J=3.3 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.25- 7.20 (m, 3H), 7.11 (m, 1H), 6.94-6.86 (m, 1H), 6.67 (d, J=3.3 Hz, 1H), 5.27 (s, 2H), 4.81 (p, J=6.8 Hz, 1H), 4.13 (s, 2H), 3.60 (s, 2H), 1.49 (d, J=6, 6 Hz, 6H); MS (ESI-): 427.5 (M-1).

Scheme-110

Preparation of 2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (110c).

Stage-1. Preparation of ethyl 2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (110b).

Compound 110b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (330 mg, 0.76 mmol) in dioxane (10 ml), using (2-chloropyridin-4-yl)methanamine hydrochloride (110a) (203

- 183 045626 mg, 1.14 mmol), bis(triphenylphosphine) palladium(11) chloride (80 mg, 0.11 mmol) and a solution of K2CO3 (314 mg, 2.27 mmol) in water (1 ml) in an Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(4(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (110b) (220 mg, 70% yield), HCl salt, as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.82 (d, J=5.1 Hz, 1H), 8.73 (s, 3H, D2O replaceable), 8.41 (s, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7, 63 (dd, J=5.2, 1.5 Hz, 1H), 7.32-7.18 (m, 2H), 7.17-7.10 (m, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.23 (k, J=6.0 Hz, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 417.3 (M+1); (ESI-): 451.4 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (110c).

Compound 110c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (110b) (133 mg, 0.32 mmol) in MeOH/THF (20 ml), using a solution of lithium hydroxide monohydrate (27 mg, 0.64 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (4(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (110c) (72 mg, 58% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.83 (d, J=5.1 Hz, 1H), 8.68 (s, 3H, D2O replaceable), 8.39 (d, J=1, 5 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.87 (d, J=1.6 Hz , 1H), 7.63 (dd, J=5.3, 1.5 Hz, 1H), 7.267.19 (m, 2H), 7.14-7.06 (m, 2H), 6.90 ( t, J=7.4 Hz, 1H), 5.30 (s, 2H), 4.23 (k, J=5.9 Hz, 2H), 3.59 (s, 2H); MS (ESI+): 389.3 (M+1); (ESI-): 387.3 (M-1); 423.3 (M+Cl).

Scheme-111 he

109е 111а Шь

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetic acid (111b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetate (111a).

Compound 111a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e) ( 0.4 g, 0.93 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.29 g, 1.39 mmol), K ₂ CO ₃ (0 .39 g, 2.79 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.10 g, 0.14 mmol) in an Ar atmosphere and heating at 100°C for 2 h oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 20%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1isopropyl-1H-indol-6-yl)methoxy)phenyl )acetate (111a) (0.31 g, 70% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.44 (s, 4H), 7.68 (s, 1H), 7.62-7.55 (m, 3H), 7.39 (t, J =7.6 Hz, 1H), 7.29-7.17 (m, 2H), 7.16-7.10 (m, 2H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.38 (t, J=3.0 Hz, 1H), 5.24 (s, 2H), 4.81 (m, 1H), 4.16 (s, 2H), 3, 91 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.49 (d, J=6.6 Hz, 6H), 0.98 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -118.90; MS (ESI+): 475.4 (M+1); MS (ESI-): 509.5 (M+Cl). Purity after HPLC: 91.15%.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetic acid (111b).

Compound 111b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl )methoxy)phenyl)acetate (111a) (0.15 g, 0.32 mmol) in THF/MeOH (8 ml), using a solution of lithium hydroxide monohydrate (0.066 g, 1.58 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (111b) (0.03 g, 23% yield) as a white solid;

- 184 045626

1H NMR (300 MHz, DMSO- _d6 ) δ 12.20 (s, 1H), 8.46 (s, 4H), 7.71 (s, 1H), 7.66-7.56 (m, 3H ), 7.38 (t,

J=7.6 Hz, 1H), 7.25-7.19 (m, 2H), 7.17-7.08 (m, 2H), 6.90 (t, J=7.4 Hz, 1H ), 6.37 (t, J=3.0 Hz, 1H), 5.26 (s, 2H),

4.82 (m, 1H), 4.16 (d, J=5.7 Hz, 2H), 3.59 (s, 2H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 118.84; MS (ESI+): 447.3 (M+1); MS (ESI-): 445.4 (M-1), 481.4 (M+Cl). Purity after HPLC: 90.91%.

Scheme-112

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (112c).

Stage-1. Preparation of ethyl 2-(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (112a) .

Compound 112a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d) (5 g, 12.40 mmol), using bis(pinacolato)diboron (4.72 g, 18.60 mmol, CAS No: 73183-34-3), potassium acetate (3.65 g, 37.2 mmol) and Pd(dppf )Cl ₂ -CH ₂ Cl ₂ (1.01 g, 1.240 mmol) in anhydrous dioxane (100 ml) under Ar and heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((2methyl-7-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (112a) (5.2 g, 93% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.69 (d, J=1.8 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.29-7, 17 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.96-6.85 (m, 1H), 6.58 (d, J=1.3 Hz, 1H ), 5.13 (s, 2H), 4.00 (k, J=7.2 Hz, 2H), 3.59 (s, 2H), 2.47 (s, 3H), 1.33 (s , 12H), 1.06 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (112b).

Compound 112b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (112a) (1.5 g, 3.33 mmol) in dioxane (30 ml), using (4-chloropyridin-2-yl)methanamine (74a) (0.71 g, 5.00 mmol), bis(triphenylphosphine) palladium(P) chloride (0.35 g, 0.500 mmol) and a solution of K2CO3 (1.38 g, 9.99 mmol) in water (5 ml) in an Ar atmosphere and heating at 100°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (112b) (616 mg, 43% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.77 (d, J=5.2 Hz, 1H), 8.59 (s, 3H, D2O replaceable), 8.09-8.03 (m, 1H), 7.96 (dd, J=5.3, 1.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.30-7.19 (m, 2H), 7 ,14-7.08 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.73 (d, J=1.3 Hz, 1H), 5, 24 (s, 2H), 4.36-4.23 (m, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.52 (s , 3H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 431.3 (M+1); (ESI-): 465.4 (M+Cl).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (112c).

Compound 112c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy) phenyl)acetate (112b) (332 mg, 0.77 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (65 mg, 1.54 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (112c) (278 mg, 90% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 8.01 (dd, J=5.4, 1 .6 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.26-7.16 (m, 2H ), 7.04 (d, J=8.4 Hz, 1H), 6.88 (t, J=7.4 Hz, 1H), 6.72

- 185 045626 (s, 1H), 5.25 (s, 2H), 4.25 (s, 2H), 3.54 (s, 2H), 2.52 (s, 3H); MS (ESI+): 403.3 (M+1); (ESI-): 401.3 (M-1),

437.3 (M+Cl).

Scheme-113

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (113c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (113b).

Compound 113b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (112a) (500 mg, 1.11 mmol) in dioxane (8 ml) using (3-fluoro-4-iodopyridin-2-yl)methanamine ( 113a) (200 mg, 0.79 mmol; CAS No. 1805589-86-9), bis(triphenylphosphine) palladium(II) chloride (83 mg, 0.12 mmol) and K ₂ CO ₃ solution (329 mg, 2. 38 mmol) in water (2 ml) under Ar atmosphere and heating at 100°C for 1 hour in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (113b) (170 mg, 48% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=5.0 Hz, 1H), 8.58 (s, 3H, D2O replaceable), 7.78 (t, J=5 .3 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.44 (s, 1H), 7.29-7.18 (m, 2H), 7.11 (d , J=8.0 Hz, 1H), 6.91 (td, J=7.3, 1.0 Hz, 1H), 6.73 (d, J=1.3 Hz, 1H), 5.22 (s, 2H), 4.37 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.45 (s, 4H), 1 .00 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO4) δ -128.74; MS (ESI+): 449.3 (M+1); (ESI-): 483.3 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (113c).

Compound 113c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl ) methoxy)phenyl)acetate (113b) (112 mg, 0.25 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (21 mg, 0.50 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (113c) (67 mg, 64% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.28 (s, 1H, D2O replaceable), 8.69-8.54 (m, 4H, partially D2O replaceable), 7.82-7.74 (m , 2H), 7.49 (s, 1H), 7.28-7.19 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.91 (td, J= 7.4, 1.1 Hz, 1H), 6.72 (d, J=1.3 Hz, 1H), 5.25 (s, 2H), 4.45-4.28 (m, 2H), 3.58 (s, 2H), 2.45 (s, 4H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -128.55; MS (ESI+): 421.3 (M+1); (ESI-): 455.3 (M+Cl).

Scheme-114

Preparation of 2-(2-((3 -amino-7-(3 -(aminomethyl)phenyl)benzo[d]isoxazol-5 - 186 045626 yl)methoxy)phenyl)acetic acid (114j).

Stage-1. Preparation of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzoic acid (114b).

To a solution of lithium diisopropylamide (7.23 ml, 14.45 mmol) in THF (30 ml), cooled to -78°C, was added a solution of 2-bromo-4-(dimethoxymethyl)-1-fluorobenzene (114a) (3 g , 12.04 mmol; CAS No. 81358-658) in THF (10 ml) and stirred at -78°C for 25 min. The reaction mixture was quenched with dry ice and stirred at -78°C for 1 hour and allowed to warm to RT over a period of 0.5 hours. The reaction mixture was diluted with water (50 ml), ethyl acetate (100 ml) and acidified with 4N HCl to pH 4 The aqueous layer was separated and extracted with ethyl acetate (75 ml). The organic layers were combined, washed with brine (75 mL), dried, filtered and concentrated in vacuo to give 3bromo-5-(dimethoxymethyl)-2-fluorobenzoic acid (114b) (2.56 g, 73% yield) as a yellow solid , which was used as is in the next stage; MS (ESI-): 291.1 and 293.1 (M-1).

Stage-2. Preparation of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzamide (114c

To a suspension of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzoic acid (114b) (2.4 g, 8.19 mmol), ammonium chloride (1.314 g, 24.57 mmol) and 1H-benzo[d][ 1,2,3]triazol-1-ol (0.111 g, 0.819 mmol) in DMF (35 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.355 g, 12.28 mmol), N-ethyl-N-isopropylpropan-2-amine (2.85 ml, 16.38 mmol) and stirred at RT for 15 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2x75 ml), saline (75 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 3-bromo-5-(dimethoxymethyl)-2-fluorobenzamide (114c) (435 mg, 18% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (s, 1H), 7.78-7.70 (m, 2H), 7.60 (dd, J=6.2, 2.1 Hz, 1H), 5.42 (s, 1H), 3.27 (d, J=0.7 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -108.83; MS (ESI-): 326.1 and 328.1 (M+Cl).

Stage-3. Preparation of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile (114d).

To a solution of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzamide (114c) (418 mg, 1.431 mmol) and triethylamine (0.598 ml, 4.29 mmol) in DCM (20 ml), cooled to 0°C, was added dropwise 2,2,2trifluoroacetic anhydride (0.298 ml, 2.147 mmol) and stirred at 0°C for 2 hours. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N NaHCO ₃ (50 ml), brine (50 ml) , dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give 3-bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile (114d) (366 mg, 93% ) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.01 (dd, J=6.7, 2.0 Hz, 1H), 7.90 (dd, J=5.8, 2.0 Hz, 1H) , 5.43 (s, 1H), 3.28 (s, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -103.08.

Stage-4. Preparation of 7-bromo-5-(dimethoxymethyl)benzo[d]isoxazol-3-amine (114e).

To a solution of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzonityrle (114d) (350 mg, 1.277 mmol) in DMF (12 ml) was added N-hydroxyacetamide (288 mg, 3.83 mmol), potassium carbonate (529 mg , 3.83 mmol) and heated at 90°C for 5 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 ml) and washed with water (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give 7-bromo-5-(dimethoxymethyl)benzo[d]isoxazol-3-amine (114e) ( 162 mg, 44%) as an off-white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.95 (d, J=1.3 Hz, 1H), 7.72 (d, J=1.3 Hz, 1H), 6.65 (s, 2H), 5.51 (s, 1H), 3.26 (s, 6H); MS (ESI-): 321.1 (M+Cl).

Stage-5. Preparation of 3-amino-7-bromobenzo[d]isoxazole-5-carbaldehyde (114f).

To a solution of 7-bromo-5-(dimethoxymethyl)benzo[d]isoxazol-3-amine (114e) (155 mg, 0.540 mmol) in THF (4 ml) was added conc. hydrogen chloride (0.112 ml, 1.350 mmol) and stirred at RT for 6 hours. An additional portion of conc. HCl (0.25 ml) and continued stirring the reaction mixture at RT for 24 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with 1N NaHCO ₃ (40 ml), brine (40 ml), dried, filtered and concentrated in vacuum to give 3-amino-7-bromobenzo[d]isoxazole-5-carbaldehyde (114f) (137 mg) as an off-white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.49 (d, J=1.3 Hz, 1H), 8.32 (d, J=1.3 Hz, 1H), 6.90 (s, 2H); MS (ESI-): 239.1 (M-1).

Stage-6. Preparation of (3-amino-7-bromobenzo[d]isoxazol-5-yl)methanol (114g).

Sodium borohydride (42.4 mg, 1.120 mmol) was added to a solution of 3-amino-7-bromobenzo[d]isoxazole-5-carbaldehyde (114f) (135 mg, 0.560 mmol) in THF (15 ml) cooled to 0°C. and stirred at RT for 21 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (40 ml), brine (40 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel was eluted with hexanes/ethyl acetate (from

- 187 045626

1:0 to 0:1)] to give (3-amino-7-bromobenzo[d]isoxazol-5-yl)methanol (114g) (101 mg, 78% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (s, 1H), 7.69 (s, 1H), 6.57 (s, 2H), 5.42 (t, J=5.6 Hz, 1H), 4.57 (d,

J=5.4 Hz, 2H); MS (ESI-): 241.2 (M-1).

Stage-7. Preparation of ethyl 2-(2-((3-amino-7-bromobenzo[b]isoxazol-5-yl)methoxy)phenyl)acetate (114h).

Compound 114h was prepared according to the procedure described in step-2 of Scheme-23 from (3amino-7-bromobenzo[d]isoxazol-5-yl)methanol (114g) (95 mg, 0.39 mmol) in DCM (5 ml), using triphenylphosphine (154 mg, 0.59 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (176 mg, 0.98 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 215 mg, 0 .59 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 2:1)] ethyl 2-(2-((3-amino-7- bromobenzo[d]isoxazol-5yl)methoxy)phenyl)acetate (114h) (189 mg) as a white solid; MS (ESI-): 439.2 (M+Cl).

Stage-8. Preparation of ethyl 2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5yl)methoxy)phenyl)acetate (114i).

Compound 114i was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((3-amino-7-bromobenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (114h) ( 100 mg, 0.25 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (69 mg, 0.37 mmol), tricyclohexylphosphine (41.5 mg, 0.148 mmol), tripotassium phosphate solution (0.14 ml, 0.42 mmol, 3 M), water (0.1 ml) and Pd ₂ (dba) ₃ (68 mg, 0.074 mmol) and heating in an Ar atmosphere in a microwave oven at 125°C for 2 hours This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((3amino-7 -(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (114f (5 mg, 5% yield) as a white solid; MS (ESI+): 432.3 ( M+1) and 454.3 (M+Na).

Stage-9. Preparation of 2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5yl)methoxy)phenyl)acetic acid (114j).

Compound 114j was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy )phenyl)acetate (114i) (5 mg, 0.012 mmol) in THF (3 ml) and MeOH (3 ml), using a solution of lithium hydroxide monohydrate (5 mg, 0.12 mmol) in water (3 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/DMA 80 (1:0 to 1:2)] 2-(2-((3-amino-7-(3(aminomethyl )phenyl)benzo[0]isoxazol-5-yl)methoxy)phenyl)acetic acid (114j) (3 mg, 64%) as a white solid;

^1H NMR (300 MHz, methanol^) δ 8.26 (s, 1H), 8.19 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.76 (s , 1H), 7.51 (t, J=7.7 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.24-7.14 (m, 2H), 7 .00 (d, J=8.4 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.21 (s, 2H), 3 .61 (s, 2H); MS (ESI+): 404.2 (M+1); purity after HPLC: 91.21%.

Scheme-115

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetic acid (115f).

Stage-1. Preparation of 6-(hydroxymethyl)benzofuran-4-ol (115b).

To a solution of ethyl 4-acetoxybenzofuran-6-carboxylate (115a) (2 g, 8.06 mmol; prepared according to the procedure described by Yang, Xinye et al.; in WO 2017036404 (A1) - 2017-03-09) in THF (30 ml) was cooled to 0°C, lithium aluminum hydride (0.612 g, 16.11 mmol) was added and stirred at RT for 24 hours. The reaction mixture was carefully quenched with 20% aq. Na ₂ SO ₄ (20 ml), water (100 ml) and extracted with ethyl acetate (150 and 100 ml). The combined organic layer was washed with water (100 ml), brine (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 6-(hydroxymethyl)benzofuran-4-ol (115b) (883 mg, 67% yield) in as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 6.96 (p, J=0.9 Hz, 1H), 6.89 (dd, J=2.2, 1.0 Hz, 1H), 6.60-6.58 (m, 1H), 5.17 (br.s, 1H), 4.49 (br. s, 2H); MS (ESI-): 163.1 (M-1).

Stage-2. Preparation of 6-(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate (115c).

To a solution of 6-(hydroxymethyl)benzofuran-4-ol (115b) (860 mg, 5.24 mmol) in DMF (20 ml) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide ( 1910 mg, 5.24 mmol), triethylamine (1.460 ml, 10.48 mmol) and stirred at RT for 14 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2x60 ml), brine (60 ml) , dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give 6(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate (115c) (1.239 g, 80% yield) in in the form of a light brown oil.

1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J=2.3 Hz, 1H), 7.71 (p, J=0.9 Hz, 1H), 7.36 (br.s , 1H), 7.02 (dd, J=2.3, 0.9 Hz, 1H), 5.58-5.47 (m, 1H), 4.68-4.62 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -72.88; MS (ESI-): 331.1 (M+Cl).

Stage-3. Preparation of ethyl 2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6yl)methoxy)phenyl)acetate (115d).

Compound 115d was prepared according to the procedure described in step-2 of Scheme-23 from 6(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate (115c) (1.18 g, 3.98 mmol) in DCM (30 ml) using triphenylphosphine (1.567 g, 5.98 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.077 g, 5.98 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 2.194 g, 5.98 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 5:1)] ethyl 2-(2-((4-(((trifluoromethyl )sulfonyl)oxy)benzofuran-6yl)methoxy)phenyl)acetate (115d) (1.624 g, 89% yield) as a light brown gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.23 (d, J=2.3 Hz, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.24 ( d, J=7.6 Hz, 2H), 7.10-7.01 (m, 2H), 6.96-6.89 (m, 1H), 5.29 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -72.74; (ESI+): 481.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetate (115e).

Compound 115e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (115d) (500 mg, 1.091 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (307 mg, 1.636 mmol), sodium bicarbonate solution (275 mg, 3.27 mmol) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ (230 mg, 0.327 mmol) and heating in an Ar atmosphere at 100°C for 3 hours. This resulted in the following work-up and purification by flash column chromatography [silica gel (12 d), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6yl)methoxy)phenyl)acetate (115e) (295 mg, 65% yield) as a brown gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 7.66 (s, 2H), 7.56-7.33 (m, 4H), 7.30-7.18 (m, 2H), 7.13-7.06 (m, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.28 (s, 2H) , 3.95 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.65 (s, 2H), 1.02 (t, J=7.1 Hz, 3H) ; MS (ESI+): 416.3 (M+1).

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetic acid (115f).

Compound 115f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetate (115e) ( 200 mg, 0.48 mmol) in THF (10 ml) and MeOH (10 ml), using a solution of lithium hydroxide monohydrate (124 mg, 2.89 mmol) in water (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] 2-(2-((4-(3(aminomethyl)phenyl)benzofuran- 6-yl)methoxy)phenyl)acetic acid (115f) (125 mg, yield: 67%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.75-7.67 (m, 3H), 7.48 (t, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.15-7.14 (m, 1H), 7.12-7 .05 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.83-6.77 (m, 1H), 5.28 (s, 2H), 4.00 ( s, 2H), 3.39 (s, 2H); MS (ESI+): 388.3 (M+1), 410.3 (M+Na); MS (ESI-): 386.3 (M-1), 422.2 (M+Cl); purity after HPLC: 99.26%.

- 189 045626

Scheme-116

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (116f).

Stage-1. Preparation of 6-(hydroxymethyl)benzo[b]thiophen-4-ol (116b).

Compound 116b was prepared according to the procedure described in step-1 of scheme-115 from methyl 4-hydroxybenzo[b]thiophene-6-carboxylate (116a) (950 mg, 4.56 mmol; CAS No. 314725-14-9) in THF (15, using lithium aluminum hydride (260 mg, 6.84 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] 6 -(hydroxymethyl)benzo[b]thiophen-4-ol (116b) (545 mg, 66% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.50 (d, J=5.5 Hz, 1H), 7.40 (dd, J=5.5, 0 .8 Hz, 1H), 7.337.30 (m, 1H), 6.72-6.70 (m, 1H), 5.20 (t, J=5.8 Hz, 1H), 4.53-4 .49 (m, 2H); MS (ESI+): 181.05 (M+1), 203.05 (M+Na); MS (ESI-): 179.10 (M-1).

Stage-2. Preparation of 6-(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (116c).

Compound 116c was prepared according to the procedure described in step-2 of scheme-116 from 6(hydroxymethyl)benzo[b]thiophen-4-ol (116b) (535 mg, 2.97 mmol) in DMF (12 ml), using 1,1,1trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1082 mg, 2.97 mmol) and triethylamine (0.828 ml, 5.94 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] 6(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (116c) (720 mg , 78% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (m, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.45 (d, J=1.1 Hz, 1H), 7.41 (dd, J=5.6, 0.8 Hz, 1H), 5.54 (t, J=5.8 Hz, 1H), 4.67 (d, J=5.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -73.06; MS (ESI+): MS (ESI-): 311.10 (M-1).

Stage-3. Preparation of ethyl 2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (116d).

Compound 116d was prepared according to the procedure described in step-2 of Scheme-23 from 6(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (116c) (110 mg, 0.352 mmol) in DCM (4 ml) using triphenylphosphine (139 mg, 0.53 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (95 mg, 0.53 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 194 mg, 0.53 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 1:1)] ethyl 2-(2-((4-(((trifluoromethyl )sulfonyl)oxy)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (116d) (115 mg, 69% yield) as a colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.58 (s, 1H), 7.46 (d , J=5.6 Hz, 1H), 7.31-7.19 (m, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.93 (t, J=7, 4 Hz, 1H), 5.30 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.06 (t, J=7, 1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -72.96; MS (ESI+): 497.1 (M+Na); MS (ESI): 473.1 (M-1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (116e).

Compound 116e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl) acetate (116d) (172 mg, 0.363 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (102 mg, 0.544 mmol), sodium bicarbonate solution (91 mg, 1.088 mmol) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ (76 mg, 0.109 mmol) and heating in an Ar atmosphere at 95°C for 3 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with di- 190 045626 chloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6yl) methoxy)phenyl)acetate (116e) (38 mg, 24% yield) as a colorless gum; MS (ESI+): 432.2 (M+1).

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (116f).

Compound 116f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate (116e) (35 mg, 0.081 mmol) in THF (4 mL) and MeOH (4 mL), using a solution of lithium hydroxide monohydrate (21 mg, 0.49 mmol) in water (4 mL). This resulted in the preparation after treatment of 2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (116f) (24 mg, 74% yield) as off-white solid 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.67-7.63 (m, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.55-7.48 (m, 2H), 7.42 (d, J= 7.6 Hz, 1H), 7.16-7.09 (m, 2H), 6.99 (d, J=8.3 Hz, 1n), 6.83 (t, J=7.3 Hz, 1H), 5.28 (s, 2H), 4.06 (s, 2H), 3.45 (s, 2H); MS (ESI+): 404.3 (M+1), 426.3 (M+Na); MC (ESI-): 402.3 (M-1); purity after HPLC: 90.05%.

Scheme-117 he

116d ^117a 117b

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (117b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (117a).

Compound 117a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl) acetate (116d) (300 mg, 0.632 mmol) in dioxane (8 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (195 mg, 0.95 mmol), sodium bicarbonate solution ( 159 mg, 1.9 mmol) in water (0.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (133 mg, 0.19 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted obtained after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 19:1)] ethyl 2-(2-((4-(3-(aminomethyl) -2fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate (117a) (225 mg, 79% yield) as a brown gum;

^1H NMR (300 MHz, DMSO-d6) δ 8.11-8.08 (m, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.59 (td, J=7 ,0, 2.5 Hz, 1H), 7.41-7.39 (m, 1H), 7.38-7.19 (m, 4H), 7.18-7.08 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.83 (s , 2H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -122.29; MS (ESI+): 450.20 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (117b).

Compound 117b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy) phenyl)acetate (117a) (200 mg, 0.445 mmol) in THF (10 ml) and MeOH (10 ml), using a solution of lithium hydroxide monohydrate (114 mg, 2.67 mmol) in water (10 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(3- (aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (117b) (91 mg, 43% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (s, 3H), 8.17 (s, 1H), 7.83 (d, J=5.5 Hz, 1H), 7.69 ( td, J=7.3, 1.9 Hz, 1H), 7.56 (td, J=7.4, 1.8 Hz, 1H), 7.47-7.36 (m, 2H), 7 .29-7.18 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.31 (s, 2H), 4.16 (s, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.48; MS (ESI+): 422.1 (M+1); purity after HPLC: 99.60%; analysis calculation for C ₂₄ H ₂₀ FNO ₃ S-1.0HCl-1.0H ₂ O: C, 60.56; N, 4.87; N, 2.94; Cl, 7.45; observed: C, 60.69; N, 4.66; N, 2.95; Cl, 7.22.

- 191 045626

Scheme-118

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetic acid (118c).

Stage-1. Preparation of ethyl 2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindol-6-yl)methoxy)phenyl)acetate (118a).

Compound 118a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e) (0.9 g, 2.09 mmol), using bis(pinacolato)diboron (0.80 g, 3.14 mmol, CAS No: 73183-34-3), potassium acetate (0.62 g, 6.27 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.26 g, 0.31 mmol) in anhydrous dioxane (30 ml) under Ar and heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH 9:1 in 0% to 10% hexane] ethyl 2-(2-(( 1 -isopropyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-indol-6yl)methoxy)phenyl)acetate (118a) (0.6 g, 60% yield) as clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.70 (s, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.46 (d, J=1.3 Hz, 1H), 7.29-7.17 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.89 (t, J=7.4 Hz, 1H), 6, 76 (d, J=3.3 Hz, 1H), 5.18 (s, 2H), 4.76 (p, J=6.7 Hz, 1H), 4.00 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.44 (d, J=6.6 Hz, 6H), 1.32 (d, J=2.0 Hz, 12H), 1.04 ( t, J=7.1 Hz, 3H); MS (ESI+) 479.4 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetate (118b).

Compound 118b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(( 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1 H-indol-6-yl)methoxy)phenyl)acetate (118a) (0.6 g, 1.26 mmol) in dioxane (10 ml) using (4-chloropyridin-2-yl) methaneamine (74a) (0.216 ml, 1.885 mmol), bis(triphenylphosphine) palladium(P) chloride (0.13 g, 0.19 mmol) and a solution of K ₂ CO ₃ (0.43 g, 3.14 mmol) in water (1 ml) in an Ar atmosphere and heating at 100°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(2(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy )phenyl)acetate (118b) (0.3 g, 52% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J=5.2 Hz, 1H), 8.38 (s, 3H), 7.83 (s, 1H), 7.75 ( s, 1H), 7.72 (d, J=5.2 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.33 (s, 1H), 7.28- 7.20 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.73 (d, J=3 .3 Hz, 1H), 5.27 (s, 2H), 4.92-4.77 (m, 1H), 4.30 (k, J=6.0 Hz, 2H), 3.92 (k , J=7.1 Hz, 2H), 3.64 (s, 2H), 1.50 (d, J=6.7 Hz, 6H), 0.97 (t, J=7.1 Hz, 3H ); MS (ESI+): 458.5 (M+1); MS (ESI-): 492.5 (M+Cl). Purity after HPLC: 96.70%.

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)phenyl)acetic acid (118c).

Compound 118c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indole-6- yl)methoxy)phenyl)acetate (118b) (0.15 g, 0.33 mmol) in MeOH/THF (6 ml), using a solution of sodium hydroxide (0.07 g, 1.64 mmol) in water (2 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (118c) (0.04 g, 27% yield) as a yellow solid;

1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J=5.2 Hz, 1H), 8.44 (s, 3H), 7.86 (d, J=1.6 Hz, 1H ), 7.78 (s, 1H), 7.74 (dd, J=5.2, 1.7 Hz, 1H), 7.68 (d, J=3.3 Hz, 1H), 7.37 (d, J=1.2 Hz, 1H), 7.27-7.21 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.90 (td, J= 7.3, 1.0 Hz, 1H), 6.74 (d, J=3.2 Hz, 1H), 5.29 (s, 2H), 4.84 (p, J=6.6 Hz, 1H), 4.30 (s, 2H), 3.61 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); MS (ESI+): 430.5 (M+1); MS (ESI-): 428.5 (M-1), 464.5 (M+Cl). Purity after HPLC: 96.70%.

- 192 045626

Scheme-119

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetic acid (119e).

Stage-1. Preparation of (7-bromofuro[3,2-b]pyridin-5-yl)methanol (119b).

Compound 119b was prepared according to the procedure described in step-1 of Scheme-23 from 7bromofuro[3,2-b]pyridine-5-carboxylic acid (119a) (800 mg, 3.31 mmol, purchased from PharmaBlock, PB95208) using N-methylmorpholine (0.44 ml, 3.97 mmol) in THF (10 ml), isobutyl chloroformate (0.52 ml, 3.97 mmol) and NaBH4 (375 mg, 9.92 mmol) in water (5 ml). This resulted in (7-bromofuro[3,2-b]pyridin-5-yl)methanol (119b) (580 mg, 77% yield) as a white solid upon treatment;

^1H NMR (300 MHz, DMSO-d6) δ 8.41 (d, J=2.3 Hz, 1H), 7.66 (s, 1H), 7.20 (d, J=2.3 Hz, 1H), 5.59 (t, J=6.0 Hz, 1H, D2O replaceable), 4.64 (d, J=6.0 Hz, 2H); MS (ESI-): 226.0, 227.0 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c).

Compound 119c was prepared according to the procedure described in step-2 of Scheme-23 from (7bromofuro[3,2-b]pyridin-5-yl)methanol (119b) (380 mg, 1.67 mmol) in DCM (15 ml), using triphenylphosphine (481 mg, 1.83 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (330 mg, 1.83 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 673 mg, 1 .83 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromofuro[3,2-b] pyridin-5-yl)methoxy)phenyl)acetate (119c) (450 mg, 69% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J=2.3 Hz, 1H), 7.70 (s, 1H), 7.28 (d, J=2.2 Hz, 1H ), 7.25 (d, J=7.3 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.05 (k, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.11 (t, J=7.1 Hz, 3H); MS (ESI+): 412.1; 414.1 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetate (119d).

Compound 119d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c) ( 110 mg, 0.28 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (79 mg, 0.42 mmol), bis(triphenylphosphine) palladium(P) chloride (39.6 mg, 0.056 mmol) and K ₂ CO ₃ (117 mg, 0.85 mmol) in water (1 ml) in an Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2b]pyridin-5-yl)methoxy)phenyl)acetate (119d) (95 mg, 81% yield), HCl salt, as an off-white solid;

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.45 (d, J=2.3 Hz, 1H), 8.37 (s, 3H, D ₂ O replaceable), 8.13 (s, 1H) , 8.068.00 (m, 1H), 7.73 (s, 1H), 7.68-7.63 (m, 2H), 7.27-7.21 (m, 3H), 7.10 (d , J=8.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 4.15 (k, J=5, 8 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.69 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 417.2 (M+1); (ESI-): 415.3 (M-1); 451.2 (M+Cl).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetic acid (119e).

Compound 119e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy )phenyl)acetate (119d) (60 mg, 0.14 mmol) in MeOH/THF (6 ml), using a solution of lithium hydroxide monohydrate (15 mg, 0.36 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetic acid (119e) (36 mg, 64% yield), HCl salt, as a white solid;

- 193 045626

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.52-8.34 (m, 4H, partly D ₂ O replaceable), 8.14 (s, 1H), 8.06 (dt,

J=6.6, 2.0 Hz, 1H), 7.79 (s, 1H), 7.69-7.62 (m, 2H), 7.27-7.20 (m, 3H), 7 .08 (d, J=8.1 Hz, 1H), 6.92 (td, J=7.4,

1.0 Hz, 1H), 5.34 (s, 2H), 4.16 (k, J=5.9 Hz, 2H), 3.66 (s, 2H); MS (ESI+): 389.4 (M+1); (ESI-): 387.4 (M-1);

423.4 (M+Cl).

Scheme-120

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (120c).

Stage-1. Preparation of ethyl 2-(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate ( 120a).

Compound 120a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (96c) ( 3 g, 6.25 mmol) using bis(pinacolato)diboron (2.38 g, 9.37 mmol), potassium acetate (1.84 g, 18.74 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.77 g, 0.94 mmol) in anhydrous dioxane (30 ml) under Ar and heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((2-(methoxymethyl)-7-(4 ,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (120a) (1.8 g, 60% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.29-7.18 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 6.92-6.90 (m, 1H), 5.16 (s , 2H), 4.55 (s, 2H), 4.04-3.98 (m, 2H), 3.59 (s, 2H), 3.33 (s, 3H), 1.34 (s, 12H), 1.05-1.01 (m, 3H); MS (ESI+): 503.4 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (120b).

Compound 120b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (120a) (1334 mg, 2.78 mmol) in dioxane (10 ml), using (3-fluoro-4iodopyridin-2-yl)methanamine (113a) 500 mg, 1.99 mmol), bis(triphenylphosphine) palladium(P) chloride (209 mg, 0.30 mmol) and a solution of K2CO3 (823 mg, 5.95 mmol) in water (3 ml) in an Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (80 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran5-yl) methoxy)phenyl)acetate (120b) (455 mg, 48% yield) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (d, J=4.9 Hz, 1H), 8.56 (s, 3H, D2O replaceable), 7.86 (d, J=1, 6 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.31-7.19 (m, 2H) , 7.15-7.09 (m, 1H), 7.07 (s, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H ), 4.54 (s, 2H), 4.38 (d, J=6.1 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.63 (s, 2H ), 3.30 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (339 MHz, DMSO) δ -128.76; MS (ESI+): 479.2 (M+1); 501.2 (M+Na); (ESI-): 477.3 (M-1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran5-yl)methoxy)phenyl)acetic acid (120c).

Compound 120c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran- 5-yl)methoxy)phenyl)acetate (120b) (255 mg, 0.53 mmol) in MeOH/THF (8 ml), using a solution of lithium hydroxide monohydrate (56 mg, 1.33 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (120c) (140 mg, 58% yield) as a white solid;

1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H, D2O replaceable), 8.63 (dd, J=4.9, 1.3 Hz, 1H), 8.49 (s, 3H ,

- 194 045626

D2O replaceable), 7.88 (d, J=1.7 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.27-7 .18 (m, 2H), 7.09 (d, J=8.1

Hz, 1H), 7.04 (d, J=1.4 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.27 (s, 2H), 4.53 ( s, 2H), 4.37 (d, J=5.9 Hz, 2H), 3.58 (s, 2H), 3.29 (s, 3H); ¹⁹ F NMR (339 MHz, DMSO) δ -128.57; MS (ESI+): 451.2 (M+1); (ESI-): 449.3 (M-1).

Scheme-121

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetic acid (121b).

Stage-1. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)phenyl)acetate (121a).

Compound 121a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (118a) (0.85 g, 1.79 mmol) in dioxane (10 ml) using (3-fluoro-4-iodopyridine-2 -yl)methanamine (113a) (0.3 g, 1.19 mmol), bis(triphenylphosphine) palladium(P) chloride (0.13 g, 0.18 mmol) and K2CO3 solution (0.41 g, 2. 98 mmol) in water (1.0 ml) under Ar atmosphere and heating at 100°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1 H-indole-6 -yl)methoxy)phenyl)acetate (121a) (0.1 g, 18% yield) as a yellow solid; MS (ESI+): 475.5 (M+1); MS (ESI-): 474.5 (M-1).

Stage-2. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)phenyl)acetic acid (121b).

Compound 121b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H- indol-6-yl)methoxy)phenyl)acetate (121a) (0.1 g, 0.210 mmol) in MeOH/THF (4 ml), using a solution of lithium hydroxide monohydrate (44 mg, 1.05 mmol) in water (1 ,0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(2- (aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (121b) (0.04 g, 43% yield) as a yellow solid;

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.57 (d, J=4.9 Hz, 1H), 8.52-8.46 (br. s, 3H), 7.81 (s, 1H), 7.69 (t, J=5.3 Hz, 1H), 7.65 (d, J=3.3 Hz, 1H), 7.27 (s, 1H), 7.26-7, 20 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.90 (td, J=7.3, 1.1 Hz, 1H), 6.40 (t, J =3.0 Hz, 1H), 5.28 (s, 2H), 4.84 (p, J=6.7 Hz, 1H), 4.36 (m, 2H), 3.59 (s, 2H ), 1.49 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -129.76; MS (ESI+): 448.5 (M+1); MS (ESI-): 446.5 (M-1), 482.5 (M+Cl). Purity after HPLC: 95.70%.

Scheme-122

122a 122b

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)acetic acid (122b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6yl)methoxy)phenyl)acetate (122a).

Compound 122a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (115d) (500 mg, 1.091 mmol) in dioxane (10 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (336 mg, 1.636 mmol), sodium bicarbonate solution (275 mg, 3.27 mmol) in water (1 ml) and bis(triphenylphosphine) palladium(P) chloride (230 mg, 0.327 mmol) and heating under nitrogen at 95°C for 3 hours. This gave, after work-up and purification by flash chromatography, column [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl) methoxy)phenyl)acetate (122a) (147 mg) as a yellow gum (147 mg, 31%). MS (ESI+): 434.4 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-195 045626 yl)methoxy)phenyl)acetic acid (122b).

Compound 122b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)acetate ( 122a) (147 mg, 0.339 mmol) in THF (7 ml) and MeOH (7 ml), using a solution of lithium hydroxide monohydrate (87 mg, 2.04 mmol) in water (7 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] 2-(2-((4(3-(aminomethyl)-2-fluorophenyl)benzofuran -6-yl)methoxy)phenyl)acetic acid (122b) (44 mg, 32% yield) as a white solid ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2, 2 Hz, 1H), 7.72 (s, 1H), 7.55 (t, J=7.2 Hz, 1H), 7.48 (s, 1H), 7.47-7.43 (m, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.25-7.18 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6, 92-6.86 (m, 1H), 6.86-6.82 (m, 1H), 5.30 (s, 2H), 3.89 (s, 2H), 3.56 (s, 2H) ; MS (ESI+): 406.4 (M+1), 428.4 (M+Na); MC (ESI-): 404.5 (M-1); purity after HPLC: 96.40%.

Scheme-123

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetic acid (123d).

Stage-1. Preparation of ethyl 2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-6-yl)methoxy)phenyl)acetate (123b).

Compound 123b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (115d) (500 mg, 1.09 mmol) in dioxane (10 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridin-2-yl) methyl carbamate (123a) (547 mg, 1.64 mmol; CAS No. 1425334-54-8), solution of sodium bicarbonate (275 mg, 3.27 mmol) in water (1 ml) and bis(triphenylphosphine) palladium(P) chloride (230 mg, 0.327 mmol) and heating under nitrogen at 95°C for 3 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with hexanes/ethyl acetate (from 1: 0 to 1:1)] ethyl 2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-6-yl)methoxy)phenyl)acetate (123b) ( 177 mg, 31%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.62 (dd, J=5.0, 0.9 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H), 7, 79-7.77 (m, 1H), 7.59-7.49 (m, 4H), 7.31-7.19 (m, 2H), 7.15-7.06 (m, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.93 (k , J=7.1 Hz, 2H), 3.65 (s, 2H), 1.40 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 539.5 (M+Na); MS (ESI-): 515.5 (M-1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6yl)methoxy)phenyl)acetate (123c).

Compound 123c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-6 -yl)methoxy)phenyl)acetate (123b) (160 mg, 0.31 mmol) in DCM (10 ml) using TFA (0.24 ml, 3.10 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DCM/methanol (1:0 to 9:1)] ethyl 2-(2-((4-(2-( aminomethyl)pyridin-4-yl)benzofuran-6yl)methoxy)phenyl)acetate (123c) (136 mg, 83% yield) as a light brown gum.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.76 (d, J=5.1 Hz, 1H), 8.36 (s, 3H), 8.21 (d, J=2.3 Hz, 1H), 7.82 (d, J=5.8 Hz, 2H), 7.74 (dd, J=5.2, 1.7 Hz, 1H), 7.61 (d, J=1.3 Hz, 1H), 7.33-7.18 (m, 3H), 7.10 (d, J=8.1 Hz, 1H), 6.95-6.88 (m, 1H), 5.30 (s, 2H), 4.33 (s, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.02 (t, J=7, 1 Hz, 3H); MS (ESI+): 417.4 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6yl)methoxy)phenyl)acetic acid (123d).

Compound 123d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate (123c) (100 mg, 0.19 mmol) in THF (6 mL) and MeOH (6 mL), using a solution of lithium hydroxide monohydrate (62 mg, 1.44 mmol) in water (7 mL). This resulted in, after work-up and purification by flash chromatography,

- 196 045626 column [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] 2-(2-((4-(2(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy) phenyl)acetic acid (123d) (25 mg, 33% yield) as an off-white solid.

1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=5.2 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.15 (s, 1H ), 7.81 (d, J=13.5 Hz, 2H), 7.72 (dd, J=5.1, 1.7 Hz, 1H), 7.26-7.25 (m, 1H) , 7.15-7.10 (m, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 5.31 ( s, 2H), 4.09 (s, 2H), 3.45 (s, 2H); MS (ESI+): 389.4 (M+1); MS (ESI-): 387.3 (M-1), 423.3 (M+Cl).

Scheme-124

124e

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1 H-indazol-6-yl)methoxy)phenyl)acetic acid (124g) and ethyl 2-(2-((4 -(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)acetate (124h).

Stage-1. Preparation of 4-bromo-1-tosyl-1H-indazole-6-carboxylic acid (124b).

Compound 124b was prepared according to the procedure described in Step-1 of Scheme-40 from 4bromo-1H-indazole-6-carboxylic acid (124a) (1.00 g, 4.15 mmol; CAS No. 885523-43-3) in DMF (25 ml), using NaH (60% in mineral oil, 0.332 g, 8.30 mmol), tosyl-Cl (0.870 g, 4.56 mmol). This resulted in 4-bromo-1-tosyl-1H-indazole-6-carboxylic acid (124b) (1.292 g, 79% yield) as a white solid upon treatment; MS (ESI+): 395.0; 397.0 (M+2).

Stage-2. Preparation of (4-bromo-1-tosyl-1H-indazol-6-yl)methanol (124c).

Compound 124c was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-tosyl-1H-indazole-6-carboxylic acid (124b) (1.28 g, 3.24 mmol) using Nmethylmorpholine ( 0.427 ml, 3.89 mmol) in THF (30 ml), isobutyl chloroformate (0.51 ml, 3.89 mmol) and NaBH ₄ (0.368 g, 9.72 mmol) in water (3 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] (4-bromo-1-tosyl-1H-indazol-6-yl)methanol (124c ) (0.438 g, 36% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J=0.9 Hz, 1H), 8.16-8.09 (m, 1H), 7.88-7.77 (m , 2H), 7.59 (d, J=1.0 Hz, 1H), 7.49-7.36 (m, 2H), 5.64 (t, J=5.8 Hz, 1H), 4 .71 (d, J=5.8 Hz, 2H), 2.34 (s, 3H); MS (ESI+): 403.1, 405.1 (M+Na); MS (ESI-): 479.1, 481.1 (M+Cl), 415.1, 417.1 (M+Cl).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d).

Compound 124d was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-tosyl-1H-indazol-6-yl)methanol (124c) (0.422 g, 1.107 mmol) in THF (25 ml) using triphenylphosphine (0.377 g, 1.439 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.259 g, 1.439 mmol) and DIAD (0.280 mL, 1.439 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 25 g, eluted with ethyl acetate in 0 to 100% hexanes] ethyl 2(2-((4-bromo-1-tosyl-1H-indazol-6-yl) methoxy)phenyl)acetate (124d) (0.406 g, 68% yield) as a pale yellow solid; MS (ESI+): 543.1; 545.1 (M+2).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl1 H-indazol-6-yl)methoxy)phenyl)acetate (124e) .

Compound 124e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d) ( 400 mg, 0.74 mmol) in dioxane (6 ml) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate ( 34a) (0.388 g, 1.104 mmol), tripotassium phosphate (1.3 M solution, 0.736 ml, 2.208 mmol), tricyclohexylphosphine (0.062 g, 0.221 mmol) and Pd ₂ (dba) ₃ (0.067 g, 0.074 mmol) in an Ar atmosphere and heating at 125°C for 45 minutes in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, 25 g, eluted with methanol in DCM 0 to 100%] ethyl 2(2-((4-(3-(((tert-butoxycarbonyl)amino )Methyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6yl)methoxy)phenyl)acetate (124e) (0.175 g, 35% yield) as a yellow solid; MS (ESI+): 710.3 (M+Na); MS (ESI-): 722.2 (M+Cl).

Stage-5. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6yl)methoxy)phenyl)acetate (124f).

Compound 124f was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl -1H-indazol-6yl)methoxy)phenyl)acetate (124e) (0.17 g, 0.247 mmol) in DCM (10 ml) using TFA (0.29 ml, 3.71 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4 -(3(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124f) (0.061 g, 42% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=3.4 Hz, 1H), 8.43-8.10 (m, 3H), 7.84 (d, J=8 .3 Hz, 2H), 7.717.57 (m, 2H), 7.53 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.39 (d, J=8 .3 Hz, 2H), 7.32-7.21 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H ), 5.42 (s, 2H), 4.14 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.69 (s, 2H), 2.34 (s , 3H), 0.94 (t, J=7.1 Hz, 3H); MS (ESI+): 588.3 (M+1); MS (ESI-): 622.4 (M+Cl).

Stage-6. Preparation of 2-(2-((4-(3 -(aminomethyl)-2-fluorophenyl)-1 H-indazol-6yl)methoxy)phenyl)acetic acid (124g).

Compound 124g was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl )methoxy)phenyl)acetate (124f) (0.058 g, 0.099 mmol) in THF (3 ml) and methanol (6 ml), using sodium hydroxide solution (2 M aq, 0.493 ml, 0.987 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)acetic acid (124g) (0.027 g, 68% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.30 (s, 1H), 8.39 (s, 3H), 8.05 (d, J=3.1 Hz, 1H), 7.70 ( s, 1H), 7.697.61 (m, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.28 (s, 1H), 7.25-7.19 (m, 2H ), 7.09 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.33 (s, 2H), 4.25-4.13 (m, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.45; MS (ESI+): 406.3 (M+1), 811.4 (2M+1); MS (ESI-): 404.4 (M-1), 440.3 (M+Cl), 809.5 (2M-1); purity after HPLC: 92.19%.

Stage-7. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6yl)methoxy)phenyl)acetate (124h).

Compound 124h was prepared according to the procedure described in step-1 of Scheme-58 from ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6- yl)methoxy)phenyl)acetate (124f) in THF (20 ml) using tetrabutylammonium fluoride (1.415 g, 5.41 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4 -(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6yl)methoxy)phenyl)acetate (124h) (0.014 g, 6% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.32 (s, 1H, D ₂ O replaceable), 8.38 (s, 4H, D2O replaceable, 3H), 8.06 (d, J=3, 0 Hz, 1H), 7.71-7.61 (m, 3H), 7.44 (t, J=7.6 Hz, 1H), 7.28-7.20 (m, 3H), 7, 12 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.30 (s, 2H), 4.31-4.10 (m, 2H ), 3.93 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 0.98 (t, J=7.1 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.55; MS (ESI+): 434.4 (M+1); 456.3 (M+Na); MS (ESI-): 468.4 (M+Cl); 901.6 (2М+Ш).

- 198 045626

Scheme-125

Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetic acid (125c).

Stage-1. Preparation of ethyl 2-(2-(8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2a]pyridine-6-carboxamido)phenyl)acetate (125a).

Compound 125a was prepared according to the procedure described in step-4 of Scheme-1 from 8-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylic acid ( 102c) (0.350 g, 0.953 mmol) in DMF (10 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (0.205 g, 1.143 mmol), DIPEA (0.830 ml, 4.76 mmol) and HATU ( 0.543 g, 1.429 mmol). This resulted, after work-up and purification by flash column chromatography (silica gel, 24 g eluted with methanol in 0 to 20% DCM), ethyl 2-(2-(8-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)imidazo[1,2-a]pyridine6-carboxamido)phenyl)acetate (125a) (0.388 g, 77% yield) as yellow syrup; MS (ESI-): 527.4 (M1).

Stage-2. Preparation of ethyl 2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6carboxamido)phenyl)acetate (125b).

Compound 125b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a] pyridine-6carboxamido)phenyl)acetate (125a) (0.371 g, 0.702 mmol) in DCM (10 ml) using TFA (0.811 ml, 10.53 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2(8-( 3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate (125b) (0.138 g, 46% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 9.54 (s, 1H), 8.63 (s, 3H), 8.57-8.50 (m, 2H ), 8.25-8.12 (m, 2H), 8.07-7.92 (m, 1H), 7.76-7.61 (m, 2H), 7.43-7.27 (m , 4H), 4.25-4.12 (m, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.01 (t, J= 7.1 Hz, 3H); MS (ESI+): 429.4 (M+1); MS (ESI-): 463.3 (M+Cl).

Stage-3. Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6carboxamido)phenyl)acetic acid (125c).

Compound 125c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl) acetate (125b) (0.065 g, 0.152 mmol) in THF (3 ml) and methanol (6 ml), using sodium hydroxide solution (2 M aq, 0.379 ml, 0.758 mmol). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%]2-(2-(8-( 3(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetic acid (125c) (0.027 g, 44% yield), HCl salt, as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 12.3 (br.s, 1H, D2O replaceable), 10.61 (s, 1H, D2O replaceable), 9.52 (s, 1H), 8.61 (s, 3H, D2O exchangeable), 8.52 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 8.01 (s , 1H), 7.757.62 (m, 2H), 7.48-7.22 (m, 4H), 4.24-4.13 (m, 2H), 3.72 (s, 2H); MS (ESI+): 401.3 (M+1); 801.5 (2M+1); MS (ESI-): 399.3 (M-1); 799.5 (2M-1); purity after HPLC: 98.60%.

- 199 045626

Scheme-126

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetic acid (126h).

Stage-1. Preparation of methyl 4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylate (126b) and methyl 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylate (126c).

Compounds 126b and 126c were prepared according to the procedure described in step-1 of Scheme-109 from methyl 4-bromo-1H-indazole-6-carboxylate (126a) (2.103 g, 8.24 mmol; CAS No. 885518-47- 8) in DMF using (bromomethyl)cyclopropane (1.201 ml, 12.37 mmol) and potassium carbonate (2.279 g, 16.49 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with 0% to 50% EtOAc in hexane] methyl 4-bromo-1-(cyclopropylmethyl)-1Hindazole-6-carboxylate (126b) (0.952 g, 37% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.18 (d, J=1.0 Hz, 1H), 7.83 (d, J=1.0 Hz, 1H), 4.46 (d, J=7.0 Hz, 2H), 3.92 (s, 3H), 1.39-1.21 (m, 1H), 0.56-0.36 (m , 4H) and methyl 4-bromo-2-(cyclopropylmethyl)-2Nindazole-6-carboxylate (126c) (0.821 g, 32% yield) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (d, J=0.9 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H), 4.37 (d, J=7.3 Hz, 2H), 3.90 (s, 3H), 1.55-1.32 (m, 1H), 0. 67-0.44 (m, 4H).

Stage-2. Preparation of 4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylic acid (126d).

Compound 126d was prepared according to the procedure described in step-4 of Scheme-4 from methyl 4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylate (126b) (0.930 g, 3.01 mmol) in THF (5 ml) and methanol (10 ml), using sodium hydroxide solution (2 M aq, 6.02 ml, 12.03 mmol). This resulted in 4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylic acid (126d) (0.839 g, 95% yield) as a white solid upon treatment;

1H NMR (300 MHz, DMSO-d6) δ 13.43 (s, 1H), 8.40 (d, J=1.2 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H ), 7.82 (d, J=1.0 Hz, 1H), 4.44 (d, J=7.1 Hz, 2H), 1.39-1.19 (m, 1H), 0.56 -0.45 (m, 2H), 0.45-0.35 (m, 2H); MS (ESI+): 293.2 (M-2).

Stage-3. Preparation of (4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methanol (126e).

Compound 126e was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylic acid (126d) (0.821 g, 2.78 mmol) using N- methylmorpholine (0.367 ml, 3.34 mmol) in THF (20 ml), isobutyl chloroformate (0.438 ml, 3.34 mmol) and NaBH ₄ (0.316 g, 8.35 mmol) in water (2 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] (4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methanol (126e) (0.735 g, 94% yield) as a thick yellow syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.00-7.94 (m, 1H), 7.68-7.62 (m, 1H), 7.36-7.29 (m, 1H), 5.44 (t, J=5.8 Hz, 1H), 4.62 (dd, J=5.8, 0.9 Hz, 2H), 4.30 (d, J=7.0 Hz, 2H ), 1.33-1.21 (m, 1H), 0.53-0.43 (m, 2H), 0.42-0.34 (m, 2H); MS (ESI+): 303.1 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetate (126f).

Compound 126f was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methanol (126e) (0.722 g, 2.57 mmol) in DCM (30 ml) using triphenylphosphine (0.741 g, 2.82 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.509 g, 2.82

- 200 045626 mmol) and di-(4-chlorobenzyl) azodicarboxylate (1.037 g, 2.82 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with EtOAc in 0 to 50% hexanes], ethyl 2-(2-((4-bromo-1-(cyclopropylmethyl)-1H- indazol-6yl)methoxy)phenyl)acetate (126f) (1.01 g, 89% yield) as a white solid; MS (ESI+):

465.2; 467.2 (M+Na).

Stage-5. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetate (126g).

Compound 126g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate (126f ) (0.500 g, 1.128 mmol) in dioxane (6 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.255 g, 1.692 mmol), tripotassium phosphate (1.3 M, 2.60 ml, 3.38 mmol), tricyclohexylphosphine (0.190 g, 0.677 mmol) and Pd ₂ (dba) ₃ (0.207 g, 0.226 mmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. This resulted in the following work-up and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 40%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetate ( 126g) (119 mg, 79% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 3H, D2O replaceable), 8.33-8.27 (m, 1H), 7.91 (s, 1H), 7.80 ( s, 1H), 7.78-7.72 (m, 1H), 7.65-7.51 (m, 2H), 7.36-7.30 (m, 1H), 7.26-7. 20 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 6.966.86 (m, 1H), 5.32 (s, 2H), 4.35 (d, J=6 .9 Hz, 2H), 4.21-4.09 (m, 2H), 4.02-3.87 (m, 2H), 3.67 (s, 2H), 1.41-1.20 ( m, 1H), 1.06-0.93 (m, 3H), 0.56-0.34 (m, 4H); MS (ESI+): 470.4 (M+1); 939.6 (2M+1); MS (ESI-): 504.4 (M+Cl), 973.7 (2M+a); analysis calculation for C ₂₉ H ₃₁ N ₃ O ₃ -HCl-1.25H ₂ O: C, 65.90; N, 6.58; Cl, 6.71; N, 7.95; observed C, 65.92; N, 6.46; Cl, 7.14; N, 7.94.

Stage-6. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(oppropylmethyl ring)-1H-indazol-6yl)methoxy)phenyl)acetic acid (126h).

Compound 126h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3 -(aminomethyl)phenyl)-1 -(cyclopropylmethyl)-1 H-indazol-6-yl )methoxy)phenyl)acetate (126g) (0.056 g, 0.119 mmol) in THF (3 ml) and methanol (6 ml), using sodium hydroxide solution (2 M aq, 0.298 ml, 0.596 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(3- (aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetic acid (126h) (0.016 g, 30% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.1 (br.s, 1H, D2O replaceable), 8.42-8.29 (m, 3H, D2O replaceable), 8.30 (s, 1H) , 7.91 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H) , 7.54 (d, J=7.6 Hz, 1H), 7.36 (s, 1H), 7.29-7.19 (m, 2H), 7.13-7.06 (m, 1H ), 6.92 (t, J=7.4 Hz, 1H), 5.34 (s, 2H), 4.35 (d, J=6.9 Hz, 2H), 4.22-4.06 (m, 2H), 3.64 (s, 2H), 1.40-1.20 (m, 1H), 0.53-0.35 (m, 4H); MS (ESI+): 442.3 (M+1); 883.5 (2M+1); MS (ESI-): 440.4 (M-1); 476.3 (M+Cl), 881.7 (2M-1); purity after HPLC: 94.67%.

Scheme-127

127a 127b

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetic acid (127b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1Hindazol-6-yl)methoxy)phenyl)acetate (127a).

Compound 127a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate (126f ) (0.45 g, 1.015 mmol) in dioxane (6 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid (56a) (0.257 g, 1.523 mmol), tripotassium phosphate (1.3 M, 2.342 ml, 3 .05 mmol), tricyclohexylphosphine (0.171 g, 0.609 mmol) and Pd ₂ (dba) ₃ (0.186 g, 0.203 mmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 40% MeOH in DCM] compound 127a (0.255 g, 52% yield) as the free base, 120 mg of this free base was subjected to reverse phase chromatography on a [C18 (30 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((4-(3 - (aminomethyl)-2-fluorophenyl)-1 -(cyclopropylmethyl)-1 H-indazol-6yl)methoxy)phenyl)acetate (127a) (44 mg, 37%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-06) δ 8.43 (s, 3H, D2O replaceable), 8.02 (d, J=2.9 Hz, 1H), 7.85 (s, 1H), 7 .66

- 201 045626 (t, J=7.4 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.31-7.17 (m, 3H), 7.11 (d , J=8.0 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.32 (s, 2H), 4.35 (d, J=7.0 Hz, 2H ), 4.24-4.12 (m, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.39-1.21 (m, 1H), 0.99 (t, J=7.1 Hz, 3H), 0.56-0.36 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.61; MS (ESI+): 488.3 (M+1);

975.6 (2M+1); MS (ESI-): 522.4 (M+Cl); purity after HPLC: 99.48%; analysis calculation for:

C2 _s H ₃₀ FN ₃ O ₃ 2.0H ₂ O 1.0HCl: C, 62.19; N, 6.30; N, 7.50; observed: C, 62.22; N, 6.23; N, 7.54.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetic acid (127b).

Compound 127b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazole-6 -yl)methoxy)phenyl)acetate (127a) (0.132 g, 0.271 mmol) in THF (3 mL) and methanol (6 mL) using sodium hydroxide solution (2 M aq, 0.677 mL, 1.354 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6yl)methoxy)phenyl)acetic acid (127b) (0.050 g, 40% yield), HCl salt, as a white solid society;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.2 (br.s, 1H, D2O replaceable), 8.44 (s, 3H, D2O replaceable), 8.01 (d, J=2.9 Hz , 1H), 7.87 (s, 1H), 7.74-7.61 (m, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.31-7.20 ( m, 3H), 7.09 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.33 (s, 2H), 4.34 ( d, J=7.0 Hz, 2H), 4.27-4.08 (m, 2H), 3.63 (s, 2H), 1.41-1.17 (m, 1H), 0.59 -0.33 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.56; MS (ESI+): 460.3 (M+1); 919.5 (2M+1); MS (ESI-): 458.4 (M-1); 494.3 (M+Cl), 917.7 (2M-1); purity after HPLC: 98.97%.

Scheme-128

128d 128е

128f 128g

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetic acid (128g).

Stage-1. Preparation of methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate (128a) and methyl 4-bromo-2methyl-2H-indazole-6-carboxylate (128b).

Compounds 128a and 128b were prepared according to the procedure described in step-1 of Scheme-109 from methyl 4-bromo-1H-indazole-6-carboxylate (126a) (2.00 g, 8.30 mmol) in DMF using iodomethane (1.291 ml, 20.74 mmol) and potassium carbonate (4.01 g, 29.0 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with 0% to 60% EtOAc in hexane] methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate (128a) (1.003 g, 45% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.38-8.33 (m, 1H), 8.17-8.11 (m, 1H), 7.86-7.81 (m, 1H) , 4.16 (s, 3H), 3.92 (s, 3H) and methyl 4-bromo-2-methyl-2H-indazole-6-carboxylate (128b) (0.591 g, 27% yield) as dirty white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.22 (m, 1H), 7.71 (d, J=1.1 Hz, 1H), 4.25 (s, 3H), 3.89 (s, 3H).

- 202 045626

Stage-2. Preparation of 4-bromo-1-methyl-1H-indazole-6-carboxylic acid (128c).

Compound 128c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate (128a) (1.655 g, 6.15 mmol) in THF (15 ml) and methanol (30 ml), using sodium hydroxide solution (2 M aq, 12.30 ml, 24.60 mmol). This resulted in 4-bromo-1-methyl-1H-indazole-6-carboxylic acid (128c) (1.479 g, 94% yield) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 13.36 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 4, 15 (s, 3H); MS (ESI-): 255.1, 253.0 (M-2).

Stage-3. Preparation of (4-bromo-1-methyl-1H-indazol-6-yl)methanol (128d).

Compound 128d was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-methyl-1H-indazole-6-carboxylic acid (128c) (1.43 g, 5.61 mmol) using Nmethylmorpholine ( 0.74 ml, 6.73 mmol) in THF (20 ml), isobutyl chloroformate ((0.883 ml, 6.73 mmol) and NaBH ₄ (0.636 g, 16.82 mmol) in water (20 ml). This resulted in obtained after work-up and purification by flash column chromatography [silica gel 40 g, eluted with ethyl acetate in 0% to 100% hexanes] (4-bromo-1-methyl-1H-indazol-6-yl)methanol (128d) (1 .21 g, 5.02 mmol, 90% yield) as a yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.99-7.91 (m, 1H), 7.63-7.53 (m, 1H), 7.36-7.30 (m, 1H), 5.41 (td, J=5.8, 1.0 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.04 (s, 3H); MS (ESI-): 241.1, 239.1 (M-2).

Stage-4. Preparation of ethyl 2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e).

Compound 128e was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-methyl-1H-indazol-6-yl)methanol (128d) (1.2 g, 4.98 mmol) in DCM (30 ml) using triphenylphosphine (1.436 g, 5.48 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.987 g, 5.48 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 2.010 g , 5.48 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with EtOAc in 0% to 100% hexanes], ethyl 2-(2-((4-bromo-1-methyl-1H-indazole -6-yl)methoxy)phenyl)acetate (128e) (1.22 g, 3.03 mmol, 60.8% yield) as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.09-7.94 (m, 1H), 7.81-7.70 (m, 1H), 7.46-7.35 (m, 1H) , 7.32-7.20 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.93 (td, J=7.4, 1.0 Hz, 1H), 5.24 (s, 2H), 4.10-3.99 (m, 5H), 3.67 (s, 2H), 1.08 (t, 3H); MS (ESI+): 425.1 (M+Na); MS (ESI-): 401.2 (M-2).

Stage-5. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetate (128f).

Compound 128f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e) ( 0.609 g, 1.510 mmol) in dioxane (6 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.383 g, 2.265 mmol), tripotassium phosphate (1.3 M, 3.48 ml , 4.53 mmol), tricyclohexylphosphine (0.254 g, 0.906 mmol) and Pd ₂ (dba) ₃ (0.277 g, 0.302 mmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. This resulted in the following work-up and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 40%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl )acetate (128f) (0.358 g, 53% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.50-8.36 (m, 3H), 8.02 (d, J=3.0 Hz, 1H), 7.80 (s, 1H), 7 .66 (t, J=7.1 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.32-7.19 (m, 3H), 7.12 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.32 (s, 2H), 4.22-4.15 (m, 2H), 4, 10 (s, 3H), 3.93 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.62; MS (ESI+): 448.3 (M+1); MS (ESI-): 482.3 (M+Cl); purity after HPLC: 98.19%; analysis calculation for: C ₂₆ H ₂₆ FN ₃ O ₃ 0.25H ₂ O1.0HCl: C, 63.93; N, 5.67; Cl, 7.26; N, 8.60; observed: C, 63.81; N, 5.77; Cl, 7.11; N, 8.62.

Stage-6. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetic acid (128g).

Compound 128g was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl )methoxy)phenyl)acetate (128f) (0.179 g, 0.40 mmol) in THF (3 ml) and methanol (6 ml), using sodium hydroxide solution (2 M aq, 1.0 ml, 2.0 mmol ). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetic acid (128g) (0.079 g, 47% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.2 (br.s, 1H, D2O replaceable), 8.44 (s, 3H, D2O replaceable), 8.02 (d, J=3.0 Hz , 1H), 7.83 (s, 1H), 7.66 (t, J=7.3 Hz, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.29 (s , 1H), 7.24 (d, J=7.2 Hz, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H ), 5.34 (s, 2H), 4.24-4.13 (m, 2H), 4.09 (s, 3H), 3.63 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.58; MS (ESI+): 420.3 (M+1); 839.5 (2M+1); MS (ESI-): 418.3 (M-1); 454.3 (M+Cl), 837.6 (2M-1); purity after HPLC: 98.76%; analysis calculation for:

- 203 045626

C ₂₄ H ₂₂ FN ₃ O ₃ -2.0H ₂ O-1.05HC1: C, 58.38; N, 5.52; Cl, 7.54; N, 8.51; observed: C, 58.32; N, 5.45; Cl, 7.76;

N, 8.56.

Receipt

Scheme-129

2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6yl)methoxy)phenyl)acetic acid (129e).

Stage-1. Preparation of 4-bromo-2-methyl-2H-indazole-6-carboxylic acid (129a).

Compound 129a was prepared according to the procedure described in step-4 of Scheme-4 from methyl 4-bromo-2-methyl-2H-indazole-6-carboxylate (128b) (1.2 g, 4.46 mmol) in THF (15 ml) and methanol (30 ml), using sodium hydroxide solution (2 M aq, 8.92 ml, 17.84 mmol). This resulted in 4-bromo-2-methyl-2H-indazole-6-carboxylic acid (129a) (1.06 g, 93% yield) as an off-white solid upon treatment;

^1H NMR (300 MHz, DMSO- _d6 ) δ 13.15 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.77-7.61 (m, 1H), 4.24 (s, 3H).

Stage-2. Preparation of (4-bromo-2-methyl-2H-indazol-6-yl)methanol (129b).

Compound 129b was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-2-methyl-2H-indazole-6-carboxylic acid (129a) (1.00 g, 3.92 mmol) using Nmethylmorpholine ( 0.517 ml, 4.70 mmol) in THF (20 ml), isobutyl chloroformate (0.618 ml, 4.70 mmol) and NaBH ₄ (0.445 g, 11.76 mmol) in water (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] (4-bromo-2-methyl-2H-indazol-6-yl)methanol (129b ) (0.684 g, 72% yield) as an off-white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.48-8.24 (m, 1H), 7.65-7.38 (m, 1H), 7.32-7.15 (m, 1H) , 5.43-5.22 (m, 1H), 4.55 (d, J=5.5 Hz, 2H), 4.34-4.02 (m, 3H).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate (129c).

Compound 129c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-2-methyl-2H-indazol-6-yl)methanol (129b) (0.670 g, 2.78 mmol) in DCM (30 ml), using triphenylphosphine (0.802 g, 3.06 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.551 g, 3.06 mmol) and di-(4chlorobenzyl) azodicarboxylate (1.122 g, 3.06 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with EtOAc in 0% to 100% hexanes], ethyl 2-(2-((4-bromo-2-methyl-2H-indazol- 6-yl)methoxy)phenyl)acetate (129c) (0.681 g, 61% yield) as a waxy white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.39 (s, 1H), 7.73-7.65 (m, 1H), 7.30-7.28 (m, 1H), 7.26 -7.21 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.17 ( s, 2H), 4.18 (d, J=1.4 Hz, 3H), 4.05 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.12 ( t, J=7.2 Hz, 3H); MS (ESI+): 425.2; 427.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6yl)methoxy)phenyl)acetate (129d).

Compound 129d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate (129c) ( 0.655 g, 1.624 mmol) in dioxane (6 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.412 g, 2.436 mmol), tripotassium phosphate (1.3 M, 3.75 ml , 4.87 mmol), tricyclohexylphosphine (0.273 g, 0.975 mmol) and Pd ₂ (dba) ₃ (0.297 g, 0.325 mmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. This resulted in the following work-up and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 40%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl )acetate (129d) (0.458 g, 63% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 3H, D2O replaceable), 8.43-8.35 (m, 1H), 7.73 (s, 1H), 7.73-7 .51 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.29-7.18 (m, 2H), 7.16 (s, 1H), 7.11 ( d, J=8.2 Hz, 1H), 6.96-6.85 (m, 1H), 5.24 (s, 2H), 4.17 (s, 5H), 3.95 (k, J =7.1 Hz, 2H), 3.68-3.59 (m, 2H), 1.03 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz,

- 204 045626

DMSO-d ₆ ) δ -118.09; MS (ESI+): 448.3 (M+1), 895.6 (2M+1); MS (ESI-): 482.3 (M+Cl); analysis calculation for: C ₂₆ H ₂₆ FN ₃ O ₃ -1.75H ₂ O-1.25HC1: C, 59.53; N, 5.91; Cl, 8.45; N, 8.01; observed: C, 59.50; N, 5.69; Cl,

9.05;N, 8.01.

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6yl)methoxy)phenyl)acetic acid (129e).

Compound 129e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl )methoxy)phenyl)acetate (129d) (0.219 g, 0.489 mmol) in THF (4 mL) and methanol (8 mL) using sodium hydroxide solution (2 M aq, 1.223 mL, 2.447 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetic acid (129e) (0.060 g, 29% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.68-8.49 (m, 3H, D2O replaceable), 8.44-8.38 (m, 1H), 7.74 (s, 1H), 7.71-7.59 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.28-7.18 (m, 3H), 7.09 (d, J= 8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.27-4.08 (m, 5H), 3.59 ( s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -117.96; MS (ESI+): 420.3 (M+1); 839.5 (2M+1); MS (ESI-): 454.3 (M+Cl), 837.7 (2M-1), 873.5 (2M+a); purity after HPLC: 98.12%.

Scheme-130

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5cyclopropylphenyl)acetic acid (130g).

Stage-1. Preparation of ethyl 2-(5-cyclopropyl-2-hydroxyphenyl)acetate (130b).

Cyclopropylboronic acid (0.249 g, 2.89 mmol), dicyclohexyl(2',6'diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.090 g, 0.193 mmol), Pd ₂ (dba) ₃ (0.088 g, 0.096 mmol) and Na ₂ CO ₃ solution (0.82 g, 7.72 mmol) in water (2 ml) under nitrogen and heated at 100°C for 2.5 hours. The reaction mixture was cooled to RT, diluted with EtOAc (100 ml), washed with brine ( 50 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with EtOAc in 0% to 40% hexanes] to give ethyl 2-(5-cyclopropyl-2-hydroxyphenyl) acetate (130b) (0.256 g, 1.162 mmol, 60. 2% yield) in the form of a thick yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 6.86-6.73 (m, 2H), 6.66 (d, J=8.2 Hz, 1H) , 4.05 (k, J=8.8, 8.0 Hz, 2H), 3.48 (s, 2H), 1.86-1.70 (m, 1H), 1.17 (t, J =7.1 Hz, 3H), 0.91-0.74 (m, 2H), 0.62-0.42 (m, 2H).

Stage-2. Preparation of 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (130c).

Compound 130c was prepared according to the procedure described in step-3 of Scheme-1 from 7-bromobenzofuran-5-carboxylic acid (15a) (3 g, 12.45 mmol) in dioxane (100 ml) using (3-((tert-butoxycarbonyl )amino)methyl)phenylboronic acid (1d) (4.38 g, 17.42 mmol), a solution of potassium carbonate (5.16 g, 37.3 mmol) in water (10 ml) and bis(triphenylphosphine) palladium (P ) chloride (1.310 g, 1.867 mmol) and heating under nitrogen at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 50%] 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5-carboxylic acid (130c) (2.7 g, 7.35 mmol, 59.0% yield) as a clear oil;

- 205 045626

1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=1.5 Hz, 1H), 8.12-8.05 (m, 2H), 7.76-7.68 (m, 2H), 7.56-7.43 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 4, 23 (d, J=6.2 Hz, 2H), 1.39 (s, 9H); MS (ESI-) 366.3 (M-1).

Stage-3. Preparation of tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d).

Compound 130d was prepared according to the procedure described in step-1 of Scheme-23 from 7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (130c) (1.7 g, 4.63 mmol) using N-methylmorpholine (0.610 ml, 5.55 mmol) in THF (40 ml), isobutyl chloroformate (0.729 ml, 5.55 mmol) and NaBH4 (0.525 g, 13.88 mmol) in water ( 5 ml). This resulted in tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1.1 g, 3.11 mmol, 67.3% yield) as a white solid after workup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.02 (d, J=2.2 Hz, 1H), 7.73 (m, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.52-7.38 (m, 3H), 7.28 (d, J=7.6 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 5, 23 (t, J=5.7 Hz, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 1.40 ( s, 9H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-cyclopropylphenyl)acetate (130e).

Compound 130e was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.400 g, 1.132 mmol) in THF (15 ml) using triphenylphosphine (0.327 g, 1.245 mmol), ethyl 2-(5-cyclopropyl-2-hydroxyphenyl) acetate (130b) (0.249 g, 1.132 mmol) and DIAD (0.252 g, 1.245 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-cyclopropylphenyl)acetate (130e) (0.113 mmol, 10% yield) as a pale yellow waxy solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.79-7.64 (m, 3H), 7.56-7.40 (m , 3H), 7.30 (d, J=7.7 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.99-6.91 (m, 3H), 5 .18 (s, 2H), 4.22 (d, J=6.1 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.58 (s, 2H), 1 .91-1.77 (m, 1H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H), 0.91-0.81 (m, 2H), 0.66-0.50 (m, 2H); MS (ESI+): 578.4 (M+Na); MS (ESI-): 590.4 (M+Cl).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5cyclopropylphenyl)acetate (130f).

Compound 130f was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-5cyclopropylphenyl)acetate (130e) (0.062 g, 0.112 mmol) in DCM (5 ml) using TFA (0.172 ml, 2.232 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 100%], ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-5-cyclopropylphenyl)acetate (130f) (0.031 g, 61% yield) as a white solid; MS (ESI+): 456.3 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5cyclopropylphenyl)acetic acid (130g).

Compound 130g was prepared according to the procedure described in step-4 of scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate ( 130f) (0.030 g, 0.066 mmol) in THF (3 mL) and methanol (6 mL) using sodium hydroxide solution (2 M aq, 0.165 mL, 0.329 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetic acid (130g) (0.008 g, 28% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.2 (br.s, 1H, D2O replaceable), 8.36 (br.s, 3H, D2O replaceable), 8.13-8.05 (m, 1H), 7.99 (s, 1H), 7.97-7.89 (m, 1H), 7.75 (s, 1H), 7.69-7.50 (m, 3H), 7.05 (t, J=1.8 Hz, 1H), 7.026.88 (m, 3H), 5.22 (s, 2H), 4.14 (s, 2H), 3.56 (s, 2H), 1 .93-1.76 (m, 1H), 0.94-0.80 (m, 2H), 0.69-0.46 (m, 2H); MS (ESI+): 428.3 (M+1), 855.5 (2M+1); MS (ESI-): 426.4 (M-1), 462.3 (M+Cl).

Scheme-131

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetic acid (131b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-206 045626 yl)methoxy)phenyl)acetate (131a).

Compound 131a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e) ( 0.750 g, 1.860 mmol) in dioxane (30 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.453 g, 2.418 mmol), bis(triphenylphosphine) palladium(P) chloride (PdCl ₂ (PPh ₃ ) ₂ , 0.196 g, 0.279 mmol) and a solution of potassium carbonate (0.771 g, 5.58 mmol) in water (5 ml) under a nitrogen atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 100% MeOH in DCM] compound 131a (0.395 g, 49% yield), the free base as off-white solid matter. The free base (216 mgs) was further purified by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2- ((4-(3(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (131a) (0.215 mg, 89% yield), HCl salt, as a white solid;

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.35 (br. s, 3H, D2O replaceable), 8.31 (s, 1H), 7.93-7.86 (m, 1H), 7.787 .72 (m, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.35 (d, J=1.2 Hz, 1H), 7.29-7.20 (m, 2H), 7.15-7.09 (m, 1H), 6.92 (td, J=7.4, 1.0 Hz, 1H), 5 .32 (s, 2H), 4.15 (k, J=5.8 Hz, 2H), 4.10 (s, 3H), 3.94 (k, J=7.1 Hz, 2H), 3 .67 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 430.4 (M+1), 859.9 (2M+1); MS (ESI-): 464.4 (M+Cl); purity after HPLC: 98.8%.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1 -methyl-1 H-indazol-6yl)methoxy)phenyl)acetic acid (131b).

Compound 131b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy) phenyl)acetate (131a) (0.175 g, 0.407 mmol) in THF (2 ml) and methanol (4 ml), using a solution of lithium hydroxide monohydrate (0.051 g, 1.22 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(3- (aminomethyl)phenyl)-1-methyl-1 H-indazol-6-yl)methoxy)phenyl)acetic acid (131b) (0.102 g, 62% yield), HCl salt, as a white solid;

1H NMR (500 MHz, DMSO-d ₆ ) δ 12.24 (br.s, 1H, D2O replaceable), 8.37 (br.s, 3H, D2O replaceable), 8.30 (s, 1H), 7 .90 (s, 1H), 7.80-7.74 (m, 2H), 7.59 (t, J=7.6 Hz, 1H), 7.56-7.52 (m, 1H), 7.38 (d, J=1.1 Hz, 1H), 7.29-7.20 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (t , J=7.4 Hz, 1H), 5.34 (s, 2H), 4.15 (k, J=5.9 Hz, 2H), 4.10 (s, 3H), 3.64 (s , 2H); MS (ESI+): 402.2 (M+1), 803.8 (2M+1); MS (ESI-): 400.5 (M-1), 436.4 (M+Cl), 801.8 (2M-1); purity after HPLC: 97.33%; analysis calculation for C ₂₄ H ₂₃ N ₃ O ₃ -2H ₂ O-1.25HCl: C, 59.67; N, 5.89; Cl, 9.17; N, 8.70; observed: C, 59.63; N, 5.53; Cl, 9.64; N, 8.76.

Scheme-132

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (132b).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (132a).

Compound 132a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (120a) (600 mg, 1.25 mmol) in dioxane (6 ml), using (4-chloropyridin-2yl)methanamine (74a) (267 mg, 1.874 mmol), bis(triphenylphosphine) palladium(P) chloride (132 mg, 0.19 mmol) and a solution of K ₂ CO ₃ (432 mg, 3.12 mmol) in water (3 ml) in an Ar atmosphere and heating at 100 °C for 2 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (132a) (223 mg, 39% yield), HCl salt, as a yellow solid;

1H NMR (500 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.51 (s, 3H, D2O exchangeable), 8.05 (d, J=1.6 Hz, 1H), 7.97 (dd, J=5.4, 1.7 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.77 (d, J=1 .6 Hz, 1H), 7.28-7.19 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.06 (s, 1H), 6.91 (t , J=7.3 Hz, 1H), 5.25 (s, 2H), 4.60 (s, 2H), 4.30 (k, J=5.9 Hz, 2H), 3.94 (k , J=7.1 Hz, 2H), 3.64 (s, 2H), 3.33 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 461.5 (M+1); (ESI-): 495.5 (M+Cl).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (132b).

- 207 045626

Compound 132b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl )methoxy)phenyl)acetate (132a) (156 mg, 0.34 mmol) in MeOH/THF (10 ml), using a solution of lithium hydroxide monohydrate (43 mg, 1.02 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (132b) (105 mg, 72% yield), HCl salt, as a white solid;

^1H NMR (500 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.47 (s, 3H, D2O replaceable), 8.04 (s, 1H), 7 .98 (dd, J=5.2, 1.7 Hz, 1H), 7.84 (d, J=1.7 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H) , 7.26-7.20 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 6.91 (td, J=7.3 , 1.0 Hz, 1H), 5.28 (s, 2H), 4.61 (s, 2H), 4.33-4.29 (m, 2H), 3.61 (s, 2H), 3 .34 (s, 3H); MS (ESI+): 433.2 (M+1); (ESI-): 431.3 (M-1).

Scheme-133

2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indole-6 Preparation of yl)methoxy)phenyl)acetic acid (133c).

Stage-1. Preparation of ethyl 2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindol-6-yl)methoxy)phenyl)acetate (133a).

Compound 133a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) (0.78 g, 1.94 mmol) using bis(pinacolato)diboron (0.74 g, 2.91 mmol), potassium acetate (0.57 g, 5.82 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.24 g, 0.29 mmol) in anhydrous dioxane (12 ml) under Ar and heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH (9:1) in 0% to 10% hexane] ethyl 2-(2-((1-methyl -4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (133a) (0.58 g, 67% yield ) in the form of a clear oil; MS (ESI+): 450.4 (M+1), 472.5 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetate (133b).

Compound 133b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(( 1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1 H-indol-6-yl)methoxy)phenyl)acetate (133a) (0.65 g, 1.45 mmol) in dioxane (6 ml) using (4-chloropyridin-2-yl) methaneamine (74a) (0.22 ml, 1.88 mmol), bis(triphenylphosphine) palladium(P) chloride (0.15 g, 0.22 mmol) and K ₂ CO ₃ solution (0.50 g, 3. 62 mmol) in water (0.8 ml) under Ar atmosphere and heating at 100°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(2(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy )phenyl)acetate (133b) (0.1 g, 16% yield) as a yellow solid; MS (ESI+): 430.5 (M+1); MS (ESI-): 428.5 (M-1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -methyl-1 H-indol-6yl)methoxy)phenyl)acetic acid (133c).

Compound 133c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indole-6- yl)methoxy)phenyl)acetate (133b) (0.1 g, 0.23 mmol) in MeOH/THF (4 ml), using a solution of lithium hydroxide monohydrate (0.05 g, 1.16 mmol) in water (0 .8 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (133c) (0.04 g, 39% yield) as a yellow solid;

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.71 (d, J=5.1 Hz, 1H), 8.35 (s, 3H), 7.83 (d, J=1.5 Hz, 1H), 7.73 (dd, J=5.2, 1.7 Hz, 1H), 7.70 (s, 1H), 7.52 (d, J=3.1 Hz, 1H), 7, 39 (d, J=1.3 Hz, 1H), 7.26-7.21 (m, 2H), 7.11 (d, J=8.0

- 208 045626

Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.70 (dd, J=3.1, 0.9 Hz, 1H), 5.30 (s , 2H), 4.30 (s, 2H), 3.86 (s, 3H), 3.61 (s, 2H); MS (ESI+): 402.4 (M+1); MS (ESI-): 400.5 (M-1), 436.4 (M+Cl). Purity after HPLC: 98.98%.

Scheme-134

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetic acid (134b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetate (134a).

Compound 134a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c) ( 120 mg, 0.31 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (95 mg, 0.46 mmol), bis(triphenylphosphine) palladium(P ) chloride (43 mg, 0.062 mmol) and K ₂ CO ₃ (127 mg, 0.92 mmol) in water (1 ml) under Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy) phenyl)acetate (134a) (102 mg, 76% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 3H, D2O replaceable), 8.42 (d, J=2.3 Hz, 1H), 7.83-7.72 (m, 2H), 7.55 (s, 1H), 7.50 (t, J=7.7 Hz, 1h), 7.29-7.19 (m, 3H), 7.11 (dd, J=8 ,3, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.33 (s, 2H), 4.24-4.12 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -117.89; MS (ESI+): 435.2 (M+1); (ESI-): 433.3 (M-1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetic acid (134b).

Compound 134b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridine-5- yl)methoxy)phenyl)acetate (134a) (60 mg, 0.14 mmol) in MeOH/THF (6 ml), using a solution of lithium hydroxide monohydrate (15 mg, 0.36 mmol) in water (1.0 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetic acid (134b) (50 mg, 89% yield), HCl salt, as a white solid ;

1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H, D2O replaceable), 8.46-8.34 (m, 4H, D2O replaceable, 3H), 7.78-7.71 (m , 2H), 7.61-7.58 (m, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.26-7.24 (m, 1H), 7.23 ( d, J=1.7 Hz, 1H), 7.21 (s, 1H), 7.09-7.05 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz , 1H), 5.34 (s, 2H), 4.19 (k, J=5.9 Hz, 2H), 3.60 (s, 2H); MS (ESI+): 407.2 (M+1); (ESI-): 405.3 (M-1).

Scheme-135

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetic acid (135c).

- 209 045626

Stage-1. Preparation of ethyl 2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-1methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (135a) .

Compound 135a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e) ( 700 mg, 1.736 mmol) in dioxane (30 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate (123a) (1.160 g, 3.47 mmol), K ₂ CO ₃ (0.720 g, 5.21 mmol) in water (5 ml), bis(triphenylphosphine) palladium(P) chloride (0.183 g, 0.260 mmol) and heating in a nitrogen atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with methanol in 0% to 50% DCM] ethyl 2-(2-((4-(2-(((tert-butoxycarbonyl) amino)methyl)pyridin-4-yl)-1-methyl-N-indazol-6-yl)methoxy)phenyl)acetate (135a) (0.539 g, 59% yield) as a white solid; MS (ESI+): 553.5 (M+Na); MC (ESI-): 529.6 (M1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetate (135b).

Compound 135b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-1 - Methyl-1H-indazol-6yl)methoxy)phenyl)acetate (135a) (0.523 g, 0.986 mmol) in DCM (30 ml) using TFA (0.759 ml, 9.86 mmol). This resulted in 135b (0.537 g, 100% yield), TFA salt, as a yellow waxy solid upon workup. Purify 239 mg of this TFA salt of compound 135b by reverse phase chromatography on a [C18 (50 g) column, eluting with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2- ((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1Hindazol-6-yl)methoxy)phenyl)acetate (135b) (0.073 g, 43% yield), HCl salt, as white solid matter;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.80-8.74 (m, 1H), 8.43 (s, 3H, D2O replaceable), 8.38-8.35 (m, 1H) , 7.93 (s, 1H), 7.87 (s, 1H), 7.80 (dd, J=5.2, 1.7 Hz, 1H), 7.51 (s, 1H), 7, 31-7.22 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.986.88 (m, 1H), 5.34 (s, 2H), 4.34 (t , J=5.9 Hz, 2H), 4.13 (s, 3H), 3.94 (k, J=7.1 Hz, 2H), 3.68 (s, 2H), 0.98 (t , J=7.1 Hz, 3H); MS (ESI+): 431.4 (M+1), 861.8 (2M+1); MS (ESI-): 465.5 (M+Cl); purity after HPLC: 97.33%.

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetic acid (135c).

Compound 135c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -methyl-1 H-indazol-6 -yl)methoxy)phenyl)α acetate α (135b) (0.238 g, 0.437 mmol) in THF (4 ml) and MeOH (8 ml), using a solution of lithium hydroxide monohydrate (0.092 g, 2.185 mmol) in water (4 ml). This resulted in, after workup and purification by flash column chromatography, [silica gel, eluted with methanol in DCM from 0% to 100%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1 % HCl) from 0% to 100%] 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetic acid (135c) (0.092 g, 0.229 mmol, 52.3% yield), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.2 (br.s, 1H, D2O replaceable), 8.81-8.72 (m, 1H), 8.44 (s, 3H, D2O replaceable) , 8.37 (d, J=1.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.92-7.88 (m, 1H), 7.81 (dd, J =5.2, 1.7 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.30-7.19 (m, 2H), 7.14-7.05 ( m, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.36 (s, 2H), 4.38-4.30 (m, 2H), 4.12 (s, 3H ), 3.65 (s, 2H); MS (ESI+): 403.4 (M+1), 805.7 (2M+1); MS (ESI-): 401.4 (M-1), 437.4 (M+Cl), 803.7 (2M-1); purity after HPLC: 94.73%; analysis calculation for: C ₂₃ H ₂₂ N40 ₃ -2, OH ₂ 0-2, OHCI: C, 54.02; N, 5.52; Cl, 13.87; N, 10.96; observed: C, 53.79; N, 5.52; Cl, 13.62; N, 10.90.

Scheme-136

^136d 136e

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (136e).

Stage-1. Preparation of (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b).

Compound 136b was prepared according to the procedure described in step-1 of Scheme-23 from 7bromo-4-fluorobenzofuran-5-carboxylic acid (136a) (900 mg, 3.47 mmol, purchased from PharmaBlock, PB95207) using N- methylmorpholine (0.44 ml, 3.97 mmol) in THF (10 ml), isobutyl chloroformate (0.55 ml, 4.17 mmol) and NaBH ₄ (394 mg, 10.42 mmol) in water (5 ml). This gave, after work-up and purification by flash chromatography [silica gel (12 g), eluted with 0% to 60% EtOAc in hexane] (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (760 mg, 89% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.17 (dt, J=2.2, 0.5 Hz, 1H), 7.60 (dt, J=6.4, 0.6 Hz, 1H ), 7.21 (d, J=2.2 Hz, 1H), 5.39 (t, J=5.8 Hz, 1H), 4.65-4.57 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -126.62.

Stage-2. Preparation of ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c).

Compound 136c was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-4-fluorobenzofuran-5-yl)methanol (136b) (760 mg, 3.10 mmol) in DCM (15 ml) using triphenylphosphine (895 mg, 3.41 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (615 mg, 3.41 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 1253 mg, 3.41 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5- yl)methoxy)phenyl)acetate (136c) (758 mg, 60% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=2.2 Hz, 1H), 7.71 (d, J=6.1 Hz, 1H), 7.30-7, 25 (m, 2H), 7.22 (dd, J=7.5, 1.7 Hz, 1H), 7.15 (dd, J=8.3, 1.1 Hz, 1H), 6.94 (td, J=7.4, 1.1 Hz, 1H), 5.21 (d, J=1.4 Hz, 2H), 3.96 (k, J=7.1 Hz, 2H), 3 .57 (s, 2H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -124.63; MS (ESI+): 407.0 and 409.0 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetate (136d).

Compound 136d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c) (120 mg, 0 .29 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (83 mg, 0.44 mmol), bis(triphenylphosphine) palladium(II) chloride (41 mg, 0.059 mmol) and K ₂ CO ₃ (122 mg, 0.88 mmol) in water (1 ml) under Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136d) (98 mg, 77% yield), HCl salt, as a white solid;

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.32 (s, 3H, D2O replaceable), 8.19 (d, J=2.3 Hz, 1H), 7.96 (s, 1H), 7.907 .85 (m, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.64-7.57 (m, 1H), 7.57-7.51 (m, 1H), 7.33-7.16 (m, 4H), 6.93 (td, J=7.3, 1.2 Hz, 1H), 5.27 (s, 2H), 4.18-4.07 ( m, 2H), 3.86 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 0.91 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.64; MS (ESI+): 434.1 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (136e).

Compound 136e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate ( 136d) (60 mg, 0.14 mmol) in MeOH/THF (6 ml), using a solution of lithium hydroxide monohydrate (15 mg, 0.36 mmol) in water (1.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (136e) (28 mg, 50% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.21 (s, 1H, D2O replaceable), 8.42 (s, 3H, D2O replaceable), 8.19 (d, J=2.2 Hz, 1H ), 7.97 (d, J=1.9 Hz, 1H), 7.89 (dt, J=7.1, 1.8 Hz, 1H), 7.74 (d, J=6.8 Hz , 1H), 7.64-7.50 (m, 2H), 7.33-7.13 (m, 4H), 6.92 (td, J=7.3, 1.2 Hz, 1H), 5.30 (s, 2H), 4.22-4.03 (m, 2H), 3.55 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.69; MS (ESI+): 406.2 (M+1); (ESI-): 404.2 (M-1).

Scheme-137

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)-211 045626 acetic acid (137b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetate (137a).

Compound 137a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c) (140 mg, 0 .34 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (106 mg, 0.52 mmol), bis(triphenylphosphine) palladium(P) chloride (48 mg, 0.069 mmol) and K ₂ CO ₃ (143 mg, 1.03 mmol) in water (1 ml) under Ar and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4fluorobenzofuran-5-yl)methoxy)phenyl)acetate (137a ) (112 mg, 72% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 3H, D2O replaceable), 8.15 (d, J=2.3 Hz, 1H), 7.76-7.68 (m, 1H), 7.65 (td, J=7.5, 1.8 Hz, 1H), 7.54 (d, J=6.7 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.34-7.25 (m, 1H), 7.25-7.16 (m, 3H), 6.93 (td, J=7.4, 1.2 Hz, 1H) , 5.27 (s, 2H), 4.17 (s, 2H), 3.85 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.67, -123.58; MS (ESI+): 452.2 (M+1); purity after HPLC: 96.40%.

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (137b).

Compound 137b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl )acetate (137a) (75 mg, 0.17 mmol) in MeOH/THF (6 ml), using a solution of lithium hydroxide monohydrate (17 mg, 0.42 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (137b) (41 mg, 58% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H, D2O replaceable), 8.55 (s, 3H, D2O replaceable), 8.14 (d, J=2.3 Hz, 1H ), 7.74-7.61 (m, 2H), 7.58 (d, J=6.7 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.30 -7.12 (m, 4H), 6.92 (td, J=7.3, 1.2 Hz, 1H), 5.29 (s, 2H), 4.16 (s, 2H), 3, 52 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.47, -123.58; MS (ESI+): 424.2 (M+1); (ESI-): 422.2 (M-1).

Scheme-138

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (138f).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (138a).

Compound 138a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl )acetate (76c) (9.2 g, 15.85 mmol) in dioxane (80 ml), using (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1d) (7.92 g, 23 .77 mmol), a solution of potassium carbonate (6.57 g, 47.5 mmol) in water (30 ml) and bis(triphenylphosphine) palladium(P) chloride (1.11 g, 1.59 mmol)

- 212 045626 and heating in a nitrogen atmosphere at 100°C for 3 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (80 g), eluted

DMA80 in DCM from 0% to 50%] ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran- 5-yl)methoxy)phenyl)acetate (138a) (9.1 g, 13.79 mmol, 87% yield) as a yellow oil.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (138b).

Compound 138b was prepared according to the procedure described in step-1 of Scheme-58 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((( tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (138a) (9.1 g, 13.79 mmol) in THF (60 ml), using TBAF (1 M in THF) (17.2 ml, 17.24 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 70% EtOAc in hexane] ethyl 2-(2-((7-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (138b) (5.58 g, 74% yield) as a semi-solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.78-7.68 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.53-7.43 (m , 3H), 7.34-7.25 (m, 2H), 7.25-7.17 (m, 1H), 7.11 (dd, J=8.2, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.84 (s, 1H), 5.51 (t, J=5.9 Hz, 1H), 5.22 (s , 2H), 4.60 (dd, J=5.9, 0.8 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (k, J=7, 1 Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (138c).

To a solution of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (138b) (2, 39 g, 4.38 mmol) to DCM (50 mL) at 0°C was added methanesulfonyl chloride (0.38 mL, 4.82 mmol) and TEA (0.92 mL, 6.57 mmol). The mixture was stirred for 1 hour at 0°C and left to warm to RT and stirred for 2 days. The reaction mixture was diluted with DCM, washed with brine (2x), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with 0% to 100% EtOAc in hexane] to give ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (138c) (2.2 g, 89% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.79-7.66 (m, 3H), 7.57 (d, J=1.7 Hz, 1H), 7.53-7.44 (m, 2H), 7.35-7.28 (m, 1H), 7.28-7.18 (m, 2H), 7.14-7.06 (m, 2H), 6.91 (td, J= 7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 5.02 (s, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.91 ( k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 586.3 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (138d)

Solution of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5yl)methoxy)phenyl)acetate (138c) (400 mg, 0 .71 mmol) and methamine (2 M in THF, 7.0 mL, 14.18 mmol) were heated at 80°C for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] to give ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (138d) (320 mg, 81% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d6) δ 7.79-7.69 (m, 2H), 7.62 (d, J=1.6 Hz, 1H), 7.52-7.44 (m, 3H), 7.33-7.25 (m, 2H), 7.25-7.19 (m, 1H), 7.14-7.07 (m, 1H), 6.91 (td, J= 7.4, 1.1 Hz, 1H), 6.80 (s, 1H), 5.21 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 ( k, J=7.2 Hz, 2H), 3.83 (s, 2H), 3.62 (s, 2H), 2.34 (s, 3H), 1.39 (s, 9H), 0, 97 (t, J=7.1 Hz, 3H); MS (ESI+): 559.3 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (138e).

Compound 138e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methylamino) methyl)benzofuran-5yl)methoxy)phenyl)acetate (138d) (320 mg, 0.57 mmol) in DCM (10 ml) using TFA (0.88 ml, 11.46 mmol). This resulted in, after workup and purification by flash column chromatography, [silica gel 24 g, eluted with methanol in DCM from 0% to 100%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl) acetate (138e) (220 mg, 84% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.68 (s, 2H, D ₂ O replaceable), 8.57 (s, 3H, D2O replaceable), 8.24 (d, J=1.8 Hz , 1H), 7.95 (dt, J=7.3, 1.8 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.68 (d, J=1, 7 Hz, 1H), 7.63-7.52 (m, 2H), 7.30-7.18 (m, 3H), 7.11 (dd, J=8.3, 1.1 Hz, 1H ), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.43 (s, 2H), 4.18 (s, 2H), 3 .94 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.62 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 459.2 (M+1);

- 213 045626 (ESI-): 457.3 (M-1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (138f).

Compound 138f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (138e) (144 mg, 0.31 mmol) in THF (6 ml) and methanol (6 ml), using a solution of lithium hydroxide monohydrate (33 mg, 0.79 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (138f) (69 mg, 51% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H, D2O replaceable), 9.83 (s, 2H, D2O replaceable), 8.65 (s, 3H, D2O replaceable), 8.26 (s, 1H), 8.01-7.89 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.74-7.67 (m, 1H), 7. 61-7.48 (m, 2H), 7.29-7.14 (m, 3H), 7.14-7.03 (m, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.42 (s, 2H), 4.17 (s, 2H), 3.60 (s, 2H), 2.60 (s, 3H); MS (ESI+): 431.2 (M+1); (ESI-): 429.3 (M-1).

Scheme-139

Receipt

139s

2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (139c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate (139a).

Compound 139a was prepared according to the procedure described in step-4 of scheme-138 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl) benzofuran-5yl)methoxy)phenyl)acetate (138c) (500 mg, 0.89 mmol) and morpholine (0.77 ml, 8.86 mmol) in ACN (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate (139a) (400 mg, 73% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.76-7.70 (m, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.53-7.44 (m , 3H), 7.33-7.19 (m, 3H), 7.14-7.08 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.87 (s, 1H), 5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.72 (s, 2H), 3.62 (s, 2H), 3.61-3.55 (m, 4H), 2.49-2.43 (m, 4H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 615.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5yl)methoxy)phenyl)acetate (139b).

Compound 139b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(morpholinomethyl)benzofuran -5yl)methoxy)phenyl)acetate (139a) (400 mg, 0.65 mmol) in DCM (10 ml) using TFA (1.0 ml, 13.01 mmol). This resulted in, after workup and purification by flash column chromatography, [silica gel 24 g, eluted with methanol in DCM from 0% to 100%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate (139b ) (202 mg, 60% yield), HCl salt, as an off-white solid;

1H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H, D2O replaceable), 8.70 (s, 3H, D2O replaceable), 8.29 (s, 1H), 8.00-7, 89 (m, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.57 (d, J=4.7 Hz, 2H), 7.33 (s, 1H), 7.28-7.18 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.91 (t, J =7.3 Hz, 1H), 5.26 (s, 2H), 4.69 (s, 2H), 4.17 (k, J=5.8 Hz, 2H), 4.01-3.85 (m, 6H), 3.64 (s, 2H), 3.43-3.35 (m, 2H), 3.31-3.13 (m, 2H), 1.01 (t, J=7 ,1 Hz, 3H); MS (ESI+): 515.3 (M+1); (ESI-): 513.3 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (139c).

- 214 045626

Compound 139c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl )acetate (139b) (154 mg, 0.30 mmol) in THF (6 ml) and methanol (6 ml), using a solution of lithium hydroxide monohydrate (32 mg, 0.75 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (139c) (70 mg, 48% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.05 (s, 1H, D2O replaceable), 8.62 (s, 3H, D2O replaceable), 8.27 (d, J=1.8 Hz, 1H), 7.97 (dt, J=6.7, 2.1 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.64-7.51 (m, 2H), 7.31 (s, 1H), 7.27-7.17 (m, 2H), 7.12-7.04 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.68 (s, 2H), 4.18 (k, J=5 .8 Hz, 2H), 4.06-3.77 (m, 4H), 3.60 (s, 2H), 3.45-3.35 (m, 2H), 3.31-3.11 ( m, 2H); MS (ESI+): 487.2 (M+1); (ESI-): 485.3 (M-1).

Scheme-140

Preparation of 2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (140c).

Stage-1. Preparation of ethyl 2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl) acetate (140a).

Compound 140a was prepared according to the procedure described in step-4 of scheme-138 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl) benzofuran-5yl)methoxy)phenyl)acetate (138c) (350 mg, 0.62 mmol) and imidazole (211 mg, 3.10 mmol) in ACN (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((2-((1H-imidazol-1- yl)methyl)7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (140a) (280 mg, 76% yield) as a yellow oil; MS (ESI+): 596.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (140b).

Compound 140b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-(( 1 H-imidazol-1 -yl)methyl)-7-(3-(((tert -butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 yl)methoxy)phenyl)acetate (140a) (280 mg, 0.47 mmol) in DCM (10 ml), using TFA (0.72 ml, 9.40 mmol ). This resulted in, after workup and purification by flash column chromatography, [silica gel 24 g, eluted with methanol in DCM from 0% to 100%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5- yl)methoxy)phenyl)acetate (140b) (133 mg, 57% yield), HCl salt, as a white solid;

1H NMR (500 MHz, DMSO-d ₆ ) δ 15.11 (s, 1H, D2O replaceable), 9.55 (t, J=1.5 Hz, 1H), 8.82 (s, 3H, D2O replaceable ), 8.08 (d, J=1.8 Hz, 1H), 7.96 (t, J=1.7 Hz, 1H), 7.86 (dt, J=6.7, 1.9 Hz , 1H), 7.78-7.71 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.64-7.51 (m, 2H), 7.29- 7.16 (m, 3H), 7.14-7.07 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.87 (s, 2H) , 5.25 (s, 2H), 4.18-4.08 (m, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1, 00 (t, J=7.1 Hz, 3H); MS (ESI+): 496.2 (M+1); (ESI-): 494.3 (M-1).

Stage-3. Preparation of 2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (140c).

Compound 140c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl) benzofuran-5-yl)methoxy)phenyl)acetate (140b) (85 mg, 0.17 mmol) in THF (6 ml) and methanol (6 ml), using lithium hydroxide monohydrate solution (18 mg, 0.43 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((2- ((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-215 045626 yl)methoxy)phenyl)acetic acid (140c) (37 mg, 46% yield), salt HCl, as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 15.00 (s, 1H, D2O replaceable), 9.50 (t, J=1.5 Hz, 1H), 8.72 (s, 3H, D2O replaceable), 8.09-8.02 (m, 1H), 7.94 (t, J=1.7 Hz, 1H), 7.92-7.83 (m, 1H), 7.80-7 .69 (m, 3H), 7.62-7.52 (m, 2H), 7.27-7.19 (m, 2H), 7.17 (s, 1H), 7.12-7.04 (m, 1H), 6.95-6.79 (m, 1H), 5.84 (s, 2H), 5.27 (s, 2H), 4.13 (k, J=6.0 Hz, 3H), 3.60 (s, 2H); MS (ESI+): 468.2 (M+1); (ESI-): 466.3 (M-1).

Scheme-141

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (141c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (141a).

Compound 141a was prepared according to the procedure described in step-4 of scheme-138 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl) benzofuran-5yl)methoxy)phenyl)acetate (138c) (350 mg, 0.62 mmol) and dimethylamine (2 M in THF, 1.6 ml, 3.10 mmol) in ACN (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH (9:1) in 0% to 100% hexane] ethyl 2-(2-((7-( 3(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (141a) (260 mg, 73% yield) as a clear oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.77-7.68 (m, 2H), 7.65-7.59 (m, 1H), 7.53-7.39 (m, 3H ), 7.33-7.25 (m, 2H), 7.25-7.18 (m, 1H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6, 91 (td, J=7.4, 1.1 Hz, 1H), 6.84 (s, 1H), 5.21 (s, 2H), 4.22 (d, J=6.1 Hz, 2H ), 3.92 (t, J=7.1 Hz, 2H), 3.63 (d, J=8.0 Hz, 4H), 2.23 (s, 6H), 1.39 (s, 9H ), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 573.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (141b).

Compound 141b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((dimethylamino) methyl)benzofuran-5yl)methoxy)phenyl)acetate (141a) (260 mg, 0.45 mmol) in DCM (10 ml) using TFA (0.70 ml, 9.08 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel 24 g, eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (141b) (215 mg, 87% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.49 (s, 1H, D2O replaceable), 8.67 (s, 3H, D2O replaceable), 8.25 (k, J=1.2 Hz, 1H), 7.99-7.90 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7, 62-7.53 (m, 2H), 7.31 (s, 1H), 7.28-7.19 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.62 (s, 2H), 4.254.10 (m, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.81 (s, 6H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 473.3 (M+1); (ESI-): 471.3 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (141c).

Compound 141c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (141b) (155 mg, 0.33 mmol) in THF (6 ml) and methanol (6 ml), using a solution of lithium hydroxide monohydrate (34 mg, 0.82 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (141c) (89 mg, 61% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.46 (s, 1H, D2O replaceable), 8.63 (s, 3H, D2O replaceable), 8.23 (d,

- 216 045626

J=1.8 Hz, 1H), 8.00-7.92 (m, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.61-7.51 (m, 2H), 7.29 (s, 1H),

7.22 (d, J=7.4 Hz, 2H), 7.13-7.04 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5 .28 (s, 2H), 4.62 (d, J=4.4 Hz, 2H), 4.17 (k, J=5.8 Hz, 2H), 3.60 (s, 2H), 2 .81 (d, J=4.3 Hz, 6H); MS (ESI+): 445.2 (M+1); (ESI-): 443.3 (M-1).

Scheme-142

34s _142b 142s

Preparation of 2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)thiophen-3-yl)acetic acid (142d) .

Stage-1. Preparation of ethyl 2-(4-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophene- 3-yl)acetate (142b).

Compound 142b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-carboxylic acid (34c) (150 mg, 0.388 mmol) in DMF (8 ml), using ethyl 2-(4-aminothiophen-3-yl) acetate (142a) (223 mg, prepared according to with the procedure described by Kenda, Benoit et al.; in PCT international application, 2008132139, November 06, 2008; CAS No. 1076191-69-6), DIPEA (0.338 ml, 1.941 mmol) and HATU (369 mg, 0.971 mmol ). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 3:1)] ethyl 2-(4-(2-(3-(( (tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophene-3yl)acetate (142b) (180 mg, 84% yield) in the form of a yellow resin;

^1H NMR (300 MHz, DMSO- _d6 ) δ 10.77 (s, 1H), 8.43-8.39 (m, 1H), 8.25-8.15 (m, 1H), 7. 92 (d, J=3.4 Hz, 1H), 7.61 (dd, J=4.6, 1.4 Hz, 1H), 7.56-7.43 (m, 3H), 7.36 (t, J=7.6 Hz, 1H), 7.30 (dd, J=4.6, 2.6 Hz, 1H), 4.28 (d, J=6.0 Hz, 2H), 4 .03 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.41 (s, 9H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -119.38; MS (ESI+): 576.4 (M+Na); MC (ESI-): 552.4 (M-1).

Stage-2. Preparation of ethyl 2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4carboxamido)thiophen-3-yl)acetate (142c) .

Compound 142c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1 -f][1,2,4]triazin-4carboxamido)thiophen-3-yl)acetate (142b) (170 mg, 0.307 mmol) in DCM (15 mL), using TFA (0.95 mL, 12.28 mmol ). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1) ethyl 2-(4-(2-(3(aminomethyl)- 2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate (142c) (152 mg) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.48-8.41 (m, 1H), 8.39 (dd, J=2.6, 1.3 Hz, 1H), 8.28 (s, 3H), 7.92 (d, J=3.4 Hz, 1H), 7.75-7.68 (m, 1H), 7.63 (dd, J=4 ,6, 1.3 Hz, 1H), 7.52-7.43 (m, 2H), 7.33 (dd, J=4.6, 2.6 Hz, 1H), 4.22 (s, 2H), 4.05 (k, J=7.1 Hz, 2H), 3.85 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -116.62; MS (ESI+): 454.3 (M+1) and 476.3 (M+Na).

Stage-3. Preparation of 2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)thiophen-3-yl)acetic acid (142d) .

Compound 142d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2, 4]triazine-4-carboxamido)thiophen-3-yl)acetate (142c) (110 mg, 0.243 mmol) in THF/MeOH (20 ml, 1:1), using lithium hydroxide monohydrate (62 mg, 1.455 mmol) in water (10 ml). This resulted in the production after treatment of 2-(4-(2-(3-(aminomethyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-carboxamido)thiophen-3-yl) acetic acid (142d) (35 mg, 37% in two steps) as a yellow solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 8.41 (dd, J=2.6, 1.4 Hz, 1H), 8.18 (t, J=7 .5 Hz, 1H), 7.88 (d, J=3.4 Hz, 1H), 7.73-7.61 (m, 2H), 7.42 (t, J=7.7 Hz, 1H ), 7.34-7.25 (m, 2H), 4.12 (s, 2H), 3.55 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -114.80; MS (ESI+): 426.2 (M+1); MS (ESI-): 424.3 (M-1); purity after HPLC: 99.74%.

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Scheme-143

Preparation of 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4carboxamido)furan-2-yl)acetic acid (143g) .

Stage-1. Preparation of methyl 2-(3-((tert-butoxycarbonyl)amino)furan-2-yl)acetate (143c).

To a solution of 2-(2-methoxy-2-oxoethyl)furan-3-carboxylic acid (143a) (900 mg, 4.64 mmol; CAS No. 1479004-17-5) in THF (30 ml) was added triethylamine (0.647 ml , 4.64 mmol) and diphenylphosphorazidate (1.035 ml, 4.64 mmol). The reaction mixture was stirred at RT overnight and concentrated in vacuo to give methyl 2-(3-(azidocarbonyl)furan-2-yl)acetate (143b) (970 mg), which was used as is in the next step.

A solution of methyl 2-(3-(azidocarbonyl)furan-2-yl)acetate (143b) (970 mg, 4.64 mmol) in toluene (30 ml) was refluxed for 0.5 h. The reaction mixture was cooled to RT and add 2-methylpropan-2-ol (2.66 ml, 27.8 mmol), triethylamine (1.293 ml, 9.28 mmol) followed by reflux for 2 hours. The reaction mixture was cooled to RT and diluted ethyl acetate (150 ml) and water (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (75 ml). The combined organic layers were washed with brine (75 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash silica gel column chromatography with hexanes/ethyl acetate (1:0 to 4:1, then 1:1) to give methyl 2-(3-((tert-butoxycarbonyl)amino)furan-2-yl) acetate (143c) (756 mg, 64% in two steps) as a yellow gum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 3.78 (s, 2H), 3.60 (s, 3H), 1.44 (s, 9H); MS (ESI-): 254.3 (M-1).

Stage-2. Preparation of methyl 2-(3-aminofuran-2-yl)acetate (143d).

Compound 143d was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(3-((tert-butoxycarbonyl)amino)furan-2-yl)acetate (143c) (400 mg, 1.567 mmol) in DCM (25 ml) using TFA (2.415 ml, 31.3 mmol). This resulted in methyl 2-(3aminofuran-2-yl)acetate (143d) (614 mg) as a dark brown gum upon workup, which was used as is in the next step.

Stage-3. Preparation of methyl 2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan- 2-yl)acetate (143e).

Compound 143e was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-1][1,2 ,4]triazine-4-carboxylic acid (34c) (115 mg, 0.298 mmol) in DMF (6 ml), using methyl 2-(3-aminofuran-2-yl) acetate (143d) (175 mg), DIPEA ( 0.259 ml, 1.488 mmol) and HATU (283 mg, 0.744 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 2:1)] methyl 2-(3-(2-(3-(( (tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate (143e) (18 mg, 12%) in the form of a yellow resin; MS (ESI+): 524.4 (M+1) and 546.3 (M+Na); MS (ESI-): 522.3 (M-1) and 558.4 (M+Cl).

Stage-4. Preparation of methyl 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,14][1,2,4]triazin-4carboxamido)furan-2-yl)acetate (143f).

Compound 143f was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2. 1-f][1,2,4]triazin-4carboxamido)furan-2-yl)acetate (143e) (18 mg, 0.034 mmol) in DCM (6 mL), using TFA (0.318 mL,

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4.13 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1)] methyl 2-(3-(2-(3(aminomethyl) -2-fluorophenyl)pyrrolo[2,1-1:][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate (143f) (14 mg, 96%) as a yellow gum; MS (ESI+): 424.2 (M+1) and 446.3 (M+Na).

Stage-5. Preparation of 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4carboxamido)furan-2-yl)acetic acid (143g) .

Compound 143g was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-carboxamido)furan-2-yl)acetate (143f) (14 mg, 0.033 mmol) in THF/MeOH (4 ml each), using lithium hydroxide monohydrate (9 mg, 0.198 mmol) in water (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel with dichloromethane/methanol (1:0 to 9:1)] 2-(3-(2-(3(aminomethyl)-2-fluorophenyl)pyrrolo[2 ,1-f][1,2,4]triazin-4-carboxamido)furan-2-yl)acetic acid (143g) (11 mg, 81%) as a yellow solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 12.44 (s, 1H), 8.40 (s, 1H), 8.17-8.03 (m, 1H), 7.71-7.64 (m, 1H), 7.61 (d, J=4.5 Hz, 1H), 7.46 (s, 1H), 7.42-7.31 (m, 1H), 7.30-7, 23 (m, 1H), 7.11 (s, 1H), 4.05 (s, 2H); ¹⁹ F NMR (282

MHz, DMSO-d6) δ -113.61; MS (ESI+): 410.27 (M+1) and 432.28 (M+Na); MC (ESI-): 408.34 (M-1); purity after HPLC: 92.67%.

Scheme-144

Preparation of 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)thiophen-2-yl)acetic acid (144d) .

Stage-1. Preparation of methyl 2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophene- 2-yl)acetate (144b).

Compound 144b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-carboxylic acid (34c) (140 mg, 0.362 mmol) in DMF (8 ml), using methyl 2-(3-aminothiophen-2-yl) acetate (144a) (120 mg, 0.701 mmol, obtained in accordance with the procedure described by Kenda, Benoit et al.; in international application PCT, 2008132139, 06 November 2008; CAS No. 22288-78-4), DIPEA (0.244 ml, 1.402 mmol) and HATU (266 mg , 0.701 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 3:1)] methyl 2-(3-(2-(3((( tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)thiophen-2-yl)acetate (144b) (102 mg, 52%) in as a yellow solid.

Ή NMR (300 MHz, DMSO- _d6 ) δ 10.67 (s, 1H), 8.41-8.37 (m, 1H), 8.29-8.18 (m, 1H), 7.57 -7.40 (m, 5H), 7.37 (t, J=7.8 Hz, 1H), 7.28 (dd, J=4.5, 2.6 Hz, 1H), 4.28 ( d, J=6.1 Hz, 2H), 3.96 (s, 2H), 3.61 (s, 3H), 1.40 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -119.32; MS (ESI+): 540.3 (M+1), MS (ESI-): 538.4 (M-1).

Stage-2. Preparation of methyl 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4carboxamido)thiophen-2-yl)acetate (144c) .

Compound 144c was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2. 1-f][1,2,4]triazin-4carboxamido)thiophen-2-yl)acetate (144b) (85 mg, 0.158 mmol) in DCM (8 mL), using TFA (0.485 mL, 6.30 mmol) . This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1)] methyl 2-(3-(2-(3(aminomethyl) -2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate (144c) (109 mg) as a yellow solid;

Ή NMR (500 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.47 (td, J=7.6, 1.8 Hz, 1H), 8.37 (dd, J=2 ,6, 1.3 Hz, 1H), 8.32 (s, 3H), 7.75-7.70 (m, 1H), 7.56 (dd, J=4.6, 1.3 Hz, 1H), 7.51 (d, J=5.4 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.42 (d, J=5.4 Hz, 1H) , 7.31 (dd, J=4.6, 2.5 Hz, 1H), 4.22 (s, 2H), 3.97 (s, 2H), 3.62 (s, 3H); MS (ESI+): 440.3 (M+1) and 462.3 (M+Na).

Stage-3. Preparation of 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4carboxamido)thiophen-2-yl)acetic acid (144d) .

Compound 144d was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-carboxamido)thiophen-2-yl)acetate (144c) (79 mg, 0.180 mmol) in THF/MeOH (8 mL each), using lithium hydroxide monohydrate (46 mg, 1.08 mmol) in water (8 ml). This resulted in the production after treatment of 2-(3-(2-(3-(aminomethyl)-2fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-carboxamido)thiophen-2-yl) acetic acid (144d) (43 mg,

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89% in two stages) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.42 (dd, J=2.6, 1.4 Hz, 1H), 7.96 (td, J=7, 4, 1.7 Hz, 1H), 7.68-7.59 (m, 3H), 7.37 (t, J=7.6 Hz, 1H), 7.31-7.27 (m, 2H ), 4.05 (s, 2H), 3.43 (s, 2H); ¹⁹ F NMR (282 MHz,

DMSO-d ₆ ) δ -112.88; MS (ESI+): 426.2 (M+1); purity after HPLC: 95.25%.

Scheme-145

Preparation of 2-(4-(7-(3 -(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3yl)acetic acid (145c).

Stage-1. Preparation of ethyl 2-(4-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (145a).

Compound 145a was prepared according to the procedure described in step-4 of Scheme-1 from 7chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a) (140 mg, 0.673 mmol) in DMF using ethyl 2-( 4Aminothiophen-3-yl)acetate (142a) (387 mg), DIPEA (0.586 ml, 3.37 mmol) and HATU (640 mg, 1.683 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 3:1)] ethyl 2-(4-(7-chlorofuro[2,3c ]pyridin-5-carboxamido)thiophen-3-yl)acetate (145a) (168 mg, 68%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.54 (s, 1H), 8.50 (d, J=2.1 Hz, 1H), 7.83 ( d, J=3.5 Hz, 1H), 7.44 (d, J=3.5 Hz, 1H), 7.37 (d, J=2.1 Hz, 1H), 4.15 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI+): 387.1 and 389.1 (M+Na), MS (ESI-): 363.2 and 365.2 (M-1).

Stage-2. Preparation of ethyl 2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridin-5carboxamido)thiophen-3-yl)acetate (145b).

Compound 145b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-(7-chlorofuro[2,3-c]pyridin-5-carboxamido)thiophen-3-yl)acetate (145a) (100 mg, 0.274 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (77 mg, 0.411 mmol), tripotassium phosphate (1.3 M solution, 0.155 ml, 0.466 mmol), tricyclohexylphosphine (46 mg, 0.164 mmol) and Pd ₂ (dba) ₃ (75 mg, 0.082 mmol) under Ar and heating at 125°C for 2 hours in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(4-(7-(3(aminomethyl) Phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (145b) (52 mg, 44%) as a brown gum.

1H NMR (300 MHz, DMSO- _d6 ) δ 10.76 (s, 1H), 8.53-8.51 (m, 1H), 8.51 (s, 1H), 8.48 (d, J =2.2 Hz, 1H), 8.41-8.32 (m, 1H), 7.92 (d, J=3.5 Hz, 1H), 7.54 (d, J=4.8 Hz , 2H), 7.47 (d, J=3.5 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 4.01 (k, J=7.1 Hz, 2H ), 3.90 (s, 2H), 3.87 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 436.3 (M+1), MS (ESI): 434.3 (M-1).

Stage-3. Preparation of 2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3yl)acetic acid (145c).

Compound 145c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophene- 3-yl)acetate (145b) (52 mg, 0.119 mmol) in THF/MeOH (5 mL each), using lithium hydroxide monohydrate (31 mg, 0.72 mmol) in water (5 mL). This resulted in the production after treatment of 2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3c]pyridin-5-carboxamido)thiophen-3-yl)acetic acid (145c) (47 mg, 97 %) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 9.29 (s, 1H), 8.55 (d, J=7.7 Hz, 1H), 8.48- 8.44 (m, 3H), 7.76 (d, J=3.4 Hz, 1H), 7.61-7.44 (m, 2H), 7.32 (d, J=2.2 Hz , 1H), 7.13 (d, J=3.4 Hz, 1H), 4.04 (s, 2H), 3.37 (s, 2H); MS (ESI+): 408.2 (M+1) and 430.2 (M+Na); purity after HPLC: 94.80%.

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Scheme-146

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-1 -tosyl-1 H-indol-5 -yl)methoxy)phenyl)acetic acid (146g).

Stage-1. Preparation of methyl 7-bromo-1-tosyl-1H-indole-5-carboxylate (146b).

Compound 146b was prepared according to the procedure described in step-1 of scheme-40 from methyl 7-bromo-1H-indole-5-carboxylate (146a) (0.6 g, 2.361 mmol; CAS No. 885523-35-3) in DMF (9.5 ml) using NaH (60% in mineral oil, 0.236 g, 5.90 mmol) and Tosyl-Cl (0.540 g, 2.83 mmol). This resulted in methyl 7-bromo-1-tosyl-1H-indole-5-carboxylate (146b) (0.83 g, 86% yield) as a tan solid, which was used directly in the next step;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.31 (d, J=1.6 Hz, 1H), 8.12 (d, J=3.8 Hz, 1H), 7.97 (d , J=1.7 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.12 (d, J =3.9 Hz, 1H), 3.86 (s, 3H), 2.37 (s, 3H).

Stage-2. Preparation of 7-bromo-1-tosyl-1H-indole-5-carboxylic acid (146c).

Compound 146c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-bromo-1-tosyl-1H-indole-5-carboxylate (146b) (800 mg, 1.960 mmol) in MeOH/THF (30 ml each) using a solution of lithium hydroxide monohydrate (329 mg, 7.84 mmol) in water (30 ml). This resulted in 7-bromo-1-tosyl-1H-indole-5-carboxylic acid (146c) (738 mg, 96%) as an off-white solid upon treatment;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.27 (s, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.11 (d, J=3.8 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.82-7.72 (m, 2H), 7.43 (d, J=8.2 Hz, 2H), 7, 10 (d, J=3.8 Hz, 1H), 2.38 (s, 3H); MS (ESI-): 392.1 and 394.1 (M-1).

Stage-3. Preparation of (7-bromo-1-tosyl-1H-indol-5-yl)methanol (146d).

Compound 146d was prepared according to the procedure described in step-1 of Scheme-23 from 7bromo-1-tosyl-1H-indole-5-carboxylic acid (146c) (218 mg, 0.553 mmol) using Nmethylmorpholine (0.073 ml, 0.664 mmol) in THF (10 ml), isobutyl chloroformate (0.087 ml, 0.664 mmol) and NaBH ₄ (63 mg, 1.659 mmol) in water (0.8 ml). This gave (7-bromo-1tosyl-1H-indol-5-yl)methanol (146d) (251 mg) as a colorless gum, which was used as is in the next step; MS (ESI+): 402.1 (M+Na), MS (ESI-): 378.2 and 380.2 (M-1).

Stage-4. Preparation of ethyl 2-(2-((7-bromo-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146e).

Compound 146e was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-1-tosyl-1H-indol-5-yl)methanol (146d) (179 mg, 0.995 mmol) in DCM (5 ml) using triphenylphosphine (189 mg, 0.719 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.739 g, 4.1 mmol) and a solution of di-(4chlorobenzyl) azodicarboxylate (264 mg, 0.719 mmol) in DCM ( 5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 2:1)] ethyl 2-(2-((7-bromo-1- tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146e) (190 mg, 63% in two steps) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.02 (d, J=3.9 Hz, 1H), 7.76-7.68 (m, 3H), 7.56-7.50 ( m, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.28-7.16 (m, 2H), 7.03 (d, J=8.1 Hz, 1H), 6.96 (d, J=3.8 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.12 (s, 2H), 3.97 (k, J=7 .1 Hz, 2H), 3.60 (s, 2H), 2.37 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5yl)methoxy)phenyl)acetate (146f).

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Compound 146f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146e) ( 180 mg, 0.332 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (93 mg, 0.498 mmol), tripotassium phosphate (1.3 M solution, 0.188 ml, 0.564 mmol), tricyclohexylphosphine ( 55.8 mg, 0.199 mmol) and Pd ₂ (dba) ₃ (91 mg, 0.100 mmol) under Ar and heating at 125°C for 2 hours in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((7-(3(aminomethyl) )phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146f) (74 mg, 39%) as a colorless gum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.79 (d, J=3.8 Hz, 1H), 7.59 (s, 1H), 7.36-6.99 (m, 12H) , 6.95-6.83 (m, 2H), 5.13 (s, 2H), 3.85 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 3, 58 (s, 2H), 2.31 (s, 3H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 569.3 (M+1), MS (ESI-): 567.5 (M-1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5yl)methoxy)phenyl)acetic acid (146g).

Compound 146g was prepared according to the procedure described in step-4 of scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy) phenyl)acetate (146f) (37 mg, 0.065 mmol) in MeOH (10 ml), using a solution of sodium hydroxide (0.325 ml, 0.651 mmol, 2 M aq) in water (3 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1, then 3:2)] 2-(2-((7-(3(aminomethyl )phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetic acid (146g) (12 mg, 34%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.37 (d, J=7.2 Hz, 1H), 7.31-7.00 (m, 8H), 6.92-6.86 (m, 2H), 6.80 (t , J=7.3 Hz, 1H), 5.15 (s, 2H), 3.95 (s, 2H), 3.34 (s, 2H), 2.29 (s, 3H); MS (ESI+): 541.3 (M+1).

Scheme-147

Preparation of 2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2yl)acetic acid (147c).

Stage-1. Preparation of methyl 2-(3-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)acetate (147a).

Compound 147a was prepared according to the procedure described in step-4 of Scheme-1 from 7chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a) (100 mg, 0.481 mmol) in DMF (10 ml) using methyl 2-(3-aminothiophen-2-yl)acetate (144a) (140 mg, 0.817 mmol), DIPEA (0.335 ml, 1.923 mmol) and HATU (366 mg, 0.962 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 2:1)] methyl 2-(3-(7-chlorofuro[2,3-c ]pyridin-5-carboxamido)thiophen-2-yl)acetate (147a) (112 mg, 66%) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.50 (s, 1H), 8.48 (d, J=2.1 Hz, 1H), 7.44 (d , J=5.4 Hz, 1H), 7.38-7.34 (m, 2H), 3.91 (s, 2H), 3.67 (s, 3H); MS (ESI+): 373.1 (M+Na), MS (ESI-): 349.1 (M-1).

Stage-2. Preparation of 2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2yl)acetic acid (147c).

Compound 147c was prepared according to the procedure described in step-3 of Scheme-1 from methyl 2-(3-(7-chlorofuro[2,3-c]pyridin-5-carboxamido)thiophen-2-yl)acetate (147a ) (0.108 g, 0.308 mmol) in dioxane (6 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.070 g, 0.462 mmol), tripotassium phosphate (1.3 M solution, 0.711 ml, 0.924 mmol), tricyclohexylphosphine (0.052 g, 0.185 mmol) and Pd ₂ (dba) ₃ (0.056 g, 0.062 mmol) under Ar and heating at 125°C for 45 min in a microwave oven. This resulted in, after workup and purification by flash column chromatography, [silica gel 8 g, eluted with methanol in 0% to 40% DCM] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (0. 1% HCl) 0% to 100%] methyl 2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2yl)acetate (147b) (0.027 g, 0.064 mmol, 21% yield); MS (ESI+): 422.2 (M+1); MS (ESI-): 456.3 (M+Cl) and 2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridin-5-carboxamido)thiophen-2-yl )acetic acid (147c) (0.012 g, 10% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.78 (s, 1H, D2O replaceable), 10.60 (s, 1H, D2O replaceable), 8.73 (s, 1H), 8.63- 8.56 (m, 1H), 8.52 (s, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.50-8.37 (m, 3H, D2O replaceable), 7.74-7.63 (m,

- 222 045626

2H), 7.56 (d, J=5.5 Hz, 1H), 7.46 (d, J=5.4 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H) , 4.31-4.10 (m, 2H), 3.89 (s, 2H); MS (ESI+): 408.2 (M+1); MS (ESI-): 406.3 (M-1); 442.2 (M+Cl), 813.4 (2M-1).

Scheme-148

148с ijoj 148е

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (148e).

Stage-1. Preparation of 4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid (148a).

Compound 148a was prepared according to the procedure described in step-1 of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (15 g, 59.0 mmol) in DMF (50 ml) using NaH (60% in mineral oil) (5.90 g, 148 mmol) and (bromomethyl)cyclopropane (16.69 ml, 177 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc/MeOH=9:1 in 0% to 50% hexane] 4-bromo-1-(cyclopropylmethyl)-1H- indole-6carboxylic acid (148a) (10 g, 58% yield) as a white solid; MS (ESI-): 292.2, 294.2 (M-1).

Stage-2. Preparation of (4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methanol (148b).

Compound 148b was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid (148a) (15 g, 51.0 mmol) using Nmethylmorpholine ( 6.73 ml, 61.2 mmol) in THF (100 ml), isobutyl chloroformate (8.04 ml, 61.2 mmol) and NaBH ₄ (5.79 g, 153 mmol) in water (8 ml). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc/MeOH=9:1 in hexane from 0% to 100%] (4-bromo-1-(cyclopropylmethyl)-1H -indol-6-yl)methanol (148b) (9.7 g, 68% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ): δ 7.51 (d, J=3.2 Hz, 1H), 7.48 (t, J=1.0 Hz, 1H), 7.22 (d , J=1.1 Hz, 1H), 6.35 (dd, J=3.1, 0.9 Hz, 1H), 5.24 (t, J=5.7 Hz, 1H), 4.58 (d, J=4.3 Hz, 2H), 4.04 (d, J=7.0 Hz, 2H), 1.33-1.11 (m, 1H), 0.57-0.32 ( m, 4H); MS (ESI+): 280.1 (M+1).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6yl)methoxy)phenyl)acetate (148c).

Compound 148c was prepared according to the procedure described in step-2 of Scheme-23 from ((4bromo-1-(cyclopronylmethyl)-1H-indol-6-yl)methanol (148b) (2.51 g, 13.92 mmol ) in toluene (30 ml), using triphenylphosphine (3.65 g, 13.92 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) 2.51 g, 13.92 mmol) and solution (E)- diazen-1,2-diylbis(piperidin-1-ylmethanone) (3.51 g, 13.92 mmol) in toluene (20 ml). This resulted in, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc/MeOH (9:1) in hexane from 0% to 10% for 40 min, then 10% to 50%] ethyl 2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (148c) (1.68 g, 36% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ): δ 7.65 (t, J=1.0 Hz, 1H), 7.57 (dd, J=5.3, 3.2 Hz, 1H), 7 .30 (d, J=1.1 Hz, 1H), 7.28-7.19 (m, 2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6, 90 (td, J=7.4, 1.1 Hz, 1H), 6.39 (td, J=3.2, 0.8 Hz, 1H), 5.19 (s, 2H), 4.09 -4.01 (m, 4H), 3.63 (s, 2H), 1.31-1.21 (m, 1H), 1.08 (t, J=7.1 Hz, 3H), 0. 54-0.34 (m, 4H); MS (ESI+): 442.3, 444.3 (M+1); MS (ESI-): 440.1, 442.0 (M-1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6yl)methoxy)phenyl)acetate (148d).

Compound 148d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (148c ) (0.64 g, 1.45 mmol) in dioxane (7 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.41 g, 2.17 mmol), K2CO3 (0.60 g, 4.34 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.15 g, 0.22 mmol) in an Ar atmosphere and heating at 100 °C for 4 h in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM from 0% to 20%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1(cyclopropylmethyl)-1H-indol-6-yl )methoxy)phenyl)acetate (148d) (0.26 g, 38% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.35 (s, 3H), 7.81 (s, 1H), 7.72-7.63 (m, 2H), 7.60-7, 52 (m, 2H), 7.527.45 (m, 1H), 7.28-7.18 (m, 3H), 7.16-7.09 (m, 1H), 6.89 (td, J= 7.4, 1.1 Hz, 1H), 6.66 (dd, J=3.2, 0.8 Hz, 1H), 5.26 (s, 2H), 4.18-4.05 (m , 4H), 3.93 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.37-1.13 (m, 1H), 0.99 (t, J= 7.1 Hz, 3H), 0.56-0.34 (m, 4H); MS (ESI+): 469.5 (M+1); MS (ESI-): 503.4 (M+Cl).

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1 -(cyclopropylmethyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (148e).

Compound 148e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3 -(aminomethyl)phenyl)-1 -(cyclopropylmethyl)-1 H-indol-6-yl )methoxy)phenyl)acetate (148d) (0.16 g, 0.34 mmol) in THF/MeOH (4 ml each), using a solution of sodium hydroxide (0.07 g, 1.71 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (148e) (0.07 g, 47% yield), HCl salt, as a white solid ;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.44 (s, 3H), 7.82 (s, 1H), 7.75-7.64 (m, 2H), 7.62-7, 46 (m, 3H), 7.297.17 (m, 3H), 7.11 (d, J=8.2 Hz, 1H), 6.95-6.85 (m, 1H), 6.65 (d , J=3.2 Hz, 1H), 5.27 (s, 2H), 4.17-4.04 (m, 4H), 3.60 (s, 2H), 1.36-1.19 ( m, 1H), 0.57-0.29 (m, 4H); MS (ESI+): 441.4 (M+1); MS (ESI-): 439.4 (M-1), 475.4 (M+Cl). Purity after HPLC: 88.53%.

Scheme-149

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (149b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol6-yl)methoxy)phenyl)acetate (149a).

Compound 149a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (148c ) (0.64 g, 1.45 mmol) in dioxane (7 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.45 g, 2.17 mmol), K ₂ CO ₃ (0.60 g, 4.34 mmol) in water (0.7 ml) and bis(triphenylphosphine) palladium(P) chloride (0.15 g, 0.22 mmol) in an Ar atmosphere and heating at 100 °C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 20%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy )phenyl)α acetate (149a) (0.36 g, 51% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.38 (s, 3H), 7.69 (s, 1H), 7.65-7.55 (m, 2H), 7.52 (d, J =3.2 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29-7.17 (m, 2H), 7.16-7.09 (m, 2H) , 6.90 (td, J=7.3, 1.1 Hz, 1H), 6.35 (t, J=2.7 Hz, 1H), 5.25 (s, 2H), 4.17 ( s, 2H), 4.10 (d, J=7.0 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.34- 1.21 (m, 1H), 0.99 (t, J=7.1 Hz, 3H), 0.57-0.35 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.84; MS (ESI+): 487.4 (M+1); MS (ESI-): 521.5 (M+Cl). Purity after HPLC: 96.57%.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (149b).

Compound 149b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (149a) (0.24 g, 0.49 mmol) in THF/MeOH (4 ml each), using a solution of sodium hydroxide (0.10 g, 2.47 mmol) in water (0.8 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(3- (aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (149b) (0.08 g, 35% yield), HCl salt, as a white solid substances;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.79 (s, 3H), 7.71 (s, 1H), 7.66-7.54 (m, 2H), 7.52 (d, J =3.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.7 Hz, 2H), 7.19-7.07 (m , 2H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 6.35 (t, J=2.9 Hz, 1H), 5.27 (s, 2H), 4 .16 (s, 2H), 4.09 (d, J=7.0 Hz, 2H), 3.59 (s, 2H), 1.35-1.19 (m, 1H), 0.56- 0.34 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.79; MS (ESI+): 459.4 (M+1); MS (ESI-): 457.3 (M-1), 493.4 (M+Cl).

- 224 045626

Purity after HPLC: 92.06%.

Scheme-150

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -methyl-1 H-indol-6yl)methoxy)phenyl)acetic acid (150b).

Stage-1. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetate (150a).

Compound 150a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (133a) (0.65 g, 1.45 mmol) in dioxane (6 ml) using (3-fluoro-4-iodopyridine-2 -yl)methanamine (113a) (0.30 g, 1.21 mmol), bis(triphenylphosphine) palladium(P) chloride (0.13 g, 0.18 mmol) and K ₂ CO ₃ solution (0.42 g , 3.01 mmol) in water (1.0 ml) under Ar atmosphere and heating at 100°C for 2 h in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indole-6- yl)methoxy)phenyl)acetate (150a) (0.12 g, 22% yield) as a yellow solid; MS (ESI+): 448.5 (M+1).

Stage-2. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6yl)methoxy)phenyl)acetic acid (150b).

Compound 150b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H- indol-6-yl)methoxy)phenyl)acetate (150a) (0.12 g, 0.27 mmol) in MeOH/THF (4 ml each) using sodium hydroxide solution (0.05 g, 1.34 mmol ) in water (0.8 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)-3-fluoropyridin-4-yl)-1 -methyl-1 H-indol-6-yl)methoxy)phenyl)acetic acid (15 0b) (0.03 g, 23% yield), salt HCl, as a yellow solid;

^1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=4.9 Hz, 1H), 8.46 (br. s, 4H), 7.73 (s, 1H), 7, 68 (t, J=5.3 Hz, 1H), 7.48 (d, J=3.1 Hz, 1H), 7.29 (s, 1H), 7.27-7.20 (m, 2H ), 7.11 (d, J=8.1 Hz, 1H), 6.90 (m, 1H), 6.37 (t, J=3.0 Hz, 1H), 5.29 (s, 2H ), 4.37 (d, J=6.0 Hz, 2H), 3.86 (s, 3H), 3.60 (s, 2H); MS (ESI+): 420.4 (M+1), 442.3 (M+Na); MS (ESI-): 418.4 (M-1), 454.4 (M+Cl). Purity after HPLC: 92.20%.

Scheme-151

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -methyl-1 H-indazol-6yl)methoxy)phenyl)acetic acid (151c).

Stage-1. Preparation of ethyl 2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindazol-6-yl)methoxy)phenyl)acetate (151a).

Compound 151a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e) (2.00 g, 4.96 mmol) using bis(pinacolato)diboron (1.889 g, 7.44 mmol), potassium acetate (1.460 g, 14.88 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.608 g, 0.744 mmol) in anhydrous dioxane (30 ml) under Ar atmosphere and heating at 100°C for

- 225 045626 nights. This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with 0% to 100% EtOAc in hexane] ethyl 2-(2-((1-methyl-4-(4,4, 5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methoxy)phenyl)acetate (151a) (1.105 g, 50% yield) as a white solid; MS (ESI+): 451.5 (M+1), 473.5 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6yl)methoxy)phenyl)acetate (151b).

Compound 151b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(( 1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1 H-indazol-6-yl)methoxy)phenyl)acetate (151a) (0.7 g, 1.554 mmol) in dioxane (30 ml) using (3-fluoro-4-iodopyridine-2- yl)methanamine (113a) (0.47 g, 1.865 mmol), bis(triphenylphosphine) palladium(P) chloride (0.164 g, 0.233 mmol) and a solution of K2CO3 (0.644 g, 4.66 mmol) in water (5 ml) in an Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM 0% to 40%], compound 151b (0.219 g, 31% yield), free base, as a yellow waxy solid matter. 105 mg of free base was further purified by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((4 -(2-(aminomethyl)-3-fluoropyridin4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (151b) (0.060 g, 57% yield), HCl salt, as yellow solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J=4.9 Hz, 1H), 8.49 (s, 3H, D2O exchangeable), 8.06 (dd, J=3, 1, 1.0 Hz, 1H), 7.91 (s, 1H), 7.76 (t, J=5.3 Hz, 1H), 7.40 (s, 1h), 7.31-7, 21 (m, 2H), 7.17-7.08 (m, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.33 (s, 2H), 4 .47-4.31 (m, 2H), 4.12 (s, 3H), 3.93 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 0.98 ( t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -128.80; MS (ESI+): 449.2 (M+1); MS (ESI-): 447.3 (M-1); purity after HPLC: 89.52%.

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -methyl-1 H-indazol-6yl)methoxy)phenyl)acetic acid (151c).

Compound 151c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H- indazol-6-yl)methoxy)phenyl)acetate (151b) (0.107 g, 0.239 mmol) in THF (4 mL) and MeOH (8 mL), using 2 M LiOH (0.596 mL, 1.193 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2-(aminomethyl)-3fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetic acid (151c) (0.052 g, 52% yield), HCl salt, as yellow solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.2 (br.s, 1H, D2O replaceable), 8.61 (d, J=5.0 Hz, 1H), 8.55 (br.s, 3H, D2O replaceable), 8.06 (dd, J=3.2, 1.0 Hz, 1H), 7.97-7.90 (m, 1H), 7.76 (t, J=5.3 Hz, 1H), 7.43 (s, 1H), 7.307.20 (m, 2H), 7.14-7.05 (m, 1H), 6.96-6.88 (m, 1H), 5 .35 (s, 2H), 4.46-4.30 (m, 2H), 4.11 (s, 3H), 3.64 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.67; MS (ESI+): 421.3 (M+1), 841.6 (2M+1); MS (ESI-): 419.4 (M-1), 455.3 (M+Cl), 839.6 (2M-1); purity after HPLC: 94.47%.

Scheme-152

Preparation of lithium 2-(2-(((7-(3 -(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (152d).

Stage-1. Preparation of 7-bromo-5-(bromomethyl)benzofuran (152a).

To a solution of (7-bromobenzofuran-5-yl)methanol (23a) (3.00 g, 13.21 mmol), CBr ₄ (8.76 g, 26.4 mmol) in DCM (100 ml) was added at 0° C solution of triphenylphosphine (6.93 g, 26.4 mmol) in DCM (50 ml) over 15 min and stirred at 0°C for 2 h. The reaction mixture was diluted with water (200 ml) and extracted with DCM (2x150 ml) . The combined organic layers were dried, filtered and evaporated

- 226 045626 until dry. The resulting residue was purified by flash column chromatography [silica gel 40 g, eluted with ethyl acetate in 0% to 100% hexanes] to give 7-bromo-5(bromomethyl)benzofuran (152a) (2.38 g, 62% yield) in as a pale yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.16 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 4.84 (s, 2H).

Stage-2. Preparation of ethyl 2-(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b).

To a stirred solution of ethyl 2-(2-aminophenyl)acetate (5e) (1.125 g, 6.28 mmol) in DMF (10 ml) was added K ₂ CO ₃ (4.34 g, 31.4 mmol) followed by the addition of 7 -bromo-5(bromomethyl)benzofuran (152a) (1.82 g, 6.28 mmol). The resulting mixture was stirred at room temperature for 12 hours and diluted with EtOAc (100 ml) and brine (100 ml). The organic layers were dried, filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel 40 g, eluted with ethyl acetate in 0% to 100% hexanes] to give ethyl 2-(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate ( 152b) (1.9 g, 4.89 mmol, 78% yield) as a thick yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.2 Hz, 1H), 7.63 (d, J=1.4 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.02-6.93 (m, 2H), 6.52 (td, J=7.4 , 1.2 Hz, 1H), 6.45 (dd, J=8.1, 1.1 Hz, 1H), 5.83 (t, J=5.9 Hz, 1H), 4.42 (d , J=5.9 Hz, 2H), 4.11 (k, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.20 (t, J=7.1 Hz, 3H ).

Stage-3. Preparation of ethyl 2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (152c).

Compound 152c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b) (0.700 g, 1.803 mmol ) in dioxane (30 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.481 g, 2.344 mmol), bis(triphenylphosphine) palladium(P) chloride (PdCl ₂ (PPh ₃ ) ₂ ) (0.190 g, 0.270 mmol) and K ₂ CO ₃ (0.748 g, 5.41 mmol) in water (3 ml) heating in an Ar atmosphere at 125 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel 40 g, eluted with methanol in 0% to 40% DCM] ethyl 2-(2-(((7-(3-(aminomethyl)-2fluorophenyl) benzofuran-5-yl)methyl)amino)phenyl)acetate (152c) (0.503 g, 65% yield) as an oily off-white solid; MS (ESI+): 433.2 (M+1).

Stage-4. Preparation of lithium 2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (152d).

To a solution of ethyl 2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (152c) (0.165 g, 0.382 mmol) in THF (10 ml ) and MeOH (20 mL), lithium hydroxide monohydrate (2 M, 0.954 mL, 1.908 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours and evaporated under vacuum. The residue was purified by flash column chromatography [silica gel 40 g, eluted with methanol in DCM 0% to 100%] and the product was lyophilized to give lithium-2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl )benzofuran-5yl)methyl)amino)phenyl)acetate (152d) (0.033 g, 0.080 mmol, 21.08% yield) as an off-white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 7.98 (s, 1H), 7.69 (s, 1H), 7.62-7.47 (m, 3H), 7.37-7.21 (m, 1H), 7.066.84 (m, 3H), 6.58-6.39 (m, 2H), 4.45 (s, 2H), 3.89 (s, 2H), 3.41 ( s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 119.51; MS (ESI+): 405.2 (M+1); MS (ESI-): 403.3 (M-1); purity after HPLC: 87.33%; analysis calculation for: C ₂ 4H ₂ 0FLiN ₂ O3-0.75H ₂ O: C, 68.00; N, 5.11; N, 6.61; observed: C, 67.69; N, 5.44; N, 6.48.

Scheme-153

Preparation of lithium 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate (153b).

Stage-1. Preparation of ethyl 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (153a).

Compound 153a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b) (0.600 g, 1.545 mmol ) in dioxane (30 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.377 g, 2.009 mmol), bis(triphenylphosphine) palladium(P) chloride (PdCl ₂ (PPh ₃ ) ₂ ) ( 0.163 g, 0.232 mmol) and K2CO3 (0.641 g, 4.64 mmol) in water (3 ml) heating in an Ar atmosphere at 125°C for 3 hours in an oil bath. This resulted in, after workup and purification by flash column chromatography [silica gel 40

- 227 045626 g, eluted with methanol in DCM from 0% to 40%] ethyl 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (153a) ( 0.531 g, 1.281 mmol, 83% yield) as a waxy off-white solid; MS (ESI+): 415.2 (M+1).

Stage-2. Preparation of lithium 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methyl)amino)phenyl)acetate (153b).

To a solution of ethyl 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate (153a) (0.251 g, 0.606 mmol) in THF (10 ml) and MeOH (20 mL), lithium hydroxide monohydrate (1.514 mL, 3.03 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours and evaporated to dryness. The residue was purified by flash column chromatography [silica gel 40 g, eluted with methanol in DCM from 0% to 100%] and the product was lyophilized to give lithium-2-(2-(((7-(3(aminomethyl)phenyl)benzofuran-5 -yl)methyl)amino)phenyl)acetate (153b) (0.051 g, 22% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.28 (s, 1H), 8.14-8.08 (m, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7, 36-7.28 (m, 1H), 7.01 (d, J=2.2 Hz, 1H), 6.89 (dd, J=7.3, 1.6 Hz, 1H), 6.80 (td, J=7.7, 1.6 Hz, 1H), 6.51-6.35 (m, 2H), 4.51 (d, J=5.8 Hz, 2H), 4.02 ( s, 2H), 3.33 (s, 2H); MS (ESI+): 387.3 (M+1); MS (ESI-): 385.4 (M-1); purity after HPLC: 92.66%; analysis calculation for: C ₂₄ H ₂₁ LiN ₂ O ₃ -0.25H ₂ O: C, 72.63; N, 5.46; N, 7.06; observed: C, 72.62; N, 5.45; N, 6.95.

Scheme-154

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (154g).

Stage-1. Preparation of methyl 7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5carboxylate (154b).

To a solution of 2,2,2-trifluoroethanamine HCl (1.71 g, 17.26 mmol; CAS No. 373-88-6) in DCM (15 ml) at 0°C, add sodium nitrite solution (1.27 g, 18.41 mmol) in water (1.5 ml). The mixture was kept in an ice bath for 1 hour, cooled to -78°C and methyl 3-bromo-5-formyl-4-hydroxybenzoate (154a) (0.522 g, 2.015 mmol; CAS No. 706820-79-3) was added and trifluoroboron etherate (1.2 ml, 9.47 mmol). The mixture was stirred at -78°C for 12 hours, warmed to room temperature over a period of 12 hours. The reaction was quenched with methanol (8 ml), diluted with saturated aq. NaHCO ₃ and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with ethyl acetate/hexanes, 0-30%] to give methyl 7-bromo-2hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate (154b) (503 mg, 73% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.60 (d, J=6.0 Hz, 1H), 8.11 (dd, J=1.7, 0.6 Hz, 1H), 7, 91 (dt, J=1.8, 0.9 Hz, 1H), 6.28 (dd, J=5.9, 2.4 Hz, 1H), 4.67-4.46 (m, 1H) , 3.85 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -69.45.

Stage-2. Preparation of methyl 7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (154c)

A solution of methyl 7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate (154b) (495 mg, 1.451 mmol) in sulfuric acid (5 ml, 94 mmol) was stirred at room temperature in for 30 minutes. The mixture was poured into ice water and the resulting white solid was collected by filtration, dried under vacuum to give methyl 7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (154c) (462 mg, 99% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.11 (t, J=1.7 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.20 (dt, J=1.5, 0.9 Hz, 1H), 3.92 (s, 3H).

Stage-3. Preparation of (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d).

Compound 154d was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (154c) (927 mg, 2.87 mmol) in THF (12 ml ), using LiBH ₄ (2.20 ml, 8.80 mmol, 2 M solution in THF) and MeOH (385 μl, 9.52 mmol). This resulted in (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (836 mg, 99% yield) as a white solid after workup.

'H NMR (300 MHz, methanol^) δ 8.41 (d, J=1.7 Hz, 1H), 7.61 (k, J=1.6 Hz, 2H), 4.69 (s, 2H ).

Stage-4. Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (154e).

Compound 154e was prepared according to the procedure described in step-2 of Scheme-23, from (7bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (80 mg, 0.271 mmol) in DCM (6 ml), using triphenylphosphine (82 mg, 0.313 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (74 mg, 0.411 mmol) and di(4-chlorobenzyl) azodicarboxylate (117 mg, 0.319 mmol) in DCM (2 ml) . This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with ethyl acetate/hexanes, 0-40%] ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran- 5yl)methoxy)phenyl)acetate (154e) (67 mg, 54% yield) as a white solid.

'H NMR (300 MHz, DMSO-d6) δ 8.97 (k, J=1.6 Hz, 1H), 7.81 (s, 2H), 7.37-7.17 (m, 2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4 .01 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.25.

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (154f).

Compound 154f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (154e) (220 mg, 0.481 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (111 mg, 0.735 mmol), solution of K ₂ CO ₃ (206 mg, 1.491 mmol) in water (0.5 ml), bis(triphenylphosphine)palladium(11) chloride (60 mg, 0.085 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (154f) (145 mg, 62% yield) as a dark oil. The analytical sample was obtained by further purification by reverse phase chromatography column [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give compound 154f, HCl salt, as a white solid substances.

'H NMR (300 MHz, methanol-d4) δ 8.47 (k, J=1.6 Hz, 1H), 8.07-7.89 (m, 2H), 7.88-7.74 (m , 2H), 7.71-7.45 (m, 2H), 7.34-7.14 (m, 2H), 7.09 (dd, J=8.3, 1.1 Hz, 1H), 6.94 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.25 (s, 2H), 3.96 (k, J=7.1 Hz , 2H), 3.67 (s, 2H), 1.02 (t, J=7.1 Hz, 3H); MS (ESI+): 484.2 (M+1); (ESI-): 482.3 (M-1); purity after HPLC 98.43%.

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (154g).

Compound 154g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl )acetate (154f) (96 mg, 0.199 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (40 mg, 1.670 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (154g) (67 mg, 74% yield), HCl salt, as a white solid.

'H NMR (300 MHz, methanol-d4) δ 8.45 (k, J=1.6 Hz, 1H), 8.05-7.96 (m, 2H), 7.81 (dd, J=9 ,7, 1.6 Hz, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.53 (dt, J=7.7, 1.5 Hz, 1H), 7.30 -7.19 (m, 2H), 7.06 (d, J=8.0 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.30 ( s, 2H), 4.23 (s, 2H), 3.70 (s, 2H); MS (ESI+): 456.1 (M+1); MS (ESI-): 454.2 (M-1). HPLC: purity 97.47%. Analysis calculation for C ₂₅ H ₂₀ F ₃ NO ₄ -HCl: C, 61.04; N, 4.30; Cl, 7.21; N, 2.85; observed: C, 60.83; N, 4.63; Cl, 7.61; N, 2.65.

Scheme-155

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-229 045626 yl)methoxy)phenyl)acetic acid (155c).

Stage-1. Preparation of ethyl 2-(2-((1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1H-indol-6-yl)methoxy)phenyl )acetate (155a).

Compound 155a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-bromo-1-(cyclopropylmethyl)-III-indol-6-yl)methoxy)phenyl)acetate ( 148c) (3.5 g, 7.91 mmol), using bis(pinacolato)diboron (3.01 g, 11.87 mmol), potassium acetate (2.33 g, 23.74 mmol) and Pd(dppf) Cl ₂ CH ₂ Cl ₂ (0.97 g, 1.19 mmol) in anhydrous dioxane (50 ml) under Ar and heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(2-((1(cyclopropylmethyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III-indol-6yl)methoxy)phenyl)acetate (155a) (1.9 g, 49% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (k, J=1.7, 1.0 Hz, 1H), 7.53-7.41 (m, 2H), 7.22 ( ddd, J=7.2, 3.6, 1.6 Hz, 2H), 7.09 (dd, J=8.3, 1.1 Hz, 1H), 6.89 (td, J=7, 4, 1.1 Hz, 1H), 6.73 (dd, J=3.1, 0.8 Hz, 1H), 5.19 (s, 2H), 4.12-3.94 (m, 4H ), 3.60 (s, 2H), 1.33 (s, 12H), 1.26-1.18 (m, 1H), 1.05 (t, J=7.1 Hz, 3H), 0 .52-0.28 (m, 4H); MS (ESI+): 490.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol6-yl)methoxy)phenyl) acetate (155b).

Compound 155b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (155a) (0.7 g, 1.43 mmol) in dioxane (6 ml), using (4-chloropyridin-2yl)methanamine (74a ) (0.13 ml, 1.10 mmol), bis(triphenylphosphine) palladium(P) chloride (0.12 g, 0.17 mmol) and K ₂ CO ₃ solution (0.38 g, 2.75 mmol) in water (0.7 ml) under Ar atmosphere and heating at 100°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 50% DCM] followed by purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)1H-indole-6- yl)methoxy)phenyl)acetate (155b) (0.07 g, 14% yield), HCl salt, as a yellow solid; MS (ESI+): 470.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -(cyclopropylmethyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (155c).

Compound 155c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol- 6-yl)methoxy)phenyl)acetate (155b) (0.07 g, 0.15 mmol) in THF (3 ml) and MeOH (3 ml), using sodium hydroxide (0.02 g, 0.45 mmol) in water (0.6 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (155c) (0.05 g, 70% yield), HCl salt, in as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J=5.2 Hz, 1H), 8.40 (s, 3H), 7.85 (d, J=1.5 Hz, 1H ), 7.78 (s, 1H), 7.74 (dd, J=5.2, 1.6 Hz, 1H), 7.63 (d, J=3.2 Hz, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.22 (d, J=7.4 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.94-6 .86 (m, 1H), 6.71 (d, J=3.2 Hz, 1H), 5.29 (s, 2H), 4.31 (s, 2H), 4.12 (d, J= 7.0 Hz, 2H), 3.60 (s, 2H), 1.34-1.20 (m, 1H), 0.57-0.33 (m, 4H); MS (ESI-): 440.3 (M-1). Purity after HPLC: 98.99%.

Scheme-156

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)acetic acid (156b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indazol-6yl)methoxy)phenyl)acetate (156a).

Compound 156a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d) ( 0.335 g, 0.616 mmol) in dioxane (6 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.140 g, 0.925 mmol), tripotassium phosphate (1.3 M solution, 1.423 ml, 1.849 mmol), tricyclohexylphosphine ( 0.052 g, 0.185 mmol) and Pd ₂ (dba) ₃ (0.056 g, 0.062 mmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, 25 g, eluted with methanol in 0% to 40% DCM] ethyl 2-(2-((4-230 045626 (3-(aminomethyl)phenyl)- 1-Tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (156a) (0.266 g, 76% yield) as an off-white solid; MS (ESI+): 570.3 (M+Na).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)acetic acid (156b).

To a solution of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (156a) (0.075 g, 0.132 mmol) in THF (3.0 mL) and methanol (6.0 mL), sodium hydroxide (2 M aq) (0.658 mL, 1.317 mmol) was added and stirred at room temperature for 6 h and concentrated in vacuo to remove THF/MeOH. The aqueous layer was acidified with cold 2N aq. HCl, and the residue was purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to obtain, after lyophilization, 2-(2-((4-(3(aminomethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)acetic acid (156b) (0.034 g, 0.088 mmol, 66.7% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 13.31 (s, 1H, D2O replaceable), 8.44-8.22 (m, 4H, D2O replaceable, 3H), 7.91 (s, 1H) , 7.77 (d, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.56-7.50 ( m, 1H), 7.40-7.33 (m, 1H), 7.28-7.19 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.33 (s, 2H), 4.24-4.09 (m, 2H), 3.62 (s, 2H); MS (ESI+): 388.3 (M+1); 775.5 (2M+1); MS (ESI-): 386.3 (M-1); 422.4 (M+Cl); 773.6 (2M-1); purity after HPLC: 93.41%; analysis calculation for C ₂₃ H ₂₁ N ₃ O ₃ -2.25H ₂ O-2.0HCl: C, 55.15; N, 5.53; N, 8.39; observed: C, 54.94; N, 5.34; N, 8.00.

Scheme-157

Preparation of 2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2yl)acetic acid (157d).

Stage-1. Preparation of ethyl 2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1f][1,2,4]triazin-4-carboxamido)pyridin-2-yl )acetate (157b).

Compound 157b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4] triazine-4-carboxylic acid (1e) (0.144 g, 0.391 mmol) in DMF (2 ml), using ethyl 2-(3-aminopyridin-2-yl) acetate (157a) (0.13 g, 0.469 mmol; obtained according to the procedure described by Mikami, Satoshi et al.; in Journal of Medicinal Chemistry, 60(18), 7677-7702; 2017), DIPEA (0.341 ml, 1.954 mmol) and HATU (0.781 g, 0.469 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with MeOH:EtOAc (9:1) in 0 to 100% hexanes], ethyl 2-(3-(2-(3-(( (tertbutoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2yl)acetate (157b) (0.15 g, 0.283 mmol, 72.3 % yield) as an orange solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.90 (s, 1H), 8.50-8.41 (m, 2H), 8.41-8.32 (m, 2H), 8.15 (dd, J=8.2, 1.6 Hz, 1H), 7.59-7.39 (m, 4H), 7.26 (dd, J=4.6, 2.5 Hz, 1H), 4.27 (d, J=6.2 Hz, 2H), 4.10-3.97 (m, 4H), 1.41 (s, 9H), 1.02 (t, J=7.1 Hz , 3H); MS (ESI+): 531.4 (M+1), 553.4 (M+Na).

Stage-2. Preparation of ethyl 2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-1][1,2,4]triazine-4carboxamido)pyridin-2-yl)acetate (157c).

Compound 157c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f] [1,2,4]triazin-4carboxamido)pyridin-2-yl)acetate (157b) (0.15 g, 0.283 mmol) in DCM (4 mL) using TFA (0.218 mL, 2.83 mmol). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 30 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] ethyl 2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido) pyridin-2yl)acetate (157c) (0.028 g, 23% yield), as HCl salt; MS (ESI+): 431.4 (M+1).

Stage-3. Preparation of 2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4- 231 045626 carboxamido)pyridin-2-yl)acetic acid (157d ).

Compound 157d was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(3-(2-(3-(aminomethyl)phenyl)n-pyrrolo[2,1-f][1,2,4]triαzine -4-carboxαmido)pyridin-2-yl)acetate (157c) (0.1 g, 0.232 mmol) in THF (3 ml) and methanol (3 ml), using sodium hydroxide (2 M, 0.348 ml, 0.697 mmol) . This resulted in the following workup and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] followed by flash column chromatography [silica gel 12 g, eluted with methanol in DCM from 0% to 100%] 2-(3(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-G][1,2,4]triazine-4-carboxamido) pyridin-2-yl)acetic acid (157d) (0.007 g, 8% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.61 (s, 1H, D2O replaceable), 9.33 (s, 1H), 9.15 (s, 3H, D2O replaceable), 8.42- 8.36 (m, 1H), 8.34-8.22 (m, 3H), 7.62 (dd, J=4.6, 1.3 Hz, 1H), 7.56 (d, J= 4.8 Hz, 2H), 7.35 (dd, J=8.1, 4.7 Hz, 1H), 7.26 (dd, J=4.6, 2.6 Hz, 1H), 4, 14 (s, 2H), 3.74 (s, 2H); MS (ESI+): 403.3 (M+1), 425.3 (M+Na); MS (ESI-): 401.4 (M-1), 803.5 (2M-1); purity after HPLC: 90.71%.

Scheme-158

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)acetic acid (158c).

Stage-1. Preparation of ethyl 2-(2-(7-bromo-1-tosyl-1H-indole-5-carboxamido)phenyl)acetate (158a).

Compound 158a was prepared according to the procedure described in step-4 of Scheme-1 from 7bromo-1-tosyl-1H-indole-5-carboxylic acid (146c) (200 mg, 0.507 mmol) in DMF (15 ml) using ethyl 2-(2-aminophenyl) acetate (5e) (182 mg, 1.015 mmol), DIPEA (0.353 ml, 2.029 mmol) and HATU (386 mg, 1.015 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] ethyl 2-(2-(7-bromo-1tosyl-III-indole -5-carboxamido)phenyl)acetate (158a) (102 mg) as a brown gum, MS (ESI+): 555.10 and 557.10 (M+1); MS (ESI-): 553.20 and 555.20 (M-1).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)acetate (158b).

Compound 158b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromo-1-tosyl-1P-indole-5-carboxamido)phenyl)acetate (158a) (90 mg, 0.162 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (46 mg, 0.243 mmol), tripotassium phosphate (1.3 M solution, 0.092 ml, 0.275 mmol), tricyclohexylphosphine (0.027 g, 0.097 mmol) and Pd ₂ (dba) ₃ (0.045 g, 0.049 mmol) under nitrogen when heated at 125°C for 2 hours in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, 25 g, eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-(7-(3(aminomethyl)phenyl) )-III-indole-5-carboxamido)phenyl)acetate (158b) (5 mg, 3% in two steps) as a white solid. MS (ESI+): 428.3 (M+1) and 450.3 (M+Na); MS (ESI-): 426.5 (M-1) and 462.4 (M+Cl).

Stage-3. Preparation of 2-(2-(7-(3 -(aminomethyl)phenyl)-1 P-indole-5-carboxamido)phenyl)acetic acid (158c).

Compound 158c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)-III-indole-5-carboxamido)phenyl)acetate (158b) ( 5 mg, 0.012 mmol) in THF (2 mL) and methanol (2 mL), using lithium hydroxide monohydrate (5.01 mg, 0.117 mmol) in water (2 mL). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 3:1)] 2-(2-(7-(3-(aminomethyl)phenyl)-1 Nindole -5-carboxamido)phenyl)acetic acid (158c) (4 mg, 86%) as a light brown solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.54 (s, 1H), 11.44 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8 .13 (s, 1H), 8.02

- 232 045626 (d, J=7.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7, 49-7.38 (m, 2H), 7.25-7.15 (m, 2H), 7.01 (t,

J=7.4 Hz, 1H), 6.71 (s, 1H), 4.10 (s, 2H), 3.47 (s, 2H); MS (ESI-): 398.4 (M-1).

Scheme-159

Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7yl)methoxy)phenyl)acetic acid (159f).

Stage-1. Preparation of 5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (159b).

To a solution of tert-butyl 5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (159a) (950 mg, 3.67 mmol; CAS No. 1246759-50-1) in CH ₂ Cl ₂ (30 ml), 2,2,2-trifluoroacetic acid (4.24 ml, 55.0 mmol) was added and stirred at RT for 17 hours. The reaction mixture was concentrated to dryness to give 5-chloro-[1 ,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (159b), which was used as is in the next step. MS (ESI-): 196.1 and 198.1 (M-1).

Stage-2. Preparation of (5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (159c).

Compound 159c was prepared according to the procedure described in step-1 of Scheme-23 from 5chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (159b) (1.84 mmol) using Nmethylmorpholine (0.726 ml, 6.61 mmol) in THF (30 ml), isobutyl chloroformate (0.868 ml, 6.61 mmol) and NaBH ₄ (278 mg, 7.34 mmol) in water (1 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with dichloromethane/methanol (1:0 to 19:1)] (5-chloro-[1,2,4]triazolo[ 4,3-a]pyridin-7-yl)methanol (159c) (84 mg, 25% in two steps) as a white solid.

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.36 (s, 1H), 7.68-7.62 (m, 1H), 7.16 (s, 1H), 5.60 (t, J=5.7 Hz, 1H), 4.59-4.53 (m, 2H).

Stage-3. Preparation of ethyl 2-(2-((5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate (159d).

Compound 159d was prepared according to the procedure described in step-2 of Scheme-23 from (5chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (159c) (80 mg, 0.436 mmol) in DCM (5 ml) and THF (5 ml), using triphenylphosphine (149 mg, 0.566 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (2.51 g, 13.92 mmol) and a solution of di-(4-chlorobenzyl) azodicarboxylate (DCAD, 208 mg, 0.566 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] ethyl 2-(2-((5- chloro[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate (159d) (140 mg, 93%) as a white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 9.45 (s, 1H), 7.83 (s, 1H), 7.53-7.22 (m, 3H), 7.04 (d, J =8.4 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5.22 (s, 2H), 4.06 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.15 (t, J=7.1 Hz, 3H); MS (ESI+): 368.1 and 370.1 (M+Na); MC (ESI-): 344.2 (M-1).

Stage-4. Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7yl)methoxy)phenyl)acetate (159e).

Compound 159e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl) methoxy)phenyl)acetate (159d) (116 mg, 0.335 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (94 mg, 0.503 mmol), tripotassium phosphate (0.190 ml, 0.570 mmol, 3 M solution), water (0.05 ml) and Pd ₂ (dba) ₃ (92 mg, 0.101 mmol) under Ar atmosphere and heating at 125°C for 2 hours in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/DMA 80 (1:0 to 1:1)] ethyl 2-(2-((5-(3- (aminomethyl)phenyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate (159e) (25 mg, 18%) as a colorless gum; MS (ESI+): 417.3 (M+1) and 439.3 (M+Na); MS (ESI-): 451.4 (M+Cl).

Stage-5. Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7

- 233 045626 yl)methoxy)phenyl)acetic acid (159f).

Compound 159f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a ]pyridin-7-yl)methoxy)phenyl)acetate (159e) (25 mg, 0.060 mmol) in THF/MeOH (4 ml each), using a solution of lithium hydroxide monohydrate (15 mg, 0.36 mmol) in water ( 4 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with dichloromethane/methanol (1:0 to 3:1)] 2-(2((5-(3-(aminomethyl)phenyl) -[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetic acid (159f) (12 mg, 52%) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.40 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.85-7.79 (m, 1H), 7.69-7.60 (m, 2H), 7.27-7.19 (m, 2H), 7.16 (br. s, 1H), 7.04 (d, J=8, 5 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.28 (s, 2H), 4.11 (s, 2H), 3.58 (s, 2H); MS (ESI+): 389.3 (M+1) and 411.3 (M+Na); MS (ESI-): 387.2 (M-1) and 423.2 (M+Cl).

Scheme-160

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetic acid (160e).

Stage-1. Preparation of ethyl 2-(2-(7-bromo-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate (160b).

Compound 160b was prepared according to the procedure described in step-4 of Scheme-1 from 7bromo-2,3-dihydro-1H-indene-5-carboxylic acid (160a) (2.0 g, 8.29 mmol; prepared in following the procedure described by Johansson, Anders and Persson, Joachim in international application PCT, 2004110344 dated December 23, 2004) in DMF (40 ml), using ethyl 2-(2-aminophenyl) acetate (5e) (1, 78 g, 9.95 mmol), DIPEA (3.21 g, 24.88 mmol) and HATU (3.78 g, 9.95 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with ethyl acetate in n-hexane (020%)] ethyl 2-(2-(7-bromo-2,3-dihydro-1H-inden-5 -carboxamido)phenyl)acetate (160b) (1.2 g, 36%) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (s, 1H), 7.33 (dd, J=8.2, 1.7 Hz, 1H), 7.09-6.87 (m, 1H), 6.65 (dd, J=7.8, 1.3 Hz, 1H), 6.51 (td, J=7.4, 1.3 Hz, 1H), 4.87 (s, 2H), 4.08 (t, J=7.1 Hz, 2H), 3.49 (s , 2H), 3.06 (t, J=7.5 Hz, 3H): MS (ESI+) 404.0 (M+1); (ESI-) 401.9 (M-1).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1Nindene-5-carboxamido)phenyl)acetate (160c).

Compound 160c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromo-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate (160b) (0 .5 g, 1.24 mmol) in dioxane (3 ml), using (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1d) (0.37 g, 1.49 mmol), Na ₂ CO ₃ (0.39 g, 3.72 mmol) and Pd(dppf)Cl ₂ (0.10 g, 0.12 mmol) under nitrogen atmosphere while heating at 60°C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-30% EtOAc in n-hexane] ethyl 2(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)-2,3-dihydro-1H-indene-5 carboxamido)phenyl)acetate (160c) (0.15 g, 22.90%) as an oil;

^1H NMR (300 MHz, CDCI3) δ 9.60 (s, 1H), 7.96 (dd, J=8.2, 1.3 Hz, 1H), 7.83-7.67 (m, 2H ), 7.44-7.26 (m, 4H), 7.26-7.17 (m, 1H), 7.06 (td, J=7.5, 1.3 Hz, 1H), 4, 89 (s, 1H), 4.30 (d, J=5.9 Hz, 2H), 4.10 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 2, 96 (dt, J=10.4, 7.4 Hz, 4H), 2.10-1.91 (m, 2H), 1.39 (s, 9H), 1.24-1.06 (m, 3H).

Stage-3. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5carboxamido)phenyl)acetate (160d).

Compound 160d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H -indene-5carboxamido)phenyl)acetate (160c) (0.070 g, 0.132 mmol) in DCM (3 ml) using TFA (0.204 ml, 2.65 mmol). This resulted in ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro1H-indene-5-carboxamido)phenyl)acetate α (160d) (0.057 g, 100% yield) after workup. , TFA salt, as a yellow solid; MS (ESI+): 429.3 (M+1).

- 234 045626

Stage-4. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5 carboxamido)phenyl)acetic acid (160e).

Compound 160e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl )acetate (160d) (0.056 g, 0.131 mmol) in THF (2 ml) and methanol (4 ml), using sodium hydroxide (2 M aq, 0.457 ml, 0.915 mmol). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 30 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetic acid (160e) ( 0.012 g, 23% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.35 (s, 1H, D2O replaceable), 10.04 (s, 1H, D2O replaceable), 8.34 (br. s, 3H, D2O replaceable), 7.89-7.81 (m, 2H), 7.69 (s, 1H), 7.62-7.42 (m, 4H), 7.37-7.26 (m, 2H), 7. 21 (td, J=7.5, 1.5 Hz, 1H), 4.12 (s, 2H), 3.66 (s, 2H), 3.01 (t, J=7.3 Hz, 4H ), 2.15-1.98 (m, 2H); MS (ESI+): 401.3 (M+1), 801.5 (2M+1); MS (ESI-): 399.4 (M-1), 799.6 (2M-1); purity after HPLC: 99.35%.

Scheme-161

Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (161e).

Stage-1. Preparation of ethyl 7-bromo-2-chloropyrrolo[2,1-G][1,2,4]triazine-4-carboxylate (161a).

To a solution of ethyl 2-chloropyrrolo[2,1-G][1,2,4]triazine-4-carboxylate (1c) (1.5 g, 6.65 mmol) in acetonitrile (30 ml) at 0°C was added a solution of NBS (1.302 g, 7.31 mmol) in acetonitrile (10 ml) and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (silica gel, 25 g eluted with ethyl acetate and hexanes) to give ethyl 7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (161a) (650 mg, 32% yield) as an orange solid;

1H NMR (300 MHz, DMSO-d6) δ 7.55 (d, J=5.0 Hz, 1H), 7.48 (d, J=5.1 Hz, 1H), 4.48 (k, J =7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of 2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (161b).

To a solution of ethyl 7-bromo-2-chloropyrrolo[2,1-G][1,2,4]triazine-4-carboxylate (161a) (0.5 g, 1.642 mmol) in 1,4-dioxane (10 ml ) add a solution of cesium carbonate (1.605 g, 4.93 mmol) in water (1 ml), potassium trifluoro(methyl)borate (0.400 g, 3.28 mmol), PdCl ₂ (dppf) (0.120 g, 0.164 mmol) and heated with stirring at 100°C for 16 hours. The reaction mixture was cooled to RT, partitioned between water (100 ml) and EtOAc (80 ml). The aqueous layer was extracted with EtOAc (40 ml). The combined organics were washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with EtOAc in 0 to 60% hexanes] to give 2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4 -carboxylic acid (161b) (410 mg) as a dark brown solid; MS (ESI-): 210.1 (M-1).

Stage-3. Preparation of ethyl 2-(2-(2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (161c).

Compound 161c was prepared according to the procedure described in step-4 of Scheme-1 from 2chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (161b) (400 mg, 1.890 mmol) in DMF (5 ml) using ethyl 2-(2-aminophenyl) acetate (5e) (508 mg, 2.84 mmol), DIPEA (0.990 ml, 5.67 mmol) and HATU (1078 mg, 2 .84 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with EtOAc/MeOH (9:1) in 0% to 60% hexane] ethyl 2-(2-(2-chloro-7-methylpyrrolo[ 2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (161c) (125 mg, 18% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 7.72-7.62 (m, 1H), 7.59 (d, J=4.7 Hz, 1H), 7.40-7.31 (m,

- 235 045626

2H), 7.23 (m, 2H), 4.07 (k, J=7.1 Hz, 2H), 3.78 (s, 2H), 2.60 (s, 3H), 1.13 ( t, J=7.1 Hz, 3H); MS (ESI+) 395.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1f][1,2,4]triazine-4-carboxamido)phenyl)acetate (161d).

Compound 161d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido )phenyl)acetate (161c) (60 mg, 0.161 mmol) in dioxane (3 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (50 mg, 0.241 mmol), tripotassium phosphate (1.3 M solution, 0.134 ml, 0.402 mmol), tricyclohexylphosphine (0.014 g, 0.048 mmol) and Pd ₂ (dba) ₃ (0.015 g, 0.016 mmol) under nitrogen while heating at 125°C for 90 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, 25 g, eluted with ethyl acetate in hexanes (0 to 40 to 100%)] ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl )-7-methylpyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetate (161d) (25 mg, 34% yield) as a sticky material;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.23-8.10 (m, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.74-7.63 (m, 1H), 7.57 (m, 1H), 7.38 (m, 3H), 7.26 (d, J=7.1 Hz, 1H), 7.17 (d, J=4.5 Hz, 1H), 3.96 (k, J=6.9 Hz, 2H), 3.87 (d, J=4.1 Hz, 2H), 3.83 (s , 2H), 2.65 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 462.3 (M+1).

Stage-5. Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (161e).

Compound 161e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1 ,2,4]triazine-4-carboxamido)phenyl)acetate (161d) (24 mg, 0.052 mmol) in THF (2 ml) and ethanol (1 ml), using sodium hydroxide (2.5 M aqueous solution) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-(2-(3-( aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4carboxamido)phenyl)acetic acid (161e) (22 mg, 98% yield), HCl salt, as light orange solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O replaceable), 8.42 (t, J=7.6 Hz, 1H), 7.92-7.83 (m, 1H), 7.75 (t, J=7.0 Hz, 1H), 7.61 (d, J=4.5 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H) , 7.42-7.34 (m, 2H), 7.25 (d, J=7.4 Hz, 1H), 7.20 (d, J=4.7 Hz, 1H), 4.21 ( s, 2H), 3.74 (s, 2H), 2.66 (s, 3H); MS (ESI+): 434.3 (M+1), 456.2 (M+Na), (ESI-): 432.4 (M-1).

Scheme-162

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetic acid (162e).

Stage-1. Preparation of ethyl 2-(2-hydroxy-5-methylphenyl)acetate (162a).

Compound 162a was prepared according to the procedure described in step-1 of scheme-130, from ethyl 2-(5-bromo-2-hydroxyphenyl) acetate (130a) (0.750 g, 2.89 mmol) in toluene (20 ml), using methyl boronic acid (0.260 g, 4.34 mmol), dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.135 g, 0.289 mmol), Pd ₂ (dba) ₃ (0.133 g, 0.145 mmol) and a solution of Na ₂ CO ₃ (1.23 g, 11.58 mmol) in water (2 ml) under a nitrogen atmosphere and heating at 100°C for 1.5 hours. This resulted in the following treatment and purification by Flash column chromatography [silica gel 24 g, eluted with EtOAc in 0 to 30% hexanes] of ethyl 2-(2-hydroxy-5-methylphenyl) acetate (162a) (0.242 g, 43% yield) as a thick clear oil ;

- 236 045626

1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 6.92-6.82 (m, 2H), 6.67 (d, J=8.0 Hz, 1H), 4 .05 (k, J=7.0

Hz, 2H), 3.48 (s, 2H), 2.17 (s, 3H), 1.17 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of tert-butyl 3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b).

Compound 162b was prepared according to the procedure described in step-1 of scheme-152 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.398 g, 1.126 mmol) in DCM (10 ml) using CBr ₄ (0.747 g, 2.252 mmol) and triphenylphosphine (0.591 g, 2.252 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with ethyl acetate in 0% to 30% hexanes] tert-butyl 3-(5-(bromomethyl)benzofuran-7yl)benzylcarbamate (162b) ( 0.328 g, 70% yield) as a thick, pale yellow syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.2 Hz, 1H), 7.79-7.68 (m, 3H), 7.58 (d, J=1 .8 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.09-7.02 (m, 1H ), 4.90 (s, 2H), 4.23 (d, J=6.1 Hz, 2H), 1.40 (s, 9H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-methylphenyl)acetate (162c).

Compound 162c was prepared according to the procedure described in step-2 of Scheme-152 from tert-butyl 3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b) (0.309 g, 0.742 mmol) in DMF (10 ml) using potassium carbonate (0.256 g, 1.856 mmol) and ethyl 2-(2-hydroxy-5-methylphenyl) acetate (162a) (0.144 g, 0.742 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate (162c) (0.228 g, 58% yield) as a white solid; MS (ESI+): 552.3 (M+Na); MS (ESI-): 528.4 (M-1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5methylphenyl)acetate (162d).

Compound 162d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-5-methylphenyl)acetate (162c) (0.223 g, 0.421 mmol) in DCM (10 ml) using TFA (0.649 ml, 8.42 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 100% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-5-methylphenyl)acetate (162d) (0.221 g, 97% yield), TFA salt, as yellow wax; MS (ESI+): 430.3 (M+1), 452.3 (M+Na).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5methylphenyl)acetic acid (162e).

Compound 162e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate ( 162d) (0.108 g, 0.199 mmol) in THF (5 mL) and methanol (10 mL) using sodium hydroxide solution (2 M aq, 0.497 mL, 0.994 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetic acid (162e) (0.005 g, 6% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H, D2O replaceable), 8.28 (s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H ), 7.98 (s, 1H), 7.95-7.89 (m, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.62 (dd, J=6, 8, 5.0 Hz, 2H), 7.55 (t, J=8.5 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 7.05-6.95 ( m, 3H), 5.23 (s, 2H), 4.15 (s, 2H), 3.55 (s, 2H), 2.22 (s, 3H); MS (ESI+): 402.3 (M+1), 803.5 (2M+1); MS (ESI-): 400.3 (M-1), 436.3 (M+Cl).

Scheme-163

Preparation of 2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (163d).

Stage-1. Preparation of tert-butyl 3-(5-(((3-bromopyridin-4-yl)oxy)methyl)benzofuran-7

- 237 045626 yl)benzylcarbamate (163b).

Compound 163b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.5 g, 1.415 mmol) in DCM (30 ml ), using triphenylphosphine (0.408 g, 1.556 mmol), 3-bromopyridin-4-ol (163a) (0.295 g, 1.698 mmol; CAS No. 36953-41-0) and di-(4-chlorobenzyl) azodicarboxylate solution (DCAD, 0.571 g, 1.556 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] tert-butyl 3-(5-(((3bromopyridin-4-yl)oxy)methyl )benzofuran-7-yl)benzylcarbamate (163b) (320 mg, 44% yield) as a white waxy substance;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.09 (d, J=2.2 Hz , 1H), 7.78 (d, J=1.7 Hz, 1H), 7.74 (m, 2H), 7.63 (d, J=1.7 Hz, 1H), 7.47 (m , 2H), 7.35 (d, J=5.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H ), 5.46 (s, 2H), 4.23 (d, J=6.1 Hz, 2H), 1.39 (s, 9H); MS (ESI+): 531.2; 533.2 (M+Na).

Stage-2. Preparation of tert-butyl 2-(4-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetate (163c).

To a stirred solution of tert-butyl 3-(5-(((3-bromopyridin-4-yl)oxy)methyl)benzofuran-7yl)benzylcarbamate (163b) (150 mg, 0.294 mmol) in THF (4 ml) was added Pd ₂ (dba) ₃ (27.0 mg, 0.029 mmol), Q-Phos (20.93 mg, 0.029 mmol), (2-tert-butoxy-2-oxoethyl)zinc(P) chloride (0.5 M solution in ether) (1.178 ml, 0.589 mmol), degassed for 4 min, and heated at 70°C for 4 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 ml) and brine (5 ml). The mixture was stirred for 10 minutes and filtered through a small pad of celite. The aqueous layer was separated and extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine (25 ml), dried, filtered and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in hexanes (0-40 to 100%)] to give tert-butyl 2-(4-((7-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetate (163c) (100 mg, 62% yield) as a sticky material;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.38 (d, J=5.6 Hz, 1H), 8.26 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.84-7.66 (m, 3H), 7.58 (s, 1H), 7.49 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.16 (d, J=5.8 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 5.34 (s, 2H), 4.22 (d, J=6 .2 Hz, 2H), 3.55 (s, 2H), 1.39 (s, 9H), 1.22 (s, 9H); MS (ESI+): 545.5 (M+1), 567.3 (M+Na), (ESI-): 579.5 (M+Cl).

Stage-3. Preparation of 2-(4-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3 yl)acetic acid (163d).

Compound 163d was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 2-(4-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)pyridin-3yl)acetate (163c) (100 mg, 0.184 mmol) in DCM (5 ml) using TFA (0.424 ml, 5.51 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel 12 g, eluted with DMA80 in DCM 0% to 100%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(4-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (163d) ( 32 mg, 45% yield), HCl salt, as an off-white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.83 (d, J=6.8 Hz, 1H), 8.75 (s, 1H), 8.62 (br. s, 3H), 8.14 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.97-7.87 (m, 1H), 7.83-7.75 (m, 2H), 7. 71 (d, J=1.6 Hz, 1H), 7.59 (s, 1H), 7.58 (s, 1H), 7.09 (d, J=2.2 Hz, 1H), 5, 66 (s, 2H), 4.12 (k, J=5.8 Hz, 2H), 3.81 (s, 2H); MS (ESI+): 389.2 (M+1), 411.3 (M+Na), (ESI-): 387.3 (M-1), 423.3 (M+Cl).

- 238 045626

Scheme-164

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6yl)methoxy)phenyl)acetic acid (164e).

Stage-1. Preparation of 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylic acid (164a).

Compound 164a was prepared according to the procedure described in step-4 of Scheme-4 from methyl 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylate (126c) (0.802 g, 2.59 mmol) in THF (10 ml) and methanol (20 ml), using sodium hydroxide solution (2 M aq, 5.19 ml, 10.38 mmol). This resulted in 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylic acid (164a) (0.755 g, 99% yield) as an off-white solid upon treatment;

1H NMR (300 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.68-8.55 (m, 1H), 8.33-8.23 (m, 1H), 7.72 ( d, J=1.1 Hz, 1H), 4.36 (d, J=7.3 Hz, 2H), 1.43 (m, 1H), 0.62-0.53 (m, 2H), 0.52-0.45 (m, 2H); MS (ESI+): 297.1, 295.1 (M+2); MS (ESI-): 295.2, 293.2 (M-2).

Stage-2. Preparation of (4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methanol (164b).

Compound 164b was prepared according to the procedure described in step-1 of Scheme-23 from 4bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylic acid (164a) (0.731 g, 2.477 mmol) using N-methylmorpholine ( 0.327 ml, 2.97 mmol) in THF (20 ml), isobutyl chloroformate (0.390 ml, 2.97 mmol) and NaBH ₄ (0.281 g, 7.43 mmol) in water (2 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] (4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methanol (164b) (0.377 g, 54% yield) as yellow syrup;

^1H NMR (300 MHz, DMSO-06) δ 8.38 (s, 1H), 7.58-7.42 (m, 1H), 7.23 (s, 1H), 5.29 (t, J =5.8 Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 4.28 (d, J=7.2 Hz, 2H), 1.53-1.28 (m , 1H), 0.64-0.51 (m, 2H), 0.49-0.41 (m, 2H).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-2-(cyclopropylmethyl)-2H-indazol-6yl)methoxy)phenyl)acetate (164c).

Compound 164c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methanol (164b) (0.361 g, 1.284 mmol) in DCM (30 ml), using triphenylphosphine (0.370 g, 1.412 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.255 g, 1.412 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 0.519 g, 1.412 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with EtOAc in 0% to 50% hexanes], ethyl 2-(2-((4-bromo-2-(cyclopropylmethyl)-2H -indazol6-yl)methoxy)phenyl)acetate (164c) (0.232 g, 41% yield) as a white wax;

1H NMR (300 MHz, DMSO-d6) δ 8.53-8.37 (m, 1H), 7.80-7.56 (m, 1H), 7.31-7.26 (m, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5, 18 (s, 2H), 4.29 (d, J=7.2 Hz, 2H), 4.14-3.97 (m, 2H), 3.64 (s, 2H), 1.51-1 .32 (m, 1H), 1.20-1.01 (m, 3H), 0.62-0.50 (m, 2H), 0.50-0.39 (m, 2H); MS (ESI+): 465.2; 467.1 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2Nindazol-6-yl)methoxy)phenyl)acetate (164d).

Compound 164d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate (164c ) (0.223 g, 0.503 mmol) in dioxane (6 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.127 g, 0.755 mmol), tripotassium phosphate (1.3 M, 1.161 ml, 1.509 mmol ), tricyclohexylphosphine (0.085 g, 0.302 mmol) and Pd ₂ (dba) ₃ (0.092 g, 0.101 mmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. This resulted in, after workup and purification by flash column chromatography [silica gel (24 g), eluted with MeOH in DCM from 0% to 40%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6yl )methoxy)phenyl)acetate (164d) (0.125 g, 51.0% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.54-8.37 (m, 4H), 7.75 (s, 1H), 7.72-7.58 (m, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.16 (s, 1H), 7.11 (d, J=8.2 Hz, 1H) , 6.91 (t, J=7.3 Hz, 1H), 5.25 (s, 2H), 4.28 (d, J=7.2 Hz, 2H), 4.22-4.11 ( m, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.46-1.31 (m, 1H), 1.03 (t, J =7.1 Hz, 3H), 0.600.48 (m, 2H), 0.48-0.38 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.24; MS (ESI+): 488.3 (M+1); 975.6 (2M+1); MS (ESI-): 522.4 (M+Cl); purity after HPLC: 97.03%.

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6yl)methoxy)phenyl)acetic acid (164e).

Compound 164e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazole-6 -yl)methoxy)phenyl)acetate (164d) (0.061 g, 0.125 mmol) in THF (3 ml) and methanol (7 ml), using a solution of lithium hydroxide monohydrate (0.026 g, 0.626 mmol) in water (1.5 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6yl)methoxy)phenyl)acetic acid (164e) (0.037 g, 64% yield), HCl salt, as a white solid stva;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.58-8.48 (m, 3H, D2O replaceable), 8.48-8.41 (m, 1H), 7.76 (s, 1H), 7.73-7.60 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.29-7.18 (m, 3H), 7.09 (d, J= 8.2 Hz, 1H), 6.98-6.83 (m, 1H), 5.26 (s, 2H), 4.28 (d, J=7.2 Hz, 2H), 4.21- 4.12 (m, 2H), 3.60 (s, 2H), 1.51-1.31 (m, 1H), 0.61-0.47 (m, 2H), 0.48-0, 40 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.03; MS (ESI+): 460.3 (M+1); 919.5 (2M+1); MS (ESI-): 458.4 (M-1), 494.3 (M+Cl).

Scheme-165

165e 165f

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetic acid (165f).

Stage-1. Preparation of ethyl 2-(3-methyl-2-nitrophenyl)acetate (165b).

To a solution of 2-(3-methyl-2-nitrophenyl)acetic acid (165a) (1.00 g, 5.12 mmol CAS No. 18710-866) in ethanol (30 ml) was added _H2SO4 ( _0.273 ml, 5 .12 mmol) and heated at 80°C for 16 hours. The reaction mixture was cooled to RT, and the resulting residue was diluted with aq. us. NaHCO ₃ solution. The aqueous layer was extracted with EtOAc (2x50 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel 25 g, eluted with ethyl acetate in 0% to 100% hexanes] to give ethyl 2-(3-methyl-2-nitrophenyl) acetate (165b) (1.023 g, 89% yield) in in the form of a thick yellow syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.54-7.47 (m, 1H), 7.45-7.34 (m, 2H), 4.07 (k, J=7.1 Hz , 2H), 3.77 (s, 2H), 2.31 (s, 3H), 1.17 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-amino-3-methylphenyl)acetate (165c).

- 240 045626

To a solution of ethyl 2-(3-methyl-2-nitrophenyl)acetate (165b) (0.500 g, 2.240 mmol) in EtOAc (15 ml) was added palladium hydroxide on carbon (0.315 g, 2.240 mmol) and stirred under a hydrogen atmosphere (balloon ) for 3 hours. The reaction mixture was filtered through a pad of celite, the celite was washed with EtOAc (3x25 ml) and the combined filtrate was concentrated and dried under vacuum to give ethyl 2-(2-amino-3-methylphenyl) acetate (165c) (0.079 g, 18% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.87 (dd, J=7.2, 1.5 Hz, 1H), 6.81 (dd, J=7.6, 1.6 Hz, 1H), 6.45 (t, J=7.4 Hz, 1H), 4.61 (s, 2H), 4.06 (k, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.08 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5carboxamido)-3-methylphenyl)acetate (165d).

Compound 165d was prepared according to the procedure described in step-4 of Scheme-1 from 7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (130c) (0.12 g, 0.327 mmol) in DMF (5 ml), using ethyl 2-(2-amino-3-methylphenyl) acetate (165 s) (0.076 g, 0.392 mmol), DIPEA (0.171 ml, 0.980 mmol) and HATU (0.149 g, 0.392 mmol). This resulted, after workup and purification by flash column chromatography [silica gel, 25 g eluted with ethyl acetate/methanol (9:1) in 0% to 100% hexanes], to form ethyl 2-(2-(7-(3-( ((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate (165d) (0.142 g, 80% yield) as a pale yellow solid; MS (ESI+): 565.4 (M+Na); MS (ESI-): 577.4 (M+Cl).

Stage-4. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3methylphenyl)acetate (165e).

Compound 165e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxamido)-3methylphenyl )acetate (165d) (0.139 g, 0.256 mmol) in DCM (5 ml) using TFA (0.395 ml, 5.12 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 30% DCM] ethyl 2-(2-(7-(3(aminomethyl)phenyl)benzofuran-5- carboxamido)-3-methylphenyl)acetate (165e) (0.088 g, 62% yield) as TFA adduct; MS (ESI+): 443.3 (M+1); MS (ESI-): 477.4 (M+Cl).

Stage-5. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3methylphenyl)acetic acid (165f).

Compound 165f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate (165e) ( 0.108 g, 0.199 mmol) in THF (3 mL) and methanol (6 mL) using sodium hydroxide solution (2 M aq, 0.288 mL, 0.576 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (30 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetic acid (165f) (0.004 g, 8% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 12.2 (br.s, 1H, D2O replaceable), 10.05 (s, 1H, D2O replaceable), 8.35 (d, J=1.7 Hz, 1H), 8.26-8.19 (m, 2H), 8.10-8.05 (m, 1H), 8.04-7.97 (m, 1H), 7.69-7.53 ( m, 2H), 7.45-6.95 (m, 6H, D2O replaceable, 2H), 4.16 (s, 2H), 3.59 (s, 2H), 2.24 (s, 3H);

1H NMR (300 MHz, DMSO-d6 D2O) δ 8.28 (d, J=1.7 Hz, 1H), 8.17-8.08 (m, 2H), 8.01-7.93 (m , 2H), 7.61 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.26-7.13 (m, 4H), 4 .12 (s, 2H), 3.54 (s, 2H), 2.20 (s, 3H); MS (ESI+): 415.3 (M+1), 437.2 (M+Na); 829.4 (2M+1); MS (ESI-): 413.3 (M-1), 449.3 (M+Cl), 827.5 (2M-1); purity after HPLC: 93.27%.

Scheme-166

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-1 H-indol-5-yl)methoxy)phenyl)acetic acid

- 241 045626 (166d).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-1H-indol-5-yl)methoxy)phenyl)acetate (166b).

Compound 166b was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-1H-indol-5-yl)methanol (166a) (440 mg, 1.946 mmol; prepared according to the procedure described by Fairfax, David John et al.; in US Patent Pub 2014/0140956 (incorporated by reference), May 22, 2014) in DCM (20 mL) using triphenylphosphine (766 mg, 2.92 mmol) ethyl 2-( 2hydroxyphenyl)acetate (23b) (877 mg, 4.87 mmol) and a solution of di-(4-chlorobenzyl) azodicarboxylate (1072 mg, 2.92 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with hexanes/ethyl acetate (1:0 to 4:1, then 0:1)] ethyl 2-(2-((7 -bromo-1H-indol-5-yl)methoxy)phenyl)α acetate α (166b) (350 mg) as a brown gum; MS (ESI+): 410.1 and 412.1 (M+Na); MS (ESI-): 386.2 and 388.2 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)acetate (166c).

Compound 166c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-1H-indol-5-yl)methoxy)phenyl)acetateα (166b) (240 mg, 0.618 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (174 mg, 0.927 mmol), tripotassium phosphate (1.3 M solution, 0.350 ml, 1.051 mmol), tricyclohexylphosphine (104 mg, 0.371 mmol) and Pd ₂ (dba) ₃ (170 mg, 0.185 mmol) in an Ar atmosphere when heated at 125°C for 2 hours in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((7-(3(aminomethyl) )phenyl)-1H-indol-5-yl)methoxy)phenyl)acetate (166c) (60 mg) as a brown solid; MS (ESI+): 415.4 (M+1) and 437.3 (M+Na); MS (ESI-): 449.3 (M+Cl).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)acetic acid (166d).

Compound 166d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)acetate ( 166c) (55 mg, 0.133 mmol) in THF (6 ml) and MeOH (6 ml), using a solution of lithium hydroxide monohydrate (34 mg, 0.796 mmol) in water (6 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] 2-(2-((7-(3(aminomethyl)phenyl)-1H -indol-5-yl)methoxy)phenyl)acetic acid (166d) (11 mg, 2.3% in three steps) as a light brown solid;

^1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.15 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.59 ( s, 1H), 7.527.41 (m, 2H), 7.38-7.28 (m, 2H), 7.13-7.02 (m, 2H), 6.97 (d, J=8, 2 Hz, 1H), 6.78 (t, J=7.2 Hz, 1H), 6.52 (s, 1H), 5.21 (s, 2H), 3.98 (s, 2H), 3 .37 (s, 2H); MS (ESI-): 771.7 (2M-1).

Scheme-167

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-1 H-benzo[d]imidazol-5 -yl)methoxy)phenyl)acetic acid (167e).

Stage-1. Preparation of (7-bromo-1H-benzo[d]imidazol-5-yl)methanol (167b).

Lithium aluminum hydride was added to a solution of methyl 7-bromo-1H-benzo[d]imidazole-5-carboxylate (167a) (300 mg, 1.176 mmol; CAS No. 1354756-19-6) in THF (10 ml) cooled to 0°C (44.6 mg, 1.176 mmol) and stirred at RT for 18 hours. Additional lithium aluminum hydride (90 mg) was added and the reaction mixture continued to stir at RT for 6 hours. The reaction was carefully quenched with 20% aq. Na ₂ SO ₄ (10 ml), water (40 ml) and extracted with ethyl acetate (100 ml, 50 ml). The combined organic extracts were washed with brine (50 ml), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] to give (7-bromo-1H-benzo[d]imidazol-5-yl)methanol

- 242 045626 (167b) (195 mg, 73%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.69 (br.s, 1H), 8.26 (s, 1H), 7.49 (br.s, 1H), 7.36 (br.s , 1H), 5.30 (br. s, 1H), 4.58 (s, 2H); MS (ESI+): 249.1 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-bromo-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate (167c).

Compound 167c was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-1H-benzo[d]imidazol-5-yl)methanol (167b) (180 mg, 0.793 mmol) in DCM (9 ml) , THF (4 ml) and DMF (4 ml), using triphenylphosphine ((312 mg, 1.189 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (357 mg, 1.982 mmol) and di-(4-chlorobenzyl) solution )azodicarboxylate (437 mg, 1.189 mmol in DCM (9 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with dichloromethane/methanol (1:0 to 19:1) ] ethyl 2-(2-((7-bromo-1Hbenzo[d]imudazol-5-yl)methoxy)phenyl)acetate (167c) (54 mg) as a light brown gum; MS (ESI-): 387, 2 and 389.2 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5yl)methoxy)phenyl)acetate (167d).

Compound 167d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate (167c) ( 50 mg, 0.128 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (36.1 mg, 0.193 mmol), Pd(PPh ₃ )Cl ₂ (27.0 mg, 0.039 mmol ) and potassium carbonate (35.5 mg, 0.257 mmol) in water (0.6 ml) under Ar and heating at 95°C for 3 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with dichloromethane/DMA 80 (1:0 to 1:1)] ethyl 2-(2-((7-(3- (aminomethyl)phenyl)-1H-benzo[d]imidazol-5yl)methoxy)phenyl)acetate (167d) (7 mg, 2% in two steps) as a colorless gum; MS (ESI+): 416.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5yl)methoxy)phenyl)acetic acid (167e).

Compound 167e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imudazol-5-yl)methoxy) phenyl)acetate (167d) (7 mg, 0.017 mmol) in THF (3 ml) and MeOH (3 ml), using a solution of lithium hydroxide monohydrate (7.21 mg, 0.168 mmol) in water (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/DMA 50 (1:0 to 1:1)] 2-(2-((7-(3(aminomethyl)phenyl)-1H- benzo[d]imidazol-5-yl)methoxy)phenyl)acetic acid (167e) (4 mg, 61%) as a white solid;

¹ H NMR (300 MHz, methanol-d ₄ ) δ 8.26 (s, 1H), 8.09 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.78 -7.64 (m, 3H), 7.57 (t, J=7.7 Hz, 1H), 7.45 (t, J=8.9 Hz, 1H), 7.26-7.17 ( m, 2H), 7.07-7.02 (m, 1H), 6.93-6.87 (m, 1H), 5.30 (d, J=3.0 Hz, 2H), 4.20 (s, 2H), 3.66 (s, 2H); MS (ESI+): 388.3 (M+1); MS (ESI-): 386.3 (M-1); purity after HPLC: 87.87%.

Scheme-168

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetic acid (168c).

Stage-1. Preparation of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2b]pyridin-5-yl)methoxy)phenyl) acetate (168a).

Compound 168a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c) (430 mg, 1.102 mmol) using bis(pinacolato)diboron (420 mg, 1.65 mmol), potassium acetate (324 mg, 3.31 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ (135 mg, 0.17 mmol) in anhydrous dioxane (10 ml) under Ar atmosphere by heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((7-(4,4,5,5- tetramethyl-1,3,2dioxaborolan-2-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (168a) (150 mg, 31% yield) as

- 243 045626 transparent oil; MS (ESI+): 460.4 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetate (168b).

Compound 168b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (168a) (70 mg, 0.16 mmol) in dioxane (6 ml) using (4-chloropyridin-2-yl)methanamine ( 74a) (34 mg, 0.24 mmol), bis(triphenylphosphine) palladium(P) chloride (17 mg, 0.02 mmol) and a solution of K ₂ CO ₃ (55 mg, 0.40 mmol) in water (3 ml ) in an Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(2-(aminomethyl)pyridinium- 4yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (168b) (21 mg, 31% yield) as a yellow oil; MS (ESI+): 418.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5yl)methoxy)phenyl)acetic acid (168c).

Compound 168c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5 -yl)methoxy)phenyl)acetate (168b) (21 mg, 0.050 mmol) THF/MeOH (6 ml each), using lithium hydroxide monohydrate (12.67 mg, 0.30 mmol) in water (2.0 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetic acid (168c) (3 mg, 14% yield), HCl salt, as dirty white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.88 (d, J=5.2 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.25-8 .19 (m, 2H), 8.17 (dd, J=5.2, 1.7 Hz, 1H), 7.33-7.23 (m, 3H), 7.11-7.04 (m , 1H), 6.99 (td, J=7.4, 1.0 Hz, 1H), 5.55 (s, 2H), 4.45 (s, 2H), 3.78 (s, 2H) ; MS (ESI+): 390.2 (M+1); (ESI-): 388.2 (M-1).

Scheme-169

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetic acid (169f).

Stage-1. Preparation of methyl 7-bromo-2-chlorobenzofuran-5-carboxylate (169b).

To a stirred solution of methyl 7-bromobenzofuran-5-carboxylate (169a) (3.06 g, 12.00 mmol; CAS No. 286836-79-1) in dry THF (10 ml) at -78°C under N ₂ atmosphere was added dropwise LDA (1.5 M in THF, 11 ml, 16.50 mmol). The mixture was kept at -78°C for 1.5 h followed by the addition of a solution of perchloroethane (4.06 g, 17.15 mmol) in dry THF (8 ml). The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with a saturated aqueous solution of NH ₄ Cl and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography [silica gel (40 g), eluted with ethyl acetate/hexanes, 0-30%] to give methyl 7-bromo-2-chlorobenzofuran-5carboxylate (169b) (1.56 g, 45% yield) in as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (d, J=1.6 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.31 (s , 1H), 3.89 (s, 3H).

Stage-2. Preparation of (7-bromo-2-chlorobenzofuran-5-yl)methanol (169c).

Compound 169c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-chlorobenzofuran-5-carboxylate (169b) (1.67 g, 5.77 mmol) in THF (20 ml) using LiBH ₄ (4.25 ml, 4 M, 17.00 mmol) and MeOH (0.7 ml, 17.30 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in hexane] (7-bromo-2-chlorobenzofuran-5-yl)methanol (169c) ( 1.01 g, 67.0% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53 (m, 2H), 7.17 (s, 1H), 5.39 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H).

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate (169d).

Compound 169d was prepared according to the procedure described in step-2 of Scheme-23 from (7-244 045626 bromo-2-chlorobenzofuran-5-yl)methanol (169c) (1.02 g, 3.90 mmol) in DCM (30 ml) using triphenylphosphine (1.12 g, 4.27 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (862 mg, 4.78 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 1.55 g, 4.22 mmol) in DCM (2 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-chlorobenzofuran-5- yl)methoxy)phenyl)acetate (169d) (839 mg, 51% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.69-7.60 (m, 2H), 7.30-7.19 (m, 3H), 7.06 (dd, J=8.2 , 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.02 (k, J=7.1 Hz , 2H), 3.63 (s, 2H), 1.09 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5yl)methoxy)phenyl)acetate (169e).

Compound 169e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate (169d) (230 mg, 0.543 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (142 mg, 0.941 mmol), K2CO3 solution (231 mg, 1.671 mmol) in water (0.5 ml), bis(triphenylphosphine )palladium(P) chloride (61 mg, 0.087 mmol) by heating at 100°C for 3 hours in an oil bath. This resulted in 169e (160 mg, 66% yield) as a clear oil after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%]. An analytical sample was obtained by purification using a reverse phase chromatography column [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((7- (3(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate (169e), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.53 (s, 3H), 7.89 (d, J=1.8 Hz, 1H), 7.84-7.73 (m, 1H) , 7.60 (d, J=1.6 Hz, 1H), 7.58-7.50 (m, 3H), 7.24-7.12 (m, 2H), 7.10 (s, 1H ), 7.04 (dd, J=8.2, 1.1 Hz, 1H), 6.85 (td, J=7.4, 1.1 Hz, 1H), 5.17 (s, 2H) , 4.06 (s, 2H), 3.87 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 0.93 (t, J=7.1 Hz, 3H) ; MS (ESI+): 450.2 (M+1); purity after HPLC 100%. Analysis calculation for C ₂₆ H ₂₄ ClNO ₄ -HCl-H ₂ O: C, 61.91; N, 5.40; N, 2.78; observed: C, 62.28; N, 5.13; N, 2.82.

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5yl)methoxy)phenyl)acetic acid (169f).

Compound 169f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate ( 169e) (112 mg, 0.249 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (60 mg, 2.505 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetic acid (169f) (68 mg, 65% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 3H), 7.95 (s, 1H), 7.87 (s, 1H), 7.73-7.56 (m, 4H) , 7.22 (d, J=7.8 Hz, 2H), 7.11 (d, J=13.2 Hz, 2H), 6.91 (s, 1H), 5.26 (s, 2H) , 4.13 (s, 2H), 3.60 (s, 2H);

1H NMR (300 MHz, DMSO-d ₆ , D2O substitution) δ 8.01-7.78 (m, 2H), 7.78-7.43 (m, 4H), 7.36-7.14 (m , 2H), 7.06 (d, J=8.1 Hz, 2H), 6.91 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.12 (s , 2H), 3.58 (s, 2H); MS (ESI+): 422.1 (M+1); MS (ESI-): 420.2 (M-1). HPLC: 100% purity. Analysis calculation for C ₂₄ H ₂₀ ClNO ₄ -HCl-H ₂ O: C, 60.51; N, 4.87; Cl, 14.89; N, 2.94; observed: C, 60.81; N, 4.75; Cl, 14.95; N, 3.04.

Scheme-170

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (170b).

Stage-1. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)1 H-indol-6-yl)methoxy)phenyl)acetate (170a).

Compound 170a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(cyclopronylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (155a) (0.7 g, 1.43 mmol) in dioxane (7 ml) using (3-fluoro-4iodopyridin-2-yl )methanamine (113a) (0.28 g, 1.10 mmol), bis(triphenylphosphine) palladium(P) chloride (0.12 g, 0.17 mmol) and K2CO3 solution (0.38 g, 2.75 mmol ) in water (0.7 ml) in an Ar atmosphere when heated at 100°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 50%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-245 045626 (cyclopropylmethyl )-1H-indol-6-yl)methoxy)phenyl)acetate (170a) (0.1 g, 19% yield) as a yellow solid; MS (ESI+): 488.3 (M+1).

Stage-2. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-Shindol-6-yl)methoxy)phenyl)acetic acid (170b).

Compound 170b was prepared according to the procedure described in step-4 of scheme-4, ethyl 2-(2((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -(cyclopropylmethyl)-1 H -indol-6-yl)methoxy)phenyl)acetate (170a) (0.1 g, 0.21 mmol) THF (4 ml) and MeOH (4 ml), using sodium hydroxide (0.04 g, 1.03 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (170b) (0.01 g, 12% yield), salt HCl, as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=4.9 Hz, 1H), 8.50 (s, 3H), 7.81 (s, 1H), 7.70 ( t, J=5.3 Hz, 1H), 7.59 (d, J=3.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.22 (d, J=7 .4 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.38 (t, J =3.1 Hz, 1H), 5.29 (s, 2H), 4.37 (d, J=5.8 Hz, 2H), 4.11 (d, J=7.0 Hz, 2H), 3.59 (s, 2H), 1.38-1.16 (m, 1H), 0.58-0.31 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.89; MS (ESI+): 460.3 (M+1); MS (ESI-): 458.3 (M-1). Purity after HPLC: 96.70%.

Scheme-171

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (171c).

Stage-1. Preparation of ethyl 2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (171a) .

Compound 171a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c) (510 mg, 1.25 mmol), using bis(pinacolato)diboron (477 mg, 1.88 mmol), potassium acetate (369 mg, 3.76 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (153 mg, 0 .19 mmol) in anhydrous dioxane (10 ml) under Ar atmosphere by heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((4-fluoro-7-(4,4, 5,5-Tetramethyl1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (171a) (400 mg, 70% yield) as a white solid; MS (ESI+): 477.2 (M+Na); (ESI-): 453.3 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetate (171b).

Compound 171b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (171a) (190 mg, 0.42 mmol) in dioxane (6 ml) using (3-fluoro-4-iodopyridin-2-yl)methanamine ( 113a) (137 mg, 0.54 mmol), bis(triphenylphosphine) palladium(P) chloride (44 mg, 0.063 mmol) and a solution of K2CO3 (173 mg, 1.26 mmol) in water (2 ml) in an Ar atmosphere at heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl) methoxy)phenyl)acetate (171b) (88 mg, 47% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70-8.56 (m, 4H, Partially D2O replaceable), 8.21 (d, J=2.3 Hz, 1H), 7.79 (t , J=5.3 Hz, 1H), 7.70 (d, J=6.6 Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.17 (m, 2H), 6.94 (td, J=7.3, 1.2 Hz, 1H), 5.30 (s, 2H), 4.43-4.29 (m, 2H), 3.86 (k , J=7.1 Hz, 2H), 3.57 (s, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.23, -128.69; MS (ESI+): 453.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-246 045626 yl)methoxy)phenyl)acetic acid (171c).

Compound 171c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl )methoxy)phenyl)acetate (171b) (60 mg, 0.13 mmol) THF (6 ml) and MeOH (6 ml), using lithium hydroxide monohydrate (7.23 mg, 0.17 mmol) in water (2, 0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (171c) (22 mg, 39% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.69-8.51 (m, 4H, partially D ₂ O replaceable), 8.21 (d, J=2.3 Hz, 1H), 7.79 ( t, J=5.3 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.30-7.15 (m, 4H), 6.93 (td, J=7 ,3, 1.2 Hz, 1H), 5.32 (s, 2H), 4.42-4.30 (m, 2H), 3.54 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.30, -128.46; MS (ESI+): 425.2 (M+1); (ESI-): 423.3 (M-1).

Scheme-172

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (172b).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetate (172a).

Compound 172a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (171a) (190 mg, 0.42 mmol) in dioxane (6 ml), using (4-chloropyridin-2-yl)methanamine (74a) (78 mg, 0.54 mmol), bis(triphenylphosphine) palladium(P) chloride (44.0 mg, 0.063 mmol) and a solution of K ₂ CO ₃ (173 mg, 1.26 mmol) in water (2 ml) in an Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy )phenyl)acetate (172a) (70 mg, 39% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (dd, J=5.3, 0.7 Hz, 1H), 8.51 (s, 3H, D ₂ O replaceable), 8.26 ( d, J=2.3 Hz, 1H), 8.09-8.05 (m, 1H), 7.98-7.89 (m, 2H), 7.34-7.26 (m, 2H) , 7.25-7.17 (m, 2H), 6.94 (td, J=7.3, 1.2 Hz, 1H), 5.29 (s, 2H), 4.30 (k, J =5.7 Hz, 2H), 3.87 (k, J=7.1 Hz, 2H), 3.58 (s, 2H), 0.91 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.63; MS (ESI+): 435.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (172b).

Compound 172b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy) phenyl)acetate (172a) (56 mg, 0.13 mmol) THF (6 ml) and MeOH (6 ml), using lithium hydroxide monohydrate (7.03 mg, 0.17 mmol) in water (2.0 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (172b) (15 mg, 27% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.80 (d, J=5.3 Hz, 1H), 8.64 (s, 3H, D ₂ O replaceable), 8.26 (d, J=2 .3 Hz, 1H), 8.17-8.10 (m, 1H), 8.05-7.93 (m, 2H), 7.34-7.16 (m, 4H), 6.94 ( td, J=7.3, 1.2 Hz, 1H), 5.32 (s, 2H), 4.394.24 (m, 2H), 3.57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.35; MS (ESI+): 407.2 (M+1); (ESI-): 405.3 (M-1).

Scheme-173 he

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (173b).

- 247 045626

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (173a).

Compound 173a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (154e) (222 mg, 0.486 mmol) in dioxane (30 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (165 mg, 0.805 mmol), bis(triphenylphosphine) palladium(P) chloride (PdCl ₂ (PPh ₃ ) ₂ ) (55 mg, 0.078 mmol) and K ₂ CO ₃ (220 mg, 1.592 mmol) in water (0.5 ml) in an Ar atmosphere, heating at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with DMA80 in DCM 0% to 50%], compound 173a (181 mg, 74% yield), the free base as a clear oil. An analytical sample was prepared by purifying the free base using reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-(( 7-(3-(aminomethyl)-2-fluorophenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (173a), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.66 (s, 3H), 7.82 (s, 1H), 7.73 (t, J=7.4 Hz, 1H), 7.68-7.43 (m, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.19 (k, J=7.8 Hz, 2H), 7.06 (d, J=8.2 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.10 (s, 2H), 3.85 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 0.91 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.08, -118.78. MS (ESI+): 502.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (173b).

Compound 173b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl) methoxy)phenyl)acetate (173a) (121 mg, 0.241 mmol) THF/MeOH (6 ml each), using lithium hydroxide (75 mg, 3.13 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (173b) (53 mg, 46% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.81 (d, J=2.0 Hz, 1H), 8.66 (s, 2H), 7.85 (s, 1H), 7.79- 7.67 (m, 1H), 7.67-7.52 (m, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.26-7.09 (m, 2H) , 7.03 (d, J=8.1 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 5.26 (s, 2H), 4.10 (s, 2H) , 3.52 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.02, -118.61. MS (ESI+): 474.1 (M+1); MS (ESI-): 472.2 (M-1). HPLC: purity 99.28%. Analysis calculation for C ₂₅ H ₁₉ F ₄ NO ₄ -HCl-0.25H ₂ O: C, 58.37; N, 4.02; Cl, 6.89; N, 2.72; observed: C, 58.34; N, 3.88; Cl, 6.80; N, 2.78.

Scheme-174

174b 174c

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6yl)methoxy)phenyl)acetic acid (174c).

Stage-1. Preparation of ethyl 2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-6yl)methoxy)phenyl)acetate (174a).

Compound 174a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (115d ) (500 mg, 1.091 mmol), using bis(pinacolato)diboron (415 mg, 1.636 mmol), potassium acetate (321 mg, 3.27 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (134 mg, 0.164 mmol) in anhydrous dioxane (20 ml) under Ar atmosphere by heating at 100°C for 15 hours. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g eluted with hexanes/ethyl acetate (from 1:0 up to 5:1)] ethyl 2(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-6-yl)methoxy)phenyl)acetate ( 174a) (235 mg) as a colorless resin; MS (ESI+): 459.4 (M+Na).

- 248 045626

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6yl)methoxy)phenyl)acetate (174b).

Compound 174b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-6-yl)methoxy)phenyl)acetate (174a) (220 mg, 0.504 mmol) in dioxane (4 ml), using (3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (191 mg, 0.756 mmol), bis(triphenylphosphine) palladium(P) chloride (106 mg, 0.151 mmol) and a solution of K ₂ CO ₃ (209 mg, 1.513 mmol) in water (1 ml) in an Ar atmosphere when heated at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2-((4-(2-( aminomethyl)-3fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate (174b) (51 mg) as a light brown gum; MS (ESI ⁺ ): 435.20 (M+1).

Stage-3.

Receipt

2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6 yl)methoxy)phenyl)acetic acid (174c).

Compound 174c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy) phenyl)acetate (174b) (48 mg, 0.110 mmol) THF/MeOH (3 mL each), using lithium hydroxide monohydrate (28 mg, 0.663 mmol) in water (3.0 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetic acid (174c) (5 mg, 1.3% in three steps), HCl salt, as a white solid .

^1H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J=4.9 Hz, 1H), 8.50 (s, 3H), 8.16 (d, J=2.3 Hz, 1H), 7.87 (s, 1H), 7.71 (t, J=5.4 Hz, 1H), 7.56 (s, 1H), 7.28-7.19 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.99-6.95 (m, 1H), 6.94-6.87 (m, 1H), 5.32 (s, 2H) , 4.43-4.32 (m, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.89; MS (ESI+): 407.2 (M+1); MS (ESI-): 405.2 (M-1); purity after HPLC: 92.60%.

Scheme-175

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5 Preparation of yl)methoxy)phenyl)acetic acid (175c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (175a) .

Compound 175a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (154e) (229 mg, 0.501 mmol) in dioxane (5 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methylcarbamate (123a) (380 mg, 1.137 mmol), K ₂ CO ₃ (245 mg, 1.773 mmol) in water (0.5 ml), bis(triphenylphosphine) palladium(P) chloride (56 mg, 0.080 mmol) and heating under nitrogen at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 20 to 100% ethyl acetate in hexane] ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl )amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (175a) (263 mg, 90% yield) as a pale yellow oil. MS (ESI+): 585.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (175b).

Compound 175b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3- (trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (175a) (263 mg, 0.450 mmol) in DCM (6 ml) using TFA (0.5 ml, 6.49 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA/DCM (0-80%)] compound 175b (205 mg, 94% yield), free base, as a white solid. The analytical sample was further purified using reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((7 -(2-(aminomethyl)pyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (175b), HCl salt, as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.00 (k, J=1.6 Hz, 1H), 8.83 (dd, J=5.3, 0.7 Hz, 1H), 8 .68 (s, 3H), 8.188.09 (m, 1H), 8.06-7.83 (m, 3H), 7.36-7.18 (m, 2H), 7.13 (dd, J =8.3, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.34 (s, 2H), 4.32 (k, J= 5.8 Hz, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 485.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (175c).

Compound 175c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl )methoxy)phenyl)acetate (175b) (140 mg, 0.289 mmol) in THF/MeOH (6 mL each), using a solution of lithium hydroxide monohydrate (81 mg, 3.38 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (175c) (71 mg, 54% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.99 (d, J=1.8 Hz, 1H), 8.82 (d, J=5.3 Hz, 1H), 8.65 (br .s, 3H), 8.11 (d, J=1.6 Hz, 1H), 8.07-7.92 (m, 3H), 7.34-7.18 (m, 2H), 7, 11 (d, J=8.0 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 5.36 (s, 2H), 4.32 (d, J=5.5 Hz, 2H), 3.62 (s, 2H); MS (ESI+): 457.2 (M+1); MS (ESI-): 455.3 (M-1). HPLC: purity 97.6%.

Scheme-176

Vg

Preparation of 2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (176c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5yl)methoxy)phenyl)acetate (176b).

Compound 176b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (241 mg, 0.552 mmol) in dioxane (5 ml), using 7-bromo-1H-indazol-3-amine (176a) (160 mg, 0.755 mmol; CAS No. 1234616-28-4), bis(triphenylphosphine) palladium(P) chloride (72 mg, 0.103 mmol) and a solution of K2CO3 (355 mg, 2.57 mmol) in water (0.5 ml) under Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with ethyl acetate in hexane from 40-100%], compound 176b (209 mg, 86% yield), free base, as pale yellow oils The analytical sample was obtained by purification using a reverse phase chromatography column [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((7 -(3-amino-1H-indazol-7-yl)benzofuran-5yl)methoxy)phenyl)acetate (176b), HCl salt, as a white solid.

% NMR (300 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.90-7.73 (m, 2H), 7.67-7.57 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.31-7 .19 (m, 2H), 7.15 (d, J=8.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.91 (t, J=7, 3 Hz, 1H), 5.29 (s, 2H), 3.85 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 0.93 (t, J=7, 1 Hz, 3H); MS (ESI+): 442.2 (M+1); MS (ESI-): 440.3 (M-1).

Stage-2. Preparation of 2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (176c).

Compound 176c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl) acetate (176b) (159 mg, 0.360 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (92 mg, 2.19 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-amino1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (176c) (79 mg, 53% yield) as a white solid.

% NMR (300 MHz, DMSO- _d6 ) δ 12.66 (s, 2H), 8.06-7.92 (m, 2H), 7.76 (s, 1H), 7.67 (d, J =7.1 Hz, 1H), 7.57 (s, 1H), 7.35-7.10 (m, 3H), 7.05 (d, J=8.2 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 5.24 (s, 2H), 3.53 (s, 2H); MS (ESI+): 414.2 (M+1); MS (ESI-): 412.2 (M-1).

- 250 045626

Scheme-177

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetic acid (177f).

Stage-1. Preparation of (7-bromo-2,3-dihydro-1H-inden-5-yl)methanol (177a).

Compound 177a was prepared according to the procedure described in step-1 of Scheme-23 from 7bromo-2,3-dihydro-1H-indene-5-carboxylic acid (160a) ((5.0 g, 20.74 mmol), using Nmethylmorpholine ((2.30 g, 22.81 mmol) in THF (50 ml), isobutyl chloroformate (3.11 g, 22.81 mmol) and NaBH ₄ (1.17 g, 31.11 mmol) in water ( 6.5 ml) This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-30% ethyl acetate in n-hexane] (7-bromo-2,3-dihydro-1H-inden-5 -yl)methanol (177a) (1.9 g, 42%) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.14 (s, 1H), 5.26 (t, J=5.7 Hz, 1H), 4.44 ( d, J=5.1 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.10-1, 96 (m, 2H).

Stage-2. Preparation of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-indene (177b).

To a stirred solution of (7-bromo-2,3-dihydro-1H-inden-5-yl)methanol (177a) (2.0 g, 8.80 mmol) in DCM (40.0 ml) was added at 0°C thionyl chloride (3.1 g, 26.42 mmol), a drop of DMF and stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo to give 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-indene (177b) (1.93 g, 89%) as a colorless oil.

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate (177c).

To a stirred solution of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-indene (177b) (crude from previous step, 1.9 g, 7.73 mmol) in DMF (19.0 mL) was added at room temperature, potassium carbonate (5.3 g, 38.69 mmol) and ethyl 2-(2-hydroxyphenyl) acetate (23b) (2.0 g, 11.59 mmol), stirred for 14 h and quenched with water ( 100 ml). The reaction mixture was extracted with ethyl acetate (2x200.0 ml) and the combined organic extracts were washed with brine (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography, eluting with 0-20% ethyl acetate in n-hexane to give ethyl 2-(2-((7-bromo-2,3-dihydro-1H-inden-5yl)methoxy)phenyl) acetate (177c) (1.4 g, 49.12%) as an oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.37 (s, 1H), 7.24 (m, 3H), 7.02 (d, J=8.1 Hz, 1H), 6.91 ( t, J=7.4 Hz, 1H), 5.04 (s, 2H), 4.03 (m, 2H), 3.57 (s, 2H), 2.98 (m, 2H), 2, 85 (t, J=7.5 Hz, 2H), 2.04 (p, J=7.7 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro1H-inden-5-yl)methoxy)phenyl)acetate (177d).

Compound 177d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate (177c ) (0.5 g, 1.28 mmol) in acetonitrile (14 ml), dioxane (6 ml), using (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1d) (0. 48 g, 1.92 mmol), Na ₂ CO ₃ (0.40 g, 3.85 mmol) and Pd(dppf)Cl ₂ (0.10 g, 0.12 mmol) in a nitrogen atmosphere when heated at 90° C for 14 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-20% EtOAc in nhexane], ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)-2,3-dihydro-1H-inden-5yl)methoxy)phenyl)acetate (177d) (0.13 g, 20%) as a colorless liquid;

1H NMR (300 MHz, DMSO-d6) δ 7.45 (m, 1H), 7.35 (m, 2H), 7.29-7.17 (m, 6H), 7.07 (d, J= 8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.09 (s, 2H), 4.18 (d, J=6.2 Hz, 2H), 3 .92 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 3.03-2.82 (m, 4H), 2.00 (t, J=7.3 Hz, 2H), 1.39 (s, 9H), 1.03 (t, J=7.0 Hz, 3H).

- 251 045626

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5yl)methoxy)phenyl)acetate (177e).

Compound 177e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro- 1H-inden-5yl)methoxy)phenyl)acetate (177d) (0.1 g, 0.194 mmol) in DCM (7 ml) using TFA (0.223 ml, 2.91 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro1H-inden-5-yl)methoxy)phenyl)acetate (177e) (0.103 g, 100 % yield), TFA salt, as a solid; MS (ESI+): 416.3 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5yl)methoxy)phenyl)acetic acid (177f).

Compound 177f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl) methoxy)phenyl)acetate (177e) (0.194 mmol) in THF/methanol (3:1 ml), using lithium hydroxide monohydrate (163 mg, 3.88 mmol) in water (3.9 ml, 1N). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 30 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] and [C18 (12 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7-(3 -(aminomethyl)phenyl)-2,3dihydro-1H-inden-5-yl)methoxy)phenyl)acetic acid (177f) (1 mg, 1.2% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.61 (s, 1H), 7.53-7.49 (m, 2H), 7.48-7.41 (m, 1H), 7. 34 (s, 1H), 7.28 (s, 1H), 7.26-7.18 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.89 (t , J=7.2 Hz, 1H), 5.13 (s, 2H), 4.10 (s, 2H), 3.56 (s, 2H), 2.93 (t, J=7.2 Hz , 4H), 2.01 (t, J=7.3 Hz, 2H); MS (ESI+): 388.2 (M+1); (ESI-): 386.30 (M-1).

Scheme-178

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (178g).

Stage-1. Preparation of methyl 7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (178a).

Compound 178a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (15 g, 48.4 mmol) in pyridine (500 ml) using but -3-in-1-ol (3.39 g, 48.4 mmol) and copper(I) oxide (3.46 g, 24.20 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 80% EtOAc in hexane] methyl 7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate ( 178a) (8.1 g, 56% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (d, J=1.6 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 6.94-6, 90 (m, 1H), 4.954.82 (m, 1H, D2O replaceable), 3.88 (s, 3H), 3.78 (t, J=6.5 Hz, 2H), 2.99 (td, J=6.4, 1.0 Hz, 2H); MS (ESI+): 299.0 (M+1).

Stage-2. Preparation of methyl 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5carboxylate (178b).

To a solution of methyl 7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (178a) (6 g, 20.06 mmol) and imidazole (1.37 g, 20.06 mmol) in anhydrous DCM (120 ml ) at 0°C, TBS-Cl (3.02 g, 20.06

- 252 045626 mmol). The mixture was stirred at 0°C for 2 hours and overnight at RT. The reaction mixture was diluted with DCM and water. The aqueous layer was separated and extracted with DCM (2x). The combined organic layers were washed with water and brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with 0% to 50% EtOAc in hexane] to give methyl 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5 -carboxylate (178b) (7.5 g, 90% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d6) δ 8.19 (d, J=1.6 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 6.93-6, 86 (m, 1H), 3.94 (t, J=6.1 Hz, 2H), 3.86 (s, 3H), 3.02 (t, J=6.1 Hz, 2H), 0. 77 (s, 9H), -0.05 (s, 6H).

Stage-3. Preparation of (7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol (178c).

Compound 178c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate (178b) (7.32 g, 17.71 mmol) in THF (60 ml), using LiBH ₄ (17.71 ml, 53.1 mmol, 3 M solution in THF) and MeOH (2.2 ml, 53.1 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 60% EtOAc in hexane] (7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl) benzofuran-5-yl)methanol (178c) (6.36 g, 93% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.49-7.45 (m, 1H), 7.40-7.37 (m, 1H), 6.75-6.71 (m, 1H) , 5.29 (t, J=5.8 Hz, 1H, D ₂ O replaceable), 4.54 (d, J=5.8 Hz, 2H), 3.94 (t, J=6.1 Hz , 2H), 2.98 (t, J=6.1 Hz, 2H), 0.79 (s, 9H), 0.04 (s, 6H); MS (ESI+) 387.1 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5yl)methoxy)phenyl)acetate (178d).

Compound 178d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol (178c) (6.11 g, 15.85 mmol) in DCM (100 ml), using triphenylphosphine (4.16 g, 15.85 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (2.86 g, 15.85 mmol ) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 5.82 g, 15.85 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 20% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-(2-( (tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178d) (6.5 g, 75% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.53 (s, 1H), 7.32-7.22 (m, 2H), 7.10 (d, J =8.1 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.81 (s, 1H), 5.18 (s, 2H), 4.12-3.90 (m, 4H), 3.65 (s, 2H), 3.03 (t, J=6.1 Hz, 2H), 1.11 (t, J=7.0 Hz, 3H), 0.83 (d, J=0.9 Hz, 9H), 0.00 (s, 6H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tertbutyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178e).

Compound 178e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl) methoxy)phenyl)acetate (178d) (650 mg, 1.19 mmol) in dioxane (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (334 mg, 1.78 mmol), K2CO3 solution (492 mg, 3.56 mmol) in water (3 ml), bis(triphenylphosphine) palladium(P) chloride (125 mg, 0.18 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7(3-(aminomethyl)phenyl)-2- (2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5yl)methoxy)phenyl)acetate (178e) (441 mg, 65% yield) as a clear oil; MS (ESI+): 574.3 (M+1).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetate (178f).

To a solution of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178e) (200 mg, 0.349 mmol) in THF (10 ml) was added HCl (2N, 1.5 ml), stirred at RT for 3 hours and concentrated in vacuo. The residue was supplemented with EtOAc and washed with water and brine. The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] to obtain ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetate (178f) (114 mg, 65% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 3H, D2O replaceable), 7.98 (t, J=1.6 Hz, 1H), 7.91 (dt, J=7, 1, 1.9 Hz, 1H), 7.65-7.48 (m, 4H), 7.31-7.18 (m, 2H), 7.14-7.05 (m, 1H), 6 .91 (td, J=7.4, 1.1 Hz, 1H), 6.72 (s, 1H), 5.22 (s, 2H), 4.89 (t, J=5.4 Hz, 1H, D2O replaceable), 4.12 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.84-3.71 (m, 2H), 3.63 (s, 2H), 2.96 (t, J=6.6 Hz, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 460.3 (M+1).

- 253 045626

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (178g).

To a solution of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tertbutyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178e) (212 mg, 0.369 mmol) in MeOH/THF (6 mL each) was added lithium hydroxide monohydrate (20 mg, 0.480 mmol) in water (2.0 mL). The resulting mixture was stirred at RT for 12 hours and acidified to pH~4. The resulting residue was purified by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give 2-(2-((7-(3- (aminomethyl)phenyl)-2-(2hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (178g) (120 mg, 75% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (s, 1H, D ₂ O replaceable), 8.48 (s, 3H, D ₂ O replaceable), 8.01-7.96 (m, 1H), 7.93 (dt, J=7.2, 1.8 Hz, 1H), 7.66-7.60 (m, 1H), 7.60-7.52 (m, 3H), 7 ,27-7.18 (m, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6, 72 (s, 1H), 5.24 (s, 2H), 4.88 (t, J=5.4 Hz, 1H), 4.13 (s, 2H), 3.78 (k, J=6 ,1 Hz, 2H), 3.59 (s, 2H), 2.96 (t, J=6.6 Hz, 2H); MS (ESI+): 432.2 (M+1); (ESI-): 430.3 (M-1).

Scheme-179 he

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (179b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-((tertbutyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (179a) .

Compound 179a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl) methoxy)phenyl)acetate (178d) (225 mg, 1.10 mmol) in dioxane (5 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (225 mg, 1.10 mmol), solution K ₂ CO ₃ (303 mg, 2.19 mmol) in water (1 ml), bis(triphenylphosphine) palladium(R) chloride (103 mg, 0.15 mmol) when heated at 100 ° C for 3 hours in oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-((tertbutyldimethylsilyl)oxy)ethyl )benzofuran-5-yl)methoxy)phenyl)acetate (179a) (330 mg, 76% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.70-7.58 (m, 3H), 7.48 (td, J=7.4, 1.8 Hz, 1H), 7.38- 7.32 (m, 2H), 7.327.23 (m, 2H), 7.18-7.12 (m, 1H), 6.95 (td, J=7.4, 1.1 Hz, 1H) , 5.24 (s, 2H), 3.98-3.90 (m, 4H), 3.87 (s, 2H), 3.65 (s, 2H), 2.98 (t, J=6 .2 Hz, 2H), 1.03 (t, J=7.1 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H); 19F NMR (282 MHz, DMSOd ₆ ) δ -121.84; MS (ESI+): 592.4 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (179b).

Compound 179b was prepared according to the procedure described in step-7 of scheme-178 from ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-((tert-butyldimethylsilyl )oxy)ethyl)benzofuran-5yl)methoxy)phenyl)acetate (179a) (175 mg, 0.30 mmol) in MeOH/THF (6 ml each), using lithium hydroxide monohydrate (50 mg, 1.18 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-2-fluorophenyl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (179b) (80 mg, 60% yield) as a white solid;

1H NMR (300 MHz, DMSO-de) δ 12.12 (s, 1H, D2O replaceable), 8.54 (s, _2H , _D2O replaceable), 7.74-7.62 (m, 3H ), 7.42 (t, J=7.7 Hz, 1H), 7.39-7.33 (m, 1H), 7.27-7.16 (m, 2H), 7.08 (d, J=7.9 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 6.76-6.67 (m, 1H), 5.23 (s, 2H ), 4.85 (t, J=5.4 Hz, 1H, D ₂ O replaceable), 4.17 (s, 2H), 3.72 (k, J=6.3 Hz, 2H), 3, 57 (s, 2H), 2.95-2.82 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.65; MS (ESI+): 450.2 (M+1); (ESI-): 448.3 (M-1).

- 254 045626

Scheme-180

Br

Preparation of 2-(2-((7-(3-αminobenzo[d]isoxazol-7-yl)benzofurαn-5-yl)methoxy)phenyl)acetic acid (180e).

Stage-1. Preparation of tert-butyl (7-bromobenzo[d]isoxazol-3-yl)carbamate (180b)

Mixture of 7-bromobenzo[d]isoxazol-3-amine (90 mg, 0.422 mmol; CAS No. 1260860-32-9), Boc ₂ O (0.298 ml, 1.283 mmol), DMAP (17 mg, 0.139 mmol) in THF ( 3 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 25% EtOAc in hexane] to give tert-butyl (7-bromobenzo[d]isoxαzol-3-yl)carbamateα ( 180b) (132 mg, 100% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (dd, J=8.1, 1.0 Hz, 1H), 7.90 (dd, J=8.1, 1.0 Hz, 1H), 7.35-7.26 (m, 1H), 1.51 (s, 9H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-((tert-butoxycarbonyl)amino)benzo[d]isoxazol-7yl)benzofuran-5-yl)methoxy)phenyl)acetate (180c).

Compound 180c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (153 mg, 0.351 mmol) in dioxane (5 ml), using tert-butyl (7-bromobenzo[d]isoxazol-3-yl)carbamate (180b) ( 130 mg, 0.415 mmol), bis(triphenylphosphine) palladium(P) chloride (41 mg, 0.058 mmol) and a solution of K2CO3 (162 mg, 1.172 mmol) in water (0.5 ml) in an Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with ethyl acetate in 0% to 50% hexane] ethyl 2(2-((7-(3-((tert-butoxycarbonyl)amino) benzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate (180c) (168 mg, 0.310 mmol, 88% yield) as a pale yellow oil; MS (ESI+): 543.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5yl)methoxy)phenyl)acetate (180d).

Compound 180d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-((tert-butoxycarbonyl)amino)benzo[d]isoxazol-7-yl)benzofuran- 5-yl)methoxy)phenyl)acetate (180c) (168 mg, 0.310 mmol) in DCM (5 ml) using TFA (0.3 ml, 3.89 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 40-100% EtOAc in hexane] ethyl 2-(2-((7-(3-aminobenzo[d]isoxazol- 7-yl)benzofuran-5yl)methoxy)phenyl)acetate (180d) (55 mg, 40% yield) as a pale yellow oil.

1H NMR (300 MHz, chloroform-d) δ 8.14 (dd, J=7.4, 1.1 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.59-7.51 (m, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.32-7.22 (m, 2H), 7.05-6.92 (m, 2H), 6.85 (d, J=2.2 Hz, 1H), 5.26 (s, 2H), 4.51 (s, 2H), 4.08 (k, J=7.2 Hz, 2H), 3.74 (s, 2H), 1.13 (t, J =7.1 Hz, 3H); MS (ESI+): 443.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (180e).

Compound 180e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl) acetate (180d) (55 mg, 0.124 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (31 mg, 0.74 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-255 045626 aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (180e) (26 mg, 51% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ , D ₂ O replacement) δ 8.01 (d, J=2.2 Hz, 1H), 7.91 (dd, J=7.4, 1.2 Hz, 1H), 7.85 (dd, J=7.9, 1.1 Hz, 1H), 7.79-7.69 (m, 2H), 7.37 (t, J=7.6 Hz, 1H ), 7.22-7.10 (m, 2H), 7.09-7.01 (m, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.84 (td, J=7.3, 1.1 Hz, 1H), 5.22 (s, 2H), 3.53 (s, 2H); MS (ESI+): 415.1 (M+1); MS (ESI-): 413.2 (M-1).

Scheme-181

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (181d).

Stage-1. Preparation of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (181a).

Compound 181a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (154e) ( 250 mg, 0.547 mmol) using bis(pinacolato)diboron (212 mg, 0.835 mmol), potassium acetate (175 mg, 1.783 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (51 mg, 0.062 mmol) in anhydrous dioxane (6 ml) under Ar atmosphere while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, (12 g), eluted with ethyl acetate in 0% to 40% hexane] ethyl 2-(2-((7-(4,4,5, 5tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (181a) (146 mg, 53% yield) as a pale yellow oil.

^1H NMR (300 MHz, chloroform-d) δ 8.09 (k, J=1.6 Hz, 1H), 7.95-7.87 (m, 2H), 7.32-7.19 (m , 2H), 7.036.93 (m, 2H), 5.19 (s, 2H), 4.13 (p, J=7.1 Hz, 3H), 3.69 (s, 2H), 1.44 (s, 12H), 1.16 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, chloroform-d) δ -59.32.

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (181c).

Compound 181c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (181a) (142 mg, 0.282 mmol) in dioxane (5 ml) using (4chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (181b) ( 80 mg, 0.404 mmol; CAS No. 1646565-99-2), bis(triphenylphosphine) palladium(P) chloride (35 mg, 0.050 mmol) and a solution of K2CO3 (220 mg, 1.592 mmol) in water (0.5 ml) in Ar atmosphere and heating at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 80% DMA80/DCM] ethyl 2-(2-((7-(2-(aminomethyl)-3 -fluoropyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (181c) (147 mg, 72% yield) as a pale yellow oil. MS (ESI+): 503.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)phenyl)acetic acid (181d).

Compound 181d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran- 5-yl)methoxy)phenyl)acetate (181c) (147 mg, 0.293 mmol) THF/MeOH (6 mL each), using lithium hydroxide monohydrate (65 mg, 1.55 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (181d) (14 mg, 10% yield), HCl salt, as a white solid substances.

1H NMR (300 MHz, DMSO-d ₆ , D2O substitution) δ 8.84 (d, J=1.9 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 7.75 (dd, J=10.5, 5.2 Hz, 2H), 7.25-7.13 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.3 Hz, 1H), 5.28 (s, 2H),

- 256 045626

4.33 (s, 2H), 3.53 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.02, -128.49. MS (ESI+): 475.2 (M+1); MS (ESI-): 473.3 (M-1).

Scheme-182

Vg

130d

Br

182s

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)acetic acid (182d).

Stage-1. Preparation of ethyl 2-(4-bromo-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (182b).

Compound 182b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1.910 g, 5.40 mmol) in DCM (20 ml), using triphenylphosphine (1.559 g, 5.94 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl) acetate (182a) (1.4 g, 5.40 mmol) and (E)-bis(4 -chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.182 g, 5.94 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 80 g, eluted with ethyl acetate in 0% to 100% hexanes] to ethyl 2-(4-bromo-2-((7-(3-(( (tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (182b) (1.97 g, 61% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.78-7.66 (m, 3H), 7.54 (d, J=1 .7 Hz, 1H), 7.557.43 (m, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.31 (dt, J=7.6, 1.3 Hz, 1H ), 7.23-7.17 (m, 1H), 7.16-7.10 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.27 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 494.10, 496.10 (M+2, loss of Boc).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4bromophenyl)acetate (182c).

Compound 182c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (0.250 g, 0.421 mmol) in DCM (10 ml) using TFA (0.324 ml, 4.21 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 40% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-4-bromophenyl)acetate (182c) (0.126 g, 49% yield), TFA salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (s, 3H, D2O replaceable), 8.12 (d, J=2.2 Hz, 1H), 8.00-7.96 (m, 1H), 7.91 (dt, J=7.7, 1.5 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.65-7.51 (m, 3H ), 7.35 (d, J=1.8 Hz, 1H), 7.23-7.18 (m, 1H), 7.16-7.11 (m, 1H), 7.10 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.16 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 496.10, 494.10 (M+2); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -73.47; MS (ESI-): 494.20, 492.20 (M-2); purity after HPLC: 84.72%.

Stage-3. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4bromophenyl)acetic acid (182d).

Compound 182d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)acetate ( 182c) (0.100 g, 0.202 mmol) in THF (4 ml) and methanol (8 ml) using 2 M LiOH (0.506 ml, 1.011 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 100%] followed by reverse phase column chromatography [C18 (30 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)acetic acid (182d) (0.076 g, 81% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.34 (br.s, 1H, D2O replaceable), 8.33 (br.s, 3H, D2O replaceable),

- 257 045626

8.12 (d, J=2.2 Hz, 1H), 8.01-7.97 (m, 1H), 7.97-7.87 (m, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.65-7.62 (m, 1H), 7.617.52 (m, 2H), 7.32 (d, J=1.8 Hz, 1H), 7.24- 7.17 (m, 1H), 7.12 (dd, J=8.0, 1.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),

5.30 (s, 2H), 4.24-4.06 (m, 2H), 3.57 (s, 2H); MS (ESI+): 468.10, 466.10 (M+2); MS (ESI-): 466.15, 464.20 (M-2); purity after HPLC: 90.92%.

Scheme-183

Preparation of 2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (183c).

Stage-1. Preparation of ethyl 2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (183b).

Compound 183b was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (500 mg, 1.285 mmol) in dioxane (10 ml), using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (183a) (310 mg, 1.413 mmol; CAS No. 214360-73-3 ), bis(triphenylphosphine)palladium(P) chloride (90 mg, 0.128 mmol) and K2CO3 (533 mg, 3.85 mmol) under nitrogen and heating at 80°C for 16 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel eluted with 0-30% EtOAc in hexane], ethyl 2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl) acetate (183b) (0.38 g, 74% yield) as a yellow oil.

Ή NMR (300 MHz, chloroform-d) δ 7.81-7.67 (m, 3H), 7.59 (d, J=1.7, 0.8 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.34-7.19 (m, 2H), 7.06-6.92 (m, 2H), 6.92-6.80 (m, 3H), 5 .22 (s, 2H), 4.07 (k, J=7.1 Hz, 2H), 3.70 (s, 2H), 1.13 (t, J=7.1 Hz, 3H); MS (ESI+): 402 (M+1).

Stage-2. Preparation of 2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (183c).

Compound 183c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (183b) (0.22 g, 0.548 mmol) in THF (1 mL) and MeOH (2 mL each), using NaOH (0.088 g, 2.192 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (4-aminophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (183c) (73 mg, 36% yield), HCl salt, as an off-white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 8.00-7.86 (m, 2H), 7.73 (d, J=1 .6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.41-7.30 (m, 2H), 7.24 (t, J=7.7 Hz, 2H ), 7.10 (d, J=8.0 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz , 1H), 5.26 (s, 2H), 3.59 (s, 2H); purity after HPLC: 98.9; MS (ESI-): 372 (M-1).

Scheme-184

Preparation of 2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (184c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (184b).

Compound 184b was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (200 mg, 0.514 mmol) in dioxane (2 ml), using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (184a) (124 mg, 0.565 mmol; CAS No. 210907-84-9 ), bis(triphenylphosphine)palladium(P) chloride (36 mg, 0.051 mmol) and K ₂ CO ₃ (213 mg, 1.541 mmol) in water (1 ml) under nitrogen and heating at 80°C for 16 h for oil bath. This gave, after work-up and purification by flash column chromatography [silica gel eluted with 0-30% EtOAc in hexane], ethyl 2-(2-((7-(3-aminophenyl)benzofuran-5yl)methoxy)phenyl)acetate ( 184b) (134 mg, 65.0% yield) as a thick, opaque yellow oil.

1H NMR (300 MHz, chloroform-d) δ 7.72 (d, J=2.2 Hz, 1H), 7.64 (d, 1H), 7.52 (d, J=1.7 Hz, 1H ), 7.377.21 (m, 6H), 7.04-6.93 (m, 2H), 6.84 (d, J=2.2 Hz, 1H), 6.82-6.74 (m, 1H), 5.23 (s, 2H), 4.07 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.13 (t, J=7.1 Hz, 7H); MS (ESI+): 424 (M+Na).

Stage-2. Preparation of 2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (184c).

- 258 045626

Compound 184c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (184b) (130 mg, 0.324 mmol) in THF (1 ml) and MeOH (2 ml each), using NaOH (52 mg, 1.295 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-aminophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (184c) (34 mg, 28% yield), HCl salt, as an off-white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.75-7, 65 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.23 (dd, J=8.4 , 6.9 Hz, 3H), 7.14-7.04 (m, 2H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H) , 3.59 (s, 2H); MS (ESI-): 372 (M-1).

Scheme-185

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-hydroxyethyl)benzofuran-5 Preparation of yl)methoxy)phenyl)acetic acid (185c).

Stage-1. Preparation of ethyl 2-(2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzofuran- 5-yl)methoxy)phenyl)acetate (185a).

Compound 185a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl )methoxy)phenyl)acetate (178d) (1.4 g, 2.56 mmol), using bis(pinacolato)diboron (0.97 g, 3.84 mmol), potassium acetate (0.75 g, 7.67 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.31 g, 0.38 mmol) in anhydrous dioxane (20 ml) in an Ar atmosphere by heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, (40 g), eluted with ethyl acetate in 0% to 40% hexane] ethyl

2-(2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5 -yl)methoxy)phenyl)acetate (185a) (1.04 g, 68% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.72 (d, J=1.9 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.31-7, 20 (m, 2H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.3, 1.1 Hz, 1H), 6.67 -6.62 (m, 1H), 5.15 (s, 2H), 4.07-3.93 (m, 4H), 3.61 (s, 2H), 3.01 (t, J=6 .2 Hz, 2H), 1.19 (s, 12H), 1.07 (t, J=7.1 Hz, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

Stage-2.

ethyl

Receipt

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (185b) .

Compound 185b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (185a) (500 mg, 0.84 mmol) in dioxane (6 ml) using (4chloropyridine-2- yl)methanamine (74a) (180 mg, 1.26 mmol), bis(triphenylphosphine) palladium(P) chloride (89 mg, 0.13 mmol) and a solution of K2CO3 (291 mg, 2.10 mmol) in water (3 ml) in an Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 70% DMA80/DCM] ethyl 2-(2-((7-(2-(aminomethyl)pyridinium- 4-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5yl)methoxy)phenyl)acetate (185b) (320 mg, 66% yield) as a clear oil; MS (ESI+): 575.4 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (185c).

Compound 185c was prepared according to the procedure described in step-7 of Scheme-178 from ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-((tert- butyldimethylsilyl)oxy)ethyl)benzofuran-5yl)methoxy)phenyl)acetate (185b) (212 mg, 0.37 mmol) THF/MeOH (6 ml each), using lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)pyridin-4-yl)-2-(2-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (185c) (28 mg, 18% yield in 2 steps) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.82 (d, J=5.5 Hz, 1H), 8.75 (s, 3H, D2O replaceable), 8.26 (s, 1H), 8.13

- 259 045626 (dd, J=5.5, 1.7 Hz, 1H), 7.82-7.75 (m, 2H), 7.28-7.17 (m, 2H), 7.12- 7.04 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H),

6.78 (d, J=1.0 Hz, 1H), 5.26 (s, 2H), 4.43-4.28 (m, 2H), 3.80 (t, J=6.5 Hz , 2H), 3.60 (s, 2H), 3.00 (t, J=6.5 Hz,

2H); MS (ESI+): 433.2 (M+1); (ESI-): 431.3 (M-1).

Scheme-186

Preparation of 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (186c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (186b).

Compound 186b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (400 mg, 0.92 mmol) in dioxane (10 ml), using 1-(3-bromophenyl)-2-fluoroethanamine (186a) (180 mg, 1 .26 mmol; CAS No. 929972-40-7), bis(triphenylphosphine) palladium(P) chloride (97 mg, 0.14 mmol) and a solution of K ₂ CO ₃ (380 mg, 2.75 mmol) in water (3 ml) in an Ar atmosphere and heating at 100°C for 3 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA80/DCM 0% to 70%] followed by purification by reverse phase chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 186b) (246 mg, 60% yield) as a clear oil); MS (ESI+): 448.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (186c).

Compound 186c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl )acetate (186b) (166 mg, 0.37 mmol) THF/MeOH (6 mL each), using lithium hydroxide monohydrate (31 mg, 0.74 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(1amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (186c) (110 mg, 71% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 2H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 8.08 (s, 1H), 7 .98 (dt, J=6.6, 1.9 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.71-7.60 (m, 3H), 7. 28-7.18 (m, 2H), 7.13-7.08 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.91 (td, J=7, 4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.99-4.90 (m, 1H), 4.89-4.72 (m, 2H), 3.61 (s , 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -222.55; MS (ESI+): 420.2 (M+1); (ESI-): 418.3 (M-1).

Scheme-187 o

187e 1»7f

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetic acid (187f).

Stage-1. Preparation of methyl 7-iodo-2-propylbenzofuran-5-carboxylate (187a).

Compound 187a was prepared according to the procedure described in step-1 of Scheme-55 from methyl

- 260 045626

4-Hydroxy-3,5-diiodobenzoate (55a) (12.00 g, 29.71 mmol) in pyridine (30 ml), using 1-pentine (2.93 ml, 29.71 mmol) and copper oxide (T ) (2.13 g, 14.85 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0% to 10% EtOAc in hexanes], methyl 7-iodo-2-propylbenzofuran-5-carboxylate (187a) (3.36 g, 33 % exit).

^1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 6.89 (s, 1H), 3.86 (s, 3H), 2.81 (t, J=7.4 Hz, 2H), 1.84-1.57 (m, 2H), 0.98 (t, J=7 ,4 Hz, 3H).

Stage-2. Preparation of 7-iodo-2-propylbenzofuran-5-carboxylic acid (187b).

Compound 187b was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-iodo-2-propylbenzofuran-5-carboxylate (187a) ((3.30 g, 9.59 mmol) in MeOH/THF ( 20 ml each) using a solution of lithium hydroxide monohydrate (805 mg, 19.18 mmol) in water (3 ml) This resulted in 7-iodo-2-propylbenzofuran-5-carboxylic acid (187b) (3, 08 g, 97% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.05 (s, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 6.88 (s, 1H), 2.80 (t, J=7.4 Hz, 2H), 1.87-1.55 (m, 2H), 0.98 (t, J=7 ,4 Hz, 3H); MS (ESI-): 329.1 (M-1).

Stage-3. Preparation of (7-iodo-2-propylbenzofuran-5-yl)methanol (187c).

Compound 187c was prepared according to the procedure described in step-1 of Scheme-23 from 7iodo-2-propylbenzofuran-5-carboxylic acid (187b) (2.50 g, 7.57 mmol) using Nmethylmorpholine (1.00 ml , 9.09 mmol) in THF (50 ml), isobutyl chloroformate (1.18 ml, 9.09 mmol) and NaBH ₄ (860 mg, 22.72 mmol) in water (4.0 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0% to 20% EtOAc in hexanes], (7iodo-2-propylbenzofuran-5-yl)methanol (187c) (1.65 g, 69 % yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.54 (d, J=1.4 Hz, 1H), 7.44 (d, J=1.4 Hz, 1H), 6.72 (s, 1H ), 5.26 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 2.76 (t, J=7.4 Hz, 2H), 1.86-1.53 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d).

Compound 187d was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-propylbenzofuran-5-yl)methanol (187c) (1.60 g, 5.06 mmol) in DCM (20 ml) using triphenylphosphine (1.86 g, 7.08 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.28 g, 7.08 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 2. 60 g, 7.08 mmol) in DCM (40 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0% to 15% EtOAc in hexane] ethyl 2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy) phenyl)acetate (187d) (2.10 g, 87% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.33-7.17 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.95-6.86 (m, 1H), 6.76 (s, 1H), 5.12 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 1.86-1, 57 (m, 2H), 1.08 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H); MS (ESI+): 501.2 (M+Na).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetate (187e).

Compound 187e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d) (500 mg, 1 .05 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (294 mg, 1.57 mmol), tripotassium phosphate (378 mg, 1.78 mmol) in water (0.6 ml ), tricyclohexylphosphine (92 mg, 0.35 mmol) and Pd ₂ (dba) ₃ (96 mg, 0.105 mmol) in an Ar atmosphere when heated at 125 °C for 45 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0 to 10% methanol in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2propylbenzofuran-5-yl )methoxy)phenyl)acetate (187e) (32 mg, 7% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H ), 7.50-7.42 (m, 2H), 7.38 (d, J=7.7 Hz, 1H), 7.30-7.18 (m, 2H), 7.11 (d, J=8.2 Hz, 1H), 6.90 (t, J=7.7 Hz, 1H), 6.67 (s, 1H), 5.21 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.62 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 1.84-1, 64 (m, 2H), 1.020.93 (m, 6H); MS (ESI+): 458.3 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (187f).

Compound 187f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate ( 187e) (30 mg, 0.066 mmol) in MeOH/THF (12 mL each), using a solution of lithium hydroxide monohydrate (10 mg, 0.238 mmol) in water (4 mL). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 10% MeOH in DCM), 2-(2-((7-(3(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy )phenyl)acetic acid (187f) (17 mg, 60% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H ), 7.56 (d, J=1.5 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.16-7.00 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.81 (t, J=7.3 Hz, 1H), 6.68 (s , 1H), 5.24 (s, 2H), 4.00 (s, 2H), 3.38 (s, 2H), 2.79 (t, J=7.4 Hz, 2H), 1.83 -1.62 (m, 2H),

- 261 045626

0.98 (t, J=7.4 Hz, 3H); MS (ESI+): 430.3 (M+1); MS (ESI-): 464.3 (M+Cl); purity after HPLC: 98.33%.

Scheme-188 he

187d _188a 188b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (188b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetate (188a).

Compound 188a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d) (2.00 g , 4.18 mmol) in dioxane (30 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (1.41 g, 6.88 mmol), K ₂ CO ₃ solution (1.90 g , 13.75 mmol) in water (5 ml), bis(triphenylphosphine) palladium(P) chloride (484 mg, 0.69 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with methanol in 0% to 10% DCM] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)- 2-propylbenzofuran-5yl)methoxy)phenyl)acetate (188a) (1.85 g); MS (ESI+): 476.4 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (188b).

Compound 188b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl )acetate (188a) ((880 mg, 2.03 mmol) in MeOH/THF (30 mL each), using lithium hydroxide monohydrate (341 mg, 8.12 mmol) in water (7 mL). This gave after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7-(3(aminomethyl )-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetic acid (188b) (220 mg, 25% yield in two steps), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 3H), 7.74-7.61 (m, 3H), 7.42 (t, J=7.7 Hz, 1H), 7.37 (t, J=1.3 Hz, 1H), 7.28-7.15 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.89 (td , J=7.4, 1.1 Hz, 1H), 6.69-6.67 (m, 1H), 5.23 (s, 2H), 4.16 (s, 2H), 3.57 ( s, 2H), 2.73 (t, J=7.4 Hz, 2H), 1.69 (g, J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.66; MS (ESI+): 448.4 (M+1); MS (ESI-): 446.3 (M-1) and 482.4 (M+Cl); purity after HPLC: 99.20%.

Scheme-189

^187d 189a

189b 189c

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (189c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2propylbenzofuran-5-yl)methoxy)phenyl)acetate (189a).

Compound 189a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d) (844 mg, 1 .76 mmol) in dioxane (30 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate (123a ) (1.18 g, 3.53 mmol), K ₂ CO ₃ (732 mg, 5.30 mmol) in water (5 ml), bis(triphenylphosphine) palladium(P) chloride (186 mg, 0.265 mmol) and heating in a nitrogen atmosphere at 100°C for 3.5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0 to 2.5% methanol in DCM] ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl) amino)methyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (189a) (597 mg, 61% yield);

^1H NMR (300 MHz, DMSO-d6) δ 8.62 (dd, J=5.2, 0.8 Hz, 1H), 7.82 (s, 1H), 7.75 (dd, J=5 ,2, 1.7 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.65-7.53 (m, 1H), 7.49 (t, J=6, 2 Hz, 1H), 7.33-7.17 (m, 2H), 7.13-7.08 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H ), 6.73-6.72 (m, 1H), 5.22 (s, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.91 (k, J=7, 1 Hz, 2H), 3.62 (s, 2H), 2.80 (t, J=7.4 Hz, 2H), 1.76 (g, J=7.3 Hz, 2H), 1.39 (s, 9H), 1.04-0.90 (m, 6H); MS (ESI+): 559.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetate (189b).

Compound 189b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2- propylbenzofuran-5yl)methoxy)phenyl)acetate (189a) (575 mg, 1.029 mmol) in DCM (30 ml) using TFA (0.8 ml, 10.29 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-10% methanol in DCM), ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)2- propylbenzofuran-5-yl)methoxy)phenyl)acetate (189b) (402 mg, 85% yield) as a viscous brown solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (dd, J=5.2, 0.8 Hz, 1H), 8.36 (s, 3H), 8.02-8.00 (m , 1H), 7.97 (dd, J=5.3, 1.7 Hz, 1H), 7.70 (dd, J=13.0, 1.6 Hz, 2H), 7.32-7, 18 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.75 (d, J =1.0 Hz, 1H), 5.23 (s, 2H), 4.40-4.23 (m, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.82 (t, J=7.4 Hz, 2H), 1.76 (g, J=7.4 Hz, 2H), 1.02-0.95 (m, 6H) ; MS (ESI+): 459.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (189c).

Compound 189c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy) phenyl)acetate (189b) (385 mg, 0.840 mmol) in THF/MeOH (10 mL each), using a solution of lithium hydroxide monohydrate (141 mg, 3.36 mmol) in water (10 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetic acid (189c) (123 mg, 34% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.3 Hz, 1H), 8.63 (s, 3H), 8.13 (s, 1H), 8.04 ( dd, J=5.4, 1.7 Hz, 1H), 7.75 (s, 2H), 7.31-7.17 (m, 2H), 7.11-7.04 (m, 1H) , 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.75-6.73 (m, 1H), 5.26 (s, 2H), 4.40-4.27 (m, 2H), 3.60 (s, 2H), 2.82 (t, J=7.4 Hz, 2H), 1.76 (g, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H); MS (ESI+): 431.2 (M+1); MS (ESI-): 429.3 (M-1); purity after HPLC: 96.66%.

Scheme-190

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (190c).

Stage-1. Preparation of ethyl 2-(2-((2-propyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (190a) .

Compound 190a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d) (5.00 g, 10.45 mmol) using bis(pinacolato)diboron (3.98 g, 15.68 mmol), potassium acetate (3.08 g, 31.36 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (761 mg, 1.04 mmol) in anhydrous dioxane (120 ml) under Ar by heating at 90°C for 14 h. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with ethyl acetate in hexane from 0% to 10%] ethyl 2-(2-((2-propyl-7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl) methoxy)phenyl)acetate (190a) (1.84 g, not particularly pure, used as is in next step).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetate (190b).

Compound 190b was prepared according to the procedure described in step-3 of scheme-1 ethyl 2-(2-263 045626 ((2-propyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (190a) (1.162 g, 2.428 mmol) in dioxane (30 ml) using (3-fluoro-4-iodopyridin-2-yl)methanamine (113a ) (0.510 g, 2.024 mmol), bis(triphenylphosphine) palladium(II) chloride (245 mg, 0.304 mmol) and a solution of K ₂ CO ₃ (839 mg, 6.07 mmol) in water (5 ml) in an Ar atmosphere at heating at 100°C for 3.5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with DMA80 in 0% to 20% DCM] ethyl 2-(2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl) -2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (190b) (70 mg, 2.7% in two steps);

1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=5.0 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.60 (t, J =5.3 Hz, 1H), 7.44-7.42 (m, 1H), 7.34-7.19 (m, 2H), 7.13-7.09 (m, 1H), 6, 91 (td, J=7.4, 1.1 Hz, 1H), 6.73-6.71 (m, 1H), 5.22 (s, 2H), 3.99-3.87 (m, 4H), 3.61 (s, 2H), 2.75 (t, J=7.3 Hz, 2H), 1.70 (g, J=7.3 Hz, 2H), 1.02-0, 88 (m, 6H); MS (ESI+): 477.25 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5yl)methoxy)phenyl)acetic acid (190c).

Compound 190c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl )methoxy)phenyl)acetate (190b) (23 mg, 0.546 mmol) THF/MeOH (3 ml each), using lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetic acid (190c) (2 mg, 3.27%), HCl salt, as a fluffy white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=5.0 Hz, 1H), 8.42 (s, 3H), 7.84-7.74 (m, 2H), 7.49 (s, 1H), 7.27-7.17 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.3 Hz , 1H), 6.73 (s, 1H), 5.25 (s, 2H), 4.46-4.32 (m, 2H), 3.57 (s, 2H), 2.78-2, 73 (m, 2H), 1.86-1.56 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 128.55; 449.2 (M+1); purity after HPLC: 91.91%.

Scheme-191

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5 yl)methoxy)phenyl)acetic acid (191h).

Stage-1. Preparation of (E/Z)-methyl 3-bromo-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (191b).

To a solution of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (191a) (1 g, 3.66 mmol; CAS No. 160753-84-4) in ethanol (30 ml) and dichloromethane (30 ml) at room temperature was added aminooxysulfonic acid (0.621 g, 5.49 mmol) and stirred for 24 hours. The reaction mixture was quenched with a solution of sodium bicarbonate (1.538 g, 18.31 mmol) in water (20 ml) and stirred at RT for 6 hours. Reaction mixture filtered to remove separated solids and the filtrate was extracted with ethyl acetate (3x50 ml). The organic layers were combined, washed with water, brine, dried, filtered and concentrated in vacuo to give (E/Z)-methyl 3-bromo-4-hydroxy-5-(1(hydroxyimino)ethyl)benzoate (191b) (700 mg, 66.4% yield), which was used directly in the next step without further purification;

1H NMR (300 MHz, DMSO-d6) δ 13.48 (s, 1H), 12.16 (d, J=19.2 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H ), 8.06 (s, 1H), 3.84 (s, 3H), 2.33 (s, 3H); MS (ESI+): 290.00; 288.00 (M+1), (ESI-): 288.10, 286.10 (M-1).

Stage-2. Preparation of methyl 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylate (191c)

A solution of (E/Z)-methyl 3-bromo-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (191b) (640 mg, 2.221 mmol) and carbonyldiimidazole (720 mg, 4.44 mmol) in tetrahydrofuran (10 ml) was heated at reflux for 90 min. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water and acidified with conc. HCl. The solution was extracted three times with EtOAc.

The organic layers were combined, washed with water, brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography

[silica gel (40 g), eluted with ethyl acetate and hexanes] to give methyl 7-bromo-3methylbenzo[d]isoxazole-5-carboxylate (191c) (369 mg, 62% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=1.4 Hz, 1H), 8.35 (d, J=1.4 Hz, 1H), 3.91 (s, 3H ), 2.63 (s, 3H).

Stage-3. Preparation of 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylic acid (191d).

Compound 191d was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylate (191c) (340 mg, 1.259 mmol) in MeOH/THF (10 ml each) using a solution of lithium hydroxide monohydrate (90 mg, 3.78 mmol) in water (2 ml) This gave, upon workup, 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylic acid (191d) ( 313 mg, 97% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.48 (s, 1H), 8.45 (d, J=1.4 Hz, 1H), 8.31 (d, J=1.4 Hz , 1H), 2.62 (s, 3H).

Stage-4. Preparation of (7-bromo-3-methylbenzo[d]isoxazol-5-yl)methanol (191e).

Compound 191e was prepared according to the procedure described in step-1 of Scheme-23 from 7bromo-3-methylbenzo[d]isoxazole-5-carboxylic acid (191d) (300 mg, 1.172 mmol) using Nmethylmorpholine (0.155 ml, 1.406 mmol) in THF (10 ml), isobutyl chloroformate (0.185 ml, 1.406 mmol) and NaBH ₄ (133 mg, 3.51 mmol) in water (1 ml).

This gave, after work-up and purification by flash column chromatography [silica gel (25 g), eluted with methanol in DCM 0% to 100%] (7-bromo-3methylbenzo[d]isoxazol-5-yl)methanol (191e ) (190 mg, 67% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.83 (m, 1H), 7.78 (m, 1H), 5.47 (t, J=5.7 Hz, 1H), 4.62 (dt , J=5.7, 0.8 Hz, 2H), 2.56 (s, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-bromo-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (191f).

Compound 191f was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-3-methylbenzo[d]isoxazol-5-yl)methanol (191e) (180 mg, 0.744 mmol) in DCM (15 ml) using triphenylphosphine (215 mg, 0.818 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (167 mg, 0.929 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 300 mg, 0.818 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-3-methylbenzo[d]isoxazol-5yl) methoxy)phenyl)acetate (191f) (190 mg, 63% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.31-7.19 (m, 2H), 7.08 (dd, J=8.2, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3, 64 (s, 2H), 2.58 (s, 3H), 1.06 (t, J=7.1 Hz, 3H); MS (ESI+): 406.10; 404.05 (M+1).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetate (191g).

Compound 191g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (191f) ( 187 mg, 0.463 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (139 mg, 0.740 mmol), bis(triphenylphosphine) palladium(P) chloride (48.7 mg, 0.069 mmol ) and potassium carbonate (192 mg, 1.388 mmol) in water (1 ml) under Ar atmosphere by heating at 100°C for 5 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (25 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (191g) (30 mg, 15% yield); MS (ESI+): 431.20 (M+1).

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetic acid (191h).

Compound 191h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy) phenyl)acetate (191g) (25 mg, 0.058 mmol) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (6 mg, 0.232 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetic acid (191h) (8 mg, 34% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.31 (br.s, 3H), 8.06 (d, J=1.8 Hz, 1H), 7.97 (m, 3H), 7.69 -7.53 (m, 2H), 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.16 (s, 2H), 3.62 (s, 2H), 2.61 (s, 3H); MS (ESI+): 403.2 (M+1), (ESI-): 401.3 (M-1).

- 265 045626

Scheme-192

192f

Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-1 -(methylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (192e).

Stage-1. Preparation of methyl 4-bromo-1-(methylsulfonyl)-1H-indole-6-carboxylate (192a).

Compound 192a was prepared according to the procedure described in step-1 of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g, 7.87 mmol) in DMF (15 ml) using NaH (60% in mineral oil, 0.94 g, 23.61 mmol) and methanesulfonyl chloride (1.83 ml, 23.61 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH=9:1 in 0% to 50% hexane] methyl 4-bromo-1-(methylsulfonyl)-1H -indole-6carboxylate (192a) (1.4 g, 54% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.48 (t, J=1.0 Hz, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.96 (d, J=3.7 Hz, 1H), 6.90 (dd, J=3.7, 0.9 Hz, 1H), 3.91 (s, 3H), 3.59 (s, 3H); MS (ESI-): 334.0, 332.1 (M-1).

Stage-2. Preparation of (4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methanol (192b).

Compound 192b was prepared according to the procedure described in step-2 of Scheme-76 from methyl 4-bromo-1-(methylsulfonyl)-1H-indole-6-carboxylate (192a) (0.8 g, 2.41 mmol) in THF (8 ml) using LiBH ₄ (2.41 ml, 7.23 mmol) and MeOH (0.29 ml, 7.23 mmol). This resulted in (4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methanol (192b) (0.57 g, 78% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.84 (p, J=0.9 Hz, 1H), 7.67 (d, J=3.7 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 6.74 (dd, J=3.7, 0.8 Hz, 1H), 5.42 (t, J=5.8 Hz, 1H), 4.63 ( d, J=5.7 Hz, 2H), 3.48 (s, 3H).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (192c).

Compound 192c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-(methylsulfonyl)-1H-indol-6-yl)methanol (192b) (0.57 g, 1.87 mmol) in toluene (8 ml) using triphenylphosphine (0.639 g, 2.436 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.44 g, 2.44 mmol) and (E)-diazen-1,2 -diylbis(piperidin-1-ylmethanone) (0.62 g, 2.44 mmol) in toluene (5 ml). This resulted in, after workup and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH (9:1) in hexane from 0% to 10% for 40 min, then 10% to 50%] ethyl 2-(2-((4bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (192c) (0.68 g, 78% yield) as a yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.95 (t, J=1.0 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.61 (d, J =1.2 Hz, 1H), 7.30-7.19 (m, 2H), 7.10 (dd, J=8.2, 1.1 Hz, 1H), 6.92 (td, J= 7.4, 1.1 Hz, 1H), 6.78 (dd, J=3.7, 0.8 Hz, 1H), 5.24 (s, 2H), 4.03 (k, J=7 .1 Hz, 2H), 3.63 (s, 2H), 3.52 (s, 3H), 1.08 (t, J=7.1 Hz, 3H). MS (ESI-): 466.1, 464.2 (M1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (192d).

Compound 192d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (192c ) (0.23 g, 0.49 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.14 g, 0.74 mmol), K ₂ CO ₃ (0. 10 g, 0.74 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.05 g, 0.07 mmol) in an Ar atmosphere when heated at 90°C for 2 hours in oil bath. This led to getting

- 266 045626 after work-up and purification by flash column chromatography [silica gel (12 g), eluted

MeOH in DCM 0% to 20%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (192d) ( 0.04 g, 15% yield) as a white solid; MS (ESI+):

493.2 (M+1).

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1 -(methylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (192e).

Compound 192e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl) methoxy)phenyl)acetate (192d) (0.04 g, 0.08 mmol) in MeOH/THF (3 ml, 1:1), using a solution of lithium hydroxide monohydrate (3 mg, 0.08 mmol) in water (0 .5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (4 g), eluted with 0% to 50% MeOH in DCM] 2-(2-((4-(3(aminomethyl)phenyl)-1-( methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (192e) (0.02 g, 43% yield) as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.12 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.72-7.64 (m, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.15-7.05 (m, 2H), 7. 02 (s, 1H), 6.97 (m, 1H), 6.81 (t, J=7.2 Hz, 1H), 5.31 (s, 2H), 4.01 (s, 2H), 3.51 (s, 3H), 3.40 (s, 2H); MS (ESI+): 465.2 (M+1), MS (ESI-): 463.2 (M-1) and methyl 2(2-((4-(3 -(aminomethyl)phenyl)-1 - (methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (192f (0.02 g, 58% yield) as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 7.95 (s, 1H), 7.70-7.65 (m, 3H), 7.55-7.49 (m, 2H), 7.49 -7.40 (m, 1H), 7.30-7.19 (m, 2H), 7.17-7.12 (m, 1H), 6.96-6.87 (m, 2H), 5 .30 (s, 2H), 3.92 (s, 2H), 3.66 (s, 2H), 3.50 (s, 3H), 3.45 (s, 3H); MS (ESI+) 479.2 (M+1).

Scheme-193

Preparation of 2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (193c).

Stage-1. Preparation of ethyl 2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (193b).

Compound 193b was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (200 mg, 0.514 mmol) in dioxane (2 ml) and H2O (1 ml), using (4-(aminomethyl)phenyl)boronic acid hydrochloride (193a) (106 mg, 0.565 mmol; CAS No. 75705-21-4), bis(triphenylphosphine)palladium(P ) chloride (36.1 mg, 0.051 mmol) and K2CO3 (213 mg, 1.541 mmol) under nitrogen and heating at 80°C for 16 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel eluted with 0-15% MeOH in DCM], ethyl 2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl )acetate (193b) (73 mg, 34% yield) as a pale yellow semi-solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.86-7.79 (m, 2H), 7.68 (d, J=1 .7 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.32-7.19 (m, 2H ), 7.12 (d, J=8.1 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz , 1H), 5.24 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.79 (s, 2H), 3.63 (s, 2H), 0.99 (t, J=7.1 Hz, 3H). MS (ESI+): 416 (M+1), 438 (M+Na).

Stage-2. Preparation of 2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (193c).

Compound 193c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (193b) ( 70 mg, 0.168 mmol) in THF (1 ml) and MeOH (2 ml), using NaOH (34 mg, 0.842 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (4-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (193c) (50 mg, 77% yield) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 8.02-7.89 (m, 2H), 7.75 (d, J=1.6 Hz, 1H), 7.69-7.59 (m, 3H), 7.31-7.18 (m, 2H), 7.10 (d, J= 7.8 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.11 (s, 2H), 3.59 (s, 2H). MS (ESI+): 388 (M+1).

- 267 045626

Scheme-194

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (194d).

Stage-1. Preparation of tert-butyl 3-((((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2- yl)methyl)amino)methyl)piperidine-1-carboxylate (194b).

Compound 194b was prepared according to the procedure described in step-4 of Scheme-138 from 2-(2((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran- 5yl)methoxy)phenyl)acetate (138c) (400 mg, 0.71 mmol) and tert-butyl 3-(aminomethyl)piperidine-1carboxylate (194a) (608 mg, 2.84 mmol; CAS No. 162167-97-7 ) in ACN (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] tert-butyl 3-((((7-(3-(((tert -butoxycarbonyl)amino)methyl)phenyl)-5-((2(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methyl)amino)methyl)piperidine-1-carboxylate (194b) (330 mg, 63% yield) as a clear oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.78-7.71 (m, 2H), 7.62-7.59 (m, 1H), 7.52-7.43 (m, 3H ), 7.32-7.19 (m, 3H), 7.13-7.08 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6, 78 (s, 1H), 5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.96-3.83 (m, 5H), 3.77-3 .68 (m, 1H), 3.62 (s, 2H), 2.82-2.70 (m, 1H), 2.46-2.40 (m, 2H), 2.33-2.21 (m, 1H), 1.79-1.68 (m, 1H), 1.61-1.48 (m, 2H), 1.37 (d, J=8.7 Hz, 18H), 1, 32-1.20 (m, 2H), 1.17-1.04 (m, 1H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 742.4 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (194c).

Compound 194c was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 3-((((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2- (2-ethoxy-2oxoethyl)phenoxy)methyl)benzofuran-2-yl)methyl)amino)methyl)piperidine-1-carboxylate (194b) (320 mg, 0.43 mmol) in DCM (10 ml) using TFA ( 0.332 ml, 4.31 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate ( 194c) (211 mg, 90% yield) as a yellow oil; MS (ESI+): 542.4 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (194d).

Compound 194d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3 -(aminomethyl)phenyl)-2-(((piperidin-3 -ylmethyl)amino)methyl )benzofuran-5 yl)methoxy)phenyl)acetate (194c) (169 mg, 0.31 mmol) in THF (6 ml) and methanol (6 ml), using lithium hydroxide monohydrate solution (17 mg, 0.41 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-(((piperidin-3ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (194d) (58 mg, 36% yield) as a white solid ;

^1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H, D2O replaceable), 10.03 (s, 2H, D2O replaceable), 9.409.26 (m, 1H, D2O replaceable), 9, 23-9.04 (m, 1H, D2O replaceable), 8.66 (s, 3H, D2O replaceable), 8.30-8.22 (m, 1H), 7.97 (dt, J=6.8 , 2.1 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.61-7.52 (m , 2H), 7.28-7.17 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.44 (s, 2H), 4.17 (d, J=5.8 Hz, 2H), 3.60 (s, 2H), 3.47 ( d, J=10.9 Hz, 2H), 3.15 (d, J=12.1 Hz, 1H), 3.07-2.87 (m, 2H), 2.79-2.64 (m , 2H), 2.45-2.29 (m, 1H), 1.95-1.85 (m, 1H), 1.83-1.60 (m, 2H), 1.36-1.17 (m, 1H); MS (ESI+): 514.3 (M+1); (ESI-): 512.4 (M1).

- 268 045626

Scheme-195

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (195d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((3-((tertbutoxycarbonyl)amino)propyl)amino)methyl)benzofuran-5 -yl)methoxy)phenyl)acetate (195b).

Compound 195b was prepared according to the procedure described in step-4 of Scheme-138 from 2-(2((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran- 5yl)methoxy)phenyl)acetate (138c) (400 mg, 0.71 mmol) and tert-butyl (3-aminopropyl)carbamate (195a) (494 mg, 2.84 mmol; CAS No. 75178-96-0) in ACN (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)-2-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (195b) (368 mg, 74% yield) in the form of a clear oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.78-7.70 (m, 2H), 7.60 (s, 1H), 7.52-7.43 (m, 3H), 7. 32-7.24 (m, 2H), 7.24-7.18 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.95-6.87 (m, 1H), 6.82-6.75 (m, 2H), 5.76 (s, 1H), 5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.62 (s, 2H), 2.96 (k, J=6.5 Hz, 2H), 2.61-2.52 (m, 2H), 1.55 (k, J=6.9 Hz, 2H), 1.39 (s, 9H), 1.34 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 702.4 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (195c).

Compound 195c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((3 -((tert-butoxycarbonyl)amino)propyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (195b) (365 mg, 0.52 mmol) in DCM (10 ml), using TFA (0.40 ml , 5.20 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (195c) as a clear oil, which was used as is in the next step; MS (ESI+) 502.3 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (195d).

Compound 195d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran -5-yl)methoxy)phenyl)acetate (195c) (266 mg, 0.53 mmol) in THF (6 ml) and methanol (6 ml), using lithium hydroxide monohydrate solution (28.9 mg, 0.69 mmol ) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (195d) (138 mg, 55% yield), HCl salt, as white solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H, D ₂ O replaceable), 9.82 (s, 2H, D ₂ O replaceable), 8.52 (s, 3H, D ₂ O replaceable), 8.16-8.13 (m, 1H, D ₂ O replaceable), 8.12-7.98 (m, 3H), 7.79 (d, J=1.6 Hz, 1H) , 7.71 (d, J=1.6 Hz, 1H), 7.65-7.47 (m, 2H), 7.29-7.18 (m, 3H), 7.12-7.03 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.46 (s, 2H), 4.18 (d, J=5.1 Hz, 2H), 3.60 (s, 2H), 3.10 (s, 2H), 2.98-2.81 (m, 2H), 2.07-1.93 (m , 2H); MS (ESI+): 474.3 (M+1); (ESI-): 472.4 (M-1).

- 269 045626

Scheme-196

Preparation of 2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (196d).

Stage-1. Preparation of ethyl 2-(2-((2-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5-yl)methoxy)phenyl)acetate (196b).

Compound 196b was prepared according to the procedure described in step-4 of Scheme-138 from 2-(2((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran- 5yl)methoxy)phenyl)acetate (138c) (400 mg, 0.709 mmol) and tert-butyl (2-aminoethyl)carbamate (196a) (454 mg, 2.84 mmol; CAS No. 57260-73-8) in ACN ( 5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((2-(((2-((tert -butoxycarbonyl)amino)ethyl)amino)methyl)-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (196b) (323 mg, 66% yield) in the form of a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.79-7.70 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.52-7.43 (m , 3H), 7.32-7.25 (m, 2H), 7.25-7.19 (m, 1H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.83-6.72 (m, 2H), 5.21 (s, 2H), 4.23 (d, J= 6.2 Hz, 2H), 3.99-3.79 (m, 4H), 3.62 (s, 2H), 3.04 (k, J=6.2 Hz, 2H), 2.61 ( t, J=6.4 Hz, 2H), 2.29 (s, 1H), 1.39 (s, 9H), 1.34 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 688.4 (M+1).

Stage-2. Preparation of ethyl 2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (196c).

Compound 196c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-7-( 3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (196b) (318 mg, 0.46 mmol) in DCM (10 ml), using TFA (0.36 ml , 4.62 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (196c) (224 mg, 99% yield) as a clear oil; MS (ESI+): 488.3 (M+1).

Stage-3. Preparation of 2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (196d).

Compound 196d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran -5-yl)methoxy)phenyl)acetate (196c) (185 mg, 0.38 mmol) in THF (6 ml) and methanol (6 ml), using lithium hydroxide monohydrate solution (20.70 mg, 0.49 mmol ) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((2- (((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (196d) (90 mg, 52% yield), HCl salt, as white solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 12.29 (s, 1H, D2O replaceable), 10.45 (s, 2H, D2O replaceable), 8.61 (d, J=30.3 Hz, 6H , D2O replaceable), 8.31 (d, J=1.9 Hz, 1H), 8.03-7.93 (m, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.63-7.51 (m, 2H), 7.28-7.20 (m, 3H), 7.09 (d, J= 8.1 Hz, 1H), 6.90 (td, J=7.4, 1.0 Hz, 1H), 5.28 (s, 2H), 4.54 (s, 2H), 4.21 ( k, J=5.7 Hz, 2H), 3.61 (s, 2H), 3.33 (s, 4H); MS (ESI+): 460.2 (M+1); (ESI-): 458.4 (M-1).

- 270 045626

Scheme-197

Preparation of 2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (197c).

Stage-1. Preparation of ethyl 2-(4-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (197a) .

To a degassed solution of ethyl 2-(4-bromo-2-((7-(3-((tertbutoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (182b) (0.250 g, 0.421 mmol) in toluene (10 ml), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-PHOS, 0.020 g, 0.042 mmol), tert-butyl carbamate (0.074 g, 0.631 mmol), Pd ₂ was added (dba) ₃ (0.019 g, 0.021 mmol), cesium carbonate (0.137 g, 0.421 mmol), and the mixture was heated at 95°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 ml), filtered through celite layer, celite layer was rinsed with EtOAc (2x50 ml). The combined organic layers were dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] to give ethyl 2-(4-((tert-butoxycarbonyl)amino)-2-((7-(3-( ((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (197a) (0.221 g, 83% yield) as a pale brown wax; MS (ESI+): 531.3 (M+1, -Boc).

Stage-2. Preparation of ethyl 2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (197b).

Compound 197b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (197a) (0.201 g, 0.319 mmol) in DCM (10 ml) using TFA (0.491 ml, 6.37 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 100%] ethyl 2-(4-amino-2-((7-(3(aminomethyl)phenyl )benzofuran-5-yl)methoxy)phenyl)acetate (197b) (0.102 g, 59% yield) pale yellow solid as TFA;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (br.s, 3H, D2O replaceable), 8.12 (d, J=2.2 Hz, 1H), 8.02-7.97 ( m, 1H), 7.95-7.88 (m, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.67-7.49 (m, 3H), 7.08 (d, J=2.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.32 (d, J=8.0 Hz , 1H), 5.16 (s, 2H), 4.16 (d, J=5.7 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.49 (s , 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -73.82; MS (ESI+): 431.20 (M+1).

Stage-3. Preparation of 2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (197c).

Compound 197c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (197b) (0.090 g, 0.209 mmol) in THF (4 mL) and methanol (8 mL) using 2 M LiOH (0.523 mL, 1.045 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 100%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(4-amino-2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (197c) ( 0.036 g, 43% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d ₆ ) δ 12.32 (br.s, 1H, D2O replaceable), 10.12 (br.s, 2H, D2O replaceable), 8.53 (s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 8.09-8.02 (m, 1H), 7.99-7.90 (m, 1H), 7.77 (d , J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.63-7.53 (m, 2H), 7.29 (d, J=8, 0 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.06 (d, J=2.2 Hz, 1h), 6.86 (dd, J=7.9, 1.9 Hz, 1H), 5.27 (s, 2H), 4.14 (k, J=5.8 Hz, 2H), 3.61 (s, 2H); MS (ESI+): 403.2 (M+1); MS (ESI-): 401.3 (M-1); purity after HPLC: 99.34%.

- 271 045626

Scheme-198

198b ^198c

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (198b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (198a).

Compound 198a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (192c ) (0.23 g, 0.49 mmol) in dioxane (4 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.15 g, 0.74 mmol), K2CO3 (0.10 g, 0.74 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.05 g, 0.07 mmol) in Ar atmosphere when heated at 85°C for 2 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 20% MeOH in DCM] ethyl 2-(2-((4-(3-(aminomethyl)-2 -fluorophenyl)-1(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (198a) (0.17 g, 67% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.99 (s, 1H), 7.64 (d, J=3.7 Hz, 1H), 7.58 (t, J=7.4 Hz , 1H), 7.41 (s, 1H), 7.38-7.09 (m, 5H), 6.95-6.85 (m, 1H), 6.61 (t, J=3.3 Hz, 1H), 5.29 (s, 2H), 3.93-3.78 (m, 4H), 3.61 (s, 2H), 3.51 (s, 3H), 0.95 (t , J=7.1 Hz, 3H); MS (ESI+): 511.2 (M+1); MS (ESI-): 509.3 (M-1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (198b).

Compound 198b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (198a) (0.13 g, 0.25 mmol) in MeOH/THF (4 ml, 1:1), using lithium hydroxide monohydrate solution (0.02 g, 0.50 mmol ) in water (1.0 ml). This gave, after work-up and purification by flash column chromatography [silica gel (4 g), eluted with 0% to 50% MeOH in DCM] 2-(2-((4-(3(aminomethyl)-2-fluorophenyl)- 1 -(methylsulfonyl)-1 H-indol-6-yl)methoxy)phenyl)acetic acid (198b) (0.05 g, 40% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (s, 1H), 7.66 (d, J=3.7 Hz, 1H), 7.58 (t, J=7.3 Hz, 1H), 7.52 (s, 1H), 7.48 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.68 (s, 1H) , 5.32 (s, 2H), 3.97 (s, 2H), 3.54 (s, 2H), 3.51 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 120.18; MS (ESI+) 483.2 (M+1), MS (ESI-) 481.3 (M-1). and methyl 2-(2-((4-(3-(aminomethyl)-2fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (198c) (0.03 g, 22 % yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (s, 1H), 7.67 (d, J=3.7 Hz, 1H), 7.61 (t, J=7.0 Hz, 1H), 7.49 (t, J=6.7 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.31-7, 19 (m, 2H), 7.18-7.10 (m, 1H), 6.96-6.87 (m, 1H), 6.67 (t, J=3.4 Hz, 1H), 5 .30 (s, 2H), 4.03 (s, 2H), 3.65 (s, 2H), 3.52 (s, 3H), 3.44 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -120.43; MS (ESI+): 497.2 (M+1).

- 272 045626

Receipt

Scheme-199

2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (199f).

Stage-1. Preparation of methyl 7-bromo-2-(trifluoromethyl)benzofuran-5-carboxylate (199b).

Compound 199b was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (25 g, 81 mmol; CAS: 41727-47-3) in pyridine ( 100 ml) using 3,3,3-trifluoroprop-1-yne (8 g, 85 mmol; CAS No. 661-54-1) and copper(T) oxide (11.5 g, 80 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (220 g), eluted with 0% to 40% EtOAc in hexane] methyl 7-bromo-2-(trifluoromethyl)benzofuran-5-carboxylate (199b) (9 .4 g, 36% yield) as a white solid.

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (d, J=1.5 Hz, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.03 (m, 1H), 3.92 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -63.74.

Stage-2. Preparation of (7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methanol (199c).

Compound 199c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-(trifluoromethyl)benzofuran-5-carboxylate (199b) (3 g, 9.29 mmol) in THF (36 ml ), using LiBH ₄ (7 ml, 4 M, 28.0 mmol) and MeOH (1.12 ml, 27.7 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexane 10 to 60%] followed by purification by reverse phase chromatography [C18 (150 g), eluted with ACN in water ( with 0.1% HCl) 0% to 100%] (7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methanol (199c) (1.85 g, 68% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.92 (k, J=1.2 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H), 5.47 (s, 1H), 4.62 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -63.49.

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (199d).

Compound 199d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-(trifluoromethyl)benzofuran-5-yl)methanol (199c) (1.80 g, 6.10 mmol) in DCM ( 35 ml), using triphenylphosphine ((1.67 g, 6.37 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.40 g, 7.77 mmol) and di-(4chlorobenzyl) azodicarboxylate ( DCAD, 2.53 g, 6.89 mmol) in DCM (8 ml) This gave after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0% to 40% ]ethyl 2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (199d) (2.28 g, 82% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 7.97 (k, J=1.2 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.32-7.20 (m, 2H), 7.08 (dd, J=8.2, 1.1 Hz, 1H), 6.93 (td, J =7.4, 1.1 Hz, 1H), 5.24 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -63.53.

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (199e).

Compound 199e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (199d) (360 mg, 0.787 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (159 mg, 1.053 mmol), solution of K2CO3 (345 mg, 2.496 mmol) in water (0.5 ml), bis(triphenylphosphine)palladium(P) chloride (84 mg, 0.120 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (199e) (297 mg, 78% yield) as a pale yellow oil. The analytical sample was obtained by further purification by reverse phase chromatography column [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to obtain compound 199e, HCl salt, as a white solid.

- 273 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (s, 3H), 7.90 (k, J=1.2 Hz, 1H), 7.87-7.79 (m, 3H), 7.76 (d, J=1.6

Hz, 1H), 7.62-7.54 (m, 2H), 7.25-7.12 (m, 2H), 7.05 (dd, J=8.2, 1.1 Hz, 1H) , 6.86 (td, J=7.4, 1.1 Hz, 1H), 5.23 (s,

2H), 4.07 (s, 2H), 3.87 (k, J=7.1 Hz, 2H), 3.58 (s, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ

-63.34. MS (ESI+): 484.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (199f).

Compound 199f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl )acetate (199e) (200 mg, 0.414 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (84 mg, 2.0 mmol) in water (2.0 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (199f) (43 mg, 23% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 12.13 (s, 1H), 8.66 (s, 3H), 7.98 (s, 1H), 7.95-7.83 (m, 4H ), 7.71-7.56 (m, 2H), 7.28-7.19 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H), 3.62 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -63.37. MS (ESI+): 456.2 (M+1); MS (ESI-): 454.3 (M-1).

Scheme-200

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (200e).

Stage-1. Preparation of methyl 7-iodo-2-isobutylbenzofuran-5-carboxylate (200a).

Compound 200a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (16.80 g, 41.6 mmol) in pyridine (50 ml) using 4-methylpent-1yne (4.90 ml, 41.6 mmol) and copper(I) oxide (2.98 g, 20.8 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0% to 10% EtOAc in hexanes], methyl 7-iodo-2-isobutylbenzofuran-5-carboxylate (200a) (6.57 g, 44 % exit);

1H NMR (500 MHz, DMSO-d6) δ 8.19 (d, J=1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 6.91-6.88 (m, 1H), 3.87 (s, 3H), 2.73-2.70 (m, 2H), 2.13-1.95 (m, 1H), 0.97 (d, J=6 .7 Hz, 6H).

Stage-2. Preparation of (7-iodo-2-isobutylbenzofuran-5-yl)methanol (200b).

Compound 200b was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-iodo-2-isobutylbenzofuran-5-carboxylate (200a) (6.28 g, 17.53 mmol) in THF (60 ml) using LiBH ₄ (17.53 ml, 35.1 mmol) and MeOH (1.419 ml, 35.1 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0 to 25% EtOAc in hexane] (7-iodo-2-isobutylbenzofuran-5-yl)methanol (200b) (5.73 g, 99% yield) in the form of a clear oil.

1H NMR (300 MHz, DMSO-d6) δ 7.56-7.51 (m, 1H), 7.46-7.44 (m, 1H), 6.73-6.72 (m, 1H), 5.25 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H), 2.66 (dd, J=7.0, 0.8 Hz, 2H ), 2.12-1.94 (m, 1H), 0.95 (d, J=6.7 Hz, 6H).

Stage-3. Preparation of ethyl 2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c).

Compound 200c was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-isobutylbenzofuran-5-yl)methanol (200b) (5.60 g, 16.96 mmol) in DCM (100 ml) using triphenylphosphine (6.23 g, 23.75 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (4.28 g, 23.75 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 8, 72 g, 23.75 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0% to 20% EtOAc in hexane] ethyl 2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy) phenyl)acetate (200c) (6.17 g, 74% yield) as an off-white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.32-7, 17 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.3, 1.0 Hz, 1H), 6.76 (s, 1H ), 5.12 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 2.68 (d, J=7.0 Hz, 2H ), 2.13-1.95 (m, 1H), 1.07 (t, J=7.1 Hz, 3H), 0.96 (d, J=6.6 Hz, 6H); MS (ESI+): 515.1

- 274 045626 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetate (200d).

Compound 200d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c) (750 mg, 1.523 mmol) in dioxane (20 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (469 mg, 2.285 mmol), solution of K ₂ CO ₃ (632 mg, 4.57 mmol) in water (5 ml), bis(triphenylphosphine) palladium(P) chloride (1.231 g, 1.523 mmol) by heating at 100°C for 3.5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with DMA80 in 0% to 20% DCM] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)- 2-isobutylbenzofuran5-yl)methoxy)phenyl)acetate (200d) (79 mg). MS (ESI+): 490.3 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (200e).

Compound 200e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl )acetate (200d) (70 mg, 0.143 mmol) in MeOH/THF (5 mL each), using a solution of lithium hydroxide monohydrate (24 mg, 0.572 mmol) in water (5 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetic acid (200e) (16 mg, 2.5% in two steps), HCl salt, as a fluffy white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 3H), 7.72-7.60 (m, 3H), 7.42 (t, J=7.7 Hz, 1H), 7.37 (s, 1H), 7.28-7.16 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.69 (s, 1H), 5.23 (s, 2H), 4.15 (s, 2H), 3.57 (s, 2H), 2.63 (d, J=7.0 Hz, 2H), 2.16-1.87 (m, 1H), 0.93 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.68; MS (ESI+): 462.2 (M+1); purity after HPLC: 99.57%.

Scheme-201 nh ₂ hci

PdCI ₂ (PPh ₃ ) ₂

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetic acid (201b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetate (201a).

Compound 201a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c) (1.0 g , 2.031 mmol) in dioxane (20 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.571 g, 3.05 mmol), a solution of K2CO3 (0.842 g, 6.09 mmol) in water ( 5 ml), bis(triphenylphosphine) palladium(P) chloride (0.214 g, 0.305 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 10% MeOH in DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran -5-yl)methoxy)phenyl)acetate (201a) (610 mg) as brown oil; MS (ESI+): 472.3 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (201b).

Compound 201b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate ( 201a) (560 mg, 1.187 mmol) in MeOH/THF (10 mL each), using a solution of lithium hydroxide monohydrate (199 mg, 4.75 mmol) in water (10 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetic acid (201b) (93 mg, 11% in two steps), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.25 (s, 1H), 8.55 (s, 3H), 7.99-7.95 (m, 1H), 7.92 (dt, J =6.6, 2.2 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.62-7.53 (m, 3H), 7.28-7.17 ( m, 2H), 7.11-7.07 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.69 (s, 1H), 5.24 (s, 2H), 4.12 (s, 2H), 3.60 (s, 2H), 2.70 (d, J=7.0 Hz, 2H), 2.20-1.89 (m, 1H), 0.96 (d, J=6.6 Hz, 6H); MS (ESI+): 444.3 (M+1), MS (ESI-): 442.3 (M-1); purity after HPLC: 99.80%.

- 275 045626

Scheme-202

202b 202c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (202c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (202a)

Mixture of ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (182b) (0.306 g, 0.515 mmol), methyl boronic acid (0.046 g, 0.772 mmol), dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.024 g, 0.051 mmol), Pd ₂ (dba) ₃ (0.024 g, 0.026 mmol) in toluene ( 20 ml) and a solution of Na ₂ CO ₃ (0.214 g, 2.02 mmol) in water (2 ml) was degassed and saturated with nitrogen. The reaction mixture was heated at 100°C for 10 h, cooled to room temperature, diluted with EtOAc (100 ml) and saline (50 ml). The aqueous layer was separated, dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with EtOAc in 0% to 100% hexanes] to give ethyl 2-(2-((7(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (202a) (0.183 g, 67% yield) as a pale yellow waxy substance;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.2 Hz, 1H), 7.79-7.66 (m, 3H), 7.54 (d, J=1 .6 Hz, 1H), 7.547.42 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7. 06 (d, J=2.2 Hz, 1H), 7.00-6.93 (m, 1H), 6.77-6.68 (m, 1H), 5.21 (s, 2H), 4 .23 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.30 (s, 3H), 1 .39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 430.2 (M+1, -Boc).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (202b).

Compound 202b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4-methylphenyl)acetate (202a) (0.172 g, 0.325 mmol) in DCM (20 ml) using TFA (0.5 ml, 6.5 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 100% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-4-methylphenyl)acetate (202b) (0.053 g, 0.123 mmol, 38.0% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 7.99-7.87 (m, 2H), 7.73 (d, J=1 .6 Hz, 1H), 7.617.57 (m, 2H), 7.56-7.50 (m, 1H), 7.13-7.05 (m, 2H), 6.98-6.94 ( m, 1H), 6.74 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 430.25 (M+1); MS (ESI-): 428.30 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (202c).

Compound 202c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate ( 202b) (0.05 g, 0.116 mmol) in THF (4 mL) and methanol (8 mL) using LiOH (2M, 0.582 mL, 1.164 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 100%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (202c) (0.022 g, 47% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (br.s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 8.05-7.98 ( m, 1H), 7.93 (dt, J=7.6, 1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.65 (d, J=1 .7 Hz, 1H), 7.63-7.51 (m, 2H), 7.15-7.03 (m, 2H), 6.94 (d, J=1.5 Hz, 1H), 6 .72 (d, J=7.4 Hz, 1H), 5.24 (s, 2H), 4.14 (s, 2H), 3.53 (s, 2H), 2.29 (s, 3H) ; MS (ESI+): 402.20 (M+1); MS (ESI-): 400.30 (M-1).

- 276 045626

Scheme-203

203b 203c

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-4cyclopropylphenyl)acetic acid (203 s).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-cyclopropylphenyl)acetate (203a).

Compound 203a was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (182b) (0.250 g, 0.421 mmol) in toluene (20 ml) and a solution of Na ₂ CO ₃ (0.178 g, 1.682 mmol) in water (2 ml), using cyclopropylboronic acid (0.054 g, 0.631 mmol ), dicyclohexyl(2',6'diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.020 g, 0.042 mmol), Pd ₂ (dba) ₃ (0.019 g, 0.021 mmol) when heated at 100°C for 10 h This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with EtOAc in 0% to 70% hexanes] ethyl 2-(2-((7-(3-((tert-butoxycarbonyl )amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4cyclopropylphenyl)acetate (203a) (0.208 g, 89% yield) as a waxy solid;

Ή NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=2.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.73-7.69 (m, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.54-7.43 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 7, 11-7.01 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.62 (dd, J=7.7, 1.6 Hz, 1H), 5.22 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.55 (s, 2H), 1.97 -1.81 (m, 1H), 1.39 (s, 9H), 1.22-1.13 (m, 3H), 0.95-0.89 (m, 2H), 0.73-0 .64 (m, 2H); MS (ESI+): 456.30 (M+1, loss of Boc).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyclopropylphenyl)acetate (203b).

Compound 203b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4cyclopropylphenyl)acetate (203a) (0.200 g, 0.360 mmol) in DCM (20 ml) using TFA (0.555 ml, 7.20 mmol). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 30 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate (203b) (0.102 g, 62% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.31 (br.s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 7.99 (s, 1H ), 7.94-7.88 (m, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.66-7.50 (m, 3H), 7.11-7, 04 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.63 (dd, J=7.8, 1.6 Hz, 1H), 5.23 (s, 2H ), 4.14 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.55 (s, 2H), 1.96-1.82 (m, 1H), 1 .02-0.87 (m, 5H), 0.73-0.62 (m, 2H); MS (ESI+): 456.27 (M+1), MS (ESI-): 454.20 (M-1); purity after HPLC: 93.97%.

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyclopropylphenyl)acetic acid (203c).

Compound 203c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate ( 203b) (0.083 g, 0.182 mmol) in THF (4 ml) and methanol (8 ml) using 2 M LiOH (0.455 ml, 0.911 mmol). This resulted in, after workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 50% DCM] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetic acid (203c) (0.003 g, 3.85% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.14-8.06 (m, 2H), 7.89 (s, 1H), 7.69 (s, 1H) , 7.49 (t, J=7.7 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6 .95 (d, J=7.5 Hz, 1H), 6.73-6.63 (m, 1H), 6.52 (d, J=7.5 Hz, 1H), 5.25 (s, 2H), 4.01 (s, 2H), 3.33 (s, 2H), 1.90-1.75 (m, 1H), 0.94-0.80 (m, 2H), 0.67 -0.57 (m, 2H); MS

- 277 045626 (ESI+): 428.2 (M+1); MS (ESI-): 426.30 (M-1).

Scheme-204 o

Preparation of 2-(2-((7-(7-aminopyrrolo[2,1-G][1,2,4]triazin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (204e).

Stage-1. Preparation of 4-chloro-7-nitropyrrolo[2,1-1][1,2,4]triazine (204b).

To a stirred solution of 7-nitropyrrolo[2,1-f][1,2,4]triazin-4(1H)-one (204a) (1.0 g, 5.55 mmol, CAS No. 1620778-25-7; obtained in accordance with the procedure described by Kumar, Pradeep et al.; in international application PCT, 2014115171) in toluene (20.0 ml) was added POCl ₃ (3.0 ml), DIPEA (6.0 ml) and heated at 120°C for 3 hours. The reaction mixture was cooled to RT, poured into ice water (20 ml) and extracted with EtOAc (2x100 ml). The combined organic extracts were washed with saturated NaHCO ₃ solution (50.0 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with (0-20%) EtOAc in nhexane] to give 4-chloro-7-nitropyrrolo[2,1-1][1,2,4]triazine (204b) (0.63 g, 57%) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (d, J=1.8 Hz, 1H), 8.72 (s, 1H), 7.76 (d, J=1.9 Hz , 1H).

Stage-2. Preparation of ethyl 2-(2-((7-(7-nitropyrrolo[2,1-G][1,2,4]triazin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (204c).

Compound 204c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (1.0 g, 2.29 mmol) in dioxane (20 ml), using 4-chloro-7-nitropyrrolo[2,1-1][1, 2,4]triazine (204b) (0.54 g, 2.75 mmol; CAS No. 58971-11-2), tripotassium phosphate solution (0.9 g, 4.58 mmol) in DMW (2.0 ml), tricyclohexylphosphine (0.12 g, 0.45 mmol) and Pd ₂ (dba) ₃ (0.31 g, 0.34 mmol) heating under nitrogen at 90°C for 14 hours in a sealed tube. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with EtOAc in n-hexane (0-20%)] ethyl 2-(2-((7-(7-nitropyrrolo[2,1-P ][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (204c) (0.135 g, 13%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (d, J=1.8 Hz, 1H), 9.00 (s, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.99 (d, J=1.7 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H) , 7.33-7.20 (m, 2H), 7.20-7.11 (m, 2H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.34 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 473.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(7-aminopyrrolo[2,1-1][1,2,4]triazin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (204d).

To a solution of ethyl 2-(2-((7-(7-nitropyrrolo[2,1-P][1,2,4]triazin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (204c) (19 mg, 0.04 mmol) iron powder (19 mg, 0.34 mmol) was added to AcOH (1 ml) at 0°C. The mixture was warmed to room temperature and stirred for two hours. The mixture was poured into a saturated aqueous solution of NaHCO ₃ and extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The crude residue was purified by chromatography [silica gel (12 g), eluted with DMA/DCM, 0-30%] to give ethyl 2-(2-((7-(7aminopyrrolo[2,1-1][1,2,4] triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (204d) (8 mg, 45%) as a yellow foam.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.91-7.78 (m, 3H), 7.66 (d, J=1.7 Hz, 1H), 7.30-7.16 (m, 2H), 7.07 (dd, J=8.3, 1.2 Hz, 1H), 6.98 (d, J=2.2 Hz, 1H), 6 .96-6.88 (m, 1H), 6.28 (d, J=1.7 Hz, 1H), 5.25 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.65 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 443.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(7-aminopyrrolo[2,1-G][1,2,4]triazin-4-yl)benzofuran-5

- 278 045626 yl)methoxy)phenyl)acetic acid (204e).

Compound 204e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl )benzofuran-5-yl)methoxy)phenyl)acetate (204d) (94 mg, 0.212 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (51 mg, 2.13 mmol) in water ( 2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(7- aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (204e) (17 mg, 9% yield), HCl salt, as orange solid.

1H NMR (300 MHz, DMSO-d6, D2O substitution) δ 8.72 (s, 1H), 8.15 (d, J=22.3 Hz, 2H), 7.96 (d, J=42.4 Hz, 2H), 7.36-6.99 (m, 4H), 6.91 (t, J=7.4 Hz, 1H), 6.68 (s, 1H), 5.30 (s, 2H ), 3.58 (s, 2H);

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.75 (s, 1H), 8.19 (s, 2H), 8.16 (s, 1H), 8.03 (s, 1H), 7 .91 (s, 1H), 7.347.19 (m, 3H), 7.16-7.05 (m, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.71 ( s, 1H), 5.32 (s, 2H), 3.59 (s, 2H); MS (ESI+): 415.1 (M+1); MS (ESI-): 413.2 (M-1). Purity after HPLC: 97.4%.

Scheme-205

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-5-fluorophenyl)acetic acid (205d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetate (205b).

Compound 205b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (250 mg, 0.707 mmol) in DCM (8 ml) using triphenylphosphine (195 mg, 0.743 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (147 mg, 0.743 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2 -dicarboxylate (DCAD, 273 mg, 0.743 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 40 g, eluted with ethyl acetate in 0% to 40% hexanes] ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (205b) (220 mg, 58% yield) as a brownish solid;

1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=2.2 Hz, 1H), 7.76-7.67 (m, 3H), 7.53 (d, J=1, 7 Hz, 1H), 7.527.44 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.17-7.08 (m, 3H), 7.05 (d, J=2.2 Hz, 1H), 5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H) , 3.64 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetate (205c).

Compound 205c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-5-fluorophenyl)acetate (205b) (140 mg, 0.262 mmol) in DCM (5 ml) using TFA (121 µl, 1.574 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 40% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-5-fluorophenyl)acetate (205c) (0.14 g, 98% yield), TFA salt, as a solid;

1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.01-7.94 (m, 1H), 7 .91 (dt, J=7.8, 1.5 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.66-7.47 (m, 3H), 7. 20-7.03 (m, 4H), 5.23 (s, 2H), 4.15 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.65 (s , 2H), 0.99 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (205d).

Compound 205d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate ( 205c) (0.14 g, 0.256 mmol) in THF (3 ml) and methanol (2.25 ml), using lithium hydroxide monohydrate (107 mg, 2.56 mmol) in water (3.00 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-279 045626 (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (205d) (60 mg, 0.136 mmol, 53.1% yield), HCl salt, as a white solid ;

^1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.35 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.99 ( s, 1H), 7.92 (dt, J=7.5, 1.6 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.63 (d, J=1 .8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.56-7.50 (m, 1H), 7.16-7.07 (m, 3H), 7 .06 (d, J=2.2 Hz, 1H), 5.25 (s, 2H), 4.14 (s, 2H), 3.61 (s, 2H); MS (ESI+): 406.2 (M+1); (ESI-): 404.3 (M-1).

Scheme-206

206b 206c

Preparation of 2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (206c).

Stage-1. Preparation of ethyl 2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (206b).

Compound 206b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (520 mg, 1.192 mmol) in dioxane (9 ml), using (5-bromothiophen-2-yl)methanamine hydrochloride (206a) (300 mg, 1.311 mmol; CAS No. 1001414-56-7), bis(triphenylphosphine) palladium(P) chloride (125 mg, 0.179 mmol), solution of K ₂ CO ₃ (659 mg, 4.77 mmol) in water (1 ml) in an Ar atmosphere and heating at 90°C for 14 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 100% EtOAc in hexane] ethyl 2-(2-((7(5-(aminomethyl)thiophen-2-yl )benzofuran-5-yl)methoxy)phenyl)acetate (206b) (250 mg, 50% yield) as a brownish oily residue;

1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 3H), 8.18 (d, J=2.2 Hz, 1H), 7.76 (d, J=3.7 Hz, 1H ), 7.72 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.38 (d, J=3.7 Hz, 1H), 7.30-7.19 (m, 2H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6 .91 (td, J=7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 4.30 (s, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.01 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of 2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (206c).

Compound 206c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (206b) (150 mg, 0.356 mmol) in MeOH/THF (5 mL each), using a solution of lithium hydroxide monohydrate (149 mg, 3.56 mmol) in water (3 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (5(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (206c) (118 mg, 46% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=2.2 Hz, 1H), 7.78 (d, J=3.7 Hz, 1H), 7.76 (d, J =1.6 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.33 (d, J=3.8 Hz, 1H), 7.27-7.18 (m , 2H), 7.10 (d, J=1.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.6, 0, 9 Hz, 1H), 5.26 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H); MS (ESI-): 392.2 (M-1).

Scheme-207

207b 207c

Preparation of 2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (207c).

Stage-1. Preparation of ethyl 2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (207b).

Compound 207b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (458

- 280 045626 mg, 1.050 mmol) in dioxane (9 ml), using (5-bromofuran-2-yl)methanamine (207a) (194 mg, 1.102 mmol; CAS No. 263169-37-5), bis(triphenylphosphine) palladium (II) chloride (111 mg, 0.157 mmol), solution of K ₂ CO ₃ (450 mg, 3.25 mmol) in water (1 ml) under Ar atmosphere and heating at 90°C for 14 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 100% EtOAc in hexane] ethyl 2-(2-((7-(5-(aminomethyl)furan2- yl)benzofuran-5-yl)methoxy)phenyl)acetate (207b) (200 mg, 47.0% yield) as a yellow foam;

^1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.13-7.06 (m, 2H), 7.04 (d, J=2.2 Hz, 1H ), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.45-6.42 (m, 1H), 5.22 (s, 2H), 3.99 (k, J=7.1 Hz, 2H), 3.78 (s, 2H), 3.62 (s, 2H), 1.02 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of 2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (207c).

Compound 207c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (207b) (200 mg, 0.493 mmol) in MeOH/THF (3 mL each), using a solution of lithium hydroxide monohydrate (207 mg, 4.93 mmol) in water (3 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (5(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (207c) (6 mg, 3% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-06) δ 8.38 (s, 3H), 8.16 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.27-7.19 (m, 2H), 7.17 (d, J=3.4 Hz, 1H), 7, 10-7.05 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 5.25 (s, 2H), 4.23 (s, 2H), 3.60 (s, 2H).

Scheme-208

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)acetic acid (208d).

Stage-1. Preparation of methyl 2-(5-bromo-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (208b).

Compound 208b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1167 mg, 3.30 mmol) in DCM (10 ml ), using triphenylphosphine (953 mg, 3.63 mmol), methyl 2-(5-cyclopropyl-2-hydroxyphenyl) acetate (208a) (850 mg, 3.47 mmol) and di-(4-chlorobenzyl) azodicarboxylate (1334 mg, 3.63 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 40 g, eluted with ethyl acetate in 0% to 40% hexanes] methyl 2-(5-bromo-2-((7-(3-((( tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (208b) (950 mg, 1.637 mmol, 49.5% yield) as a brownish amorphous solid;

1H NMR (300 MHz, DMSO-06) δ 8.08 (d, J=2.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.68 (d, J=1, 6 Hz, 1H), 7.50 (dd, J=13.0, 2.1 Hz, 2H), 7.47-7.41 (m, 2H), 7.34-7.27 (m, 1H ), 7.13-7.08 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.25 (s, 2H), 4.23 (d, J=6, 2 Hz, 2H), 3.67 (s, 2H), 3.47 (s, 3H), 1.39 (s, 9H).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5bromophenyl)acetate (208c).

Compound 208c was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5-yl)methoxy)phenyl)acetate (208b) (400 mg, 0.689 mmol) in DCM (5 ml) using TFA (531 µl, 6.89 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with methanol in 0% to 20% DCM] methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-5-bromophenyl)acetate (208c) (0.32 g, 78% yield) as a solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.22 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.97 (t, J=1.7 Hz , 1H), 7.90 (dt, J=7.7, 1.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.61 (t, J=7, 7 Hz, 1H), 7.57-7.50 (m, 2H), 7.47-7.41 (m, 2H), 7.11- 281 045626

7.04 (m, 2H), 5.26 (s, 2H), 4.15 (s, 2H), 3.67 (s, 2H), 3.48 (d, J=1.3 Hz, 3H ).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5bromophenyl)acetic acid (208d).

Compound 208d was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)acetate (208c) (350 mg, 0.589 mmol) in THF (4 mL) and methanol (3 mL), using a solution of lithium hydroxide monohydrate (173 mg, 4.12 mmol) in water (4.0 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)acetic acid (208d) (200 mg, 73% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.35 (s, 1H), 8.39 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.99 ( s, 1H), 7.92 (dt, J=7.5, 1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.62 (d, J=1 .8 Hz, 1H), 7.60-7.52 (m, 2H), 7.45-7.38 (m, 2H), 7.09-7.04 (m, 2H), 5.27 ( s, 2H), 4.14 (s, 2H), 3.61 (s, 2H).

Scheme-209

209b 209c

Preparation of 2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (209c).

Stage-1. Preparation of methyl 2-(5-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (209a) .

To a mixture of methyl 2-(5-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (208b) (400 mg, 0.689 mmol) in toluene (6 ml) dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-PHOS, 0.032 g, 0.067 mmol), tert-butylcarbamate (121 mg, 1.034 mmol) and cesium carbonate (225) were added mg, 0.689 mmol) and degassed by purging with nitrogen for 15 min. Pd ₂ (dba) ₃ (31.6 mg, 0.034 mmol) was added and the mixture was degassed for a further 10 minutes. The mixture was heated with stirring at 95°C for 16 hours, cooled to room temperature, diluted with EtOAc (50 ml) and filtered through a pad of celite. The celite layer was rinsed with EtOAc (2x50 ml) and the filtrate was dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 100% hexanes] to give methyl 2-(5-((tert-butoxycarbonyl)amino)-2-((7-(3-( ((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (209a) (0.300 g, 71% yield) as a pale brown foam;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.77-7.70 (m, 2H) , 7.67 (d, J=1.6 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 1H), 7.37- 7.21 (m, 3H), 7.06 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.9 Hz, 1H), 5.18 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.60 (s, 2H), 3.47 (s, 3H), 1.45 (s, 9H), 1.39 (s, 9H ).

Stage-2. Preparation of methyl 2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (209b).

Compound 209b was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(5-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (209a) (300 mg, 0.486 mmol) in DCM (5 ml) using TFA (0.375 ml, 4.86 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 20%] methyl 2-(5-amino-2-((7-(3(aminomethyl)phenyl )benzofuran-5-yl)methoxy)phenyl)acetate (209b) (0.23 g, 73% yield) as a solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (s, 3H), 8.28 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.98 ( t, J=1.7 Hz, 1H), 7.90 (dt, J=7.8, 1.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7, 65-7.50 (m, 3H), 7.16-6.99 (m, 4H), 5.22 (s, 2H), 4.16 (s, 2H), 3.67 (s, 2H) , 3.48 (s, 3H).

- 282 045626

Stage-3. Preparation of 2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (209c).

Compound 209c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl) acetate (209b) (220 mg, 0.341 mmol) in THF (3 ml) and methanol (2 ml), using a solution of lithium hydroxide monohydrate (143 mg, 3.41 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(5-amino-2-((7 -(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (209c) (130 mg, 80% yield), HCl salt, as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 12.38 (s, 1H), 9.85 (s, 3H), 8.39 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.00 (s, 1H), 7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.67-7.51 (m, 3H), 7.19 (d, J=2.7 Hz, 3H), 7.06 (d, J=2.2 Hz, 1H), 5.29 (s , 2H), 4.14 (d, J=5.6 Hz, 2H), 3.65 (s, 2H).

Scheme-210

HN ^X

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (210c) .

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methyl(1methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (210a).

Compound 210a was prepared according to the procedure described in step-4 of Scheme-138 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl) benzofuran-5yl)methoxy)phenyl)acetate (138c) (450 mg, 0.80 mmol) and N,1-dimethylpiperidin-4-amine (113 mg, 0.88 mmol) in ACN (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)-2-((methyl(1-methylpiperidin-4yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (210a) (230 mg, 44% yield) as a clear oil; MS (ESI+): 656.4 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (210b) .

Compound 210b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methyl( 1-Methylpiperidin-4yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (210a) (223 mg, 0.34 mmol) in DCM (10 ml), using TFA (0.26 ml, 3. 40 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5yl)methoxy)phenyl) acetate (210b) (122 mg, 65% yield) as a clear oil; MS (ESI+): 556.4 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (210c) .

Compound 210c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl) amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (210b) (120 mg, 0.22 mmol) in THF (6 ml) and methanol (6 ml), using lithium hydroxide monohydrate solution (21 mg, 0.86 mmol) in water (2.0 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-((methyl(1methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (210c) (30 mg, 26% yield), salt HCl, as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H, D2O replaceable), 11.90 (s, 1H, D2O replaceable), 10.92 (s,

- 283 045626

1H, D2O replaceable), 8.65 (s, 3H, D2O replaceable), 8.23 (s, 1H), 8.01-7.93 (m, 1H), 7.81 (d, J=1, 6 Hz, 1H),

7.75 (d, J=1.7 Hz, 1H), 7.62-7.53 (m, 2H), 7.39 (s, 1H), 7.27-7.19 (m, 2H) , 7.10 (d, J=8.1 Hz, 1H), 6.96-6.86 (m,

1H), 5.29 (s, 2H), 4.71 (s, 2H), 4.24-4.09 (m, 2H), 3.62-3.48 (m, 6H), 3.08 -2.90 (m, 2H), 2.87-2.77 (m, 3H), 2.71 (d, J=4.2 Hz, 3H), 2.42-2.32 (m, 1H ), 2.30-2.13 (m, 2H); MS (ESI+): 528.3 (M+1); (ESI-): 526.3 (M-1).

Scheme-211

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -(methylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (211с) and 2-(2 -((4-(2-(aminomethyl)pyridin-4-yl)-1H-indol-6yl)methoxy)phenyl)acetic acid (211e).

Stage-1. Preparation of ethyl 2-(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indol-6-yl)methoxy)phenyl )acetate (211a).

Compound 211a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate ( 192c) (0.23 g, 0.49 mmol), using bis(pinacolato)diboron (0.19 g, 0.74 mmol), potassium acetate (0.01 g, 0.99 mmol) and Pd(dppf) Cl ₂ CH ₂ Cl ₂ (0.06 g, 0.07 mmol) in anhydrous dioxane (5 ml) under Ar atmosphere by heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(2-((1(methylsulfonyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (211a) (0.23 g, 91% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (dd, J=1.5, 0.8 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J= 1.5 Hz, 1H), 7.66 (d, J=3.6 Hz, 1H), 7.31-7.19 (m, 1H), 7.15-7.10 (m, 1H), 7.08 (dd, J=3.7, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 4 .00 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.41 (s, 3H), 1.11-0.98 (m, 15H); MS (ESI-): 512.3 (M1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (211b).

Compound 211b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-III-indol-6yl)methoxy)phenyl)acetate (211a) (0.22 g, 0.43 mmol) in dioxane (5 ml), using (4-chloropyridin-2yl)methanamine (74a ) (0.07 ml, 0.64 mmol), bis(triphenylphosphine) palladium(P) chloride (0.05 g, 0.06 mmol) and a solution of K2CO3 (0.09 g, 0.64 mmol) in water ( 0.5 ml) in an Ar atmosphere when heated at 85°C for 2 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 50% DCM] followed by purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonal)-1Nindol-6-yl )methoxy)phenyl)acetate (211b) (0.07 g, 33% yield) as a yellow solid;

1H NMR (300 MHz, methanol-d ₄ ) δ 8.41 (d, J=5.4 Hz, 1H), 8.06 (t, J=1.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=3.8 Hz, 1H), 7.58-7.47 (m, 3H), 7.32 (dd, J=5.4, 2.0 Hz, 1H ), 7.25-7.12 (m, 2H), 7.02 (dd, J=8.3, 1.1 Hz, 1H), 6.93 (dd, J=3.8, 0.9 Hz, 1H), 6.87 (td, J=7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 3.97-3.88 (m, 4H), 3.61 (s, 2H), 3.25 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 494.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -(methylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (211с) and 2-(2 -((4-(2-(aminomethyl)pyridin-4-yl)-1H-indol-6yl)methoxy)phenyl)acetic acid (211e).

Compounds 211c and 211e were prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H -indol-6-yl)methoxy)phenyl)acetate (211b) (0.07 g, 0.14 mmol) in THF (3 ml) and MeOH (3 ml), using lithium hydroxide monohydrate (0.01 g, 0 .28 mmol) in water (0.5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (211c) (0.02 g, 35% yield), HCl salt, as yellow solid - 284 045626;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (d, J=5.2 Hz, 1H), 8.36 (s, 3H), 8.09 (s, 1H), 7.78 ( d, J=3.9 Hz, 2H), 7.70 (d, J=4.7 Hz, 1H), 7.63 (s, 1H), 7.29-7.19 (m, 2H), 7.13 (d, J=7.9 Hz, 1H), 7.04 (d, J=3.8 Hz, 1H), 6.92 (t, J=7.5 Hz, 1H), 5, 34 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H), 3.53 (s, 3H); MS (ESI+): 466.2 (M+1), MS (ESI-): 464.3 (M-1). Purity after HPLC: 99.48%; Methyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (211d) (0.01 g, 9% yield), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.77 (d, J=5.1 Hz, 1H), 8.42 (s, 3H), 8.07 (s, 1H), 7.83- 7.74 (m, 2H), 7.70 (d, J=5.3 Hz, 1H), 7.59 (s, 1H), 7.34-7.19 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.05 (d, J=3.8 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.33 (s , 2H), 4.31 (d, J=5.8 Hz, 2H), 3.65 (s, 2H), 3.53 (s, 3H), 3.46 (s, 3H); MS (ESI+): 480.2 (M+1), followed by 2-(2-((4-(2-(aminomethyl)niridin-4-yl)-1H-indol-6-yl)methoxy) phenyl)acetic acid (211e) (0.004 g, 7% yield), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.49 (s, 1H), 8.71 (d, J=5.2 Hz, 1H), 8.35 (s, 3H), 7.84 ( d, J=1.6 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.61 (s, 1H), 7.53 (t, J=2.8 Hz, 1H), 7.36 (d, J=1.4 Hz, 1H), 7.22 (d, J=7.4 Hz, 2H), 7.11 (d, J=8.2 Hz, 1H) , 6.96-6.85 (m, 1H), 6.72 (s, 1H), 5.27 (s, 2H), 4.31 (s, 2H), 3.59 (s, 2H); MS (ESI+): 388.2 (M+1).

Receipt

Scheme-212

2-(2-((4-(3-(aminomethyl)phenyl)-1 -(cyclopropylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (212e).

Stage-1. Preparation of methyl 4-bromo-1-(cyclopropylsulfonyl)-1H-indole-6-carboxylate (212a).

Compound 212a was prepared according to the procedure described in step-1 of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g, 7.87 mmol) in DMF (15 ml) using NaH (60% in mineral oil, 0.94 g, 23.61 mmol) and cyclopropanesulfonyl chloride (2.41 ml, 23.61 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH=9:1 in 0% to 50% hexane] methyl 4-bromo-1-(cyclopropylsulfonyl)1H- indole-6-carboxylate (212a) (2.52 g, 89% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (t, J=1.0 Hz, 1H), 8.04 (d, J=1.2 Hz, 1H), 8.01 (d , J=3.7 Hz, 1H), 6.91 (dd, J=3.7, 0.9 Hz, 1H), 3.91 (s, 3H), 3.32-3.19 (m, 1H), 1.38-1.04 (m, 4H); MS (ESI+) 358.0, 360.0 (M+1); MS (ESI-) 358.1, 356.1 (M-1).

Stage-2. Preparation of (4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methanol (212b).

To a solution of methyl 4-bromo-1-(cyclopropylsulfonyl)-1H-indole-6-carboxylate (212a) (0.5 g, 1.40 mmol) in dichloromethane (10 ml), cooled to -78°C, was slowly added diisobutylaluminum hydride (1 M solution in dichloromethane) (3.49 ml, 3.49 mmol) and allowed to gradually warm to a temperature of 0 to 5°C. After 10 min, the reaction mixture was quenched by adding methanol (75 ml). The mixture was diluted with additional dichloromethane (100 ml) and stirred vigorously for about 1 hour. The organic phases were washed with brine (100 ml), dried and concentrated under reduced pressure to give (4-bromo-1-(cyclopropylsulfonyl)-1H-indole -6-yl)methanol (212b) (0.37 g, 80% yield) as a crystalline solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (p, J=0.9 Hz, 1H), 7.70 (d, J=3.7 Hz, 1H), 7.49 (dd, J=1.2, 0.6 Hz, 1H), 6.75 (dd, J=3.7, 0.8 Hz, 1H), 5.44 (t, J=5.9 Hz, 1H), 4.63 (dt, J=5.9, 0.8 Hz, 2H), 3.14-3.05 (m, 1H), 1.331.04 (m, 4H); MS (ESI-): 364.1, 366.1 (M+Cl).

Stage-3.

Obtaining ethyl

2-(2-((4-bromo-1 -(cyclopropylsulfonyl)-1 H-indol-6 yl)methoxy)phenyl)acetate (212c).

Compound 212c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-(cyclopropylsulfonyl)-1H-undol-6-ul)methanol (212b) (1.2 g, 3.63 mmol) in toluene (15 ml), using triphenylphosphine (1.24 g, 4.72 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.85 g, 4.72 mmol) and (E)-diazen- 1,2-diylbis(piperidin-1-ylmethanone) (1.19 g, 4.72 mmol) in toluene (15 ml). This

- 285 045626 resulted after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH (9:1) in hexane from 0% to 10% for 40 min, then 10%50% ]ethyl 2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (212c) (1.2 g,

67% yield) as a yellow oil;

^1H NMR (300 MHz, DMSO- _d6 ): δ 7.99 (t, J=1.0 Hz, 1H), 7.77 (d, J=3.7 Hz, 1H), 7.60 (d, J=1.1 Hz, 1H), 7.30-7.19 (m, 2H), 7.09 (dd, J=8.0, 1.0 Hz, 1H), 6.92 ( td, J=7.4, 1.1 Hz, 1H), 6.79 (dd, J=3.7, 0.8 Hz, 1H), 5.26 (s, 2H), 4.03 (k , J=7.1 Hz, 2H), 3.63 (s, 2H), 3.15-3.09 (m, 1H), 1.33-1.24 (m, 2H), 1.13- 1.06 (m, 5H); MS (ESI-): 491.1, 493.2 (M-1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (212d).

Compound 212d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (212c ) (0.6 g, 1.22 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.34 g, 1.83 mmol), K ₂ CO ₃ (0. 34 g, 2.44 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.13 g, 0.18 mmol) in an Ar atmosphere when heated at 90°C for 2 hours in oil bath. This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4 -(3-(aminomethyl)phenyl)-1(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (212d) (0.28 g, 44% yield), HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.33 (s, 3H), 8.03 (s, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.74 ( d, J=3.7 Hz, 1H), 7.69-7.61 (m, 1H), 7.61-7.50 (m, 2H), 7.47 (d, J=1.3 Hz , 1H), 7.31-7.18 (m, 2H), 7.17-7.09 (m, 1H), 7.01 (dd, J=3.7, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H), 3.91 (k, J=7.1 Hz , 2H), 3.63 (s, 2H), 3.20-3.03 (m, 1H), 1.34-1.03 (m, 4H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 519.2 (M+1), MS (ESI-): 517.3 (M1).

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (212e).

Compound 212e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3 -(aminomethyl)phenyl)-1 -(cyclopropylsulfonyl)-1 H-undol-6-yl )methoxy)phenyl)acetate (212d) (0.21 g, 0.41 mmol) in MeOH/THF (4 ml, 1:1), using a solution of lithium hydroxide monohydrate (0.14 g, 3.24 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (212e) (0.09 g, 45% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.19 (s, 1H), 8.35 (s, 3H), 8.04 (s, 1H), 7.78 (s, 1H), 7. 73 (d, J=3.7 Hz, 1H), 7.70-7.63 (m, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.56-7.48 (m, 2H), 7.24 (t, J=7.9 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.01 (dd, J=3.8, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.33 (s, 2H), 4.14 (d, J=5.9 Hz, 2H), 3.60 (s, 2H), 3.20-3.05 (m, 1H), 1.35-1.00 (m, 4H); MS (ESI+): 491.2 (M+1), MS (ESI-): 489.3 (M-1).

Scheme-213

_212c 213a 213b

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (213b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1Hindol-6-yl)methoxy)phenyl)acetate (213a).

Compound 213a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (212c ) (0.6 g, 1.22 mmol) in dioxane (5 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.38 g, 1.83 mmol), K ₂ CO ₃ (0.34 g, 2.44 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.13 g, 0.18 mmol) in Ar atmosphere when heated at 85°C for 2 h in an oil bath. This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4 -(3-(aminomethyl)-2-fluorophenyl)1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (213a) (0.35 g, 54% yield), HCl salt, as white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (s, 3H), 8.06 (t, J=1.0 Hz, 1H), 7.71 (d, J=3.8 Hz, 1H), 7.69-7.64 (m, 1H), 7.59 (td, J=7.5, 1.8 Hz, 1H), 7.47-7.39 (m, 2H), 7 .30-7.19 (m, 2H), 7.14 (dd, J=8.3, 1.1 Hz, 1H), 6.91

- 286 045626 (td, J=7.3, 1.1 Hz, 1H), 6.78-6.73 (m, 1H), 5.31 (s, 2H), 4.16 (s, 2H) , 3.90 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 3.223.06 (m, 1H), 1.34-1.03 (m, 4H), 0, 97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.66; MS (ESI+):

537.2 (M+1), MS (ESI-): 535.3 (M-1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-III-indol6-yl)methoxy)phenyl)acetic acid (213b).

Compound 213b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (213a) (0.24 g, 0.45 mmol) in MeOH/THF (4 ml, 1:1), using lithium hydroxide monohydrate solution (0.15 g, 3.58 mmol ) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)-2-fluorophenyl)-1 -(cyclopropylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (213b) (0.11 g, 46% yield), HCl salt, as white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 3H), 8.08 (d, J=1.2 Hz, 1H), 7.70 (d, J=3.7 Hz, 1H), 7.69-7.61 (m, 1H), 7.58 (dd, J=7.4, 1.7 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H ), 7.41 (d, J=7.6 Hz, 1H), 7.29-7.18 (m, 2H), 7.157.08 (m, 1H), 6.91 (td, J=7, 4, 1.1 Hz, 1H), 6.74 (t, J=3.5 Hz, 1H), 5.33 (s, 2H), 4.17 (s, 2H), 3.59 (s, 2H), 3.213.07 (m, 1H), 1.36-1.01 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.54; MS (ESI+): 509.2 (M+1), MS (ESI-): 507.3 (M-1).

Scheme-214

214a ^214b 214c

HE

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (214f).

Stage-1. Preparation of 5-(hydroxymethyl)benzo[b]thiophen-7-ol (214b).

Compound 214b was prepared according to the procedure described in step-1 of Scheme-115 from methyl 7-acetoxybenzo[b]thiophene-5-carboxylate (214a) (0.66 g, 2.64 mmol; prepared according to procedure described by Shimizu, Kazuo et al.; from PCT International Application 2010044404, April 22, 2010) in THF (10 ml) using lithium aluminum hydride (0.300 g, 7.91 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-3% MeOH in DCM], 5-(hydroxymethyl)benzo[b]thiophen-7-ol (214b) (350 mg, 74% yield ) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 7.65 (d, J=5.3 Hz, 1H), 7.35 (d, J=5.3 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 6.76 (s, 1H), 5.18 (t, J=5.7 Hz, 1H), 4.52 (d, J=4.9 Hz, 2H); MS (ESI-): 179 (M-1).

Stage-2. Preparation of 5-(hydroxymethyl)benzo[b]thiophen-7-yl trifluoromethanesulfonate (214c).

Compound 214c was prepared according to the procedure described in step-2 of scheme-115 from 5(hydroxymethyl)benzo[b]thiophen-7-ol (214b) (340 mg, 1.887 mmol) in THF (3 ml), DMF ( 5 ml) using 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (674 mg, 1.887 mmol) and triethylamine (0.526 ml, 3.77 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-40% EtOAc in hexanes], 5(hydroxymethyl)benzo[b]thiophen-7-yl trifluoromethanesulfonate (214c) (430 mg, 1.377 mmol, 73.0% yield) as a pale yellow thick oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.01-7.90 (m, 2H), 7.61 (d, J=5.3 Hz, 1H), 7.47 (d, J=1 .2 Hz, 1H), 5.53 (s, 1H), 4.68 (s, 2H); MS (ESI-): 311 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5yl)methoxy)phenyl)acetate (214d).

Compound 214d was prepared according to the procedure described in step-2 of Scheme-23 from 5(hydroxymethyl)benzo[b]thiophen-7-yl trifluoromethanesulfonate (214c) (420 mg, 1.345 mmol) in DCM (10

- 287 045626 ml), using triphenylphosphine (388 mg, 1.479 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (267 mg, 1.479 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 543 mg, 1.479 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-15% EtOAc in hexane], ethyl 2-(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophene -5yl)methoxy)phenyl)acetate (214d) (0.46 g, 72% yield) as a thick, clear, colorless oil which settled to a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=3.2 Hz, 1H), 8.01 (dd, J=5.6, 3.2 Hz, 1H), 7, 63 (dt, J=10.4, 3.4 Hz, 2H), 7.40-7.16 (m, 2H), 7.10 (dd, J=8.2, 3.2 Hz, 1H) , 6.94 (td, J=7.5, 2.9 Hz, 1H), 5.31 (d, J=3.2 Hz, 2H), 4.00 (cd, J=7.1, 3 .3 Hz, 2H), 3.66 (d, J=3.3 Hz, 2H), 1.05 (td, J=7.2, 3.4 Hz, 3H); MS (ESI+): 475 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5yl)methoxy)phenyl)acetate (214e).

Compound 214e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5-yl)methoxy)phenyl) acetate (214d) (103 mg, 0.217 mmol) in dioxane (2 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (49 mg, 0.261 mmol), K ₂ CO ₃ solution (90 mg, 0.651 mmol) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ (15.24 mg, 0.022 mmol) and heating in an Ar atmosphere at 100°C for 16 hours. This gave, after work-up and purification by flash chromatography on a column (silica gel, eluted with 0-15% MeOH in DCM) ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (214e) as a pale yellow oil, which was directly transferred to the next step.

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (214f).

Compound 214f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (214e) (from previous step) in THF (1 mL) and MeOH (2 mL), using a solution of NaOH (87 mg, 2.171 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((7-(3-( aminomethyl)phenyl)benzo[b]thiophen-5yl)methoxy)phenyl)acetic acid (214f) (28 mg, 32% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=1.5 Hz, 1H), 7.91-7.78 (m, 3H), 7.67-7.51 (m, 4H), 7.23 (dd, J=8.0, 6.4 Hz, 2H), 7.09 (d, J=8.2 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H), 3.59 (s, 2H); MS (ESI+): 404 (M+1); (ESI-): 402 (M-1).

Scheme-215

215g ^215h

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (215h).

Stage-1. Preparation of (E)-4-(5-chlorothiophen-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (215b)

Potassium tert-butoxide (1.148 g, 10.23 mmol) was suspended in t-BuOH (10 ml), followed by dropwise addition of dimethyl succinate (1.994 g, 13.64 mmol) in t-BuOH (5 ml). The mixture was stirred at 80°C for 30 minutes, during which time it turned cloudy yellow. 5-Chlorothiophene-2-carbaldehyde (215a) (1.0 g, 6.82 mmol; CAS No. 7283-96-7) in t-BuOH (5 mL) was then added. The mixture was stirred at 110°C for 3 hours, during which time it turned dark black. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (25 ml) and 6 M HCl (50 ml). After stirring for 15 minutes, the two layers were separated and the aqueous layer was extracted with EtOAc (25 ml x 2). The combined organic extract was washed with H2O (25 ml x 2), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , eluting with 0-40% EtOAc in hexane) to give (E)-4-(5-chlorothiophen-2-yl)-3-(methoxycarbonyl)but -3-enoic acid (215b) (0.82 g, 46% yield) as a thick orange oil;

1H NMR (300 MHz, DMSO-d6) δ 7.86 (d, J=0.7 Hz, 1H), 7.46 (dd, J=4.0, 0.7 Hz, 1H), 7.28 (d, J=4.0 Hz,

1H), 3.74 (s, 3H), 3.55 (s, 2H); MS (ESI+): 261/263 (M+1).

Stage-2. Preparation of methyl 4-acetoxy-2-chlorobenzo[b]thiophene-6-carboxylate (215c).

To a solution of (E)-4-(5-chlorothiophen-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (215b) (0.82 g, 3.15 mmol) in acetic anhydride (10 ml) NaOAc (1.032 g, 12.58 mmol) was added. The orange mixture was stirred at 180°C for 5 hours, during which time it turned dark black, additional acetic anhydride (10 ml x 2) was added to replace the evaporated acetic anhydride. The cooled black solution was evaporated to remove acetic anhydride. The concentrate was slightly alkalinized (pH 8) with 15% aq. Na ₂ CO ₃ (50 ml), diluted with EtOAc (25 ml), and stirred for 15 minutes. The two layers were separated. The aqueous layer was extracted with EtOAc (25 ml x 2). The combined organic extract was washed with brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , 0-15% EtOAc in hexanes) to give methyl 4-acetoxy-2-chlorobenzo[b]thiophene-6-carboxylate (215c) (0.47 g, 53% yield) as a yellow solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 7.70 (s, 2H), 3.89 (s, 3H), 2.40 (s, 3H); MS (ESI+): 285/287 (M+1).

Stage-3. Preparation of 2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-ol (215d).

Compound 215d was prepared according to the procedure described in step-2 of Scheme-212 from methyl 4-acetoxy-2-chlorobenzo[b]thiophene-6-carboxylate (215c) (0.47 g, 1.651 mmol) in DCM (10 ml) using 1 M DIBAL-H in DCM (8.01 ml, 8.01 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-3% MeOH in DCM), 2chloro-6-(hydroxymethyl)benzo[b]thiophen-4-ol (215d) (140 mg, 40 % yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.25 (s, 1H), 6.74 (dd , J=2.4, 1.2 Hz, 1H), 5.25 (s, 1H), 4.50 (s, 2H); MS (ESI-): 213/215 (M-1).

Stage-4. Preparation of 2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (215e).

Compound 215e was prepared according to the procedure described in step-2 of scheme-116 from 2chloro-6-(hydroxymethyl)benzo[b]thiophen-4-ol (215d) (140 mg, 0.652 mmol) in DMF (2 ml) and THF (3 mL) using 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (233 mg, 0.652 mmol) and triethylamine (132 mg, 1.304 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-20% EtOAc in hexane), 2-chloro-6(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (215e) (163 mg , 72% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.49 (s, 1H), 7.48 (s, 1H), 5.58 (t, J=5.8 Hz , 1H), 4.65 (d, J=5.8, 0.8 Hz, 2H). MS (ESI-): 345 (M-1).

Stage-5. Preparation of ethyl 2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (215f).

Compound 215f was prepared according to the procedure described in step-2 of Scheme-23 from 2chloro-6-(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (215e) (163 mg, 0.470 mmol) in DCM (10 ml ), using triphenylphosphine (136 mg, 0.517 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (93 mg, 0.517 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 190 mg, 0.517 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 015% EtOAc in hexane), ethyl 2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b] thiophen-6yl)methoxy)phenyl)acetate (215f) (190 mg, 79% yield) as a thick, clear, colorless oil that settled to a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.56 (s, 1H), 7.31-7 .20 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 3.99 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.06 (t, J=7.1 Hz, 3H); MS (ESI+) 509/511 (M+1).

Stage-6. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetate (215g).

Compound 215g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl) methoxy)phenyl)acetate (215f) (100 mg, 0.196 mmol) in dioxane (2 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (44 mg, 0.236 mmol), K2CO3 solution (81 mg, 0.589 mmol ) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.020 mmol) and heating in an Ar atmosphere at 100°C for 16 hours. This resulted in the preparation after work-up and purification by flash chromatography on column (silica gel, eluted with 0-10% MeOH in DCM) ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate ( 215g) as a pale yellow oil, which was used as is in the next step.

- 289 045626

Stage-7. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (215h).

Compound 215h was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy) phenyl)acetate (215g) (from previous step) in THF (1 ml) and MeOH (2 ml), using a solution of NaOH (39.3 mg, 0.982 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((4-(3-( aminomethyl)phenyl)-2chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (215h) (32 mg, 37% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.05 (s, 1H), 7.74 (s, 1H), 7.65-7.45 (m, 5H), 7.28-7, 17 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.97-6.84 (m, 1H), 5.29 (s, 2H), 4.14 (s , 2H), 3.60 (s, 2H). Purity after HPLC: 96.8%; MS (ESI+): 438/440, (ESI-): 436/438 (M-1).

Scheme-216

Preparation of 2-amino-H-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)benzamide (216d).

Stage-1. Preparation of tert-butyl (7-bromobenzofuran-5-yl)carbamate (216a)

Diphenylphosphoryl azide (1.256 g, 4.56 mmol) in dioxane (3 ml) was added to a suspension of 7bromobenzofuran-5-carboxylic acid (15a) (1.0 g, 4.15 mmol), TEA (0.504 g, 4.98 mmol) and t-BuOH (9.84 mL, 104 mmol) in dioxane (17 mL) at rt. The mixture was heated at 80°C for 16 h, cooled to rt and evaporated to dryness. The concentrate was diluted with H ₂ O and extracted with EtOAc (25 ml x 3). The extract was washed with H ₂ O (25 ml) and brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-5% EtOAc in hexanes) to give tert-butyl (7-bromobenzofuran-5-yl)carbamate (216a) (1.03 g) as a clear colorless oil , which after settling turned into a white solid;

^1H NMR (300 MHz, CDCl3) δ 7.68 (d, J=2.2 Hz, 1H), 7.66-7.59 (m, 1H), 7.48 (d, J=2.0 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.50 (s, 1H), 1.55 (s, 9H); MS (ESI-): 310/312 (M-1).

Stage-2. Preparation of 7-bromobenzofuran-5-amine hydrochloride (216b) A solution of tert-butyl (7bromobenzofuran-5-yl)carbamate (216a) (from the previous step) in 1 M methanolic HCl (24.89 ml, 24.89 mmol) was heated at 60°C for 2 hours, during which a white precipitate formed. The reaction mixture was cooled to room temperature and evaporated to dryness. The resulting residue was triturated with acetone and the solid was collected by filtration to give 7-bromobenzofuran-5-amine (216b) (0.7 g, 80% yield), HCl salt, as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (d, J=2.2 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.43 (d , J=2.0 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H). MS (ESI+): 212/214 (M+1).

Stage-3. Preparation of 2-amino-N-(7-bromobenzofuran-5-yl)benzamide (216c).

Compound 216c was prepared according to the procedure described in step-4 of Scheme-1 from 7-bromobenzofuran-5-amine hydrochloride (216b) (0.30 g, 1.207 mmol) using 2-aminobenzoic acid (0.174 g, 1.268 mmol ), DIPEA (0.468 g, 3.62 mmol) and HATU (0.551 g, 1.449 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-20% EtOAc in hexane), 2-amino-H-(7-bromobenzofuran-5-yl)benzamide (216c) (290 mg, 73 % yield) as a pale yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.05 (d, J=1.9 Hz , 1H), 7.92 (d, J=1.9 Hz, 1H), 7.64 (dd, J=8.0, 1.5 Hz, 1H), 7.26-7.16 (m, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.3, 1.2 Hz, 1H), 6.67-6.54 (m, 1H ), 6.35 (s, 2H). MS (ESI+): 331/333 (M+1); (ESI-): 329/331 (M-1).

Stage-4. Preparation of 2-amino-K-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)benzamide (216d).

Compound 216d was prepared according to the procedure described in step-3 of Scheme-1 of 2- 290 045626 amino-N-(7-bromobenzofuran-5-yl)benzamide (216c) (100 mg, 0.302 mmol) in dioxane (4 ml ), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (68 mg, 0.362 mmol), solution of K ₂ CO ₃ (125 mg, 0.906 mmol) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ ( 21.19 mg, 0.030 mmol) and heating in an Ar atmosphere at 100°C for 16 hours. This resulted in the following work-up and purification by flash column chromatography (silica gel, eluted with 0-10% MeOH in DCM) followed by purified by reverse phase chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-amino-N-(7-(3(aminomethyl)phenyl)benzofuran-5-yl)benzamide (216d) (82 mg, 76% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.35 (s, 3H), 7.99 (dd, J=9.0, 2.1 Hz, 2H), 7 .88 (s, 1H), 7.80 (dd, J=8.9, 1.9 Hz, 2H), 7.67 (dd, J=8.0, 1.5 Hz, 1H), 7. 60-7.46 (m, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.81 (d, J =8.2 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 5.70 (d, J=1.0 Hz, 1H), 4.07 (k, J=5 ,9 Hz, 2H). MS (ESI+): 358 (M+1); (ESI-): 356 (M-1).

Scheme-217

Preparation of (trans)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2fluorobenzyl)cyclopentane-1,2-dicarboxamide (217e).

Stage-1. Preparation of (trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxylic acid (217b).

Compound 217b was prepared according to the procedure described in step-4 of Scheme-1 from (1R,2R)-cyclopentane-1,2-dicarboxylic acid (217a) (1.00 g, 6.32 mmol; CAS No. 17224- 73-6) using (3-chloro-2-fluorophenyl)methanamine (1.009 g, 6.32 mmol), DIEA (3.31 ml, 18.97 mmol) and HATU (2.89 g, 7.59 mmol ) in DCM (10 ml). This resulted, after work-up and purification by flash column chromatography (silica gel, eluted with 0-50% EtOAc in hexane), of a mixture of mono- and diamide products as indicated by 1H NMR as a pale yellow solid. The crude solid was suspended in 1 M NaOH (20 ml) and stirred for 20 minutes. The mixture was washed with EtOAc (25 ml x 2). The aqueous layer was separated and acidified with concentrated HCl to pH 1. The acidified aqueous layer was extracted with EtOAc (25 ml x 2), washed with H2O (20 ml x 2), brine (20 ml), dried, filtered and concentrated to dryness to give (trans )-2-((3-chloro-2fluorobenzyl)carbamoyl)cyclopentanecarboxylic acid (217b) (0.55 g, 1.835 mmol, 29.0% yield) as a pale yellow solid;

1H NMR (300 MHz, CDCl3) δ 7.36 (ddd, J=8.6, 7.1, 1.7 Hz, 1H), 7.26 (m, 1H), 7.08 (td, J= 7.9, 1.2 Hz, 1H), 6.31 (s, 1H), 4.55 (d, 2H), 3.10 (k, J=8.7 Hz, 1H), 2.91 ( k, J=8.7 Hz, 1H), 2.14-1.96 (m, 3H), 1.96-1.66 (m, 3H). MS (ESI+): 300/302 (M+1); (ESI-): 298/300 (M-1).

Stage-2. Preparation of tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c).

Compound 217c was prepared according to the procedure described in step-3 of Scheme-1 from 7-bromobenzofuran-5-amine (216b) (0.3 g, 1.207 mmol) in dioxane (2 ml) using tert-butyl 3-(4, 4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (0.483 g, 1.449 mmol), solution of K2CO3 (0.501 g, 3.62 mmol) in water (2 ml), Pd( PPh ₃ ) ₂ Cl ₂ (0.085 g, 0.121 mmol) and heating under Ar at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-40% EtOAc in hexane) tert-butyl 3-(5-aminobenzofuran-7yl)benzylcarbamate (217c) (0.37 g, 91% yield) as a pale yellow semi-solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 (d, J=2.2 Hz, 1H), 7.62 (dd, J=7.0, 1.4 Hz, 2H), 7, 52-7.39 (m, 2H), 7.25 (d, J=7.6 Hz, 1H), 6.76 (dd, J=10.1, 2.2 Hz, 3H), 4.94 (s, 2H), 4.20 (d, J=6.2 Hz, 2H), 1.40 (s, 9H). MS (ESI+): 339 (M+1).

Stage-3. Preparation of tert-butyl 3-(5-((trans)-2-((3-chloro-2fluorobenzyl)carbamoyl)cyclopentanecarboxamido)benzofuran-7-yl)benzylcarbamate (217d).

Compound 217d was prepared according to the procedure described in step-4 of Scheme-1 from tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c) (119 mg, 0.350 mmol) using (trans)-2-( (3chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxylic acid (217b) (100 mg, 0.334 mmol), DIEA (129 mg, 1.0 mmol) and HATU (152 mg, 0.4 mmol) in DCM (10 ml). This resulted in the preparation, after treatment, of tert-butyl 3-(5-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxamido)benzofuran-7-291 045626 yl)benzylcarbamate (217d), which was used as is in the next stage.

Stage-4. Preparation of (trans)-N 1 -(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2fluorobenzyl)cyclopentane-1,2-dicarboxamide (217e)

The crude intermediate 217d from step-3 was suspended in 1.5 M methanolic HCl (25.6 mL, 38.4 mmol) and stirred at 60°C for 1 h until the solid dissolved completely. The solution was evaporated to remove most of the MeOH and purified by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H2O with 0.1% HCl) to give (trans)-1H-(7-(3(aminomethyl )phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)cyclopentane-1,2-dicarboxamide (217e) (124 mg, 72% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.14 (s, 1H), 8.54 (t, J=5.9 Hz, 1H), 8.26 (s, 3H), 8.05 (d, J=2.2 Hz, 1H), 7.99-7.86 (m, 2H), 7.86-7.74 (m, 2H), 7.68-7.51 (m, 2H ), 7.47-7.34 (m, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.05 (dd, J=2.2, 0.6 Hz, 1H) , 6.98 (t, J=7.9 Hz, sch), 4.45-4.23 (m, 2H), 4.13 (s, 2H), 3.11 (dt, J=16.2 , 8.1 Hz, 1H), 2.14-1.93 (m, 2H), 1.72 (m, 5H); purity after HPLC: 98.5%; MS (ESI+): 520 (M+1); (ESI-): 518 (M-1).

Scheme-218

R(Su) ₃ 218е 218f

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetic acid (218f).

Stage-1. Preparation of methyl 7-bromo-1-methyl-1H-indole-5-carboxylate (218b).

Compound 218b was prepared according to the procedure described in step-1 of Scheme-40 from methyl 7-bromo-1H-indole-5-carboxylate (218a) (400 mg, 1.574 mmol; CAS No. 885523-35-3) in DMF (5 mL) using NaH (60% in mineral oil, 157 mg, 3.94 mmol) and iodomethane (0.245 mL, 3.94 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 6:1)] methyl 7-bromo-1-methyl-1H-indole-5-carboxylate (218b) ( 401 mg, 95%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.23 (d, J=1.5 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.52 (d, J=3.2 Hz, 1H), 6.68 (d, J=3.2 Hz, 1H), 4.15 (s, 3H), 3.85 (s, 3H).

Stage-2. Preparation of (7-bromo-1-methyl-1H-indol-5-yl)methanol (218с).

Compound 218c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-1-methyl-1H-indole-5-carboxylate (218b) (380 mg, 1.417 mmol) in THF (12 ml) using LiBH ₄ (3.54 ml, 7.09 mmol) and MeOH (0.287 ml, 7.09 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 5:1)] (7-bromo-1-methyl-1H-indol-5-yl)methanol (218c) (196 mg, 58%) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.46-7.44 (m, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.28-7.27 ( m, 1H), 6.43 (d, J=3.1 Hz, 1H), 5.16 (t, J=5.8 Hz, 1H), 4.52-4.49 (m, 2H), 4.08 (s, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-bromo-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate (218d).

Compound 218d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-1-methyl-1H-indol-5-yl)methanol (218c) (185 mg, 0.771 mmol) in DCM (10 ml) using triphenylphosphine (303 mg, 1.156 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (347 mg, 1.926 mmol) and (E)diazen-1,2-diylbis(piperidin-1-ylmethanone) (424 mg, 1.156 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 5:1), ethyl 2-(2-((7-bromo-1-methyl-1H-indole -5yl)methoxy)phenyl)acetate (218d) (112 mg) as a yellow gum; MS (ESI-): 400.4 and 402.3 (M-1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5yl)methoxy)phenyl)acetate (218e).

Compound 218e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate (218d) ( 108 mg, 0.268 mmol) in dioxane (3

- 292 045626 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (75 mg, 0.403 mmol), solution of tripotassium phosphate (0.152 ml, 0.456 mmol) in water (0.1 ml), tricyclohexylphosphine (45.2 mg , 0.161 mmol) and Pd ₂ (dba) ₃ (74 mg, 0.081 mmol) under argon when heated at 125°C for 60 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] ethyl 2-(2((7-(3-(aminomethyl)phenyl)-1- methyl 1H-indol-5-yl)methoxy)phenyl)acetate (218e) (12 mg) as a yellow solid; MS (ESI+): 429.20 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-1 -methyl-1 H-indol-5yl)methoxy)phenyl)acetic acid (218f).

Compound 218f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy) phenyl)acetate (218e) (12 mg, 0.028 mmol) in MeOH/THF (3 ml, 1:1), using a solution of lithium hydroxide monohydrate (8 mg, 0.17 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetic acid (218f) (2.0 mg, 18% in three steps) as a pink solid;

1H NMR (300 MHz, DMSO-d ₆ , D2O substitution) δ 7.65 (d, J=1.6 Hz, 1H), 7.56-7.39 (m, 4H), 7.28 (d, J=3.1 Hz, 1H), 7.25-7.12 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.90-6.84 (m, 1H), 6.50 (d, J=3.1 Hz, 1H), 5.16 (s, 2H), 4.09 (s, 2H ), 3.53 (s, 2H), 3.27 (s, 3H); MS (ESI-): 399.30 (M-1) and 435.20 (M+Cl).

Scheme-219

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (219c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (219a).

Compound 219a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c) (750 mg, 1.523 mmol) in dioxane (30 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methyl)carbamate (123a) (1018 mg, 3.05 mmol), solution of K2CO3 (632 mg, 4.57 mmol) in water (5 ml), bis(triphenylphosphine) palladium(P) chloride (160 mg, 0.228 mmol) when heated at 100°C for 3.5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with methanol in 0% to 5% DCM] ethyl 2-(2-((7(2-(((tert-butoxycarbonyl)amino )methyl)pyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetate (219a) (208 mg, 24%) as a brown tarry solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (dd, J=5.2, 0.8 Hz, 1H), 7.81 (s, 1H), 7.76-7.73 (m , 1H), 7.69 (d, J=1.6 Hz, 1H), 7.61-7.59 (m, 1H), 7.47 (t, J=6.1 Hz, 1H), 7 .31-7.19 (m, 2H), 7.13-7.09 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.73 (s , 1H), 5.21 (s, 2H), 4.32 (d, J=6.0 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.61 (s , 2H), 2.71 (d, J=7.1 Hz, 2H), 2.19-1.99 (m, 1H), 1.39 (s, 9H), 1.00-0.91 ( m, 9H); MS (ESI+): 573.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetate (219b).

Compound 219b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2- isobutylbenzofuran-5yl)methoxy)phenyl)acetate (219a) (200 mg, 0.349 mmol) in DCM (20 ml) using TFA (0.269 ml, 3.49 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 10% DCM] ethyl 2-(2-((7-(2(aminomethyl)pyridin-4-yl )-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (219b) (145 mg, 88% yield) as a clear oil;

- 293 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (dd, J=5.3, 0.8 Hz, 1H), 8.35 (s, 3H), 8.01-7.99 (m , 1H), 7.97 (dd,

J=5.2, 1.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.31- 7.19 (m, 2H), 7.11 (dd, J=8.2, 1.1 Hz,

1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.76 (d, J=0.8 Hz, 1H), 5.24 (s, 2H), 4, 32 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.73 (d, J=6.9 Hz, 2H), 2, 19-1.93 (m, 1H), 1.05-0.87 (m, 9H); MS (ESI+): 473.3 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (219c).

Compound 219c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy) phenyl)acetate (219b) (620 mg, 1.312 mmol) in MeOH/THF (10 mL each), using a solution of lithium hydroxide monohydrate (220 mg, 5.25 mmol) in water (10 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetic acid (219c) (167 mg, 86%), HCl salt, as a fluffy white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.59 (s, 3H), 8.09 (s, 1H), 8.02 (dd , J=5.3, 1.7 Hz, 1H), 7.75 (d, J=2.3 Hz, 2H), 7.30-7.17 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.74 (s, 1H), 5.26 (s, 2H), 4.41-4, 20 (m, 2H), 3.60 (s, 2H), 2.73 (d, J=7.0 Hz, 2H), 2.20-1.95 (m, 1H), 0.97 (d , J=6.6 Hz, 6H); MS (ESI+): 445.2 (M+1).

Scheme-220

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (220g).

Stage-1. Preparation of (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (220b).

To a solution of 4-chloro-3-fluoropicolinaldehyde (220a) (6.73 g, 42.2 mmol; CAS No. 1260878-78-1) and Cs ₂ CO ₃ (27.5 g, 84 mmol) in DCM (350 ml ) (S)-2-methylpropane-2-sulfinamide (5.88 g, 48.5 mmol) was added and stirred at rt for 1 hour. The reaction mixture was diluted with DCM and washed with brine (3x200 ml). The organic layer was dried, filtered and concentrated in vacuo to give (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (220b) (11.08 g, 100% yield), which was used in the next reaction without further purification;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (d, J=5.1 Hz, 1H), 8.56 (s, 1H), 7.97 (dd, J=5.6, 5 .0 Hz, 1H), 1.21 (s, 9H).

Stage-2. Preparation of (+)-(S)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropan-2sulfinamide (220c).

To a solution of (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropan-2-sulfinamide (220b) (11.08 g, 42.2 mmol) in methanol (211 ml) at 0°C, NaBH ₄ (1.595 g, 42.2 mmol) was added and stirred for 0.5 h. The reaction mixture was quenched with acetone (20 ml) and concentrated in vacuo. The residue was taken up in EtOAc and saturated with aq. _NH4Cl . The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (120 g), eluted with 9:1 ethyl acetate/methanol in hexanes] to give (+)-(S)-N-((4-chloro-3-fluoropyridine-2 -yl)methyl)-2-methylpropane-2-sulfinamide (220c) (9.34 g, 84% yield) as a thick clear syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.36 (d, J=5.2 Hz, 1H), 7.72-7.62 (m, 1H), 5.86 (t, J=5 .9 Hz, 1H), 4.34 (dd, J=5.9, 2.2 Hz, 2H), 1.09 (s, 9H); optical rotation [a] _D = +53.88 (c = 0.49, MeOH).

- 294 045626

Stage-3. Preparation of ethyl 2-(2-((2-isobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (220d) .

Compound 220d was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c) (750 mg, 1.523 mmol), using bis(pinacolato)diboron (580 mg, 2.285 mmol), potassium acetate (449 mg, 4.57 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ (373 mg, 0.457 mmol) in anhydrous dioxane (25 ml) under Ar atmosphere while heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with 0% to 10% EtOAc in hexane] ethyl 2-(2-((2-isobutyl-7-(4,4, 5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (220d) (370 mg) as an off-white solid.

Stage-4. Preparation of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate ( 220e).

Compound 220e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-isobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (220d) (350 mg, 0.711 mmol) in dioxane (8 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (282 mg, 1.066 mmol), bis(triphenylphosphine) palladium(P) chloride (150 mg, 0.213 mmol) and K ₂ CO ₃ solution ( 295 mg, 2.132 mmol) in water (0.8 ml) under Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (8)-ethyl 2-(2-((7- (2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (220e) (196 mg) as a light brown gum.

Stage-5. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetate (220f)

Solution of (8)-ethyl 2-(2-((7-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2isobutylbenzofuran-5-yl)methoxy)phenyl)acetate ( 220e) (186 mg, 0.313 mmol) in ethanol (5 ml) was cooled to 0°C, hydrochloric acid (4 M in 1,4-dioxane, 0.235 ml, 0.938 mmol) was added and stirred at rt for 1 hour. Reaction the mixture was concentrated to dryness to give ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (220f), which was used as is in the next stage; MS (ESI+): 491.3 (M+1) and 513.2 (M+Na).

Stage-6. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5yl)methoxy)phenyl)acetic acid (220g).

Compound 220g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl )methoxy)phenyl)acetate (220f) (154 mg, 0.313 mmol) in THF (8 ml) and MeOH (8 ml), using lithium hydroxide monohydrate (134 mg, 3.13 mmol) in water (8 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetic acid (220g) (34 mg, 5.4% over 4 steps) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.57-8.46 (m, 3H) , 7.82-7.75 (m, 2H), 7.51-7.49 (m, 1H), 7.29-7.18 (m, 2H), 7.09 (d, J=8, 0 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.74 (s, 1H), 5.25 (s, 2H), 4.46-4, 30 (m, 2H), 3.58 (s, 2H), 2.66 (d, J=7.0 Hz, 2H), 2.18-1.82 (m, 1H), 0.94 (d , J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.52; MS (ESI+): 463.2 (M +1), MS (ESI-): 461.3 (M-1); purity after HPLC: 95.28%.

Scheme-221

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (221c).

- 295 045626

Stage-1. Preparation of ethyl 2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetateα (221a).

Compound 221a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl) acetate (116d) (240 mg, 0.506 mmol) in dioxane (6 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridin-2 -yl)methyl)carbamate (123a) (254 mg, 0.759 mmol), solution of NaHCO ₃ (127 mg, 1.517 mmol) in water (0.6 ml), bis(triphenylphosphine) palladium(P) chloride (107 mg, 0.152 mmol) when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] ethyl 2-(2-((4-(2-(((tert- butoxycarbonyl)αmino)methyl)pyridin-4-yl)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (221a) (195 mg, 72%) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (dd, J=5.0, 0.9 Hz, 1H), 8.17-8.15 (m, 1H), 7.89 (d , J=5.5 Hz, 1H), 7.57-7.44 (m, 5H), 7.30-7.18 (m, 2H), 7.13-7.09 (m, 1H), 6.95-6.89 (m, 1H), 5.29 (s, 2H), 4.32 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz , 2H), 3.64 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 533.2 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6yl)methoxy)phenyl)acetate (221b).

Compound 221b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzo[b ]thiophen-6yl)methoxy)phenyl)acetate (221a) (185 mg, 0.347 mmol) in DCM (10 ml) using TFA (0.268 ml, 3.47 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/DMA 80 (1:0 to 2:1)] ethyl 2-(2-((4-(2(aminomethyl)pyridinium- 4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate (221b) (131 mg, 87%) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.89 (d, J=5.6 Hz, 1H), 7.71-7.69 (m, 1H), 7.55-7.41 (m, 3H), 7.31-7.17 (m, 2H), 7.11 (dd, J= 8.2, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.01-3.86 (m , 4H), 3.65 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 433.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (221c).

Compound 221c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy )phenyl)acetate (221b) (120 mg, 0.277 mmol) in MeOH/THF (7 mL each), using a solution of lithium hydroxide monohydrate (71 mg, 1.67 mmol) in water (8 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (221c) (43 mg, 38%) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.78-8.75 (m, 1H), 8.52 (s, 3H), 8.22-8.20 (m, 1H), 7.93 ( d, J=5.6 Hz, 1H), 7.82-7.80 (m, 1H), 7.68 (dd, J=5.2, 1.7 Hz, 1H), 7.63-7 .52 (m, 2H), 7.28-7.17 (m, 2H), 7.13-7.04 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz , 1H), 5.32 (s, 2H), 4.35-4.26 (m, 2H); MS (ESI+): 405.15 (M+1); MS (ESI-): 403.30 (M-1); purity after HPLC: 89.53%.

Scheme-222

Preparation of 2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (222f).

Stage-1. Preparation of 2-acetamido-2-(2-hydroxyphenyl)acetic acid (222b) To a solution of 2-amino-2-(2-hydroxyphenyl)acetic acid (222a) (1 g, 5.98 mmol; CAS No. 25178-38-5) in water (20 ml), add sodium hydroxide (0.502 g, 12.56 mmol), acetic anhydride (1.411 ml, 14.96 mmol) and stir for 30 min at rt. The solution was acidified with 3N HCl and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and concentrated in vacuo to give 2-acetamido-2-(2-hydroxyphenyl)acetic acid (222b)

- 296 045626 (1.1 g, 88% yield) in the form of a white solid; MS (ESI+) 210.10 (M+1), (ESI-) 208.20 (M-1).

Stage-2. Preparation of ethyl 2-acetamido-2-(2-hydroxyphenyl)acetate (222c).

To a solution of 2-acetamido-2-(2-hydroxyphenyl)acetic acid (222b) (1.06 g, 5.07 mmol) in ethanol (20 ml) was added sulfuric acid (0.270 ml, 5.07 mmol) and heated with reflux for 2 hours. The reaction mixture was cooled to room temperature, neutralized with sodium bicarbonate and concentrated in vacuo to remove excess ethanol. The residue was diluted with water (30 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with water (2x20 ml), brine (20 ml), dried, filtered and concentrated in vacuo to give ethyl 2-acetamido-2-(2hydroxyphenyl)acetate (222c) (700 mg, 58% yield) as thick syrup;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.38 (d, J=7.5 Hz, 1H), 7.21-7.07 (m, 2H) , 6.93-6.69 (m, 2H), 5.63 (d, J=7.5 Hz, 1H), 4.18-3.91 (m, 2H), 1.86 (s, 3H ), 1.11 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-acetamido-2-(2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (222d).

Compound 222d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.453 g, 1.283 mmol) in DCM (15 ml) using triphenylphosphine (0.370 g, 1.411 mmol), ethyl 2-acetamido-2-(2-hydroxyphenyl) acetate (222c) (0.35 g, 1.475 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 0.518 g , 1.411 mmol). This resulted, after workup and purification by flash column chromatography (silica gel 40 g, eluted with ethyl acetate in 0% to 50% hexanes), ethyl 2-acetamido-2-(2-((7-(3-((( tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (222d) (480 mg, 65% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=7.8 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.81-7.70 (m, 3H), 7.61 (d, J=1.6 Hz, 1H), 7.48 (t, J=7.4 Hz, 2H), 7.36-7.23 (m, 3H) , 7.22-7.10 (m, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.016.92 (m, 1H), 5.82 (d, J=7.8 Hz, 1H), 5.31 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 4.07-3.97 (m, 2H), 1.86 (d, J =0.8 Hz, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 473.25 (M+1-Vos), (ESI-) 571.40 (M-1).

Stage-4. Preparation of ethyl 2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (222e).

Compound 222e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2acetamido-2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl) methoxy)phenyl)acetate (222d) (100 mg, 0.175 mmol) in DCM (10 ml) using TFA (0.135 ml, 1.746 mmol). This resulted in the production after treatment of ethyl 2-acetamido-2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (222e) (83 mg, 100% yield), which was used in the next step without further purification; MS (ESI+): 473.25 (M+1).

Stage-5. Preparation of 2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (222f).

Compound 222f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 222e) (83 mg, 0.176 mmol) in THF (5 ml) and methanol (5 ml), using a solution of lithium hydroxide monohydrate (21 mg, 0.878 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-acetamido-2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (222f) (43 mg, 55% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.71 (s, 1H), 8.56 (d, J=7.9 Hz, 1H), 8.38 (s, 3H), 8.11 ( d, J=2.2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.95 (dt, J=7.5, 1.7 Hz, 1H), 7, 78 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.637.52 (m, 2H), 7.32 (td, J=7.4 , 6.8, 1.8 Hz, 2H), 7.21-7.13 (m, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.98 (td, J= 7.4, 1.1 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.32 (s, 2H), 4.16 (d, J=5.8 Hz, 2H), 1.86 (s, 3H); MS (ESI+): 445.2 (M+1), (ESI-): 443.3 (M-1).

Scheme-223

223a 223b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-297 045626 (cyclopropanecarboxamido)acetic acid (223e).

Stage-1. Preparation of 2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetic acid (223a).

To a solution of 2-amino-2-(2-hydroxyphenyl)acetic acid (222a) (1 g, 5.98 mmol; CAS No. 2517838-5) in water (20 ml/THF (10 ml), cooled to 0°C , add sodium bicarbonate (2.010 g, 23.93 mmol), a solution of cyclopropanecarbonyl chloride (1.629 ml, 17.95 mmol) in tetrahydrofuran (10 ml) and allow to warm to rt.The solution is acidified with 3N HCl and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and concentrated in vacuo to give 2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetic acid (223a) (2.03 g) as a thick syrup, which used in the next step without further purification;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (d, J=7.8 Hz, 1H), 7.31-7.05 (m, 2H), 6.93-6.60 ( m, 2H), 5.62 (d, J=7.8 Hz, 1H), 1.84-1.69 (m, 1H), 0.71-0.58 (m, 4H); MS (ESI+): 236.1 (M+1), (ESI-): 270.3 (M+Cl).

Stage-2. Preparation of ethyl 2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetate (223b).

Compound 223b was prepared according to the procedure described in step-2 of Scheme-222 from 2(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetic acid (223a) (2.03 g, 8.63 mmol) in ethanol (30 ml) using sulfuric acid (0.920 ml, 17.26 mmol). This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetate (223b) (585 mg, 26% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.59 (d, J=7.5 Hz, 1H), 7.22-7.04 (m, 2H), 6 .92-6.68 (m, 2H), 5.66 (d, J=7.5 Hz, 1H), 4.13-4.02 (m, 2H), 1.82-1.65 (m , 1H), 1.11 (t, J=7.1 Hz, 3H), 0.74-0.51 (m, 4H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate (223c).

Compound 223c was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (642 mg, 1.816 mmol) in DCM (15 ml) using triphenylphosphine (548 mg, 2.089 mmol), ethyl 2-(cyclopropanecarboxamido)-2-(2hydroxyphenyl)acetate (223b) (550 mg, 2.089 mmol) and di-(4-chlorobenzyl) azodicarboxylate (DCAD, 800 mg, 2.180 mmol). This resulted, after work-up and purification by flash chromatography on a column (silica gel 40 g, eluted with ethyl acetate in 0% to 50% hexanes), ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)benzofuran-5-yl)methoxy)phenyl)-2(cyclopropanecarboxamido)acetate (223c) (1.15 g, 106% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J=8.0 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.84-7.69 (m, 3H), 7.62 (d, J=1.6 Hz, 1H), 7.52-7.42 (m, 2H), 7.42-7.34 (m, 1H), 7. 34-7.25 (m, 2H), 7.22-7.14 (m, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.98 (td, J=7, 5, 1.1 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.31 (s, 2H), 4.22 (d, J=6.2 Hz, 2H) , 3.98 (dd, J=7.1, 5.3 Hz, 2H), 1.76 (m, 1H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H), 0.63 (m, 4H); MS (ESI+): 499.20 (M+1-Vos), 599.25 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2(cyclopropanecarboxamido)acetate (223d).

Compound 223d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )phenyl)-2(cyclopropanecarboxamido)acetate (223c) (1 g, 1.670 mmol) in DCM (15 ml) using TFA (1.287 ml, 16.70 mmol). This resulted in 223d (840 mg, 101% yield) as the TFA salt upon workup. 100 mg of this material was purified by reverse phase chromatography on a [C18 (30 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give ethyl 2-(2-((7-( 3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate (223d), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=7.9 Hz, 1H), 8.29 (s, 3H), 8.11 (d, J=2.2 Hz, 1H ), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J =1.6 Hz, 1H), 7.63-7.51 (m, 2H), 7.38-7.26 (m, 2H), 7.20 (d, J=8.2 Hz, 1H) , 7.06 (d, J=2.2 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 5.88 (d, J=7.9 Hz, 1H), 5 .31 (s, 2H), 4.14 (s, 2H), 3.99 (cd, J=7.1, 4.0 Hz, 2H), 1.76 (p, J=6.5 Hz, 1H), 0.99 (t, J=7.1 Hz, 3H), 0.64 (dt, J=18.0, 6.9 Hz, 4H); MS (ESI+): 499.3 (M+1), 521.2 (M+Na).

Stage-5. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2(cyclopropanecarboxamido)acetic acid (223e).

Compound 223e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido )acetate (223d) (833 mg, 1.67 mmol) in THF (10 ml) and methanol (5 ml), using a solution of lithium hydroxide monohydrate (160 mg, 6.68 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2(cyclopropanecarboxamido)acetic acid (223e) (250 mg, 32% yield), HCl salt, as a white solid;

- 298 045626

1H NMR (300 MHz, DMSO4) δ 12.73 (s, 1H), 8.73 (d, J=8.1 Hz, 1H), 8.56 (s, 3H), 8.11 (d, J =2.2 Hz,

1H), 8.03 (k, J=1.3 Hz, 1H), 7.93 (m, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.63-7.53 (m, 2H), 7.31 (ddd, J=13.0, 7.6, 1.7 Hz, 2H), 7.16 (dd, J=8.3, 1.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.98 (td, J=7.5, 1.1 Hz, 1H),

5.89 (d, J=8.0 Hz, 1H), 5.33 (s, 2H), 4.13 (s, 2H), 1.76 (m, 1H), 0.76-0.48 (m, 4H); MS (ESI+): 471.2 (M+1), (ESI-): 469.3 (M-1).

Scheme-224

Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (224c).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (224a)

A mixture of ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (182b) (0.300 g, 0.505 mmol), acetamide ( 0.089 g, 1.514 mmol), (note: before use, acetamide was dried over P ₂ O ₅ ), Cs ₂ CO ₃ (0.164 g, 0.505 mmol), dicyclohexyl (2',4',6'triisopropylbiphenyl-2-yl)phosphine (X-PHOS) (0.048 g, 0.101 mmol), Pd ₂ (dba) ₃ (0.046 g, 0.050 mmol) was purged with a forced stream of nitrogen for 10 min, followed by the addition of anhydrous toluene (10 ml) under a forced stream of nitrogen. The flask was heated at 95°C for 4 hours, cooled to room temperature, and diluted with ethyl acetate (100 ml) and saline (100 ml). Vodn. the layer was separated and extracted with ethyl acetate (100 ml). The combined organic layer was washed with brine, dried, filtered and evaporated to dryness. The resulting residue was purified by column chromatography [silica gel 12 g, eluted with methanol in DCM 0 to 40%] to give ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (224a) (0.233 g, 81% yield) as orange syrup;

1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.75 (d, J=9.1 Hz, 2H ), 7.70 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.54-7.42 (m, 2H), 7.30 (d, J=7.5 Hz, 1H), 7.15-7.08 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 5.17 (s, 2H) , 4.23 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.03 (s, 3H) , 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 473.3 (M+1, -Boc).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (224b).

Compound 224b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl )methoxy)phenyl)acetate (224a) (0.205 g, 0.358 mmol) in DCM (20 ml) using TFA (0.552 ml, 7.16 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 100% DCM] ethyl 2-(4-acetamido-2-((7-(3(aminomethyl)phenyl )benzofuran-5-yl)methoxy)phenyl)acetate (224b) (0.133 g, 79% yield) as a brown solid; MS (ESI+): 473.25 (M+1); MS (ESI-): 471.3 (M-1).

Stage-3. Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (224c).

Compound 224c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (224b) (0.130 g, 0.275 mmol) in THF (4 mL) and methanol (8 mL) using 2 M LiOH (0.688 mL, 1.376 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in DCM 0% to 100%] followed by reverse phase column chromatography [C18 (30 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(4-acetamido-2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (224c) ( 0.032 g, 26% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.21 (br.s, 1H, D2O replaceable), 10.10 (s, 1H, D2O replaceable), 8.54

- 299 045626 (br. s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H), 8.08-8.04 (m, 1H), 7.99-7.92 (m, 1H), 7.76 (d, J=1.6 Hz,

1H), 7.67 (d, J=1.6 Hz, 1H), 7.60-7.56 (m, 2H), 7.54-7.50 (m, 1H), 7.14-7 .09 (m, 2H), 7.06 (d, J=2.2 Hz, 1H),

5.21 (s, 2H), 4.13 (k, J=5.9 Hz, 2H), 3.53 (s, 2H), 2.04 (s, 3H); MS (ESI+): 445.2 (M+1); MS (ESI-): 443.3 (M-1); purity after HPLC: 86.98%; analysis calculation for C2 ₆ H ₂₄ N ₂ O ₅ -HCl-1.25H ₂ O: C, 62.03; N, 5.51; N,

5.56; observed: C, 61.88; N, 5.45; N, 5.51.

Scheme-225

Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetic acid (225h).

Stage-1. Preparation of 4-(5-chlorofuran-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (225b).

Compound 225b was prepared according to the procedure described in step-1 of scheme-215 from 5chlorofuran-2-carbaldehyde (225a) (2.47 g, 18.92 mmol; CAS No. 21508-19-0) in t-BuOH ( 5 ml) using potassium tert-butoxide (3.5 g, 30.6 mmol) in t-BuOH (20 ml) and dimethyl succinate (7.1 g, 48.6 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 120 g, eluted with 0-60% ethyl acetate in hexane), 4-(5-chlorofuran-2-yl)-3-(methoxycarbonyl)but-3enoic acid ( 225b) (3.43 g, 74% yield) as a yellow solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.36 (s, 1H), 7.42 (s, 1H), 7.06 (dd, J=3.6, 0.5 Hz, 1H) , 6.71 (d, J=3.5 Hz, 1H), 3.73 (s, 3H), 3.62 (s, 2H).

Stage-2. Preparation of methyl 4-acetoxy-2-chlorobenzofuran-6-carboxylate (225c).

Compound 225c was prepared according to the procedure described in step-2 of Scheme-215 from 4-(5chlorofuran-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (225b) (3.43 g, 14. 02 mmol) in acetic anhydride (20 ml), using NaOAc (5.1 g, 62.2 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 40 g, eluted with 0-40% ethyl acetate in hexane) methyl 4-acetoxy-2-chlorobenzofuran-6-carboxylate (225c) (1.68 g, 45 % yield) as a yellow solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (t, J=1.1 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H).

Stage-3. Preparation of 2-chloro-6-(hydroxymethyl)benzofuran-4-ol (225d).

Compound 225d was prepared according to the procedure described in step-2 of Scheme-76 from methyl 4-acetoxy-2-chlorobenzofuran-6-carboxylate (225c) (698 mg, 2.60 mmol) in THF (20 ml) using LiBH ₄ (3.3 ml, 13.20 mmol) and MeOH (0.53 ml, 13.10 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with 20 to 75% EtOAc in hexane] 2-chloro-6-(hydroxymethyl)benzofuran-4-ol (225d) (274 mg, 53% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 6.95 (p, J=0.9 Hz, 1H), 6.91 (d, J=0.9 Hz, 1H), 6.65 (t, J=0.9 Hz, 1H), 5.24 (t, J=5.8 Hz, 1H), 4.49 (d, J=5.5 Hz, 2H) .

Stage-4. Preparation of 2-chloro-6-(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate (225e).

Compound 225e was prepared according to the procedure described in step-2 of scheme-116 from 2chloro-6-(hydroxymethyl)benzofuran-4-ol (225d) (644 mg, 3.24 mmol) in DMF (15 ml) using 1,1,1trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.19 g, 3.26 mmol) itriethylamine (1 ml, 7.17 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 24 g, eluted with 0-50% EtOAc in hexane) 2-chloro-6(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate (225e) (1.01 g, 94 % yield) as white

- 300 045626 solid matter.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (t, J=1.0 Hz, 1H), 7.42 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H),

4.66 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -72.68.

Stage-5. Preparation of ethyl 2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6yl)methoxy)phenyl)acetate (225f).

Compound 225f was prepared according to the procedure described in step-2 of Scheme-23 from 2chloro-6-(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate (225e) ((970 mg, 2.93 mmol) in DCM (35 ml) using triphenylphosphine (778 mg, 2.97 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (699 mg, 3.88 mmol) and di-(4-chlorobenzyl) azodicarboxylate (1.19 g, 3 .24 mmol) in DCM (8 ml) This gave, after work-up and purification by flash column chromatography (silica gel 40 g, 040% EtOAc in hexanes), ethyl 2-(2-((2-chloro-4- (((trifluoromethyl)sulfonyl)oxy)benzofuran-6yl)methoxy)phenyl)acetate (225f) (839 mg, 58% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.86 (t, J=1.0 Hz, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.31-7, 21 (m, 3H), 7.05 (d, J=7.9 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H ), 4.01 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.08 (t, J=7.1 Hz, 3H).

Stage-6. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6yl)methoxy)phenyl)acetate (225g).

Compound 225g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl) acetate (225f) (280 mg, 0.568 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (102 mg, 0.676 mmol), K ₂ CO ₃ solution (280 mg, 2.026 mmol) in water (0.5 ml), Pd(PPh ₃ ) ₂ Cl ₂ (62 mg, 0.088 mmol) and heating in an Ar atmosphere at 100°C for 3 hours. This gave, after work-up and purification by flash chromatography on a column (silica gel 12 g, eluted with DMA80 in DCM from 0 to 70%) ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate ( 225g) (137 mg, 54% yield) as a clear oil.

1H NMR (300 MHz, chloroform-d) δ 7.61-7.44 (m, 4H), 7.44-7.34 (m, 2H), 7.32-7.21 (m, 2H), 6.98 (dd, J=8.8, 5.7, 1.5 Hz, 2H), 6.78 (d, J=1.0 Hz, 1H), 5.23 (s, 2H), 4 .10 (k, J=7.1 Hz, 2H), 3.98 (s, 2H), 3.72 (s, 2H), 1.17 (t, J=7.1 Hz, 3H); MS (ESI+): 450.2 (M+1).

Stage-7. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6yl)methoxy)phenyl)acetic acid (225h).

Compound 225h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate ( 225g) (137 mg, 0.304 mmol) in MeOH/THF (6 ml), using a solution of lithium hydroxide (62 mg, 1.478 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((4-(3-( aminomethyl)phenyl)-2-chlorobenzofuran6-yl)methoxy)phenyl)acetic acid (225h) (51 mg, 40% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ , D ₂ O substitution) δ 7.74 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.50 (s, 3H) , 7.27 (s, 1H), 7.16 (d, J=7.2 Hz, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.84 (t, J= 7.4 Hz, 1H), 5.22 (s, 2H), 4.07 (s, 2H), 3.55 (s, 2H); MS (ESI+): 422.1 (M+1); MS (ESI-): 420.2 (M-1).

Scheme-226

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (226c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-301 045626 (trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (226a).

Compound 226a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (199d) (229 mg, 0.501 mmol) in dioxane (5 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methyl)carbamate (123a) (259 mg, 0.775 mmol), solution of K ₂ CO ₃ (214 mg, 1.548 mmol) in water (0.5 ml), bis(triphenylphosphine) palladium(P) chloride (62 mg, 0.088 mmol) when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with ethyl acetate in 20 to 100% hexanes] ethyl 2-(2-((7-(2-((tert-butoxycarbonyl)amino )methyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (226a) (166 mg, 57% yield) as a pale yellow oil.

^1H NMR (300 MHz, chloroform-d) δ 8.71 (dd, J=5.3, 0.9 Hz, 1H), 7.90-7.65 (m, 4H), 7.38-7 .18 (m, 4H), 7.07-6.86 (m, 2H), 5.28 (s, 2H), 4.60 (d, J=5.5 Hz, 2H), 4.13- 4.04 (m, 2H), 3.72 (s, 2H), 1.47 (s, 9H), 1.15 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, chloroform-d) δ -64.74; MS (ESI+): 585.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (226b).

Compound 226b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2- (trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (226a) (166 mg, 0.284 mmol) in DCM (5 ml) using TFA (0.3 ml, 3.89 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with DMA80/DCM, 0% to 80%] ethyl 2-(2-((7-(2(aminomethyl)pyridine-4- yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (226b) (112 mg, 81% yield) as a pale yellow oil; MS (ESI+): 485.2 (M+1); MS (ESI-): 483.2 (M-1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (226c).

Compound 226c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl )methoxy)phenyl)acetate (226b) (112 mg, 0.231 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (63 mg, 1.50 mmol) in water (2.0 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (226c) (58 mg, 55% yield), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J=5.3 Hz, 1H), 8.67 (s, 3H), 8.11 (d, J=1.7 Hz, 1H), 8.05 (s, 2H), 8.00 (dd, J=5.3, 1.7 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7, 31-7.20 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.00-6.87 (m, 1H), 5.34 (s, 2H), 4 .34 (d, J=5.6 Hz, 2H), 3.63 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -63.34. MS (ESI+): 457.2 (M+1); MS (ESI-): 455.2 (M-1). HPLC: purity 99.24%.

Scheme-227

227a 227b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (227e).

Stage-1. Preparation of methyl 7-bromo-2-fluorobenzofuran-5-carboxylate (227a).

To a stirred solution of methyl 7-bromobenzofuran-5-carboxylate (169a) (5 g, 19.60 mmol) in dry THF (90 ml) at -78°C under N2 was added LDA (19.6 ml, 1. 5 M, 29.4 mmol). The mixture was kept at -78°C for 1.5 h followed by the addition of a solution of Ν-Φτορ-Ν(phenylsulfonyl)benzenesulfonamide (12.5 g, 39.6 mmol) in THF (60 ml). The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with a saturated aqueous solution of NH ₄ Cl and extracted with ethyl acetate. The organic layers were combined, washed with saline, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography [silica gel (40 g), eluted with ethyl acetate/hexanes, 0-40%] to give methyl 7-bromo-2fluorobenzofuran-5-carboxylate (227a) (453 mg, 9% yield) as yellow solid matter.

¹ H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J=1.6 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 6.64 (d, J=6.5 Hz, 1H), 3.89 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO4;) δ -109.09.

Stage-2. Preparation of (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b).

Compound 227b was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-fluorobenzofuran-5-carboxylate (227a) (495 mg, 1.813 mmol) in THF (15 ml) using LiBH ₄ (1.45 ml, 5.80 mmol) and MeOH (0.225 ml, 5.56 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] followed by purification using reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (90 mg, 20% yield) as a white solid;

^1H NMR (300 MHz, chloroform-d) δ 7.46-7.25 (m, 2H), 5.89 (d, J=6.6 Hz, 1H), 4.65 (s, 2H), 2.84 (s, 1H); ¹⁹ F NMR (282 MHz, chloroform-d) δ -109.55.

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (227c).

Compound 227c was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-fluorobenzofuran-5-yl)methanol (227b) (90 mg, 0.367 mmol) in DCM (8 ml) using triphenylphosphine ( 107 mg, 0.408 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (91 mg, 0.505 mmol) and di-(4chlorobenzyl) azodicarboxylate (DCAD, 162 mg, 0.441 mmol) in DCM (2 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5- yl)methoxy)phenyl)acetate (227c) (116 mg, 78% yield) as a white solid.

^1H NMR (300 MHz, chloroform-d) δ 7.51 (p, J=0.9 Hz, 2H), 7.28 (t, J=7.6 Hz, 2H), 7.05-6, 89 (m, 2H), 5.97 (d, J=6.6 Hz, 1H), 5.12 (s, 2H), 4.17 (k, J=7.1 Hz, 2H), 3, 71 (s, 2H), 1.24 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, chloroform-d) δ -109.43.

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetate (227d).

Compound 227d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (227c) (116 mg, 0.285 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (60 mg, 0.397 mmol), solution of K ₂ CO ₃ (121 mg, 0.876 mmol) in water (0.5 ml), bis(triphenylphosphine)palladium(P) chloride (32 mg, 0.046 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 90%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2-fluorobenzofuran-5yl)methoxy)phenyl)acetate (227d) (48 mg, 39% yield) as a pale yellow oil.

1H NMR (300 MHz, chloroform-d) δ 7.76-7.53 (m, 2H), 7.39 (dt, J=8.0, 1.6 Hz, 3H), 7.27 (dd, J=7.1, 1.8 Hz, 1H), 7.15 (m, 3H), 6.86 (t, J=7.0 Hz, 2H), 5.82 (dd, J=6.6 , 1.8 Hz, 1H), 5.09 (d, J=3.0 Hz, 2H), 4.06-3.79 (m, 4H), 3.59 (s, 2H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, chloroform-d) δ -110.82. MS (ESI+): 434.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (227e).

Compound 227e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate ( 227d) (48 mg, 0.111 mmol) in MeOH/THF (4 mL each), using a solution of lithium hydroxide monohydrate (32 mg, 0.763 mmol) in water (1.6 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (227e) (25 mg, 56% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 3H), 7.89 (d, J=1.6 Hz, 1H), 7.82-7.74 (m, 1H), 7.59 (dd, J=14.2, 1.7 Hz, 2H), 7.55-7.49 (m, 2H), 7.17 (dd, J=8.2, 6.5 Hz, 2H), 7.06-6.98 (m, 1H), 6.84 (td, J=7.4, 1.1 Hz, 1H), 6.37 (d, J=6.4 Hz, 1H ), 5.19 (s, 2H), 4.06 (s, 2H), 3.53 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.56. MS (ESI+): 406.1 (M+1); MS (ESI-): 404.2 (M-1). HPLC: purity 97.63%.

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Scheme-228

228с ^{228d 228е}

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (228e).

Stage-1. Preparation of methyl 4-bromo-1-(isopropylsulfonyl)-1H-indole-6-carboxylate (228a).

Compound 228a was prepared according to the procedure described in step-1 of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g, 7.87 mmol) in DMF (25 ml) using NaH (60% in mineral oil, 0.94 g, 23.61 mmol) and propane-2-sulfonyl chloride (2.66 ml, 23.61 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH=9:1 in 0% to 50% hexane] methyl 4-bromo-1-(isopropylsulfonyl)-III indole-6-carboxylate (228a) (2.79 g, 98% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.46 (t, J=1.1 Hz, 1H), 8.04 (d, J=1.2 Hz, 1H), 7.99 (d, J=3.7 Hz, 1H), 6.91 (dd, J=3.7, 0.9 Hz, 1H), 3.99-3.92 (m, 1H), 3.91 (s, 3H ), 1.22 (d, J=6.8 Hz, 6H); MS (ESI+): 360.0, 362.0 (M+1); MS (ESI-): 358.1, 360.2 (M-1).

Stage-2. Preparation of (4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methanol (228b).

Compound 228b was prepared according to the procedure described in step-2 of Scheme-212 from methyl 4-bromo-1-(isopropylsulfonyl)-1H-indole-6-carboxylate (228a) (1 g, 2.79 mmol) in dichloromethane (10 ml) using diisobutylaluminum hydride (1 M solution in dichloromethane) (6.98 ml, 6.98 mmol). This resulted in (4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methanol (228b) (0.88 g, 95% yield) as a crystalline solid upon treatment;

^1H NMR (300 MHz, DMSO-d6) δ 7.85 (p, J=0.9 Hz, 1H), 7.69 (d, J=3.7 Hz, 1H), 7.49 (dd, J=1.2, 0.6 Hz, 1H), 6.75 (dd, J=3.7, 0.8 Hz, 1H), 5.43 (t, J=5.9 Hz, 1H), 4.62 (dt, J=5.9, 0.7 Hz, 2H), 3.91-3.70 (m, 1H), 1.291.09 (m, 6H).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (228c).

Compound 228c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methanol (228b) (0.88 g, 2.65 mmol) in toluene (15 ml) using triphenylphosphine (0.90 g, 3.44 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.621 g, 3.44 mmol) and (E)-diazen-1 ,2-diylbis(piperidin-1-ylmethanone) (0.87 g, 3.44 mmol) in toluene (15 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH (9:1) in 0% to 10% hexane for 40 min, then 10% 50%] ethyl 2-(2-((4-bromo-1-(isonropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (228c) (1.15 g, 88% yield) as a yellow oil; MS (ESI-): 493.2, 495.2 (M-1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetate (228d).

Compound 228d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (228c ) (0.24 g, 0.49 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.14 g, 0.73 mmol), K ₂ CO ₃ (0. 13 g, 0.97 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(I) chloride (0.051 g, 0.073 mmol) in an Ar atmosphere by heating at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4 -(3-(aminomethyl)phenyl)-1(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (228d) (0.12 g, 48% yield), HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.39 (s, 3H), 7.98 (s, 1H), 7.78 (s, 1H), 7.72 (dd, J=3.8 , 0.9 Hz, 1H), 7.70-7.50 (m, 3H), 7.50-7.43 (m, 1H), 7.32-7.17 (m, 2H), 7. 12 (d, J=8.2 Hz, 1H), 7.02 (d, J=3.8 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.30 ( s, 2H), 4.13 (s, 2H), 3.96-3.86 (m, 2H), 3.86-3.77 (m, 1H), 3.62 (s, 2H), 1 .21 (d, J=6.7 Hz, 6H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 521.3 (M+1), MS (ESI-): 519.3 (M-1).

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Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1 -(isopropylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (228e).

Compound 228e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl) methoxy)phenyl)acetate (228d) (0.09 g, 0.16 mmol) in MeOH/THF (4 ml, 1:1), using a solution of lithium hydroxide monohydrate (0.06 g, 1.31 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (228e) (0.05 g, 56% yield), HCl salt, as a white solid substances;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.16 (s, 1H), 8.38 (s, 3H), 8.00 (s, 1H), 7.79 (s, 1H), 7 .71 (d, J=3.7 Hz, 1H), 7.67 (dt, J=7.4, 1.7 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H) , 7.58-7.54 (m, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.24 (t, J=7.7 Hz, 2H), 7.11 ( d, J=8.1 Hz, 1H), 7.01 (d, J=3.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5, 32 (s, 2H), 4.14 (s, 2H), 3.83 (k, J=6.8 Hz, 1H), 3.60 (s, 2H), 1.21 (d, J=6 .7 Hz, 6H); MS (ESI+): 493.2 (M+1), MS (ESI-): 491.3 (M-1).

Scheme-229

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (229b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1Nindol-6-yl)methoxy)phenyl)acetate (229a).

Compound 229a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (228c ) (0.24 g, 0.49 mmol) in dioxane (4 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.15 g, 0.73 mmol), K ₂ CO ₃ (0.13 g, 0.97 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(P) chloride (0.051 g, 0.073 mmol) in Ar atmosphere when heated at 90°C for 3 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% MeOH in DCM] ethyl 2-(2-((4-(3-(aminomethyl)-2 -fluorophenyl)-1(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (229a) (0.14 g, 54% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.58 (td, J=7.2, 2 .0 Hz, 1H), 7.437.35 (m, 2H), 7.35-7.18 (m, 3H), 7.13 (dd, J=8.3, 1.1 Hz, 1H), 6 .91 (td, J=7.4, 1.1 Hz, 1H), 6.61 (t, J=3.3 Hz, 1H), 5.28 (s, 2H), 3.93-3, 78 (m, 5H), 3.61 (s, 2H), 1.21 (d, J=6.7 Hz, 6H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 539.3 (M+1), MS (ESI-): 537.3 (M-1). Purity after HPLC: 96.40%.

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (229b).

Compound 229b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (229a) (0.2 g, 0.37 mmol) in MeOH/THF (4 ml, 1:1), using lithium hydroxide monohydrate solution (0.13 g, 2.97 mmol ) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3-(aminomethyl)-2-fluorophenyl)-1 -(isopropylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (229b) (0.12 g, 63% yield), HCl salt, as white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.49 (s, 3H), 8.04 (t, J=1.0 Hz, 1H), 7.69 (d, J=3.7 Hz, 1H), 7.68-7.55 (m, 2H), 7.48-7.37 (m, 2H), 7.28-7.18 (m, 2H), 7.15-7.07 ( m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.75 (t, J=3.5 Hz, 1H), 5.32 (s, 2H), 4.16 (s, 2H), 3.85 (p, J=6.7 Hz, 1H), 3.58 (s, 2H), 1.21 (d, J=6.8 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.54; MS (ESI+): 511.2 (M+1), MS (ESI-): 509.3 (M-1).

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Scheme-230

Preparation of 2-(3 -((7-(3 -(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)pyridin-2-yl)acetic acid (230e).

Stage-1. Preparation of tert-butyl 2-(3-(benzyloxy)pyridin-2-yl)acetate (230b).

Compound 230b was prepared according to the procedure described in step-2 of Scheme-163 from 3(benzyloxy)-2-chloropyridine (230a) (0.3 g, 1.366 mmol; CAS No. 108082-72-0) in THF (5 ml), using Pd ₂ (dba) ₃ (0.125 g, 0.137 mmol), Q-Phos (0.097 g, 0.137 mmol) and (2-tert-butoxy-2oxoethyl)zinc(P) chloride (0.5 M solution in ether) (5.46 ml, 2.73 mmol). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in hexanes (0-40 to 100%)] tert-butyl 2-(3-(benzyloxy)pyridin-2-yl)acetate (230b) (165 mg, 40% yield) as an oil;

1H NMR (300 MHz, DMSO-d6) δ 8.06 (dd, J=4.8, 1.3 Hz, 1H), 7.48-7.41 (m, 4H), 7.40 (d, J=0.9 Hz, 1H), 7.38-7.32 (m, 1H), 7.28 (dd, J=8.3, 4.7 Hz, 1H), 5.16 (s, 2H ), 3.72 (s, 2H), 1.33 (s, 9H); MS (ESI+): 300.2 (M+1).

Stage-2. Preparation of tert-butyl 2-(3-hydroxypyridin-2-yl)acetate (230c) To a solution of tert-butyl 2-(3-(benzyloxy)pyridin-2-yl)acetate (230b) (160 mg, 0.534 mmol) in ethyl acetate (20 ml) was added Pd/C (10% on carbon, 57 mg, 0.053 mmol) and hydrogenated under pressure for 3 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give tert-butyl 2-(3- hydroxypyridin-2-yl)acetate (230c) (112 mg, 100% yield) as a light pink solid;

1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.93 (dd, J=4.1, 2.0 Hz, 1H), 7.18-7.03 (m, 2H), 3.61 (s, 2H), 1.39 (s, 9H); MS (ESI+) 210.1 (M+1), (ESI-) 208.3 (M-1).

Stage-3. Preparation of tert-butyl 2-(3-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)acetate (230d).

Compound 230d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) 169 mg, 0.478 mmol) in DCM (10 ml), using triphenylphosphine (144 mg, 0.550 mmol), tert-butyl 2-(3-hydroxypyridin-2-yl) acetate (230c) (115 mg, 0.550 mmol) and di-(4-chlorobenzyl) azodicarboxylate solution (DCAD, 211 mg , 0.573 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel 24 g, eluted with ethyl acetate in 0% to 50% hexanes] tert-butyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2yl)acetate (230d) (250 mg, 96% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10-8.02 (m, 2H), 7.76-7.70 (m, 3H), 7.56 (dd, J=13.9, 1.5 Hz, 1H), 7.52-7.42 (m, 3H), 7.29 (dd, J=8.1, 4.7 Hz, 2H), 7.04 (d, J=2 .2 Hz, 1H), 5.30 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.72 (s, 2H), 1.39 (d, J=1 ,1 Hz, 9H), 1.24 (s, 9H); MS (ESI+): 545.3 (M+1), 567.3 (M+Na).

Stage-4. Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2yl)acetic acid (230e).

Compound 230e was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)pyridin-2yl)acetate (230d) (245 mg, 0.450 mmol) in DCM (5 ml) using TFA (0.347 ml, 4.50 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(3-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)acetic acid (230e) (200 mg, 96% yield), HCl salt, as a white solid;

1H NMR (300 MHz, methanol-d4) δ 8.40-8.32 (m, 2H), 8.05 (s, 1H), 7.99 (dt, J=7.7, 1.5 Hz, 1H), 7.93 (dd, J=8.7, 5.7 Hz, 1H), 7.89 (d, J=2.2 Hz, 1n), 7.78 (d, J=1.7 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.49 (m, 1H), 6.96 (d, J=2.2 Hz, 1H), 5.57 (s, 2H), 4.29-4.12 (m, 4H); MS (ESI+) 389.20 (M+1), (ESI+): 387.25 (M-1); purity after HPLC: 93.23%.

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Scheme-231

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (231c).

Stage-1. Preparation of 2-(2-((7-bromobenzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (231b).

To a solution of (7-bromobenzofuran-5-yl)methanol (23a) (500 mg, 2.202 mmol) and 2-(2-chloropyridin-3yl)acetic acid (231a) (378 mg, 2.202 mmol; CAS No. 61494-55- 1) Potassium tert-butoxide (741 mg, 6.61 mmol) was added to 1,4-dioxane (10 ml) and heated at 110°C for 2 hours. The reaction mixture was cooled to rt, diluted with water and acidified to pH 6 The reaction mixture was extracted with ethyl acetate (3x50 ml) and the combined organic layers were washed with brine, dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel 25 g, eluted with 9:1 (ethyl acetate and methanol) in hexanes (0 to 100%)] to give 2-(2-((7bromobenzofuran-5-yl)methoxy) pyridin-3-yl)acetic acid (231b) (380 mg, 48% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 8.13 (d, J=2.2 Hz, 1H), 8.07 (dd, J=5.0, 1 .9 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.67-7.60 (m, 2H), 7.08 (d, J=2.2 Hz, 1H ), 6.98 (dd, J=7.2, 5.0 Hz, 1H), 5.45 (s, 2H), 3.59 (s, 2H); MS (ESI+): 362.00; 364.00 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3yl)acetic acid (231c).

Compound 231c was prepared according to the procedure described in step-3 of Scheme-1 from 2-(2((7-bromobenzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (231b) (300 mg, 0.828 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (233 mg, 1.242 mmol), K2CO3 (343 mg, 2.485 mmol) in water (2 ml) and bis(triphenylphosphine) palladium ( 11) chloride (87 mg, 0.124 mmol) under nitrogen atmosphere by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (25 g), eluted with DMA80 in DCM 0% to 50%] 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran -5yl)methoxy)pyridin-3-yl)acetic acid (231c) (102 mg, 32% yield) as a tan solid;

1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J=2.0 Hz, 1H), 8.14-8.06 (m, 2H), 7.93 (dd, J=5, 0, 1.9 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.52-7.43 ( m, 2H), 7.39-7.31 (m, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.88 (dd, J=7.1, 5.0 Hz , 1H), 5.55 (s, 2H), 4.03 (s, 2H), 3.37 (s, 2H); MS (ESI+): 389.20 (M+1), (ESI-): 387.30 (M-1).

Scheme-232

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (232c).

Stage-1. Preparation of ethyl 2-(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indol-6-yl)methoxy) phenyl)acetate (232a).

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Compound 232a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate ( 212c) (0.9 g, 1.83 mmol), using bis(pinacolato)diboron (0.70 g, 2.74 mmol), potassium acetate (0.36 g, 3.66 mmol) and Pd(dppf) Cl ₂ -CH ₂ Cl ₂ (0.22 g, 0.27 mmol) in anhydrous dioxane (7 ml) under Ar atmosphere by heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(2-((1-(cyclopropylsulfonyl)-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (232a) (0.67 g, 67% yield) in in the form of yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.67 (d, J=3.6 Hz , 1H), 7.29-7.17 (m, 2H), 7.15-7.06 (m, 2H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.24 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.082.93 (m, 1H), 1.34 (s, 12H ), 1.25-1.11 (m, 2H), 1.11-0.93 (m, 5H).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1Hindol-6-yl)methoxy)phenyl)acetate (232b).

Compound 232b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (232a) (0.3 g, 0.56 mmol) in dioxane (4 ml), using (4-chloropyridin-2yl)methanamine (74a ) (0.10 ml, 0.83 mmol), bis(triphenylphosphine) palladium(P) chloride (0.06 g, 0.08 mmol) and K ₂ CO ₃ solution (0.12 g, 0.83 mmol) in water (0.4 ml) in an Ar atmosphere when heated at 90°C for 4 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 50% DCM] followed by purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1(cyclopropylsulfonyl)-1H-indole-6- yl)methoxy)phenyl)acetate (232b) (0.1 g, 35% yield), HCl salt, as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (d, J=5.3 Hz, 1H), 8.08 (s, 1H), 7.78-7.71 (m, 2H) , 7.62-7.54 (m, 2H), 7.36 (dd, J=5.4, 2.1 Hz, 1H), 7.30-7.19 (m, 2H), 6.99 (dd, J=3.8, 0.9 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 3.91- 3.89 (m, 2H), 3.80 (s, 2H), 3.63 (s, 2H), 3.16-3.06 (m, 1H), 1.33-1.03 (m, 4H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 520.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol6-yl)methoxy)phenyl)acetic acid (232c).

Compound 232c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -(cyclopropylsulfonyl)-1 H-indole -6-yl)methoxy)phenyl)acetate (232b) (0.1 g, 0.19 mmol) in THF (4 ml) and MeOH (4 ml), using lithium hydroxide monohydrate (0.07 g, 1.54 mmol) in water (0.4 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (232c) (0.04 g, 44% yield), HCl salt, as yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.76 (dd, J=5.2, 0.7 Hz, 1H), 8.58 (s, 3H), 8.13 (t, J=1 .0 Hz, 1H), 7.87 (t, J=1.1 Hz, 1H), 7.80 (d, J=3.7 Hz, 1H), 7.73 (dd, J=5.2 , 1.7 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.24 (dd, J=9.0, 6.6 Hz, 2H), 7.16-7 .06 (m, 2H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.35 (s, 2H), 4.31 (s, 2H), 3.61 ( s, 2H), 3.24-3.05 (m, 1H), 1.37-0.99 (m, 4H); MS (ESI+): 492.2 (M+1), MS (ESI-): 490.2 (M-1).

Scheme-233

C.I.

233b 233с

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (233c).

Stage-1. Preparation of ethyl 2-(2-((1-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl )acetate (233a).

- 308 045626

Compound 233a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate ( 228c) (0.6 g, 1.21 mmol), using bis(pinacolato)diboron (0.46 g, 1.82 mmol), potassium acetate (0.24 g, 2.43 mmol) and Pd(dppf) Cl ₂ CH ₂ Cl ₂ (0.15 g, 0.18 mmol) in anhydrous dioxane (7 ml) under Ar atmosphere by heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(2-((1(isopropylsulfonyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (233a) (0.43 g, 66% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (dd, J=1.5, 0.8 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7 .66 (d, J=3.7 Hz, 1H), 7.28-7.18 (m, 2H), 7.13-7.06 (m, 2H), 6.91 (td, J=7 ,4, 1.1 Hz, 1H), 5.23 (s, 2H), 4.05-3.96 (m, 2H), 3.75 (p, J=6.7 Hz, 1H), 3 .59 (s, 2H), 1.34 (s, 12H), 1.07 (s, 6H), 1.03 (t, J=7.2 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1Nindol-6-yl)methoxy)phenyl)acetate (233b).

Compound 233b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (233a) (0.2 g, 0.37 mmol) in dioxane (4 ml), using (4-chloropyridin-2yl)methanamine (74a ) (0.064 ml, 0.554 mmol), bis(triphenylphosphine) palladium(P) chloride (0.04 g, 0.06 mmol) and a solution of K ₂ CO ₃ (0.08 g, 0.55 mmol) in water (0 .4 ml) in an Ar atmosphere when heated at 90°C for 4 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase column chromatography [C18 (50 g), eluted ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1(isopropylsulfonyl)-1H-indol- 6-yl)methoxy)phenyl)acetate (233b) (0.06 g, 29% yield), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.77-7.70 (m, 2H), 7 .57 (dd, J=10.0, 1.7 Hz, 2H), 7.30-7.19 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H ), 6.99 (dd, J=3.8, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H) , 3.94-3.89 (m, 2H), 3.88-3.82 (m, 1H), 3.80 (s, 2H), 3.63 (s, 2H), 1.21 (d , J=6.8 Hz, 6H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 522.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (233c).

Compound 233c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol- 6-yl)methoxy)phenyl)acetate (233b) (0.05 g, 0.1 mmol) in THF (4 ml) and MeOH (4 ml), using lithium hydroxide monohydrate (0.03 g, 0.77 mmol ) in water (0.4 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (233c) (0.03 g, 66% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J=5.1 Hz, 1H), 8.50 (s, 3H), 8.09 (s, 1H), 7.83 (d , J=1.6 Hz, 1H), 7.79 (d, J=3.7 Hz, 1H), 7.71 (dd, J=5.2, 1.6 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.15-7.05 (m, 2H), 6.91 (td, J= 7.4, 1.1 Hz, 1H), 5.34 (s, 2H), 4.31 (d, J=5.7 Hz, 2H), 3.87 (p, J=6.8 Hz, 1H), 3.60 (s, 2H), 1.22 (d, J=6.8 Hz, 6H); MS (ESI+): 494.1 (M+1), MS (ESI-): 492.3 (M-1).

Scheme-234

234b 234c

234e ²³⁴ '

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-309 045626 phenylcyclopropanecarboxamido)acetic acid (234f).

Stage-1. Preparation of 2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetic acid (234b).

To a stirred solution of (1R,2R)-2-phenylcyclopropanecarboxylic acid (234a) (1.019 g, 6.28 mmol; CAS No. 939-90-2) in dCm (10 ml) was added thionyl chloride (0.504 ml, 6.91 mmol) , DMF (0.02 ml) and refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in THF (20 ml), added to a solution of 2-amino-2-(2hydroxyphenyl)acetic acid ( 0.7 g, 4.19 mmol) and sodium bicarbonate (1.759 g, 20.94 mmol) in water (15 ml) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was acidified with 3N HCl to pH 4 and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (25 ml), dried and concentrated in vacuo. The resulting residue was triturated with hexanes and collected by filtration to give 2(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetic acid (234b) (1.45 g, 111% yield) as a white solid . It was used as is in the next step without further purification; MS (ESI+): 312.20 (M+1), (ESI-): 310.2 (M-1).

Stage-2. Preparation of ethyl 2-(2-hydroxyphenyl)-2-((1R,2R)-2phenylcyclopropanecarboxamido)acetate (234c).

Compound 234c was prepared according to the procedure described in step-2 of Scheme-222 from 2-(2hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetic acid (234b) (1.42 g, 4. 56 mmol) in ethanol (30 ml) using sulfuric acid (0.486 ml, 9.12 mmol). This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate (234c) (1.14 g, 74% yield ) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.81 (d, J=2.8 Hz, 1H), 8.66 (t, J=7.1 Hz, 1H), 7.34-7 .17 (m, 2H), 7.197.06 (m, 5H), 6.89-6.74 (m, 2H), 5.70 (dd, J=7.6, 1.8 Hz, 1H), 4.14-3.99 (m, 2H), 2.32-2.14 (m, 1H), 2.20-2.08 (m, 1H), 1.42-1.27 (m, 1H ), 1.27-1.12 (m, 1H), 1.11 (m, 3H); MS (ESI+): 340.2 (M+1), 338.3 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate (234d).

Compound 234d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (600 mg, 1.698 mmol) in DCM (20 ml) using triphenylphosphine (512 mg, 1.952 mmol), ethyl 2-(2-hydroxyphenyl)-2-((1R,2R)-2phenylcyclopropanecarboxamido)acetate (234c) (663 mg, 1.952 mmol) and di-(4chlorobenzyl) azodicarboxylate solution ( DCAD, 748 mg, 2.037 mmol) in DCM (15 ml). This resulted, after work-up and purification by flash column chromatography (silica gel 24 g, eluted with ethyl acetate in 0% to 50% hexanes), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2phenylcyclopropanecarboxamido)acetate (234d) (855 mg, 75% yield) as a white foam; MS (ESI+): 575.30 (M+1-Vos).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2((1R,2R)-2-phenylcyclopropanecarboxamido)acetate (234e).

Compound 234e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )phenyl)-2-((1R,2R)-2phenylcyclopropanecarboxamido)acetate (234d) (750 mg, 1.111 mmol) in DCM (10 mL) using TFA (0.856 mL, 11.11 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2phenylcyclopropanecarboxamido)acetate (234e) ( 639 mg, 100% yield) as TFA salt, which was used in the next step without further purification; MS (ESI+): 575.30 (M+1).

Stage-5. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(( 1 R,2R)2-phenylcyclopropanecarboxamido)acetic acid (234f).

Compound 234f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(( 1R,2R)-2phenylcyclopropanecarboxamido)acetate (234e) (500 mg, 0.870 mmol) in THF (5 ml) and methanol (5 ml), using a solution of lithium hydroxide monohydrate (83 mg, 3.48 mmol) in water (2 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetic acid (234f) (332 mg, 70% yield), hydrochloride salt, as white solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.75 (s, 1H), 8.80 (dd, J=13.2, 8.1 Hz, 1H), 8.52 (s, 3H), 8.11 (t, J=2.3 Hz, 1H), 8.04 (d, J=3.0 Hz, 1H), 8.00-7.90 (m, 1H), 7.79 (dd , J=6.7, 1.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.63-7.51 (m, 2H), 7.30 (ddd, J=13 ,1, 7.5, 2.6 Hz, 3H), 7.25-7.07 (m, 4H), 7.06-6.93 (m, 3H), 5.92 (dd, J=8 ,0, 1.9 Hz, 1H), 5.33 (d, J=5.5 Hz, 2H), 4.23-4.05 (m, 2H), 2.33-2.08 (m, 2H), 1.43-1.04 (m, 2H); MS (ESI+): 547.2 (M+1),

- 310 045626 (ESI-): 545.3 (M-1); purity after HPLC: 98.60%.

Scheme-235 but _{x x} he is in

235a 235b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (235b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (235a).

Compound 235a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (199d) (198 mg, 0.433 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (125 mg, 0.610 mmol) solution of K2CO3 (164 mg, 1.187 mmol) in water (0 .5 ml), bis(triphenylphosphine) palladium(P) chloride (46 mg, 0.066 mmol) when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 60%], ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-2(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (235a) (156 mg, 72% yield) as a clear oil; MS (ESI+): 502.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (235b).

Compound 235b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl) methoxy)phenyl)acetate (235a) (156 mg, 0.311 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (72 mg, 1.72 mmol) in water (2.0 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (235b) (33 mg, 22% yield), HCl salt, as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (s, 2H), 7.92 (d, J=1.5 Hz, 1H), 7.81 (d, J=1.4 Hz , 1H), 7.76-7.59 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.6 Hz, 2H), 7 .03 (d, J=8.0 Hz, 1H), 6.85 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.11 (s, 2H), 3.53 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -63.41, -118.91. MS (ESI+): 474.1 (M+1); MS (ESI-): 472.3 (M-1). HPLC: purity 98.86%.

Scheme-236

182b 236a

236с 236d

Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (236d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (236a)

Mixture of ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (182b) (0.600 g, 1.009 mmol), dicyanozinc ( 0.142 g, 1.211 mmol), Pd(Ph ₃ P) ₄

- 311 045626 (0.350 g, 0.303 mmol) was purged with nitrogen for 10 min. Anhydrous DMF (6.0 ml) was added and the suspension was heated in a microwave oven for 40 min at 120°C. The reaction mixture was cooled to rt, diluted with ethyl acetate (100 ml) and saline (100 ml). The aqueous layer was separated and extracted with ethyl acetate (100 ml). The combined organics were washed with brine, dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography (silica gel 12 g, eluted with ethyl acetate in 0 to 100% hexanes) to give ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (236a) (0.435 g, 80% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 7.73 (dd, J=9.1, 1.5 Hz, 3H), 7 .64 (d, J=1.3 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.55-7.37 (m, 3H), 7.30 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.31 (s, 2H), 4.23 (d, J=6.2 Hz, 2H) , 3.89 (k, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.39 (s, 9H), 0.93 (t, J=7.1 Hz, 3H) ; MS (ESI-): 539.4 (M-1).

Stage-2. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (236b).

To a solution of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (236a) (0.150 g, 0.277 mmol) in methanol (10 ml), cooled to 0°C, add nickel(II) chloride hexahydrate (0.016 g, 0.069 mmol), followed by the addition of sodium borohydride (0.063 g, 1.665 mmol) over 10 min and stir for 1 h The reaction mixture was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.060 ml, 0.555 mmol), stirred at RT for 1 hour and concentrated in vacuo. The resulting residue was partitioned between brine (100 ml) and extracted with EtOAc (2x150 ml). The combined organic substances were dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel 24 g, eluted with methanol in DCM 0 to 40%) to give ethyl 2-(4(aminomethyl)-2-((7-(3-((tert-butoxycarbonyl )amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (236b) (0.138 g, 91% yield) as a white solid; MS (ESI+): 545.1 (M+1); MS (ESI-): 579.0 (M+Cl).

Stage-3. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (236c).

Compound 236c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran -5yl)methoxy)phenyl)acetate (236b) (0.132 g, 0.242 mmol) in DCM (20 ml) using TFA (0.373 ml, 4.85 mmol). This gave, after work-up and purification by reverse phase column chromatography (C-18 column, 50 g, eluted with 0.1% aq. HCl in water and 0% to 100% acetonitrile), ethyl 2-(4-( aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (236c) (0.068 g, 63% yield) as a white solid; MS (ESI+): 445.0 (M+1).

Stage-4. Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (236d).

Compound 236d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl )acetate (236c) (0.065 g, 0.146 mmol) in THF (3 ml) and methanol (6 ml), using 2 M LiOH (0.731 ml, 1.462 mmol). This resulted in the following workup and purification by reverse phase column chromatography [C-18, steel column (250 mm x 30 mm) eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (236d) (0.032 g, 53% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.24 (s, 1H, D2O replaceable), 8.54 (br. s, 6H, D2O replaceable), 8.11 (d, J=2.2 Hz , 1H), 8.08-8.03 (m, 1h), 7.99-7.90 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 ( d, J=1.6 Hz, 1H), 7.637.54 (m, 2H), 7.45 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.02 (dd, J=7.7, 1.5 Hz, 1H), 5.28 (s, 2H), 4, 14 (s, 2H), 3.99 (s, 2H), 3.60 (s, 2H); MS (ESI+): 417.00 (M+1); MS (ESI-): 415.00 (M1).

Scheme-237

CN CN CN

236a 237a 237b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (237b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (237a).

- 312 045626

Compound 237a was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4-cyanophenyl)acetate (236a) (0.210 g, 0.388 mmol) in DCM (20 ml) using TFA (0.6 ml, 7.77 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with methanol in DCM 0% to 100%), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-4-cyanophenyl)acetate (237a) (0.159 g, 0.361 mmol, 93% yield) as a white solid; MS (ESI+): 441.2 (M+1); MS (ESI-): 439.3 (M-1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (237b).

Compound 237b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate ( 237a) (0.142 g, 0.322 mmol) in THF (4 ml) and methanol (8 ml) using 2 M LiOH (0.806 ml, 1.612 mmol). This resulted in the following workup and purification by flash column chromatography (silica gel 12 g, eluted with methanol in DCM 0% to 100%) followed by reverse phase column chromatography [EZ-PREP, C-18 column, 100 g , eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (237b) (0.034 g , 0.082 mmol, 25.6% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.48 (br.s, 1H, D2O replaceable), 8.58 (br.s, 3H, D2O replaceable), 8.12 (d, J=2, 2 Hz, 1H), 8.03-7.98 (m, 1H), 7.92 (td, J=4.5, 1.8 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.63-7.56 (m, 3H), 7.49-7.38 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.35 (s, 2H), 4.13 (s, 2H), 3.70 (s, 2H); MS (ESI+): 413.2 (M+1); purity after HPLC: 98.84%; analysis calculation for C ₂₅ H ₂₀ N ₂ O ₄ -HCl-1.25H ₂ O: C, 63.69; N, 5.02; N, 5.94; observed: C, 63.84; N, 4.96; N 5.92.

Scheme-238

238b 238c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetic acid (238c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-carbamoylphenyl)acetate (238a)

A mixture of ethyl 2-(2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (236a) (0.185 g, 0.342 mmol), acetamide (0.121 g, 2.053 mmol), palladium(II) chloride (9.10 mg, 0.051 mmol) in THF (2.00 ml) and water (0.25 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and brine (100 ml). The aqueous layer was separated and extracted with ethyl acetate (100 ml). The combined organics were washed with brine, dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography (silica gel 12 g, eluted with 0 to 100% methanol in DCM) to give ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)benzofuran-5yl)methoxy)-4-carbamoylphenyl)acetate (238a) (0.166 g, 87% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 8.00 (s, 1H), 7.81-7.69 (m, 3H) , 7.63 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.55-7.41 (m, 2H), 7.39 ( s, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.29 (s, 2H), 4, 23 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 1.39 (s, 9H), 0, 95 (t, J=7.1 Hz, 3H); MS (ESI+): 581.3 (M+Na); MS (ESI-): 593.4 (M+Cl).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetate (238b).

Compound 238b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4carbamoylphenyl)acetate (238a) (0.162 g, 0.290 mmol) in DCM (20 ml), using TFA (0.447 ml, 5.80

- 313 045626 mmol). This gave, after work-up and purification by phase flash column chromatography (silica gel 12 g, eluted with methanol in DCM from 0% to 100%), ethyl 2-(2((7-(3-(aminomethyl)phenyl)benzofuran-5- yl)methoxy)-4-carbamoylphenyl)acetate (238b) (0.072 g, 43% yield) TFA salt as clear wax; MS (ESI+): 459.2 (M+1); MS (ESI-): 457.3 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (238c).

Compound 238c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate ( 238b) (0.070 g, 0.122 mmol) in THF (3 ml) and methanol (6 ml) using 2 M LiOH (0.306 ml, 0.611 mmol). This resulted in the following work-up and purification by flash column chromatography (silica gel 12 g, eluted with methanol in DCM 0% to 100%) followed by reverse phase column chromatography (EZ-PREP, C-18 column, 50 g , eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%) 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl) acetic acid (238c) (0.034 g, 65% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H, D2O replaceable), 8.42 (s, 3H, D2O replaceable), 8.11 (d, J=2.2 Hz, 1H) , 8.01 (t, J=1.7 Hz, 2H), 7.93 (dt, J=7.3, 1.8 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.6 Hz,

1H), 7.64-7.53 (m, 3H), 7.45 (dd, J=7.7, 1.5 Hz, 1H), 7.38 (s, 1H), 7.30 (d , J=7.8 Hz, 1H), 7.07 (d, J=2.2 Hz,

1H), 5.33 (s, 2H), 4.14 (s, 2H), 3.65 (s, 2H); MS (ESI+): 431.1 (M+1); analysis calculation for

C25H22N2O5-HC1-2H2O: C, 59.70; N, 5.41; N, 5.57; observed: C, 59.80; N, 5.30; N, 5.70.

Scheme-239

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetic acid (239c).

Stage-1. Preparation of methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-cyanophenyl)acetate (239a).

Compound 239a was prepared according to the procedure described in step-1 of scheme-236 from methyl 2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl )methoxy)phenyl)acetate (208b) (0.4 g, 0.69 mmol) in DMF (5 ml), using dicyanozinc (0.10 g, 0.83 mmol), Pd(Ph ₃ P) ₄ (0 .16 g, 0.14 mmol) when heated at 100°C in an oil bath for 3 hours. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with EtOAc in 0 to 60 hexanes %) methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate (239a) (0.3 g, 83 % yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.95 (s, 2H), 7.79 (dd, J=8.5, 2, 2 Hz, 1H), 7.767.70 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.49 (t, J=7.8 Hz, 2H), 7.31 (dd, J=8.2, 3.5 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5 .36 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.71 (s, 2H), 3.46 (s, 3H), 1.39 (s, 9H) ; MS (ESI): 525.3 (M-1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5cyanophenyl)acetate (239b).

Compound 239b was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5cyanophenyl)acetate (239a) (0.3 g, 0.57 mmol) in DCM (8 ml) using TFA (0.88 ml, 11.39 mmol). This resulted in compound (239b) (0.24 g, 100% yield) as a clear wax after work-up and purification by flash column chromatography (silica gel 12 g, eluted with 0% to 100% MeOH in DCM). This sample was purified by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HC1) from 0% to 100%] to give methyl 2-(2-((7-(3 (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate (239b), salt HC1, as white

- 314 045626 solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (s, 3H), 8.12 (t, J=1.8 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.93-7.87 (m, 1H), 7.80 (dt, J=8.5, 1.7 Hz, 1H), 7.73 (dt, J=3.6, 1, 5 Hz, 2H), 7.64-7.49 (m, 3H), 7.32 (dd, J=8.6, 1.3 Hz, 1H), 7.10 (t, J=1.8 Hz, 1H), 5.37 (s, 2H), 4.14 (d, J=5.7 Hz, 2H), 3.71 (s, 2H), 3.47 (s, 3H); MS (ESI+): 427.0 (M+1).

Stage-3. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5 cyanophenyl)acetic acid (239c).

Compound 239c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate (239b) (0.2 g, 0.37 mmol) in THF/methanol (4 mL each), using a solution of lithium hydroxide monohydrate (0.16 g, 3.70 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetic acid (239c) (0.10 g, 65% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.45 (s, 1H), 8.43 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.00 ( s, 1H), 7.92 (dt, J=7.2, 1.8 Hz, 1H), 7.80-7.69 (m, 3H), 7.67-7.61 (m, 1H) , 7.61-7.51 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.39 ( s, 2H), 4.13 (s, 2H), 3.66 (s, 2H); MS (ESI+) 413.2 (M+1), MS (ESI-) 411.2 (M-1).

Scheme-240

Preparation of 2-(2-((7-(2-(aminomethyl)fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (240d).

Stage-1. Preparation of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (240a).

Compound 240a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (199d) ( 316 mg, 0.691 mmol) using bis(pinacolato)diboron (266 mg, 1.047 mmol), potassium acetate (217 mg, 2.211 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (72 mg, 0.088 mmol) in anhydrous dioxane (6 ml) under Ar atmosphere while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-(4,4,5,5tetramethyl -1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (240a) (326 mg, 94% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=1.8 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.307.19 (m, 2H), 7.13-7.06 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5, 23 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.17 (s, 12H), 1.05 (t, J=7 ,1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -63.17.

Stage-2. Preparation of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl )acetate (240b).

Compound 240b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (240a) (326 mg, 0.646 mmol) in dioxane (5 ml) using (S)-N-((4-chloro-3fluoropyridin-2-yl )methyl)-2-methylpropane-2-sulfinamide (220c) (230 mg, 0.869 mmol), bis(triphenylphosphine) palladium(P) chloride (73 mg, 0.104 mmol) and a solution of K2CO3 (309 mg, 2.236 mmol) in water (0.5 ml) in an Ar atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA/DCM 0% to 80%] (S)-ethyl 2-(2-((7-(2-( (1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (240b) (392 mg, 100% yield) as a pale yellow oil . MS (ESI+): 607.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (240c).

- 315 045626

Compound 240c was prepared according to the procedure described in step-5 of scheme-220 from (S)ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridine-4 -yl)-2(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (240b) (392 mg, 0.65 mmol) in methanol (8 ml) using hydrochloric acid (4 M in 1,4-dioxane , 0.5 ml, 2 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran5-yl)methoxy)phenyl)acetate (240c) ( 324 mg, 100% yield), HCl salt, as a yellow solid. The analytical sample was obtained by further purification using a reverse phase chromatography column [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give compound 240c, HCl salt, as white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.59 (k, J=6.1, 5.6 Hz, 4H), 8.03-7.95 (m, 1H), 7.90 (s , 1H), 7.75 (d, J=10.1 Hz, 2H), 7.22-7.13 (m, 2H), 7.06 (d, J=8.2 Hz, 1H), 6 .86 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.31 (d, J=5.9 Hz, 2H), 3.87 (k, J=7, 1 Hz, 2H), 3.59 (d, J=8.7 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -63.44, -128.97. MS (ESI+): 503.2 (M+1); MS (ESI-): 501.2 (M-1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran5-yl)methoxy)phenyl)acetic acid (240d).

Compound 240d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran- 5-yl)methoxy)phenyl)acetate (240c) (230 mg, 0.458 mmol) in MeOH/THF (3 ml each), using lithium hydroxide monohydrate (121 mg, 2.88 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (240d) (63 mg, 29.0% yield), HCl salt, as white solid.

¹ H NMR (300 MHz, DMSO-d6) δ 8.62 (dd, J=11.0, 5.4 Hz, 4H), 8.01 (d, J=1.6 Hz, 1H), 7, 86 (d, J=1.4 Hz, 1H), 7.83-7.72 (m, 2H), 7.17 (t, J=7.6 Hz, 2H), 7.03 (d, J =8.0 Hz, 1H), 6.85 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.40-4.25 (m, 2H) , 3.53 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -63.46, -128.80. MS (ESI+): 475.2 (M+1); MS (ESI-): 473.2 (M-1).

Scheme-241

241b 241с

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetic acid (241c).

Stage-1. Preparation of ethyl 2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a).

Compound 241a was prepared according to the procedure described in step-4 of Scheme-1 from 7bromo-4-fluorobenzofuran-5-carboxylic acid (136a) (380 mg, 1.467 mmol) in DMF (10 ml) using ethyl 2-( 2-Aminophenyl)acetate (5e) (334 mg, 1.864 mmol), DIPEA (1.3 ml, 7.46 mmol) and HATU (891 mg, 2.343 mmol). This resulted, after workup and purification by flash column chromatography (silica gel 12 g, eluted with ethyl acetate in 0% to 50% hexane), ethyl 2-(2-(7-bromo-4fluorobenzofuran-5-carboxamido)phenyl)acetate (241a) (608 mg, 99% yield) as a yellow solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.30 (d, J=2.2 Hz, 1H), 7.84 (d, J=5.9 Hz , 1H), 7.48 (d, J=7.7 Hz, 1H), 7.40-7.30 (m, 3H), 7.28-7.20 (m, 1H), 4.06 ( cd, J=7.1, 2.8 Hz, 2H), 3.78 (s, 2H), 1.16 (dt, J=14.2, 7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5carboxamido)phenyl)acetate (241b).

Compound 241b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a) (125 mg, 0.297 mmol) to dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (71 mg, 0.379 mmol),

- 316 045626 bis(triphenylphosphine) palladium(11) chloride (35 mg, 0.050 mmol) and a solution of K ₂ CO ₃ (148 mg, 1.071 mmol) in water (0.5 ml) in an Ar atmosphere when heated at 100 ° C in for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM, 0% to 80%] ethyl 2-(2-(7-(3-(aminomethyl)phenyl) -4-fluorobenzofuran-5carboxamido)phenyl)acetate (241b) (94 mg, 71% yield) as a pale yellow oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.25 (d, J=2.2 Hz, 1H), 7.82 (d, J=6.6 Hz, 2H), 7.72 (d, J=7.6 Hz, 1H), 7.48 (dk, J=16.2, 8.0 Hz, 3H), 7.39-7.29 (m, 3H ), 7.29-7.19 (m, 1H), 4.03 (cd, J=7.1, 2.8 Hz, 2H), 3.81 (d, J=7.0 Hz, 4H) , 1.09 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.55. MS (ESI+): 447.2 (M+1).

Stage-3. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5carboxamido)phenyl)acetic acid (241c).

Compound 241c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241b) ( 92 mg, 0.206 mmol) in MeOH/THF (3 mL each), using a solution of lithium hydroxide monohydrate (52 mg, 1.24 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetic acid (241c) (43 mg, 50% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (d, J=2.2 Hz, 1H), 8.54 (s, 2H), 8.20 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 7.86 (dd, J=6.2, 3.9 Hz, 2H), 7.53 (dd, J=5.7, 3.8 Hz, 3H ), 7.32-7.21 (m, 3H), 7.15 (td, J=7.3, 1.4 Hz, 1H), 4.07 (s, 2H), 3.67 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -119.62. MS (ESI+): 419.0 (M+1); MS (ESI-): 417.9 (M-1). HPLC: purity 99.53%.

Scheme-242

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -(cyclopropylsulfonyl)-1 H-indol-6yl)methoxy)phenyl)acetic acid (242b).

Stage-1. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (242a).

Compound 242a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (232a) (0.33 g, 0.61 mmol) in dioxane (5 ml) using (4-chloro-3fluoropyridin-2-yl) )methanamine (181b) (0.15 g, 0.92 mmol), bis(triphenylphosphine) palladium(P) chloride (0.06 g, 0.09 mmol) and K2CO3 solution (0.211 g, 1.53 mmol) in water (0.5 ml) in an Ar atmosphere while heating at 90°C for 4 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase column chromatography [C 18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4yl)-1-(cyclopropylsulfonyl)-1H -indol-6-yl)methoxy)phenyl)acetate (242a) (0.11 g, 33% yield), HCl salt, as a yellow solid; MS (ESI+): 538.2 (M+1).

Stage-2. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)1H-indol-6-yl)methoxy)phenyl)acetic acid (242b).

Compound 242b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H -indol-6yl)methoxy)phenyl)acetate (242a) (0.11 g, 0.21 mmol) in THF/MeOH (4 ml each), using lithium hydroxide monohydrate (0.09 g, 2.05 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)1H-indol-6-yl)methoxy)phenyl)acetic acid (242b) (0.01 g, 10% yield), salt HCl, as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.61 (d, J=5.0 Hz, 1H), 8.46 (s, 3H), 8.16 (s , 1H), 7.78 (d, J=3.8 Hz, 1H), 7.70 (t, J=5.3 Hz, 1H), 7.56 (s, 1H), 7.29-7 .19 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.92 (dd, J=7.9, 6.8 Hz, 1H), 6.75 (t, J=3.5 Hz, 1H), 5.35 (s, 2H), 4.38 (d, J=6.0 Hz, 2H), 3.59 (s, 2H), 3.25-3, 07 (m, 1H), 1.351.06 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.57; MS (ESI+): 510.9 (M+1), MS (ESI-): 508.9 (M-1). Purity after HPLC: 96.58%.

- 317 045626

Scheme-243

Preparation of 2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (243d).

Stage-1. Preparation of ethyl 2-(2-((7-(2-cyanophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243a).

Compound 243a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (500 mg, 1.146 mmol) in dioxane (2 ml), using 2-bromobenzonitrile (229 mg, 1.261 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (80 mg, 0.115 mmol) and a solution of K ₂ CO ₃ (475 mg, 3.44 mmol) in water (1 ml) under nitrogen while heating at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 15% hexane), ethyl 2-(2-((7-(2-cyanophenyl)benzofuran-5-yl)methoxy )phenyl)acetate (243a) (293 mg, 62% yield) as a pale purple thick oil.

^1H NMR (300 MHz, chloroform-d) δ 7.90-7.83 (m, 1H), 7.81-7.68 (m, 4H), 7.58-7.49 (m, 2H) , 7.28 (m, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.04-6.94 (m, 2H), 6.89 (d, J=2.2 Hz, 1H), 5.26 (s, 2H), 4.07 (k, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.14 (t, J=7.1 Hz, 3H); MS (ESI+): 412 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (243b).

Compound 243b was prepared according to the procedure described in step-2 of scheme-236 from ethyl 2-(2-((7-(2-cyanophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243a) (0. 28 g, 0.681 mmol) in methanol (10 ml), using Boc anhydride (0.297 g, 1.361 mmol), nickel(N) chloride hexahydrate (0.016 g, 0.068 mmol), sodium borohydride (0.180 g, 4.76 mmol) and N1-(2-aminoethyl)ethane-1,2-diamine (0.147 ml, 1.361 mmol). This resulted, after workup and purification by flash column chromatography, of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate ( 243b).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243c).

Compound 243c was prepared according to the procedure described in step-5 of scheme-220 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (243b) (from step-2) in methanol (8 ml) using hydrochloric acid (1.5 M in methanol, 24.95 ml, 37.4 mmol). This resulted in ethyl 2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243c) as a thick transparent colorless oil.

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (243d).

Compound 243d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243c) ( from step-3) in MeOH (2 ml), THF (1 ml each), using a solution of lithium hydroxide monohydrate (0.143 g, 3.40 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (243d) (75 mg, 28% yield in 3 steps), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.02 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.75 (d , J=7.5 Hz, 1H), 7.64-7.43 (m, 3H), 7.39 (d, J=1.7 Hz, 1H), 7.32-7.19 (m, 2H), 7.15-7.02 (m, 2H), 6.91 (dd, J=7.9, 6.8 Hz, 1H), 5.26 (s, 2H), 3.87 (s , 2H), 3.59 (s, 2H). Purity after HPLC: 98.7%; MS (ESI+): 388 (M+1); MS (ESI-): 386 (M-1); analysis calculation for C ₂₄ H ₂₁ NO ₄ -HCl-1.5H ₂ O: C, 63.93; N, 5.59; N, 3.11; Cl, 7.86; observed: C, 64.11; N, 5.33; N, 3.11; Cl, 8.06.

- 318 045626

Scheme-244

244a

244s

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetic acid (244c).

Stage-1. Preparation of methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-carbamoylphenyl)acetate (244a).

Compound 244a was prepared according to the procedure described in step-1 of scheme-238 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5cyanophenyl)acetate (239a) (0.32 g, 0.61 mmol), using acetamide (0.22 g, 3.65 mmol), palladium(P) chloride (0.02 g, 0.09 mmol ) in THF (4 ml) and water (0.4 ml). This gave, after work-up and purification by flash phase column chromatography (silica gel 12 g, eluted with 0 to 100% methanol in DCM), methyl 2-(2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-carbamoylphenyl)acetate (244a) (0.18 g, 54% yield) as a white solid; MS (ESI+): 543.0 (M-1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5carbamoylphenyl)acetate (244b).

Compound 244b was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl) methoxy)-5 carbamoylphenyl)acetate (244a) (0.18 g, 0.33 mmol) in DCM (6 ml) using TFA (0.51 ml, 6.61 mmol). This gave, after work-up and purification by flash phase column chromatography (silica gel 12 g, eluted with 0% to 50% methanol in DCM), methyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran- 5-yl)methoxy)-5-carbamoylphenyl)acetate (244b) (0.12 g, 82% yield) as a white waxy substance;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (s, 4H), 8.12 (d, J=2.2 Hz, 1H), 7.98 (d, J=1.8 Hz , 1H), 7.91 (dt, J=7.8, 1.5 Hz, 1H), 7.85-7.77 (m, 3H), 7.74 (d, J=1.6 Hz, 1H), 7.65-7.57 (m, 2H), 7.57-7.50 (m, 1H), 7.24-7.14 (m, 2H), 7.10 (d, J= 2.2 Hz, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 3.68 (s, 2H), 3.47 (s, 3H); MS (ESI+): 445.1 (M+1), MS (ESI-): 443.0 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5carbamoylphenyl)acetic acid (244c).

Compound 244c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate (244b) (0.11 g, 0.25 mmol) in THF/MeOH (4 mL each), using a solution of lithium hydroxide monohydrate (0.10 g, 2.48 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography (EZ-PREP, C-18 column, 50 g, eluted with 0.1% aq. HCl in water and 0% to 100% acetonitrile), 2-( 2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5carbamoylphenyl)acetic acid (244c) (0.06 g, 58% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.35 (s, 1H), 8.39 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.00 ( d, J=1.9 Hz, 1H), 7.93 (dt, J=7.4, 1.7 Hz, 1H), 7.84-7.75 (m, 4H), 7.65 (d , J=1.6 Hz, 1H), 7.63-7.52 (m, 2H), 7.22-7.11 (m, 2H), 7.07 (d, J=2.2 Hz, 1H), 5.35 (s, 2H), 4.14 (s, 2H), 3.62 (s, 2H); MS (ESI+): 431.0 (M+1), MS (ESI-): 429.0 (M-1). Purity after HPLC: 99.75%.

- 319 045626

Scheme-245

Preparation of 2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo^]isoxazol-5yl)methoxy)phenyl)acetic acid (245g).

Stage-1. Preparation of tert-butyl ((3'-cyano-5'-(dimethoxymethyl)-2,2'-difluoro-[1,1'-biphenyl]-3yl)methyl)carbamate (245a).

Compound 245a was prepared according to the procedure described in step-3 of Scheme-1 from 3bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile (114d) (600 mg, 2.189 mmol) in dioxane (30 ml) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (1153 mg, 3.28 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (307 mg, 0.438 mmol) and a solution of K ₂ CO ₃ (908 mg, 6.57 mmol) in water (3 ml) under a nitrogen atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] tert-butyl ((3'-cyano-5'-(dimethoxymethyl)-2 ,2'-difluoro-[1,1'biphenyl]-3-yl)methyl)carbamate (245a) (549 mg, 60%) as a light yellow gum;

¹ H NMR (300 MHz, DMSO-d6) δ 7.96 (dd, J=5.9, 2.2, 0.6 Hz, 1H), 7.78 (dd, J=7.1, 2, 2 Hz, 1H), 7.537.28 (m, 4H), 5.55-5.42 (m, 1H), 4.24 (d, J=6.1 Hz, 2H), 3.29 (s, 6H), 1.40 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -110.59 (d, J=17.5 Hz), -121.69 (d, J=17.5 Hz); MS (ESI+): 441.20 (M+Na).

Stage-2. Preparation of tert-butyl 3-(3-amino-5-(dimethokCimethyl)benzo[d]isoxazol-7-yl)-2fluorobenzylcarbamate (245b).

Compound 245b was prepared according to the procedure described in step-4 of Scheme-114 from tert-butyl ((3'-cyano-5'-(dimethoxymethyl)-2,2'-difluoro-[1,1'-biphenyl] -3-yl)methyl)carbamate (245a) (535 mg, 1.279 mmol) in DMF (15 ml), using Nhydroxyacetamide (297 mg, 3.84 mmol), potassium carbonate (530 mg, 3.84 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] tert-butyl 3-(3-amino-5(dimethoxymethyl)benzo[d] isoxazol-7-yl)-2-fluorobenzylcarbamate (245b) (382 mg, 69%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (dd, J=1.6, 0.7 Hz, 1H), 7.58-7.56 (m, 1H), 7.54-7 .45 (m, 2H), 7.427.27 (m, 2H), 6.55 (s, 2H), 5.56 (s, 1H), 4.25 (d, J=6.1 Hz, 2H) , 3.29 (s, 6H), 1.40 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.39; MS (ESI+): 432.20 (M+1) and 454.20 (M+Na); MS (ESI-): 430.20 (M-1).

Stage-3. Preparation of tert-butyl 3-(3-amino-5-formylbenzo[d]isoxazol-7-yl)-2fluorobenzylcarbamate (245c).

Compound 245c was prepared according to the procedure described in step-5 of Scheme-114 from tert-butyl 3-(3-amino-5-(dimethoxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245b) (3 00 mg, 0.695 mmol) in THF (12 ml) using conc. hydrogen chloride (0.145 ml, 1.738 mmol). This resulted in tert-butyl 3-(3-amino-5-formylbenzo[d]isoxazol-7-yl)-2fluorobenzylcarbamate (245c) (267 mg) being treated as a white solid, which was used as is in the next step ; MS (ESI+): 408.10 (M+Na).

Stage-4. Preparation of tert-butyl 3-(3-amino-5-(hydroxymethyl)benzo[d]isoxazol-7-yl)-2fluorobenzylcarbamate (245d).

Compound 245d was prepared according to the procedure described in step-6 of scheme-114 from

- 320 045626 tert-butyl 3-(3-amino-5-formylbenzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245c) (264 mg, 0.685 mmol) in THF (20 ml) using sodium borohydride ( 52 mg, 1.370 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] tert-butyl 3-(3-amino-5(hydroxymethyl) benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245d) (179 mg, 68% in 2 steps) as a white solid;

Ή NMR (300 MHz, DMSO- _d6 ) δ 7.86-7.83 (m, 1H), 7.52-7.44 (m, 3H), 7.42-7.26 (m, 2H) , 6.47 (s, 2H), 5.37 (t, J=5.6 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H), 4.25 (d, J= 6.1 Hz, 2H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -121.17; MS (ESI+): 388.20 (M+1) and 410.10 (M+Na).

Stage-5. Preparation of ethyl 2-(2-((3-amino-7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (245e) .

Compound 245e was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(3-amino-5-(hydroxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245d) (170 mg, 0.439 mmol) in DCM (12 mL) and THF (12 mL), using triphenylphosphine (173 mg, 0.658 mmol), ethyl 2-(2hydroxyphenyl) acetate (23b) (198 mg, 1.097 mmol) and di-( 4-chlorobenzyl)azodicarboxylate (DCAD, 242 mg, 0.658 mmol) in DCM (12 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)], ethyl 2-(2-((3-amino-7-(3-( ((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzo[d]isoxazol5-yl)methoxy)phenyl)acetate (245e) (240 mg, 100%) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.55-7.17 (m, 6H), 7.15-7.11 (m, 1H), 6.97-6.87 (m, 1H), 6.52 (s, 2H), 5.20 (s, 2H), 4.25 (d, J=6.1 Hz, 2H), 3.85 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.40 (s, 9H), 0.93 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.90; MS (ESI+): 550.20 (M+1) and 572.30 (M+Na).

Stage-6. Preparation of ethyl 2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5yl)methoxy)phenyl)acetate (245f).

Compound 245f was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((3-amino-7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl) benzo[d]isoxazol-5yl)methoxy)phenyl)acetate (245e) (220 mg, 0.400 mmol) in DCM (12 ml) using TFA (0.308 ml, 4.00 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/DMA 80 (1:0 to 3:1)] ethyl 2-(2-((3-amino-7-(3( aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (245f) (125 mg, 70%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.94 (d, J=1.6 Hz, 1H), 7.67-7.57 (m, 2H), 7.54-7.47 (m , 1H), 7.34 (t, J=7.6 Hz, 1H), 7.30-7.19 (m, 2H), 7.15-7.11 (m, 1H), 6.96- 6.88 (m, 1H), 6.52 (s, 2H), 5.20 (s, 2H), 3.92-3.82 (m, 4H), 3.61 (s, 2H), 0 .94 (t, J=7.1 Hz, 3H); MS (ESI+): 450.20 (M+1) and 472.20 (M+Na).

Stage-7. Preparation of 2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5 yl)methoxy)phenyl)acetic acid (245g).

Compound 245g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazole-5- yl)methoxy)phenyl)acetate (245f) (85 mg, 0.189 mmol) in THF/MeOH (6 mL each), using a solution of lithium hydroxide monohydrate (81 mg, 1.891 mmol) in water (6 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((3 -amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5yl)methoxy)phenyl)acetic acid (245g) (54 mg, 68%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (s, 3H), 7.98 (d, J=1.5 Hz, 1H), 7.74-7.63 (m, 3H), 7.43 (t, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 7.13-7.08 (m, 1H), 6.92 (td, J= 7.4, 1.1 Hz, 1H), 5.24 (s, 2H), 4.21-4.11 (m, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.35; MS (ESI+): 422.0 (M+1); MS (ESI-): 419.90 (M-1).

Scheme-246

Preparation of 2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5carboxamido)phenyl)acetic acid (246b).

Stage-1. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5carboxamido)phenyl)acetate (246a).

Compound 246a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2

- 321 045626 (2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a) (125 mg, 0.297 mmol) in dioxane (5 ml), using hydrochloride (3-(aminomethyl)-2- fluorophenyl)boronic acid (56a) (92 mg, 0.451 mmol), bis(triphenylphosphine) palladium(P) chloride (42 mg, 0.060 mmol) and a solution of K2CO3 (131 mg, 0.948 mmol) in water (0.5 ml) in Ar atmosphere when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM, 0% to 50%] ethyl 2-(2-(7-(3-(aminomethyl)-2 -fluorophenyl)-4fluorobenzofuran-5-carboxamido)phenyl)acetate (246a) (138 mg, 100% yield) as a pale yellow oil; MS (ESI+): 465.0 (M+1).

Stage-2. Preparation of 2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5carboxamido)phenyl)acetic acid (246b).

Compound 246b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate ( 246a) (132 mg, 0.284 mmol) in MeOH/THF (3 mL each), using a solution of lithium hydroxide monohydrate (66 mg, 1.57 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-(7-(3-( aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetic acid (246b) (48 mg, 39% yield), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.96 (d, J=2.3 Hz, 1H), 8.56 (s, 3H), 8.16 ( d, J=2.3 Hz, 1H), 7.76-7.62 (m, 3H), 7.49 (d, J=7.8 Hz, 1H), 7.38 (t, J=7 .7 Hz, 1H), 7.32-7.20 (m, 3H), 7.20-7.11 (m, 1H), 4.11 (s, 2H), 3.65 (s, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.44, -118.68. MS (ESI+): 437.0 (M+1); MS (ESI-): 434.9 (M-1). HPLC: purity 98.76%.

Scheme-247

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (247b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5yl)methoxy)phenyl)acetate (247a).

Compound 247a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5-yl)methoxy)phenyl) acetate (214d) (104 mg, 0.219 mmol) in dioxane (4 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (54.0 mg, 0.263 mmol), K2CO3 solution (91 mg, 0.658 mmol) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ (15 mg, 0.022 mmol) and heating in an Ar atmosphere at 100°C for 16 hours. This resulted in the following treatment and purification by flash column chromatography (silica gel) of ethyl 2-(2-((7-(3(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (247a) as a transparent pale - yellow oil; MS (ESI+): 450 (M+1); 472 (M+Na).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5yl)methoxy)phenyl)acetic acid (247b).

Compound 247b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy) phenyl)acetate (247a) (from previous step) in THF (1 ml) and MeOH (2 ml), using a solution of LiOH-H ₂ O (28 mg, 0.658 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((7-(3-( aminomethyl)-2fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (247b) (53 mg, 57% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (d, J=5.4 Hz, 1H), 7.77 (k, J=5.6, 5.0 Hz, 1H), 7, 62 (dt, J=9.6, 5.1 Hz, 2H), 7.49 (k, J=5.6, 5.0 Hz, 1H), 7.37 (k, J=7.1, 6.3 Hz, 2H), 7.15 (dd, J=8.4, 5.0 Hz, 2H), 7.02 (t, J=6.8 Hz, 1H), 6.83 (k, J=7.1 Hz, 1H), 5.22 (d, J=5.3 Hz, 2H), 4.10 (d, J=5.4 Hz, 2H), 3.51 (d, J= 5.5 Hz, 2H). MS (ESI+): 422 (M+1); (ESI-): 420 (M-1); analysis calculation for C24H20FNO ₃ S-HCl-H ₂ O: C, 60.56; N, 4.87; Cl, 7.45; N, 2.94; observed: C, 60.24; N, 4.81; Cl: 7.68; N: 2.98.

- 322 045626

Scheme-248

Preparation of 2-(2-((7-(3-(aminomethyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (248c).

Stage-1. Preparation of tert-butyl 3-bromo-2-hydroxybenzylcarbamate (248a).

Compound 248a was prepared according to the procedure described in step-2 of scheme-236 from 3bromo-2-hydroxybenzonitrile (500 mg, 2.53 mmol; CAS No. 13073-28-4) in methanol (10 ml) using Boc anhydride (1102 mg, 5.05 mmol), nickel(I) chloride hexahydrate (60 mg, 0.253 mmol), sodium borohydride (669 mg, 17.68 mmol) and Na-(2-aminoethyl)ethane-1,2-diamine (0.147 ml, 1.361 mmol). This resulted in tert-butyl 3-bromo-2-hydroxybenzylcarbamate (248a) (541 mg, 71% yield) as a thick solid after work-up and purification by flash column chromatography (SiO ₂ , 0-15% EtOAc in hexanes). clear colorless oil; MS (ESI-): 300 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetate (248b).

Compound 248b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (918 mg, 2.104 mmol) in dioxane (4 ml), using tert-butyl 3-bromo-2-hydroxybenzylcarbamate (248a) (763 mg, 2.52 mmol ), Pd(PPh ₃ ) ₂ Cl ₂ (148 mg, 0.210 mmol) and a solution of K2CO3 (872 mg, 6.31 mmol) in water (1 ml) under a nitrogen atmosphere when heated at 100 ° C for 16 hours in oil bath. This gave, after work-up and purification by flash column chromatography (SiO ₂ , 0-20% EtOAc in hexane), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) -2-hydroxyphenyl)benzofuran-5yl)methoxy)phenyl)acetate (248b) as a clear pale yellow oil; MS (ESI+) 554 (M+Na), (ESI-): 530 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-hydroxyphenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (248c)

A solution of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-hydroxyphenyl)benzofuran-5yl)methoxy)phenyl)acetate (248b) (from step-2) in 1 .5 M HCl in MeOH (21.04 mL, 42.1 mmol) was heated at 60°C for 1 h and concentrated in vacuo. The residue was purified by flash column chromatography (SiO ₂ , 0-10% MeOH in DCM) to give ethyl 2-(2-((7-(3-(aminomethyl)-2hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl) acetate in the form of a thick, transparent, colorless oil. This oil and LiOH-H ₂ O (353 mg, 8.42 mmol) were suspended in MeOH (2 ml), THF (1 ml) and water (1 ml) and stirred at rt for 16 hours. The solution was then concentrated in vacuo , and the residue was purified by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H2O with 0.1% HCl) to give 2-(2-((7-(3-(aminomethyl)-2- Hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (248c) (183 mg, 22% yield in 2 steps), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (s, 4H), 7.98 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.43 (dd, J=7.6, 1.7 Hz, 1H), 7.40-7.29 (m, 2H), 7.29-7.16 (m, 2H), 7 ,10 (d, J=8.0 Hz, 1H), 7.07-6.95 (m, 2H), 6.90 (td, J=7.3, 1.1 Hz, 1H), 5, 24 (s, 2H), 4.09 (s, 2H), 3.58 (s, 2H). Purity after HPLC: 98.1%; MS (ESI+): 404 (M+1).

- 323 045626

Scheme-249

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)acetic acid (249f).

Stage-1. Preparation of 5-(tert-butyldimethylsilyloxy)benzofuran-2(3H)-one (249b).

To a solution of 5-hydroxybenzofuran-2(3H)-one (249a) (1 g, 6.66 mmol; CAS No. 2688-48-4) in DMF (10 ml) was added N-imidazole (0.45 g, 6. 66 mmol) and tert-butylchlorodimethylsilane (1.21 g, 7.99 mmol). The mixture was stirred at RT for 8 hours, diluted with EtOAc and washed with water and brine. The organic layer was dried, concentrated, and the resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] to give 5-{tert-butyldimethylsilyloxy)benzofuran-2(3H)-one (249b ) (1.13 g, 64% yield) as a pale yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.05 (dd, J=8.6, 0.5 Hz, 1H), 6.90-6.84 (m, 1H), 6.76 ( m, 1H), 3.88 (k, J=0.9 Hz, 2H), 0.95 (s, 9H), 0.17 (s, 6H); MS (ESI-): 263.3 (M-1).

Stage-2. Preparation of methyl 2-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)acetate (249c).

To a solution of 5-(tert-butyldimethylsilyloxy)benzofuran-2(3H)-one (249b) (0.5 g, 1.89 mmol) in MeOH (10 ml) was added sodium methanolate (0.11 g, 2.08 mmol ) at 0°C.

The mixture was stirred at 0°C for 1 hour and concentrated in vacuo. The residue was dissolved in water and the pH was adjusted to 6 using AcOH. The mixture was diluted with DCM and washed with water and saline. The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] to give methyl 2-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)acetate ( 249c) (0.31 g, 55% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 6.68-6.59 (m, 2H), 6.55 (dd, J=8.5, 3.0 Hz , 1H), 3.58 (s, 3H), 3.50 (s, 2H), 0.93 (s, 9H), 0.13 (s, 6H); MS (ESI+): 297.2 (M+1), MS (ESI-): 295.2 (M-1).

Stage-3. Preparation of methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acetate (249d) .

Compound 249d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.28 g, 0.78 mmol) in DCM ( 10 ml), using triphenylphosphine (0.27 g, 1.01 mmol), methyl 2-(5-((tert-butyldimethylsilyl)oxy)-2hydroxyphenyl)acetate (249c) (0.3 g, 1.01 mmol) and di-(4-chlorobenzyl)azodicarboxylate di-(4-chlorobenzyl)azodicarboxylate (0.37 g, 1.01 mmol). This gave, after work-up and purification by flash column chromatography [silica gel column 12 g, eluted with EtOAc/MeOH=9:1 in 0% to 30% hexanes] methyl 2-(2-((7-(3- (((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-((tertbutyldimethylsilyl)oxy)phenyl)acetate (249d) (0.24 g, 49% yield) as a brownish amorphous solid ; MS (ESI-): 530.8 (M-Vos-1).

Stage-4. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5hydroxyphenyl)acetate (249e).

Compound 249e was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acetate (249d) (0.24 g, 0.38 mmol) in DCM (6 mL) using TFA (0.59 mL, 7.60 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with MeOH in DCM 0% to 50%), methyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl )methoxy)-5-hydroxyphenyl)acetate (249e) (0.13 g, 82% yield) as a white wax; MS (ESI+): 418.1 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5hydroxyphenyl)acetic acid (249f).

Compound 249f was prepared according to the procedure described in step-6 of Scheme-1 from methyl

- 324 045626

2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)acetate (249e) (0.13 g, 0.31 mmol) in THF/methanol ( 4 ml each) using a solution of lithium hydroxide monohydrate (0.13 g, 3.11 mmol) in water (4 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)acetic acid (249f) (0.01 g, 10% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.96 (s, 1H), 8.35 (s, 3H), 8.09 (dd, J=4.2, 2.2 Hz, 1H), 7.98 (t, J=1.7 Hz, 1H), 7.97-7.89 (m, 2H), 7.74 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.06 (d, J=2.2 Hz, 1H), 6, 90 (d, J=8.7 Hz, 1H), 6.66 (d, J=2.9 Hz, 1H), 6.60 (dd, J=8.7, 3.0 Hz, 1H), 5.14 (s, 2H), 4.14 (d, J=5.8 Hz, 2H), 3.51 (s, 2H); MS (ESI+): 404.0 (M+1), MS (ESI-): 402.0 (M-1). Purity after HPLC: 97.78%.

Scheme-250

Preparation of (8)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1yl)acetic acid (250f).

Stage-1. Preparation of (S)-tert-butyl 2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1carboxylate (250b).

Compound 250b was prepared according to the procedure described in step-4 of Scheme-1 from 7-bromobenzofuran-5-amine hydrochloride (216b) (450 mg, 1.811 mmol) using (S)-1-(tert-butoxycarbonyl)pyrrolidine-2 -carboxylic acid (250a) (487 mg, 2.264 mmol), DIPEA (1.262 ml, 7.24 mmol) and HATU (1033 mg, 2.72 mmol) in DMF (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] (S)-tert-butyl 2-((7-bromobenzofuran-5-yl )carbamoyl)pyrrolidine-1-carboxylate (250b) (687 mg, 93%) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.95-7.89 (m, 1H), 7.84-7.78 (m, 1H), 7.12-7.05 (m, 1H), 4.30-4.12 (m, 1H), 3.49-3.35 (m, 2H ), 2.31-2.10 (m, 1H), 1.97-1.74 (m, 3H), 1.40 (s, 3H), 1.27 (s, 6H); MS (ESI-): 407.1 and 409.10 (M-1).

Stage-2. Preparation of (S)-N-(7-bromobenzofuran-5-yl)n-irrolidin-2-carboxamide (250c).

Compound 250c was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (250b) (650 mg, 1.588 mmol) in DCM (25 ml) using TFA (1.224 ml, 15.88 mmol). This resulted in (S)-N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide (250c) being treated as a brown gum, which was used as is in the next step. MS (ESI+): 308.95 and 310.90 (M+1).

Stage-3. Preparation of (S)-ethyl 2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (250d).

To a solution of (S)-N-(7-bromobenzofuran-5-yl)pyrrolidin-2-carboxamide (250c) (491 mg, 1.588 mmol) in DMF (12 ml) was added potassium carbonate (1097 mg, 7. 94 mmol), ethyl 2 bromoacetate (0.264 ml, 2.382 mmol) and stirred at RT for 15 hours. The reaction mixture was diluted with ethyl acetate (110 ml), washed with water (60 ml), brine (60 ml), dried, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give (S)-ethyl 2-(2-((7bromobenzofuran-5-yl)carbamoyl)pyrrolidine- 1-yl)acetate (250d) (466 mg, 74% in 2 steps) as a colorless gum;

1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.9 Hz, 1H ), 7.86 (dd, J=1.9, 0.5 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 4.11 (k, J=7.1 Hz , 2H), 3.74-3.42 (m, 3H), 3.25-3.10 (m, 1H), 2.68 (td, J=9.0, 6.6 Hz, 1H), 2.25-2.06 (m, 1H), 1.96-1.65 (m, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI+): 394.90 and 396.95 (M+1).

Stage-4. Preparation of (S)-ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)carbamoyl)pyrrolidin-1-yl)acetate (250e).

- 325 045626

Compound 250e was prepared according to the procedure described in step-3 of Scheme-1 from (S)ethyl 2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (250d) (460 mg, 1.164 mmol) in dioxane (16 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (327 mg, 1.746 mmol), solution of K2CO3 (483 mg, 3.49 mmol) in water (1.6 ml ), Pd(PPh ₃ ) ₂ Cl ₂ (163 mg, 0.233 mmol) and heating under Ar at 100°C for 3 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted ( 1:0 to 9:1) MeOH in DCM] (S)ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate ( 250e) (321 mg, 65%) as a light brown resin;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=2.1 Hz , 1H), 7.80-7.75 (m, 1H), 7.71-7.65 (m, 2H), 7.51-7.36 (m, 2H), 7.03 (d, J =2.2 Hz, 1H), 4.11 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.753.44 (m, 3H), 3.24-3.17 (m, 1H), 2.69 (td, J=8.9, 6.6 Hz, 1H), 2.29-1.63 (m, 4H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI+): 422.00 (M+1).

Stage-5. Preparation of (S)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin1-yl)acetic acid (250f).

Compound 250f was prepared according to the procedure described in step-6 of Scheme-1 from (S)ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidine-1 -yl)acetate (250e) (300 mg, 0.712 mmol) in THF/methanol (15 mL each), using a solution of lithium hydroxide monohydrate (183 mg, 4.27 mmol) in water (15 mL). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-2-(2- ((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetic acid (250f) (248 mg, 89%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.58 (s, 3H), 8.08 (d, J=2.2 Hz, 1H), 8.02 ( d, J=2.0 Hz, 1H), 7.92 (s, 1H), 7.85-7.76 (m, 2H), 7.65-7.54 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 4.49 (br.s, 1H), 4.40-4.03 (m, 4H), 3.69 (br.s, 1H), 2, 67-2.55 (m, 1H), 2.16-2.01 (m, 3H), 2.00-1.86 (m, 1H); MS (ESI+): 394.00 (M+1).

Scheme-251

Preparation of 2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-methoxybenzofuran-5carboxamido)phenyl)acetic acid (251c).

Stage-1. Preparation of ethyl 2-(2-(7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4fluorobenzofuran-5-carboxamido)phenyl)acetate (251a).

Compound 251a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a) (153 mg, 0.364 mmol) to dioxane (5 ml), using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methyl)carbamate (123a) (241 mg , 0.721 mmol), solution of K ₂ CO ₃ (159 mg, 1.150 mmol) in water (0.5 ml), bis(triphenylphosphine) palladium (11) chloride (42 mg, 0.060 mmol) when heated at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 30 to 100% hexanes in ethyl acetate] ethyl 2-(2-(7-(2-(((tert-butoxycarbonyl)amino) methyl)pyridin-4-yl)-4-fluorobenzofuran-5carboxamido)phenyl)acetate (251a) (182 mg, 91% yield) as a yellow foam. MS (ESI+): 548.0 (M+1).

Stage-2. Preparation of ethyl 2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5carboxamido)phenyl)acetate (251b).

Compound 251b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-(7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran -5carboxamido)phenyl)acetate (251a) (180 mg, 0.329 mmol) in DCM (8 ml) using TFA (0.3 ml, 3.89 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with DMA-80 in DCM 0% to 100%), ethyl 2-(2-(7-(2-326 045626 (aminomethyl)pyridine -4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (251b) (109 mg, 74% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 7.99 (s, 2H), 7. 78 (s, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 4.06-4.02 (m, 2H), 3.92 (s, 2H), 3.80 (s, 2H), 1.22-1.13 (m, 3H); ¹⁹ F NMR (282 MHz,

DMSO4) δ -117.94. MS (ESI+): 448.0 (M+1).

Stage-3. Preparation of 2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-methoxybenzofuran-5 carboxamido)phenyl)acetic acid (251c).

Compound 251c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (251b) (107 mg, 0.239 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (86 mg, 2.05 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-(7-(2-( aminomethyl)pyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)acetic acid (251c) (75 mg, 73% yield) as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 10.00 (s, 1H), 8.97-8.58 (m, 4H), 8.36-8.18 (m, 3H), 8.12 (dd, J=5.6, 1.8 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7 .34 (t, J=7.5 Hz, 2H), 7.26-7.06 (m, 1H), 4.36 (d, J=8.6 Hz, 5H), 3.75 (s, 2H); MS (ESI+): 432.0 (M+1); MS (ESI-): 430.0 (M-1).

Scheme-252

Preparation of 2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (252d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (252a).

Compound 252a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98c) ( 1.5 g, 3.12 mmol) in dioxane (40 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (1.732 g, 4.68 mmol), solution of K ₂ CO ₃ (1.295 g, 9.37 mmol) in water (4 ml), bis(triphenylphosphine) palladium(P) chloride (0.438 g, 0.625 mmol) when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel eluted with hexanes in ethyl acetate (1:0 to 2:1)] ethyl 2-(2-((7(3-(((tert-butoxycarbonyl)amino) Methyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5yl)methoxy)phenyl)acetate (252a) (1.115 g) as a yellow gum MS (ESI+): 582.00 (M+Na);

Stage-2. Preparation of ethyl 2-(2-((2-acetyl-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (252b).

To a solution of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (252a) (500 mg, 0.893 mmol) in DCM (10 ml), Dess-Martin periodinane (798 mg, 1.787 mmol) was added at room temperature and stirred at RT for 8 hours. The reaction mixture was diluted with DCM (100 ml), washed with 1 M NaHCO ₃ ( 50 ml), water (50 ml), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give ethyl 2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl )amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (252b) (490 mg, 63% in 2 steps) as a brown gum;

1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.81-7.73 (m, 3H), 7 .58-7.44 (m, 2H), 7.37-7.31 (m, 1H), 7.30-7.19 (m, 2H), 7.14-7.10 (m, 1H) , 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.91 ( k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.60 (s, 3H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (252c).

Compound 252c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate

- 327 045626 (252b) (470 mg, 0.843 mmol) in DCM (25 ml) using TFA (0.649 ml, 8.43 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with DCM/methanol (1:0 to 9:1)], ethyl 2-(2-((2-acetyl-7-(3-( aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (252c) (445 mg) as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.28 (s, 3H), 8.02 (s, 1H), 7.99-7.94 (m, 2H), 7.91 (d, J =1.6 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.69-7.60 (m, 1H), 7.57 (dt, J=7.8, 1.5 Hz, 1H), 7.31-7.20 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 6.93 (td, J=7 ,4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.22-4.09 (m, 2H), 3.93 (k, J=7.1 Hz, 2H), 3 .64 (s, 2H), 2.60 (s, 3H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 458.00 (M+1).

Stage-4.

Receipt

2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (252d).

Compound 252d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (252c) (400 mg, 0.874 mmol) in MeOH/THF (16 mL each), using a solution of lithium hydroxide monohydrate (225 mg, 5.25 mmol) in water (16 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((2-acetyl-7 -(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (252d) (51 mg, 16% in 2 steps), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.21 (s, 1H), 8.54 (s, 3H), 8.05-8.01 (m, 1H), 8.00-7.95 (m, 2H), 7.93 (d, J=1.6 Hz, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.69-7.56 (m, 2H) , 7.30-7.19 (m, 2H), 7.13-7.07 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.14 (s, 2H), 3.61 (s, 2H), 2.60 (s, 3H). MS (ESI+): 430.0 (M+1).

Scheme-253

2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3Preparation of phenylpropanamido)acetic acid (253f).

Stage-1. Preparation of 2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetic acid (253b).

To a stirred solution of 2-amino-2-(2-hydroxyphenyl)acetic acid (222a) (1 g, 5.98 mmol) and sodium bicarbonate (2.010 g, 23.93 mmol) in water (20 ml)/THF (10 ml) at 0°C, a solution of 3-phenylpropanoyl chloride (253a) (3.03 g, 17.95 mmol) in tetrahydrofuran (10 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred for 12 hours and concentrated in vacuo to remove THF. The reaction mixture was acidified with 3N HCl to pH 4 and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 mL), dried and concentrated in vacuo to give 2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetic acid (253b) (2.03 g, 113% yield) as thick syrup.

The crude material was used as is in the following reaction without further purification. MS (ESI+): 322.00 (M+Na), (ESI-): 299.00 (M-1).

Stage-2. Preparation of ethyl 2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetate (253c).

Compound 253c was prepared according to the procedure described in step-2 of Scheme-222 from 2-(2hydroxyphenyl)-2-(3-phenylpropanamido)acetic acid (253b) (2.5 g, 8.35 mmol) in ethanol ( 30 ml) using sulfuric acid (1.113 ml, 20.88 mmol). This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-hydroxyphenyl)-2-(3phenylpropanamido)acetate (253c) (345 mg, 13% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.40 (d, J=7.4 Hz, 1H), 7.35-7.07 (m, 7H) , 6.91-6.72 (m, 2H), 5.66 (d, J=7.4 Hz, 1H), 4.14-3.93 (m, 2H), 2.80 (t, J =7.9 Hz, 2H), 2.48-2.40 (m, 2H), 1.11 (t, J=7.1 Hz, 3H); MS (ESI+): 328.00 (M+1), (ESI-): 326.00 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate (253d).

Compound 253d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (300 mg, 0.849 mmol) in DCM (20

- 328 045626 ml), using triphenylphosphine (256 mg, 0.976 mmol), ethyl 2-(2-hydroxyphenyl)-2-(3phenylpropanamido) acetate (253c) (320 mg, 0.976 mmol) and di-(4-chlorobenzyl) solution azodicarboxylate (DCAD, 374 mg, 1.019 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 50% hexanes), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)2-(3-phenylpropanamido)acetate (253d) (365 mg, 0.551 mmol, 64.9% yield) as a white foam; MS (ESI+): 563.00 (M+1-Vos).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3phenylpropanamido)acetate (253e).

Compound 253e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )phenyl)-2-(3phenylpropanamido)acetate (253d) (350 mg, 0.528 mmol) in DCM (10 ml) using TFA (0.407 ml, 5.28 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 25 g, eluted with DMA 80 in DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran5-yl)methoxy)phenyl )-2-(3-phenylpropanamido)acetate (253e) (160 mg, 54% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (d, J=7.8 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.86 (d , J=1.8 Hz, 1H), 7.80-7.69 (m, 2H), 7.64 (d, J=1.7 Hz, 1H), 7.51-7.27 (m, 3H), 7.26-7.07 (m, 7H), 7.02 (d, J=2.2 Hz, 1H), 6.976.91 (m, 1H), 5.83 (d, J=7 .8 Hz, 1H), 5.30 (s, 2H), 4.02-3.89 (m, 2H), 3.85 (s, 2H), 2.77 (dd, J=9.1, 6.4 Hz, 2H), 2.51-2.39 (m, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 563.25(M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3phenylpropanamido)acetic acid (253f).

Compound 253f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3 -phenylpropanamido)acetate (253e) (160 mg, 0.284 mmol) in THF/MeOH (3 mL each), using a solution of lithium hydroxide monohydrate (21 mg, 0.85 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3phenylpropanamido)acetic acid (253f) (100 mg, 66% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.72 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 8.42 (s, 3H), 8.11 ( d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.95 (dt, J=6.9, 2.1 Hz, 1H), 7.79 (d, J=1 .6 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.57 (d, J=6.6 Hz, 2H), 7.36-7.23 (m, 2H ), 7.23-7.10 (m, 6H), 7.04 (d, J=2.2 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.32 (s, 2H), 4.14 (s, 2H), 2.82-2.66 (m, 2H), 2.54-2, 39 (m, 2H); MS (ESI+): 535.2 (M+1), (ESI-): 533.10 (M1).

Scheme-254

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-5 (hydroxymethyl)phenyl)acetic acid (254c).

Stage-1. Preparation of methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-(hydroxymethyl)phenyl)acetate (254a).

Compound 254a was prepared according to the procedure described in step-1 of scheme-236 from methyl 2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl )methoxy)phenyl)acetate (208b) (0.1 g, 0.17 mmol) in DMF (4 ml), using (tributylstannyl)methanol (0.08 g, 0.26 mmol), Pd(Ph ₃ P) ₄ (0.04 g, 0.03 mmol) when heated at 80°C in an oil bath for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with MeOH in DCM from 0 to 60%) methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate (254a)

- 329 045626 (0.04 g, 39% yield) in the form of a white solid; MS (ESI+): 554.2 (M+Na). MC (ESI-): 530.2 (M1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5(hydroxymethyl)phenyl)acetate (254b).

Compound 254b was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5(hydroxymethyl)phenyl)acetate (254a) (0.04 g, 0.07 mmol) in DCM (3 ml) using TFA (0.10 ml, 1.35 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with MeOH in DCM 0% to 50%), methyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-5-(hydroxymethyl)phenyl)acetate (254b) (0.03 g, 99% yield) as a clear wax, which was used as is in the next step.

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5(hydroxymethyl)phenyl)acetic acid (254c).

Compound 254c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl) phenyl)acetate (254b) (0.03 g, 0.07 mmol) in THF/methanol (4 ml each), using a solution of lithium hydroxide monohydrate (0.02 g, 0.54 mmol) in water (1 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetic acid (254c) (0.004 g, 14% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.22 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=7.7 Hz , 1H), 7.52 (d, J=7.7 Hz, 1H), 7.16 (d, J=6.8 Hz, 2H), 7.087.00 (m, 2H), 5.26 (s , 2H), 5.12-4.99 (m, 1H), 4.40 (d, J=4.2 Hz, 2H), 4.15 (d, J=5.5 Hz, 2H), 3 .58 (s, 2H); MS (ESI+): 418.1 (M+1); MS (ESI-): 416.0 (M-1).

Scheme-255

Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)acetic acid (255c).

Stage-1. Preparation of ethyl 2-(2-(7-bromofuro[3,2-b]pyridine-5-carboxamido)phenyl)acetate (255a).

Compound 255a was prepared according to the procedure described in step-4 of Scheme-1 from 7bromofuro[3,2-b]pyridine-5-carboxylic acid (119a) (223 mg, 0.921 mmol) in DMF (6 ml) using ethyl 2-(2-aminophenyl) acetate (5e) (246 mg, 1.373 mmol), DIPEA (0.65 ml, 3.73 mmol) and HATU (546 mg, 1.436 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with ethyl acetate in 0% to 50% hexane), ethyl 2-(2-(7bromofuro[3,2-b]pyridine-5-carboxamido )phenyl)acetate (255a) (322 mg, 87% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 7.69 ( dd, J=8.3, 1.3 Hz, 1H), 7.46-7.30 (m, 3H), 7.22 (td, J=7.4, 1.4 Hz, 1H), 4 .04 (k, J=7.1 Hz, 2H), 3.79 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI+): 402.9 (M+1).

Stage-2. Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5carboxamido)phenyl)acetate (255b).

Compound 255b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(7-bromofuro[3,2-b]pyridine-5-carboxamido)phenyl)acetate (255a) (120 mg, 0.298 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (73 mg, 0.390 mmol), bis(triphenylphosphine) palladium(P) chloride (40 mg, 0.057 mmol) and K2CO3 solution ( 137 mg, 0.991 mmol) in water (0.5 ml) under Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography, [silica gel (12 g),

- 330 045626 eluted with DMA80/DCM, 0% to 80%] ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5carboxamido)phenyl)acetate (255b) (47 mg, 37% yield) as a pale yellow oil. MS (ESI+): 430.0 (M+1).

Stage-3. Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5carboxamido)phenyl)acetic acid (255c).

Compound 255c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl) acetate (255b) (46 mg, 0.107 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (42 mg, 1.0 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 3(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)acetic acid (255c) (24 mg, 56% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 12.63 (s, 1H), 10.55 (s, 1H), 8.77-8.43 (m, 4H), 8.36 (s, 1H ), 8.19-7.98 (m, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.70-7.49 (m, 2H), 7.42-7, 20 (m, 3H), 7.14 (t, J=7.4 Hz, 1H), 4.11 (d, J=5.7 Hz, 2H), 3.67 (s, 2H). MS (ESI+): 402.0 (M+1); MS (ESI-): 400.0 (M-1).

Scheme-256

Preparation of 2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (256c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-cyano-2,5-difluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (256a).

Compound 256a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (500 mg, 1.146 mmol) in dioxane (2 ml) using 3-bromo-2,5-difluorobenzonitrile (250 mg, 1.146 mmol; CAS No. 1638487-41 -8), Pd(PPh ₃ ) ₂ Cl ₂ (80 mg, 0.115 mmol) and a solution of K ₂ CO ₃ (475 mg, 3.44 mmol) in water (1 ml) under nitrogen atmosphere and heating at 100 ° C in for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with ethyl acetate in 0% to 15% hexane), ethyl 2-(2-((7-(3-cyano-2,5-difluorophenyl )benzofuran-5yl)methoxy)phenyl)acetate (256a) (0.26 g, 51% yield) as a clear, colorless thick oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.17-8.09 (m, 2H), 8.03 (ddd, J=8.9, 5.7, 3.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.55 (s, 1H), 7.33-7.19 (m, 2H), 7.16-7.08 (m, 2H) , 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.64 ( s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 447.9 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (256b).

To a mixture of ethyl 2-(2-((7-(3-cyano-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (256a) (0.26 g, 0.581 mmol), Boc anhydride ( 0.254 g, 1.162 mmol) and NiCl ₂ 6H ₂ O (0.014 g, 0.058 mmol) in MeOH (10 ml) at 0°C NaBH ₄ (0.154 g, 4.07 mmol) was added portionwise. The resulting black mixture was then stirred at rt for 16 h, quenched with diethylenetriamine (0.126 mL, 1.162 mmol) and stirred at rt for an additional 15 min. The solution was concentrated in vacuo to remove MeOH, and the resulting residue was diluted with saturated NaHCO ₃ (25 ml) and extracted with EtOAc (20 ml x 3). The combined organic extracts were washed with H ₂ O (20 ml), brine (20 ml), dried, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, eluted with 0-20% EtOAc in hexane). The resulting product was dissolved in 2 M HCl in MeOH (0.212 g, 5.81 mmol), which was freshly prepared by adding acetyl chloride dropwise to cold MeOH at 0°C. The solution was stirred at 60°C for 1 hour and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , 12 g, eluted with 0-10% MeOH in DCM) to give methyl 2-(2-((7-(3-(aminomethyl)-2,5difluorophenyl)benzofuran- 5-yl)methoxy)phenyl)acetate (256b) (0.13 g) in the form of a thick, transparent, colorless oil; MS (ESI+): 437.9 (M+1), (ESI-): 435.9 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (256c).

Compound 256c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl )acetate (256b) (from step-2) in MeOH (2 ml), THF (1 ml each), using a solution of lithium hydroxide monohydrate (0.073 g, 1.743 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (256c) (12 mg, 5% yield in two steps), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 3H), 8.08 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.69-7.53 (m, 2H), 7.51 (s, 1H), 7.23 (dd, J=8.8, 7.0 Hz, 2H), 7.15-7 .01 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.26 (s, 2H), 4.15 (s, 2H), 3.58 (s, 2H) .

Scheme-257

Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (257k).

Stage-1. Preparation of methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a).

Compound 257a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (3 g, 7.42 mmol) in pyridine (30 ml) using 1- (trimethylsilyl)1-propyne (0.83 g, 7.42 mmol) and copper(I) oxide (0.53 g, 3.71 mmol). This resulted in methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a) (1.1 g, 46%) as an off-white solid after work-up and purification by crystallization from n-heptane;

1H NMR (300 MHz, DMSO-d6) δ 8.22-8.05 (m, 2H), 6.86 (d, J=1.3 Hz, 1H), 3.86 (s, 3H), 2 .51 (s, 3H).

Stage-2. Preparation of 7-iodo-2-methylbenzofuran-5-carboxylic acid (257b).

Compound 257b was prepared according to the procedure described in step-4 of Scheme-4 from methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a) (4.0 g, 12.65 mmol) in THF (40 ml) MeOH (120 ml) using a solution of sodium hydroxide (1015 g, 37.96 mmol) in water (40 ml). This resulted in 7-iodo-2-methylbenzofuran-5-carboxylic acid (257b) (3.0 g, 79%) as an off-white solid upon treatment.

1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.14 (s, 2H), 6.86 (d, J=1.3 Hz, 1H), 2.51 (s , 3H).

Stage-3. Preparation of (7-iodo-2-methylbenzofuran-5-yl)methanol (257c).

- 332 045626

Compound 257c was prepared according to the procedure described in step-1 of Scheme-23 from 7iodo-2-methylbenzofuran-5-carboxylic acid (257b) (3.0 g, 9.93 mmol) using N-methylmorpholine (1, 2 g, 11.91 mmol) in THF (90 ml), isobutyl chloroformate (1.62 g, 11.91 mmol) and NaBH ₄ (1.12 g, 29.79 mmol) in water (10 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-30% EtOAc in n-heptane), (7-iodo-2methylbenzofuran-5-yl)methanol (257c) (1.9 g, 66%) in the form of syrup.

^1H NMR (300 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.43 (s, 1H), 6.70 (s, 1H), 5.25 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H), 2.46 (s, 3H).

Stage-4. Preparation of 5-(chloromethyl)-7-iodo-2-methylbenzofuran (257d).

To a stirred solution of (7-iodo-2-methylbenzofuran-5-yl)methanol (257c) (1.5 g, 5.20 mmol) in DCM (30.0 ml) was added SOCl ₂ (1.23 g, 10.40 mmol). The resulting reaction mixture was stirred for 2 hours at 0°C, poured into saturated NaHCO ₃ solution (200 ml) and extracted with DCM (2x100 ml). The combined organics were washed with brine, dried, filtered and concentrated in vacuo to give 5-(chloromethyl)-7-iodo-2-methylbenzofuran (257d) (1.5 g, 94%) as a thick oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.65 (m, 2H), 6.73 (d, J=7.2 Hz, 1H), 4.83 (m, 2H), 2.48 ( s, 3H).

Stage-5. Preparation of ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f).

To a solution of ethyl 2-(4-cyano-2-methoxyphenyl) acetate (257e) (1.9 g, 8.67 mmol; CAS No. 1261674-45-6) in dichloromethane (35 ml), cooled to -78°C , boron tribromide (3.28 mL, 34.7 mmol) was added and allowed to warm to room temperature overnight. The reaction mixture was poured onto ice/water treated with ethanol (20 ml) and concentrated under vacuum to dryness. The residue was again treated with ethanol (20 ml) and concentrated to dryness. The residue was dissolved in ethyl acetate (150 ml), washed with water (2x60 ml), brine (60 ml), dried, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give ethyl 2-(4-cyano-2hydroxyphenyl)acetate (257f) (1.25 g, 70 %) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.39 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.7, 1 ,6 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 4.06 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1, 17 (t, J=7.1 Hz, 3H).

Stage-6. Preparation of ethyl 2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (257g).

To a stirred solution of 5-(chloromethyl)-7-iodo-2-methylbenzofuran (257d) (1.5 g, 4.89 mmol) in DMSO (15.0 mL) was added ethyl 2-(4-cyano- 2-Hydroxyphenyl)acetate (257f) (1.00 g, 4.89 mmol), Cs ₂ CO ₃ (4.87 g, 14.68 mmol) and stirred at room temperature for 18 hours. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layer was washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-10% EtOAc in n-heptane) to give ethyl 2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5yl)methoxy)phenyl )acetate (257g) (0.5 g, 22%) as an off-white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.66-7.49 (m, 3H), 7.51-7.34 (m, 2H), 6.75 (d, J=1.2 Hz, 1H), 5.19 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.70 (s, 2H), 2.48-2.47 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).

Stage-7. Preparation of ethyl 2-(4-cyano-2-((7-(3-cyanophenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (257h).

Compound 257h was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (257g) ( 1 g, 2.1 mmol) in acetonitrile (50 ml), using (3-cyanophenyl)boronic acid (0.206 g, 1.40 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.221 g, 0.104 mmol) and solution Na ₂ CO ₃ (0.668 g, 6.31 mmol) in water (5.0 ml) and heating under nitrogen at 90°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-40% EtOAc in n-heptane), ethyl 2-(4cyano-2-((7-(3-cyanophenyl)-2-methylbenzofuran- 5-yl)methoxy)phenyl)acetate (257h) (800 mg, 84% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.29 (t, J=1.6 Hz, 1H), 8.24 (dt, J=7.7, 1.5 Hz, 1H), 7.90 (dt, J=7.8, 1.4 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.62 (dd, J=7.9, 1.5 Hz, 2H), 7.57 (d, J=1.6 Hz, 1H), 7.49-7.38 (m, 2H), 6.70 (d, J=1.3 Hz, 1H), 5, 29 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.73 (s, 2H), 2.49 (s, 3H), 0.97 (t, J=7 ,1 Hz, 3H); MS (ESI+): 430.3 (M+1).

Stage-8. Preparation of ethyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy) phenyl)acetate (257i).

Compound 257i was prepared according to the procedure described in step-2 of scheme-256 from ethyl 2-(4-cyano-2-((7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl) acetate (257h) in methanol (20 ml), using Boc anhydride (1.55 g, 7.10 mmol), nickel(II) chloride hexahydrate (0.21 g, 0.88 mmol) and sodium borohydride (0.58 g, 14.2 mmol). This resulted in, after workup, purification by flash column chromatography (silica gel, eluted with 0-30% EtOAc in n-heptane) ethyl 2-(4-333 045626 (((tert-butoxycarbonyl)amino)methyl)-2-( (7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2methylbenzofuran-5-yl)methoxy)phenyl)acetate (257i) (0.5 g, 43%) as an oil;

1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.64-7.53 (m, 2H), 7.52-7.34 (m, 2H), 7.28 ( d, J=7.6 Hz, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.01 (s, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.65 (s, 1H), 5.16 (s, 2H), 4.22 (d, J=6.1 Hz, 2H), 4.11 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.48 (s, 3H), 1.46-1.27 (m, 18H), 0.96 (t, J=7.1 Hz, 3H).

Stage-9. Preparation of 2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy )phenyl)acetic acid (257j).

Compound 257j was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl) )amino)methyl)phenyl)-2methylbenzofuran-5-yl)methoxy)phenyl)acetate (257i) (0.3 g, 0.44 mmol) in MeOH (10 ml) using NaOH solution (54 mg, 1.32 mmol) in water (5 ml). This resulted in the preparation after treatment of 2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2methylbenzofuran-5-yl) methoxy)phenyl)acetic acid (257j) (0.2 g, 69.47%) as an off-white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 7.78-7.69 (m, 2H), 7.65-7.56 (m, 1H), 7.54-7.40 (m, 2H) , 7.40-7.23 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.66 (s, 1H), 5.18 (s, 2H), 4.23 (d, J=6.2 Hz, 1H), 4.09 (d, J=6.2 Hz, 1H), 4.02 (k, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.47 (s, 3H), 1.38 (d, J=5.5 Hz, 18H), 1.17 (t, J=7.1 Hz, 3H).

Stage-10. Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (257k).

To a stirred solution of 2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy )phenyl)acetic acid (257j) (0.2 g, 0.31 mmol) in 1,4-dioxane (2.0 ml) was added at room temperature 1,4-dioxane.HCl (28%, 2.0 ml ) and stirred for 2 hours. The resulting solid was collected by filtration, dried and purified by reverse phase column chromatography [C-18, steel column (250 mm x 30 mm) eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to obtain 2-(4-(aminomethyl)-2-((7-(3(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acids (257k) (0.045 g) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (s, 5H), 8.01 (s, 1H), 7.93 (dt, J=7.3, 1.8 Hz, 1H), 7.65-7.50 (m, 4H), 7.41 (s, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.01 (dd, J=7.6, 1.5 Hz, 1H), 6.67 (d, J=1.3 Hz, 1H), 5.24 (s, 2H), 4.14 (s, 2H), 3.99 (s, 2H) , 3.59 (s, 2H), 2.49 (s, 3H); MS (ESI+): 431.20 (M+1); (ESI-) 429.20 (M-1); analysis calculation for C ₂₆ H ₂₆ N ₂ O ₄ -2HCl-2.75H ₂ O: C, 56.47; N, 6.11; Cl, 12.82; N, 5.07; observed: C, 56.61; N, 5.93; Cl, 12.79; N, 5.11.

Receipt

Scheme-258

(-)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic

- 334 045626 acid (258f).

Stage-1. Preparation of (-)-(S)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (258b).

To a solution of 1-(3-bromophenyl)-2-fluoroethanone (258a) (3 g, 13.82 mmol; CAS No. 1219632-64-0) and (S)-2methylpropane-2-sulfinamide (3.35 g, 27 .6 mmol) in tetrahydrofuran (50 ml), tetraethoxytitanium (6.31 g, 27.6 mmol) was added and stirred overnight at rt. The reaction mixture was quenched with saline (20 ml) and stirred for 20 min. The separated solid was filtered off and the precipitate was washed with ethyl acetate (200 ml). The organic layer was separated, washed with brine (2x20 ml), dried and concentrated in vacuo. The crude residue was purified by flash column chromatography [(silica gel, 40 g, eluted with ethyl acetate in hexanes (0 to 20%)] to give (-)-(S)-N-(1-(3-bromophenyl)-2-fluoroethylidene) -2-methylpropane-2-sulfinamide (258b) (2.456 g, 7.67 mmol, 56% yield) as brown syrup; MS (ESI+) 320.0, 322.0 (M+1); optical rotation [ a] _D = -2.43 (c = 1.65, MeOH).

Stage-2. Preparation of (+)-(S)-N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (258с).

To a solution of (-)-(S)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (258b) (2.4 g, 7.49 mmol) in tetrahydrofuran ( 50 ml) and water (1 ml), sodium borohydride (0.851 g, 22.48 mmol) was added portionwise at a temperature below -56°C over 2 minutes. The reaction mixture was then stirred at the same temperature for 30 minutes and allowed to warm to -12°C over 30 minutes. The reaction mixture was quenched with acetone (3 ml) and stirred for 10 min, diluted with water and concentrated in vacuo to remove organic solvents. The aqueous layer was extracted with ethyl acetate (2x100 ml), and the combined organic layer was washed (2x50 ml), brine (50 ml), dried and concentrated in vacuo to give a clear oil. The crude residue was purified by flash column chromatography [(silica gel, 80 g, eluted with ethyl acetate in hexanes (0 to 100%)] to give (+)-(S)-N-(1-(3-bromophenyl)-2-fluoroethyl )-2-methylpropane-2-sulfinamide (258c) (1.25 g, 52% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (t, J=1.8 Hz, 1H), 7.53-7.43 (m, 2H), 7.32 (t, J=7 .8 Hz, 1H), 6.04 (d, J=8.9 Hz, 1H), 4.68-4.53 (m, 2H), 4.42 (d, J=6.3 Hz, 1H ), 1.12 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 217.83; optical rotation [a] _D = +5.26 (c = 0.69, MeOH).

Stage-3. Preparation of (-)-ethyl 2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (258d ).

Compound 258d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (500 mg, 1.146 mmol) in dioxane (10 ml) using (+)-(S)-N-(1-(3-bromophenyl)-2- fluoroethyl)-2-methylpropane2-sulfinamide (258c) (443 mg, 1.375 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (121 mg, 0.172 mmol) and a solution of K2CO3 (475 mg, 3.44 mmol) in water (1 ml) in a nitrogen atmosphere when heated at 100°C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes), (-)-ethyl 2-(2-((7-(3-(1 -((S)1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (258d) (3 92 mg, 62% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.93 (s, 1H), 7.83 (td, J=4.6, 1 .7 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.67-7.56 (m, 1H), 7.56-7.50 (m, 2H), 7 .25 (ddd, J=16.0, 8.1, 1.7 Hz, 2H), 7.17-7.09 (m, 1H), 7.06 (d, J=2.2 Hz, 1H ), 6.91 (td, J=7.3, 1.1 Hz, 1H), 6.05 (d, J=8.3 Hz, 1H), 5.24 (s, 2H), 4.76 -4.63 (m, 2H), 4.52 (d, J=6.3 Hz, 1H), 3.96-3.86 (m, 2H), 3.63 (s, 2H), 1, 13 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -216.98; MS (ESI+): 552.2 (M+1); optical rotation [a] _D = -1.78 (c = 0.23, MeOH).

Stage-4. Preparation of (-)-ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (258e).

Compound 258e was prepared according to the procedure described in step-10 of scheme-257 from (-)ethyl 2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2 -fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (258d) (450 mg, 0.82 mmol) in THF (10 ml), using HCl (4 M in 1,4-dioxane) (0.408 ml, 1 .63 mmol) and stirred for 30 minutes. This gave, after work-up and purification by flash column chromatography (silica gel, 25 g eluted with DMA 80 in dichloromethane) (-)-ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl )phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (258e) (260 mg, 71% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.82-7.75 (m, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.51-7.46 (m, 2H) , 7.29-7.19 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.75-3 .66 (m, 1H), 3.63 (s, 2H), 2.09 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 448.0 (M+1); optical rotation [a] _D = -37.78 (c = 0.09, MeOH).

Stage-5. Preparation of (-)-2-(2-((7-(3 -(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (258f).

- 335 045626

Compound 258f was prepared according to the procedure described in step-6 of Scheme-1 from (-)ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl )methoxy)phenyl)acetate (258e) (250 mg, 0.56 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide monohydrate (54 mg, 2.24 mmol) in water (2 ml ). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (-)-2-(2- ((7(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (258f) (115 mg, 49% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 8.00-7.95 (m, 1H), 7 .77 (d, J=1.6 Hz, 1H), 7.68-7.63 (m, 2H), 7.63-7.56 (m, 1H), 7.24 (t, J=7 .6 Hz, 2H), 7.10 (d, J=8.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.94-6.87 (m, 1H ), 5.27 (s, 2H), 4.95-4.83 (m, 1H), 4.83-4.69 (m, 2H), 3.60 (s, 2H); MS (ESI+): 420.1 (M+1), (ESI-): 418.1 (M-1); optical rotation [a] _D = -11.76 (c = 0.51; MeOH); chiral HPLC: AD-H column; solvent: 80/20 (0.1% DEA in heptane/0.1% DEA in ethanol); flow rate: 1.0 ml/min; UV detection at 271 nm; analysis time=15 min; temperature 40°C; R _t =10.033 [peak-1 compound (258f), 96.90%]; R=11.44] peak-2; compounds (259e) 3.10%] 93.80% ee.

Scheme-259

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (259e).

Stage-1. Preparation of (+)-(R)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (259a).

Compound 259a was prepared according to the procedure described in Step-1 of Scheme-258 from 1-(3bromophenyl)-2-fluoroethanone (258a) (3 g, 13.82 mmol; CAS No. 1219632-64-0) and (R )-2-methylpropane-2sulfinamide (3.35 g, 27.6 mmol) in tetrahydrofuran (50 ml) using tetraethoxytitanium (6.31 g, 27.6 mmol). This gave, after work-up and purification by flash column chromatography [(silica gel, 40 g, eluted with ethyl acetate in hexanes (0 to 20%)] (+)-(R)-N-(1-(3bromophenyl)- 2-fluoroethylidene)-2-methylpropane-2-sulfinamide (259a) (2.08 g, 47% yield) as brown syrup; MS (ESI+): 320.0, 322.0 (M+1); optical rotation [a] _D = +2.76 (c = 1.02, MeOH).

Stage-2. Preparation of (-)-(R)-N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (259b).

Compound 259b was prepared according to the procedure described in step-2 of Scheme-258 from (+)(R)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (259a ) (2.0 g, 6.25 mmol) in tetrahydrofuran (40 ml) and water (1 ml), using sodium borohydride (0.709 g, 18.74 mmol). This gave, after work-up and purification by flash column chromatography [(silica gel, 80 g, eluted with ethyl acetate in hexanes (0 to 100%)] (-)-(R)-N-(1-(3-bromophenyl) -2-fluoroethyl)-2methylpropane-2-sulfinamide (259b) (1.5 g, 75% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 7.71 (t, J=1.9 Hz, 1H), 7.56-7.41 (m, 2H), 7.33 (t, J=7 .8 Hz, 1H), 6.05 (d, J=8.9 Hz, 1H), 4.65-4.50 (m, 2H), 4.42 (d, J=6.3 Hz, 1H ), 1.13 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 217.83; optical rotation [a] _D = -7.16 (c = 1.01, MeOH).

Stage-3. Preparation of (-)-ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2

- 336 045626 fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (259c).

Compound 259c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (500 mg, 1.146 mmol) in dioxane (10 ml) using (-)-(R)-N-(1-(3-bromophenyl)-2- fluoroethyl)-2-methylpropane-2sulfinamide (259b) (443 mg, 1.375 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (121 mg, 0.172 mmol) and a solution of K2CO3 (475 mg, 3.44 mmol) in water (1 ml) in a nitrogen atmosphere when heated at 100°C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes), (-)-ethyl 2-(2-((7-(3-(1 -((R)1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (259c) (392 mg, 0.711 mmol, 62.0% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.93 (s, 1H), 7.83 (td, J=4.6, 1 .7 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.67-7.56 (m, 1H), 7.56-7.50 (m, 2H), 7 .25 (ddd, J=16.0, 8.1, 1.7 Hz, 2H), 7.17-7.09 (m, 1H), 7.06 (d, J=2.2 Hz, 1H ), 6.91 (td, J=7.3, 1.1 Hz, 1H), 6.05 (d, J=8.3 Hz, 1H), 5.24 (s, 2H), 4.76 -4.63 (m, 2H), 4.52 (d, J=6.3 Hz, 1H), 3.96-3.86 (m, 2H), 3.63 (s, 2H), 1, 13 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -216.98; MS (ESI+): 552.2 (M+1); optical rotation [a] _D = -6.40 (c = 0.13, MeOH).

Stage-4. Preparation of (+)-ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (259d).

Compound 259d was prepared according to the procedure described in step-10 of scheme-257 from (-)ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2 -fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (259c) (370 mg, 0.67 mmol) in THF (10 ml), using HCl (4 M in 1,4-dioxane) (0.335 ml, 1 , 34 mmol) and stirred for 30 min. This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with DMA 80 in dichloromethane), (+)-ethyl 2-(2-((7-(3-(1-amino-2- fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (259d) (245 mg, 82% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.82-7, 75 (m, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.54-7.43 (m, 2H ), 7.32-7.19 (m, 2H), 7.12 (dd, J=8.2, 1.1 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H) , 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.25 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.63 ( s, 2H), 3.34 (s, 1H), 2.09 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 448.0 (M+1); optical rotation [a] _D = +10.57 (c = 0.44, MeOH).

Stage-5. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (259e).

Compound 259e was prepared according to the procedure described in step-6 of Scheme-1 from (+)ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl )methoxy)phenyl)acetate (259d) (235 mg, 0.53 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide monohydrate (50 mg, 2.1 mmol) in water (2 ml ). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (+)-2-(2- ((7(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (259e) (70 mg, 0.167 mmol, 31.8% yield) as white hydrochloride salt ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 7.97 (dt, J=7.3, 1 .7 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.67-7.63 (m, 2H), 7.65-7.55 (m, 1H), 7 .24 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.9 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.95 -6.84 (m, 1H), 5.27 (s, 2H), 4.94-4.85 (m, 1H), 4.88-4.68 (m, 2H), 3.60 (s , 2H); MS (ESI+): 420.1 (M+1), (ESI-): 418.1 (M-1); optical rotation [a] _D = +11.83 (c = 0.49, MeOH); chiral HPLC: AD-H column; solvent: 80/20 (0.1% DEA in heptane/0.1% DEA in ethanol); flow rate: 1.0 ml/min; UV detection at 271 nm; analysis time=15 min; temperature 40°C; Rt=10.05 [compound peak-1 (258f), 6.56%]; R _t =11.36] peak-2; compounds (259e) 93.44%] 86.88% ee.

Scheme-260

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid

- 337 045626 slots (260g).

Stage-1. Preparation of 2-(4-fluoro-2-hydroxyphenyl)-1-morpholinoethanethione (260b).

Compound 260b was prepared according to the procedure described in step-1 of scheme-265, from 1-(4fluoro-2-hydroxyphenyl)ethanone (260a) (25 g, 162 mmol; CAS No. 1481-27-2) in N-methyl -2-pyrrolidinone (150 ml) using powdered sulfur (10.40 g, 324 mmol), morpholine (28.0 ml, 324 mmol) and heating at 100°C for 1.5 hours. This resulted in treatment and purification by flash column chromatography [silica gel (220 g), eluted with 0 to 50% ethyl acetate in hexanes] 2-(4-fluoro-2-hydroxyphenyl)-1-morpholinoethanethione (260b) (21.29 g, 51% yield).

^1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.16 (dd, J=9.4, 6.8 Hz, 1H), 6.72-6.54 (m , 2H), 4.24 (dd, J=5.7, 4.2 Hz, 2H), 4.06 (s, 2H), 3.68-3.61 (m, 4H), 3.45 ( dd, J=5.7, 4.0 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -114.69.

Stage-2. Preparation of 2-(4-fluoro-2-hydroxyphenyl)acetic acid (260c).

Compound 260c was prepared according to the procedure described in step-2 of scheme-265 from 2-(4fluoro-2-hydroxyphenyl)-1-morpholinoethanethione (260b) (25.39 g, 99 mmol) in ethanol (200 ml) and water (50 ml) using sodium hydroxide (15.91 g, 398 mmol) and reflux for 9 hours. This resulted in 2-(4-fluoro-2-hydroxyphenyl)acetic acid (260c) after workup. 15.5 g, 92% yield), which was used in the next reaction without further purification.

1H NMR (300 MHz, DMSO-d6) δ 7.23-6.96 (m, 1H), 6.62-6.45 (m, 2H), 3.44 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -114.71.

Stage-3. Preparation of ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d).

Compound 260d was prepared according to the procedure described in step-3 of scheme-265 from 2-(4fluoro-2-hydroxyphenyl)acetic acid (260c) (15.5 g, 91 mmol) in ethanol (150 ml) using sulfuric acid (5.34 ml, 100 mmol) and reflux for 6 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 20% ethyl acetate and hexanes), ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (13.94 g, 77% yield).

1H NMR (300 MHz, DMSO- _d6 ) δ 9.99 (s, 1H), 7.29-6.96 (m, 1H), 6.71-6.37 (m, 2H), 4.05 (k, J=7.1 Hz, 2H), 3.51 (s, 2H), 1.17 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -114.38.

Stage-4. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e).

Compound 260e was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (2.63 g, 9.08 mmol) using ethyl 2-(4-fluoro- 2Hydroxyphenyl)acetate (260d) (1.8 g, 9.08 mmol), K ₂ CO ₃ (3.77 g, 27.2 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash column chromatography (SiO ₂ , 40 g, eluted with 0 to 50% EtOAc in hexane), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4 -fluorophenyl)acetate (260e) (3.224 g, 87% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.60 (d, J =1.5 Hz, 1H), 7.25 (dd, J=8.3, 6.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.02 (dd , J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.20 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 112.61.

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (260f).

Compound 260f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e) (200 mg, 0.491 mmol ) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (89 mg, 0.589 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (52 mg , 0.074 mmol), potassium carbonate (204 mg, 1.473 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This resulted, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260f) (147 mg, 69% yield) as a clear oil.

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.88-7.78 (m, 1H), 7.78-7.65 (m, 2H), 7.57 (d, J=1.7 Hz, 1H), 7.51-7.33 (m, 2H), 7.25 (dd, J=8.3, 6.9 Hz, 1H ), 7.12-6.97 (m, 2H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.26 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.60 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.66. MS (ESI+): 434.2 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (260g).

Compound 260g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate ( 260f) (145 mg, 0.335 mmol) in MeOH (5 ml), THF (5 ml), using 1N lithium hydroxide (1.004 ml, 1.004 mmol). This resulted in, after work-up and purification by reverse phase column chromatography,

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[C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy) -4-fluorophenyl)acetic acid (260g) (127 mg, 94% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 7.99 (t, J=1.8 Hz, 1H), 7.93 (dt, J=7.6, 1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.61- 7.52 (m, 2H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.02 (dd , J=11.4, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.29 (s, 2H), 4.14 (s, 2H), 3.57 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -113.00; MS (ESI+): 406.1 (M+1); (ESI-): 404.1 (M-1); analysis calculation for C ₂₄ H ₂₀ FNO ₄ -HCl: C, 65.23; N, 4.79; Cl, 8.02; N, 3.17; observed: C, 65.11; N, 4.89; Cl, 7.79; N, 3.10.

Scheme-261

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(cyclopropylmethyl)phenyl)acetic acid (261c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate (261a).

Compound 261a was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (182b) (0.6 g, 1.01 mmol) in toluene (20 ml) and water (2 ml), using potassium (cyclopropylmethyl) trifluoroborate (0.245 g, 1.514 mmol), dicyclohexyl (2',6'diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.047 g, 0.101 mmol), Pd ₂ (dba) ₃ (0.046 g, 0.050 mmol), sodium carbonate (0.43 g, 4.04 mmol) when heated at 100°C for 10 hours. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with EtOAc in 0 to 70% hexanes], ethyl 2-(2-((7-( 3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate (261a) (0.381 g, 66% yield) as a waxy white solid. MS (ESI+): 470.2 (M+1Voc).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(cyclopropylmethyl)phenyl)acetate (261b).

Compound 261b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4(cyclopropylmethyl)phenyl)acetate (261a) (0.371 g, 0.651 mmol) in DCM (20 ml) using TFA (0.502 ml, 6.51 mmol). This gave, upon treatment, ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate (261b) (0.38 g, 100 % yield) in the form of yellow wax; MS (ESI+): 470.10 (m+1); MS (ESI-): 468.15 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(cyclopropylmethyl)phenyl)acetic acid (261c).

Compound 261c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl )acetate (261b) (0.37 g, 0.634 mmol) in THF (10 ml) and methanol (20 ml) using 2 M aq. LiOH (3.17 ml, 6.34 mmol). This resulted in, after workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 50% DCM] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetic acid (261c ) (0.021 g, 8% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.39-8.29 (m, 1H), 8.12-8.08 (m, 2H), 7.95-7.89 (m, 1H) , 7.73-7.68 (m, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.42-7.31 (m, 1H), 7.06 (d, J =2.2 Hz, 1H), 7.04-6.96 (m, 1H), 6.91-6.82 (m, 1H),

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6.74-6.62 (m, 1H), 5.25 (s, 2H), 4.00 (s, 2H), 3.36 (s, 2H), 2.42 (d, J=7, 0 Hz, 2H), 0.99-0.84 (m, 1H), 0.47-0.26 (m, 2H), 0.21-0.02 (m, 2H); MS (ESI+): 442.10 (M+1); MS (ESI-): 440.10 (M-1).

Scheme-262

262b ^262с

Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (262c).

Stage-1. Preparation of ethyl 2-(4-acetyl-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (262a).

To a solution of ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (182b) (0.5 g, 0.841 mmol) in toluene (150 ml), tributyl(1ethoxyvinyl)stannane (0.38 g, 1.05 mmol) and Pd(Ph ₃ P) ₄ (0.097 g, 0.084 mmol) were added, the resulting mixture was stirred at 120°C for 31 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc (500 ml), quenched with 6N aq. HCl (0.421 ml, 2.52 mmol) and stirred for 10 min. The reaction mixture was diluted with water (500 ml), filtered through a pad of celite, rinsed with ethyl acetate (500 ml). The organic layer was separated, dried, filtered and evaporated to dryness. The resulting residue was purified twice by flash column chromatography [silica gel, 120 g, eluted with ethyl acetate in 0% to 100% hexanes] to form ethyl 2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (262a) (0.309 g, 66% yield) as a yellow solid; MS (ESI+): 558.10 (M+1).

Stage-2. Preparation of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (262b).

Compound 262b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (262a) (0.302 g, 0.542 mmol) in DCM (20 ml) using TFA (0.834 ml, 10.83 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in DCM 0 to 100%), ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl) phenyl)benzofuran5-yl)methoxy)phenyl)acetate (262b) (0.239 g, 77% yield) as a yellow oily wax; MS (ESI+): 458.2 (M+1).

Stage-3. Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (262c).

Compound 262c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (262b) (0.23 g, 0.4 mmol) in THF (5 ml) and methanol (10 ml) using 2 M aq. LiOH (2 ml, 4 mmol). This resulted in, after workup and purification by flash column chromatography [silica gel 12 g, eluted with methanol in 0% to 50% DCM] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water ( with 0.1% HCl) from 0% to 100%] 2-(4-acetyl-2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (262c) ( 0.059 g, 34% yield), HCl salt, as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.41 (br.s, 1H, D2O replaceable), 8.41 (br.s, 3H, D2O replaceable), 8.12 (d, J=2 .2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.94 (dt, J=7.3, 1.7 Hz, 1H), 7.79 (d, J =1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.65-7.52 (m, 4H), 7.40 (d, J=7.6 Hz , 1H), 7.08 (d, J=2.2 Hz, 1H), 5.37 (s, 2H), 4.14 (s, 2H), 3.70 (s, 2H), 2.58 (s, 3H); MS (ESI+): 430.1 (M+1); MS (ESI-): 428.1 (M-1); analysis calculation for CANOyHCM^HO: C, 63.35; N, 5.52; Cl, 7.19; N, 2.84; observed: C, 63.32; N, 5.28; Cl, 7.35; N, 2.82.

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Scheme-263

263b 263с

Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl)acetic acid (263c).

Stage-1. Preparation of ethyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-[1,1'-biphenyl]-4-yl)acetate (263a ).

Compound 263a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (182b) (530 mg, 1.248 mmol) in dioxane (20 ml), using phenylboronic acid (0.152 g, 1.248 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (63 mg, 0.089 mmol) and solution K2CO3 (370 mg, 2.67 mmol) in water (2 ml) under nitrogen while heating at 90°C for 10 hours in an oil bath. This resulted in the production after treatment of ethyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4 -yl)acetate (263a) (0.358 g, 68% yield) as a yellow solid; MS (ESI+): 492.2 (M+1, -Boc).

Stage-2. Preparation of ethyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetate (263b).

Compound 263b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-[1,1'-biphenyl]-4yl)acetate (263a) (0.345 g, 0.583 mmol) in DCM (20 mL) using TFA (0.898 mL, 11.66 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in DCM 0 to 100%), ethyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran5- yl)methoxy)-[1,1'-biphenyl]-4-yl)acetate (263b) (0.149 g, 42% yield) as a white solid; MS (ESI+): 492.2 (M+1).

Stage-3. Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4yl)acetic acid (263c).

Compound 263 c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1' -biphenyl]-4-yl)acetate (263b) (0.143 g, 0.236 mmol) in THF (5 ml) and methanol (10 ml) using 2 M aq. LiOH (1.181 ml, 2.361 mmol). This resulted in the following workup and purification by flash column chromatography [silica gel, 25 g, eluted with methanol in DCM 0% to 100%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(3-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4 -yl)acetic acid (263c) (0.049 g, 45% yield), HCl salt, as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.39-8.33 (m, 1H), 8.15-8.05 (m, 2H), 7.94 (d, J=1.7 Hz , 1H), 7.73 (d, J=1.6 Hz, 1H), 7.68-7.60 (m, 2H), 7.54-7.41 (m, 3H), 7.34 ( dt, J=9.2, 7.2 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.227.16 (m, 1H), 7.11 (dd, J=7 .7, 1.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.39 (s, 2H), 4.03 (s, 2H), 3.44 (s , 2H); MS (ESI+): 464.1 (M+1); MS (ESI-): 462.2 (M-1); analysis calculation for C ₃₀ H ₂₅ NO ₄ -HCl-0.75H ₂ O: C, 70.17; N, 5.40; Cl, 6.90; N, 2.73; observed: C, 70.33; H, 5.03; Cl, 6.98; N, 2.78.

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Scheme-264

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetic acid (264c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-3-fluorophenyl)acetate (264a).

Compound 264a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1.07 g, 3.303 mmol) in DCM (50 ml), using triphenylphosphine (0.73 g, 2.78 mmol), ethyl 2-(3-fluoro-2-hydroxyphenyl) acetate (0.500 g, 2.52 mmol; CAS No. 1261451-84-6) and solution ( E)-bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 1.019 g, 2.78 mmol) in DCM (5 ml).

This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate in 0% to 70% hexanes), ethyl 2-(2-((7-(3-((tert-butoxycarbonyl)amino )methyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (264a) (0.719 g, 53% yield) as yellow syrup;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.78-7.67 (m, 3H), 7.57-7.43 (m , 2H), 7.36-7.20 (m, 2H), 7.13-7.06 (m, 3H), 5.19 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.40 (s, 9H), 1.00 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetate (264b).

Compound 264b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-3-fluorophenyl)acetate (264a) (0.709 g, 1.33 mmol) in DCM (30 ml) using TFA (1.024 ml, 13.29 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with methanol in DCM 0 to 100%), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-3-fluorophenyl)acetate (264b) (0.259 g, 45.0% yield) as a white solid; MS (ESI+): 434.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetic acid (264c).

Compound 264c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate ( 264b) (0.256 g, 0.591 mmol) in MeOH (20 mL), THF (10 mL), using 2 M aqueous lithium hydroxide (4.43 mL, 8.86 mmol). This resulted in the following workup and purification by flash column chromatography (silica gel, 25 g, eluted with methanol in DCM from 0 to 100%) followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0 .1% HCl) from 0% to 100%] 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetic acid (264c) (0.021 g, 9% yield) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 (d, J=2.2 Hz, 1H), 8.01-7.97 (m, 1H), 7.96-7.89 ( m, 1H), 7.78-7.74 (m, 1H), 7.67-7.63 (m, 1H), 7.62-7.51 (m, 2H), 7.27-7. 17 (m, 1H), 7.13-7.06 (m, 3H), 5.19 (s, 2H), 4.15 (s, 2H), 3.61 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -129.84; MS (ESI+): 406.10 (M+1); MS (ESI-): 404.1 (M-1).

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Scheme-265

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetic acid (265g).

Stage-1. Preparation of 2-(4-ethoxy-2-hydroxyphenyl)-1-morpholinoethanethione (265b)

A suspension of 1-(4-ethoxy-2-hydroxyphenyl)ethanone (265a) (2.0 g, 11.10 mmol; CAS No. 37470-42-1), powdered sulfur (0.712 g, 22.20 mmol) and morpholine ( 1.934 g, 22.20 mmol) was heated at 130°C for 16 hours. The resulting black mixture was quenched with H2O (25 ml) and extracted with EtOAc (3x25 ml). The combined organic extracts were washed with H2O (4x25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , 24 g, eluted with 0-30% EtOAc in hexane) to give 2-(4-ethoxy-2hydroxyphenyl)-1-morpholinoethanethione (265b) (1.61 g, 52% yield ) as a thick dark red semi-solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.46-6.30 (m, 2H) , 4.23 (t, J=5.7, 4.1 Hz, 2H), 4.04 (s, 2H), 3.92 (k, J=6.9 Hz, 2H), 3.63 ( dd, J=5.9, 3.4 Hz, 4H), 3.40 (t, J=5.5, 4.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H ); MS (ESI+): 282 (M+1), (ESI-): 280 (M-1).

Stage-2. Preparation of 2-(4-ethoxy-2-hydroxyphenyl)acetic acid (265c).

To a solution of 2-(4-ethoxy-2-hydroxyphenyl)-1-morpholinoethanethione (265b) (1.61 g, 5.72 mmol) in EtOH (20 ml) was added 4 M aq. NaOH (4.29 ml, 17.17 mmol) and heated at 85°C for 16 hours. The resulting mixture was concentrated to remove EtOH. The concentrate was suspended in H2O (10 ml), cooled to 0°C and acidified with 3 M aq. HCl to pH=1, during which a semi-solid substance was formed. The mixture was extracted with EtOAc (3x25 ml). The combined organic extract was washed with H2O (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo to give 2-(4ethoxy-2-hydroxyphenyl)acetic acid (265c) (1.27 g) as a thick yellow oil of acceptable purity, which was used in the next step without further purification; MS (ESI-): 195 (M-1).

Stage-3. Preparation of ethyl 2-(4-ethoxy-2-hydroxyphenyl)acetate (265d).

To a solution of 2-(4-ethoxy-2-hydroxyphenyl)acetic acid (265c) (1.27 g, 6.47 mmol) in ethanol (22.68 ml, 388 mmol) was added sulfuric acid (1.943 g, 19.42 mmol) and heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with water and extracted with DCM (3x25 ml). The combined organic extracts were washed with saturated NaHCO ₃ (25 ml), H2O (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , 24 g, eluted with 0-15% EtOAc in hexanes) to give ethyl 2-(4ethoxy-2-hydroxyphenyl) acetate (265d) (0.85 g, 59% yield) in in the form of a thick yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 6.31 (dd, J=8.2, 2.5 Hz, 1H), 4.04 (k, J=7.1 Hz, 2H), 3.92 (k, J=7.0 Hz, 2H), 3.44 (s, 2H), 1.29 (t, J=7.0 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI+): 225 (M+1), (ESI-): 223 (M-1).

Stage-4. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate (265e).

Compound 265e was prepared according to the procedure described in Step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.099 g, 3.79 mmol) using ethyl 2-(4-ethoxy-2hydroxyphenyl) acetate (265d) (0.85 g, 3.79 mmol) and K2CO3 (1.572 g, 11.37 mmol) in DMF (20 ml). This gave, after work-up and purification by flash column chromatography (SiO ₂ , 24 g, eluted with 0-10% EtOAc in hexane), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4ethoxyphenyl )acetate (265e) (1.37 g, 83% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.17-7.06 (m, 2H), 6.64 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.2 , 2.3 Hz, 1H), 5.17 (s, 2H), 4.07-3.95 (m, 4H), 3.54 (s, 2H), 1.31 (t, J=7, 0 Hz, 3H), 1.08 (dd, J=7.4, 6.7 Hz, 3H). MS (ESI+): 433/435 (M+1).

- 343 045626

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4ethoxyphenyl)acetate (265f).

Compound 265f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate (265e) (160 mg, 0.369 mmol ) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (104 mg, 0.554 mmol), bis(triphenylphosphine)palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (38, 9 mg, 0.055 mmol) and 3.3 M aq. K2CO3 (0.336 ml, 1.108 mmol) heating under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with methanol in 0% to 5% DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran5- yl)methoxy)-4-ethoxyphenyl)acetate (265f) (104 mg, 61% yield) as a clear, colorless oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.71 (dt, J=7.7, 1.7 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.46 ( t, J=7.5 Hz, 1H), 7.40 (dt, J=7.6, 1.5 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7, 05 (d, J=2.2 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.2, 2.4 Hz, 1H), 5.23 (s, 2H), 4.01 (k, J=7.0 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.54 (s, 2H), 1.31 (t, J=7.0 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 460 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4ethoxyphenyl)acetic acid (265g).

Compound 265g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate ( 265f) (104 mg, 0.226 mmol) in MeOH (3 mL), THF (10 mL), using 2 M aqueous lithium hydroxide (0.566 mL, 1.132 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetic acid (265g) (70 mg, 72% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.93 (dt, J=7.4, 1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.60 ( t, J=7.5 Hz, 1H), 7.57-7.52 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.07 (d, J=2 .2 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.3 Hz, 1H), 5.26 (s, 2H ), 4.13 (s, 2H), 4.00 (k, J=7.0 Hz, 2H), 3.50 (s, 2H), 1.30 (t, J=7.0 Hz, 3H ); MS (ESI+): 432 (M+1), (ESI-): 430 (M-1); analysis calculation for C^sNOs-HCl-G^O: C, 65.47; N, 5.71; Cl, 7.43; N, 2.94; observed: C, 65.63; N, 5.46; Cl, 7.03; N, 2.87.

Scheme-266

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)acetic acid (266g).

Stage-1. Preparation of 2-hydroxy-4-propylbenzaldehyde (266b).

To a suspension of 3-propylphenol (266a) (2.0 g, 14.69 mmol; CAS No. 621-27-2) and MgCl ₂ (2.097 g, 22.03 mmol) in anhydrous MeCN (20 ml) was added at room temperature Et ₃ N (3.34 g, 33.0 mmol). The reaction mixture was stirred at room temperature for 30 minutes and paraformaldehyde (2.205 g, 73.4 mmol) was added. The resulting mixture was stirred at 85°C for 16 hours, cooled

- 344 045626 to room temperature, diluted with H2O (20 ml) and EtOAc (30 ml). The reaction mixture was thoroughly stirred with the addition of 1.2 M aq. dropwise. HCl until excess solid paraformaldehyde dissolves to obtain a two-phase solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (25 ml x 2). The combined organic extracts were washed with WO (2x25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , 24 g, eluted with 0-10% EtOAc in hexane) to give 2-hydroxy-4-propylbenzaldehyde (266b) (1.23 g, 51.0% yield) in in the form of a pale yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 7.66-7.52 (m, 1H), 6.89-6.77 (m, 2H), 2.60 -2.52 (m, 2H), 1.71-1.49 (m, 2H), 0.89 (t, J=7.3 Hz, 3H).

Stage-2. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-propylbenzaldehyde (266c).

Compound 266c was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (2.03 g, 7.0 mmol) using 2-hydroxy-4-propylbenzaldehyde ( 266b) (1.150 g, 7.0 mmol) and K ₂ CO ₃ (2.90 g, 21.0 mmol) in DMF (20 ml). This gave, after work-up and purification by flash column chromatography (SiO2, 24 g, eluted with 0-5% EtOAc in hexane) 2-((7-bromobenzofuran-5-yl)methoxy)-4-propylbenzaldehyde (266c) (1.84 g, 70% yield) as a pale yellow solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.36 (d, J=0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.85 (d , J=1.5 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.20 (d, J =1.4 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 5.37 (s, 2H), 2.62 (dd, J=8.4, 6.7 Hz, 2H), 1.74-1.53 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ESI+): 395/397 (M+Na).

Stage-3. Preparation of (E)-7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5propylphenoxy)methyl)benzofuran (266d).

To a solution of 2-((7-bromobenzofuran-5-yl)methoxy)-4-propylbenzaldehyde (266c) (1.00 g, 2.68 mmol), methyl(methylsulfinylmethyl)sulfane (0.533 g, 4.29 mmol) in THF (20 ml) was added at room temperature with Triton-B (40 wt% in methanol) (0.605 ml, 1.340 mmol) and heated at 70°C for 16 hours. The resulting black solution was cooled to room temperature and diluted with H2O (30 ml ) and EtOAc (30 ml). After stirring for 30 minutes, the two layers were separated. The aqueous layer was extracted with EtOAc (2x25 ml). The combined organic extract was washed with H ₂ O (30 ml), brine (30 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO2, 24 g, eluted with 0-40% EtOAc in hexane) to give (E)-7bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio) vinyl)-5-propylphenoxy)methyl)benzofuran (266d) (0.98 g, 76% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.2 Hz, 1H), 7.97 (d, 1H), 7.83 (s, 1H), 7.75 (d , J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.08 (d, J =1.5 Hz, 1H), 6.90 (d, 1H), 5.29 (s, 2H), 2.71 (s, 3H), 2.57 (t, J=8.5, 6, 6 Hz, 2H), 2.27 (s, 3H), 1.71-1.50 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ESI+): 479/481 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-propylphenyl)acetate (266e).

To a solution of (E)-7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5propylphenoxy)methyl)benzofuran (266d) (0.98 g, 2.044 mmol) in EtOH (20 ml) was added 4 M HCl in dioxane (1.533 ml, 6.13 mmol) and heated at 80°C for 16 hours. The cooled yellow solution was evaporated to remove EtOH. The concentrate was diluted with saturated NaHCO ₃ (20 ml) and EtOAc (20 ml). After stirring for 30 minutes, the two layers were separated. The aqueous layer was extracted with EtOAc (2x20 ml). The combined organic extract was washed with H2O (30 ml), brine (30 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO2, 24 g, eluted with 0-40% EtOAc in hexane) to give ethyl 2-(2-((7bromobenzofuran-5-yl)methoxy)-4-propylphenyl)acetate (266e) ( 0.59 g, 67% yield) as a clear, colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.1 Hz, 1H), 7.72 (t, J=1.1 Hz, 1H), 7.60 (d, J =1.4 Hz, 1H), 7.19-7.03 (m, 2H), 6.96-6.88 (m, 1H), 6.74 (dd, J=7.6, 1.5 Hz, 1H), 5.16 (s, 2H), 4.01 (cd, J=7.1, 0.8 Hz, 2H), 3.57 (s, 2H), 2.54 (d, J =7.2 Hz, 2H), 1.68-1.48 (m, 2H), 1.07 (td, J=7.1, 0.7 Hz, 3H), 0.95-0.81 ( m, 3H); MS (ESI+): 431/433 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4propylphenyl)acetate (266f).

Compound 266f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-propylphenyl)acetate (266e) (160 mg, 0.371 mmol ) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (174 mg, 0.93 mmol), bis(triphenylphosphine)palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) ( 39 mg, 0.056 mmol) and 3.3 M aq. K2CO3 (0.337 ml, 1.113 mmol) heating under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in 0% to 5% DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran -5yl)methoxy)-4-propylphenyl)acetate (266f) (140 mg, 82% yield) as a clear, colorless oil;

- 345 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.77-7, 66 (m, 2H), 7.58 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (dt, J=7.6 , 1.5 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.05 (d, J=2.2 Hz,

1H), 6.98 (d, J=1.5 Hz, 1H), 6.73 (dd, J=7.6, 1.5 Hz, 1H), 5.22 (s, 2H), 3, 91 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.57 (s, 2H), 2.54 (t, J=5.3 Hz, 2H), 1, 69-1.50 (m, 2H), 0.98 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.3 Hz, 3H); MS (ESI+):

458 (M+1).

Stage-6. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-4propylphenyl)acetic acid (266g).

Compound 266g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)acetate ( 266f) (135 mg, 0.295 mmol) in MeOH (3 ml) using 2 M aqueous lithium hydroxide (0.738 ml, 1.475 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)acetic acid (266g) (78 mg, 62% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.94 (dt, J=7.5, 1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.60 ( t, J=7.6 Hz, 1H), 7.54 (dt, J=7.7, 1.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7, 07 (d, J=2.2 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.73 (dd, J=7.6, 1.5 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 3.53 (s, 2H), 2.57-2.52 (m, 2H), 1.68-1.48 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ESI+): 430 (M+1), (ESI): 428 (M-1).

Receipt

Scheme-267

2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetic acid (267h).

Stage-1. Preparation of methyl 5-acetyl-3'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-6-hydroxy[1,1'-biphenyl]-3-carboxylate (267a).

Compound 267a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 3-acetyl-5-bromo-4-hydroxybenzoate (191a) (1 g, 3.66 mmol) in dioxane (40 ml) using tert-butyl 2fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (2.06 g, 5.86 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.386 g, 0.549 mmol) and a solution of K2CO3 (1.518 g, 10.99 mmol) in water (4 ml) under a nitrogen atmosphere while heating at 100°C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and 0-50% hexanes), methyl 5-acetyl-3'-(((tert-butoxycarbonyl)amino)methyl)- 2'-fluoro-6-hydroxy-[1,G biphenyl]-3-carboxylate (267a) (1.25 g, 82% yield) as a white foam;

1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.54 (s, 1H), 8.04 (dd, J=2.1, 0.6 Hz, 1H), 7 .58-7.13 (m, 4H), 4.22 (d, J=6.1 Hz, 2H), 3.87 (s, 3H), 2.80 (s, 3H), 1.41 ( s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.83; MS (ESI+): 440.10 (M+Na), (ESI-): 416.10 (M-1).

Stage-2. Preparation of (E)-methyl 3'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-6-hydroxy-5-(1(hydroxyimino)ethyl)-[1,1'-biphenyl]-3 -carboxylate (267b).

To a stirred solution of methyl 5-acetyl-3'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-6hydroxy-[1,1'-biphenyl]-3-carboxylate (267a) (1.14 g , 2.73 mmol) in methanol (20 ml), hydroxylamine hydrochloride (0.759 g, 10.92 mmol) and sodium acetate (0.896 g, 10.92 mmol) were added. The mixture was heated with

- 346 045626 reflux for 1 hour, cooled to room temperature and concentrated under vacuum. Water (25 ml) was added to the residue and triturated. The separated solid was collected by filtration and dried to give (E)-methyl 3'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-6hydroxy-5-(1-(hydroxyimino)ethyl)-[1, 1'-biphenyl]-3-carboxylate (267b) (1.15 g, 97% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 11.95 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.79 ( d, J=2.1 Hz, 1H), 7.46 (t, J=6.2 Hz, 1H), 7.27 (dk, J=14.9, 7.8 Hz, 3H), 4, 22 (d, J=6.1 Hz, 2H), 3.84 (s, 3H), 2.38 (s, 3H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO46) δ -120.79.

Stage-3. Preparation of methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3methylbenzo[d]isoxazole-5-carboxylate (267c).

Compound 267c was prepared according to the procedure described in step-2 of Scheme-191 from (E)methyl 3'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-6-hydroxy-5-(1- (hydroxyimino)ethyl)-[1,1'biphenyl]-3-carboxylate (267b) (1 g, 2.312 mmol) in THF (20 ml) using carbonyldiimidazole (750 mg, 4.62 mmol) and reflux within 90 min. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with ethyl acetate and hexanes] methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3methylbenzo [d]isoxazole-5-carboxylate (267c) (560 mg, 58% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=1.6 Hz, 1H), 8.24 (t, J=1.3 Hz, 1H), 7.60 (td, J=7.3, 1.9 Hz, 1H), 7.50 (k, J=5.6, 5.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.37 (t, J=7.6 Hz, 1H), 4.27 (d, J=6.1 Hz, 2H), 3.93 (s, 3H), 2.67 (s, 3H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO46) δ -121.39.

Stage-4. Preparation of 7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3methylbenzo[d]isoxazole-5-carboxylic acid (267d).

Compound 267d was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5 -carboxylate (267c) (500 mg, 1.206 mmol) in THF/MeOH (10 mL each), using a solution of lithium hydroxide monohydrate (116 mg, 4.83 mmol) in water (2 mL). This gave upon treatment 7-(3-(((tertbutoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylic acid (267d) (509 mg) as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.23 (t, J=1.3 Hz, 1H), 7.60 (td, J=7.3, 2.0 Hz, 1H), 7.51 (t, J=6.0 Hz, 1H), 7.48-7.39 (m, 1H ), 7.37 (t, J=7.6 Hz, 1H), 4.28 (d, J=6.1 Hz, 2H), 2.66 (s, 3H), 1.41 (s, 9H ); ¹⁹ F NMR (282 MHz, DMSO46) δ -121.35; MS (ESI-): 399.0 (M-1).

Stage-5. Preparation of tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7yl)benzylcarbamate (267e).

Compound 267e was prepared according to the procedure described in step-1 of Scheme-23 from 7-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylic acid acid (267d) (500 mg, 1.249 mmol) using N-methylmorpholine (0.165 ml, 1.499 mmol) in THF (10 ml), isobutyl chloroformate (0.197 ml, 1.499 mmol) and NaBH ₄ (142 mg, 3.75 mmol) in water (1 ml). This gave, after work-up and purification by flash column chromatography [silica gel (25 g), eluted with 9:1 ethyl acetate/methanol in 0-100% hexanes] tert-butyl 2-fluoro-3-(5(hydroxymethyl) -3-methylbenzo[d]isoxazol-7-yl)benzylcarbamate (267e) (420 mg, 87% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.82 (dd, J=1.6, 0.8 Hz, 1H), 7.65 (t, J=1.2 Hz, 1H), 7, 52 (td, J=7.3, 2.2 Hz, 2H), 7.46-7.37 (m, 1H), 7.34 (t, J=7.5 Hz, 1H), 5.43 (t, J=5.7 Hz, 1H), 4.68 (d, J=5.6 Hz, 2H), 4.27 (d, J=6.1 Hz, 2H), 2.59 (s , 3H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.14; MS (ESI+): 387.00 (M+1), 409.00 (M+Na).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (267f).

Compound 267f was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)benzylcarbamate (267e) (400 mg, 1.035 mmol) in DCM (10 ml) using triphenylphosphine (339 mg, 1.294 mmol), ethyl 2-(2hydroxyphenyl)acetate (23b) (233 mg, 1.294 mmol) and (E)-bis(4-chlorobenzyl) solution )diazene-1,2dicarboxylate (DCAD, 532 mg, 1.449 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography (silica gel 25 g, eluted with EtOAc in 0% to 50% hexane), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)-2-fluorophenyl)-3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (267f) (550 mg, 97% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (d, J=1.5 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.53 (dtd, J=10.8, 7.9, 3.9 Hz, 2H), 7.38 (dt, J=11.5, 8.1 Hz, 2H), 7.31-7.20 (m, 2H) , 7.13 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.27 (d, J=6.1 Hz, 2H), 3.88 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.60 (s, 3H), 1.41 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -120.88.

Stage-7. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-347 045626 yl)methoxy)phenyl)acetate (267g).

Compound 267g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo [d]isoxazol-5yl)methoxy)phenyl)acetate (267f) (525 mg, 0.957 mmol) in DCM (5 ml) using TFA (0.737 ml, 9.57 mmol). This resulted in ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (267g) (429 mg, 100% yield), which was used in the next reaction without further purification; MS (ESI+): 449.1 (M+1).

Stage-8. Preparation of 2-(2-((7-(3 -(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5 yl)methoxy)phenyl)acetic acid (267h).

Compound 267h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl )methoxy)phenyl)acetate (267g) (429 mg, 0.957 mmol) in THF/MeOH (10 ml each), using a solution of lithium hydroxide monohydrate (229 mg, 9.57 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetic acid (267h) (250 mg, 62% yield), hydrochloride salt, as white solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=1.5 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 7.71 (td, J=7.2, 1.6 Hz, 2H), 7.46 (t, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 7.13-7.07 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.19 (s, 2H), 3.60 (s, 2H), 2.61 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.31; MS (ESI+): 421.1 (M+1), (ESI-): 419.1 (M-1); analysis calculation for C ₂₄ H ₂₁ FN ₂ O ₄ -1.05HCl-H ₂ O: C, 60.47; N, 5.08; Cl, 7.81; N, 5.88; observed: C, 60.50; N, 4.78; Cl, 8.10; N, 5.71.

Scheme-268

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5 Preparation of yl)methoxy)phenyl)acetic acid (268h).

Stage-1. Preparation of methyl 3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4hydroxybenzoate (268a).

Compound 268a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 3-acetyl-5-bromo-4-hydroxybenzoate (191a) (0.5 g, 1.831 mmol) in dioxane (10 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate (123a) (0.734 g, 2.19 mmol ), Pd(PPh ₃ ) ₂ Cl ₂ (0.193 g, 0.275 mmol) and a solution of K2CO3 (0.759 g, 5.49 mmol) in water (2 ml) under a nitrogen atmosphere when heated at 100 ° C for 5 hours in oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and 0-50% hexanes), methyl 3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl )pyridin-4yl)-4-hydroxybenzoate (268a) (406 mg, 1.014 mmol, 55.4% yield) as a white foam;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.43 (s, 1H), 8.57 (d, J=0.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.55-7.42 (m, 3H), 4.28 (d, J=6.1 Hz, 2H), 3, 88 (s, 3H), 2.80 (s, 3H), 1.40 (s, 9H); MS (ESI+): 401.00 (M+1).

- 348 045626

Stage-2. Preparation of (E)-methyl 3-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (268b).

Compound 268b was prepared according to the procedure described in step-2 of scheme-267 from methyl 3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxybenzoate (268a ) (0.4 g, 1.0 mmol) in methanol (20 mL), using hydroxylamine hydrochloride (278 mg, 4.0 mmol), sodium acetate (328 mg, 4.0 mmol) and reflux for 1 hour in an oil bath. This resulted in the preparation after treatment of (E)-methyl 3-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (268b ) (370 mg, 89% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.31 (s, 1H), 12.02 (s, 1H), 8.53 (dd, J=5.2, 0.8 Hz, 1H) , 8.15 (d, J=2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.50 (dd, J=5.1, 1.7 Hz, 2H), 7.44 (s, 1H), 4.28 (d, J=6.2 Hz, 2H), 3.85 (s, 3H), 2.38 (s, 3H), 1.40 ( s, 9H).

Stage-3. Preparation of methyl 7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3methylbenzo[d]isoxazole-5-carboxylate (268c).

Compound 268c was prepared according to the procedure described in step-2 of Scheme-191 from (E)methyl 3-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxy-5- (1(hydroxyimino)ethyl)benzoate (268b) (360 mg, 0.867 mmol) in THF (10 ml) using carbonyldiimidazole (703 mg, 4.33 mmol) and reflux for 90 min. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with ethyl acetate and hexanes] methyl 7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)- 3methylbenzo[d]isoxazole-5-carboxylate (268c) (413 mg) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.68 (dd, J=5.1, 0.9 Hz, 1H), 8.60 (d, J=1.5 Hz, 1H), 8 .47 (d, J=1.5 Hz, 1H), 7.84 (dd, J=7.1, 1.9 Hz, 2H), 7.67-7.55 (m, 1H), 4, 33 (d, J=6.2 Hz, 2H), 3.95 (s, 3H), 2.68 (s, 3H), 1.43 (s, 9H).

Stage-4. Preparation of 7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3methylbenzo[d]isoxazole-5-carboxylic acid (268d).

Compound 268d was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol- 5-carboxylate (268c) (400 mg, 1.006 mmol) in THF/MeOH (10 mL each), using a solution of lithium hydroxide monohydrate (96 mg, 4.03 mmol) in water (2 mL). This gave upon treatment 7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylic acid (268d) (320 mg, 83% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J=5.5 Hz, 1H), 8.61 (d, J=1.5 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 8.08-7.96 (m, 2H), 7.67 (t, J=6.0 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H), 2.68 (s, 3H), 1.42 (s, 9H); MS (ESI+): 384.2 (M+1).

Stage-5. Preparation of tert-butyl ((4-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)pyridin-2yl)methyl)carbamate (268e).

Compound 268e was prepared according to the procedure described in step-1 of Scheme-23 from 7-(2(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5- carboxylic acid (268d) (300 mg, 0.782 mmol) using N-methylmorpholine (0.103 ml, 0.939 mmol) in THF (10 ml), isobutyl chloroformate (0.123 ml, 0.939 mmol) and NaBH ₄ (89 mg, 2.347 mmol) in water (1 ml). This gave, after work-up and purification by flash column chromatography [silica gel (25 g), eluted with 9:1 ethyl acetate/methanol in 0-100% hexanes] tert-butyl ((4-(5-(hydroxymethyl)- 3methylbenzo[d]isoxazol-7-yl)pyridin-2-yl)methyl)carbamate (268e) (131 mg, 45% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 8.65 (dd, J=5.2, 0.8 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7, 88 (d, J=1.4 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J=5.2, 1.8 Hz, 1H), 7.56 (t, J =6.1 Hz, 1H), 5.47 (t, J=5.6 Hz, 1H), 4.71 (d, J=5.2 Hz, 2H), 4.32 (d, J=6 .2 Hz, 2H), 2.61 (s, 3H), 1.42 (s, 9H); MS (ESI+): 370.1 (M+1).

Stage-6. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (268f) .

Compound 268f was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl ((4-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)pyridin-2-yl)methyl) carbamate (268e) (125 mg, 0.338 mmol) in DCM (5 ml), using triphenylphosphine (111 mg, 0.423 mmol), ethyl 2-(2hydroxyphenyl) acetate (23b) (76 mg, 0.423 mmol) and solution (E) -bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 174 mg, 0.474 mmol) in DCM (3 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with 0% to 50% EtOAc in hexane), ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl )amino)methyl)pyridin-4-yl)-3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (268f) (110 mg, 61% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.67 (dd, J=5.2, 0.8 Hz, 1H), 8.10 (d, J=1.5 Hz, 1H), 8, 03 (d, J=1.5 Hz, 1H), 7.91 (s, 1H), 7.81 (dd, J=5.2, 1.8 Hz, 1H), 7.54 (t, J =6.1 Hz, 1H), 7.32-7.19 (m, 2H), 7.19-7.08 (m, 1H),

- 349 045626

6.93 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.33 (d, J=6.2 Hz, 2H), 3.91 (k , J=7.1 Hz, 2H), 3.65 (s, 2H), 2.63 (s,

3H), 1.41 (s, 9H), 0.94 (t, J=7.1 Hz, 3H); MS (ESI+): 532.2 (M+1).

Stage-7. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetate (268g).

Compound 268g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3- methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetate (268f) (110 mg, 0.207 mmol) in DCM (2 mL) using TFA (0.159 mL, 2.064 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate (268g) (90 mg ), which was used in this form in the next step without further purification;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.82 (dd, J=5.3, 0.8 Hz, 1H), 8.37 (s, 3H), 8.16 (d, J=1 .6 Hz, 1H), 8.128.05 (m, 2H), 8.01 (dd, J=5.2, 1.7 Hz, 1H), 7.32-7.21 (m, 2H), 7 .16-7.08 (m, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.35 (k, J=5 .8 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.63 (s, 3H), 0.96 (t, J=7 ,1 Hz, 3H); MS (ESI+): 432.20 (M+1).

Stage-8. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetic acid (268h).

Compound 268h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5- yl)methoxy)phenyl)acetate (268g) (89 mg, 0.207 mmol) in THF/MeOH (2 ml each), using a solution of lithium hydroxide monohydrate (20 mg, 0.828 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5yl)methoxy)phenyl)acetic acid (268h) (50 mg, 60% yield), HCL salt, as white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.81 (dd, J=5.3, 0.7 Hz, 1H), 8.55 (s, 3H), 8.20 (d, J=1, 5 Hz, 1H), 8.178.11 (m, 1H), 8.10 (s, 1H), 8.03 (dd, J=5.3, 1.7 Hz, 1H), 7.26 (t, J=7.5 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.34 ( s, 2H), 4.33 (d, J=5.7 Hz, 2H), 3.64 (s, 2H), 2.64 (s, 3H); MS (ESI+): 404.1 (M+1), (ESI-): 402.1 (M-1).

Scheme-269

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (269h).

Stage-1. Preparation of (2-(2-(benzyloxy)-4-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (269b).

Compound 269b was prepared according to the procedure described in step-3 of scheme-266 from 2(benzyloxy)-4-methylbenzaldehyde (269a) (2 g, 8.84 mmol; CAS No. 154478-35-0) in THF (20 ml), using methyl(methylsulfinylmethyl)sulfane (2.196 g, 17.68 mmol), Triton-B (40% methanol solution) (2.009 ml, 4.42 mmol) and reflux for 12 hours. This resulted in obtained after workup and purification by flash column chromatography (silica gel, 80 g, eluted

- 350 045626

9:1 mixture of ethyl acetate and methanol in hexanes) (E)-(2-(2-(benzyloxy)-4-methylphenyl)-1(methylsulfinyl)vinyl)(methyl)sulfane (269b) (2.32 g, 79% output) in the form of a thick syrup;

^1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.51-7.31 (m, 5H), 7.05 (t, J=1.1

Hz, 1H), 6.88 (dtd, J=8.0, 1.5, 0.7 Hz, 1H), 5.19 (s, 2H), 2.70 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H).

Stage-2. Preparation of ethyl 2-(2-(benzyloxy)-4-methylphenyl)acetate (269c).

Compound 269c was prepared according to the procedure described in step-4 of scheme-266 from (E)(2-(2-(benzyloxy)-4-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (269b) ( 1 g, 3.01 mmol) in ethanol (10 ml) using HCl (1.25 M solution in ethanol, 9.62 ml, 12.03 mmol) and reflux for 2 hours. This gave after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and methanol in hexanes) ethyl 2-(2(benzyloxy)-4-methylphenyl) acetate (269c) (511 mg, 60% yield) as a colorless oil ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.46-7.28 (m, 5H), 7.08 (d, J=7.5 Hz, 1H), 6.89 (t, J= 1.1 Hz, 1H), 6.72 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 5.07 (s, 2H), 3.99 (k, J=7 ,1 Hz, 2H), 3.56 (s, 2H), 2.28 (s, 3H), 1.10 (t, J=7.1 Hz, 3H); MS (ESI+): 285.1 (M+1).

Stage-3. Preparation of ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d).

To a solution of ethyl 2-(2-(benzyloxy)-4-methylphenyl)acetate (269c) (500 mg, 1.758 mmol) in ethanol (30 ml) was added Pd/C (187 mg, 0.176 mmol) and hydrogenated (pressure bottle ) for 4 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel) to give ethyl 2-(2hydroxy-4-methylphenyl)acetate (269d) (285 mg, 83% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.62-6.57 (m, 1H), 6.54 (ddd, J=7.5, 1.8, 0.8 Hz, 1H), 4.04 (k, J=7.1 Hz, 2H), 3.47 (s, 2H), 2 .19 (s, 3H), 1.16 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e).

Compound 269e was prepared according to the procedure described in step-1 of Scheme-59 from (7bromobenzofuran-5-yl)methanol (23a) (6.5 g, 28.6 mmol) using bis(pinacolato)diboron (10, 9 g, 42.9 mmol), potassium acetate (8.43 g, 86 mmol) and Pd(dppf)Cl ₂ -DCM (2.34 g, 2.86 mmol) in anhydrous dioxane (200 ml) under argon when heated at 90°C for 18 hours. This gave, after work-up and purification by flash column chromatography [silica gel (120 g), eluted with EtOAc in hexane from 0% to 60%] (7-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5yl)methanol (269e) (6.81 g, 87% yield) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J=2.2 Hz, 1H), 7.71 (dd, J=1.8, 0.9 Hz, 1H), 7, 59 (d, J=2.2 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 5.22 (t, J=5.8 Hz, 1H), 4.58 ( dt, J=5.8, 0.7 Hz, 2H), 1.34 (s, 12H).

Stage-5. Preparation of (-)-(R)-N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2methylpropane-2-sulfinamide (269f).

Compound 269f was prepared according to the procedure described in step-3 of Scheme-1 from (7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (3 g, 10.94 mmol) in dioxane (40 ml) using (-)-(S)-N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2- sulfinamide (259b) (4.23 g, 13.13 mmol), bis(triphenylphosphine) palladium(P) chloride (PdCl ₂ (PPh ₃ ) ₂ ) (1.152 g, 1.642 mmol) and K2CO3 solution (4.54 g, 32.8 mmol) in water (8 ml) heating under N2 at 100°C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes) (-)-(R)-N-(2-fluoro-1-(3-( 5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (269f) (2.8 g, 66% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=2.2 Hz, 1H), 7.90 (s, 1H), 7.81 (ddd, J=5.5, 3 ,7, 1.8 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.55-7.44 (m, 3H), 7.03 (d, J=2, 2 Hz, 1H), 6.07 (d, J=8.3 Hz, 1H), 5.28 (t, J=5.7 Hz, 1H), 4.71-4.62 (m, 4H) , 4.51 (d, J=6.3 Hz, 1H), 1.14 (s, 9H); MS (ESI+): 412.1 (M+Na), (ESI-): 388.1 (M-1); optical rotation [a] _D = -1.10 (c = 0.95, MeOH).

Stage-6. Preparation of (-)-ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl) acetate (269g).

Compound 269g was prepared according to the procedure described in step-2 of Scheme-23 from (-)(R)-N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl )ethyl)-2-methylpropane-2-sulfinamide (269f) (400 mg, 1.027 mmol) in DCM (15 ml), using triphenylphosphine (337 mg, 1.284 mmol), ethyl 2-(2hydroxy-4-methylphenyl) acetate ( 269d) (249 mg, 1.284 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 528 mg, 1.438 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate in 0% to 50% hexanes), (-)-ethyl 2-(2-((7-(3-(1 -((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (269g) (340 mg, 59% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.92 (s, 1H), 7.83 (td, J=4.5, 1 .7 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.53 (d, J=4.7 Hz, 2H), 7.12-7.02 (m, 2H), 7.01-6.88 (m, 1H), 6.78-

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6.66 (m, 1H), 6.05 (d, J=8.2 Hz, 1H), 5.21 (s, 2H), 4.68 (s, 2H), 4.52 (d, J =6.3 Hz, 1H), 3.90 (k, J=7.1 Hz, 2H),

3.57 (s, 2H), 2.30 (s, 3H), 1.13 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 566.2 (M+1), 568.2 (M+Na), (ESI-): 564.2 (M-1); optical rotation [a] _D = -2.29 (c = 0.18, MeOH).

Stage-7. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (269h).

To a stirred solution of (-)-ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4- methylphenyl)acetate (269g) (331 mg, 0.585 mmol) in THF (5 ml), methanol (5 ml) and water (2 ml) was added lithium hydroxide (70.1 mg, 2.93 mmol) and stirred for 12 h. The reaction mixture was concentrated to remove organic solvents, suspended in 1:1 THF:water (10 ml), HCl (3N in water) (2.93 ml, 8.78 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated to remove organic solvents. The mixture was purified by reverse phase column chromatography (C18, 50 g, 0-60% MeCN in H2O with 0.1% HCl) to give (+)-2-(2-((7-(3-(1- amino-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (269h) (25 mg, 10% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.98 (dd, J=7.4, 1.7 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.69-7.63 (m, 2H), 7.63-7.55 (m, 2H), 7.12-7.05 (m, 2H), 6.95 (d, J=1.5 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H) , 5.24 (s, 2H), 4.94-4.83 (m, 1H), 4.77 (k, J=3.8 Hz, 1H), 3.54 (s, 2H), 2, 29 (s, 3H); MS (ESI+): 434.1 (M+1), (ESI-): 432.1 (M-1); optical rotation [afo = +15.69 (c = 0.26, MeOH).

Scheme-270

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (270c).

Stage-1. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (270a).

Compound 270a was prepared according to the procedure described in step-2 of scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (0.6 g, 2.069 mmol) using ethyl 2-(2-hydroxy-4methylphenyl)acetate (269d) (0.442 g, 2.276 mmol), K ₂ CO ₃ (0.858 g, 6.21 mmol) in acetone (10 ml) and reflux for 2 hours. This gave, after work-up and flash purification -column chromatography (SiO ₂ , 40 g, eluted with EtOAc in hexane) ethyl 2-(2-((7bromobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (270a) (628 mg, 75% yield) in as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.60 (d, J =1.5 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.94-6.91 (m , 1H), 6.73 (ddd, J=7.4, 1.6, 0.8 Hz, 1H), 5.15 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.29 (s, 3H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI+): 403.00; 405.00 (M, M+2).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (270b).

Compound 270b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (270a) (600 mg, 1.488 mmol ) in dioxane (10 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (489 mg, 2.381 mmol), bis(triphenylphosphine) palladium(II) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (157 mg, 0.223 mmol) and potassium carbonate (617 mg, 4.46 mmol) in water (3 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl) benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (270b) (565 mg, 85% yield) as colorless syrup;

^1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.67-7, 54 (m, 1H), 7.45

- 352 045626 (td, J=7.4, 1.9 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H ), 7.08 (d, J=7.5 Hz, 1H), 7.05 (d, J=2.2 Hz,

1H), 6.97 (d, J=1.5 Hz, 1H), 6.72 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 5.20 (s, 2H ), 3.89 (k, J=7.1 Hz, 2H), 3.83 (s,

2H), 3.55 (s, 2H), 2.30 (s, 3H), 1.93 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.75;

MS (ESI+): 448.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (270c).

Compound 270c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl )acetate (270b) (550 mg, 1.229 mmol) in MeOH (10 ml), THF (10 ml), using a solution of lithium hydroxide (118 mg, 4.92 mmol) in water (5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (270c) (187 mg, 36% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.67 (td, J=7.2, 2.8 Hz, 2H), 7.46 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.11-7.04 (m, 2H ), 6.94 (s, 1H), 6.72 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.18 (s, 2H), 3.52 (s , 2H), 2.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO4) δ -118.38; MS (ESI+): 420.1 (M+1), (ESI-): 418.1 (M-1).

Scheme-271

^271d 271e

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (271e).

Stage-1. Preparation of tert-butyl ((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2yl)methyl)carbamate (271b).

Compound 271b was prepared according to the procedure described in step-3 of Scheme-1 from (7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (0.5 g, 1.824 mmol) in dioxane (10 ml) using tert-butyl ((4-chloropyridin-2-yl)methyl)carbamate (271a) (0.531 g, 2.189 mmol; CAS No. 96628- 86-3), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.192 g, 0.274 mmol) and a solution of K ₂ CO ₃ (0.756 g, 5.47 mmol) in water (2 ml) heating in N2 atmosphere at 100°C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes) tert-butyl ((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin- 2-yl)methyl)carbamate (271b) (313 mg, 48% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.68-8.55 (m, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.77 (d, J=4 .9 Hz, 2H), 7.71 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.53 (t, J=6.2 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 4.31 (d, J=6.1 Hz, 2H), 1.42 (s, 9H); MS (ESI+): 355.1 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (271c).

Compound 271c was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl ((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate (271b) ((330 mg, 0.931 mmol) in DCM (15 ml) using triphenylphosphine (305 mg, 1.164 mmol), ethyl 2-(2-hydroxy-4methylphenyl) acetate (269d) (226 mg, 1.164 mmol) and (E)-bis solution (4-chlorobenzyl)diazene-1,2dicarboxylate (DCAD, 479 mg, 1.304 mmol) in DCM (10 ml) This gave after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate in hexanes from 0% to 50%) ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate ( 271c) (450 mg, 91% yield) as a colorless oil; MS (ESI+): 531.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (271d).

- 353 045626

Compound 271d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5 -yl)methoxy)-4methylphenyl)acetate (271c) (450 mg, 0.848 mmol) in DCM (5 ml) using TFA (1.307 ml, 16.96 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with 9:1 ethyl acetate/methanol in hexanes), ethyl 2-(2-((7-(2(aminomethyl)pyridine-4- yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (271d) (189 mg, 52% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (d, J=5.2 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.09-7, 97 (m, 1H), 7.92 (dd, J=5.2, 1.7 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.76 (d, J =1.6 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.97 (d, J=1 .6 Hz, 1H), 6.74 (dd, J=7.4, 1.4 Hz, 1H), 5.24 (s, 2H), 4.22 (s, 2H), 3.92 (k , J=7.1 Hz, 2H), 3.58 (s, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI(+): 431.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (271e).

Compound 271e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4- methylphenyl)acetate (271d) (185 mg, 0.430 mmol) in THF/MeOH (5 mL each), using a solution of lithium hydroxide monohydrate (41 mg, 1.719 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-(( 7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (271e) (84 mg, 49% yield), hydrochloride salt, as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.53 (s, 3H), 8.18 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.83 (s, 1H), 7.12 ( d, J=2.2 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.73 (dd, J=7.4, 1.5 Hz, 1H), 5.27 (s, 2H), 4.32 (d, J=4.8 Hz, 2H), 3.55 (s, 2H), 2, 29 (s, 3H); MS (ESI+): 403.1 (M+1), (ESI-): 401.1 (M-1); analysis calculation for C ₂₄ H ₂₂ N ₂ O ₄ -1.75HCl-1.75H ₂ O: C, 57.91; N, 5.52; Cl, 12.46; N, 5.63; observed: C, 57.83; N, 5.28; Cl, 12.81; N, 5.70.

Scheme-272

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (272e).

Stage-1. Preparation of (R)-N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)niridin-2-yl)methyl)-2methylpropan-2-sulfinamide (272b).

Compound 272b was prepared according to the procedure described in step-3 of Scheme-1 from (7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (0.5 g, 1.824 mmol) in dioxane (10 ml) using (-)-(R)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane -2sulfinamide (272a) (0.579 g, 2.189 mmol; prepared according to the procedure described in Scheme-220 for compound 220c from compound 220a using (R)-2-methylpropane-2-sulfinamide), bis(triphenylphosphine)palladium( P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.192 g, 0.274 mmol) and a solution of K2CO3 (0.756 g, 5.47 mmol) in water (2 ml) heating in an N2 atmosphere at 100 ° C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes) (R)-N-((3-fluoro-4-(5(hydroxymethyl)benzofuran -7-yl)pyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (272b) (435 mg, 63% yield) as a thick syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (dd, J=4.9, 0.7 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 7, 74 (dt, J=1.6, 0.8 Hz, 1H), 7.65 (dd, J=5.6, 4.9 Hz, 1H), 7.42 (s, 1H), 7.06 (d, J=2.2 Hz, 1H), 5.86 (t, J=5.8 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.72-4 .54 (m, 2H), 4.40 (dd, J=5.7, 2.1 Hz, 2H), 1.11 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 128.15; MS (ESI+): 377.2 (M+1).

Stage-2. Preparation of (+)-(R)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3

- 354 045626 fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (272c).

Compound 272c was prepared according to the procedure described in step-2 of Scheme-23 from (R)N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl )-2-methylpropane-2-sulfinamide (272b) (430 mg, 1.142 mmol) in DCM (20 ml), using triphenylphosphine (374 mg, 1.428 mmol), ethyl 2-(2hydroxy-4-methylphenyl) acetate (269d) (277 mg, 1.428 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 587 mg, 1.599 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate in 0% to 50% hexanes), (+)-(R)-ethyl 2-(2-((7-( 2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (272c) (300 mg, 48% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=4.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.67 (t, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.12-7.05 (m, 2H), 6, 97 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.86 (t, J=5.8 Hz, 1H), 5.22 (s, 2H), 4, 48-4.35 (m, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.30 (s, 3H), 1.11 (s , 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -127.99; MS (ESI+): 553.2 (M+1); optical rotation [a]D = +17.14 (c = 0.11, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (272d).

To a stirred solution of (+)-(R)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)- 4-methylphenyl)acetate (272c) (300 mg, 0.543 mmol) in THF (5 ml) was added 3N aq. HCl (0.543 mL, 1.628 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo to give ethyl 2-(2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran -5-yl)methoxy)-4-methylphenyl)acetate (272d) (263 mg, 0.543 mmol, 100% yield), HCl salt, as a white solid, which was used as is without further purification; MS (ESI+): 449.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (272e).

Compound 272e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -4-methylphenyl)acetate (272d) (260 mg, 0.536 mmol) in THF/MeOH (5 mL each), using a solution of lithium hydroxide monohydrate (51 mg, 2.145 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (272e) (200 mg, 89%), hydrochloride salt, as a white solid substances;

1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=5.0 Hz, 1H), 8.58 (t, J=6.1 Hz, 3H), 8.12 (d, J =2.2 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.81 (d, J=5.3 Hz, 1H), 7.60 (s, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 6, 73 (d, J=8.3 Hz, 1H), 5.25 (s, 2H), 4.44-4.33 (m, 2H), 3.52 (s, 2H), 2.29 (s , 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.36; MS (ESI+): 421.10 (M+1), (ESI-): 419.10 (M-1); analysis calculation for C ₂₄ H ₂₁ FN ₂ O ₄ -1.0HCl-1.5H ₂ O: C, 59.57; N, 5.21; N, 5.79; Cl, 7.33; observed: C, 59.41; H, 5.09; N, 5.77; Cl, 7.54.

Scheme-273

Preparation of (1R,3S,5R)-2-(2-(7-(3-(aminomethyl)phenyl)benzofurαn-5-yl)acetyl)-N-(3-chloro-2fluorobenzyl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide (273g).

- 355 045626

Stage-1. Preparation of 2-(7-bromobenzofuran-5-yl)acetonitrile (273a).

To a stirred solution of 7-bromo-5-(bromomethyl)benzofuran (152a) (2 g, 6.90 mmol) in acetonitrile (40 ml) was added potassium cyanide (0.431 g, 6.62 mmol) and stirred at room temperature for 48 hours. The reaction mixture was diluted with brine and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. The crude residue was purified by flash column chromatography to give pure 2-(7-bromobenzofuran-5yl)acetonitrile (273a) (845 mg, 52% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J=2.2 Hz, 1H), 7.68 (dt, J=1.6, 0.7 Hz, 1H), 7, 56 (dd, J=1.7, 0.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 4.14 (d, J=0.7 Hz, 2H).

Stage-2. Preparation of methyl 2-(7-bromobenzofuran-5-yl)acetate (273b).

Conc. sulfuric acid (1.806 ml, 33.9 mmol) and refluxed for 12 hours. The reaction mixture was cooled to room temperature and concentrated to remove methanol. The residue was dissolved in ethyl acetate (200 ml), washed with water, brine, dried and concentrated in vacuo. The crude residue was purified by flash column chromatography to give methyl 2-(7-bromobenzofuran-5-yl)acetate (273b) (410 mg, 45% yield) as a light brown syrup;

^1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 3.80 (s, 2H), 3.62 (s, 3H).

Stage-3. Preparation of methyl 2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)acetate (273c).

Compound 273c was prepared according to the procedure described in step-3 of Scheme-1 from methyl 2-(7-bromobenzofuran-5-yl)acetate (273b) (400 mg, 1.486 mmol) in dioxane (10 ml) using tert -butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (594 mg, 1.784 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd (PPh ₃ ) ₂ Cl ₂ ) (157 mg, 0.223 mmol) and a solution of K2CO3 (616 mg, 4.46 mmol) in water (2 ml) heating under N2 at 100°C for 7 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate in 0% to 100% hexanes), methyl 2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl )benzofuran-5-yl)acetate (273c) (470 mg, 80% yield) as a colorless syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J=2.2 Hz, 1H), 7.77-7.67 (m, 2H), 7.55 (d, J=1, 7 Hz, 1H), 7.537.43 (m, 2H), 7.38 (d, J=1.7 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 4.22 (d, J=6.3 Hz, 2H), 3.84 (s, 2H), 3.63 (s, 3H), 1.40 (s, 9H).

Stage-4. Preparation of 2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)acetic acid (273d).

Compound 273d was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate (273c) (460 mg, 1.163 mmol) in THF (5 ml) MeOH (5 ml), using a solution of sodium hydroxide (140 mg, 3.49 mmol) in water (2 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with 9:1 ethyl acetate/methanol in hexanes) 2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) benzofuran-5-yl)acetic acid (273d) (340 mg, 77% yield) as a thick syrup;

1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.71 (dt, J=9.6, 1, 8 Hz, 2H), 7.54 (d, J=1.7 Hz, 1H), 7.48 (td, J=7.6, 7.1, 3.6 Hz, 2H), 7.37 ( d, J=1.7 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.72 (s, 2H), 1.40 (s, 9H).

Stage-5. Preparation of tert-butyl 3-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2azabicyclo[3.1.0]hexan-2-yl)-2 -oxoethyl)benzofuran-7-yl)benzylcarbamate (273f).

Compound 273f was prepared according to the procedure described in step-4 of Scheme-1 from 2-(7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetic acid (273d) ( 200 mg, 0.524 mmol) in DMF (4 ml) using (1R,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2azabicyclo[3,1,0]hexane-3-carboxamide hydrochloride (273e ) (200 mg, 0.655 mmol; prepared according to the procedure described by Wiles, Jason Allan et al.; PCT International Application, 2017035349, March 02, 2017), DIPEA (0.365 ml, 2.097 mmol) and HATU (299 mg, 0.787 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 to 100% EtOAc/MeOH=9:1 in hexane] tert-butyl 3-(5-(2-(( 1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate (273f) ( 410 mg) in the form of a clear syrup. MS (ESI+): 532.2 (M-Vos), (ESI-): 631.2 (M-1).

Stage-6. Preparation of (1R,3S,5R)-2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro2-fluorobenzyl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide (273g).

Compound 273g was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 3-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl) -2-azabicyclo[3,1,0]hexan-2-yl)-2-356 045626 oxoethyl)benzofuran-7-yl)benzylcarbamate (273f) (410 mg, 0.649 mmol) in DCM (10 ml) using TFA (0.5 ml, 6.49 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (1R,3S,5R)-2-( 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2azabicyclo[3,1,0]hexane-3-carboxamide (273g) (210 mg, 61% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.48 (t, J=6.0 Hz, 1H), 8.38 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.97 (s, 1H), 7.88 (dt, J=7.2, 1.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.56-7 .51 (m, 1H), 7.47 (d, J=4.8 Hz, 1H), 7.45-7.39 (m, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.10 (td, J=7.9, 1.1 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 4.34 (k, J=8.1 , 7.0 Hz, 2H), 4.23 (dd, J=9.1, 4.9 Hz, 1H), 4.12 (s, 2H), 4.07-3.92 (m, 2H) , 3.71-3.62 (m, 1H), 2.30-2.01 (m, 2H), 1.77 (p, J=6.8 Hz, 1H), 0.93 (dt, J =9.1, 5.3 Hz, 1H), 0.50 (dd, J=5.2, 2.4 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.77; MS (ESI+): 532.10; 534.10 (M+1), (ESI-): 530.20, 532.20 (M-1); analysis calculation for C30H27CFN3O3'HCH,25H ₂ O: C, 60.97; N, 5.20; Cl, 12.00; N, 7.11; observed: C, 60.91; N, 5.01; Cl, 11.81; N, 7.04.

Scheme-274

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetic acid (274g).

Stage-1. Preparation of (2-(2-methoxy-3-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (274b).

Compound 274b was prepared according to the procedure described in step-3 of scheme-266 from 2methoxy-3-methylbenzaldehyde (274a) (5 g, 33.3 mmol) in THF (50 ml) using methyl(methylsulfinylmethyl)sulfane (6, 62 g, 53.3 mmol), Triton-B (40% methanol solution) (7.57 ml, 16.65 mmol) and reflux for 12 hours. This resulted in after workup (2-(2 -methoxy-3-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (274b) (8.54 g, 100% yield) as a light brown syrup; MS (ESI+): 257.0 (M+1), 279.0 (M+Na).

Stage-2. Preparation of ethyl 2-(2-methoxy-3-methylphenyl)acetate (274c).

Compound 274c was prepared according to the procedure described in step-4 of scheme-266 from (2-(2methoxy-3-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (274b) (8.54 g, 33. 3 mmol) in ethanol (100 ml) using conc. HCl (13.88 ml, 167 mmol) and reflux for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-methoxy-3-methylphenyl) acetate (274c) (2.65 g, 38% yield) as a thick syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.16-7.03 (m, 2H), 6.97 (t, J=7.5 Hz, 1H), 4.08 (k, J=7 ,1 Hz, 2H), 3.63 (s, 3H), 3.62 (s, 2H), 2.23 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI+): 231.1 (M+Na).

Stage-3. Preparation of ethyl 2-(2-hydroxy-3-methylphenyl)acetate (274d).

Compound 274d was prepared according to the procedure described in step-5 of scheme-257 from ethyl 2-(2-methoxy-3-methylphenyl) acetate (274c) (2.6 g, 12.48 mmol) in dichloromethane (30 ml ), using boron tribromide (4.72 ml, 49.9 mmol). This resulted in ethyl 2-(2-hydroxy-3methylphenyl)acetate (274d) (0.6 g, 25% yield) as a clear syrup after work-up;

1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.01-6.90 (m, 2H), 6.68 (t, J=7.4 Hz, 1H), 4 .06 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.16 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274e).

Compound 274e was prepared according to the procedure described in step-2 of Scheme-152 from 7-357 045626 bromo-5-(bromomethyl)benzofuran (152a) (0.411 g, 1.416 mmol) using ethyl 2-(2-hydroxy-3methylphenyl) )acetate (274d) (0.275 g, 1.416 mmol), K ₂ CO ₃ (0.587 g, 4.25 mmol) in DMF (5 ml) and stirring at room temperature for 2 hours. This resulted in the following work-up and purification: via flash column chromatography (SiO ₂ , 40 g, eluted with EtOAc in hexane) ethyl 2-(2-((7bromobenzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274e) (465 mg, 81% yield ) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.16 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.65 (d , J=1.5 Hz, 1H), 7.22-7.08 (m, 3H), 7.03 (t, J=7.4 Hz, 1H), 4.87 (s, 2H), 4 .01 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.30 (s, 3H), 1.10 (t, J=7.1 Hz, 3H); MS (ESI+): 403.00; 405.00 (M, M+2); 425.0; 427.0 (M+Na).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3methylphenyl)acetate (274f).

Compound 274f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274e) (450 mg, 1.116 mmol ) in dioxane (10 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (335 mg, 1.785 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (117 mg, 0.167 mmol) and a solution of K2CO3 (463 mg, 3.35 mmol) in water (3 ml) heating under N2 at 100°C for 6 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography (silica gel 40 g, eluted with DMA80 in DCM 0% to 50%] followed by purification by reverse phase chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) 0% to 100%] ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274f) (242 mg , 51% yield) in the form of a colorless syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.75 (d, J =1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.6 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.47 (t , J=7.6 Hz, 1H), 7.43-7.38 (m, 1H), 7.20-7.16 (m, 1H), 7.15-7.10 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 4.94 (s, 2H), 3.98 (k, J=7 ,1 Hz, 2H), 3.82 (s, 2H), 3.68 (s, 2H), 2.33 (s, 3H), 1.05 (t, J=7.1 Hz, 3H); MS (ESI+): 430.2 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3methylphenyl)acetic acid (274g).

Compound 274g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetate ( 274f) (245 mg, 0.570 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide (55 mg, 2.282 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetic acid (274g) (225 mg, 90% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 (d, J=2.2 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.92 (dt, J=6.6, 2.2 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.59 ( d, J=6.5 Hz, 2H), 7.19-7.11 (m, 2H), 7.10 (d, J=2.2 Hz, 1H), 7.02 (t, J=7 .5 Hz, 1H), 4.94 (s, 2H), 4.14 (s, 2H), 3.64 (s, 2H), 2.32 (s, 3H); MS (ESI+): 402.20 (M+1), (ESI-): 400.10 (M-1); analysis calculation for C ₂ 5H2 ₃ NO4'HCl; C, 68.57; N, 5.52; Cl, 8.10; N, 3.20; observed C, 68.40; N, 5.51; Cl, 7.97; N, 3.25.

Scheme-275

Preparation of (1R,3S,5R)-2-(2-(7-(4-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2fluorobenzyl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide (275e).

Stage-1. Preparation of methyl 2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)acetate (275b).

Compound 275b was prepared according to the procedure described in step-3 of Scheme-1 from methyl

- 358 045626

2-(7-bromobenzofuran-5-yl)acetate (273b) (200 mg, 0.743 mmol) in dioxane (10 ml), using tert-butyl 4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)benzylcarbamate (275a) (297 mg, 0.892 mmol; CAS No. 330794-35-9), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (78 mg , 0.111 mmol) and a solution of K2CO3 (308 mg, 2.230 mmol) in water (2 ml) heating under N2 at 100°C for 7 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate in 0% to 100% hexanes), methyl 2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl )benzofuran-5-yl)acetate (275b) (140 mg, 48% yield) as a colorless syrup; MS (ESI+): 418.1 (M+Na).

Stage-2. Preparation of 2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)acetic acid (275c).

Compound 275c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate (275b) (140 mg, 0.354 mmol) in THF (5 ml) MeOH (5 ml), using a solution of sodium hydroxide (42 mg, 1.062 mmol) in water (2 ml). This resulted in 2-(7-(4-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetic acid (275c) (132 mg, 98% yield) as a thick syrup after treatment; MS (ESI+): 404.1 (M+Na), (ESI-) 380.1 (M-1).

Stage-3. Preparation of tert-butyl 4-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2azabicyclo[3.1.0]hexan-2-yl)-2 -oxoethyl)benzofuran-7 -yl)benzylcarbamate (275d).

Compound 275d was prepared according to the procedure described in step-4 of Scheme-1 from 2-(7(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetic acid (275c) ( 132 mg, 0.346 mmol) in DMF (4 ml) using (1R,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2azabicyclo[3,1,0]hexane-3-carboxamide hydrochloride (273e ) (132 mg, 0.433 mmol), DIPEA (0.241 ml, 1.384 mmol) and HATU (197 mg, 0.519 mmol). This gave, after work-up and purification by flash chromatography on a column [silica gel (12 g), eluted with 0 to 100% EtOAc/MeOH=9:1 in hexane] tert-butyl 4-(5-(2-((1R, 3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2oxoethyl)benzofuran-7-yl)benzylcarbamate (275d) (160 mg , 73% yield) in the form of a clear syrup; MS (ESI+): 654.2, 655.2 (M+Na).

Stage-4. Preparation of (1R,3S,5R)-2-(2-(7-(4-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro2-fluorobenzyl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide (275e).

Compound 275e was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 4-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl) -2-azabicyclo[3,1,0]hexan-2-yl)-2oxoethyl)benzofuran-7-yl)benzylcarbamate (275d) (150 mg, 0.237 mmol) in DCM (5 mL), using TFA (0.183 mL, 2.375 mmol). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (1R,3S,5R)-2 -(2-(7-(4-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2azabicyclo[3,1,0]hexane-3-carboxamide ( 275e) (65 mg, 0.122 mmol, 51.4% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.46 (t, J=6.0 Hz, 1H), 8.36 (s, 3H), 8.05 (d, J=2.2 Hz, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.57 (d, J=1.6 Hz, 1H) , 7.47 (d, J=1.7 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 7 .10 (t, J=7.9 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 4.37-4.28 (m, 2H), 4.23 (dd, J=9.1, 5.0 Hz, 1H), 4.10 (s, 2H), 4.00 (d, J=9.1 Hz, 2H), 3.73-3.60 (m, 1H ), 2.30-2.15 (m, 1H), 2.09 (dt, J=12.9, 5.9 Hz, 1H), 1.77 (s, 1H), 0.92 (dt, J=9.3, 5.3 Hz, 1H), 0.50 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.79; MS (ESI+): 532.3, 533.0, (ESI-): 530.2, 532.0 (M-1); analysis calculation for C ₃₀ H ₂₇ ClFN ₃ O ₃ -HCl-2.25H ₂ O: C, 59.17; N, 5.38; Cl, 11.64; N, 6.90; observable; C, 58.96; N, 4.99; Cl, 11.54; N, 7.30.

Scheme-276

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetic acid

- 359 045626 acid (276f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylbenzaldehyde (276b).

Compound 276b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.931 g, 6.66 mmol) using 2-hydroxy-4,5dimethylbenzaldehyde (276a) ( 1 g, 6.66 mmol), K ₂ CO ₃ (2.76 g, 19.98 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This resulted in, after work-up and flash purification -column chromatography (SiO ₂ , 40 g, eluted with EtOAc in hexane) 2-((7bromobenzofuran-5-yl)methoxy)-4,5-dimethylbenzaldehyde (276b) (1.96 g, 82% yield) as white solid matter;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.5 Hz , 1H), 7.71 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.18 (s, 1H), 7.12 (d, J=2.2 Hz , 1H), 5.32 (s, 2H), 2.29 (s, 3H), 2.19 (s, 3H); MS (ESI+): 381.00, 383.00 (M+Na).

Stage-2. Preparation of 7-bromo-5-((4,5-dimethyl-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (276c).

Compound 276c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4,5-dimethylbenzaldehyde (276b) (1.9 g, 5.29 mmol) in THF (40 mL) using methyl(methylsulfinylmethyl)sulfane (1.051 g, 8.46 mmol), Triton-B (40% methanol solution) (1.202 mL, 2.64 mmol) and reflux for 12 h. This gave, after work-up and purification by flash column chromatography (SiO ₂ , 40 g, eluted with EtOAc in hexane), 7-bromo-5-((4,5-dimethyl-2-(2-(methylsulfinyl)-2 (methylthio)vinyl)phenoxy)methyl)benzofuran (276c) (1.62 g, 66% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=2.2 Hz, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.73 ( d, J=1.5 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.05 (s, 1H), 5.24 (s, 2H), 2.70 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H); MS (ESI+): 465.0; 467.0 (M, M+2).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d).

Compound 276d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((4,5-dimethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (276c) (1.6 g, 3.44 mmol) in ethanol (50 mL) using HCl (4 M in 1,4-dioxane, 3.44 mL, 13.75 mmol) and reflux for 12 hours This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes), ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4,5- dimethylphenyl)acetate (276d) (1.2 g, 84% yield) as a clear syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=2.2 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 5.12 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.08 ( t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetate (276e).

Compound 276e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d) (403 mg, 0.966 mmol) in dioxane (10 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (290 mg, 1.545 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (102 mg, 0.145 mmol) and a solution of K2CO3 (400 mg, 2.90 mmol) in water (3 ml) heating under N2 at 100°C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 40 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)-4,5-dimethylphenyl)acetate (276e) (315 mg, 74% yield) as a colorless syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (td, J=1.8, 0.7 Hz, 1H), 7, 71 (dt, J=7.5, 1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H ), 6.95 (s, 1H), 6.94 (s, 1H), 5.19 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.81 (s , 2H), 3.54 (s, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); (MS (ESI+): 444.2 (M+1), 442.18 (M-1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (276f).

Compound 276f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl) acetate (276e) (300 mg, 0.676 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide (65 mg, 2.71 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetic acid (276f) (150 mg, 53% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.93 ( td, J=4.5, 1.7

- 360 045626

Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.58 (d, J=4.6 Hz, 2H), 7.06 (d, J=2.2 Hz, 1H), 6.96 (s,

1H), 6.92 (s, 1H), 5.21 (s, 2H), 4.13 (s, 2H), 3.51 (s, 2H), 2.19 (s, 3H), 2. 12 (s, 3H); MS (ESI+): 416.20 (M+1), (ESI-): 414.2 (M-1), HPLC t=2.42 min, (97.03%); analysis calculation for C ₂₆ H ₂₅ NO ₄ -HCl-0.75H ₂ O: C,

67.09; N, 5.96; Cl, 7.62; N, 3.01; observed: C, 67.17; N, 5.77; Cl, 7.58; N, 3.03.

Scheme-277

Preparation of (S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2fluorobenzyl)pyrrolidine-2-carboxamide (277e).

Stage-1. Preparation of (S)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1carboxylate (277b).

Compound 277b was prepared according to the procedure described in step-4 of Scheme-1 from (S)-1(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (277a) (3 g, 13.94 mmol) and (3-chloro -2fluorophenyl)methanamine (1.927 ml, 15.33 mmol) in DMF (40 ml), using HATU (7.95 g, 20.91 mmol) and DIPEA (9.71 ml, 55.8 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 50% DMA 80 in DCM) (S)-tert-butyl 2-((3-chloro -2fluorobenzyl)carbamoyl)pyrrolidine-1-carboxylate (277b) (4.08 g, 82% yield) as a light brown solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.53-8.36 (m, 1H), 7.52-7.41 (m, 1H), 7.36-7.27 (m, 1H ), 7.23-7.09 (m, 1H), 4.46-4.21 (m, 2H), 4.17-4.03 (m, 1H), 3.45-3.22 (m , 2H), 2.23-2.02 (m, 1H), 1.86-1.69 (m, 3H), 1.40 and 1.25 (2s, 9H).

Stage-2. Preparation of (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c).

Compound 277c was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxylate (277b) (4 g, 11.21 mmol) in DCM (40 ml) using TFA (8.64 ml, 112 mmol).

This resulted in (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2carboxamide (277c) (2. 0 g, 7.79 mmol, 69.5% yield) as a brown oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.11 (t, J=5.7 Hz, 1H), 7.52 (ddd, J=8.9, 7.3, 1.8 Hz, 1H ), 7.33 (ddd, J=8.4, 6.8, 1.8 Hz, 1H), 7.22 (td, J=7.8, 1.0 Hz, 1H), 4.42 ( d, J=5.7 Hz, 2H), 4.28-4.16 (m, 1H), 3.30-3.09 (m, 3H), 2.38-2.20 (m, 1H) , 1.99-1.73 (m, 3H).

Stage-3. Preparation of (S)-tert-butyl 3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)2-oxoethyl)benzofuran-7-yl)benzylcarbamate (277d ).

Compound 277d was prepared according to the procedure described in step-4 of Scheme-1 from 2-(7(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetic acid (273d) ( 200 mg, 0.524 mmol) in DMF (4 ml), using (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (243 mg, 0.655 mmol), DIPEA (0.365 ml, 2.097 mmol) and HATU (299 mg, 0.787 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 to 100% EtOAc/MeOH=9:1 in hexane] (S)-tert-butyl 3-(5-( 2-(2-((3-chloro-2fluorobenzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate (277d) (375 mg) as a clear syrup; MS (ESI+): 642.2, 644.2 (M+Na), (ESI-): 618.2, 620.2 (M, M-2).

Stage-4. Preparation of (S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2fluorobenzyl)pyrrolidine-2-carboxamide (277e).

Compound 277e was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1 -yl)-2-oxoethyl)benzofuran-7yl)benzylcarbamate (277d) (375 mg, 0.605 mmol) in DCM (10 ml) using TFA (0.466 ml, 6.05 mmol). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-1-(2- (7-(3-361 045626 (aminomethyl)phenyl)benzofuran-5-yl)acetyl)-C-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277e) (142 mg, 45% yield) in as a white solid; MS (ESI+): 520.1 (M+1), (ESI-): 518.2 (M1).

Scheme-278

Vg

278d 278е (+)-isomer

Preparation of (+)-2-(2-((7-(3-( 1 -amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (278e).

Stage-1. Preparation of (2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methanol (278a).

Compound 278a was prepared according to the procedure described in step-1 of Scheme-59 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (2 g, 6.29 mmol) using bis(pinacolato )diboron (2.395 g, 9.43 mmol), potassium acetate (1.851 g, 18.86 mmol) and Pd(dppf)Cl ₂ -DCM (0.770 g, 0.943 mmol) in anhydrous dioxane (35 ml) under nitrogen at heating at 100°C for 43 hours. This gave, after work-up and purification by flash column chromatography [silica gel (120 g), eluted with hexanes/ethyl acetate (1:0 to 1:1)] (2-( methoxymethyl)-7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (278a) (1.32 g) as a brown gum;

1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, 1H), 7.59 (d, J=1.8 Hz, 1H), 6.87 (s, 1H), 5.20 (t , J=5.8 Hz, 1H), 4.56 (d, J=5.7, 0.7 Hz, 2H), 4.53 (s, 2H), 3.33 (s, 3H), 1 .34 (s, 12H).

Stage-2. Preparation of (R)-N-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (278b).

Compound 278b was prepared according to the procedure described in step-3 of Scheme-1 from (2(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran -5-yl)methanol (278a) (0.5 g, 1.571 mmol) in dioxane (10 ml), using (-)-(R)-N-(1-(3-bromophenyl)-2-fluoroethyl)- 2-methylpropane-2sulfinamide (259b) (0.608 g, 1.886 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.165 g, 0.236 mmol) and K ₂ CO ₃ solution (0.652 g, 4.71 mmol) in water (2 ml) heating under N2 at 100°C for 5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes) (R)-N-(2-fluoro-1-(3-(5- (hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)phenyl)ethyl)-2methylpropane-2-sulfinamide (278b) (200 mg, 29% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.85-7.75 (m, 1H), 7.59-7.55 (m, 1H), 7.54- 7.48 (m, 2H), 7.46 (d, J=1.6 Hz, 1H), 6.96 (s, 1H), 6.06 (d, J=8.3 Hz, 1H), 5.76 (s, 2H), 5.27 (t, J=5.7 Hz, 1H), 4.66 (d, J=8.8 Hz, 2H), 4.55 (s, 2H), 4.51 (d, J=6.2 Hz, 1H), 3.32 (s, 3H), 1.14 (s, 9H); MS (ESI+) 456.1 (M+Na), (ESI-) 432.2 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl) acetate (278c).

Compound 278c was prepared according to the procedure described in step-2 of Scheme-23 from (R)X-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl )phenyl)ethyl)-2-methylpropane-2sulfinamide (278b) (200 mg, 0.461 mmol) in DCM (10 ml) using triphenylphosphine (151 mg, 0.577

- 362 045626 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (104 mg, 0.577 mmol) and solution of (E)-bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 237 mg, 0.646 mmol ) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate in 0% to 50% hexanes), ethyl 2-(2-((7-(3-(1-((R )-1,1dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (278c) (425 mg) as a colorless oil; MS (ESI+): 596.2 (M+1), 618.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (278d).

To a stirred solution ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl )acetate (278c) (400 mg, 0.671 mmol) in THF (10 ml) and ethanol (2 ml) was added 3N aq. HCl (0.895 mL, 2.69 mmol) at room temperature and stirred for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel) to give ethyl 2-(2-((7-(3-(1-amino-2fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5 -yl)methoxy)phenyl)acetate (278d) (40 mg, 12% yield) as a white solid; MS (ESI+): 492.2 (M+1).

Stage-5. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (278e).

Compound 278e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5 -yl)methoxy)phenyl)acetate (278d) (40 mg, 0.081 mmol) in THF/MeOH (2.5 mL each), using a solution of lithium hydroxide monohydrate (6 mg, 0.244 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] (+)-2 -(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (278e) (18 mg, 0.039 mmol, 47 .7% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.02-7.99 (m, 1H), 7.96 (dt, J=7.6, 1.5 Hz, 1H), 7.74 (s , 1H), 7.68-7.55 (m, 3H), 7.28-7.18 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 7.00 ( s, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.94-4.71 (m, 3H), 4.58 (s, 2H ), 3.59 (s, 2H), 3.32 (s, 3H); MS (ESI+): 464.20 (M+1), (ESI-): 462.20 (M-1); optical rotation [a] _D = +16.84 (c = 0.19, MeOH).

Scheme-279

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran5-yl)methoxy)phenyl)acetic acid (279c).

Stage-1. Preparation of ethyl 2-(2-((7-iodo-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (279a).

To a stirred suspension of ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400 mg, 0.862 mmol) in ethanol (10 ml) was added 5-methoxypyridine-3 -amine (118 mg, 0.948 mmol) and stirred at room temperature for 1 hour. The reaction mixture was refluxed for 30 minutes, cooled to room temperature, sodium borohydride (65.2 mg, 1.723 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate (200 ml). The ethyl acetate layer was washed with water (2x25 ml), brine (30 ml), dried, filtered and concentrated. The crude residue was purified by flash column chromatography to give ethyl 2-(2-((7-iodo-2(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 279a) (290 mg, 59% yield) as a viscous material;

1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=2.4 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.61 (d, J =1.6 Hz, 1H),

- 363 045626

7.53 (t, J=2.8 Hz, 1H), 7.26-7.17 (m, 2H), 7.06 (dd, J=8.3, 1.1 Hz, 1H), 6 .93 (d, J=1.0 Hz, 1H), 6.91-6.85 (m,

1H), 6.67-6.56 (m, 2H), 5.12 (s, 2H), 4.53 (d, J=6.2 Hz, 2H), 4.09-3.91 (m , 2H), 3.74 (s, 3H), 3.60 (s, 2H), 1.05 (t, J=7.1 Hz, 3H); MS (ESI+): 573.1 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (279b).

Compound 279b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5- yl)methoxy)phenyl)acetate (279a) (290 mg, 0.507 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (152 mg, 0.811 mmol), bis(triphenylphosphine) palladium ( P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (53.3 mg, 0.076 mmol) and a solution of K2CO3 (210 mg, 1.52 mmol) in water (3 ml) heating in an N2 atmosphere at 100 ° C for 6 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography (silica gel, 40 g, eluted with DMA80 in DCM 0% to 50%) followed by purification by reverse phase flash column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3yl)amino)methyl )benzofuran-5-yl)methoxy)phenyl)acetate (279b) (210 mg, 75% yield) as a colorless oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.77 (s, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.71-7.66 (m, 1H) , 7.60 (d, J=1.6 Hz, 1H), 7.52 (dd, J=4.5, 2.1 Hz, 2H), 7.46-7.34 (m, 2H), 7.34-7.24 (m, 1H), 7.27-7.18 (m, 2H), 7.14-7.07 (m, 1H), 6.90 (td, J=7.4 , 1.1 Hz, 1H), 6.85 (s, 1H), 6.65 (t, J=2.4 Hz, 1H), 6.58 (t, J=6.2 Hz, 1H), 5.21 (s, 2H), 4.52 (d, J=6.1 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.79 (s, 2H), 3.72 (s, 3H), 3.70 (s, 1H), 3.61 (s, 2H), 0.96 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (279c).

Compound 279c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino )methyl)benzofuran-5yl)methoxy)phenyl)acetate (279b) (210 mg, 0.381 mmol) in THF/MeOH (3 ml each), using a solution of lithium hydroxide monohydrate (37 mg, 1.523 mmol) in water (2 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-(((5methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (279c) (155 mg, 78% yield ), hydrochloride salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 8.53 (s, 3H), 8.02 (s, 1H), 7.95 (d, J=2, 2 Hz, 1H), 7.88 (ddd, J=5.6, 3.6, 1.7 Hz, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7, 69 (d, J=1.6 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.567.51 (m, 2H), 7.35 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.1, 6.5 Hz, 2H), 7.07 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.936.85(m, 1H), 5.24 (s, 2H), 4.70 (s, 2H), 4.13 (d, J=5.7 Hz, 2H), 3.87 (s, 3H ), 3.58 (s, 2H); MS (ESI+): 524.20 (M+1), (ESI-): 522.2 (M-1).

Scheme-280

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (280c).

Stage-1. Preparation of ethyl 2-(2-((7-iodo-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (280a).

Compound 280a was prepared according to the procedure described in step-1 of scheme-279 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400 mg, 0.862 mmol) in ethanol (10 ml) using 4-methoxyaniline (118 mg, 0.948 mmol) and sodium borohydride (130 mg, 3.45 mmol). This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-((7-iodo-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy) phenyl)acetate

- 364 045626 (280a) (255 mg, 52% yield) in the form of a brown solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.67 (t, J=1.4 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.25-7.16 (m, 1H), 7.05 (dd, J=8.2, 1.1 Hz, 1H), 6.91 (dd, J =7.4, 1.1 Hz, 1H), 6.84 (d, J=1.0 Hz, 1H), 6.74-6.68 (m, 2H), 6.68-6.61 ( m, 2H), 5.90 (t, J=6.2 Hz, 1H), 5.11 (s, 2H), 4.41 (d, J=6.2 Hz, 2H), 4.00 ( k, J=7.1 Hz, 2H), 3.62 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (280b).

Compound 280b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy) phenyl)acetate (280a) (250 mg, 0.438 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (131 mg, 0.700 mmol), bis(triphenylphosphine) palladium(P) chloride ( Pd(PPh ₃ ) ₂ Cl ₂ ) (46.1 mg, 0.066 mmol) and a solution of K ₂ CO ₃ (181 mg, 1.313 mmol) in water (3 ml) heating in an N2 atmosphere at 100 ° C for 6 hours for oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl)-2-( ((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (280b) (155 mg, 64% yield) as a colorless sticky gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 7.74-7.66 (m, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7, 26 (d, J=7.4 Hz, 1H), 7.21 (dd, J=7.5, 1.7 Hz, 1H), 7.12-7.06 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.76 (s, 1H), 6.76-6.68 (m, 2H), 6.71-6.61 (m, 2H ), 5.85 (t, J=6.4 Hz, 1H), 5.20 (s, 2H), 4.41 (d, J=6.3 Hz, 2H), 3.91 (k, J =7.2 Hz, 2H), 3.80 (s, 2H), 3.62 (s, 3H), 3.61 (s, 2H), 0.97 (t, J=7.1 Hz, 3H ); MS (ESI+): 552.2 (M+1), 573.2 (M+Na).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (280c).

Compound 280c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran -5yl)methoxy)phenyl)acetate (280b) (150 mg, 0.272 mmol) in THF/MeOH (3 mL each), using a solution of lithium hydroxide monohydrate (26 mg, 1.09 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-(((4methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (280c) (110 mg, 77% yield), HCl salt , as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.44-8.33 (m, 3H), 8.01 (s, 1H), 7.88 (d, J=7.0 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7, 54 (d, J=1.9 Hz, 2H), 7.24 (d, J=7.4 Hz, 2H), 7.20 (s, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.99-6.76 (m, 5H), 5.23 (s, 2H), 4.54 (s, 2H), 4.15 (d, J=5.8 Hz, 2H ), 3.66 (s, 3H), 3.59 (s, 2H); MS (ESI+): 523.20 (M+1), (ESI-): 521.3 (M-1); analysis calculation for C ₃₂ H ₃₀ N ₂ O ₅ -1.75HCl-2H ₂ O; C, 61.75; N, 5.79; Cl, 9.97; N, 4.50; observable; C, 61.68; N, 5.48; Cl, 9.96; N, 4.62.

Scheme-281

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (281c).

Stage-1. Preparation of ethyl 2-(2-((7-iodo-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (281a).

Compound 281a was prepared according to the procedure described in step-1 of scheme-279 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400 mg, 0.862 mmol) in ethanol (10 ml) using pyridin-3-ylmethanamine (102 mg, 0.948 mmol) and sodium borohydride (130 mg, 3.45 mmol).

- 365 045626

This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-((7-iodo-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5yl)methoxy) phenyl)acetate (281a) (190 mg, 40% yield) as a sticky material;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (dd, J=2.3, 0.9 Hz, 1H), 8.44 (dd, J=4.8, 1.7 Hz, 1H ), 7.78 (dt, J=7.8, 2.0 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz , 1H), 7.34 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 7.29-7.19 (m, 2H), 7.07 (d, J=8 ,1 Hz, 1H), 6.94-6.86 (m, 2H), 5.13 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.86 (s , 2H), 3.79 (s, 2H), 3.61 (s, 2H), 2.93 (s, 1H), 1.09 (t, J=7.1 Hz, 3H); MS (ESI+): 557.1 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (281b).

Compound 281b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (281a) (190 mg, 0.341 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (102 mg, 0.546 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (36 mg, 0.051 mmol) and a solution of K ₂ CO ₃ (142 mg, 1.024 mmol) in water (3 ml) heating in an argon atmosphere at 100 ° C for 6 hours for oil bath. This gave, after work-up and purification by flash column chromatography (40 g silica gel, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl)-2-(( (pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (281b) (124 mg, 68% yield) as a colorless sticky gum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (dd, J=2.3, 0.9 Hz, 1H), 8.44 (dd, J=4.8, 1.7 Hz, 1H), 7.81 (s, 1H), 7.80-7.71 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.52 (d, J=1 .7 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.33 (ddd, J=7.8 , 4.8, 0.9 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.18 (m, 1H), 7.14-7.09 (m, 1H ), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.82 (d, J=0.9 Hz, 1H), 5.22 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.86 (s, 2H), 3.80 (d, J=3.1 Hz, 4H), 3.63 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 536.2 (M+1), 558.2 (M+Na).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (281c).

Compound 281c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl )benzofuran-5yl)methoxy)phenyl)acetate (281b) (120 mg, 0.224 mmol) in THF/MeOH (3 ml each), using a solution of lithium hydroxide monohydrate (22 mg, 0.896 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-(((pyridin3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (281c) (55 mg, 49% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67-10.46 (m, 1H), 9.04 (s, 1H), 8.81 (dd, J=5.4, 1.5 Hz , 1H), 8.58 (d, J=7.6 Hz, 4H), 8.27 (s, 1H), 7.97 (dt, J=7.0, 1.9 Hz, 1H), 7 .85 (dd, J=8.0, 5.3 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H) , 7.61-7.47 (m, 2H), 7.28-7.20 (m, 3H), 7.09 (d, J=8.0 Hz, 1H), 6.90 (td, J =7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.52 (s, 2H), 4.45 (s, 2H), 4.23-4.12 (m, 2H), 3.60 (s, 2H); MS (ESI+): 508.20 (M+1), (ESI-): 506.2 (M-1); analysis calculation for C ₃₁ H ₂₉ N ₃ O ₄ -3HC1-3.5H ₂ O: C, 54.75; N, 5.78; Cl, 15.64; N, 6.18; observable; C, 54.66; N, 5.50; Cl, 15.72; N, 6.09.

Scheme-282

B(OH) ₂

6c l ₂ HCI

I K ₃ RO ₄

282d ^RSuz

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6(trifluoromethyl)phenyl)acetic acid (282f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)benzaldehyde (282b).

Compound 282b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (0.6613 g, 2.281 mmol) using 2-hydroxy-6(trifluoromethyl)benzaldehyde (282a ) (0.434 g, 2.281 mmol), K2CO3 (0.946 g, 6.84 mmol) in DMF (7.5 ml) and stirring at room temperature for 3 hours. This resulted in the following workup:

- 366 045626 and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 20% ethyl acetate in hexanes) of 2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)benzaldehyde (282b) (150 mg,

16% yield) as a pale yellow solid;

¹ H NMR (300 MHz, DMSO-d6) δ 10.24 (d, J=0.7 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.16-8, 05 (m, 2H), 7.81 (d, J=1.5 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 5.23 (s, 2H).

Stage-2. Preparation of 7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-3(trifluoromethyl)phenoxy)methyl)benzofuran (282c).

Compound 282c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)benzaldehyde (282b) (145 mg, 0.363 mmol) in THF (40 ml), using methyl(methylsulfinylmethyl)sulfane (72.2 mg, 0.581 mmol), Triton-B (40% methanol solution) (0.083 ml, 0.182 mmol) and reflux for 2 hours. This resulted in treatment and purification by flash column chromatography (silica gel, 12 g, eluted with 0-100% EtOAc in hexane) 7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-3 (trifluoromethyl)phenoxy)methyl)benzofuran (282c) (105 mg, 57% yield);

¹ H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=7.8 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.84-7, 75 (m, 2H), 7.71 (d, J=1.5 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 5.76 (s, 1H), 4.93 (d, J=1.7 Hz, 2H), 2.79 (s, 3H), 2.37 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -59.48.

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate (282d).

Compound 282d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-3-(trifluoromethyl)phenoxy)methyl)benzofuran (282c) (100 mg, 0.198 mmol) in ethanol (10 mL) using HCl (4 M in 1,4-dioxane, 0.247 mL, 0.989 mmol) and reflux for 2 h. This resulted in treatment and purification by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% ethyl acetate and hexanes) ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl )acetate (282d) (37 mg, 41% yield);

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (d, J=2.2 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.72-7 .61 (m, 3H), 7.38 (t, J=7.7 Hz, 1H), 7.18 (d, J=2.2 Hz, 1H), 4.98 (s, 2H), 4 .04 (k, J=7.1 Hz, 2H), 3.86 (s, 2H), 1.10 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -59.01.

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6(trifluoromethyl)phenyl)acetate (282e).

Compound 282e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate (282d) ((35 mg, 0.077 mmol) in dioxane (2 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (17.33 mg, 0.115 mmol), tripotassium phosphate (1.3 M, 0.177 ml, 0.230 mmol), tricyclohexylphosphine ( 6.44 mg, 0.023 mmol) and Pd ₂ (dba) ₃ (7 mg, 7.65 µmol) under nitrogen when heated at 125°C for 45 min in a microwave oven. flash column chromatography [silica gel (4 g), eluted with 0 to 100% DMA80 in DCM] ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6- (trifluoromethyl)phenyl)acetate (282e) (22 mg, 59% yield);

^1H NMR (300 MHz, chloroform-d) δ 7.90-7.81 (m, 1H), 7.78 (dt, J=7.7, 1.5 Hz, 1H), 7.72 (dd , J=6.6, 2.0 Hz, 2H), 7.61 (d, J=4.1 Hz, 1H), 7.62-7.51 (m, 2H), 7.55-7, 43 (m, 1H), 7.43-7.30 (m, 1H), 7.25 (td, J=7.7, 0.9 Hz, 1H), 6.83 (dd, J=15, 6, 2.2 Hz, 1H), 5.07 (s, 2H), 4.14 (k, J=7.1 Hz, 2H), 4.00 (s, 2H), 3.77 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, CDCI3) δ -60.20. MS (ESI+): 484.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6(trifluoromethyl)phenyl)acetic acid (282f).

Compound 282f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl )acetate (282e) (20 mg, 0.041 mmol) in MeOH (1 ml), THF (1 ml), using a solution of lithium hydroxide (4 mg, 0.165 mmol) in water (0.2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (15 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetic acid (282f) (11 mg, 58% yield), hydrochloride salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 8.54 (s, 3H), 8.14 (d, J=2.2 Hz, 1H), 8.00 -7.98 (m, 1H), 7.96-7.85 (m, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.74-7.57 (m, 5H ), 7.37 (t, J=7.7 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 5.05 (s, 2H), 4.14 (s, 2H ), 3.83 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.91; MS (ESI+): 456.1 (M+1), (ESI): 454.1 (M-1).

- 367 045626

Scheme-283

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (283c).

Stage-1. Preparation of ethyl 2-(2-((2-((benzylamino)methyl)-7-iodobenzofuran-5yl)methoxy)phenyl)acetate (283a).

Compound 283a was prepared according to the procedure described in step-1 of scheme-279 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400 mg, 0.862 mmol) in DCM (10 ml) using benzylamine (0.104 ml, 0.948 mmol) and sodium borohydride (65 mg, 1.723 mmol) in ethanol (2 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate and hexanes), ethyl 2-(2-((2-((benzylamino)methyl)-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (283a) (334 mg, 70% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.39-7, 27 (m, 4H), 7.277.18 (m, 3H), 7.07 (d, J=8.1 Hz, 1H), 6.95-6.87 (m, 2H), 5.13 (s , 2H), 4.03 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.77 (s, 2H), 3.61 (s, 2H), 1.09 (t, J=7.1 Hz, 3H); MS (ESI+): 556.1 (M+1), 578.00 M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (283b).

Compound 283b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-((benzylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (283a) (322 mg, 0.580 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (174 mg, 0.928 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (61.0 mg, 0.087 mmol) and a solution of K2CO3 (240 mg, 1.739 mmol) in water (3 ml) heating under argon at 100°C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)2 -((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (283b) (210 mg, 68% yield) as a colorless sticky gum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (d, J=1.8 Hz, 1H), 7.74 (dt, J=7.5, 1.6 Hz, 1H), 7 .61 (d, J=1.6 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.41 -7.27 (m, 6H), 7.27-7.18 (m, 3H), 7.11 (dd, J=8.3, 1.2 Hz, 1H), 6.91 (td, J =7.4, 1.1 Hz, 1H), 6.81 (s, 1H), 5.22 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 3.63 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 535.3 (M+1), (ESI-): 557.2 (M+Na).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (283c).

Compound 283c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (283b) (200 mg, 0.374 mmol) in THF/MeOH (10:4 ml each), using a solution of lithium hydroxide monohydrate (36 mg, 1.496 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran5-yl)methoxy)phenyl)acetic acid (283c) (145 mg, 77% yield), hydrochloride salt, as a white solid substances;

^1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.07 (s, 2H), 8.51 (s, 3H), 8.20 (s, 1H), 7. 99 (d, J=7.4 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.65- 7.57 (m, 3H), 7.57-7.51 (m, 1H), 7.42 (dd, J=5.0, 1.9 Hz, 3H), 7.24 (s, 1H) , 7.21 (s, 1H), 7.20 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.94-6.86 (m, 1H), 5, 27 (s, 2H), 4.42 (s, 2H), 4.26 (s, 2H), 4.17 (s, 2H), 3.60 (s, 2H); MS (ESI+): 507.20 (M+1), (ESI-): 505.30 (M-1); analysis calculation for Сз ₂ Нз <№О4-2НС1-2Н ₂ О: С, 62.44; N, 5.90; Cl, 11.52; N, 4.55; observed: C, 62.61; N, 5.70;

- 368 045626

Cl, 11.25; N, 4.60.

Scheme-284

284d

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (284f).

Stage-1. Preparation of methyl 2-((benzyloxy)methyl)-7-iodobenzofuran-5-carboxylate (284b).

Compound 284b was prepared according to the procedure described in step-1 of scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (2 g, 4.95 mmol) in pyridine (8 ml) using (( prop-2-yn-1yloxy)methyl)benzene (284a) (0.724 mmol, 4.95 mmol), copper(D) oxide (0.354 g, 2.476 mmol) when heated at 50°C for 18 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] methyl 2-((benzyloxy)methyl)-7-iodobenzofuran-5-carboxylate ( 284b) (1.481 g, 71% yield) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 8.28 (d, J=1.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.41-7, 35 (m, 4H), 7.357.26 (m, 1H), 7.21 (d, J=0.7 Hz, 1H), 4.71 (d, J=0.7 Hz, 2H), 4, 61 (s, 2H), 3.87 (s, 3H).

Stage-2. Preparation of (2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methanol (284c).

Compound 284c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 2-((benzyloxy)methyl)-7-iodobenzofuran-5-carboxylate (284b) (1 g, 2.368 mmol) in THF (20 ml ), using LiBH ₄ (2.072 ml, 8.29 mmol, 2 M solution in THF) and MeOH (0.335 ml, 8.29 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane] (2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methanol (284c) (900 mg, 96% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d6) δ 7.69-7.62 (m, 1H), 7.55 (dd, J=1.5, 0.8 Hz, 1H), 7.42-7, 25 (m, 5H), 7.06 (s, 1H), 5.28 (t, J=5.8 Hz, 1H), 4.68-4.65 (m, 2H), 4.59 (s , 2H), 4.54 (dt, J=5.9, 0.7 Hz, 2H).

Stage-3. Preparation of ethyl 2-(2-((2-((benzyloxy)methyl)-7-iodobenzofuran-5yl)methoxy)phenyl)acetate (284d).

Compound 284d was prepared according to the procedure described in step-2 of Scheme-23 from (2((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methanol (284c) (600 mg, 1.522 mmol) in DCM (30 ml), using triphenylphosphine (479 mg, 1.826 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (274 mg, 1.522 mmol) and bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 754 mg, 2.055 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((2-((benzyloxy)methyl)-7iodobenzofuran -5-yl)methoxy)phenyl)acetate (284d) (358 mg, 42% yield) as a clear syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.75 (d, J=1.5 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.43-7, 17 (m, 7H), 7.147.02 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.15 (s, 2H), 4.69 (s , 2H), 4.60 (s, 2H), 4.03 (k, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.09 (t, J=7.1 Hz , 3H); MS (ESI+): 579.0 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5yl)methoxy)phenyl)acetate (284e).

Compound 284e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (284d) (350 mg, 0.629 mmol) in

- 369 045626 dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (118 mg, 0.629 mmol), solution of K ₂ CO ₃ (261 mg, 1.887 mmol) in water (2 ml), bis( triphenylphosphine)palladium(P) chloride (66 mg, 0.094 mmol) by heating at 100°C for 12 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 90%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (284e) (185 mg, 55% yield) as a sticky material;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (d, J=1.7 Hz, 1H), 7.72 (dt, J=7.6, 1.6 Hz, 1H), 7 .66 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.43 -7.38 (m, 1H), 7.40-7.31 (m, 4H), 7.33-7.27 (m, 1H), 7.27-7.20 (m, 2H), 7 ,12 (dd, J=8.3, 1.1 Hz, 1H), 7.01 (s, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5, 24 (s, 2H), 4.69 (s, 2H), 4.60 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.63 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 536.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (284f).

Compound 284f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (284e) (180 mg, 0.336 mmol) in MeOH/THF (2/10 ml), using a solution of lithium hydroxide monohydrate (24 mg, 1.008 mmol) in water (2.0 ml). This resulted in, after workup and purification by reverse phase column chromatography, [EZ-PREP, C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (284f ) (29 mg, 17% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.74-8.02 (m, 3H), 7.94 (dd, J=7.4, 1.5 Hz, 2H), 7.74 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.56-7.51 ( m, 1H), 7.36 (d, J=4.4 Hz, 4H), 7.33-7.25 (m, 1H), 7.24 (s, 1H), 7.21 (s, 1H ), 7.09 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.70 (s, 2H), 4.60 (s, 2H), 4.14 (s, 2H), 3.60 (s, 2H); MS (ESI+) 508.20 (M+1), (ESI-) 506.20 (M-1); Analysis calculation for C32H29NO5-1.2HCl-1.5H2O: C, C, 66.45; N, 5.79; Cl, 7.36; N, 2.42; observed, C, 66.80; N, 5.76; Cl, 7.00; N, 2.46.

Scheme-285

Preparation of 2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetic acid (285e).

Stage-1. Preparation of (8-bromoquinolin-6-yl)methanol (285b).

Compound 285b was prepared according to the procedure described in step-1 of Scheme-23 from 8-bromoquinoline-6-carboxylic acid (285a) (1 g, 3.97 mmol; CAS No. 791632-21-8) using Nmethylmorpholine (0.523 ml , 4.76 mmol) in THF (20 ml), isobutyl chloroformate (0.625 ml, 4.76 mmol) and NaBH ₄ (0.450 g, 11.90 mmol) in water (1 ml). This resulted in (8bromoquinolin-6-yl)methanol (285b) (660 mg, 70% yield) as a white solid upon treatment;

1H NMR (300 MHz, DMSO-d6) δ 8.97 (dd, J=4.2, 1.7 Hz, 1H), 8.42 (dd, J=8.3, 1.7 Hz, 1H) , 8.09 (d, J=1.8 Hz, 1H), 7.93 (k, J=1.2 Hz, 1H), 7.62 (dd, J=8.3, 4.2 Hz, 1H), 5.52 (t, J=5.8 Hz, 1H), 4.69 (dt, J=5.8, 0.7 Hz, 2H); MS (ESI+): 240.0; 238.0 (M, M+2).

Stage-2. Preparation of ethyl 2-(2-((8-bromoquinolin-6-yl)methoxy)phenyl)acetate (285c).

Compound 285c was prepared according to the procedure described in step-2 of Scheme-23 from (8bromoquinolin-6-yl)methanol (285b) (650 mg, 2.73 mmol) in DCM (35 ml) using triphenylphosphine (859 mg , 3.28 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (541 mg, 3.0 mmol) and bis(4-chlorobenzyl)diazene 1,2-dicarboxylate (DCAD, 1353 mg, 3.69 mmol ) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((8-bromoquinolin-6-yl)methoxy) phenyl) acetate (285c) (690 mg, 63% yield) as a clear syrup;

- 370 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.41 (dd, J=8.4, 1.7 Hz, 1H ), 8.17 (d, J=1.8

Hz, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.66 (dd, J=8.3, 4.2 Hz, 1H), 7.29-7.21 (m , 2H), 7.14-7.05 (m, 1H), 6.93 (td,

J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.68 (s, 2H), 1, 06 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetate (285d).

Compound 285d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((8-bromoquinolin-6-yl)methoxy)phenyl)acetate (285c) (680 mg, 1.699 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (509 mg, 2.72 mmol), solution of K ₂ CO ₃ (704 mg, 5.10 mmol) in water (3 ml), bis( triphenylphosphine)palladium(P) chloride (179 mg, 0.255 mmol) by heating at 100°C for 8 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in 0% to 50% DCM] ethyl 2-(2-((8-(3-(aminomethyl)phenyl) quinolin-6-yl)methoxy)phenyl)acetate (285d) (290 mg, 40% yield) as a colorless syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.91 (dd, J=4.1, 1.7 Hz, 1H), 8.53-8.42 (m, 1H), 8.35 (s , 3H), 8.10 (s, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J=4.6 Hz , 1H), 7.62 (dd, J=8.3, 4.2 Hz, 1H), 7.54 (d, J=4.7 Hz, 2H), 7.24 (d, J=7, 1 Hz, 2H), 7.11 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.39 (s, 2H), 4.21 -4.06 (m, 2H), 3.64 (s, 2H); MS (ESI+): 427 (m+1).

Stage-4. Preparation of 2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetic acid (285e).

Compound 285e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetate (285d) ( 280 mg, 0.656 mmol) in MeOH/THF (3/10 ml), using a solution of lithium hydroxide monohydrate (63 mg, 2.63 mmol) in water (3 ml). This resulted in, after workup and purification by reverse phase column chromatography, [EZ-PREP, C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetic acid (285e) (5 mg, 2% yield), hydrochloride salt, in the form of a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.91 (dd, J=4.2, 1.7 Hz, 1H), 8.45 (dd, J=8.4, 1.8 Hz, 1H) , 8.35 (s, 3H), 8.10 (d, J=1.9 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.78 (s, 1H) , 7.75-7.70 (m, 1H), 7.62 (dd, J=8.3, 4.2 Hz, 1H), 7.57-7.50 (m, 2H), 7.25 (dg, J=7.6, 1.8 Hz, 2H), 7.15-7.07 (m, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.39 ( s, 2H), 4.12 (k, J=6.0, 5.5 Hz, 2H), 3.64 (s, 2H); MS (ESI+): 399.10 (M+1), (ESI-): 397.20 (M-1).

Scheme-286

He

Preparation of 2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1Ninden-5-yl)acetic acid (286g).

Stage-1. Preparation of 2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)-1-morpholinoethanethione (286b).

Compound 286b was prepared according to the procedure described in step-1 of scheme-265 from 1-(4hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one (286a) ( 1 g, 5.26 mmol; CAS No. 175136-13-7) in N-methyl-2-n-pyrrolidinone (3 ml), using powdered sulfur (0.337 g, 10.51 mmol), morpholine (0.907 ml, 10.51 mmol) and heating at 130°C for 10 hours. This gave, after work-up and purification by flash column chromatography (silica gel), 2-(4-hydroxy-7-methyl-2,3dihydro-1H-indene-5 -yl)-1-morpholinoethanethione (286b) (1.15 g, 75% yield) as a tan solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.53 (s, 1H), 6.76 (s, 1H), 4.28-4.18 (m, 2H), 4.10 (s, 2H ), 3.74-3.59 (m, 4H), 3.43 (dd, J=5.7, 4.0 Hz, 2H), 2.79 (t, J=7.4 Hz, 2H) , 2.72 (t, J=7.4 Hz, 2H), 2.11-2.05 (m, 3H), 2.03-1.91 (m, 2H); MS (ESI+): 292.1 (M+1), 314.1 (M+Na), (ESI-): 290.1 (M-1).

Stage-2. Preparation of 2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetic acid (286c).

Compound 286c was prepared according to the procedure described in step-2 of scheme-265 from 2-(4hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)-1-morpholinoethanethione (286b) (1, 14 g, 3.91 mmol) in ethanol (20 ml) and water (5 ml), using sodium hydroxide (0.806 g, 20.15 mmol) and refluxing for 12 hours. This resulted in obtaining after treatment 2-(4-hydroxy-7-methyl-2,3dihydro-1H-inden-5-yl)acetic acid (286c) (704 mg, 87% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.33 (s, 1H), 6.67 (s, 1H), 3.41 (s, 2H), 2. 74 (dt, J=18.2, 7.4 Hz, 4H), 2.08 (s, 3H), 1.97 (p, J=7.5 Hz, 2H); MS (ESI+): 207.1 (M+1), 229.1 (M+Na), (ESI-): 205.1 (M1).

Stage-3. Preparation of ethyl 2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate (286d).

Compound 286d was prepared according to the procedure described in step-3 of scheme-265 from 2-(4hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetic acid (286c) (700 mg, 3 .39 mmol) in ethanol (20 ml), using sulfuric acid (0.208 ml, 3.90 mmol) and reflux for 4 hours. This resulted in the following work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes) ethyl 2-(4-hydroxy-7-methyl-2,3-dihydro1H-inden-5-yl) acetate (286d) (685 mg, 86% yield) as a white solid;

% NMR (300 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 6.68 (d, J=1.1 Hz, 1H), 4.04 (k, J=7.1 Hz, 2H), 3.49 (s, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.08 (d, J=0.7 Hz, 3H), 2.03-1.91 (m, 2H), 1.17 (t, J=7.1 Hz, 3H); MS (ESI+): 234.1 (M+1), 257.1 (M+Na).

Stage-4. Preparation of ethyl 2-(4-((7-bromobenzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden5-yl)acetate (286e).

Compound 286e was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (842 mg, 2.90 mmol) using ethyl 2-(4-hydroxy-7- methyl 2,3dihydro-1H-inden-5-yl)acetate (286d) (680 mg, 2.90 mmol), K2CO3 (1203 mg, 8.71 mmol) in DMF (5 ml) and stir at room temperature in for 12 hours. This gave, after work-up and purification by flash column chromatography (SiO ₂ , 40 g, eluted with EtOAc in hexane), ethyl 2-(4-((7-bromobenzofuran-5-yl)methoxy)-7 -methyl-2,3-dihydro-1H-inden-5-yl)acetate (286e) (700 mg, 54% yield) as a white foam;

% NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 6.83 (s, 1H), 4.93 (s, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H) , 2.21-2.11 (m, 3H), 2.09-1.94 (m, 2H), 1.09 (t, J=7.1 Hz, 3H)); MS (ESI+): 443.1, 445.1 (M, M+2), 465.0, 467.0 (M+Na).

Stage-5. Preparation of ethyl 2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3dihydro-1H-inden-5 -yl)acetate (286f).

Compound 286f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-((7-bromobenzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden- 5-yl)acetate (286e) (690 mg, 1.556 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (467 mg, 2.490 mmol), bis(triphenylphosphine) palladium (11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (164 mg, 0.233 mmol), potassium carbonate (645 mg, 4.67 mmol) in water (3 ml) heating in an argon atmosphere at 100 ° C for 8 hours in oil bath. This resulted, after workup and purification by flash column chromatography (silica gel, 40 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(4-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate (286f) (590 mg, 81% yield) as colorless syrup;

% NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.69 (tt, J=3.3, 1.6 Hz, 2H), 7.55 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.43- 7.36 (m, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.84 (s, 1H), 5.00 (s, 2H), 3.94 (k, J =7.1 Hz, 2H), 3.82 (s, 2H), 3.56 (s, 2H), 3.00 (t, J=7.4 Hz, 2H), 2.78 (t, J =7.4 Hz, 2H), 2.16 (s, 3H), 2.09-1.97 (m, 2H), 1.03 (t, J=7.1 Hz, 3H); MS (ESI+): 470.2 (M+1).

Stage-6. Preparation of 2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3dihydro-1H-inden-5-yl)acetic acid (286g).

Compound 286g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2, 3-dihydro-1H-inden-5-yl)acetate (286f) (583 mg, 1.242 mmol) in MeOH (3 ml), THF (15 ml), using lithium hydroxide monohydrate (119 mg, 4.97 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(4-((7- (3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5yl)acetic acid (286g) (320 mg, 58% yield), hydrochloride salt, as a white solid;

% NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.92 (dt, J =7.4, 1.7 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.60 (t , J=7.6 Hz, 1H), 7.55 (dt, J=7.7, 1.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.85 (s, 1H), 5.00 (s, 2H), 4.14 (s, 2H), 3.51 (s, 2H), 2.99 (t, J=7.4 Hz, 2H), 2 .77 (t, J=7.4 Hz, 2H), 2.16 (s, 3H), 2.08-1.95 (m, 2H); MS (ESI+): 442.02 (M+1), (ESI-): 440.2 (M-1); analysis calculation for C2 ₈ H27NO4-HCl-075H2O: C, 68.43; N, 6.05; Cl, 7.21; N, 2.85; observed C, 68.54; N, 6.11; Cl, 7.21; N, 2.84.

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Scheme-287

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (287c).

Stage-1. Preparation of ethyl 2-(2-((2-((benzyl(methyl)amino)methyl)-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 287a).

Compound 287a was prepared according to the procedure described in step-1 of scheme-279 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5yl )methoxy)phenyl)acetate (103a) (500 mg, 0.920 mmol) in THF (20 ml), using N-methyl-1phenylmethanamine (139 mg, 1.150 mmol) and sodium borohydride (87 mg, 2.299 mmol) in ethanol (4 ml). This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-((2-((benzyl(methyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (287a) (330 mg, 55% yield) as a light brown syrup; MS (ESI+): 649.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (287b).

Compound 287b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-((benzyl(methyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (287a) (330 mg, 0.509 mmol) in DCM (10 ml) using TFA (0.392 ml, 5.09 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (287b) (337 mg, 100% yield) as brown syrup. MS (ESI+): 549.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (287c).

Compound 287c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran- 5-yl)methoxy)phenyl)acetate (287b) (337 mg, 0.509 mmol) in THF/MeOH (10:2 ml each), using a solution of lithium hydroxide monohydrate (49 mg, 2.034 mmol) in water (2 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (287c) (174 mg, 66% yield), hydrochloride salt , as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.27 (s, 1H), 11.75 (s, 1H), 8.66 (s, 3H), 8.24 (s, 1H), 7. 98 (ddd, J=5.7, 3.2, 1.8 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz , 1H), 7.70 (d, J=5.4 Hz, 2H), 7.61-7.53 (m, 2H), 7.45 (g, J=1.9 Hz, 3H), 7 .34 (s, 1H), 7.24 (t, J=7.4 Hz, 2H), 7.13-7.07 (m, 1H), 6.90 (td, J=7.4, 1 ,1 Hz, 1H), 5.28 (s, 2H), 4.59 (s, 2H), 4.54-4.29 (m, 2H), 4.16 (d, J=5.7 Hz , 2H), 3.60 (s, 2H), 2.69 (s, 3H); MS (ESI+): 521.20 (M+1), (ESI-): 519.20 (M-1); analysis calculation for C ₃₃ H ₃ 2N2O4-2HCl-2H2O: C, 62.96; N, 6.08; Cl, 11.26; N, 4.45; observable; C, 62.59; N, 5.74; Cl, 11.27; N, 4.31.

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Scheme-288

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(trifluoromethyl)phenyl)acetic acid (288f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)benzaldehyde (288b).

Compound 288b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.525 g, 5.26 mmol) using 2-hydroxy-4(trifluoromethyl)benzaldehyde (288a ) (1 g, 5.26 mmol), K ₂ CO ₃ (2.181 g, 15.78 mmol) in DMF (5 ml) and stirring at room temperature for 12 hours. This resulted in, after work-up and flash purification -column chromatography (silica gel, 40 g, eluted with ethyl acetate in hexanes) of 2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)benzaldehyde (288b) (2.1 g, 100% yield) in as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.44 (d, J=0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.90 (dt, J=8.2, 1.1 Hz, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.71 ( d, J=1.5 Hz, 1H), 7.49-7.43 (m, 1H), 7.14 (d, J=2.2 Hz, 1H), 5.48 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -61.74 (d, J=4.8 Hz).

Stage-2. Preparation of 7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5(trifluoromethyl)phenoxy)methyl)benzofuran (288c).

Compound 288c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)benzaldehyde (288b) (2 g, 5.01 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane (0.996 g, 8.02 mmol), Triton-B (40% methanol solution, 1.139 mL, 2.505 mmol) and reflux for 12 h. This resulted in after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with EtOAc in hexane) 7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5(trifluoromethyl) phenoxy)methyl)benzofuran (288c) (1.35 g, 53% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.84-7.75 (m, 2H), 7.70 (d, J=1 .5 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 7.40-7.26 (m, 1H), 7.13 (d, J=2.2 Hz, 1H ), 6.75 (s, 1H), 5.33 (s, 2H), 2.41 (s, 3H), 2.32 (s, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate (288d).

Compound 288d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-(trifluoromethyl)phenoxy)methyl)benzofuran (288c) (1.34 g, 2.65 mmol) in ethanol (50 mL) using HCl (4 M in 1,4-dioxane, 1.326 mL, 5.30 mmol) and reflux for 15 h This gave, after work-up and purification by flash column chromatography (silica gel 40 g, eluted with ethyl acetate and hexanes), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl )acetate (288d) (961 mg, 79% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.41 (d, J=1.7 Hz, 1H), 7.35-7.25 ( m, 1H), 7.13 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.72 ( s, 2H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.77; MS (ESI+): 480.9 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(trifluoromethyl)phenyl)acetate (288e).

Compound 288e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate (288d) (0. 95 g, 2.078 mmol) in dioxane (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.623 g, 3.32 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.219 g, 0.312 mmol), potassium carbonate (0.861 g, 6.23 mmol) in water (3 ml) heating under argon at 100 ° C for 12 hours in oil

- 374 045626 bathhouse. This resulted, after workup and purification by flash column chromatography (silica gel, 40 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate (288e) (910 mg, 91% yield) as a colorless syrup; MS (ESI+): 484-2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(trifluoromethyl)phenyl)acetic acid (288f).

Compound 288f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl )acetate (288e) (910 mg, 1.882 mmol) in MeOH (2 ml), THF (10 ml), using a solution of lithium hydroxide (180 mg, 7.53 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetic acid (288f) (450 mg, 53% yield), hydrochloride salt, as a yellowish-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.96-7.87 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7, 64-7.54 (m, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.37 (s, 2H), 4.13 (s, 2H), 3.70 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.72; MS (ESI+): 456.10 (M+1); analysis calculation for MF: C ₂₅ H ₂₀ F ₃ NO ₄ -HCl-0.75H ₂ O; C, 59.41; N, 4.49; Cl, 7.01; N, 2.77; observable; C, 59.20; N, 4.54; Cl, 6.94; N, 2.75.

Scheme-289

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetic acid (289d).

Stage-1. Preparation of 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2oxoethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (289a).

To a solution of ethyl 2-(2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-2-formylbenzofuran-5yl)methoxy)phenyl)acetate (103 a) (1.5 g, 2.76 mmol) in acetonitrile (10 ml) and t-BuOH (60 ml) added water (5 ml), sodium dihydrogen phosphate (0.662 g, 5.52 mmol) and 2-methyl-2-butene (2.92 ml, 27. 6 mmol). The reaction mixture was cooled in an ice water bath and sodium chlorite (1.560 g, 13.80 mmol) in water (5 ml) was added and stirred in the cold for 1 hour. The reaction mixture was diluted with brine (50 ml) and ethyl acetate (200 ml ). The suspension was filtered through celite and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x150 ml). The combined organic layers were washed with brine (2 x 60 ml), dried, filtered and concentrated in vacuo to give 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2- oxoethyl)phenoxy)methyl)benzofuran-2carboxylic acid (289a) (650 mg, 42% yield) as a white solid; MS (ESI+): 582.2 (M+Na), (ESI-): 558.2 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate (289b).

Compound 288b was prepared according to the procedure described in step-4 of scheme-1 from 7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl) phenoxy)methyl)benzofuran-2carboxylic acid (289a) (200 mg, 0.357 mmol) and methenamine (14 mg, 0.447 mmol) in DMF (3 ml), using HATU (204 mg, 0.536 mmol) and DIPEA (0.249 ml, 1.430 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% EtOAc/MeOH=9:1 in hexane), ethyl 2-( 2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetate (289b) (148 mg, 72% yield) as white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.95 (s, 2H), 7.86-7.77 (m, 3H), 7.69 (d, J=1.7 Hz, 1H), 7.58 (s, 1H), 7.48 (dt, J=14.7, 6.9 Hz, 2H), 7.39-7.19 (m, 3H), 7.12 (d, J= 8.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.83 (d, J=4.6 Hz, 3H), 1.37 (d, J=2.1 Hz, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 595.3 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-375 045626 yl)methoxy)phenyl)acetate (289c).

Compound 289c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methylcarbamoyl)benzofuran -5yl)methoxy)phenyl)acetate (289b) (148 mg, 0.258 mmol) in DCM (10 ml) using TFA (0.199 ml, 2.58 mmol). This resulted in ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate (289c) (152 mg) as brown syrup; MS (ESI+): 473.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetic acid (289d).

Compound 289d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl )acetate (289c) (152 mg, 0.259 mmol) in THF/MeOH (10:2 ml each), using a solution of lithium hydroxide monohydrate (25 mg, 1.037 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetic acid (289d) (52 mg, 45% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.39 (s, 3H), 8.07 ( s, 1H), 7.98 (dd, J=7.4, 1.7 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.77 (d, J=1 .6 Hz, 1H), 7.68-7.52 (m, 3H), 7.23 (d, J=7.5 Hz, 2H), 7.10 (d, J=8.1 Hz, 1H ), 6.97-6.86 (m, 1H), 5.28 (s, 2H), 4.17 (d, J=5.7 Hz, 2H), 3.60 (s, 2H), 2 .83 (d, J=4.6 Hz, 3H); MS (ESI+): 445.20 (M+1), (ESI-): 443.10 (M-1).

Scheme-290

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetic acid (290c).

Stage-1. Preparation of ethyl 2-(2-((2-(benzylcarbamoyl)-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (290a).

Compound 290a was prepared according to the procedure described in step-4 of scheme-1 from 7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl) phenoxy)methyl)benzofuran-2carboxylic acid (289a) (200 mg, 0.357 mmol) and phenylmethanamine (47.9 mg, 0.447 mmol) in DMF (3 ml), using HATU (204 mg, 0.536 mmol) and DIPEA (0.249 ml , 1.430 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% EtOAc/MeOH=9:1 in hexane) ethyl 2-(2-((2-(benzylcarbamoyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (290a) (520 mg) as white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (t, J=6.1 Hz, 1H), 7.95 (s, 3H), 7.86-7.76 (m, 3H), 7.69 (d, J=1.7 Hz, 1H), 7.67 (s, 1H), 7.56-7.39 (m, 1H), 7.37-7.20 (m, 6H) , 7.12 (d, J=8.1 Hz, 1H), 6.97-6.87 (m, 1H), 5.25 (s, 2H), 4.52 (d, J=6.1 Hz, 2H), 4.24 (d, J=6.1 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.38 ( d, J=3.6 Hz, 9H), 0.97 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetate (290b).

Compound 290b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-(benzylcarbamoyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran -5yl)methoxy)phenyl)acetate (290a) (520 g, 802 mmol) in DCM (10 ml) using TFA (618 ml, 8.015 mmol). This resulted in ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate (290b) (531 g) as brown syrup; MS (ESI+): 549.3 (M+1).

- 376 045626

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetic acid (290c).

Compound 290c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl )acetate (290b) (531 mg, 0.801 mmol) in THF/MeOH (10:3 ml each), using a solution of lithium hydroxide monohydrate (77 mg, 3.21 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 100 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5yl)methoxy)phenyl)acetic acid (290c) (110 mg, 26% yield), hydrochloride salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.23 (t, J=6.2 Hz, 1H), 8.36 (s, 3H), 8.08 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.69 (s , 1H), 7.61 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.387.30 (m, 4H), 7.29-7 .18 (m, 3H), 7.10 (d, J=8.0 Hz, 1H), 6.96-6.87 (m, 1H), 5.29 (s, 2H), 4.52 ( d, J=6.1 Hz, 2H), 4.16 (s, 2H), 3.60 (s, 2H); MS (ESI+): 521.20 (M+1), (ESI-): 519.20 (M-1).

Scheme-291

He

Preparation of 2-(4-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetic acid (291g).

Stage-1. Preparation of 2-(4-hydroxybenzofuran-5-yl)-1-morpholinoethanethione (291b).

Compound 291b was prepared according to the procedure described in step-1 of scheme-265 from 1-(4hydroxybenzofuran-5-yl)ethanone (291a) [(1 g, 5.68 mmol; CAS No. 69722-46-9; prepared following the procedure described by Satyavani, Susarla R. et al.; in Medicinal Chemistry Research, 24(2), 842-850; 2015)] in N-methyl-2-pyrrolidinone (3 ml), using powdered sulfur (0.364 g, 11.35 mmol), morpholine (0.979 ml, 11.35 mmol) and heating at 130°C for 10 hours. This resulted in 2-(4-hydroxybenzofuran-5-yl)-1-morpholineethanethione after treatment (291b) (1.85 g) as a tan solid; MS (ESI+): 278.0 (M+1), 276.1 (M-1).

Stage-2. Preparation of 2-(4-hydroxybenzofuran-5-yl)acetic acid (291c).

Compound 291c was prepared according to the procedure described in step-2 of scheme-265 from 2-(4hydroxybenzofuran-5-yl)-1-morpholinoethanethione (291b) (1.85 g, 6.67 mmol) in ethanol (50 ml ) and water (10 ml), using sodium hydroxide (1.467 g, 36.7 mmol) and reflux for 10 hours. This resulted in the preparation after treatment of 2-(4-hydroxybenzofuran-5-yl)acetic acid ( 291c) (1.2 g, 94% yield) as a white solid; MS (ESI-): 190.1 (M-1).

Stage-3. Preparation of ethyl 2-(4-hydroxybenzofuran-5-yl)acetate (291 d).

Compound 291d was prepared according to the procedure described in step-3 of scheme-265 from 2-(4hydroxybenzofuran-5-yl)acetic acid (291c) (1.18 g, 6.14 mmol) in ethanol (25 ml) using sulfuric acid (0.393 ml, 7.37 mmol) and reflux for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes), ethyl 2-( 4-hydroxybenzofuran-5-yl)acetate (291d) (285 mg, 21% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.77 (s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.08-7.03 (m, 2H), 6.99 (dd, J=8.3, 0.9 Hz, 1H), 4.06 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.18 (t , J=7.1 Hz, 3H); MS (ESI+): 243.0 (M+Na).

Stage-4. Preparation of ethyl 2-(4-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291 e).

Compound 291e was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (424 mg, 1.462 mmol) using ethyl 2-(4-hydroxybenzofuran5-yl)acetate ( 291d) (280 mg, 1.271 mmol), K2CO3 (527 mg, 3.81 mmol) in DMF (5 ml) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes) ethyl 2(4-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291e) (407 mg, 75% yield) as a white solid substances;

- 377 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H),

7.69 (d, J=1.5 Hz, 1H), 7.31-7.24 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.13 (d , J=2.2 Hz, 1H), 5.37 (s, 2H), 3.98 (k,

J=7.1 Hz, 2H), 3.68 (s, 2H), 1.07 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5yl)acetate (291f).

Compound 291f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291e) (395 mg, 0.920 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (276 mg, 1.472 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (97 mg, 0.138 mmol), potassium carbonate (382 mg, 2.76 mmol) in water (3 ml) heating under argon at 100°C for 12 hours in an oil bath. This resulted, after workup and purification by flash column chromatography (silica gel, 40 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(4-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291f) (322 mg, 77% yield) as colorless syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.81 (d, J =1.9 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.72 (dt, J=7.6, 1.6 Hz, 1H), 7.63 (d , J=1.7 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.40 (dt, J=7.7, 1.5 Hz, 1H), 7.29 (d, J=1.7 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.06 (d , J=2.2 Hz, 1H), 5.45 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.69 (s , 2H), 3.32 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 456.2 (M+1), 478.1 (M+Na).

Stage-6. Preparation of 2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5yl)acetic acid (291g).

Compound 291g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291f) (315 mg, 0.692 mmol) in MeOH (3 mL), THF (15 mL), using lithium hydroxide monohydrate (66 mg, 2.77 mmol) in water (3 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(4-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetic acid (291g) (124 mg, 42% yield), hydrochloride salt, white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.42 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.01 (d , J=1.9 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.93 (dt, J=7.3, 1.8 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.657.53 (m, 2H), 7.31-7.24 (m, 2H) , 7.19 (d, J=8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 5.42 (s, 2H), 4.14 (k, J= 5.8 Hz, 2H), 3.65 (s, 2H); MS (ESI+): 428.20 (M+1), (ESI-): 426.10 (M-1); analysis calculation for C26H21NO5-HCl-2H ₂ O: C, 62.46; N, 5.24; Cl, 7.09; N, 2.80; observed: C, 62.60; N, 5.00; Cl, 7.38; N, 2.81.

Scheme-292

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (292f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylbenzaldehyde (292b).

Compound 292b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.931 g, 6.66 mmol) using 2-hydroxy-3,4dimethylbenzaldehyde (292a) ( 1 g, 6.66 mmol), K2CO3 (2.76 g, 19.98 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash chromatography on column (silica gel, 40 g, eluted with ethyl acetate in hexanes) 2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylbenzaldehyde (292b) (2.31 g, 97% yield) as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (d, J=0.8 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 5.04 (s, 2H), 2.34

- 378 045626 (s, 3H), 2.24 (s, 3H).

Stage-2. Preparation of 7-bromo-5-((2,3-dimethyl-6-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (292c).

Compound 292c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-3,4-dimethylbenzaldehyde (292b) (2.3 g, 6.40 mmol) in THF (20 mL), using methyl(methylsulfinylmethyl)sulfane (1.273 g, 10.24 mmol), Triton-B (40% methanol solution, 1.455 mL, 3.20 mmol) and reflux for 12 h. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with EtOAc in hexane) 7-bromo-5-((2,3-dimethyl-6-(2-(methylsulfinyl)-2(methylthio )vinyl)phenoxy)methyl)benzofuran (292c) (2.24 g, 75% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.83-7 .77 (m, 2H), 7.69 (d, J=1.5 Hz, 1H), 7.15-7.05 (m, 2H), 4.89-4.70 (m, 2H), 2.70 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H); MS (ESI+): 465.00; 467.00 (M, M+2).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d).

Compound 292d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((2,3-dimethyl-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (292c) (2.2 g, 4.73 mmol) in ethanol (50 mL) using HCl (4 M in 1,4-dioxane, 2.363 mL, 9.45 mmol) and reflux for 12 h This gave, after work-up and purification by flash column chromatography (silica gel 40 g, eluted with ethyl acetate and hexanes), ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d) (645 mg, 33% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.16 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.65 (d , J=1.5 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 7.05-6.88 (m, 2H), 4.81 (s, 2H), 4 .01 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.10 (t, J= 7.1 Hz, 3H); MS (ESI+): 417.00; 419.00 (M, M+2).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetate (292e).

Compound 292e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d) (635 mg, 1.522 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (456 mg, 2.435 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) ( 160 mg, 0.228 mmol), potassium carbonate (631 mg, 4.57 mmol) in water (3 ml) heated under argon at 100°C for 6 hours in an oil bath. This resulted, after workup and purification by flash column chromatography (silica gel, 40 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292e) (450 mg, 67% yield) as a colorless syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.1 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.48 ( t, J=7.6 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 4.88 (s, 2H), 4.09-3.94 (m, 2H), 3, 82 (s, 2H), 3.64 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 1.04 (t, J=7.1 Hz, 3H); MS (ESI+): 444.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetic acid (292f).

Compound 292f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl) acetate (292e) (420 mg, 0.947 mmol) in MeOH (5 ml), THF (10 ml), using a solution of lithium hydroxide (91 mg, 3.79 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (292f) (295 mg, 75% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.28 (s, 1H), 8.41 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 7.99 ( t, J=1.7 Hz, 1H), 7.92 (dt, J=7.3, 1.8 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7, 66 (d, J=1.6 Hz, 1H), 7.64-7.53 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 7.03 (d, J =7.7 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 4.89 (s, 2H), 4.15 (d, J=5.5 Hz, 2H), 3.60 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H); MS (ESI+): 416.10 (M+1), (ESI-): 414.10 (M-1); analysis calculation for C26H25NO4-HC1-0.25H2O: C, 68.42; N, 5.85; Cl, 7.77; N, 3.07; observed: C, 68.23; N, 5.84; Cl, 7.90; N, 3.24.

- 379 045626

Scheme-293

Preparation of 2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoic acid (293c).

Stage-1. Preparation of methyl 2-((7-bromobenzofuran-5-yl)methoxy)benzoate (293a).

Compound 293a was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (0.953 g, 3.29 mmol) using methyl 2-hydroxybenzoate (0.5 g, 3.29 mmol), K ₂ CO ₃ (1.363 g, 9.86 mmol) in DMF (5 ml) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash column chromatography ( silica gel, 40 g, eluted with ethyl acetate and hexanes) methyl 2-((7-bromobenzofuran-5yl)methoxy)benzoate (293 a) (979 mg, 82% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.1 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.54 (ddd, J=8.5, 7.2, 1.7 Hz, 1H), 7.26 (dd, J=8.5, 1.0 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 7.05 (td, J=7.5, 1, 0 Hz, 1H), 5.30 (s, 2H), 3.83 (s, 3H).

Stage-2. Preparation of methyl 2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoate (293b).

Compound 293b was prepared according to the procedure described in step-3 of Scheme-1 from methyl 2-((7-bromobenzofuran-5-yl)methoxy)benzoate (293a) (945 mg, 2.62 mmol) in dioxane (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (785 mg, 4.19 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (275 mg, 0.392 mmol ), potassium carbonate (1085 mg, 7.85 mmol) in water (3 ml) heating under argon at 100°C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with DMA-80 in DCM 0% to 50%), methyl 2-((7-(3(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)benzoate (293b) (750 mg, 74% yield) as a colorless syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.83 (td, J=1.8, 0.7 Hz, 2H), 7.76 (d, J=1.6 Hz, 1H), 7.77-7.62 (m, 4H), 7.59-7.48 (m, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.42-7.36 (m, 1H), 7.30 (dd, J=8.5, 1.0 Hz, 1H), 7.09-6.98 (m, 2H) , 5.36 (s, 2H), 3.82 (s, 2H), 3.80 (s, 3H); MS (ESI+): 388.1 (M+1).

Stage-3. Preparation of 2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoic acid (293c).

Compound 293c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoate (293b) (750 mg, 1.936 mmol) in MeOH (5 ml), THF (10 ml), using lithium hydroxide monohydrate (185 mg, 7.74 mmol) in water (5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-((7-(3( aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoic acid (293c) (540 mg, 75% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.33 (s, 4H), 8.11 (d, J=2.2 Hz, 1H), 7.99 (d, J=1.9 Hz, 1H), 7.91 (dt, J=7.6, 1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.66 (dd, J=7.6, 1.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.56-7.52 (m , 1H), 7.52-7.46 (m, 1H), 7.29-7.24 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 7.02 ( td, J=7.5, 1.0 Hz, 1H), 5.34 (s, 2H), 4.14 (s, 2H); MS (ESI+): 374.10 (M+1), (ESI-): 372.10 (M-1); analysis calculation for C23H19NO4-HCl-0.25H2O: C, 66.67; N, 4.99; Cl, 8.56; N, 3.38; observed: C, 66.96; H,4.96; Cl, 8.47; N, 3.38.

- 380 045626

Scheme-294

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5L)methoxy)phenyl)acetic acid (294f).

Stage-1. Preparation of (+)-(R,E)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(((tert-butylsulfinyl)imino)methyl) benzofuran-5-yl)methoxy)phenyl)acetate (294a).

Compound 294a was prepared according to the procedure described in step-1 of scheme-258 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5yl )methoxy)phenyl)acetate (103a) (2.00 g, 3.68 mmol) in tetrahydrofuran (30 ml), using (R)-2methylpropane-2-sulfinamide (0.557 g, 4.60 mmol), tetraethoxytitanium (1.543 ml, 7.36 mmol) and reflux for 16 hours. This gave, after work-up and purification by flash column chromatography [(silica gel, 120 g, eluted with ethyl acetate in hexanes (0 to 35%)] ( +)-(R,E)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutylsulfinyl)imino)methyl)benzofuran-5 -yl)methoxy)phenyl)acetate (294a) (2.24 g, 96% yield);

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.57 (s, 1H), 7.89 (s, 1H), 7.87-7.81 (m, 2H), 7.81-7, 72 (m, 2H), 7.577.39 (m, 2H), 7.36-7.28 (m, 1H), 7.28-7.19 (m, 2H), 7.12 (d, J= 8.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.38 (s, 9H), 1.20 (s, 9H), 0.98 ( t, J=7.1 Hz, 3H); optical rotation [a] _D = +112.50 (c = 0.72, MeOH).

Stage-2. Preparation of (+)-(R)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((1,1dimethylethylsulfinamido)methyl)benzofuran-5- yl)methoxy)phenyl)acetate (294b).

Compound 294b was prepared according to the procedure described in step-2 of scheme-258 from (+)(R,E)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)-2-(((tertbutylsulfinyl)imino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (294a) (1.78 g, 2.75 mmol) in tetrahydrofuran (25 ml) and methanol (10 ml) using sodium borohydride (0.312 g, 8.26 mmol). This gave, after work-up and purification by flash column chromatography [(silica gel, 40 g, eluted with 9:1 ethyl acetate/methanol in hexanes (0 to 100%)] (+)-(R)-ethyl 2-( 2-((7(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran5-yl)methoxy)phenyl)acetate (294b) (1.45 g, 81% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.76 (d, J=7.4 Hz, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.54-7 .38 (m, 3H), 7.337.18 (m, 3H), 7.11 (d, J=8.1 Hz, 1H), 6.95-6.81 (m, 2H), 5.96 ( t, J=5.8 Hz, 1H), 5.21 (s, 2H), 4.35 (d, J=5.6 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 1.15 (s, 9H), 0.98 ( t, J=7.1 Hz, 3H); MS (ESI+): 671.3 (M+Na); optical rotation [a] _D = +4.0 (c = 0.10, MeOH).

Stage-3. Preparation of ethyl 2-(2-((2-(aminomethyl)-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (294c).

To a stirred solution of (+)-(R)-ethyl 2-(2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran- 5yl)methoxy)phenyl)acetate (294b) (1.45 g, 2.235 mmol) in tetrahydrofuran (100 ml) was added HCl, 3N solution in water (0.745 ml, 2.235 mmol), at room temperature and stirred for 30 min. The reaction mixture was quenched by adding saturated sodium bicarbonate solution. The THF layer was separated, washed with brine, dried, filtered and concentrated. The crude residue was purified by flash column chromatography (silica gel, 40 g) to give ethyl 2-(2-((2-(aminomethyl)-7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (294c) (1.217 g, 100% yield) as brown syrup;

- 381 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (dd, J=6.4, 1.4 Hz, 2H), 7.60 (d, J=1.6 Hz, 1H), 7, 51-7.41 (m, 3H),

7.32-7.24 (m, 2H), 7.22 (dd, J=7.8, 1.6 Hz, 2H), 7.11 (dd, J=8.3, 1.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.75 (d, J=1.0 Hz, 1H), 5.21 (s, 2H), 4, 23 (d, J=6.2 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.86 (s, 2H), 3.62 (s, 2H), 1, 39 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 567.2 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((2-(benzamidomethyl)-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (294d).

Compound 294d was prepared according to the procedure described in step-4 of Scheme-1 from ethyl 2(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (294c) (250 mg, 0.459 mmol) and benzoic acid (84 mg, 0.689 mmol) in DMF (3 ml), using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 ml, 1.836 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 0 to 100% EtOAc in hexane), ethyl 2-(2-(( 2-(benzamidomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (294d) (174 mg, 58% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 9.15 (t, J=5.7 Hz, 1H), 7.97-7.85 (m, 2H), 7.84-7.70 (m, 2H), 7.62 (d, J=1.6 Hz, 1H), 7.59-7.38 (m, 5H), 7.32-7.16 (m, 4H), 7.14-7 .06 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1h), 6.82 (d, J=0.9 Hz, 1H), 5.21 (s, 2H), 4.67 (d, J=5.6 Hz, 2H), 4.20 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H) , 3.61 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5yl)methoxy)phenyl)acetate (294e).

Compound 294e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((2-(benzamidomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran -5yl)methoxy)phenyl)acetate (294d) (175 mg, 0.270 mmol) in DCM (15 ml) using TFA (0.208 ml, 2.70 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)acetate (294e) (148 mg) as light -brown syrup. MS (ESI+): 549.2 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (294f).

Compound 294f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl )acetate (294e) (148 mg, 0.270 mmol) in MeOH (2 ml), THF (15 ml), using a solution of lithium hydroxide monohydrate (26 mg, 1.079 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (294f) (25 mg, 18% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.24 (s, 1H), 9.26 (t, J=5.7 Hz, 1H), 8.46 (s, 3H), 8.03 ( d, J=2.1 Hz, 1H), 7.94 (dt, J=6.7, 1.6 Hz, 3H), 7.68 (d, J=1.6 Hz, 1H), 7, 61 (d, J=1.6 Hz, 1H), 7.59-7.44 (m, 5H), 7.21 (d, J=7.5 Hz, 2H), 7.08 (d, J =8.1 Hz, 1H), 6.89 (t, J=7.4 Hz, 1H), 6.83 (s, 1H), 5.24 (s, 2H), 4.68 (d, J =5.6 Hz, 2H), 4.11 (p, J=6.2 Hz, 2H), 3.58 (s, 2H); MS (ESI+): 522.20 (M+1), (ESI-): 519.20 (M-1).

Scheme-295

CN

295b 295c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (295c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((3cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (295a) .

- 382 045626

Compound 295a was prepared according to the procedure described in step-4 of Scheme-1 from ethyl 2(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (294c) (250 mg, 0.459 mmol) and 3-cyanobenzoic acid (101 mg, 0.689 mmol) in DMF (3 ml), using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 ml , 1.836 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetate (295a) (243 mg, 79% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.36 (t, J=5.6 Hz, 1H), 8.34 (t, J=1.6 Hz, 1H), 8.25-8 .17 (m, 1H), 8.03 (dt, J=7.7, 1.3 Hz, 1H), 7.95 (s, 1H), 7.79-7.67 (m, 3H), 7.63 (d, J=1.6 Hz, 1H), 7.51 (s, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.31-7.24 (m , 2H), 7.24-7.18 (m, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.94-6.85 (m, 2H), 5.22 ( s, 2H), 4.69 (d, J=5.5 Hz, 2H), 4.20 (d, J=6.1 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.38 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 574.2 (M+1-100).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((3cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (295b).

Compound 295b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((3- Cyanobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetate (295a) (240 mg, 0.356 mmol) in DCM (15 ml) using TFA (0.326 ml, 4.23 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((3cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (295b) (204 mg ), which was used as is in the next step without further purification; MS (ESI+): 574.2 (M+1), (ESI-): 572.2 (M1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (295c).

Compound 295c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5- yl)methoxy)phenyl)acetate (295b) (204 mg, 0.356 mmol) in MeOH (2 ml), THF (15 ml), using a solution of lithium hydroxide monohydrate (34 mg, 1.423 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (295c) (30 mg, 16% yield), hydrochloride salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 9.46 (t, J=5.6 Hz, 1H), 8.35 (t, J=1.7 Hz , 1H), 8.23 (dt, J=7.9, 1.5 Hz, 1H), 8.04 (dt, J=7.7, 1.4 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.95 (dt, J=7.4, 1.7 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.70- 7.66 (m, 1H), 7.63-7.48 (m, 3H), 7.23 (t, J=7.5 Hz, 2H), 7.08 (d, J=8.1 Hz , 1H), 6.95-6.84 (m, 2H), 5.25 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.13 (s, 2H) , 3.58 (s, 2H); MS (ESI+): 546.20 (M+1), (ESI-): 544.20 (M-1).

Scheme-296

296b 296c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (296c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (296a) .

Compound 296a was prepared according to the procedure described in step-4 of scheme-1 from ethyl 2

- 383 045626 (2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (294c) (250 mg, 0.459 mmol ) and 2-phenylacetic acid (94 mg, 0.689 mmol) in DMF (3 ml), using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 ml, 1.836 mmol) and stirring at room temperature for 16 hours. This resulted to be obtained after treatment and purification by flash column chromatography (silica gel) ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2-phenylacetamido)methyl) benzofuran-5yl)methoxy)phenyl)acetate (296a) (300 mg, 99% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (t, J=5.6 Hz, 1H), 7.95 (s, 1H), 7.79-7.71 (m, 2H) , 7.60 (d, J=1.7 Hz, 1H), 7.55-7.40 (m, 3H), 7.34-7.17 (m, 8H), 7.10 (dd, J =8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.72 (d, J=0.9 Hz, 1H), 5 .21 (s, 2H), 4.46 (d, J=5.6 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (k, J=7, 1 Hz, 2H), 3.62 (s, 2H), 3.50 (s, 2H), 1.38 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 585.2 (M-100+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (296b).

Compound 296b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2- phenylacetamido)methyl)benzofuran-5yl)methoxy)phenyl)acetate (296a) (245 mg, 0.370 mmol) in DCM (15 ml) using TFA (0.285 ml, 3.70 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (296b) (200 mg ), which was used in the next step without further purification; MS (ESI+): 563.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (296c).

Compound 296c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5- yl)methoxy)phenyl)acetate (296b) (200 mg, 0.355 mmol) in MeOH (2 ml), THF (15 ml), using a solution of lithium hydroxide monohydrate (34 mg, 1.423 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (296c) (70 mg, 37% yield), hydrochloride salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.81 (t, J=5.6 Hz, 1H), 8.36 (s, 3H), 8.00 ( s, 1H), 7.957.87 (m, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.59- 7.49 (m, 2H), 7.31-7.25 (m, 4H), 7.22 (dd, J=8.1, 1.8 Hz, 3H), 7.08 (d, J= 8.1 Hz, 1H), 6.94-6.86 (m, 1H), 6.75 (d, J=0.9 Hz, 1H), 5.24 (s, 2H), 4.47 ( d, J=5.6 Hz, 2H), 4.12 (s, 2H), 3.59 (s, 2H), 3.52 (s, 2H); MS (ESI+): 535.20 (M+1), (ESI-): 533.20 (M-1).

Scheme-297

297b 297с

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (297c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2,4difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 297a).

Compound 297a was prepared according to the procedure described in step-4 of Scheme-1 from ethyl 2(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (294c) (250 mg, 0.459 mmol) and 2,4-difluorobenzoic acid (109 mg, 0.689 mmol) in DMF (3 ml), using HATU (262 mg, 0.689 mmol) and DIPEA ( 0.320 ml, 1.836 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl )amino)methyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5

- 384 045626 yl)methoxy)phenyl)acetate (297a) (312 mg, 99% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=5.2 Hz, 1H), 7.75 (td, J=9.0, 7.0 Hz, 3H), 7.63 (d, J=1.6 Hz, 1H), 7.55-7.33 (m, 4H), 7.33-7.14 (m, 4H), 7.10 (d, J=8.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.83 (s, 1H), 5.22 (s, 2H), 4.65 (d, J =5.7 Hz, 2H), 4.21 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -106.29 (d, J=9.3 Hz), -109.33 (d, J=9.3 Hz).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (297b).

Compound 297b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2, 4-Difluorobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetate (297a) (305 mg, 0.445 mmol) in DCM (15 ml) using TFA (0.343 ml, 4.45 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (297b) ( 260 mg), which was used in the next step without further purification; MS (ESI+): 585.2 (M+1), (ESI-): 583.2 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran5-yl)methoxy)phenyl)acetic acid (297c).

Compound 297c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran- 5-yl)methoxy)phenyl)acetate (297b) (148 mg, 0.253 mmol) in MeOH (2 ml), THF (15 ml), using a solution of lithium hydroxide monohydrate (24 mg, 1.013 mmol) in water (2 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (297c) (15 mg, 11% yield), hydrochloride salt, as a white solid substances;

^1H NMR (300 MHz, DMSO-d6) δ 9.13-9.01 (m, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.97 (dt, J=7 ,6, 1.6 Hz, 1H), 7.75 (td, J=8.6, 6.7 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.62 -7.48 (m, 3H), 7.45-7.35 (m, 1H), 7.26-7.16 (m, 3H), 7.08 (d, J=8.1 Hz, 1H ), 6.94-6.86 (m, 1H), 6.85 (s, 1H), 5.25 (s, 2H), 4.67 (d, J=5.8 Hz, 2H), 4 .13 (s, 2H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -106.16 (d, J=10.2 Hz), -109.33; MS (ESI+): 557.20 (M+1), (ESI): 555.20 (M-1).

Scheme-298

Pd(PPh ₃ ) ₂ CI ₂ K ₂ CO ₃

Preparation of 2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetic acid (298f).

Stage-1. Preparation of 6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-carbaldehyde (298b).

Compound 298b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.413 g, 4.87 mmol) using 6-hydroxybenzofuran-5carbaldehyde (298a) (790 mg, 4.87 mmol; CAS No. 20073-22-7; prepared according to the procedure described by Sairam, Mudulkar et al.; in Tetrahedron Letters, 56(11), 1338-1343; 2015), K ₂ CO ₃ ( 2.021 g, 14.62 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This gave, upon treatment, 6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-carbaldehyde ( 298b) (1.73 g, 96% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 8.02 ( d, J=2.3 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.62 (d, J=0.9 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 7.02 (dd, J=2.2, 0.9 Hz, 1H), 5.42 ( s, 2H).

Stage-2. Preparation of 7-bromo-5-(((5-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-6yl)oxy)methyl)benzofuran (298c).

Compound 298c was prepared according to the procedure described in step-3 of scheme-266 from 6-((7bromobenzofuran-5-yl)methoxy)benzofuran-5-carbaldehyde (298b) (1.70 g, 4.58 mmol) in THF (40 mL) using methyl(methylsulfinylmethyl)sulfane (0.910 g, 7.33 mmol), Triton-B (40% methanol solution, 1.041 mL, 2.290 mmol) and reflux for 12 h. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with EtOAc in hexane) 7-bromo-5-(((5-(2-(methylsulfinyl)-2-(methylthio)vinyl) benzofuran-6yl)oxy)methyl)benzofuran (298c) (1.78 g, 81% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.94 (d, J=2.2 Hz, 1H), 7.91 (d, J=0.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H) , 7.51 (d, J=0.9 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.98 (dd, J=2.2, 0.9 Hz, 1H), 5.35 (s, 2H), 2.74 (s, 3H), 2.28 (s, 3H).

Stage-3. Preparation of ethyl 2-(6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298d).

Compound 298d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-(((5-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-6-yl)oxy)methyl) benzofuran (298c) (1.7 g, 3.56 mmol) in ethanol (50 ml), using HCl (4 M in 1,4-dioxane, 3.56 ml, 14.24 mmol) and refluxing at This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes), ethyl 2-(6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5 -yl)acetate (298d) (1.06 g, 69% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J=1.0 Hz, 1H) , 7.12 (d, J=2.2 Hz, 1H), 6.87 (dd, J=2.2, 0.9 Hz, 1H), 5.23 (s, 2H), 4.02 ( k, J=7.1 Hz, 2H), 3.69 (s, 2H), 1.07 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5yl)acetate (298e).

Compound 298e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298d) (475 mg, 1.107 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (259 mg, 1.383 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (117 mg, 0.166 mmol), potassium carbonate (459 mg, 3.32 mmol) in water (3 ml) heating under argon at 100°C for 12 hours in an oil bath. This resulted, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(6-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298e) (450 mg, 89% yield) as a sticky material;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.83 (d, J =1.7 Hz, 1H), 7.72 (tt, J=3.6, 1.6 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.50-7 .43 (m, 2H), 7.42-7.37 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 6.86 (dd, J=2.2, 0 .9 Hz, 1H), 5.29 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.70 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 456.1 (M+1).

Stage-5. Preparation of 2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5yl)acetic acid (298f).

Compound 298f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298e) (450 mg, 0.988 mmol) in MeOH (5 ml), THF (10 ml), using a solution of lithium hydroxide (95 mg, 3.95 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (150 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(6-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetic acid (298f) (250 mg, 59% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H ), 7.93 (dt, J=7.2, 1.8 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.79 (d, J=1.6 Hz , 1H), 7.68 (d, J=1.6 Hz, 1H), 7.63-7.51 (m, 2H), 7.48 (s, 1H), 7.37 (d, J= 0.9 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.86 (dd, J=2.2, 0.8 Hz, 1H), 5.32 (s, 2H), 4.14 (s, 2H), 3.67 (s, 2H); MS (ESI+): 428.10 (M+1), (ESI-): 426.10 (M-1); analysis calculation for C26H21NO5-HCl-H2O: C, 64.80; N, 5.02; Cl, 7.36; N, 2.91; observed: C, 65.00; N, 4.91; Cl, 7.40; N, 3.01.

Scheme-299

- 386 045626

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (299c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (299a).

Compound 299a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-fluorobenzofuran-5-yl)methanol (227b) (600 mg, 2.449 mmol) in DCM (35 ml) using triphenylphosphine ( 771 mg, 2.94 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (523 mg, 2.69 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2 -dicarboxylate (DCAD, 1214 mg, 3.31 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5- yl)methoxy)4-methylphenyl)acetate (299a) (425 mg, 1.009 mmol, 41.2% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.91 (t, J=1.1 Hz, 1H), 6.73 (ddd, J=7.4, 1.6, 0.8 Hz, 1H), 6.54 (d, J=6.4 Hz, 1H), 5.14 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.29 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -110.46; MS (ESI+): 421.00; 423.00 (M, M+2).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (299b).

Compound 299b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (299a) (412 mg, 0.978 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (211 mg, 1.125 mmol), solution of K2CO3 (406 mg, 2.93 mmol) in water (2 ml), bis(triphenylphosphine)palladium(P) chloride (103 mg, 0.147 mmol) by heating at 100°C for 7 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (299b) (245 mg, 56% yield) as a pale yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.76 (d, J=1.9 Hz, 1H), 7.65 (dt, J=7.5, 1.7 Hz, 1H), 7, 61 (d, J=1.7 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.44- 7.38 (m, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.99-6.91 (m, 1H), 6.77-6.69 (m, 1H) , 6.44 (d, J=6.4 Hz, 1H), 5.20 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.81 (s, 2H) , 3.57 (s, 2H), 2.29 (s, 3H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.74; MS (ESI+): 448.2 (M+1), (ESI-): 446.1 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (299c).

Compound 299c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl )acetate (299b) (230 mg, 0.514 mmol) in MeOH/THF (2/10 ml), using a solution of lithium hydroxide monohydrate (49 mg, 2.056 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography (C-18 column, 150 g, eluted with 0.1% aq. HCl in water and 0% to 100% acetonitrile), 2-(2-((7- (3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (299c) (160 mg, 74% yield), hydrochloride salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=1.7 Hz, 1H), 7.86 (dt, J=7.2, 1.8 Hz, 1H), 7, 68 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.61-7.53 (m, 2H), 7.09 (d, J =7.6 Hz, 1H), 6.93 (d, J=1.5 Hz, 1H), 6.72 (d, J=7.3 Hz, 1H), 6.45 (d, J=6 .4 Hz, 1H), 5.22 (s, 2H), 4.14 (s, 2H), 3.53 (s, 2H), 2.28 (s, 3H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -111.57; MS (ESI+): 420.10 (M+1), (ESI-): 418.10 (M-1); analysis calculation for C ₂₅ H ₂₂ FNO ₄ -HCl-H ₂ O: C, 63.36; N, 5.32; Cl, 7.48; N, 2.96; observable; C, 63.79; N, 5.57; Cl, 7.04; N, 3.03.

Scheme-300

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-387 045626 yl)methoxy)phenyl)acetic acid (300c).

Stage-1. Preparation of ethyl 2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (300a) .

Compound 300a was prepared according to the procedure described in step-1 of Scheme-59 from (7bromo-2-fluorobenzofuran-5-yl)methanol (227b) (1.00 g, 2.456 mmol) using bis(pinacolato)diboron ( 0.935 g, 3.68 mmol), potassium acetate (0.723 g, 7.37 mmol) and Pd(dppf)Cl ₂ -DCM (0.201 g, 0.246 mmol) in anhydrous dioxane (25 ml) under nitrogen atmosphere with heating at 90 °C for 18 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in 0 to 20% hexanes] ethyl 2-(2-((2-fluoro- 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (300a) (910 mg, 82% yield) as light brown oils;

¹ H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J=1.9 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.31-7, 16 (m, 2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.35 (d, J=6.3 Hz, 1H), 5.15 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.33 (s, 12H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.69.

Stage-2. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (300b).

Compound 300b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (300a) (450 mg, 0.991 mmol) in dioxane (10 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2yl)methyl)-2-methylpropane-2-sulfinamide (220c) (315 mg, 1.189 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (104 mg, 0.149 mmol) and a solution of K ₂ CO ₃ (411 mg, 2.97 mmol) in water (1 ml) heating in an argon atmosphere at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0% to 15% MeOH/DCM), ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido) methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (300b) (410 mg, 73.6%) as a brown oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (d, J=4.9 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.66 (t, J=5.2 Hz, 1H), 7.55-7.48 (m, 1H), 7.31-7.20 (m, 2H), 7.11 (dd, J=8.3, 1, 1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.88 (t, J= 5.8 Hz, 1H), 5.24 (s, 2H), 4.41 (dd, J=5.9, 2.0 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.11 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.33, -127.78; MS (ESI+): 557.2 (M+1), 580.2 (M+Na).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (300c).

To a stirred solution of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (300b) (400 mg, 0.719 mmol) in tetrahydrofuran (10 ml) was added 4 M HCl in 1-4-dioxane (0.359 ml, 1.437 mmol) and stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness. The residue was dissolved in tetrahydrofuran (10 ml), acetonitrile (2 ml), water (2 ml) and lithium hydroxide monohydrate (86 mg, 3.59 mmol) was added and stirring was continued at room temperature for 48 hours. The reaction mixture was concentrated, diluted water (5 ml) and acidified to pH 4 using 1 M HCl. The separated solid was collected by filtration and purified by reverse phase column chromatography (C-18 column, 150 g, eluted with 0.1% aq. HCl in water and 0% to 100% acetonitrile) to give 2-(2-((7 -(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (300c) (125 mg, 41.0% yield), hydrochloride salt, as a white solid substances;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, J=5.0 Hz, 1H), 8.56 (s, 4H), 7.84 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.24 (dd, J=9.1, 6.6 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.51 (d, J=6 .4 Hz, 1H), 5.27 (s, 2H), 4.38 (d, J=5.3 Hz, 2H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -111.17, -128.47; MS (ESI+): 425.10 (M+1), (ESI-): 423.10 (M-1); analysis calculation for C23H18F2N2O4-1.25HCl-1.5H2O: C, 55.58; N, 4.51; Cl, 8.92; N, 5.64; observed: C, 55.62; N, 4.49; Cl, 8.83; N, 5.69.

Scheme-301

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (301b).

- 388 045626

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetate (301a).

Compound 301a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (300a) (840 mg, 1.849 mmol) in dioxane (20 ml), using 4-chloropyridin-2-yl)methanamine (74a) (316 mg, 2.219 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (195 mg, 0.277 mmol) and a solution of K ₂ CO ₃ (767 mg, 5.55 mmol) in water (2 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with MeOH/DCM 0% to 15%), ethyl 2-(2-((7-(2(aminomethyl)pyridine-4- yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (301a) (324 mg, 0.746 mmol, 40.3% yield) as a thick syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.2 Hz, 1H), 7.91 (d, J=1.7 Hz, 1H), 7.71 (td, J =5.7, 1.7 Hz, 3H), 7.25 (dd, J=14.3, 7.3, 1.7 Hz, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.50 (d, J=6.4 Hz, 1H), 5.25 (s, 2H), 3, 94 (dd, J=14.1, 6.9 Hz, 4H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.27; MS (ESI+): 435.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (301b).

Compound 301b was prepared according to the procedure described in step-3 of Scheme-300 from ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy )phenyl)acetate (301a) (320 mg, 0.737 mmol) in THF (10 ml), ACN (2 ml), water (2 ml), using lithium hydroxide monohydrate (71 mg, 2.95 mmol) and stirred for 48 hours at room temperature. This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 150 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(2(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (301b) (88 mg, 29% yield), hydrochloride salt, as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.82-8.72 (m, 1H), 8.54 (s, 3H), 8.07-7.95 (m, 1H), 7.92 (dd, J=5.3, 1.9 Hz, 1H), 7.83-7.74 (m, 2H), 7.24 (dd, J=8.1, 6.5 Hz, 2H), 7.13-7.04 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.50 (d, J=6.4 Hz, 1H), 5 .27 (s, 2H), 4.31 (d, J=5.7 Hz, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.13 (d, J=3.1 Hz); MS (ESI+): 407.10 (M+1), (ESI-): 405.10 (M-1); analysis calculation for

C2 ₃ Hi9FN2O4-1.65HC1-2H2O: C, 54.96; N, 4.94; Cl, 11.64; N, 5.57; observable; C, 54.90; N, 5.02; Cl, 11.73; N, 5.54.

Scheme-302

He

302d

302e 302f

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5yl)methoxy)phenyl)acetic acid (302f).

Stage-1. Preparation of methyl 7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-carboxylate (302b).

Compound 302b was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (4.2 g, 13.55 mmol) in pyridine (20 ml), 3-((prop-2-yn-1yloxy)methyl)pyridine (302a) (2.194 g, 14.91 mmol; CAS No. 72421-08-0; prepared according to the procedure described by Fu, Boqiao et al.; c Faming Zhuanli Shenqing, 104945456, September 30, 2015), oxide

- 389 045626 copper(1) (0.970 g, 6.78 mmol) and heating at 50°C for 18 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] methyl 7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran5 -carboxylate (302b) (3.2 g, 63% yield) as a light brown syrup;

^1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.51 (d, J=4.8 Hz, 1H), 8.30 (d, J=1.5 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.82-7.75 (m, 1H), 7.39 (ddd, J=7.8, 4.8, 0, 8 Hz, 1H), 7.22 (d, J=0.7 Hz, 1H), 4.76 (d, J=0.7 Hz, 2H), 4.65 (s, 2H), 3.88 (s, 3H); MS (ESI+): 376.0; 378.0 (M, M+2).

Stage-2. Preparation of (7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methanol (302c).

Compound 302c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-carboxylate (302b) (1.5 g, 3 .99 mmol) in THF (30 ml) using LiBH ₄ (6.98 ml, 13.96 mmol, 2 M solution in THF) and MeOH (0.565 ml, 13.96 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane] (7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5yl)methanol (302c ) (935 mg, 67% yield) as a white semi-solid; MS (ESI+): 348.0; 350.0 (M, M+2).

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5yl)methoxy)phenyl)acetate (302d).

Compound 302d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methanol (302c) (450 mg, 1.292 mmol) in DCM (20 ml) using triphenylphosphine (407 mg, 1.551 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (279 mg, 1.551 mmol) and (E)-bis(4-chlorobenzyl)diazen-1 ,2-dicarboxylate (DCAD, 641 mg, 1.745 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((7-bromo-2-((pyridinium- 3ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (302d) (179 mg, 27% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.13 (d, J=7.9 Hz , 1H), 7.75-7.64 (m, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.29-7.19 (m, 2H), 7.12 ( s, 1H), 7.09-7.04 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.78 (s, 2H), 4.73 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.08 (t, J=7, 1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (302e).

Compound 302e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl )acetate (302d) (170 mg, 0.333 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (62 mg, 0.333 mmol), K2CO3 solution (138 mg, 1.0 mmol) in water (2 ml), bis(triphenylphosphine) palladium(P) chloride (35 mg, 0.050 mmol) by heating at 100°C for 12 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 90%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2-((pyridin-3ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (302e) (25 mg, 1% yield) as an oil; MS (ESI+): 537.3 (M+1), 579.2 (M+Na).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran5-yl)methoxy)phenyl)acetic acid (302f).

Compound 302f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran- 5-yl)methoxy)phenyl)acetate (302e) (25 mg, 0.047 mmol) in MeOH/THF (1/5 ml), using a solution of lithium hydroxide monohydrate (5 mg, 0.186 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C-18 column, 30 g, eluted with 0.1% aq. HCl in water and 0% to 100% acetonitrile), 2-(2-(( 7-(3-(aminomethyl)phenyl)-2-((pyridin-3ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (302f) (1.5 mgc), hydrochloride salt, as a white solid substances;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.36-8.16 (m, 4H), 7.94 (d, J=1.4 Hz, 2H), 7.95-7.83 ( m, 2H), 7.74 (d, J=1.6 Hz, 1H), 7.67-7.57 (m, 2H), 7.58-7.46 (m, 2H), 7.24 (t, J=7.5 Hz, 2H), 7.08 (d, J=12.1 Hz, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.26 (s , 2H), 4.75 (s, 2H), 4.67 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.60 (s, 2H); MS (ESI+): 509.2 (M+1), (ESI-): 507.1 (M-1).

- 390 045626

Scheme-303

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (303 g).

Stage-1. Preparation of 2-(2-hydroxy-4-methoxyphenyl)-1-morpholinoethanethione (303b).

Compound 303b was prepared according to the procedure described in step-1 of scheme-265 from 1-(2hydroxy-4-methoxyphenyl)ethanone (303a) (2 g, 12.04 mmol) in N-methyl-2-pyrrolidinone (6 ml ), using sulfur powder (0.772 g, 24.07 mmol), morpholine (2.076 ml, 24.07 mmol) when heated at 130°C for 10 hours. This resulted in the preparation after treatment of 2-(2-hydroxy-4 -methoxyphenyl)-1morpholinoethanethione (303b) (1.8 g, 56% yield) as dark syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.75-9.64 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.38 (d, J=7 .9 Hz, 2H), 4.22 (dd, J=5.7, 4.2 Hz, 2H), 4.05-4.01 (m, 2H), 3.67 (s, 3H), 3 .64 (dt, J=6.0, 4.3 Hz, 4H), 3.44-3.37 (m, 2H); MS (ESI+): 268.1 (M+1), (ESI-): 266.1 (M+Na).

Stage-2. Preparation of 2-(2-hydroxy-4-methoxyphenyl)acetic acid (303c).

Compound 303c was prepared according to the procedure described in step-2 of scheme-265 from 2-(2hydroxy-4-methoxyphenyl)-1-morpholinoethanethione (303b) (1.79 g, 6.70 mmol) in ethanol (20 ml) and water (5 ml) using sodium hydroxide (1.379 g, 34.5 mmol) and reflux for 10 hours. This resulted in 2-(2-hydroxy-4-methoxyphenyl)acetic acid (303c) after treatment ) (1.1 g, 90% yield) as a colorless oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.00 (s, 1H), 9.43 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 6.32 (dd, J=8.2, 2.6 Hz, 1H), 3.67 (s, 3H), 3.37 (s, 2H) .

Stage-3. Preparation of ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d).

Compound 303d was prepared according to the procedure described in step-3 of scheme-265 from 2-(2hydroxy-4-methoxyphenyl)acetic acid (303c) (1.1 g, 6.04 mmol) in ethanol (20 ml) using sulfuric acid (0.354 ml, 6.64 mmol) and reflux for 4 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes), ethyl 2-( 2-Hydroxy-4-methoxyphenyl)acetate (303d) (1.01 g, 80% yield) as a colorless oil.

Stage-4. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e).

Compound 303e was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.379 g, 4.76 mmol) using ethyl 2-(2-hydroxy-4methoxyphenyl) acetate (303d) (1 g, 4.76 mmol), K ₂ CO ₃ (1.972 g, 14.27 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This resulted in ethyl 2 after workup (2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e) (1.95 g, 98% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.59 (d, J =1.5 Hz, 1H), 7.17-7.04 (m, 2H), 6.66 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.17 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.53 (s, 2H) , 1.07 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (303f).

Compound 303f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e) (1.94 g, 4.63 mmol) in dioxane (60 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (1.301 g, 6.94 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.487 g, 0.694 mmol), potassium carbonate (1.918 g, 13.88 mmol) in water (10 ml) heating under nitrogen at 100°C for 3 hours in an oil bath. This resulted, after workup and purification by flash column chromatography (silica gel, 40 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl) benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303f) (1.276 g, 62% yield) in

- 391 045626 in the form of brown syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.77-7, 65 (m, 2H), 7.57 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.42-7.36 (m, 1H ), 7.11 (d, J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.23 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.81 (s , 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.94 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 446.2 (M+1).

Stage-6. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (303g).

Compound 303g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate ( 303f) (1.26 g, 2.83 mmol) in MeOH (10 ml), THF (15 ml), using lithium hydroxide monohydrate (0.271 g, 11.31 mmol) in water (4 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (250 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (303g) (952 mg, 81% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.93 (dt, J=7.1, 1.9 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.62-7.52 (m, 2H), 7.11 (d, J=8.3 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.67 (s, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.26 (s, 2H), 4.13 (s, 2H), 3.73 (s, 3H), 3.51 (s, 2H); MS (ESI+): 518.10 (M+1), (ESI-): 416.10 (M-1); analysis calculation for C^^NOs-HCH.S^O: C, 62.43; N, 5.66; N, 2.91; observed: C, 62.56; N, 5.53; N, 2.90.

Scheme-304

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetic acid (304b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetate (304a).

Compound 304a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d) (390 mg, 0.935 mmol) in dioxane (10 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (307 mg, 1.495 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) ((98 mg, 0.140 mmol), potassium carbonate (387 mg, 2.80 mmol) in water (3 ml) heating under argon at 100°C for 6 hours in an oil bath. This resulted in obtained after treatment and purification by flash column chromatography (silica gel 40 g, eluted with DMA-80 in DCM from 0% to 50%) ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)benzofuran- 5-yl)methoxy)-3,4-dimethylphenyl)acetate (304a) (268 mg, 62% yield) as a colorless syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.61 (td, J=7.4, 2.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.08 (d, J =2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 4.86 (s, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.64 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H ), 1.91 (d, J=13.0 Hz, 2H), 1.03 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.90; MS (ESI+): 462.2 (M+1), (ESI-): 460.1 (M-1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetic acid (304b).

Compound 304b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4 -dimethylphenyl)acetate (304a) (260 mg, 0.563 mmol) in MeOH (2 ml), THF (10 ml), using a solution of lithium hydroxide (54.0 mg, 2.253 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (40 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (304b) (210 mg, 86% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.68-8.89 (m, 4H), 8.08 (d, J=2.2 Hz, 1H), 7.87 (d, J=1 .6 Hz, 1H), 7.70 (dtd, J=10.9, 7.4, 1.8 Hz, 2H), 7.51 (t, J=1.3 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.93 (d , J=7.7 Hz, 1H), 4.88 (s, 2H), 4.18 (s, 2H), 3.59 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.60 (t, J=7.1 Hz); MS (ESI+): 434.2.10 (M+1), (ESI-): 432.2 (M-1); analysis calculation for C ₂₆ H ₂₄ FNO ₄ -HCl-0.75H ₂ O: C, 64.60; N, 5.53; Cl, 7.33; N, 2.90; observed: C, 64.75; N,

- 392 045626

5.34; Cl, 7.38; N, 2.94.

Scheme-305 ci

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetic acid (305d).

Stage-1. Preparation of ethyl 2-(3,4-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate ( 305a).

Compound 305a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d) (1, 00 g, 2.396 mmol) using bis(pinacolato)diboron (0.913 g, 3.59 mmol), potassium acetate (0.706 g, 7.19 mmol) and Pd(dppf)Cl ₂ -DCM (0.098 g, 0.120 mmol) in anhydrous dioxane (15 ml) under argon while heating at 90°C for 18 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in 0 to 60 hexanes %] ethyl 2-(3,4-dimethyl-2-((7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (305a) (430 mg, 39%) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=2.2 Hz, 1H), 7.90 (d, J=1.9 Hz, 1H), 7.69 (d, J =1.8 Hz, 1H), 7.04-6.89 (m, 3H), 4.82 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.35 (s, 12H), 1.11 (t, J=7.1 Hz, 3H); MS (ESI+): 487.2 (M+Na).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3, 4-dimethylphenyl)acetate (305b).

Compound 305b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(3,4-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (305a) (400 mg, 0.861 mmol) in dioxane (20 ml) using (+)-(S)-N-((4-chloro3-fluoropyridine -2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (342 mg, 1.292 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (91 mg, 0.129 mmol) and a solution of K2CO3 (357 mg, 2.58 mmol) in water (2.4 ml) heating under nitrogen at 100°C for 20 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with MeOH/DCM 0% to 15%) (+)-(S)-ethyl 2-(2-((7-( 2-((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetate (305b) (410 mg, 74%) as brown oil;

1H NMR (300 MHz, DMSO-d6) δ 8.52 (dd, J=4.9, 0.7 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.72-7.63 (m, 1H), 7.56 (d, J= 1.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.94 (d, J=7, 7 Hz, 1H), 4.88 (s, 2H), 4.42 (dd, J=5.8, 2.0 Hz, 2H), 3.96 (k, J=7.1 Hz, 2H) , 3.63 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H), 1.09 (s, 9H), 1.03 (t, J=7.1 Hz, 3H); MS (ESI+): 467.2 (M+1); optical rotation [a] _D = +40.0 (c = 0.33, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-3,4-dimethylphenyl)acetate (305c).

To a stirred solution of (+)-(8)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)- 3,4-Dimethylphenyl)acetate (305b) (420 mg, 0.741 mmol) in THF (13 ml) was added with HCl (3 M aq) (0.741 ml, 2.223 mmol) and stirred at room temperature for 5 hours. The reaction was concentrated to dryness and the resulting residue was purified by flash column chromatography (silica gel, 25 g eluted with DMA 80 in dichloromethane) to give ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5- yl)methoxy)-3,4-dimethylphenyl)acetate (305c) (120 mgc, 35% yield) as brown syrup;

1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=4.9 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.90 (d, J =1.7 Hz, 1H), 7.64-7.52 (m, 2H), 7.12 (d, J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz , 1H), 6.93 (d, J=7.7 Hz, 1H), 4.88 (s, 2H), 4.06-3.90 (m, 4H), 3.63 (s, 2H) , 2.22 (d, J=7.5 Hz, 6H), 2.03 (s, 2H), 1.98 (s, 0H), 1.02 (t, J=7.1 Hz, 3H) ; MS (ESI+):

- 393 045626

463.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4dimethylphenyl)acetic acid (305d).

Compound 305d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -3,4-dimethylphenyl)acetate (305c) (120 mg, 0.259 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide (67 mg, 1.557 mmol) in water (5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (150 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(2- (aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (305d) (56 mg, 50% yield), hydrochloride salt, as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, J=5.0 Hz, 1H), 8.57 (s, 4H), 8.13 (d, J=2.2 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.63 (t, J=1.3 Hz, 1H) , 7.15 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 4 .90 (s, 2H), 4.48-4.29 (m, 2H), 3.58 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -128.57; MS (ESI+): 435.2 (M+1), (ESI-): 433.2 (M-1); analysis calculation for C2 ₅ H ₂₃ FN ₂ O ₄ -1.25HCl «1.75H ₂ O: C, 58.70; N, 5.47; Cl, 8.66; N, 5.48; observed: C, 58.60; N, 5.35; Cl, 8.93; N,5,51.

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-3,4-dimethylphenyl)acetic acid (305d).

Compound 305d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl )methoxy)-3,4dimethylphenyl)acetate (305c) (120 mg, 0.259 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide (67 mg, 1.557 mmol) in water (5 ml). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (150 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%]2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-3,4-dimethylphenyl)acetic acid (305d) (56 mg, 50% yield), hydrochloride salt, as white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, J=5.0 Hz, 1H), 8.57 (s, 4H), 8.13 (d, J=2.2 Hz , 1H), 7.96 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.63 (t, J=1.3 Hz, 1H ), 7.15 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 4.90 (s, 2H), 4.48-4.29 (m, 2H), 3.58 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -128.57; MS (ESI+): 435.2 (M+1), (ESI-): 433.2 (M-1); analysis calculation for C ₂₅ H ₂₃ FN ₂ O ₄ -1.25HCl-1.75H ₂ O: C, 58.70; N, 5.47; Cl, 8.66; N, 5.48; observed: C, 58.60; N, 5.35; Cl, 8.93; N, 5.51.

Scheme-306

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(diethylamino)phenyl)acetic acid (306f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)benzaldehyde (306b).

Compound 306b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.5 g, 5.17 mmol) using 4-(diethylamino)-2hydroxybenzaldehyde (306a ) (1.0 g, 5.17 mmol; CAS No. 17754-90-4), K ₂ CO ₃ (2.146 g, 15.52 mmol) in DMF (20 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 020% EtOAc in hexane), 2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)benzaldehyde (306b) (1 .79 g, 86% yield) as an oily, pale yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.5 Hz , 1H), 7.72 (d, J=1.5 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.12 (dd, J=2.2, 0, 7 Hz, 1H), 6.35 (dd, J=9.0, 2.2 Hz, 1H), 6.24 (d, J=2.2 Hz, 1H), 5.36 (s, 2H) , 3.41 (k, J=7.0 Hz, 4H), 1.06 (t, J=7.0 Hz, 6H); MS (ESI+): 402/404 (M+1).

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Stage-2. Preparation of 3-((7-bromobenzofuran-5 -yl)methoxy)-N,N-diethyl-4-(2-(methylsulfinyl)-2(methylthio)vinyl)aniline (306c).

Compound 306c was prepared according to the procedure described in Step-3 of Scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4-(diethylamino)benzaldehyde (306b) (1.79 g, 4.45 mmol) in THF (40 mL) using methyl(methylsulfinylmethyl)sulfane (2.211 g, 17.80 mmol), Triton-B (40% methanol solution, 1.005 mL, 2.225 mmol) and reflux for 3 days. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-40% EtOAc in hexane) 3-((7-bromobenzofuran-5-yl)methoxy)-N,N-diethyl- 4-(2(methylsulfinyl)-2-(methylthio)vinyl)aniline (306c) as a thick yellow oil (1.24 g); MS (ESI+) 508/510 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate (306d).

Compound 306d was prepared according to the procedure described in step-4 of Scheme-266 from 3((7-bromobenzofuran-5-yl)methoxy)-N,N[-diethyl-4-(2-(methylsulfinyl)-2-( methylthio)vinyl)aniline (306c) (1.24 g, from step-2) in ethanol (20 ml) using HCl (4 M in 1,4-dioxane, 5.56 ml, 22.25 mmol) and heat reflux for 3 days. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-8% ethyl acetate and hexanes), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4- (diethylamino)phenyl)acetate (306d) (96 mg, 5% yield) as a clear, colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.27 (d, J= 2.4 Hz, 1H), 6.16 (dd, J=8.3, 2.3 Hz, 1H), 5.18 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.46 (s, 2H), 3.29 (k, J=7.8, 7.0 Hz, 4H), 1.10 (t, J=7.1 Hz, 3H), 1, 02 (t, J=6.9 Hz, 6H); MS (ESI+): 460/462 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(diethylamino)phenyl)acetate (306e).

Compound 306e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate (306d) (92 mg , 0.200 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (94 mg, 0.500 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (21.04 mg, 0.030 mmol), potassium carbonate (0.182 ml, 0.600 mmol) in water (1 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-5% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl )methoxy)-4-(diethylamino)phenyl)acetate (306e) (48 mg, 49% yield) as a clear, colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.76-7, 67 (m, 2H), 7.59 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.43-7.37 (m, 1H ), 7.04 (d, J=2.2 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.33 (d, J=2.3 Hz, 1H), 6.16 (dd, J=8.4, 2.4 Hz, 1H), 5.23 (s, 2H), 3.94 (k, J=7.1 Hz, 2H), 3.81 (s , 2H), 3.46 (s, 2H), 3.31-3.28 (m, 4H), 1.06-0.99 (m, 9H); MS (ESI+): 487 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(diethylamino)phenyl)acetic acid (306f).

Compound 306f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl )acetate (306e) (48 mg, 0.099 mmol) in MeOH (3 mL), using 2 M aqueous lithium hydroxide (0.247 mL, 0.493 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetic acid (306f) (19 mg, 42% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ +D ₂ O) δ 8.05 (d, J=2.2 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7, 93 (dt, J=7.8, 1.4 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.69-7.58 (m, 2H), 7.54 (dt, J=7.7, 1.4 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.317.22 (m, 1H), 7.12-6.98 ( m, 2H), 5.35 (s, 2H), 4.16 (s, 2H), 3.66 (s, 2H), 3.55 (k, J=7.1 Hz, 4H), 0, 97 (t, J=7.1 Hz, 6H); MS (ESI+): 459 (M+1), (ESI-): 457 (M-1).

- 395 045626

Scheme-307

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4isopropylphenyl)acetic acid (307f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylbenzaldehyde (307b).

Compound 307b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.766 g, 6.09 mmol) using 2-hydroxy-4isopropylbenzaldehyde (307a) (1 .0 g, 6.09 mmol; CAS No. 536-23-3), K ₂ CO ₃ (2.53 g, 18.27 mmol) in DMF (20 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-5% EtOAc in hexane), 2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylbenzaldehyde (307b) (2.00 g, 88% yield) as a pale yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.35 (d, J=0.9 Hz, 1H), 8.14 (dd, J=2.2, 0.9 Hz, 1H), 7 .86 (t, J=1.2 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.65 (dd, J=7.9, 0.9 Hz, 1H) , 7.23 (s, 1H), 7.13 (dd, J=2.2, 0.9 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 5.38 ( s, 2H), 2.96 (p, J=6.9 Hz, 1H), 1.22 (dd, J=6.9, 0.9 Hz, 6H); MS (ESI+): 395/397 (M+Na).

Stage-2. Preparation of 7-bromo-5-((5-isopropyl-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (307c).

Compound 307c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4-isopropylbenzaldehyde (307b) (970 mg, 2.60 mmol) in THF (20 ml ), using methyl(methylsulfinylmethyl)sulfane (517 mg, 4.16 mmol), Triton-B (40% methanol solution, 0.587 ml, 1.299 mmol) and reflux for 16 hours. This resulted in the following treatment and Purification by flash column chromatography (silica gel, eluted with 0-30% EtOAc in hexane) 7-bromo-5-((5-isopropyl-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl) benzofuran (307c) (0.97 g) as a thick yellow syrup; MS (ESI+): 479/481 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d).

Compound 307d was prepared according to the procedure described in step-4 of Scheme-266 from 7bromo-5-((5-isopropyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (307c ) (0.97 g, from step-2) in ethanol (20 ml), using HCl (4 M in 1,4-dioxane, 1.949 ml, 7.80 mmol) and refluxing for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-5% ethyl acetate and hexanes), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl )acetate (307d) (0.63 g, 56% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (t, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.62 (d , J=1.6 Hz, 1H), 7.18-7.06 (m, 2H), 6.98 (d, J=1.7 Hz, 1H), 6.79 (dd, J=7, 6, 1.6 Hz, 1H), 5.18 (s, 2H), 4.01 (cd, J=7.2, 1.9 Hz, 2H), 3.56 (s, 2H), 2, 86 (p, J=6.9 Hz, 1H), 1.21 (d, J=1.8 Hz, 3H), 1.19 (d, J=1.9 Hz, 3H), 1.07 ( td, J=7.1, 1.8 Hz, 3H); MS (ESI+) 431/433 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4isopropylphenyl)acetate (307e).

Compound 307e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d) (150 mg, 0.348 mmol ) in dioxane (4 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (107 mg, 0.522 mmol), bis(triphenylphosphine) palladium(I) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (24 mg, 0.035 mmol), 2 M aq. K ₂ CO ₃ (0.522 ml, 1.043 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with 0-3% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)benzofuran5-yl)methoxy)-4-isopropylphenyl)acetate (307e) (101 mg) as a clear, colorless oil; MS (ESI+): 476 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4isopropylphenyl)acetic acid (307f).

Compound 307f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl )acetate (307e) (101 mg, from previous step-4) in MeOH (3 ml), using 2 M aqueous lithium hydroxide (0.422 ml, 1.391 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetic acid (307f) (76 mg, 49% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.67 (t, J=7.3 Hz, 2H), 7.49 (t, J=1.3 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.11 (d, J= 7.7 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.78 (dd, J=7, 8, 1.6 Hz, 1H), 5.25 (s, 2H), 4.17 (s, 2H), 3.52 (s, 2H), 2.94-2.80 (m, 1H), 1.21 (s, 3H), 1.18 (s, 3H). ¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ -118.44; MS (ESI+): 448 (M+1), (ESI-): 446 (M-1); analysis calculation for C27H26FNO4-HCl-0.75H2O: C, 65.19; N, 5.77; Cl, 7.13; N, 2.82; observed: C, 65.36; N, 5.61; Cl, 7.46; N, 2.99.

Scheme-308

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5chlorophenyl)acetic acid (308h).

Stage-1. Preparation of 4-(tert-butyl)-5-chloro-2-methoxybenzaldehyde (308b).

K ₂ CO ₃ ( 3.90 g, 28.2 mmol) and refluxed for 2 hours. The reaction mixture was concentrated to remove acetone and diluted with ethyl acetate (50 ml), washed with water (2x20 ml), brine (20 ml), dried, filtered and concentrated. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes) to give 4-(tert-butyl)-5-chloro-2-methoxybenzaldehyde (308b) (298 mg, 28% yield) as white solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 3.33 (s, 3H), 1, 48 (s, 9H). MS (ESI+): 227.1 (M+1).

Stage-2. Preparation of (2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)-1(methylsulfinyl)vinyl)(methyl)sulfane (308c).

Compound 308c was prepared according to the procedure described in step-3 of scheme-266 from 4(tert-butyl)-5-chloro-2-methoxybenzaldehyde (308b) (295 mg, 1.301 mmol) in THF (20 ml) using methyl (methylsulfinylmethyl)sulfane (259 mg, 2.082 mmol), Triton-B (40% methanol solution) (0.296 ml, 0.651 mmol) and reflux for 12 h. This resulted in, after workup and purification by flash chromatography on a column (silica gel, 40 g, eluted with ethyl acetate and hexanes) (2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)-1(methylsulfinyl)vinyl)(methyl)sulfane (308c) (237 mg , 55% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 7.64 (s, 1H), 7.07 (s, 1H), 3.88 (s, 3H), 2. 74 (s, 3H), 2.32 (s, 3H), 1.47 (s, 9H).

Stage-3. Preparation of ethyl 2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)acetate (308d).

Compound 308d was prepared according to the procedure described in step-4 of scheme-266 from (2(4-(tert-butyl)-5-chloro-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (308c ) (290 mg, 0.871 mmol) in ethanol (10 ml), using HCl (4 M in 1,4-dioxane) (0.871 ml, 3.48 mmol) and heating at reflux for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes), ethyl 2(4-(tert-butyl)-5-chloro-2-methoxyphenyl)acetate (308d) (170 mg, 69% yield) in the form of a clear syrup;

^1H NMR (300 MHz, DMSO-d6) δ 7.22 (s, 1H), 6.96 (s, 1H), 4.06 (k, J=7.1 Hz, 2H), 3.77 ( s, 3H), 3.54 (s, 2H), 1.45 (s, 9H), 1.17 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(4-(tert-butyl)-5-chloro-2-hydroxyphenyl)acetate (308e).

Compound 308e was prepared according to the procedure described in step-5 of Scheme-257 from ethyl 2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)acetate (308d) (170 mg, 0.597 mmol) in dichloromethane (5 ml) using boron tribromide (0.226 ml, 2.388 mmol). This resulted in ethyl 2(4-(tert-butyl)-5-chloro-2-hydroxyphenyl)acetate (308e) (84 mg, 52% yield) as a clear syrup;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.64 (s, 1H), 7.12 (s, 1H), 6.93 (s, 1H), 4.06 (k, J=7, 1 Hz, 2H), 3.50 (s, 2H),

1.39 (s, 9H), 1.17 (t, J=7.1 Hz, 3H). MS (ESI+): 271.1 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate (308f) .

Compound 308f was prepared according to the procedure described in step-2 of Scheme-152 from tert-butyl 3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b) (135 mg, 0.325 mmol) using ethyl 2(4 -(tert-butyl)-5-chloro-2-hydroxyphenyl)acetate (308e) (80 mg, 0.295 mmol), K2CO3 (123 mg, 0.886 mmol) in DMF (5 ml) and stirring at room temperature for 12 h This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with EtOAc in hexane 0-50%), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)benzofuran-5yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate (308f) (141 mg, 79% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.76-7.68 (m, 3H), 7.56-7.44 (m , 3H), 7.34-7.23 (m, 2H), 7.13 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.27 (s, 2H) , 4.22 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.43 (s, 9H) , 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate (308g).

Compound 308g was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4-(tert-butyl)-5chlorophenyl)acetate (308f) (135 mg, 0.223 mmol) in DCM (5 mL) using TFA (0.343 mL, 4.45 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)4-(tert-butyl)-5-chlorophenyl)acetate (308g) (113 mg); mS (ESI+): 506.2 (M+1).

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5chlorophenyl)acetic acid (308h).

Compound 308h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl )-5-chlorophenyl)acetate (308g) (113 mg, 0.223 mmol) in MeOH (2 ml), THF (2 ml), using a solution of lithium hydroxide (22 mg, 0.893 mmol) in water (0.4 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (15 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetic acid (308h) (30 mg, 28% yield), hydrochloride salt, as a white solid ;

^1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.41 (s, 2H), 8.12 (d, J=2.2 Hz, 1H), 8.00 ( s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.66-7.51 (m, 2H ), 7.26 (s, 1H), 7.14-7.04 (m, 2H), 5.30 (s, 2H), 4.14 (s, 2H), 3.57 (s, 2H) , 1.42 (s, 9H); MS (ESI+): 478.1 (M+1), (ESI-): 476.1 (M-1); analysis calculation for C ₂ 8H ₂ 8ClNO4-1.25H ₂ O-HCl: C, 62.63; N, 5.91; N, 2.61; observed: C, 62.59; N, 5.85; N, 2.70.

- 398 045626

Scheme-309 o

NaOH, MeOH THF

NaOH. MeOH

OH

100°C. 12 h

309g

309h

Pd(PPh ₃ ) ₂ CI ₂

Na,CO ₃ soci ₂ ,dcm

NaOH.MeOH

RT. 12 h

About °C. 2h

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (309h).

Stage-1. Preparation of methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-carboxylate (309a).

Compound 309a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a) (500 mg, 1.44 mmol) in 1,4- dioxane (10.0 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (625 mg, 1.87 mmol) , Pd(PPh ₃ ) ₂ Cl ₂ (0.15 g, 0.216 mmol), K3PO4 (919 mg, 4.33 mmol) and heating under nitrogen at 90°C for 12 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-30% EtOAc in n-heptane) methyl 7(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-( methoxymethyl)benzofuran-5-carboxylate (309a) (200 mg, 32%) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (d, J=1.7 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.75 (d , J=7.7 Hz, 1H), 7.67 (s, 1H), 7.51 (t, J=7.5 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H ), 7.13 (s, 1H), 4.59 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (s, 3H), 3.33 (s , 3H), 1.40 (s, 9H).

Stage-2. Preparation of 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-carboxylic acid (309b).

Compound 309b was prepared according to the procedure described in step-4 of Scheme-4 from methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate (309a ) (1.3 g, 3.05 mmol) in THF (13 mL) MeOH (39 mL) using aqueous sodium hydroxide (13.0 mL, 0.36 g, 9.16 mmol). This gave, upon treatment, 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylic acid (309b) (1.2 g, 95.45%) as off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 8.05 (d, J=1.7 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.68 (s, 1H), 7.50 (dd, J=8.7, 6.7 Hz, 2H), 7, 32 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 4.59 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3, 33 (s, 3H), 1.40 (s, 9H).

Stage-3. Preparation of tert-butyl 3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7yl)benzylcarbamate (309c).

Compound 309c was prepared according to the procedure described in step-1 of Scheme-23 from 7-(3-399 045626 (((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylic acid (309b) (1.2 g, 2.91 mmol) using N-methylmorpholine (0.35 g, 3.49 mmol) in THF (24 mL), isobutyl chloroformate (0.47 g, 3.49 mmol) and NaBH ₄ (0.33 g, 8.74 mmol) in water (10 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-30% EtOAc in n-heptane), tert-butyl 3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7yl)benzylcarbamate (309c) (1.0 g, 86%) as oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.59-7.53 (m, 1H), 7.53-7.39 (m, 3H), 7.28 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 5.28 (t, J=5.7 Hz , 1H), 4.63 (d, J=5.5 Hz, 2H), 4.55 (s, 2H), 4.31-4.18 (m, 2H), 3.32 (s, 3H) , 1.40 (s, 9H).

Stage-4. Preparation of tert-butyl 3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7yl)benzylcarbamate (309d).

Compound 309d was prepared according to the procedure described in step-4 of scheme-257 from tert-butyl 3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (309c) (0.8 g, 2. 01 mmol) in DCM (16 ml) using SOCl ₂ (0.47 g, 4.02 mmol) and stirring at 0°C for 2 hours. This resulted in tert-butyl 3-(5-( chloromethyl)-2-(methoxymethyl)benzofuran-7yl)benzylcarbamate (309d) (0.8 g, 96%) as an oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.53-7.39 (m, 3H), 7.28 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 4.63 (d, J=5 .5 Hz, 2H), 4.55 (s, 2H), 4.22 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 1.40 (s, 9H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (309e).

Compound 309e was prepared according to the procedure described in step-6 of scheme-257 from tert-butyl 3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (309d) (0.7 g, 1. 68 mmol) in DMSO (7 ml), using ethyl 2-(4-cyano-2-hydroxyphenyl) acetate (257f) (0.35 g, 1.7 mmol), Cs ₂ CO ₃ (0.58 g, 1 .68 mmol) and stirring at room temperature for 24 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-10% EtOAc in n-heptane), ethyl 2-(2-(( 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (309e) (0.5 g, 51%) in in the form of oil;

1H NMR (300 MHz, DMSO-d6) δ 7.81-7.59 (m, 4H), 7.59-7.25 (m, 6H), 7.10-6.93 (m, 1H), 5.30 (s, 2H), 4.66-4.44 (m, 2H), 4.24 (s, 2H), 3.89 (m, 2H), 3.72 (dm, 2H), 3 .37 (s, 3H), 1.40 (s, 9H), 0.95 (t, 3H).

Stage-6. Preparation of 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (309f).

Compound 309f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran -5-yl)methoxy)-4cyanophenyl)acetate (309e) (0.5 g, 0.85 mmol) in MeOH (5 ml), using a solution of NaOH (0.102 g, 2.56 mmol) in water (5 ml) when heated at 100°C for 12 hours. This resulted in the preparation after treatment of 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran- 5yl)methoxy)-4-cyanophenyl)acetic acid (309f) (0.32 g, 67%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.77-7.67 (m, 3H), 7.58 (d, J=9.8 Hz, 2H), 7.53-7.36 (m , 4H), 7.30 (d, J=7.7 Hz, 1H), 6.99 (s, 1H), 5.32 (s, 2H), 4.57 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.68 (s, 2H), 3.33 (s, 3H), 1.38 (s, 9H); MS (ESI-): 555.2 (M-1).

Stage-7. Preparation of 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetic acid (309g).

Compound 309g was prepared according to the procedure described in step-4 of scheme-4, from 2-(2((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran- 5-yl)methoxy)-4cyanophenyl)acetic acid (309f) (0.3 g, 0.53 mmol) in MeOH (3 ml), using a solution of NaOH (0.043 g, 1.70 mmol) in water (3 ml) when heated at 100°C for 12 hours. This resulted in the preparation after treatment of 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran- 5yl)methoxy)-4-carbamoylphenyl)acetic acid (309g) (0.19 g, 61%) as an off-white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 7.98 (s, 1H), 7.72 (s, 3H), 7.61 (s, 2H), 7.54-7.23 (m, 6H ), 6.98 (s, 1H), 5.31 (s, 2H), 4.57 (s, 2H), 4.23 (s, 2H), 3.70-3.59 (m, 2H) , 3.33 (s, 3H), 1.39 (s, 9H).

Stage-8. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)4-carbamoylphenyl)acetic acid (309h).

Compound 309h was prepared according to the procedure described in step-10 of Scheme-257 from 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran- 5-yl)methoxy)-4carbamoylphenyl)acetic acid (309g) ((0.18 g, 0.31 mmol) in 1,4-dioxane (1.8 ml) 1,4-dioxane.HCl was added at room temperature 28%, 1.8 ml) and stirred for 2 hours. This resulted in the preparation after treatment of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy) -4-carbamoylphenyl)acetic acid (309h) (0.025 g, 16%) as an off-white solid

- 400 045626 substances;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.24 (s, 3H), 8.02-7.89 (m, 3H), 7.74 (s, 1H), 7.66-7.26 (m, 7H), 7.01 (s, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 4.20-4.08 (m, 2H), 3.64 ( s, 2H), 3.32 (s, 3H). The result was purified by reverse phase column chromatography [C18 steel column, 250 mm x 30 mm, eluted with ACN in water (containing 0.1% TFA) from 0% to 100%] to obtain compound 309h 14 mgs as TFA salt ;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.32 (s, 1H), 8.20 (s, 3H), 7.98 (s, 1H), 7.96-7.91 (m, 2H ), 7.74 (d, J=1.6 Hz, 1H), 7.66-7.58 (m, 3H), 7.53 (d, J=7.7 Hz, 1H), 7.48 -7.43 (m, 1H), 7.37 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.64 (s, 2H), 3.32 (s, 3H); MS (ESI+): 475.20 (M+1).

Scheme-310

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (310c).

Stage-1. Preparation of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5yl)methoxy)phenyl)acetate (310a) .

Compound 310a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-(trifluoromethylsulfonyloxy)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (214d) ( 200 mg, 0.422 mmol), using bis(pinacolato)diboron (161 mg, 0.632 mmol), potassium acetate (124 mg, 1.265 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (34 mg, 0.042 mmol) in anhydrous dioxane (5 ml) under nitrogen atmosphere by heating at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane 0% to 10%] ethyl 2-(2-((7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (310a) (118 mg, 62% yield) as a colorless oil.

1H NMR (300 MHz, chloroform-d) δ 8.00 (dd, J=1.8, 0.9 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.50 (dd, J=5.6, 0.5 Hz, 1H), 7.33 (d, J=5.5 Hz, 1H), 7.25-7.19 (m, 2H), 7.00- 6.90 (m, 2H), 5.20 (s, 2H), 4.11 (k, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.41 (s, 12H ), 1.16 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5yl)methoxy)phenyl)acetate (310b).

Compound 310b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (310a) (118 mg, 0.261 mmol) in dioxane (4 ml), using (4-chloropyridin-2-yl)methanamine (74a) (41 mg, 0.287 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (18 mg, 0.026 mmol) and a solution of K2CO3 (108 mg, 0.783 mmol) in water (1.0 ml) heating in nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-10% MeOH in DCM] ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4yl) benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (310b) (47 mg) as a pale yellow oil; MS (ESI+): 433 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5yl)methoxy)phenyl)acetic acid (310c).

Compound 310c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy )phenyl)acetate (310b) (47 mg, from previous step-2) in MeOH (3 ml) water (1 ml), using NaOH (52 mg, 1.304 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with water in acetonitrile from 0% to 60%] 2-(2-((7-(2-(aminomethyl)pyridinium- 4yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (310c) (30 mg, 28% yield), HCl salt, as a pale green solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.81 (d, J=5.1 Hz, 1H), 8.55-8.30 (m, 3H), 8.09 (d, J=1 .5 Hz, 1H), 7.957.88 (m, 2H), 7.84 (dd, J=5.1, 1.8 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H ), 7.61 (d, J=5.5 Hz, 1H), 7.25 (dd, J=8.1, 6.6 Hz, 2H), 7.15-7.05 (m, 1H) , 6.98-6.86 (m, 1H), 5.33 (s, 2H), 4.41-4.26 (m, 2H), 3.61 (s, 2H); MS (ESI+): 405

- 401 045626 (M+1), (ESI-): 403 (M-1).

Scheme-311

Preparation of (3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7-yl)phenyl)methanamine (311b).

Stage-1. Preparation of tert-butyl 3-(5-((2-(cyanomethyl)phenoxy)methyl)benzofuran-7yl)benzylcarbamate (311a).

Compound 311a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (500 mg, 1.415 mmol) in DCM (15 ml) using triphenylphosphine (408 mg, 1.556 mmol), 2-(2-hydroxyphenyl)acetonitrile (188 mg, 1.415 mmol) and bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 571 mg, 1.556 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] tert-butyl 3-(5-((2(cyanomethyl)phenoxy)methyl) benzofuran-7-yl)benzylcarbamate (311a) (740 mg) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.79-7, 73 (m, 2H), 7.67 (d, J=1.7 Hz, 1H), 7.51-7.44 (m, 2H), 7.39-7.33 (m, 2H), 7 ,33-7.28 (m, 1H), 7.21 (dd, J=8.3, 1.2 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6, 98 (td, J=7.5, 1.1 Hz, 1H), 5.34 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (s, 2H ), 1.40 (s, 9H); MS (ESI+) 491.2 (M+Na);

Stage-2. Preparation of (3 -(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7 yl)phenyl)methanamine (311b).

Ammonium chloride ( 211 mg, 3.95 mmol), sodium azide (308 mg, 4.74 mmol) and heated at 100°C for 6 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (30 ml) and adjusted to pH 5 using 2 M hydrochloric acid. The reaction mixture was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried, filtered and concentrated in vacuo to give crude tert-butyl 3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy )methyl)benzofuran-7yl)benzylcarbamate. The crude material was transferred to DCM (20 ml), TFA (2.43 ml, 31.6 mmol) was added and stirred for 4 hours at RT. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 100%] followed by purification by preparative reverse phase column chromatography [C18 steel column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give (3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7-yl )phenyl)methanamine (311b) (25 mg, 4% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 3H, D ₂ O replaceable), 8.10 (d, J=2.2 Hz, 1H), 7.99-7.95 ( m, 1H), 7.90 (dt, J=7.1, 1.9 Hz, 1H), 7.61-7.51 (m, 4H), 7.32-7.22 (m, 2H) , 7.14 (dd, J=8.2, 1.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.94 (td, J=7.4, 1 .1 Hz, 1H), 5.25 (s, 2H), 4.28 (s, 2H), 4.21-4.11 (m, 2H); MS (ESI+): 412.1 (M+1); (ESI-): 410.1 (M-1).

Scheme-312

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetic acid (312b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4isopropylphenyl)acetate (312a).

Compound 312a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d) (150 mg, 0.348 mmol ) in dioxane

- 402 045626 (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (98 mg, 0.522 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (24 mg , 0.035 mmol), 2 M aq. K ₂ CO ₃ (0.522 ml, 1.043 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-3% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-4isopropylphenyl)acetate (312a) (115 mg), which was used in the next reaction without further purification; MS (ESI+): 458 (M+1).

Stage-2. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-4isopropylphenyl)acetic acid (312b).

Compound 312b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate ( 312a) (115 mg, from previous step-4) in MeOH (3 ml) using 2.5 M LiOH (0.417 ml, 1.043 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran5-yl)methoxy)-4-isopropylphenyl)acetic acid (312b) (70 mg, 47% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.94 (dt, J =7.6, 1.5 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.60 (t , J=7.6 Hz, 1H), 7.54 (dt, J=7.8, 1.5 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.08 (s, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.78 (dd, J=7.7, 1.5 Hz, 1H), 5.26 (s, 2H) , 4.14 (s, 2H), 3.53 (s, 2H), 2.86 (p, J=7.0 Hz, 1H), 1.21 (s, 3H), 1.19 (s, 3H); MS (ESI+): 430 (M+1), (ESI-): 428 (M-1).

Scheme-313

^313b 313c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3yl)phenyl)acetic acid (313c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(furan-3-yl)phenyl)acetate (313a).

Compound 313a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (211 mg, 0.355 mmol) in dioxane (4 ml), water (1 ml), using furan-3-ylboronic acid (59.6 mg, 0.532 mmol), Pd( PPh ₃ ) ₂ Cl ₂ (25 mg, 0.035 mmol) and a solution of 2 M aq. K2CO3 (0.532 mL, 1.065 mmol) under nitrogen while heating at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-15% ethyl acetate in hexanes), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate (313a) (159 mg) as a clear, colorless oil; MS (ESI+): 604 (M+Na).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3yl)phenyl)acetate (313b).

Compound 313b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(furan-3yl)phenyl)acetate (313a) (159 mg, from step-1) in methanol (5 ml) using HCl (4 M in 1,4-dioxane, 0.266 ml, 1.065 mmol) and stirred for 16 hours at room temperature. This resulted in the preparation, after treatment of a mixture of methyl and ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)4-(furan-3-yl)phenyl)acetate (313b) , which was used as is in the next stage; MS (ESI+) 468 (methyl) and 482 (ethyl) (M+1).

- 403 045626

Stage-3. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3 yl)phenyl)acetic acid (313c).

Compound 313c was prepared according to the procedure described in step-6 of Scheme-1 from a mixture of methyl and ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-( furan-3-yl)phenyl)acetate (313b) (from previous step-2) in MeOH (3 ml), water (1 ml), using aq. 2.5 M LiOH (0.710 ml, 1.775 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0 to 60%] 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4-(furan-3-yl)phenyl)acetic acid ( 313c) (45 mg, 28.0% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (dd, J=1.6, 0.9 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 8, 01 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.6, 1.6 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.75 (t, J=1.7 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7, 54 (dt, J=7.7, 1.5 Hz, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.16 (dd, J=7.6, 1.4 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.98 (dd, J=1.9, 0, 9 Hz, 1H), 5.34 (s, 2H), 4.14 (s, 2H), 3.58 (s, 2H); MS (ESI+): 454 (M+1), (ESI-): 452 (M-1).

Scheme-314

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)acetic acid (314f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-6-methylbenzaldehyde (314b).

Compound 314b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (2.13 g, 7.34 mmol) using 2-hydroxy-6-methylbenzaldehyde ( 314a) (1 g, 7.34 mmol), K2CO3 (3.05 g, 22.03 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash chromatography on a column (silica gel, 40 g, eluted with EtOAc in hexane) 2-((7-bromobenzofuran-5yl)methoxy)-6-methylbenzaldehyde (314b) (1.06 g, 42% yield) as a white solid; MS (ESI+): 367.0, 369.0 (M+Na).

Stage-2. Preparation of 7-bromo-5-((3-methyl-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (314c).

Compound 314c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-6-methylbenzaldehyde (314b) (1.0 g, 2.90 mmol) in THF ( 20 mL), using methyl(methylsulfinylmethyl)sulfane (0.576 g, 4.64 mmol), Triton-B (40% methanol solution) (0.658 mL, 1.448 mmol) and reflux for 12 h. This resulted in after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with EtOAc in hexane) 7-bromo-5-((3-methyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy )methyl)benzofuran (314c) (579 mg, 44% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.44 (s, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H) , 6.99 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.18 (s, 2H), 3.33 (s, 3H) , 2.66 (s, 3H), 2.20 (s, 3H); MS (ESI+): 451.00; 452.90 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-methylphenyl)acetate (314d).

Compound 314d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((3-methyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (314c ) (550 mg, 1.218 mmol) in ethanol (40 mL) using HCl (4 M in 1,4-dioxane, 1.218 mL, 4.87 mmol) and reflux for 12 h. This resulted in treatment and purification by flash column chromatography (silica gel, eluted with ethyl acetate and hexanes) ethyl 2-(2((7-bromobenzofuran-5-yl)methoxy)-6-methylphenyl)acetate (314d) (350 mg, 71% yield ) in the form of oil;

1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.60 (d, J =1.5 Hz, 1H), 7.17-7.09 (m, 2H), 6.93 (dd, J=8.5, 3.5 Hz, 1H), 6.84-6.79 ( m, 1H), 5.17 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 2.24 (s, 3H), 1, 10 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-404 045626 methylphenyl)acetate (314e).

Compound 314e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-6-methylphenyl)acetate (314d) (340 mg, 0.843 mmol ) in dioxane (10 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (253 mg, 1.349 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (89 mg, 0.126 mmol) and a solution of K ₂ CO ₃ (350 mg, 2.53 mmol) in water (3 ml) heating in an argon atmosphere at 100 ° C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran- 5-yl)methoxy)-6-methylphenyl)acetate (314e) (197 mg, 54% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.71 (dt, J=7.8, 1.6 Hz, 2H), 7.58 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.42- 7.36 (m, 1H), 7.13 (t, J=7.9 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.97 (d, J=8 ,2 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 3.95 (k, J=7.5 Hz, 2H), 3, 81 (s, 2H), 3.68 (s, 2H), 2.23 (s, 3H), 1.02 (t, J=7.1 Hz, 3H); MS (ESI+): 430.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6methylphenyl)acetic acid (314f).

Compound 314f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)acetate ( 314e) (190 mg, 0.442 mmol) in MeOH (5 ml), THF (5 ml), using a solution of lithium hydroxide (42 mg, 1.769 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)acetic acid (314f) (120 mg, 68% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.93 (dt, J=7.5, 1.7 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.63- 7.50 (m, 2H), 7.11 (t, J=7.9 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.94 (d, J=8 ,2 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.25 (s, 2H), 4.14 (s, 2H), 3.64 (s, 2H), 2.23 (s, 3H); MS (ESI+): 402.10 (M+1), (ESI-): 400.10 (M-1); analysis calculation for C ₂ 5H _{2 3} ^4-HC1-0.75H ₂ O: C, 66.52; N, 5.69; Cl, 7.85; N, 3.10; observed C, 66.68; N, 5.99; Cl, 7.73; N, 3.17.

Scheme-315

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (315f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylbenzaldehyde (315b).

Compound 315b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (819 mg, 2.82 mmol) using 4-ethyl-2-hydroxybenzaldehyde (314a) (424 mg, 2.82 mmol; CAS No. 161876-64-8), ^CO ₃ (1171 mg, 8.47 mmol) in DMF (20 ml) and stirring at room temperature for 16 hours. This resulted in after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 0-7% EtOAc in hexane) 2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylbenzaldehyde (315b) (615 mg, 61% yield) as a pale yellow solid.

1H NMR (300 MHz, DMSO-d6) δ 10.35 (d, J=0.7 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.90-7.80 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.22 (s, 1H), 7.14 (dd, J=2.2, 0.6 Hz, 1H), 6.96 (d, 1H), 5.37 (s, 2H), 2.67 (k, J=7.6 Hz, 2H) , 1.20 (t, J=7.9, 7.3 Hz, 3H); MS (ESI+): 381/383 (M+Na).

Stage-2. Preparation of 7-bromo-5-((5-ethyl-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (315c).

Compound 315c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4-ethylbenzaldehyde (315b) (608 mg, 1.693 mmol) in THF (20 ml), using methyl(methylsulfinylmethyl)sulfane (336 mg, 2.71 mmol), Triton-B (40% methanol solution)

- 405 045626 (0.382 ml, 0.846 mmol) and reflux for 16 hours. This resulted in the preparation after treatment of 7-bromo-5-((5-ethyl-2-(2-(methylsulfinyl)-2(methylthio )vinyl)phenoxy)methyl)benzofuran (315c) (880 mg) as a pale green oil; MS (ESI+):

465/467 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d).

Compound 315d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((5-ethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (315c ) (880 mg; from previous step-2) in ethanol (20 ml), using HCl (4 M in 1,4-dioxane, 2.116 ml, 8.46 mmol) and refluxing for 16 hours. This resulted to obtain, after work-up and purification by flash column chromatography (silica gel, eluted with 0-5% ethyl acetate and hexanes), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d ) (460 mg, 65% yield) as a yellow solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.2 Hz, 1H), 7.72 (t, J=1.1 Hz, 1H), 7.63-7, 59 (m, 1H), 7.157.07 (m, 2H), 6.97-6.93 (m, 1H), 6.76 (dt, J=7.5, 1.0 Hz, 1H), 5 .17 (s, 2H), 4.00 (k, J=7.1, 0.7 Hz, 2H), 3.57 (s, 2H), 2.59 (k, J=7.6 Hz, 2H), 1.18 (t, 3H), 1.07 (t, J=7.1, 0.7 Hz, 3H); MS (ESI+): 417/419 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetate (315e).

Compound 315e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d) (257 mg, 0.616 mmol ) in dioxane (4 ml) and water (1 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (190 mg, 0.924 mmol), bis(triphenylphosphine)palladium(P) chloride ( Pd(PPh ₃ ) ₂ Cl ₂ ) (43 mg, 0.062 mmol) and 3.3 M water. K ₂ CO ₃ (0.560 ml, 1.848 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in 0% to 3% DCM), ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl) benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315e) (159 mg) as colorless oil; MS (ESI+): 462 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (315f).

Compound 315f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl )acetate (315e) (159 mg, from previous step-4) in MeOH (3 ml) using aq. 2.5 M LiOH (0.985 ml, 2.463 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7- (3-(aminomethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (315f) (113 mg, 42% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.04 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.73-7, 60 (m, 2H), 7.44 (dd, J=13.9, 6.3 Hz, 2H), 7.17-7.02 (m, 2H), 6.97 (d, J=1, 6 Hz, 1H), 6.82-6.71 (m, 1H), 5.24 (s, 2H), 4.18 (s, 2H), 3.53 (s, 2H), 2.59 ( k, 2H), 1.18 (t, J=7.6 Hz, 3H); MS (ESI+): 434 (M+1), (ESI-): 432 (M-1); analysis calculation for C ₂₆ H ₂₄ FNO ₄ -HCl-0.5H ₂ O: C, 65.20; N, 5.47; Cl, 7.40; N, 2.92; observed: C, 65.21; N, 5.43; Cl, 7.18; N, 2.91.

Scheme-316

^315d 316a 316b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (316b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetate (316a).

Compound 316a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d) (200 mg, 0.479 mmol ) in dioxane (4 ml) and water (1 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (117 mg, 0.623 mmol), bis(triphenylphosphine)palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (34 mg, 0.048 mmol) and 2 M aq. K ₂ CO ₃ (0.719 ml, 1.438 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in 0% to 5% DCM), ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran- 5-yl)methoxy)-4-ethylphenyl)acetate (316a) (165 mg) as clear

- 406 045626 colorless oil; MS (ESI+): 444 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (316b).

Compound 316b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate ( 316a) (165 mg, from previous step-1) in MeOH (3 ml) using aq. 2.5 M LiOH (0.767 ml, 1.917 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4-ethylphenyl)acetic acid (316b) (120 mg, 60% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 8.02 (t, J=1.7 Hz, 1H), 7.94 (dt , J=7.5, 1.6 Hz, 1H), 7.76 (dd, J=5.6, 1.6 Hz, 1H), 7.66 (dd, J=5.7, 1.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.14-7.03 (m, 2H), 6.98 (s, 1H), 6.75 (dd, J=7, 6, 1.5 Hz, 1H), 5.24 (s, 2H), 4.13 (s, 2H), 3.55 (s, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.30-1.13 (m, 3H); MS (ESI+): 416 (M+1), 414 (M-1); analysis calculation for C2 ₆ H25NO4-HCl-0.75H2O: C, 67.09; N, 5.96; Cl, 7.62; N, 3.01; observed: C, 67.20; N, 5.92; Cl, 7.58; N, 3.03.

Scheme-317

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetic acid (317f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)benzaldehyde (317b).

Compound 317b was prepared according to the procedure described in step-2 of Scheme-23 from (7bromobenzofuran-5-yl)methanol (23a) (1.09 g, 4.80 mmol) in DCM (20 ml) using triphenylphosphine ( 1.637 g, 6.24 mmol), 4-(tert-butyl)-2-hydroxybenzaldehyde (317a) (0.898 g, 5.04 mmol; CAS No. 6623234-6) and (E)-bis(4-chlorobenzyl)diazen -1,2-dicarboxylate (DCAD, 2.292 g, 6.24 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography (silica gel eluted with EtOAc in 0% to 5% hexane), 2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)benzaldehyde (317b ) (554 mg, 30% yield) as an oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.36 (d, J=0.8 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.86 (d , J=1.5 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30 (d, J =1.7 Hz, 1H), 7.19-7.08 (m, 2H), 5.42 (s, 2H), 1.30 (s, 9H); MS (ESI+): 409/411 (M+Na).

Stage-2. Preparation of 7-bromo-5-((5-(tert-butyl)-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (317c).

Compound 317c was prepared according to the procedure described in step-3 of Scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)benzaldehyde (317b) (554 mg, 1.431 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane (284 mg, 2.289 mmol), Triton-B (40% methanol solution) (0.323 mL, 0.715 mmol) and reflux for 16 h. This resulted in treatment of 7-bromo-5-((5-(tert-butyl)-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (317c) as a pale green oil, which was used for next stage without additional purification; MS (ESI+) 493/495 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate (317d).

Compound 317d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((5-(tert-butyl)-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl )benzofuran (317c) (crude from previous step-2) in ethanol (20 ml) using HCl (4 M in 1,4-dioxane, 1.431 ml, 5.72 mmol) and reflux for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-5% ethyl acetate and hexanes), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4- (tert-butyl)phenyl)acetate (317d)

- 407 045626 (440 mg, 69% yield) in the form of a yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.63 (d, J =1.5 Hz, 1H), 7.19-7.05 (m, 3H), 6.92 (dd, J=7.8, 1.8 Hz, 1H), 5.20 (s, 2H) , 4.02 (dd, J=7.9, 6.4 Hz, 2H), 3.56 (s, 2H), 1.27 (s, 9H), 1.08 (td, J=7.2 , 1.3 Hz, 3H); MS (ESI+) 445/447(M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate (317e).

Compound 317e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate (317d) ( 166 mg, 0.373 mmol) in dioxane (4 ml) and water (1 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (91 mg, 0.485 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (26 mg, 0.037 mmol) and 2 M aq. K2CO3 (0.559 ml, 1.118 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in 0% to 5% DCM), ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran- 5-yl)methoxy)-4-(tert-butyl)phenyl)acetate (317e) (124 mg) as a clear, colorless oil; MS (ESI+): 472 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetic acid (317f).

Compound 317f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl )phenyl)acetate (317e) (from previous step-4) in MeOH (3 ml) using aq. 2.5 M LiOH (0.596 ml, 1.491 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran5-yl)methoxy)-4-(tert-butyl)phenyl)acetic acid (317f) (80 mg, 48% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.93 (dt, J=7.0, 2.0 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.65- 7.51 (m, 2H), 7.15-7.09 (m, 2H), 7.07 (d, J=2.2 Hz, 1H), 6.91 (dd, J=7.8, 1.7 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 1.27 (s, 9H); MS (ESI+): 444 (M+1), 442 (M-1); analysis calculation for C2 ₈ H29NO4-HCl-H2O: C, 67.53; N, 6.48; Cl, 7.12; N, 2.81; observed: C, 67.55; N, 6.43; Cl, 6.97; N, 2.89.

Scheme-318

^318b 318c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2yl)phenyl)acetic acid (318c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(furan-2-yl)phenyl)acetate (318a).

Compound 318a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (304 mg, 0.511 mmol) in dioxane (4 ml), water (1 ml), using furan-2-ylboronic acid (86 mg, 0.767 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (36 mg, 0.051 mmol) and a solution of 2 M aq. K ₂ CO ₃ (0.767 ml, 1.534 mmol) under nitrogen atmosphere while heating at 100°C for 16 hours in an oil bath. This resulted, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with 0-20% ethyl acetate in hexanes) ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate (318a) (230 mg) as a clear, colorless oil; MS (ESI+): 604 (M+Na).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2

- 408 045626 yl)phenyl)acetate (318b).

Compound 318b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(furan-2yl)phenyl)acetate (318a) (230 mg, from step-1) in methanol (5 ml) using HCl (4 M in 1,4-dioxane, 0.767 ml, 3.07 mmol) and stirred for 16 hours at room temperature. This resulted in the preparation, after treatment of a mixture of methyl and ethyl esters, of 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate ( 318b), which was used as is in the next stage; MS (ESI+): 468 (methyl) and 482 (ethyl) (M+1).

Stage-3. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2yl)phenyl)acetic acid (318c).

Compound 318c was prepared according to the procedure described in step-6 of Scheme-1 from a mixture of methyl and ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-( furan-2-yl)phenyl)acetate (318b) (from previous step-2) in MeOH (3 ml), water (1 ml), using aq. 2.5 M LiOH (1.023 ml, 2.56 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0 to 60%] 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(furan-2-yl)phenyl) acetic acid (318c) (107 mg, 46% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.94 (dt, J=7.4, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.74 (dd, J=1.8, 0.7 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (dt, J=7.8, 1.5 Hz, 1H ), 7.42 (s, 1H), 7.27 (d, J=0.8 Hz, 2H), 7.08 (d, J=2.2 Hz, 1H), 6.96 (dd, J =3.4, 0.8 Hz, 1H), 6.60 (dd, J=3.4, 1.8 Hz, 1H), 5.36 (s, 2H), 4.14 (s, 2H) , 3.60 (s, 2H); MS (ESI+): 454 (M+1), 452 (M-1); analysis calculation for C28H ₂ 3NO5-HCl «H ₂ O: C, 66.21; N, 5.16; Cl, 6.98; N, 2.76; observed: C, 66.50; N, 5.00; Cl, 6.57; N, 2.69.

Scheme-319

319b _319с

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3yl)phenyl)acetic acid (319c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate (319a)

Solution of ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (182b) (240 mg, 0.404 mmol) , pyridin-3-ylboronic acid (74.4 mg, 0.606 mmol), Pd ₂ (dba) ₃ (37.0 mg, 0.040 mmol), XPhos (38.5 mg, 0.081 mmol), and 1.27 M aq . K ₃ PO ₄ (0.636 ml, 0.807 mmol) in n-BuOH (4 ml) in a scintillation assay vial was heated at 100°C under nitrogen for 16 hours. The resulting dark red mixture was filtered, and the solid was washed with EtOAc ( 50 ml). The filtrate was concentrated under vacuum to dryness to remove n-BuOH. The residue was taken up in EtOAc (50 ml), washed with H2O (2x25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-40% EtOAc in hexane) to give ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate (319a) (90 mg) as a pale yellow oil; MS (ESI+): 593 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin3-yl)phenyl)acetate (319b).

Compound 319b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(pyridin-3-409 045626 yl)phenyl)acetate (319a) (90 mg, from step-1) in methanol (5 ml), using HCl (4 M in 1,4-dioxane, 0.505 ml , 2.019 mmol) and stirring at 40°C for 1 hour. This led to the preparation after treatment of a mixture of methyl and ethyl esters 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy) -4-(pyridin-3-yl)phenyl)acetate (319b); MS (ESI+): 479 (methyl, M+1), 493 (ethyl, M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3yl)phenyl)acetic acid (319c).

Compound 319c was prepared according to the procedure described in step-6 of Scheme-1 from a mixture of methyl and ethyl esters 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4 (pyridin-3-yl)phenyl)acetate (319b) (from previous step-2) in MeOH (3 ml) using aq. 2.5 M LiOH (0.646 ml, 1.615 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with ACN in water (c 0.1% HCl) from 0 to 60%] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetic acid (319c) (55 mg, 29% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.13 (d, J=2.1 Hz, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.51 (d, 1H), 8.38 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.01 (s, 1H), 7.93 (dd, J=7.7, 1 .9 Hz, 1H), 7.87-7.76 (m, 2H), 7.70 (d, J=1.6 Hz, 1H), 7.66-7.52 (m, 3H), 7 .45-7.35 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.43 (s, 2H), 4.15 (k, J=5.9 Hz, 2H), 3.67 (s, 2H); MS (ESI+): 465 (M+1); analysis calculation for C ₂₉ H ₂₄ N ₂ O ₄ -2HCl-3.75H ₂ O: C, 57.57; N, 5.58; Cl, 11.72; N, 4.63; observed: C, 57.68; N, 5.33; Cl, 11.01; N, 4.72.

Scheme-320

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4yl)phenyl)acetic acid (320c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate (320a ).

Compound 320a was prepared according to the procedure described in step-1 of scheme-319 from ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (290 mg, 0.488 mmol), using (2-methylpyridin-4-yl)boronic acid (100 mg, 0.732 mmol), Pd ₂ (dba) ₃ (45 mg, 0.049 mmol), XPhos (47 mg, 0.098 mmol), and 1.27 M aq. K3PO4 (0.768 ml, 0.976 mmol) in n-BuOH (4 ml) in a scintillation vial when heated at 100°C under nitrogen for 16 hours. This resulted after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-60% EtOAc in hexane) ethyl 2-(2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(2- methylpyridin-4-yl)phenyl)acetate (320a) (126 mg) as a pale yellow oil; MS (ESI+): 607 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2methylpyridin-4-yl)phenyl)acetate (320b).

Compound 320b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(2methylpyridin-4-yl)phenyl)acetate (320a) (126 mg, from step-1) in methanol (5 ml) using HCl (4 M in 1,4-dioxane, 0.610 ml, 2.439 mmol) and stirring at 40°C for 1 hour. This led to the preparation after treatment of a mixture of methyl and ethyl esters 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)- 4-(2-methylpyridin-4-yl)phenyl)acetate (320b); MS (ESI+): 493 (methyl, M+1), 507 (ethyl, M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-410 045626 methylpyridin-4-yl)phenyl)acetic acid (320c).

Compound 320c was prepared according to the procedure described in step-4 of scheme-4 from a mixture of methyl and ethyl esters 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)- 4(2-methylpyridin-4-yl)phenyl)acetate (320b) (from previous step-2) in MeOH (3 ml) and water (1 ml), using NaOH (58.5 mg, 1.463 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) 0 to 60%] 2-( 2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetic acid (320c) (90 mg, 39% yield), salt HCl, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.80 (d, J=6.3 Hz, 1H), 8.74-8.48 (m, 3H), 8.36 (s, 1H) , 8.31-8.20 (m, 1H), 8.12 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.94 (t, J=4.7 Hz, 1H), 7.87-7.70 (m, 3H), 7.69-7.55 (m, 3H), 7.48 (d, J=7.9 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.46 (s, 2H), 4.14 (p, J=6.4 Hz, 2H), 3.72 (s, 2H), 2.79 (s, 3H); MS (ESI+): 479 (M+1); analysis calculation for C ₃₀ H ₂₆ N ₂ O ₄ -2HCl-3H ₂ O: C, 59.51; N, 5.66; Cl, 11.71; N, 4.63; observed: C, 59.25; N, 5.73; Cl, 11.94; N, 4.66.

Scheme-321

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2(methylthio)acetic acid (321f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxybenzaldehyde (321b).

Compound 321b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.5 g, 5.17 mmol) using 2-hydroxy-4-methoxybenzaldehyde ( 321a) (0.866 g, 5.69 mmol), K ₂ CO ₃ (2.145 g, 15.52 mmol) in DMF (15 ml) and stirring at room temperature overnight. This resulted in 2-((7-bromobenzofuran-5yl)methoxy)-4-methoxybenzaldehyde (321b) (1.739 g, 93% yield) as a white solid upon treatment;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.24 (d, J=0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.13 (d, J= 2.2 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 6.68 (ddd, J=8.7, 2.3, 0.8 Hz, 1H), 5, 37 (s, 2H), 3.86 (s, 3H).

Stage-2. Preparation of 7-bromo-5-((5-methoxy-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (321c).

Compound 321c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-4-methoxybenzaldehyde (321b) (1.73 g, 4.79 mmol) in THF ( 25 ml), using methyl(methylsulfinylmethyl)sulfane (1.19 g, 9.58 mmol), Triton-B (40% methanol solution) (1.088 ml, 2.395 mmol) and reflux for 10 hours. This resulted to be obtained after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate in hexanes) 7-bromo-5-((5-methoxy-2-(2-(methylsulfinyl)-2(methylthio)vinyl) phenoxy)methyl)benzofuran (321c) (1.92 g, 86% yield) as an oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=0.8 Hz, 1H), 8.14-8.10 (m, 1H), 7.81 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6, 77 (d, J=2.4 Hz, 1H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 5.30 (s, 2H), 3.80 (s, 3H ), 2.68 (s, 3H), 2.27 (s, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e) and ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4- methoxyphenyl)-2-(methylthio)acetate (321d).

- 411 045626

Compound 303e and 321d were prepared according to the procedure described in step-4 of scheme-266 from 7-bromo-5-((5-methoxy-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl )benzofuran (321c) (1.9 g, 4.07 mmol) in ethanol (50 ml) using HCl (4 M in 1,4-dioxane, 4.07 ml, 16.26 mmol) and reflux for 10 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate in hexanes), ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4 -methoxyphenyl)acetate (303e) and ethyl 2-(2-((7-bromobenzofuran5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate (321d) (1.002 g, 59% yield) as inseparable mixture, which was used in this form in the next stage.

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (303f) and ethyl 2-(2-((7-(3-(aminomethyl) )phenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)-2-(methylthio)acetate (321e).

Compound 303f and 321e were prepared according to the procedure described in step-3 of Scheme-1 from mixtures of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e) and ethyl 2-(2-((7bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate (321d) obtained from previous step-3 (1.00 g, 2.385 mmol) in dioxane (15 ml) and water (1 ml), using (3(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.671 g, 3.58 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.251 g, 0.358 mmol) and K2CO3 (0.989 g, 7.16 mmol) in water (3 ml) heating under nitrogen at 100°C for 11 hours in an oil bath. This resulted, after work-up and purification by flash column chromatography (silica gel, eluted with DMA80 in DCM from 0% to 50%) of a non-separable mixture of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran- 5-yl)methoxy)-4methoxyphenyl)acetate (303f) and ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)-2-(methylthio)acetate (321e) (800 mg, 75% yield), brown oil; MS (ESI+): 492.1 (M+1), (ESI-): 490.1 (M-1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2(methylthio)acetic acid (321f).

Compound 321f was prepared according to the procedure described in step-6 of Scheme-1 from a mixture containing ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4- methoxyphenyl)acetate (303f) and ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2(methylthio)acetate (321e) (883 mg , 1.796 mmol; from previous step-4) in MeOH (10 ml) THF (10 ml) water (4 ml), using lithium hydroxide monohydrate (129 mg, 5.39 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (250 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (303g) (50 mg, 0.120 mmol, 7% yield) and 2-(2-((7-(3(aminomethyl) phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetic acid (321f) (190 mg, 23% yield), hydrochloride salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.72 (s, 1H), 8.32 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.00 (s, 1H), 7.977.90 (m, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.09 (d , J=2.2 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.56 (dd, J=8.5, 2.4 Hz, 1H), 5.31 (s, 2H), 4.85 (s, 1H), 4.14 (s, 2H), 3.74 (s, 3H), 2.00 (s, 3H); MS (ESI+): 464.20 (M+1), (ESI-): 462.10 (M-1); analysis calculation for C ₂₆ H ₂₅ NO ₅ S-HCl-1.5H ₂ O: C, 59.25; N, 5.55; Cl, 6.73; N, 2.66; observed: C, 59.38; N, 5.18; Cl, 7.06; N, 2.76.

Scheme-322

322с 322d

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-412 045626 yl)phenyl)acetic acid (322с ) and 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6methoxy-5-methylpyridin-3-yl)phenyl)acetic acid (322d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl )acetate (322a).

Compound 322a was prepared according to the procedure described in step-1 of scheme-319 from ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (290 mg, 0.488 mmol), using 6-fluoro-5-methylpyridin-3-ylboronic acid (113 mg, 0.732 mmol), Pd ₂ (dba) ₃ (45 mg, 0.049 mmol), XPhos (47 mg, 0.098 mmol), and 1.27 M aq. K ₃ PO ₄ (0.768 ml, 0.976 mmol) in n-BuOH (4 ml) in a scintillation vial when heated at 100°C under nitrogen for 16 hours. This resulted in, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-20% EtOAc in hexane) ethyl 2-(2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4- (6-fluoro-5-methylpyridin-3yl)phenyl)acetate (322a) (159 mg) as a pale yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (t, J=1.6 Hz, 1H), 8.19 (ddd, J=9.6, 2.6, 0.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.73 (dt, J=7.0, 2.0 Hz, 3H), 7.59 (d, J=1.7 Hz, 1H), 7.54-7.42 (m, 3H), 7.37-7.28 (m, 2H), 7.26 (dd, J=7.7, 1.6 Hz, 1H) , 7.07 (d, J=2.2 Hz, 1H), 5.37 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (k, J= 7.1 Hz, 2H), 3.67 (s, 2H), 2.31 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H) .

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5methylpyridin-3-yl)phenyl)acetate (322b).

Compound 322b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(6-fluoro-5methylpyridin-3-yl)phenyl)acetate (322a) (159 mg, from step-1) in methanol (5 ml) using HCl (4 M in 1,4-dioxane, 0.610 ml, 2.439 mmol) and stirring at 40°C for 1 hour. This resulted in the preparation after treatment of a mixture of methyl and ethyl esters 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl )methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate (322b); MC (ESI+): 511 (methyl, M+1), 525 (ethyl, M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5methylpyridin-3-yl)phenyl)acetic acid (322с) and 2- (2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4-(6-methoxy-5-methylpyridin-3-yl)phenyl)acetic acid (322d).

Compound 322c and 322d were prepared according to the procedure described in step-4 of scheme-4 from a mixture of methyl and ethyl esters 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4 -(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate (322b) (from previous step-2) in MeOH (3 ml) and water (1 ml), using NaOH (58.5 mg, 1.463 mmol ) and stirring at room temperature for 16 hours. This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60 %] 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetic acid (322с) ( 55 mg, 23% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70-8.42 (m, 3H), 8.39 (d, J=2.5 Hz, 1H), 8.19 (dd, J=9 ,6, 2.5 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.94 (dt, J=5.5, 2, 4 Hz, 1H), 7.85-7.75 (m, 1H), 7.75-7.68 (m, 1H), 7.59 (d, J=5.2 Hz, 2H), 7, 51-7.41 (m, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.26 (dd, J=7.6, 1.5 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 5.41 (s, 2H), 4.14 (k, J=5.8 Hz, 2H), 3.65 (s, 2H), 2.32 (c, 3H). ¹⁹ F NMR (300 MHz, DMSO-d6) δ -75.59; MS (ESI+): 497 (M+1), (ESI-): 495 (M-1) and 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy) -4-(6methoxy-5-methylpyridin-3-yl)phenyl)acetic acid (322d) (16 mg, 7% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 3H), 8.33 (d, J=2.4 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H ), 8.02 (s, 1H), 7.93 (dt, J=5.7, 2.3 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.70 (dd, J=5.6, 1.6 Hz, 1H), 7.657.55 (m, 2H), 7.38 (d, J= 1.7 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.24-7.17 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.38 (d, J=8.2 Hz, 2H), 4.17-4.11 (m, 2H), 3.92 (s, 3H), 3.63 (s, 2H), 2.21 (s, 3H); MS (ESI+): 509 (M+1), (ESI-): 507 (M-1).

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Scheme-323

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4yl)phenyl)acetic acid (323 sec).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(pyridin-4-yl)phenyl) acetate (323a) .

Compound 323a was prepared according to the procedure described in step-1 of scheme-319 from ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (323 mg, 0.543 mmol), using pyridin-4-ylboronic acid (100 mg, 0.815 mmol), Pd ₂ (dba) ₃ (50 mg, 0.054 mmol), XPhos ( 52 mg, 0.109 mmol), and 1.27 M aq. K3PO4 (0.856 ml, 1.087 mmol) in n-BuOH (4 ml) in a scintillation vial when heated at 100°C under nitrogen for 16 hours. This resulted after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-60% EtOAc in hexane) ethyl 2-(2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin- 4-yl)phenyl)acetate (323a) (137 mg) as a pale yellow oil; MS (ESI+): 593 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin4-yl)phenyl)acetate (323b).

Compound 323b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(pyridin-4yl)phenyl)acetate (323a) (137 mg, from step-1) in methanol (5 ml) using HCl (4 M in 1,4-dioxane, 0.679 ml, 2.72 mmol) and stirring at 40°C for 1 hour. This led to the preparation after treatment of a mixture of methyl and ethyl esters 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4 -(pyridin-4-yl)phenyl)acetate (323b); MS (ESI+): 479 (methyl, M+1), 493 (ethyl, M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4yl)phenyl)acetic acid (323c).

Compound 323c was prepared according to the procedure described in step-4 of scheme-4 from a mixture of methyl and ethyl esters 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4 (pyridin-4-yl)phenyl)acetate (323b) (from previous step-2) in MeOH (3 ml) and water (1 ml), using NaOH (87 mg, 2.173 mmol) and stirring at room temperature for 16 h. This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0 to 60%] 2-(2-((7 -(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetic acid (323c) (55 mg, 22% yield), HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (d, J=5.9 Hz, 2H), 8.52 (s, 3H), 8.36 (d, J=5.9 Hz, 2H), 8.12 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.93 (dt, J=6.4, 2.2 Hz, 1H), 7, 81 (d, J=1.6 Hz, 1H), 7.72 (dd, J=7.3, 1.7 Hz, 2H), 7.67-7.54 (m, 3H), 7.48 (d, J=7.8 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 5.46 (s, 2H), 4.14 (k, J=5.9 Hz , 2H), 3.71 (s, 2H); MS (ESI+): 465 (M+1); analysis calculation for C ₂₉ H ₂₄ N ₂ O ₄ -2.25HCl-2.5H ₂ O: C, 58.88; N, 5.32; Cl, 13.48; N, 4.74; observed: C, 58.90; N, 5.13; Cl, 13.64; N, 4.75.

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Scheme-324

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2yl)phenyl)acetic acid (324c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate (324a ).

Compound 324a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (312 mg, 0.525 mmol) in dioxane (4 ml), using (5-cyanothiophen-2-yl)boronic acid (88 mg, 0.577 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (37 mg, 0.052 mmol) and a solution of 2 M aq. K2CO3 (0.787 mL, 1.574 mmol) under nitrogen while heating at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-25% EtOAc in hexane), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)benzofuran-5yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate (324a) (148 mg) as a clear, colorless oil;

1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 8.02 (d, J=4.0 Hz, 1H), 7.74 (dd, J =5.1, 3.6 Hz, 4H), 7.59 (d, J=1.6 Hz, 1H), 7.56-7.43 (m, 3H), 7.39-7.28 ( m, 3H), 7.07 (d, J=2.2 Hz, 1H), 5.36 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 ( k, J=7.1 Hz, 2H), 3.67 (s, 2H), 1.39 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5cyanothiophen-2-yl)phenyl)acetate (324b).

Compound 324b was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(5cyanothiophen-2-yl)phenyl)acetate (324a) (148 mg, from step-1) in methanol (5 ml) using HCl (4 M in 1,4-dioxane, 0.656 ml, 2 .62 mmol) and stirring at room temperature for 16 hours. This led to the preparation after treatment of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4-(5- cyanothiophen-2-yl)phenyl)acetate (324b); MS (ESI+): 509 (M+1), (ESI-): 507 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen2-yl)phenyl)acetic acid (324c).

Compound 324c was prepared according to the procedure described in step-4 of scheme-4 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophene -2-yl)phenyl)acetate (324b) (from previous step-2) in MeOH (3 ml) and water (1 ml), using NaOH (105 mg, 2.62 mmol) and stirring at room temperature for 16 h. This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0 to 60%] 2-(2-((7 -(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5cyanothiophen-2-yl)phenyl)acetic acid (324c) (20 mg, 8% yield), HCl salt, as a white solid substances;

1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=3.9 Hz, 2H), 7.94 (dt, J =7.7, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 7.69 (d , J=1.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.47 (d, J=1, 5 Hz, 1H), 7.39-7.26 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 5.40 (s, 2H), 4.15 (s, 2H), 3.64 (s, 2H); MS (ESI+): 495 (M+1) and 5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methoxy-2oxoethyl)phenyl) thiophene-2-carboxylic acid (324d) (65 mg, 24% yield), HCl salt, as a white solid;

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1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.94 (dt, J=7.6, 1.6 Hz,

1H), 7.86-7.78 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.64 (d, J=4.0 Hz, 1H), 7, 59 (d, J=7.5 Hz, 1H), 7.54 (d, J=7.8 Hz,

1H), 7.46 (s, 1H), 7.31 (d, J=0.9 Hz, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.40 (s, 2H), 4.14 (s, 2H), 3.84 (s, 3H), 3.63 (s,

2H); MS (ESI+): 528 (M+1).

Scheme-325

5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4 Preparation of (carboxymethyl)phenyl)thiophene-2-carboxylic acid (325a).

Compound 325a was prepared according to the procedure described in step-6 of scheme-1 from 5-(3((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methoxy-2 -oxoethyl)phenyl)thiophene-2carboxylic acid (324d) (60 mg, 0.114 mmol) in MeOH (3 ml) using aq. 2.5 M LiOH (0.455 ml, 1.137 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with ACN in water (c 0.1% HCl) from 0 to 60%] 5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)-4-(carboxymethyl)phenyl)thiophene-2-carboxylic acid ( 325a) (38 mg, 65% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.1 Hz, 1H), 8.01 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.5, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.75-7.67 (m, 2H), 7.66-7.51 (m, 3H), 7.44 (s, 1H), 7.35-7.25 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.40 (s, 2H), 4.14 (s, 2H), 3.63 (s, 2H); MS (ESI+): 514 (M+1), (ESI-): 512 (M-1).

Scheme-326

Preparation of (-)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (326g).

Stage-1. Preparation of 4-chloro-2-(1-((trimethylsilyl)oxy)vinyl)pyridine (326b).

To a solution of 1-(4-chloropyridin-2-yl)ethanone (326a) (5.0 g, 32.1 mmol; CAS No. 60159-37-7) and Et ₃ N (9.76 g, 96 mmol) in DCM (15 ml) at 0°C, TMS-OTf (14.29 g, 64.3 mmol) was added dropwise to DCM (2 ml) under nitrogen atmosphere and stirred at 0°C for 2 h.

The solution was washed with H ₂ O (25 ml) and brine (25 ml), dried, filtered and concentrated in vacuo to give 4-chloro-2-(1-((trimethylsilyl)oxy)vinyl)pyridine (326b) as orange oil, which was used as is in the next stage without purification; MS (ESI+): 228/230 (M+1).

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Stage-2. Preparation of 1-(4-chloropyridin-2-yl)-2-fluoroethanone (326с).

To a solution of 4-chloro-2-(1-((trimethylsilyl)oxy)vinyl)pyridine (326b) (from previous step-1) in MeCN (20 ml) was added SelectFluor (14.80 g, 41.8 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (30 ml) and H ₂ O (30 ml) and stirring was continued for 15 minutes. The organic layer was separated and extracted with EtOAc (2x25). The combined organic extract was washed with brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0-2% EtOAc in hexanes) to give 1-(4-chloropyridin-2-yl)-2-fluoroethanone (326c) (1.80 g, 10.37 mmol, 32.3% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.69 (dd, J=5.3, 0.6 Hz, 1H), 8.01 (dt, J=2.2, 0.5 Hz, 1H ), 7.89 (dd, J=5.3, 2.1 Hz, 1H), 6.00 (s, 1H), 5.85 (s, 1H). ¹⁹ F NMR (282 MHz, DMSO46) δ -235.43; MS (ESI+): 174/176 (M+1).

Stage-3. Preparation of (S)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (326d).

To a solution of 1-(4-chloropyridin-2-yl)-2-fluoroethanone (326c) (600 mg, 3.46 mmol), (S)-2-methylpropane2-sulfinamide (838 mg, 6.91 mmol) Ti(OEt) ₄ (2366 mg, 10.37 mmol) in THF (20 ml) and heated at 65°C for 16 h under nitrogen atmosphere. The resulting dark red solution was cooled to -48°C and added dropwise to a solution of NaBH ₄ (436 mg, 11.52 mmol) in THF (5 ml) at -48°C and stirred at -48°C for 16 h The reaction mixture was carefully quenched with MeOH, poured into saline (20 ml) and stirred vigorously for 30 min. The solid residue was removed by filtration, the precipitate was washed with EtOAc (50 ml) and the organic layer was separated. The organic layer was washed with brine (20 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-40% EtOAc in hexane) to give (S)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)- 2-methylpropane-2-sulfinamide (326d) (127 mg, 13% yield) as an orange oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.54 (d, J=5.4 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.50 (dd, J=5.3, 2.0 Hz, 1H), 6.05 (d, J=8.7 Hz, 1H), 4.92-4.48 (m, 3H), 1.15 (s, 9H ). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -222.53; MS (ESI+) 279/281 (M+1).

Stage-4. Preparation of (+)-ethyl 2-(2-((7-(2-(1-((S)-1,1-dimethylethylsulfinamido)-2fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl )acetate (326e).

Compound 326e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (219 mg, 0.501 mmol) in dioxane (9 ml) using (S)-N-(1-(4-chloropyridin-2-yl)-2- fluoroethyl)-2methylpropane-2-sulfinamide (326d) (127 mg, 0.456 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (48 mg, 0.068 mmol) and a solution of K ₂ CO ₃ (189 mg, 1.367 mmol) in water ( 1 ml) in a nitrogen atmosphere when heated at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 0-50% ethyl acetate in hexanes) (+)-ethyl 2-(2((7-(2-(1-((S) -1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (326e) (98 mg) as a colorless oil; MS (ESI+) 553 (M+1); optical rotation [a] _D = +40.0 (c = 0.01, MeOH).

Stage-5. Preparation of ethyl 2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (326f).

Compound 326f was prepared according to the procedure described in step-10 of scheme-257 from (+)ethyl 2-(2-((7-(2-(1-((S)-1,1-dimethylethylsulfinamido)-2 -fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (326e) (98 mg; from previous step-4) in MeOH (5 ml) using HCl (4 M in 1,4-dioxane); 0.569 ml, 2.278 mmol) and stirring at 40°C for 1 hour. This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with DMA 80 in dichloromethane), ethyl 2-(2-( (7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (326f), which was used as is in the next step; MS (ESI+): 435 (M+1).

Stage-6. Preparation of (-)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (326g).

Compound 326g was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl )methoxy)phenyl)acetate (326f) (from previous step-5) in MeOH (3 ml), water (1 ml), using NaOH (55 mg, 1.367 mmol). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] (-)-2-(2- ((7-(2-(1-amino-2fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (326g) (15 mg, 8% yield), HCl salt, as white solid matter;

1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 3H), 8.80 (d, J=5.2 Hz, 1H), 8.19 (dd, J=9.9, 1, 9 Hz, 2H), 8.05 (dd, J=5.2, 1.7 Hz, 1H), 7.87 (dd, J=12.0, 1.6 Hz, 2H), 7.25 ( dd, J=8.1, 6.4 Hz, 2H), 7.15-7.07 (m, 2H), 6.91 (td,

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J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 5.13-4.79 (m, 3H), 3.62 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -226.50; MS (ESI+): 421 (M+1), (ESI-): 419 (M-1); optical rotation [α]ρ = -9.23 (c = 0.13, MeOH).

Scheme-327

Preparation of (+)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (327d).

Stage-1. Preparation of (-)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropan-2-sulfinamide (327a).

Compound 327a was prepared according to the procedure described in step-3 of scheme-326 from 1-(4chloropyridin-2-yl)-2-fluoroethanone (326c) (500 mg, 2.88 mmol), (R)-2-methylpropane -2-sulfinamide (367 mg, 3.02 mmol) using a solution of Ti(OEt) ₄ (1314 mg, 5.76 mmol) in THF (20 ml) by heating at 65°C for 16 h under nitrogen with subsequent reduction of the imine achieved using a solution of NaBH ₄ (436 mg, 11.52 mmol) in THF (5 ml) and stirring at -48°C for 16 hours. This resulted in the preparation after work-up and purification by flash chromatography on column (silica gel, 24 g, eluted with 0-40% EtOAc in hexane) (-)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2methylpropane-2-sulfinamide (327a) (82 mg, 10% yield) as an orange oil;

'H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=5.3 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.50 (dd, J=5.3, 2.0 Hz, 1H), 6.05 (d, J=8.8 Hz, 1H), 4.88-4.50 (m, 3H), 1.16 (s, 9H ). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -222.53; MS (ESI+): 279/281 (M+1); optical rotation [a] _D = -40.00 (c = 0.03, MeOH).

Stage-2. Preparation of (-)-ethyl 2-(2-((7-(2-(1-(1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4yl)benzofuran-5-yl)methoxy)phenyl)acetate (327b ).

Compound 327b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (141 mg, 0.324 mmol) in dioxane (9 ml) using (-)-N-(1-(4-chloropyridin-2-yl)-2- fluoroethyl)-2methylpropane-2-sulfinamide (327a) (82 mg, 0.294 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (31 mg, 0.044 mmol) and a solution of K ₂ CO ₃ (122 mg, 0.882 mmol) in water ( 1 ml) in a nitrogen atmosphere when heated at 100°C for 16 hours in an oil bath. This resulted in (-)-ethyl 2-(2((7-(2-(1-(1,1) -dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (327b) (72 mg) as a clear, colorless oil; MS (ESI+): 553 (M+1); optical rotation [a] _D = -22.82 (c = 0.035, MeOH).

Stage-3. Preparation of methyl and ethyl esters of 2-(2-((7-(2-(1-amino-2fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (327c).

Compound 327c was prepared according to the procedure described in step-10 of scheme-257 from (-)ethyl 2-(2-((7-(2-(1-(1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridine -4-yl)benzofuran-5yl)methoxy)phenyl)acetate (327b) (72 mg; from previous step-2 in MeOH (5 ml) using HCl (4 M in 1,4-dioxane; 0.588 ml, 2.353 mmol ) and stirring at 40°C for 1 hour. This led to the preparation after treatment of a mixture of methyl and ethyl esters 2-(2-((7-(2-(1-amino-2fluoroethyl)pyridin-4-yl)benzofuran -5-yl)methoxy)phenyl)acetate (327с); MS (ESI+): 435 (methyl, M+1), 449 (ethyl, M+1).

Stage-4. Preparation of (+)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-418 045626 yl)methoxy)phenyl)acetic acid (327d).

Compound 327d was prepared according to the procedure described in step-4 of Scheme-4 from a mixture of methyl and ethyl esters 2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl )benzofuran-5yl)methoxy)phenyl)acetate (327c) (from previous step-3) in MeOH (3 ml), water (1 ml), using NaOH (47 mg, 1.177 mmol). This resulted in, after workup and purification by reverse phase column chromatography, [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] (+)-2-(2-(( 7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (327d) (19 mg, 16% yield), HCl salt, as white solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 3H), 8.80 (dd, J=5.3, 0.7 Hz, 1H), 8.19 (dd, J=1 ,8, 0.8 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.04 (dd, J=5.2, 1.7 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.24 (dd, J=8.1, 6.6 Hz, 2H), 7 .17-7.05 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 5.08-4.79 (m , 3H), 3.61 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -226.26; MS (ESI+): 421 (M+1), 419 (M-1); optical rotation [a] _D = +10.73 (c = 0.205, MeOH).

Scheme-328

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)acetic acid (328f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorobenzaldehyde (328b).

Compound 328b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (2.069 g, 7.14 mmol) using 2-fluoro-6-hydroxybenzaldehyde (328a) ( 1 g, 7.14 mmol), K ₂ CO ₃ (2.96 g, 21.41 mmol) in DMF (10 ml) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash chromatography on a column (silica gel, 40 g, eluted with 0 to 50% ethyl acetate in hexanes) 2-((7bromobenzofuran-5-yl)methoxy)-6-fluorobenzaldehyde (328b) (2.05 g, 82% yield) as a white solid substances;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.38 (dd, J=1.3, 0.6 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7, 84 (d, J=1.5 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.67 (td, J=8.5, 6.5 Hz, 1H), 7.22-7.10 (m, 2H), 6.92 (dtd, J=10.8, 8.4, 0.7 Hz, 1H), 5.38 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -115.52; MS (ESI+): 370.9 (M+Na).

Stage-2. Preparation of 7-bromo-5-((3-fluoro-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (328c).

Compound 328c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-6-fluorobenzaldehyde (328b) (2 g, 5.73 mmol) in THF (30 ml ), using methyl(methylsulfinylmethyl)sulfane (1.139 g, 9.17 mmol), Triton-B (40% methanol solution, 0.521 ml, 2.86 mmol) and reflux for 2 hours. This resulted in treatment and purification by flash column chromatography (silica gel, 40 g, eluted with 0100% EtOAc in hexane) 7-bromo-5-((3-fluoro-2-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy )methyl)benzofuran (328c) (795 mg, 31% yield) as a colorless gel;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.48-7.34 (m, 2H), 7.10 (d, J=2.2 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.91 (t, J=8.8 Hz, 1H), 5.28 (s, 2H), 2.73 (s, 3H), 2.19 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -110.68.

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorophenyl)acetate (328d).

Compound 328d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((3-fluoro-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (328c ) (790 mg, 1.735 mmol) in ethanol (20 mL) using HCl (4 M in 1,4-dioxane, 2.169 mL, 8.67 mmol) and refluxing for 2 hours. This resulted in treatment and purification by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% ethyl acetate and hexanes) ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorophenyl)acetate ( 328d) (626 mg, 89% yield).

- 419 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H),

7.31 (td, J=8.4, 7.0 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.02-6.93 (m, 1H), 6 .84 (ddd, J=9.3, 8.3, 0.9 Hz, 1H), 5.23 (s, 2H), 4.04 (k, J=7.1 Hz, 2H), 3, 64 (s, 2H), 1.09 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -116.82.

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6fluorophenyl)acetate (328e).

Compound 328e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorophenyl)acetate (328d) (300 mg, 0.737 mmol ) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (167 mg, 1.105 mmol), tripotassium phosphate (1.3 M, 1.7 ml, 2.21 mmol), tricyclohexylphosphine (62 mg , 0.221 mmol) and Pd ₂ (dba) ₃ (68 mg, 0.074 mmol) under nitrogen when heated at 125°C for 60 min in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 to 100% DMA80 in DCM] ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran- 5-yl)methoxy)-6-fluorophenyl)acetate (328e) (176 mg, 55% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 7.82 (s, 1H), 7.76-7.67 (m, 2H), 7.58 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7, 31 (td, J=8.3, 6.9 Hz, 1H), 7.09-6.97 (m, 2H), 6.83 (t, J=8.7 Hz, 1H), 5.29 (s, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.65 (s, 2H), 1.01 (t, J=7, 1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -116.84; MS (ESI+): 434.1 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6fluorophenyl)acetic acid (328f).

Compound 328f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)acetate ( 328e) (175 mg, 0.404 mmol) in MeOH (4 mL), THF (4 mL), using 2N lithium hydroxide (0.807 mL, 1.615 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)acetic acid (328f) (57 mg, 35% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.04-7.98 (m, 1H), 7.92 (dt, J=7.0, 2.0 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H ), 7.63-7.53 (m, 2H), 7.36-7.22 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.82 (t, J=8.7 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H), 3.61 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -116.60; MS (ESI+): 406.1 (M+1); analysis calculation for C ₂₄ H ₂₀ FNO ₄ -HCl-1.25H ₂ O: C, 62.07; N, 5.10; N, 3.02; observed: C, 62.26; N, 4.88; N 3.07.

Scheme-329

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (329b).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetate (329a).

Compound 329a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (90a) (0.21 g, 0.46 mmol) in dioxane (4 ml) using (4-chloropyridin-2-yl)methanamine (74a) (0.10 g, 0.69 mmol), bis(triphenylphosphine) palladium(11) chloride (0.05 g, 0.07 mmol) and a solution of K2CO3 (0.16 g, 1.16 mmol) in water (0 .5 ml) in an Ar atmosphere when heated at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in 0% to 50% DCM] ethyl 2-(2-((7-(2-(aminomethyl)pyridinium- 4yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (329a) (0.12 g, 59% yield) as a white solid; MS (ESI+): 435.2 (M+1); MS (ESI-): 433.2 (M-1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (329b).

Compound 329b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5- fluorophenyl)acetate (329a) (0.12 g, 0.27 mmol) in MeOH/THF (4 ml), using a solution of lithium hydroxide monohydrate (0.09 g, 2.17 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (329b) (0.07 g,

- 420 045626

59% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (dd, J=5.3, 0.7 Hz, 1H), 8.52 (s, 3H), 8.17 (d, J=2 .2 Hz, 1H), 8.09 (t, J=1.2 Hz, 1H), 7.99 (dd, J=5.3, 1.7 Hz, 1H), 7.86 (d, J =1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.21-7.01 (m, 4H), 5.27 (s, 2H), 4.31 (d, J=5.7 Hz, 2H), 3.62 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.05; MS (ESI+): 407.9 (M+1); analysis calculation for: C ₂₃ H ₁₉ FN ₂ O ₄ -1.75HCl-1.5H ₂ O: C, 55.56; N, 4.81; Cl, 12.48; N, 5.63; observed: C, 55.22; N, 4.58; Cl, 12.48; N, 5.67.

Scheme-330

330b 330c

Preparation of 2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (330c).

Stage-1. Preparation of methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-5-(1-ethoxyvinyl)phenyl)acetate (330a).

To a solution of methyl 2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (208b) (0.2 g, 0.35 mmol) in DMF (4 ml), tributyl(1ethoxyvinyl)stannane (0.153 ml, 0.45 mmol) and Pd(PPh ₃ ) ₄ (0.04 g, 0.03 mmol) were added, the resulting mixture was stirred at 100 °C for 2 hours in an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml), washed with water (2x50 ml), brine (50 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with ethyl acetate in 0% to 50% hexanes] to give methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)-5-(1ethoxyvinyl)phenyl)acetate (330a) (0.05 g, 25% yield) as a white solid; MS (ESI+): 494.9 (M-Boc+Na).

Stage-2. Preparation of methyl 2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (330b).

Compound 330b was prepared according to the procedure described in step-10 of scheme-257 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5-(1ethoxyvinyl)phenyl)acetate (330a) (0.05 g, 0.09 mmol) in methanol (3 ml), using hydrochloric acid (4 M in 1,4-dioxane, 0.66 ml, 2.62 mmol). This resulted in methyl 2(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (330b) (0.04 g, 100% yield) after treatment ) as a yellow solid; MS (ESI+): 440.0 (M+1).

Stage-3. Preparation of 2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (330c).

Compound 330c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl) acetate (330b) (0.05 g, 0.11 mmol) in THF (4 ml) and methanol (4 ml), using lithium hydroxide monohydrate (0.04 g, 0.90 mmol) in water (1 ml). This resulted in the following workup and purification by flash column chromatography [silica gel, 12 g, eluted with methanol in DCM 0% to 50%] followed by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (c 0.1% HCl) from 0% to 100%] 2(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (330c) (0 .02 g, 41% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.28 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.99 (s , 1H), 7.977.83 (m, 3H), 7.77 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.60 (t , J=7.7 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.07 (d, J =2.2 Hz, 1H), 5.39 (s, 2H), 4.14 (s, 2H), 3.67 (s, 2H), 2.51 (s, 3H); MS (ESI+): 430.0 (M+1).

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Scheme-331

331b 331с

Preparation of 2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (331c).

Stage-1. Preparation of methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (331a).

Compound 331a was prepared according to the procedure described in step-2 of Scheme-256 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5 cyanophenyl) acetate (239a) (0.06 g, 0.11 mmol) in anhydrous methanol (5 ml), using nickel(II) chloride hexahydrate (7 mg, 0.03 mmol), di-tert- butyl dicarbonate [(Boc) _2O )] (0.08 g, 0.34 mmol), sodium borohydride (0.03 g, 0.68 mmol) and quenched N1-(2-aminoethyl)ethane-1,2- diamine (0.03 ml, 0.23 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 4 g, eluted with 0 to 60% ethyl acetate/hexanes), methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2( (7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (331a) (0.03 g, 47% yield) as a pale yellow waxy substance ; MS (ESI+): 531.0 (M-Vos+1).

Stage-2. Preparation of methyl 2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (331b).

Compound 331b was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (331a) (0.03 g, 0.05 mmol) in DCM (3 ml), using TFA (0.08 ml, 1.08 mmol ). This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with 0% to 50% MeOH in DCM] methyl 2-(5-(aminomethyl)-2-((7-(3- (aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (331b) (0.02 g, 100% yield) as a clear waxy substance; MS (ESI+): 431.1 (M+1).

Stage-3. Preparation of 2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (331c).

Compound 331c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy) phenyl)acetate (331b) (0.04 g, 0.09 mmol) in THF (4 ml) and methanol (4 ml), using a solution of lithium hydroxide monohydrate (0.03 g, 0.74 mmol) in water (1 ml). This resulted in, after workup and purification by reverse phase column chromatography, [C-18, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (331c) (0 .02 g, 47% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 8.45 (s, 3H), 8.26 (s, 3H), 8.11 (d, J=2, 2 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.92 (dt, J=7.1, 1.9 Hz, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.63-7.58 (m, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.40-7.27 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 5, 31 (s, 2H), 4.13 (s, 2H), 3.92 (s, 2H), 3.60 (s, 2H); MS (ESI+): 417.2 (M+1); MS (ESI-): 415.1 (M-1); analysis calculation for C^H^O^HCl^HO: C, 55.25; N, 5.94; Cl, 13.05; N, 5.15; observed: C, 54.92; N, 5.64; Cl, 13.41; N, 5.17.

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Scheme-332

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (332e).

Stage-1. Preparation of (4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methanol (332b).

Compound 332b was prepared according to the procedure described in step-2 of Scheme-212 from methyl 4-bromo-2-(trifluoromethyl)-1H-indole-6-carboxylate (332a) (1.29 g, 4.01 mmol; CAS No. 2089041-22-3; prepared according to the procedure described by Yang, Xinye et al.; in Faming Zhuanli Shenqing, 106478500, March 08, 2017) in DCM (25 ml) using 1 M DIBAL-H in DCM (10.01 ml, 10.01 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-50% EtOAc in hexane), (4-bromo-2-(trifluoromethyl)-1H-indol-6yl)methanol (332b) (1.05 g, 89% yield) as a brown solid; MS (ESI-): 293.0 and 291.9 (M-1).

Stage-2. Preparation of ethyl 2-(2-((4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (332c).

Compound 332c was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-2-(trifluoromethyl)-1H-indol-6-yl)methanol (332b) (0.5 g, 1.70 mmol) in DCM (20 ml) using triphenylphosphine (0.58 g, 2.21 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.40 g, 2.21 mmol) and (E)bis( 4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 0.81 g, 2.21 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography [silica gel column 12 g, eluted with EtOAc/MeOH=9:1 in 0% to 30% hexanes], ethyl 2-(2-((4-bromo-2 (trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (332c) (0.15 g, 19% yield) as a white oil; MS (ESI-): 456.0 and 454.0 (M-1).

Stage-3. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (332d).

Compound 332d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (332c ) (0.15 g, 0.33 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.09 g, 0.49 mmol), K ₂ CO ₃ solution (0 .46 g, 0.99 mmol) in water (2 ml), Pd(PPh ₃ ) ₂ Cl ₂ (0.04 g, 0.05 mmol) and heating in an Ar atmosphere at 90 ° C for 2 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 to 30% MeOH in DCM] ethyl 2-(2((4-(3-(aminomethyl)phenyl)-2- (trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (332d) (0.1 g, 63% yield) as a white solid; MS (ESI+): 483.2 (M+1).

Stage-4. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (332e).

Compound 332e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl) methoxy)phenyl)acetate (332d) (0.1 g, 0.21 mmol) in THF (4 ml) and MeOH (4 ml), using a solution of lithium hydroxide monohydrate (0.04 g, 0.83 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(3- (aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (332e) (3 mg, 3% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 12.18 (s, 1H), 8.23 (s, 3H), 7.82 (s, 1H), 7. 70 (d, J=7.5 Hz, 1H), 7.62-7.55 (m, 2H), 7.51 (d, J=7.7 Hz, 1H), 7.34 (s, 1H ), 7.23 (t, J=7.0 Hz, 2H), 7.17 (s, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.90 (t, J =7.4 Hz, 1H), 5.31 (s, 2H), 4.16 (d, J=5.8 Hz, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -58.73; MS (ESI+): 455.1 (M+1); MS (ESI-): 453.1 (M-1).

- 423 045626

Scheme-333

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetic acid (333g).

Stage-1. Preparation of methyl 3-bromo-4-((3-oxobutan-2-yl)oxy)benzoate (333b).

K ₂ CO ₃ ( 90 g, 649 mmol) and refluxed for 24 hours. The reaction mixture was cooled to room temperature and the resulting solid was removed by filtration. The filtrate was concentrated in vacuo and the resulting residue was recrystallized from acetone-hexane. The solid was collected by filtration and the mother liquor was purified by flash column chromatography [(silica gel, 320 g, eluted with 0 to 30% ethyl acetate/hexanes)] to give methyl 3-bromo-4-((3-oxobutan-2-yl) hydroxy)benzoate (333b) (56.1 g, 86% yield).

^1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.1 Hz, 1H), 7.88 (dd, J=8.7, 2.2 Hz, 1H), 7, 07 (d, J=8.8 Hz, 1H), 5.20 (k, J=6.9 Hz, 1H), 3.83 (s, 3H), 2.24 (s, 3H), 1, 50 (d, J=6.8 Hz, 3H).

Stage-2. Preparation of methyl 7-bromo-2,3-dimethylbenzofuran-5-carboxylate (333c).

To methyl 3-bromo-4-((3-oxobutan-2-yl)oxy)benzoate (333b) (56 g, 186 mmol) was added sulfuric acid (41.7 mL, 744 mmol) under ice-cooling temperature. The reaction mixture was stirred at room temperature for one hour and heated at 50°C for 1 hour. The mixture was recrystallized from EtOH to give methyl 7-bromo-2,3-dimethylbenzofuran-5-carboxylate (333c) (29.5 g, 56% yield).

1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=1.6 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 3.88 (s, 3H ), 2.45 (d, J=1.0 Hz, 3H), 2.19 (d, J=1.0 Hz, 3H).

Stage-3. Preparation of (7-bromo-2,3-dimethylbenzofuran-5-yl)methanol (333d).

Compound 333d was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2,3-dimethylbenzofuran-5-carboxylate (333c) (10 g, 35.3 mmol) in THF (150 ml) using LiBH ₄ (17.66 ml, 70.6 mmol) and MeOH (2.86 ml, 70.6 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 60% ethyl acetate in hexane] (7-bromo-2,3-dimethylbenzofuran-5-yl)methanol (333d ) (7.05 g, 78% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.44-7.35 (m, 2H), 5.29 (t, J=5.8 Hz, 1H), 4.56 (dt, J=5, 8, 0.7 Hz, 2H), 2.41 (d, J=1.0 Hz, 3H), 2.13 (d, J=0.9 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-bromo-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate (333e).

Compound 333e was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2,3-dimethylbenzofuran-5-yl)methanol (333d) (1 g, 3.92 mmol) in DCM (10 ml) using triphenylphosphine (1.131 g, 4.31 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (0.777 g, 4.31 mmol) and (E)-bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 1.583 g, 4.31 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with ethyl acetate in 0% to 50% hexane] ethyl 2-(2-((7-bromo-2,3-dimethylbenzofuran- 5yl)methoxy)phenyl)acetate (333e) (704 mg, 43% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 7.55 (d, J=1.5 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.32-7.18 (m, 2H), 7.127.03 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.16 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.42 (d, J=1.0 Hz, 3H), 2.14 (d, J=1.0 Hz, 3H) , 1.08 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5yl)methoxy)phenyl)acetate (333f).

Compound 333f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate (333e) (300 mg , 0.719 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (163 mg, 1.078 mmol), tri- 424 045626 potassium phosphate (1.3 M, 1.7 ml, 2.2 mmol), tricyclohexylphosphine (61 mg, 0.216 mmol) and Pd ₂ (dba) ₃ (66 mg,

0.072 mmol) under nitrogen atmosphere when heated at 125°C for 60 minutes in a microwave oven. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with DCM/DMA80] ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran5- yl)methoxy)phenyl)acetate (333f) (164 mg, 51% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 7.75-7.66 (m, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.50-7.40 (m, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.32-7.20 (m, 1H), 7.26-7.17 ( m, 1H), 7.16-7.07 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.63 (s, 2H), 2.41 (d, J=1.0 Hz, 3H), 2.17 (d, J=1.0 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 444.2 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5yl)methoxy)phenyl)acetic acid (333g).

Compound 333g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl) acetate (333f) (160 mg, 0.361 mmol) in MeOH/THF (5 ml each) using aq. 1N lithium hydroxide (1.082 ml, 1.082 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetic acid (333g) (120 mg, 80% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.00-7.87 (m, 2H), 7.64-7.47 (m, 4H), 7.30-7.18 (m, 2H ), 7.09 (d, J=8.0 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 3.60 (s, 2H), 2.42 (s, 3H), 2.18 (s, 3H); MS (ESI+): 416.2 (M+1); (ESI-): 414.0 (M-1); analysis calculation for C ₂₆ H ₂₅ NO ₄ -HCl-0.75H ₂ O: C, 67.09; N, 5.96; Cl, 7.62; N, 3.01; observed: C, 67.03; N, 5.89; Cl, 7.53; N, 3.04.

Scheme-334

C.I.

Preparation of 2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-methoxybenzofuran-5carboxamido)phenyl)acetic acid (334d).

Stage-1. Preparation of ethyl 2-(2-(4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran5-carboxamido)phenyl)acetate (334a).

Compound 334a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a) (193 mg, 0.459 mmol) using bis(pinacolato)diboron (178 mg, 0.701 mmol), potassium acetate (165 mg, 1.681 mmol) and Pd(dppf)Cl ₂ -DCM (66 mg, 0.081 mmol) in anhydrous dioxane (6 ml) under argon when heated at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in 0% to 50% hexanes] ethyl 2-(2-(4-fluoro-7-(4,4, 5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-carboxamido)phenyl)acetate (334a) (128 mg, 60% yield) as a pale yellow oil. MS (ESI+): 468.0 (M+1).

Stage-2. Preparation of ethyl 2-(2-(7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)4-fluorobenzofuran-5-carboxamido)phenyl)acetate (334b).

Compound 334b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-(4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)benzofuran-5-carboxamido)phenyl)acetate (334a) (128 mg, 0.274 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro-3-fluoropyridine- 2-yl)methyl)2-methylpropane-2-sulfinamide (220c) (82 mg, 0.310 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (45 mg, 0.064 mmol) and a solution of K2CO3 (134 mg, 0.970 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 80% DMA/DCM] ethyl 2-(2-(7-(2-((1,1- dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4fluorobenzofuran-5-carboxamido)phenyl)acetate (334b) (156 mg, 100% yield) as a yellow oil; MS (ESI+): 570.1 (M+1).

- 425 045626

Stage-3. Preparation of ethyl 2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5carboxamido)phenyl)acetate (334c).

Compound 334c was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-(7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)- 4-Fluorobenzofuran-5carboxamido)phenyl)acetate (334b) (156 mg, 0.274 mmol) in methanol (8 ml), using HCl (4 M in dioxane; 0.3 ml, 1,200 mmol) and stirring at room temperature for 30 min. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 100%], ethyl 2-(2-(7-(2-(aminomethyl)-3- fluoropyridin-4-yl)-4fluorobenzofuran-5-carboxamido)phenyl)acetate (334c) (31 mg, 25% yield) as a pale yellow oil. MS (ESI+): 452.1 (M+1).

Stage-4. Preparation of 2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-methoxybenzofuran-5carboxamido)phenyl)acetic acid (334d).

Compound 334d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido) phenyl)acetate (334c) (31 mg, 0.069 mmol) in MeOH (6 ml), THF (6 ml), using a solution of lithium hydroxide (46 mg, 1.10 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] 2-(2-(7-( 2(aminomethyl)-3-fluoropyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)acetic acid (334d) (11 mg, 36% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.49 (s, 3H), 8.12 ( d, J=2.4 Hz, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.76 (t, J=5.3 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.26 (t, J=7.6 Hz, 2H), 7.18-7.02 ( m, 1H), 4.31 (d, J=6.0 Hz, 2H), 4.28 (s, 3H), 3.66 (s, 2H); MS (ESI+): 450.1 (M+1); MS (ESI-): 448.1 (M-1).

Scheme-335

Preparation of 2-(2-((5'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (335d).

Stage-1. Preparation of ethyl 2-(2-((5'-(hydroxymethyl)-[7,7'-bibenzofuran]-5yl)methoxy)phenyl)acetate (335a).

Compound 335a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (464 mg, 1.192 mmol) in dioxane (5 ml) using (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (329 mg, 1,200 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (111 mg, 0.158 mmol) and solution of K ₂ CO ₃ (530 mg, 3.83 mmol) in water (0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with ethyl acetate in 10 to 80% hexanes] ethyl 2-(2-((5'(hydroxymethyl)-[7,7' -dibenzofuran]-5-yl)methoxy)phenyl)acetate (335a) (357 mg, 66% yield) as a pale yellow oil.

1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=2.2 Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.78 (d, J =1.6 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.63 (d, J=1 .5 Hz, 1H), 7.31-7.18 (m, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H ), 7.05 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.30 (t, J=5.7 Hz , 3H), 4.66 (d, J=5.7 Hz, 2H), 3.85 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 0.92 (t , J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((5'-(azidomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (335b).

To a solution of ethyl 2-(2-((5'-(hydroxymethyl)-[7,7'-dibenzofuran]-5-yl)methoxy)phenyl)acetate (335a) (352 mg, 0.771 mmol) in CCl ₄ (8 ml) DMF (2 ml), NaN ₃ (82 mg, 1.261 mmol) and PPh ₃ (486 mg, 1.853 mmol) were added and heated at 90°C for 3 hours. The mixture was cooled to room temperature, quenched with water (10 ml) and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed

- 426 045626 with water, dried, filtered and concentrated under vacuum to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA/DCM 0% to

50%] to give ethyl 2-(2-((5'-(azidomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (335b) (253 mg, 68% yield) in in the form of a colorless oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.14-8.04 (m, 2H), 7.87-7.67 (m, 4H), 7.34-7.18 (m, 2H ), 7.18-7.05 (m, 3H), 6.97-6.86 (m, 1H), 5.27 (s, 2H), 4.97 (s, 1H), 4.63 ( s, 1H), 3.83 (k, J=7.1, 1.9 Hz, 2H), 3.62 (s, 2H), 0.90 (t, J=7.1, 2.6 Hz , 3H).

Stage-3. Preparation of ethyl 2-(2-((5'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (335c).

To a solution of ethyl 2-(2-((5'-(azidomethyl)-[7,7'-dibenzofuran]-5-yl)methoxy)phenyl)acetate (335b) (195 mg, 0.405 mmol) in EtOH (8 ml ), water (3 ml) was added with ammonium chloride (113 mg, 2.112 mmol), zinc (90 mg, 1.376 mmol) and refluxed for 90 min. The reaction mixture was stirred at room temperature and concentrated in vacuo to remove ethanol. The residue was dissolved in ethyl acetate, washed with brine, dried, filtered and concentrated in vacuo to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] to give ethyl 2-(2-((5'-(aminomethyl)[7,7'-bibenzofuran ]-5-yl)methoxy)phenyl)acetate (335c) (72 mg, 39.0% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=2.2 Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.66 (d, J= 1.7 Hz, 1H), 7.31-7.18 (m, 2H), 7.18-7.11 (m, 1H), 7.07 (dd, J=8.0, 2.2 Hz , 2H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.27 (s, 2H), 3.97 (s, 2H), 3.86 (k, J= 7.1 Hz, 2H), 3.63 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); MS (ESI+): 456.2 (M+1).

Stage-4. Preparation of 2-(2-((5'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (335d).

Compound 335d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((5'-(aminomethyl)-[7,7'-dibenzofuran]-5-yl)methoxy)phenyl)acetate (335c) (70 mg, 0.154 mmol) in MeOH (6 mL), THF (6 mL), using a solution of lithium hydroxide monohydrate (68 mg, 1.62 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((5' (aminomethyl)-[7,7'-dibenzofuran]-5-yl)methoxy)phenyl)acetic acid (335d) (51 mg, 78% yield), HCl salt, as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (s, 2H), 8.02 (dd, J=7.3, 2.2 Hz, 2H), 7.82 (d, J= 1.7 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.67 (d, J=1, 7 Hz, 1H), 7.25-7.10 (m, 2H), 7.10-6.97 (m, 3H), 6.84 (td, J=7.4, 1.1 Hz, 1H ), 5.22 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H); MS (ESI+): 428.2 (M+1); MS (ESI-): 426.1 (M1); analysis calculation for C ₂₆ H ₂₁ NO ₅ -HCl-H ₂ O:C, 64.80; N, 5.02; Cl, 7.36; N, 2.91; observed: C, 64.54; N, 4.84; Cl, 7.59; N, 2.89.

Scheme-336

C.I.

336b 336c

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (336c).

Stage-1. Preparation of ethyl 2-(2-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzo[b]thiophene-6-ul)methoxy)phenyl) acetate (336a).

Compound 336a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl )methoxy)phenyl)acetate (215f) (200 mg, 0.393 mmol), using bis(pinacolato)diboron (150 mg, 0.589 mmol), potassium acetate (116 mg, 1.179 mmol) and Pd(dppf)Cl ₂ -DCM ( 32 mg, 0.039 mmol) in anhydrous dioxane (5 ml) under argon when heated at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0 -4% EtOAc in hexane] ethyl 2-(2-((2- 427 045626 chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b] thiophen-6-yl)methoxy)phenyl)acetate (336a) (117 mg, 61% yield) as a colorless oil;

1H NMR (300 MHz, chloroform-d) δ 7.90 (dk, J=1.5, 0.8 Hz, 1H), 7.83 (dd, J=5.0, 1.2 Hz, 2H) , 7.25-7.20 (m, 2H), 6.99-6.89 (m, 2H), 5.17 (s, 2H), 4.12 (k, J=7.1 Hz, 2H ), 3.68 (s, 2H), 1.40 (s, 12H), 1.19 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetate (336b).

Compound 336b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate (336a) (154 mg, 0.316 mmol) in dioxane (4 ml), using (4-chloropyridin-2-yl)methanamine (74a) (50 mg, 0.348 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (22 mg, 0.032 mmol) and a solution of K ₂ CO ₃ (131 mg, 0.949 mmol) in water ( 1 ml) heating in a nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-4% MeOH in DCM] ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4yl) -2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate (336b) (23 mg) as a pale yellow oil (23 mg); MS (ESI+): 467/469 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (336c).

Compound 336c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophene-6- yl)methoxy)phenyl)acetate (336b) (23 mg, from previous step-2) in MeOH (3 ml), using a solution of NaOH (63.3 mg, 1.582 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((4-(2-( aminomethyl)pyridin-4-yl)-2chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (336c) (14 mg, 10% yield), HCl salt, as a pale green solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.76 (dd, J=5.2, 0.8 Hz, 1H), 8.46 (s, 3H), 8.15 (dd, J= 1.5, 0.8 Hz, 1H), 7.77 (dd, J=1.8, 0.8 Hz, 1H), 7.65 (dd, J=5.2, 1.7 Hz, 1H ), 7.62 (t, J=1.3 Hz, 2H), 7.32-7.17 (m, 2H), 7.14-7.01 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.32 (t, J=5.5 Hz, 2H), 3.61 (s, 2H). Purity after HPLC: 100%; MS (ESI+): 439/441 (M+1), (ESI-): 437/439 (M-1).

Scheme-337

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (337b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetate (337a).

Compound 337a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl) methoxy)phenyl)acetate (215f (143 mg, 0.281 mmol) in dioxane (4 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (64 mg, 0.309 mmol), bis(triphenylphosphine ) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (20 mg, 0.028 mmol) and a solution of K ₂ CO ₃ (117 mg, 0.843 mmol) in water (1 ml) heating in a nitrogen atmosphere at 100 ° C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-4% MeOH in DCM] ethyl 2-(2((4-(3- (aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate (337a) (62 mg) as a clear pale yellow oil (62 mg); MS (ESI+) : 484/486 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (337b).

Compound 337b was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl )methoxy)phenyl)acetate (337a) (62 mg, from previous step-1) in MeOH (3 ml), using a solution of NaOH (23 mg, 0.562 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(2-((4-(3-( aminomethyl)-2-fluorophenyl)-2chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (337b) (45 mg, 35% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (dd, J=1.5, 0.8 Hz, 1H), 7.66 (td, J=7.1, 1.7 Hz, 1H), 7.55 (td,

- 428 045626

J=7.5, 2.0 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.30 ( dd, J=3.3, 0.7 Hz, 1H), 7.23 (t, J=7.5

Hz, 2H), 7.11-7.03 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.16 (s, 2H), 3.59 (s, 2H); MS (ESI+):

456/458 (M+1); (ESI-): 454/456 (M-1).

Scheme-338

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (338c).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((2-chloro-4-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzo[b]thiophene-6 -yl)methoxy)phenyl)acetate (338a).

Compound 338a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl) methoxy)phenyl)acetate (215f) (117 mg, 0.240 mmol) in dioxane (4 ml), using (+)-(S)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)- 2methylpropane-2-sulfinamide (220c) (70.0 mg, 0.264 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (17 mg, 0.024 mmol) and K2CO3 solution (100 mg , 0.721 mmol) in water (1 ml) heating in a nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-2% MeOH in DCM] (+)-(S)-ethyl 2-(2-((2-chloro- 4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate (338a) (145 mg) as pale yellow oil (145 mg); MS (ESI+) 589/591; optical rotation [a] _D = +20.0 (c = 0.03, MeOH).

Stage-2. Preparation of methyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen6-yl)methoxy)phenyl)acetate (338b).

Compound 338b was prepared according to the procedure described in step-3 of scheme-305 from (+)(8)-ethyl 2-(2-((2-chloro-4-(2-(( 1,1-dimethylethylsulfinamido)methyl )-3-fluoropyridin-4-yl)benzo[b]thiophen6-yl)methoxy)phenyl)acetate (338a) (145 mg, from previous step-1) in methanol (5 ml) using HCl (4 M in dioxane; 0.18 ml, 0.721 mmol) when heated at 60°C for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-6% MeOH in DCM] methyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen6-yl)methoxy)phenyl)acetate (338b) (25 mg) as pale - yellow oil; MS (ESI+): 471/473 (methyl ester, M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6yl)methoxy)phenyl)acetic acid (338c).

Compound 338c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b] thiophen-6-yl)methoxy)phenyl)acetate (338b) (25 mg, from previous step-2) in MeOH (2 ml), THF (1 ml), using a solution of NaOH (28.8 mg, 0.721 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2(2-((4-(2- (aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetic acid (338c) (13 mg, 12% yield), HCl salt, as pale green solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (d, J=4.9 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H), 7.66 (t , J=5.3 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.23 (d, J =7.5 Hz, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.96-6.88 (m, 1H), 5.30 (s, 2H), 4.37 (d, J=1.8 Hz, 2H), 3.60 (s, 2H); MS (ESI+): 457/459, (ESI-): 455/457.

- 429 045626

Scheme-339

Preparation of 2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (339c).

Stage-1. Preparation of ethyl 2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5yl)methoxy)phenyl)acetate (339b).

Compound 339b was prepared according to the procedure described in step-3 of Scheme-1 from (4bromothiophen-2-yl)methanamine (339a) (300 mg, 1.562 mmol; CAS No. 479090-38-5) in dioxane (5 ml) using (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (496 mg, 1.137 mmol), bis(triphenylphosphine) palladium(H) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (127 mg, 0.181 mmol) and a solution of K2CO3 (498 mg, 3.60 mmol) in water (0.5 ml) heating in an argon atmosphere at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 20% MeOH/DCM] ethyl 2-(2-((7-(5-(aminomethyl)thiophene- 3yl)benzofuran-5-yl)methoxy)phenyl)acetate (339b) (475 mg, 99% yield) as a yellow oil. MS (ESI+): 422.1 (M+1), MS (ESI-): 420.1 (M-1).

Stage-2. Preparation of 2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (339c).

Compound 339c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (339b) (380 mg, 0.902 mmol) in MeOH (6 mL), THF (6 mL), using a solution of lithium hydroxide monohydrate (152 mg, 3.62 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (5(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (339c) (155 mg, 44% yield), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO-d6/D2O) δ 8.20 (d, J=1.5 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.98 ( d, J=1.5 Hz, 1H), 7.80-7.64 (m, 2H), 7.31-7.18 (m, 2H), 7.15-7.02 (m, 2H) , 6.92 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.34 (s, 2H), 3.63 (s, 2H); MS (ESI+): 394.1 (M+1); MS (ESI-): 392.1 (M-1); analysis calculation for: C ₂₂ H ₁₉ NO ₄ S-HCl-1.25H ₂ O: C, 58.40; N, 5.01; Cl, 7.84; N, 3.10; observed: C, 58.52; N, 5.07; Cl, 8.09, N, 3.20.

Scheme-340

Preparation of (trans)-2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)oxy)methyl)-N-(3-chloro-2fluorobenzyl)cyclopentanecarboxamide (340e).

Stage-1. Preparation of (trans)-N-(3-chloro-2-fluorobenzyl)-2-(hydroxymethyl)cyclopentanecarboxamide (340a).

Compound 340a was prepared according to the procedure described in step-1 of Scheme-23 from (trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentapecarboxylic acid (217b) (1.2 g, 2.91 mmol) using N-methylmorpholine (0.202 g, 2.002 mmol) in THF (15 ml), isobutyl chloroformate (0.262 ml, 2.002 mmol) and NaBH ₄ (0.189 g, 5.0 mmol) in water (2 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-3% MeOH in DCM) (trans)-H-(3-chloro-2-fluorobenzyl)-2 -(hydroxymethyl)cyclopentanecarboxamide (340a) (0.30 g, 63% yield) as a colorless oil.

^1H NMR (300 MHz, DMSO-d6) δ 8.41 (t, J=5.9 Hz, 0H), 7.47 (td, J=7.5, 1.9 Hz, 1H), 7, 35-7.08 (m, 2H), 4.42-4.21 (m, 2H), 3.34 (cd, J=10.6, 6.4 Hz, 2H), 2.35 (k, J=7.8 Hz, 1H), 2.16 (g, J=7.3 Hz, 1H), 1.93-1.43 (m, 4H), 1.33 (dk, J=13.6 , 7.2 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.75; MS (ESI+): 286/288 (M+1).

Stage-2. Preparation of (trans)-2-(bromomethyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (340b).

Compound 340b was prepared according to the procedure described in step-1 of Scheme-152 from (trans)-N-(3-chloro-2-fluorobenzyl)-2-(hydroxymethyl)cyclopentanecarboxamide (340a) (0.30 g, 1.050 mmol) in DCM (10 ml) using triphenylphosphine (0.303 g, 1.155 mmol), CBr ₄ (0.383 g, 1.155 mmol) and stirring at room temperature for 2 hours. This resulted in the following work-up and purification by flash chromatography on column (silica gel, 12 g, eluted with 0-20% EtOAc in hexane) (trans)-2-(bromomethyl)-M-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (340b) (0.21 g, 57% yield) in the form of a colorless oil; MS (ESi+): 348/350 (M+1).

Stage-3. Preparation of (trans)-2-(((7-bromobenzofuran-5-yl)oxy)methyl)-M-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (340d).

Compound 340d was prepared according to the procedure described in step-2 of Scheme-152 from (trans)-2-(bromomethyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (340b) (0.21 g, 0.602 mmol), using 7-bromobenzofuran-5-ol (340c) (0.128 g, 0.602 mmol; CAS No. 603311-31-5), K ₂ CO ₃ (0.250 g, 1.807 mmol) in MeCN (10 ml) and heating at 80°C for 5 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-30% EtOAc in hexane) (trans)-2-(((7-bromobenzofuran- 5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (340d) (150 mg, 52% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (t, J=5.8 Hz, 1H), 8.06 (dd, J=2.1, 0.5 Hz, 1H), 7 .47 (ddd, J=7.9, 7.2, 1.8 Hz, 1H), 7.27 (ddd, J=7.7, 6.7, 1.7 Hz, 1H), 7.19 -7.10 (m, 2H), 7.07 (dd, J=2.4, 0.5 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 4.48- 4.24 (m, 2H), 4.01-3.84 (m, 2H), 1.97-1.78 (m, 2H), 1.78-1.54 (m, 4H), 1. 45 (dt, J=13.0, 7.0 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.58; MS (ESI+): 480/482 (M+1), (ESI-): 478/480 (M-1).

Stage-4. Preparation of (trans)-2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)oxy)methyl)-N-(3-chloro2-fluorobenzyl)cyclopentanecarboxamide (340e).

Compound 340e was prepared according to the procedure described in step-3 of Scheme-1 from (trans)-2-(((7-bromobenzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl )cyclopentanecarboxamide (340d) (150 mg, 0.312 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (64 mg, 0.343 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd (PPh ₃ ) ₂ Cl ₂ ) (22 mg, 0.031 mmol) and K2CO3 (129 mg, 0.936 mmol) in water (1 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This resulted in the following workup and purification by flash column chromatography [silica gel, eluted with methanol in DCM] followed by purification by reverse phase flash column chromatography (C18, 100 g, 0-60% MeCN in _H2O with 0. 1% HCl) (trans)-2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)oxy)methyl)-N-(3-chloro-2fluorobenzyl)cyclopentanecarboxamide (340e) (108 mg , 68% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (t, J=5.8 Hz, 1H), 8.40 (s, 3H), 8.04 (d, J=2.2 Hz , 1H), 7.98 (d, J=1.9 Hz, 1H), 7.91 (dt, J=7.2, 1.8 Hz, 1H), 7.62-7.49 (m, 2H), 7.43 (ddd, J=8.0, 7.1, 1.7 Hz, 1H), 7.32-7.23 (m, 1H), 7.19-7.05 (m, 3H), 6.96 (d, J=2.2 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H), 4.13 (s, 2H), 4.06-3, 90 (m, 2H), 2.56 (t, J=5.3 Hz, 2H), 1.92 (t, J=6.4 Hz, 1H), 1.81-1.59 (m, 4H ), 1.51 (dt, J=12.8, 6.8 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.60; MS (ESI+): 507/509 (M+1), (ESI-): 505/507 (M-1).

- 431 045626

Scheme-341

Preparation of 2-(2-((7-(3-amino-III-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (341e).

Stage-1. Preparation of 7-bromo-3-nitro-1H-indole (341b).

To a suspension of 7-bromo-1H-indole (341a) (2.0 g, 10.20 mmol; CAS No: 51417-51-7) AgNO ₃ (1.9 g, 11.18 mmol) in acetonitrile (16 ml ) at 0°C, benzoyl chloride (1.35 ml, 11.63 mmol) was added and stirred at 0°C for 45 min. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aq. NaHCO ₃ solution, 2 M HCl solution, dried, filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with 0% to 60% ethyl acetate in hexane] followed by reverse phase column chromatography [C18 (150 g), eluted with ACN in water (0 .1% HCl) from 0% to 100%] to give 7-bromo-3-nitro-1H-indole (341b) (547 mg, 22% yield) as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.69 (s, 1H), 8.11 (dd, J=8.0, 1.0 Hz, 1H), 7.61 (dd, J=7.8, 1.0 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5yl)methoxy)phenyl)acetate (341c).

To a degassed solution of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (59a) (377 mg, 0.864 mmol) in dioxane (5 ml), 7bromo-3-nitro-1H-indole (341b) (202 mg, 0.838 mmol), Pd(dppf)Cl2-CH ₂ Cl2 adduct (109 mg, 0.133 mmol) and K2CO3 (380 mg, 2.75 mmol) in water (0.5 ml). The mixture was degassed and filled with argon and then heated at 100°C overnight. The reaction mixture was cooled to room temperature, diluted with EA, washed with water and brine. The organic layer was dried, filtered and concentrated. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EA/hex. 0% to 60%] to give ethyl 2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5yl)methoxy)phenyl)acetate (341c) (394 mg, 100% output) in the form of yellow syrup. MS (ESI+): 471.1 (M+1), MS (ESI-): 469.1 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-nitro-1H-indol-7 -yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (341d).

Compound 341d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl) acetate (341c) (50 mg, 0.106 mmol) in MeOH (3 ml), THF (3 ml), using a solution of lithium hydroxide monohydrate (15 mg, 0.357 mmol) in water (1 ml). This resulted in the production of 2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (341d) (47 mg, 100% yield) after treatment as a yellow solid. MS (ESI+): 443.1 (M+1); MS (ESI-): 441.1 (M-1).

Stage-4. Preparation of 2-(2-((7-(3-amino-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (341e).

To a solution of 2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (341d) (44 mg, 0.099 mmol), DIEA (0.128 ml, 0.735 mmol) in anhydrous acetonitrile (3 ml), trichlorosilane (0.13 ml, 1.267 mmol) was added at 0°C and allowed to warm to room temperature overnight. The reaction mixture was concentrated to dryness and the resulting residue was purified by reverse phase flash chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] to give 2-( 2-((7-(3-amino-1H-indol-7-yl)benzofuran-5- 432 045626 yl)methoxy)phenyl)acetic acid (341e) (8 mg, 20% yield), HCl salt, as white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.99 (d, J=2.9 Hz, 1H), 10.22 (s, 2H), 7.94 (d, J=2.2 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H) , 7.40-7.29 (m, 2H), 7.26-7.10 (m, 3H), 7.10-7.01 (m, 1H), 6.99 (d, J=2, 2 Hz, 1H), 6.83 (td, J=7.3, 1.1 Hz, 1H), 5.23 (s, 2H), 3.52 (s, 2H); MS (ESI+): 413.1 (M+1); MS (ESI-): 411.1 (M-1).

Scheme-342

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (342e).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342a).

Compound 342a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-4-fluorobenzofuran-5-yl)methanol (136b) (1.0 g, 4.08 mmol) in DCM (40 ml) using triphenylphosphine (1.177 g, 4.49 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (0.951 g, 4.90 mmol) and (E)bis(4-chlorobenzyl)diazen- 1,2-dicarboxylate (DCAD, 1.648 g, 4.49 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with EtOAc in 0% to 40% hexane), ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy) -4methylphenyl)acetate (342a) (972 mg, 57% yield) as a yellow solid;

1H NMR (300 MHz, DMSO4) δ 8.22 (d, J=2.3 Hz, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.28 (d, J=2 .3 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=1.3 Hz, 1H), 6.75 (ddd, J=7.5 , 1.6, 0.8 Hz, 1H), 5.18 (d, J=1.4 Hz, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.51 (s , 2H), 2.31 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -124.72.

Stage-2. Preparation of ethyl 2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342b).

Compound 342b was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342a) ( 472 mg, 1.120 mmol) using bis(pinacolato)diboron (427 mg, 1.681 mmol), potassium acetate (330 mg, 3.36 mmol) and Pd(dppf)Cl ₂ DCM (137 mg, 0.168 mmol) in anhydrous dioxane (10 ml) under argon while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in 0% to 40% hexanes] ethyl 2-(2-((4fluoro-7-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342b) (466 mg, 89% yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.3 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.13 (d, J =2.3 Hz, 1H), 7.10-6.97 (m, 2H), 6.74 (d, J=7.6 Hz, 1H), 5.17 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.45 (s, 2H), 2.31 (s, 3H), 1.33 (s, 12H), 0.96 (t, J=7, 1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -119.10.

Stage-3. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342c ).

Compound 342c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)-4

- 433 045626 methylphenyl)acetate (342b) (460 mg, 0.982 mmol) in dioxane (5 ml), using (+)-(S)-N-((4-chloro-3fluoropyridin-2-yl)methyl)-2 -methylpropane-2-sulfinamide (220c) (312 mg, 1.179 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (103 mg, 0.147 mmol) and K ₂ CO ₃ solution ( 407 mg, 2.95 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 15% MeOH/DCM] ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido )Methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (342c) (561 mg, 100% yield) as a brown oil. MS (ESI+): 571.2 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (342d).

Compound 342d was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (342c) (555 mg, 0.973 mmol) in methanol (10 ml) using HCl (4 M in dioxane; 1 ml, 4.00 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 70%], ethyl 2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342d) (268 mg, 59% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=4.9 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.66 (d, J =6.7 Hz, 1H), 7.63-7.52 (m, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.15-6.99 (m, 2H) , 6.75 (d, J=7.5 Hz, 1H), 5.26 (d, J=3.0 Hz, 2H), 3.94 (d, J=2.1 Hz, 2H), 3 .86-3.78 (m, 2H), 3.51 (s, 2H), 2.32 (s, 3H), 0.90 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -122.08, -130.74. MS (ESI+): 467.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (342e).

Compound 342e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl )methoxy)-4-methylphenyl)acetate (342d) (263 mg, 0.564 mmol) in MeOH (6 ml), THF (6 ml), using a solution of lithium hydroxide (89 mg, 2.121 mmol) in water (2 ml). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to

100%]

2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (342e) (166 mg, 67% yield ), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.73 (t, J=5.8 Hz, 3H), 8.63 (d, J=4.9 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.85-7.67 (m, 2H), 7.27 (d, J=2.3 Hz, 1H), 7, 09 (d, J=7.5 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.826.65 (m, 1H), 5.29 (s, 2H), 4, 36 (d, J=5.8 Hz, 2H), 3.49 (s, 2H), 2.31 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 121.44, -128.49; MS (ESI+): 439.1 (M+1); MS (ESI-): 437.1 (M-1); analysis calculation for C ₂₄ H2 _O F2N2O4-1.1HCi-0.25H2O: C, 59.68; N, 4.51; Cl, 8.07; N, 5.80; observed: C, 59.61; N, 4.19; Cl, 8.21; N, 5.87.

Receipt

Scheme-343

2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-434 045626 yl)methoxy)-4-methylphenyl)acetic acid (343e) .

Stage-1. Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (343a).

Compound 343a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (1.4 g, 4.74 mmol) in DCM ( 20 ml), using triphenylphosphine (1.369 g, 5.22 mmol), ethyl 2-(2-hydroxy-4-methylphenyl) acetate (269d) (1.106 g, 5.69 mmol) and (E)-bis(4- chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.916 g, 5.22 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with (EtOAc:MeOH 9:1)/hexane 0% to 40%], ethyl 2-(2-((7-bromo-3(trifluoromethyl) )benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (343a) (953 mg, 43% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (d, J=1.7 Hz, 1H), 7.80 (d, J=2.2 Hz, 2H), 7.10 (d , J=7.5 Hz, 1H), 6.93 (s, 1H), 6.74 (d, J=7.3 Hz, 1H), 5.22 (s, 2H), 3.99 (k , J=7.1 Hz, 2H), 3.57 (s, 2H), 2.29 (s, 3H), 1.06 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -58.24.

Stage-2. Preparation of ethyl 2-(4-methyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy )phenyl)acetate (343b).

Compound 343b was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate ( 343a) (493 mg, 1.046 mmol), using bis(pinacolato)diboron (398 mg, 1.569 mmol), potassium acetate (308 mg, 3.14 mmol) and Pd(dppf)Cl ₂ -DCM (128 mg, 0.157 mmol ) in anhydrous dioxane (10 ml) under argon while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in 0% to 40% hexanes] ethyl 2-(4methyl-2-((7-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (343b) (534 mg, 98% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.85 (k, J=1.7 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.81-6.67 ( m, 1H), 5.21 (s, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.30 (s, 3H), 1, 35 (s, 12H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -57.99.

Stage-3. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl) acetate (343c).

Compound 343c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (343b) (513 mg, 0.990 mmol) in dioxane (6 ml) using (+)-(S)-N-((4 -chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (314 mg, 1.188 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) ( 104 mg, 0.148 mmol) and a solution of K2CO3 (410 mg, 2.97 mmol) in water (0.6 ml) heated under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 15% MeOH/DCM] ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido )Methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (343c) (614 mg, 100% yield) as a brown oil. MS (ESI+): 621.2 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (343d).

Compound 343d was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -3-(trifluoromethyl)benzofuran5-yl)methoxy)-4-methylphenyl)acetate (343c) (610 mg, 0.983 mmol) in methanol (10 ml) using HCl (4 M in dioxane; 1 ml, 4.00 mmol ) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 70%], ethyl 2-(2-( (7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (343d) (302 mg, 60% yield) as pale yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.91 (d, J=1.9 Hz, 1H), 8.55 (d, J=4.9 Hz, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 7.62 (k, J=4.9 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 6.74 (d, J=7.4 Hz, 1H), 5.29 (s, 2H), 3.96-3.85 (m, 4H), 3.57 (s, 2H), 2.30 (s, 3H), 1.02-0.88 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.09, -130.71; MS (ESI+): 517.2 (M+1).

Stage-5. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)-4-methylphenyl)acetic acid (343e).

Compound 343e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran- 5-yl)methoxy)-4methylphenyl)acetate (343d) (300 mg, 0.581 mmol) in MeOH (6 ml), THF (6 ml), using a solution of lithium hydroxide (97 mg, 2.323 mmol) in water (2 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-435 045626 yl)methoxy)-4-methylphenyl)acetic acid (343e) (165 mg, 58% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.94 (k, J=1.6 Hz, 1H), 8.66 (d, J=4.9 Hz, 1H), 8.62 (d, J=5.9 Hz, 3H), 8.01 (s, 1H), 7.83 (t, J=5.3 Hz, 1H), 7.79 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 5.32 (s, 2H) , 4.47-4.29 (m, 2H), 3.53 (s, 2H), 2.30 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.03, 128.51; MS (ESI+): 489.1 (M+1); MS (ESI-): 487.1 (M-1); analysis calculation for: ^^(^^ONDNSSCHO: C, 54.22; H, 4.24; Cl, 8.32; N, 5.06; observed: C, 54.29; H, 4.12; Cl , 8.50, N, 5.05.

Scheme-344

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5yl)methoxy)phenyl)acetic acid (344f).

Stage-1. Preparation of methyl 7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-carboxylate (344b).

Compound 344b was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (7.66 g, 24.72 mmol) in pyridine (150 ml) 2 ,5,8,11tetraoxatetradec-13-yne (344a) (5 g, 24.72 mmol), copper(I) oxide (1.769 g, 12.36 mmol) when heated at 120°C for 3 hours in a sealed vial 350 ml in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 80% EtOAc in hexane] methyl 7-bromo-2-(2,5,8,11-tetraoxadodecyl) benzofuran-5-carboxylate (344b) (7.5 g, 70% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.30 (d, J=1.5 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.17 (s , 1H), 4.73-4.67 (m, 2H), 3.87 (s, 3H), 3.68-3.63 (m, 2H), 3.60-3.55 (m, 2H ), 3.53-3.48 (m, 6H), 3.44-3.39 (m, 2H), 3.22 (s, 3H).

Stage-2. Preparation of (7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methanol (344c).

Compound 344c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-carboxylate (344b) (3.7 g, 8.58 mmol) in THF (40 ml) using LiBH ₄ (6.43 ml, 25.7 mmol, 4 M solution in THF) and MeOH (1.041 ml, 25.7 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0-60% EtOAc in hexane] (7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran- 5yl)methanol (344c) (3.1 g, 90% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.56 (dd, J=1.5, 0.8 Hz, 1H), 7.48 (dd, J=1.5, 0.7 Hz, 1H), 7.01 (s, 1H), 5.32 (t, J=5.8 Hz, 1H), 4.66-4.61 (m, 2H), 4.56 (d, J=5 .4 Hz, 2H), 3.65-3.60 (m, 2H), 3.60-3.54 (m, 2H), 3.523.47 (m, 6H), 3.43-3.38 ( m, 2H), 3.22 (s, 3H); MS (ESI+): 436.2 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5yl)methoxy)phenyl)acetate (344d).

Compound 344d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methanol (344c) (1.85 g, 4.59 mmol) in DCM (50 ml) using triphenylphosphine (1.32 g, 5.05 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.91 g, 5.05 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 1.85 g, 5.05 mmol) in DCM (20 ml). This

- 436 045626 gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc/MeOH (9:1) in 0% to 80% hexane] ethyl 2-(2-((7 -bromo-2-(2,5,8,11tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate (344d) (1.3 g, 50% yield) as a clear oil; MS (ESI+): 587.1 and 589.1 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate (344e).

Compound 344e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy) phenyl)acetate (344d) (500 mg, 0.88 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (298 mg, 1.592 mmol), K ₂ CO ₃ solution (367 mg , 2.65 mmol) in water (3 ml), bis(triphenylphosphine) palladium(P) chloride (93 mg, 0.13 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in 0% to 50% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2-(2,5,8,11tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate (344e) (186 mg, 36% yield) as a clear oil, MS (ESI+): 592.3 (M +1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5yl)methoxy)phenyl)acetic acid (344f).

Compound 344f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran -5-yl)methoxy)phenyl)acetate (344e) (93 mg, 0.157 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (111 mg, 2.65 mmol) in water (2 mL ). This resulted in, after workup and purification by reverse phase column chromatography, [EZ-PREP, C-18 column, 30 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl )acetic acid (344f) (80 mg, 85% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (s, 1H, D2O replaceable), 8.50 (s, 3H, D2O replaceable), 7.97 (d, J=1.9 Hz, 1H ), 7.93 (dt, J=6.7, 2.1 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz , 1H), 7.61-7.55 (m, 2H), 7.24 (dd, J=8.4, 6.5 Hz, 2H), 7.14-7.06 (m, 1H), 6.99 (s, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.67 (s, 2H), 4.13 (k, J=5.8 Hz, 2H), 3.66-3.58 (m, 4H), 3.58-3.53 (m, 2H), 3.52-3.46 (m, 6H ), 3.41-3.39 (m, 2H), 3.20 (s, 3H); MS (ESI+): 564.3 (M+1); (ESI-): 562.2 (M-1); analysis calculation for C ₃₂ H ₃₇ NO ₈ -HCl-H ₂ O: C, 62.18; N, 6.52; Cl, 5.74; N, 2.27; observed: C, 61.84; N, 6.47; Cl, 5.89; N, 2.37.

Scheme-345 he

345a 345b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (345b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (345a).

Compound 345a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (343a ) (147 mg, 0.312 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (71 mg, 0.468 mmol), solution of K ₂ CO ₃ (129 mg, 0.936 mmol) in water ( 0.5 ml), bis(triphenylphosphine) palladium(11) chloride (33 mg, 0.047 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (345a) (104 mg, 67% yield) as a dark oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.89 (k, J=1.6 Hz, 1H), 7.86-7.66 (m, 4H), 7.55-7.41 (m , 2H), 7.09 (d, J=7.5 Hz, 1H), 6.98 (d, J=1.4 Hz, 1H), 6.74 (dd, J=7.5, 1, 4 Hz, 1H), 5.28 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.57 (s, 2H), 2 .30 (s, 3H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.08. MS (ESI+): 498.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)4-methylphenyl)acetic acid (345b).

Compound 345b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)- 4-methylphenyl)acetate (345a)

- 437 045626 (101 mg, 0.203 mmol) in MeOH/THF (6 ml each), using a solution of lithium hydroxide monohydrate (60 mg, 1.43 mmol) in water (2 ml). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (345b ) (69 mg, 72% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.83 (k, J=1.7 Hz, 1H), 8.49 (s, 2H), 7.94 (d , J=2.0 Hz, 1H), 7.85 (ddd, J=5.0, 3.2, 1.8 Hz, 1H), 7.81-7.71 (m, 2H), 7, 62-7.49 (m, 2H), 7.03 (d, J=7.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 6.67 (d, J =7.6 Hz, 1H), 5.23 (s, 2H), 4.07 (s, 2H), 3.48 (s, 2H), 2.22 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.01; MS (ESI+): 470.1 (M+1); MS (ESI-): 468.1 (M-1); analysis calculation for C2 _¢ H22FзNO4·HCl·0.25H ₂ O: C, 61.18; N, 4.64; Cl, 6.95; N, 2.74; observed: C, 61.17; N, 4.48; Cl, 6.91; N, 2.72.

Scheme-346

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (346c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (346a).

Compound 346a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342a) (186 mg, 0.442 mmol) in dioxane (5 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methyl)carbamate (123 a) (221 mg, 0.662 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (47 mg, 0.066 mmol) and K ₂ CO ₃ solution (183 mg, 1.325 mmol ) in water (0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(2-(((tert- butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (346a) (242 mg, 100% yield) as a dark oil. MS (ESI+): 549.2 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (346b).

Compound 346b was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4 -fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (346a) (240 mg, 0.437 mmol) in methanol (6 ml) using HCl (4 M in dioxane; 0.6 ml, 2.4 mmol) and stirring at room temperature overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 100%] methyl 2-(2-((7-(2-(aminomethyl)pyridinium- 4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (346b) (152 mg, 80% yield) as a clear oil.

1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=5.2 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.00-7.94 (m, 1H), 7.87 (d, J=6.8 Hz, 1H), 7.75 (dd, J=5.2, 1.8 Hz, 1H), 7.26 (d, J= 2.3 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.80-6.65 (m, 1H), 5.27 (d, J=1.3 Hz, 2H), 3.93 (s, 2H), 3.55 (s, 2H), 3.40 (s, 3H), 2.32 ( s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -122.71. MS (ESI+): 435.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (346c).

Compound 346c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy )-4-methylphenyl)acetate (346b) (150 mg, 0.334 mmol) in MeOH (6 ml), THF (6 ml), using a solution of lithium hydroxide (88 mg, 2.097 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7 -(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (346c) (128 mg, 91% yield), HCl salt, as a white solid substances.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (d, J=5.5 Hz, 1H), 8.69 (s, 3H), 8.18 (dd, J=4.1, 2 .0 Hz, 2H), 8.01 (dd, J=5.5, 1.7 Hz, 1H), 7.95 (d, J=6.7 Hz, 1H), 7.21 (d, J =2.3 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H), 6.76-6.60 (m , 1H), 5.22 (s, 2H), 4.28 (s, 2H), 3.45 (s, 2H), 2.24 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 120.99; MS (ESI+): 421.1 (M+1); MS (ESI-): 419.1 (M-1); analysis calculation for

C ₂₄ H ₂₁ FN ₂ O ₄ -1.9HCl-1.25H ₂ O: C, 56.28; N, 5.00; Cl, 13.15; N, 5.47; observed: C, 56.15; N, 4.64; Cl, 13.06; N, 5.31.

Scheme-347 he

347a 347b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (347b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (347a).

Compound 347a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342a) (147 mg, 0.349 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (79 mg, 0.523 mmol), solution of K ₂ CO ₃ (145 mg, 1.047 mmol) in water (0.5 ml), bis(triphenylphosphine)palladium(P) chloride (37 mg, 0.052 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (347a) (102 mg, 65% yield) as a dark oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=2.3 Hz, 1H), 7.79 (s, 1H), 7.72-7.63 (m, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7, 08 (d, J=7.5 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 5.25 ( s, 2H), 3.90-3.76 (m, 4H), 3.51 (s, 2H), 2.32 (s, 3H), 0.90 (t, J=7.1 Hz, 3H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -125.59. MS (ESI+): 448.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (347b).

Compound 347b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl )acetate (347a) (100 mg, 0.223 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (52 mg, 1.239 mmol) in water (2 mL). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (347b) (76 mg, 81% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ , D2O substitution) δ 8.09 (d, J=2.3 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.88 (dd, J=7.6, 1.6 Hz, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.64-7.45 (m, 2H), 7.17 ( d, J=2.3 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.11 (s, 2H), 3.47 (s, 2H), 2.28 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.86; MS (ESI+): 420.1 (M+1); MS (ESI-): 418.1 (M-1); analysis calculation for C25H22FNO ₄ -HCl-0.25H2O: C, 65.22; N, 5.14; Cl, 7.70; N, 3.04; observed: C, 65.15; N, 5.10; Cl, 7.85; N, 3.09.

Scheme-348 he

348a 348b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (348b).

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Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (348a).

Compound 348a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (342a) (150 mg, 0.356 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (110 mg, 0.534 mmol), K ₂ CO ₃ solution (148 mg, 1.068 mmol) in water (0.5 ml), bis(triphenylphosphine) palladium(P) chloride (38 mg, 0.053 mmol) by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-4fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (348a) (132 mg, 80% yield) as a dark oil. MS (ESI+): 466.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (348b).

Compound 348b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)- 4-Methylphenyl)acetate (348a) (129 mg, 0.277 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (75 mg, 1.787 mmol) in water (2 mL). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)4-methylphenyl)acetic acid ( 348b) (56 mg, 46% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ , D2O substitution) δ 8.09 (d, J=2.3 Hz, 1H), 7.67 (cd, J=7.8, 1.8 Hz, 2H) , 7.58 (d, J=6.7 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 7 .08 (d, J=7.5 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.83-6.67 (m, 1H), 5.27 (s, 2H), 4.19 (s, 2H), 3.48 (s, 2H), 2.31 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 118.52, -123.72. MS (ESI+): 438.1 (M+1); MS (ESI-): 436.1 (M-1); analysis calculation for C25H21F2NO ₄ -HCl-0.75H2O: C, 61.60; N, 4.86; Cl, 7.27; N, 2.87; observed: C, 61.59; N, 4.85; Cl, 7.40; N, 2.91.

Scheme-349 he

349a 349b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (349b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (349a).

Compound 349a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (343a ) (154 mg, 0.327 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (101 mg, 0.490 mmol), K ₂ CO ₃ solution (135 mg, 0.98 mmol) in water (0.5 ml), bis(triphenylphosphine) palladium(P) chloride (34 mg, 0.049 mmol) when heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in 0% to 70% DCM] ethyl 2-(2-((7(3-(aminomethyl)-2-fluorophenyl) -3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (349a) (145 mg, 86% yield) as a dark oil. MS (ESI+): 516.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (349b).

Compound 349b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl) methoxy)-4-methylphenyl)acetate (349a) (142 mg, 0.275 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (105 mg, 2.502 mmol) in water (2 mL). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (349b) (61 mg, 45% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ , D2O substitution) δ 8.78 (t, J=1.8 Hz, 1H), 7.93 (s, 1H), 7.79-7.63 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H) , 6.77 (dd, J=7.7, 1.4 Hz, 1H), 5.30 (s, 2H),

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4.21 (s, 2H), 3.54 (s, 2H), 2.30 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.02, -118.61. MS (ESI+): 488.1 (M+1); MS (ESI-): 486.1 (M-1); analysis calculation for C ₂₆ H ₂₁ F ₄ NO ₄ -HCl-0.5H ₂ O: C, 58.60; N, 4.35; Cl, 6.65; N, 2.63; observed: C, 58.81; N, 4.37; Cl, 6.49; N, 2.64.

Scheme-350

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)acetic acid (350e).

Stage-1. Preparation of tert-butyl 2-(2-(benzyloxy)-5-methoxyphenyl)acetate (350b).

To a stirred suspension of 1-(benzyloxy)-2-bromo-4-methoxybenzene (350a) (0.5 g, 1.71 mmol; CAS No. 151039-11-1), Pd ₂ (dba) ₃ (0.16 g , 0.17 mmol) and Q-Phos (0.12 g, 0.17 mmol) in THF (10 ml) was added (2-tert-butoxy-2-oxoethyl)zinc(P) chloride (0.5 M solution in ether; 6.82 ml, 3.41 mmol) and heated at 70°C for 2 hours under argon. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml) and brine (5 ml). The mixture was stirred for 10 minutes and filtered through a small pad of celite. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with brine (25 ml), dried and concentrated. The resulting crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with ethyl acetate in 0-50% hexanes) to give tert-butyl 2-(2-(benzyloxy)5-methoxyphenyl) acetate (350b) (0.5 g , 89% yield) in the form of oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.49-7.30 (m, 5H), 6.95 (d, J=8.7 Hz, 1H), 6.82 (d, J=3 .0 Hz, 1H), 6.78 (dd, J=8.7, 3.1 Hz, 1H), 5.03 (s, 2H), 3.69 (s, 3H), 3.51 (s , 2H), 1.33 (s, 9H). MS (ESI+): 351.1 (M+Na).

Stage-2. Preparation of tert-butyl 2-(2-hydroxy-5-methoxyphenyl) acetate (350c).

To a solution of tert-butyl 2-(2-(benzyloxy)-5-methoxyphenyl)acetate (350b) (0.5 g, 1.52 mmol) in MeOH (15 ml) was added palladium hydroxide on carbon, 20 wt.% loading (dry base), carbon matrix, wet support (0.107 g, 0.152 mmol) and hydrogenated at atmospheric pressure for 18 hours. The reaction mixture was filtered through celite to remove catalyst and concentrated in vacuo to give tert-butyl 2-(2-hydroxy -5-methoxyphenyl)acetate (350c) (0.25 g, 69% yield) as a light red oil;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.97-8.95 (m, 1H), 6.72-6.66 (m, 2H), 6.66-6.60 (m, 1H) , 3.64 (s, 3H), 3.41 (s, 2H), 1.39 (s, 9H). MS (ESI+): 261.1 (M+Na).

Stage-3. Preparation of tert-butyl 2-(2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)acetate (350d).

Compound 350d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.18 g, 0.51 mmol) in DCM (5 ml) using triphenylphosphine (0.17 g, 0.66 mmol), tert-butyl 2-(2-hydroxy-5-methoxyphenyl) acetate (350c) (0.16 g, 0.66 mmol) and ( E)-bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 0.24 g, 0.66 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 30% EtOAc in hexane] tert-butyl 2-(2-((7-(3-((( tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)acetate (350d) (0.1 g, 34% yield) as a white oil. MS (ESI+) 474.2 (M-Boc+1), 596.2 (M+Na).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5methoxyphenyl)acetic acid (350e).

Compound 350e was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-5methoxyphenyl)acetate (350d) (0.1 g, 0.17 mmol) in DCM (3 ml), using TFA (0.27 ml, 3.49 mmol) and stirring at room temperature for 12 h. This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5methoxyphenyl)acetic acid (350e) (0.03 g, 43% yield), HCl salt, as a white solid;

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1H NMR (300 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 8.34 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 7.99 ( s, 1H), 7.977.88 (m, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.67-7.50 (m, 3H), 7.06 (d, J =2.2 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J=3.1 Hz,

1H), 6.79 (dd, J=8.8, 3.1 Hz, 1H), 5.19 (s, 2H), 4.14 (s, 2H), 3.69 (s, 3H), 3.57 (s, 2H); MS (ESI+): 418.1 (M+1); MS (ESI-): 416.1 (M-1); analysis calculation for: C25H23NO5-HC1-H2O: C, 63.63; N, 5.55; Cl, 7.51; N,

2.97; observed: C, 63.68; N, 5.30; Cl, 7.78; N, 3.00.

Scheme-351

351a 351b 351c 351d

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1 H-indol-6-yl)methoxy)phenyl)acetic acid (351f).

Stage-1. Preparation of methyl 4-bromo-1-phenyl-1H-indole-6-carboxylate (351b).

To a solution of methyl 4-bromo-1H-indole-6-carboxylate (351a) (0.8 g, 3.15 mmol; CAS No. 882679-96-1) and iodobenzene (0.77 g, 3.78 mmol) in DMF (10 ml), cesium carbonate (1.54 g, 4.72 mmol) and copper(I) iodide (0.15 g, 0.79 mmol) were added. The mixture was heated at 140°C for 60 min under microwave conditions. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with water (50 ml), brine (30 ml), dried and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 24 g eluted with EtOAc in 0% to 50% hexanes) to give methyl 4-bromo-1-phenyl1H-indole-6-carboxylate (351b) (0.23 g, 23% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.07-8.01 (m, 2H), 7.90 (d, J=1.2 Hz, 1H), 7.75-7.58 (m , 4H), 7.58-7.47 (m, 1H), 6.78 (dd, J=3.2, 0.9 Hz, 1H), 3.85 (d, J=2.5 Hz, 3H); MS (ESI+): 330.0 and 332.0 (M+1).

Stage-2. Preparation of (4-bromo-1-phenyl-1H-indol-6-yl)methanol (351c).

Compound 351c was prepared according to the procedure described in step-2 of scheme-212 from methyl 4-bromo-1-phenyl-1H-indole-6-carboxylate (351b) (0.38 g, 1.15 mmol) in DCM (10 ml) using 1 M DIBAL-H in DCM (2.88 ml, 2.88 mmol). This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with 0-50% EtOAc in hexane) (4-bromo-1phenyl-1H-indol-6-yl)methanol (351c) (0. 3 g, 86% yield) as a white solid; MS (ESI+): 303.9 (M+1).

Stage-3. Preparation of ethyl 2-(2-((4-bromo-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate (351d).

Compound 351d was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-phenyl-1H-indol-6-yl)methanol (351c) (0.3 g, 0.99 mmol) in DCM (10 ml) using triphenylphosphine (0.34 g, 1.29 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.23 g, 1.29 mmol) and (E)-bis(4chlorobenzyl )diazene-1,2-dicarboxylate (DCAD, 0.47 g, 1.29 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel 12 g, eluted with EtOAc in 0% to 50% hexanes], ethyl 2-(2-((4-bromo-1-phenyl-1H-indol- 6yl)methoxy)phenyl)acetate (351d) (0.21 g, 46% yield) as a colorless oil; MS (ESI+): 487.1 (M+Na); MS (ESI-): 463.1 and 465.0 (M-1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6yl)methoxy)phenyl)acetate (351e).

Compound 351e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate (351d) (0 .2 g, 0.43 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.12 g, 0.65 mmol), K ₂ CO ₃ solution (0.18 g , 1.29 mmol) in water (2 ml), Pd(PPh ₃ ) ₂ Cl ₂ (0.05 g, 0.07 mmol) and heating in an Ar atmosphere at 100°C for 2 hours. This resulted in after workup and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM from 0 to 20%] followed by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0 to 100%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate (351e) (0, 15 g, 71% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (d, J=3.3 Hz, 1H), 7.68 (k, J=1.5 Hz, 1H), 7.63 (k, J=3.2 Hz, 5H), 7.55-7.41 (m, 3H), 7.41-7.34 (m, 1H), 7.32-7.17 (m, 3H), 7 .11 (dd, J=8.3, 1.2 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz,

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1H), 6.82 (dd, J=3.4, 0.8 Hz, 1H), 5.24 (s, 2H), 3.82 (d, J=2.8 Hz, 2H), 3, 80-3.72 (m, 2H), 3.58 (s, 2H), 0.90 (t,

J=7.1 Hz, 3H); MS (ESI+): 491.2 (M+1).

Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6yl)methoxy)phenyl)acetic acid (351f).

Compound 351f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy) phenyl)acetate (351e) (0.15 g, 0.31 mmol) in THF (6 ml) and MeOH (6 ml), using a solution of lithium hydroxide monohydrate (0.10 g, 2.45 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (351f) (0.04 g, 27% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 7.85 (d, J=1.8 Hz, 1H), 7.79 (d, J=3.3 Hz, 1H), 7.75-7.68 (m, 2H), 7.677.60 (m, 4H), 7.60-7.50 (m, 2H), 7.46 (dtd, J=6.8, 4.9, 3.2 Hz, 1H ), 7.36 (d, J=1.3 Hz, 1H), 7.22 (dd, J=8.9, 6.5 Hz, 2H), 7.09 (d, J=8.1 Hz , 1H), 6.94-6.85 (m, 2H), 5.26 (s, 2H), 4.14 (s, 2H), 3.56 (s, 2H); MS (ESI+): 925.3 (2M+1); MS (ESI-): 461.2 (M-1); analysis calculation for: C ₃₀ H ₂₆ N ₂ O ₃ -HCl-1.5H ₂ O: C, 68.50; N, 5.75; N, 5.33; observed: C, 68.54; N, 5.59; N, 5.49.

Scheme-352

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (352c).

Stage-1. Preparation of ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetate (352a).

Compound 352a was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-isopropyl-1H-indol-6-yl)methanol (109d) (200 mg, 0.75 mmol) in THF (8 ml), using triphenylphosphine (489 mg, 1.87 mmol), ethyl 2-(2-hydroxy-4-methylphenyl) acetate (269d) (362 mg, 1.87 mmol) and DIAD (0.36 ml, 1. 87 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with EtOAc/methanol (9:1) in 0% to 40% hexanes], ethyl 2-(2-((4-bromo-1-isopropyl-1H -indol-6-yl)methoxy)-4-methylphenyl)acetate (352a) (140 mg, 42% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, J=3.3 Hz, 2H), 7.28 (d, J=1.1 Hz, 1H), 7.08 (d, J =7.5 Hz, 1H), 6.94 (d, J=1.5 Hz, 1H), 6.74-6.67 (m, 1H), 6.43-6.38 (m, 1H) , 5.16 (s, 2H), 4.76 (p, J=6.7 Hz, 1H), 4.01 (k, J=7.1 Hz, 2H), 3.56 (s, 2H) , 2.29 (s, 3H), 1.47 (d, J=6.6 Hz, 6H), 1.06 (t, J=7.1 Hz, 3H); MS (ESI+): 444.1 and 446.1 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetate (352b).

Compound 352b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate ( 352a) (140 mg, 0.32 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (71 mg, 0.47 mmol), bis(triphenylphosphine) palladium (11 ) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (33 mg, 0.05 mmol) and a solution of K ₂ CO ₃ (131 mg, 0.95 mmol) in water (0.5 ml) heating in an argon atmosphere at 90 °C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)1 -isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (352b) (70 mg, 47% yield) as yellow syrup; δ 7.63 (s, 1H), 7.60 (s, 1H), 7.57 (d, J=3.3 Hz, 1H), 7.49 (d, J=7.4 Hz, 1H) , 7.42 (t, J=7.4 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.16 (d, J=1.3 Hz, 1H), 7 .07 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.71 (d, J=7.4 Hz, 1H), 6.58 (d, J=3, 3 Hz, 1H), 5.22 (s, 2H), 4.80 (p, J=6.5 Hz, 1H), 3.90 (dt, J=8.1, 6.6 Hz, 2H) , 3.79 (s, 2H), 3.56 (s, 2H), 2.29 (s, 3H), 1.50 (d, J=6.6 Hz, 6H), 0.97 (td, J=7.1, 1.0 Hz, 3H); MS (ESI+): 471.2 (M+1).

- 443 045626

Stage-3. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1 H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (352c).

Compound 352c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy )-4-methylphenyl)acetate (352b) (140 mg, 0.30 mmol) in MeOH (4 ml), THF (4 ml), using a solution of lithium hydroxide (100 mg, 2.38 mmol) in water (1 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (352c) (78 mg, 59% yield), HCl salt, as a white solid ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (s, 2H), 7.81 (s, 1H), 7.68 (d, J=7.6 Hz, 2H), 7.60 (d, J=3.3 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.22 (d , J=1.2 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.99-6.96 (m, 1H), 6.71 (d, J=7, 6 Hz, 1H), 6.67 (d, J=3.2 Hz, 1H), 5.24 (s, 2H), 4.82 (p, J=6.6 Hz, 1H), 4.12 (s, 2H), 3.53 (s, 2H), 2.29 (s, 3H), 1.49 (d, J=6.6 Hz, 6H); MS (ESI+): 885.4 (2M+1), MS (ESI-): 441.2 (M-1); analysis calculation for: С2 ₈ Нз(НОз-НС1-Н ₂ О. С, 67.66; Н, 6.69; Cl, 7.13; N, 5.64; observed: С, 67.90; Н , 6.47; Cl, 7.29; N, 5.66.

Scheme-353 he

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (353b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (353a).

Compound 353a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate ( 352a) (200 mg, 0.45 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (139 mg, 0.68 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (47 mg, 0.07 mmol) and a solution of K2CO3 (187 mg, 1.35 mmol) in water (1 ml) heating in a nitrogen atmosphere at 90°C for 2 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with DMA80 in DCM 0% to 50%], ethyl 2-(2-((4-(3-(aminomethyl)-2fluorophenyl) -1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (353a) (160 mg, 73% yield) as yellow syrup; MS (ESI+): 489.2 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)4-methylphenyl)acetic acid (353b).

Compound 353b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indole-6- yl)methoxy)-4-methylphenyl)acetate (353 a) (160 mg, 0.33 mmol) in MeOH (4 ml), THF (4 ml), using lithium hydroxide solution (110 mg, 2.62 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((4-(3- (aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (353b) (95 mg, 63% yield), HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.27 (s, 2H), 7.72 (s, 1H), 7.65 (td, J=7.3, 1.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J=7.5 Hz , 1H), 6.97 (d, J=1.6 Hz, 1H), 6.74-6.66 (m, 1H), 6.38 (t, J=3.0 Hz, 1H), 5 .24 (s, 2H), 4.82 (p, J=6.6 Hz, 1H), 4.14 (s, 2H), 3.53 (s, 2H), 2.29 (s, 3H) , 1.49 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.93; MS (ESI-): 459.2 (M-1); analysis calculation for C ₂₈ H ₂ 9FN ₂ O3-HCl-H ₂ O: C, 65.30; N, 6.26; Cl, 6.88; N, 5.44; observed: C, 65.48; N, 6.19; Cl, 6.76; N, 5.49.

- 444 045626

Scheme-354

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1 H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (354c).

Stage-1. Preparation of ethyl 2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindol-6-yl)methoxy)-4- methylphenyl)acetate (354a).

Compound 354a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (352a) (510 mg, 1.15 mmol) using bis(pinacolato)diboron (437 mg, 1.72 mmol), potassium acetate (338 mg, 3.44 mmol) and Pd(dppf)Cl ₂ DCM (141 mg, 0.17 mmol) in anhydrous dioxane (10 ml) under argon while heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/methanol (9:1) in 0% to 10% hexanes], ethyl 2-(2-((1-isopropyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)4-methylphenyl)acetate (354a) (310 mg, 55% yield ) as a yellow solid; MS (ESI+) 514.2 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (354b).

Compound 354b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-indol-6-yl)methoxy)-4methylphenyl)acetate (354a) (150 mg, 0.31 mmol) in dioxane (4 ml), using (4-chloropyridin-2yl)methanamine (74a) (131 mg, 0.92 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (32 mg, 0.05 mmol) and K ₂ CO ₃ solution (127 mg, 0. 26 mmol) in water (1 ml) heating in a nitrogen atmosphere at 90°C for 2 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2(2-((4-(2-(aminomethyl)pyridine-4 -yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (354b) (30 mg, 21% yield) as yellow syrup; MS (ESI+): 472.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)4-methylphenyl)acetic acid (354c).

Compound 354c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isonropyl-1H-indole-6- yl)methoxy)-4-methylphenyl)acetate (354b) (30 mg, 0.06 mmol) in MeOH (2 ml), THF (2 ml), using a solution of lithium hydroxide (22 mg, 0.51 mmol) in water (0.5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(2(aminomethyl)pyridine-4 -yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (354c) (7 mg, 25% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.78-7.70 (m, 2H) , 7.67 (d, J=3.3 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 6 .91 (s, 1H), 6.72 (d, J=3.3 Hz, 1H), 6.71-6.63 (m, 1H), 5.26 (s, 2H), 4.84 ( p, J=6.6 Hz, 1H), 4.19 (s, 2H), 3.46 (s, 2H), 2.27 (s, 3H), 1.50 (d, J=6.6 Hz, 6H); MS (ESI+): 444.2 (M+1), MS (ESI-): 442.2 (M-1).

- 445 045626

Scheme-355

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (355c).

Stage-1. Preparation of ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl )acetate (355a).

Compound 355a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-III-indol-6-yl)methoxy)-4methylphenyl)acetate (354a) (190 mg, 0.39 mmol) in dioxane (4 ml) using (+)-(S)-N-( (4-chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (205 mg, 0.77 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (41 mg, 0.06 mmol) and a solution of K2CO3 (160 mg, 1.16 mmol) in water (1 ml) heating under argon at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 15% MeOH/DCM] ethyl 2-(2-((4-(2-((1,1dimethylethylsulfinamido )Methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetate (355a) (100 mg, 44% yield) as a yellow oil; MS (ESI+): 594.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (3 5 5b) .

Compound 355b was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((4-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -1-isopropyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (355a) (150 mg, 0.25 mmol) in DCM (5 ml) using HCl (4 M in dioxane; 0.19 ml, 0.76 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 70%], ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (355b) (95 mg, 77% yield) as a pale yellow oil; MS (ESI+): 490.3 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)-4-methylphenyl)acetic acid (355c).

Compound 355c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indole -6-yl)methoxy)-4methylphenyl)acetate (355b) (90 mg, 0.18 mmol) in MeOH (4 ml), THF (4 ml), using lithium hydroxide solution (62 mg, 1.47 mmol) in water (0.5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(2-(aminomethyl)-3 -fluoropyridin-4-yl)-1-isopropyl-1 H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (355c) (30 mg, 35% yield) free base as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=4.9 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.51 (t, J=5.3 Hz, 1H), 7.27 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.70 (d, J=7.5 Hz, 1H), 6.37 (d, J=2.6 Hz, 1H), 5.25 (s, 2H), 4.83 (p, J=6.7 Hz, 1H), 3.97 (s, 2H), 3.51 (s, 2H), 2.28 (s, 3H), 1.49 (d, J=6.5 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -130.86; MS (ESI+): 462.2 (M+1), MS (ESI-): 460.2 (M-1); analysis calculation for C ₂₇ H ₂₈ FN ₃ O ₃ -H ₂ O. C, 67.62; N, 6.31; N, 8.76 observed: C, 67.63; N, 6.21; N, 8.80.

- 446 045626

Scheme-356

OMe OMe

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetic acid (356c).

Stage-1. Preparation of ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (356a).

Compound 356a was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-isopropyl-1H-indol-6-yl)methanol (109d) (0.8 g, 2.98 mmol) in THF (15 ml) using triphenylphosphine (1.57 g, 5.97 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl) acetate (303d) (1.25 g, 5.97 mmol) and DIAD (1 .16 ml, 5.97 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with EtOAc/methanol (9:1) in 0% to 40% hexanes], ethyl 2-(2-((4-bromo-1-isopropyl-1H -indol-6-yl)methoxy)-4-methoxyphenyl)acetate (356a) (0.53 g, 39% yield) as a pale yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.68-7.61 (m, 2H), 7.29 (d, J=1.1 Hz, 1H), 7.11 (d, J=8 .3 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.48 (dt, J=8.3, 2.9 Hz, 1H), 6.41 (dd, J =3.2, 0.8 Hz, 1H), 5.17 (s, 2H), 4.74 (g, J=6.7 Hz, 1H), 4.04-3.97 (m, 2H) , 3.74 (s, 3H), 3.54 (s, 2H), 1.47 (d, J=6.6 Hz, 6H), 1.07 (t, J=7.1 Hz, 3H) ; MS (ESI+) 460.1 and 462.1 (M+1); 482.1 and 484.1 (M+Na); MS (ESI+) 458.1 and 460.1 (M-1).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (356b).

Compound 356b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate ( 356a) (0.27 g, 0.59 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.13 g, 0.88 mmol), bis(triphenylphosphine ) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.06 g, 0.09 mmol) and a solution of K ₂ CO ₃ (0.24 g, 1.76 mmol) in water (1 ml) heating in a nitrogen atmosphere at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl) -1isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate (356b) (0.13 g, 46% yield) as yellow syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (s, 1H), 7.59 (s, 1H), 7.57 (d, J=3.3 Hz, 1H), 7.51- 7.46 (m, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.16 (d, J=1 .3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.5 Hz, 1H), 6.58 (d, J=3.3 Hz, 1H), 6.47 (dd, J=8.3, 2.4 Hz, 1H), 5.24 (s, 2H), 4.80 (p, J=6.7 Hz, 1H), 3.91 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.49 (d, J =6.7 Hz, 6H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 487.3 (M+1).

Stage-3. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetic acid (356c).

Compound 356c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy) -4-methoxyphenyl)acetate (356b) (120 mg, 0.28 mmol) in MeOH (2 ml), THF (2 ml), using a solution of lithium hydroxide (83 mg, 1.97 mmol) in water (0.5 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water from 0% to 100%] 2-(2-((4-(3(aminomethyl)phenyl)- 1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetic acid (356c) (60 mg, 53% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (d, J=1.8 Hz, 1H), 7.74 (dt, J=7.9, 1.4 Hz, 1H), 7, 62 (s, 1H), 7.57 (d, J=3.3 Hz, 1H), 7.48-7.39 (m, 2H), 7.30 (dt, J=7.7, 1, 3 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.63 (dd, J=3.3, 0.7 Hz, 1H), 6.59 (d, J= 2.4 Hz, 1H), 6.38 (dd, J=8.2, 2.4 Hz, 1H), 5.25 (s, 2H), 4.80 (p, J=6.6 Hz, 1H), 3.97 (s, 2H), 3.69 (s, 3H), 3.32 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); MS (ESI+): 459.2 (M+1), 917.4 (2M+1), MS (ESI-): 457.2

- 447 045626 (M-1); analysis calculation for: C ₂₈ H ₃₀ N ₂ O ₄ -0.5HCl-0.25H ₂ O. C, 70.55; N, 6.61; Cl, 1.86; N, 5.88; observable:

C, 70.78; N, 6.44; Cl, 1.76; N, 6.03.

Scheme-357

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetic acid (357b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methoxyphenyl)acetate (357a).

Compound 357a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate ( 356a) (0.27 g, 0.59 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.18 g, 0.88 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.06 g, 0.09 mmol) and a solution of K ₂ CO ₃ (0.24 g, 1.76 mmol) in water ( 1 ml) heating in a nitrogen atmosphere at 90°C for 2 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with DMA80 in DCM 0% to 50%], ethyl 2-(2-((4-(3-(aminomethyl)-2fluorophenyl) -1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate (357a) (0.22 g, 74% yield) as yellow syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (s, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.53-7.48 (m, 1H), 7.37 (td, J=7.0, 2.6 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.12-7.07 (m, 2H), 6 .71 (d, J=2.4 Hz, 1H), 6.47 (dt, J=8.3, 2.5 Hz, 1H), 6.28 (t, J=2.8 Hz, 1H) , 5.23 (s, 2H), 4.80 (p, J=6.7 Hz, 1H), 3.89 (k, J=7.1 Hz, 2H), 3.82 (s, 2H) , 3.74 (s, 3H), 3.53 (s, 2H), 1.49 (d, J=6.6 Hz, 6H), 0.97 (t, J=7.1 Hz, 3H) ; MS (ESI+): 505.2 (M+1); 527.2 (M+Na).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)4-methoxyphenyl)acetic acid (357b).

Compound 357b was prepared according to the procedure described in step-6 of Scheme-1, ethyl 2-(2((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl) methoxy)-4-methoxyphenyl)acetate (357a) (0.22 g, 0.44 mmol) in MeOH (2 ml), THF (2 ml), using lithium hydroxide solution (0.15 g, 3.49 mmol) in water (0.5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(3-(aminomethyl)2- fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetic acid (357b) (65 mg, 31% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.66 (s, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.51-7.38 (m, 2H), 7.27 (t, J=7.6 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6, 67 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.4 Hz, 1H), 6.30 (t, J=2.7 Hz, 1H), 5.25 (s, 2H), 4.80 (p, J=6.7 Hz, 1H), 3.85 (s, 2H), 3.73 (s, 3H), 3.47 (s, 2H ), 1.49 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.69; MS (ESI+): 477.2 (M+1), MS (ESI-): 475.2 (M-1); analysis calculation for: C ₂₈ H ₂₉ FN ₂ O ₄ -0.5H ₂ O. C, 69.26; N, 6.23; N, 5.77; observed: C, 69.13; N, 6.24; N, 5.67.

Scheme-358

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-448 045626 methylphenyl)acetic acid (358c).

Stage-1. Preparation of ethyl 2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (358a).

Compound 358a was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-methyl-1H-indol-6-yl)methanol (50b) (1.3 g, 5.41 mmol) in THF (30 ml) using triphenylphosphine (2.13 g, 8.12 mmol), ethyl 2-(2-hydroxy-4-methylphenyl) acetate (269d) (1.58 g, 8.12 mmol) and DIAD (1 .58 ml, 8.12 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with EtOAc/MeOH (9:1) in 0% to 40% hexane] ethyl 2-(2-((4-bromo-1- methyl 1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (358a) (1.4 g, 62% yield) as a pale yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.56 (t, J=1.1 Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 7.30 (d , J=1.2 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.72 (ddd, J=7.5, 1, 6, 0.8 Hz, 1H), 6.38 (dd, J=3.1, 0.8 Hz, 1H), 5.16 (s, 2H), 4.03-3.99 (m, 2H ), 3.57 (s, 2H), 3.47 (s, 3H), 2.29 (s, 3H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI+): 417.1 and 419.0 (M+1); 439.0 and 441.1 (M+Na); MS (ESI-): 414.1 and 416.1 (M-1).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetate (358b).

Compound 358b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate ( 358a) (250 mg, 0.60 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (118 mg, 0.78 mmol), bis(triphenylphosphine)palladium(P ) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (63 mg, 0.09 mmol) and a solution of K2CO3 (249 mg, 1.80 mmol) in water (1 ml) heating in a nitrogen atmosphere at 90 ° C for 3 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl) -1-methyl1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (358b) (130 mg, 49% yield) as yellow syrup;

1H NMR (300 MHz, DMSO- _d6 ) δ 7.66-7.62 (m, 1H), 7.53-7.47 (m, 2H), 7.43-7.39 (m, 2H) , 7.33 (d, J=7.5 Hz, 1H), 7.19 (d, J=1.3 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6 .98 (d, J=1.6 Hz, 1H), 6.72 (dd, J=7.5, 1.4 Hz, 1H), 6.56 (dd, J=3.2, 0.9 Hz, 1H), 5.22 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.57 (s, 2H), 3, 32 (s, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 443.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-1 -methyl-1 H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (358c).

Compound 358c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1 -methyl-1 H-indol-6-yl)methoxy )-4-methylphenyl)acetate (358b) (130 mg, 0.29 mmol) in MeOH (4 ml), THF (4 ml), using a solution of lithium hydroxide (99 mg, 2.35 mmol) in water (1 ml ). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water from 0% to 100%] 2-(2-((4-(3(aminomethyl)phenyl)- 1-Methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (358c) (70 mg, 58% yield) free base as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 (t, J=1.8 Hz, 1H), 7.75 (dt, J=7.9, 1.4 Hz, 1H), 7 .50 (s, 2H), 7.487.37 (m, 2H), 7.29 (dt, J=7.5, 1.4 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.62 (dd, J=6.9, 2.2 Hz, 2H), 5.24 (s, 2H), 3, 96 (s, 2H), 3.85 (s, 3H), 3.34 (s, 2H), 2.24 (s, 3H); MS (ESI-): 413.2 (M-1); analysis calculation for: C2 ₆ H2 ₆ N2O ₃ -H2O. C, 72.20; N, 6.53; N, 6.48; observed: C, 72.19; N, 6.52; N, 6.50.

Scheme-359

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1 -methyl-1 H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (359b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-III-indol-6yl)methoxy)-4-methylphenyl)acetate (359a).

Compound 359a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate ( 358a) (250 mg, 0.60 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (160 mg, 0.78 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (63 mg, 0.09 mmol) and a solution of K2CO3 (249 mg, 1.80 mmol) in water (1 ml) heating in a nitrogen atmosphere at 90 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(3-(aminomethyl)-2fluorophenyl )-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (359a) (160 mg, 58% yield) as

- 449 045626 yellow syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.55 (k, J=2.5, 1.8 Hz, 1H), 7.53-7.50 (m, 1H), 7.38 (d , J=3.2 Hz, 1H), 7.27 (t, J=7.5 Hz, 2H), 7.13 (k, J=1.6 Hz, 1H), 7.10-7.04 (m, 1H), 7.01-6.95 (m, 1H), 6.71 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 6.25 (ddd, J =3.2, 2.3, 0.9 Hz, 1H), 5.21 (s, 2H), 3.91 (t, J=7.1 Hz, 2H), 3.84 (s, 3H) , 3.56 (s, 2H), 3.17 (d, J=4.5 Hz, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz, 3H) ; MS (ESI+): 461.2 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (359b).

Compound 359b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3 -(aminomethyl)-2-fluorophenyl)-1 -methyl-1 H-indole-6- yl)methoxy)-4-methylphenyl)acetate (359a) (160 mg, 0.35 mmol) in MeOH (4 ml), THF (4 ml), using a solution of lithium hydroxide (117 mg, 2.78 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(3-(aminomethyl)2- fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (359b) (80 mg, 53% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (d, J=1.2 Hz, 1H), 7.50 (td, J=7.3, 1.9 Hz, 1H), 7, 40 (td, J=7.4, 1.9 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.19 (t, J=1.4 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 6, 70-6.65 (m, 1H), 6.29-6.23 (m, 1H), 5.22 (s, 2H), 3.84 (s, 2H), 3.83 (s, 3H) , 3.45 (s, 2H), 2.27 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.94; MS (ESI+): 433.2 (M-1); MS (ESI-): 431.2 (M-1); analysis calculation for: C ₂₆ H ₂₅ FN ₂ O ₃ -1.75H ₂ O. C, 67.30; N, 6.19; N, 6.04; observed: C, 67.35; N, 5.91; N, 6.16.

Scheme-360

Preparation of 2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (360c).

Stage-1. Preparation of methyl 2-(5-acetamido-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (360a).

Compound 360a was prepared according to the procedure described in step-1 of Scheme-224 from methyl 2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (208b) (0.3 g, 0.505 mmol) in anhydrous toluene (3 ml), using acetamide (0.05 g, 0.86 mmol), Cs ₂ CO ₃ (0.17 g , 0.517 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2yl)phosphine (X-PHOS) (0.02 g, 0.03 mmol), Pd ₂ (dba) ₃ (0.02 g, 0.03 mmol) and heating in a microwave oven at 120°C for 90 minutes. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with 0 to 50% EtOAc in hexane] methyl 2-(5acetamido-2-((7-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (360a) (0.01 g, 11% yield) as orange syrup; MS (ESI+): 459.2 (MVoc+1), 581.2 (M+Na); MS (ESI-): 557.2 (M-1).

Stage-2. Preparation of methyl 2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (360b).

Compound 360b was prepared according to the procedure described in step-5 of Scheme-1 from methyl 2-(5-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (360a) (0.04 g, 0.07 mmol) in DCM (3 ml) using TFA (0.11 ml, 1.36 mmol). This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) 0% to 100%] methyl 2-(5-acetamido2-( (7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (360b) (0.03 g, 100% yield) as a white solid; MS (ESI+): 459.2 (M+1); MS (ESI-): 457.1 (M-1).

Stage-3. Preparation of 2-(5-acetamido-2-((7-(3 -(aminomethyl)phenyl)benzofuran-5 yl)methoxy)phenyl)acetic acid (360c).

Compound 360c was prepared according to the procedure described in step-6 of Scheme-1 from methyl

- 450 045626

2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (360b) (0.03 g, 0.07 mmol) in THF (4 ml) and methanol (4 ml), using lithium hydroxide monohydrate (0.02 g, 0.41 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase chromatography on a [C18 (30 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(5acetamido-2-(( 7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (360c) (0.01 g, 43% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H), 9.81 (s, 1H), 8.32 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.93 (dt, J=7.6, 1.6 Hz, 1H), 7.75 (d, J=1 .6 Hz, 1H), 7.66-7.50 (m, 3H), 7.48-7.37 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 7 .03 (d, J=8.8 Hz, 1H), 5.22 (s, 2H), 4.19-4.10 (m, 2H), 3.56 (s, 2H), 1.99 ( s, 3H); MS (ESI+): 445.1 (M+1), 889.3 (2M+1); MS (ESI-): 443.1 (M-1), 887.3 (2M-1).

Scheme-361

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(hydroxymethyl)phenyl)acetic acid (361c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(hydroxymethyl)phenyl)acetate (361a).

Compound 361a was prepared according to the procedure described in step-1 of scheme-236 from ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (0.05 g, 0.084 mmol) in DMF (4 ml), using (tributylstannyl)methanol (0.04 g, 0.13 mmol), Pd(Ph ₃ P) ₄ (0.02 g, 0.02 mmol) when heated at 120°C for 1 hour in a microwave oven. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with MeOH in DCM 0 to 60%), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate (361a) (0.03 g, 65% yield) as a white solid; MS (ESI+): 446.2 (M-Boc+1), 568.2 (M+Na); MC (ESI-): 544.2 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(hydroxymethyl)phenyl)acetate (361b).

Compound 361b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy )-4(hydroxymethyl)phenyl)acetate (361a) (0.09 g, 0.17 mmol) in DCM (3 mL) using TFA (0.25 mL, 3.30 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((7 -(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate (361b) (0.07 g, 100% yield) as a white solid; MS (ESI+): 446.2 (M+1); MS (ESI-): 444.1 (M-1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4(hydroxymethyl)phenyl)acetic acid (361c).

Compound 361c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl )acetate (361b) (73 mg, 0.16 mmol) in THF/methanol (4 mL each), using a solution of lithium hydroxide monohydrate (83 mg, 1.97 mmol) in water (1 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetic acid (361c) (0.03 g, 42% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 8.36 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.00 ( d, J=1.7 Hz, 1H), 7.94 (dt, J=7.5, 1.6 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7, 66 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (dt, J=7.7, 1.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6, 86 (dd, J=7.5,

- 451 045626

1.4 Hz, 1H), 5.25 (s, 2H), 5.21 (t, J=5.7 Hz, 1H), 4.47 (d, J=5.4 Hz, 2H), 4 .14 (s, 2H), 3.57 (s, 2H); MS (ESI+): 418.2 (M+1), 835.3 (2M+1); MS (ESI-): 416.1 (M-1); analysis calculation for:

C ₂₅ P ₂₃ NO ₅ 1HCl 1.25P ₂ O: C, 63.02; N, 5.61; Cl, 7.44; N, 2.94; observed: C, 63.16; N, 5.35; Cl, 7.63; N,

3.00.

Scheme-362

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1 H-indol-6-yl)methoxy)phenyl)acetic acid (362e).

Stage-1. Preparation of 1-benzyl-4-bromo-1H-indole-6-carboxylic acid (362a).

Compound 362a was prepared according to the procedure described in step-1 of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g, 7.87 mmol) in DMF (25 ml) using NaH (60% in mineral oil) (0.94 g, 23.61 mmol) and (bromomethyl)benzene (1.40 ml, 11.81 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 100% EtOAc in hexane] 1-benzyl-4-bromo-1H-indole-6-carboxylic acid (362a ) (2.5 g, 96% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 8.10 (t, J=1.0 Hz, 1H), 7.89 (d, J=3.1 Hz , 1H), 7.78 (d, J=1.2 Hz, 1H), 7.38-7.22 (m, 3H), 7.22-7.13 (m, 2H), 6.56 ( dd, J=3.1, 0.9 Hz, 1H), 5.58 (s, 2H); MS (ESI+): 331.0 and 333.0 (M+1); MS (ESI-): 329.0 and 331.0 (M-1).

Stage-2. Preparation of (1-benzyl-4-bromo-1H-indol-6-yl)methanol (362b).

Compound 362b was prepared according to the procedure described in step-1 of Scheme-23 from 1benzyl-4-bromo-1H-indole-6-carboxylic acid (362a) (2 g, 6.06 mmol) using N-methylmorpholine ( 0.80 ml, 7.27 mmol) in THF (50 ml), isobutyl chloroformate (0.955 ml, 7.27 mmol) and NaBH ₄ (0.69 g, 18.17 mmol) in water (0.8 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 100% EtOAc in hexane] (1-benzyl-4bromo-1H-indol-6-yl)methanol (362b) ( 1.58 g, 82% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.59 (d, J=3.2 Hz, 1H), 7.44-7.41 (m, 1H), 7.35-7.21 ( m, 4H), 7.19-7.12 (m, 2H), 6.43 (dd, J=3.2, 0.9 Hz, 1H), 5.44 (s, 2H), 5.24 (t, J=5.8 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H). MS (ESI+): 339.1 and 341.0 (M+Na); MS (ESI-): 314.0 and 316.1 (M-1).

Stage-3. Preparation of ethyl 2-(2-((1-benzyl-4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (362c).

Compound 362c was prepared according to the procedure described in step-2 of Scheme-23 from (1benzyl-4-bromo-1H-indol-6-yl)methanol (362b) (1 g, 3.16 mmol) in DCM (20 ml), using triphenylphosphine (1.08 g, 4.11 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (0.74 g, 4.11 mmol) and solution of (E)bis(4-chlorobenzyl) )diazene-1,2-dicarboxylate (DCAD, 1.51 g, 4.11 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in 0% to 50% hexanes], ethyl 2-(2-((1-benzyl-4-bromo-1H- indol-6yl)methoxy)phenyl)acetate (362c) (0.28 g, 18% yield) as a white oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.66 (d, J=3.2 Hz, 1H), 7.62 (t, J=1.0 Hz, 1H), 7.34-7 .16 (m, 8H), 7.03 (dd, J=8.8, 1.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6, 45 (dd, J=3.2, 0.8 Hz, 1H), 5.44 (s, 2H), 5.15 (s, 2H), 3.98 (k, J=7.1 Hz, 2H ), 3.60 (s, 2H), 1.04 (t, J=7.1 Hz, 3H). MS (ESI+): 478.1 and 480.0 (M+1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6yl)methoxy)phenyl)acetate (362d).

Compound 362d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-benzyl-4-bromo-1P-indol-6-yl)methoxy)phenyl)acetate (362c) ( 0.27 g, 0.56 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.16 g, 0.85 mmol), K ₂ CO ₃ (0.23 g , 1.69 mmol) in water (2 ml) and bis(triphenylphosphine) palladium(11) chloride (0.06 g, 0.09 mmol) in an Ar atmosphere by heating at 100 °C for 3 h in an oil bath. This resulted in the following work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 20%] followed by double purification by reverse phase chromatography on

- 452 045626 column [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] ethyl 2-(2-((4-(3(aminomethyl)phenyl)-1- benzyl-1H-indol-6-yl)methoxy)phenyl)acetate (362d) (0.17 g, 58% yield), salt

HCl, as a white solid; MS (ESI+) 505.2 (M+1); 527.2 (M+Na).

Stage-5. Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-1-benzyl-1 H-indol-6yl)methoxy)phenyl)acetic acid (362e).

Compound 362e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy) phenyl)acetate (362d) (0.16 g, 0.32 mmol) in THF/MeOH (6 mL each), using a solution of lithium hydroxide monohydrate (0.11 g, 2.54 mmol) in water (2 mL) . This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((4- (3(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (362e) (0.04 g, 25% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.24 (s, 1H), 8.34 (s, 3H), 7.81 (d, J=1.8 Hz, 1H), 7.67 (ddd, J=12.2, 7.7, 2.4 Hz, 3H), 7.60-7.45 (m, 2H), 7.36-7.15 (m, 8H), 7.06 (d, J=8.1 Hz, 1H), 6.94-6.85 (m, 1H), 6.70 (d, J=3.2 Hz, 1H), 5.46 (s, 2H) , 5.24 (s, 2H), 4.12 (s, 2H), 3.59 (s, 2H); MS (ESI+): 953.4 (2M+1); MS (ESI-): 475.2 (M-1); analysis calculation for: C ₃₁ H ₂₈ N ₂ O ₃ -1.25HCl-1.25H ₂ O. C, 68.36; N, 5.88; N, 5.14; observed: C, 68.57; N, 6.00; N, 5.22.

Scheme-363 he

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (363b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (363a).

Compound 363a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e) (200 mg, 0.491 mmol ) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (125 mg, 0.610 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (52 mg, 0.074 mmol), potassium carbonate (204 mg, 1.473 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA-80 in DCM 0% to 50%), ethyl 2-(2-((7-(3-(aminomethyl)- 2fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (363a) (179 mg, 81% yield) as a clear oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.66-7, 55 (m, 1H), 7.517.18 (m, 4H), 7.13-6.97 (m, 2H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5 .24 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.59 (s, 2H), 0.97 (t, J= 7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -112.63, -121.77. MS (ESI+): 452.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (363b).

Compound 363b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl )acetate (363a) (175 mg, 0.388 mmol) in MeOH (5.5 ml), THF (5.5 ml), using 1N lithium hydroxide (1.163 ml, 1.163 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (363b) (120 mg, 73% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.68 (t, J=7.4 Hz, 2H), 7.50-7.39 (m, 2H), 7.24 (dd, J=8.4, 6.9 Hz, 1H), 7.07 (d, J =2.2 Hz, 1H), 7.02 (dd, J=11.4, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5 .28 (s, 2H), 4.18 (s, 2H), 3.55 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -112.98, -118.38. MS (ESI+): 424.1 (M+1); (ESI-): 422.1 (M-1); analysis calculation for C ₂₄ H ₁₉ F ₂ NO ₄ -HCl-0.5H ₂ O: C, 61.48; N, 4.51; Cl, 7.56; N, 2.99; observed: C, 61.67; N, 4.54; Cl, 7.38; N, 2.98.

- 453 045626

Scheme-364

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (364d).

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (364a ).

Compound 364a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e) (1.5 g , 3.68 mmol), using bis(pinacolato)diboron (1.403 g, 5.53 mmol), potassium acetate (1.084 g, 11.05 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.301 g, 0.368 mmol) in anhydrous dioxane (50 ml) under argon while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in 0% to 40% hexanes] ethyl 2-(4-fluoro-2-((7-(4,4 ,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (364a) (1.44 g, 86% yield) as a clear oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.07 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.65 (d , J=1.9 Hz, 1H), 7.24 (dd, J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.4, 2.5 Hz, 1H) , 6.97 (d, J=2.2 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.19 (s, 2H), 3.98 ( k, J=7.1 Hz, 2H), 3.57 (d, J=1.7 Hz, 2H), 1.34 (s, 12H), 1.04 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -112.67.

Stage-2. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (364b).

Compound 364b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (364a) (300 mg, 0.660 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (175 mg, 0.660 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (70 mg, 0.099 mmol) and a solution of K2CO3 (274 mg, 1.981 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 100%] ethyl 2-(2-((7-(2-((1,1 -dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (364b) (355 mg, 97% yield) as a brown oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (dd, J=4.9, 0.7 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7, 86 (d, J=1.6 Hz, 1H), 7.70-7.67 (m, 1H), 7.55-7.49 (m, 1H), 7.25 (dd, J=8, 3, 6.9 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H), 6.75 ( td, J=8.5, 2.5 Hz, 1H), 5.93-5.75 (m, 1H), 5.27 (s, 2H), 4.41 (dd, J=5.9, 2.1 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.11 (s, 9H), 0.97 (t, J= 7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.59, 128.04. MS (ESI+): 557.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (364c).

Compound 364c was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (364b) (355 mg, 0.638 mmol) in methanol (10 mL), using HCl (4 M in dioxane; 0.478 mL, 1.913 mmol) and stirring at room temperature for 30 min. This resulted in the production after treatment of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (364c) (270 mg, 94% yield) as a yellow oil, which was used in the next reaction without further purification. MS (ESI+): 453.1 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (364d).

Compound 364d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -4-fluorophenyl)acetate (364c) (270

- 454 045626 mg, 0.597 mmol) in MeOH (10 ml), THF (10 ml), using 1N lithium hydroxide (3.58 ml, 3.58 mmol). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (364d) (94 mg, 0.221 mmol, 37.1% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=5.0 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.91 (d, J =1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8 ,4, 6.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.30 (s, 2H), 4.41-4.32 (m, 2H), 3.56 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -112.95, -128.35. MS (ESI+): 425.1 (M+1); (ESI-): 423.1 (M-1); analysis calculation for C ₂₃ H ₁₈ F ₂ N ₂ O ₄ -HCi-0.5H ₂ O: C, 58.79; N, 4.29; Cl, 7.55; N, 5.96; observed: C, 58.94; N, 4.24; Cl, 7.91; N 6.17.

Scheme-365

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (365f).

Stage-1. Preparation of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (365b).

Compound 365b was prepared according to the procedure described in step-1 of scheme-220 from 4chloropicolinaldehyde (365a) (15 g, 106 mmol) in DCM (100 ml) using Cs ₂ CO ₃ (51.8 g, 159 mmol), (S)-2-methylpropane-2-sulfinamide (14.77 g, 122 mmol) and stirring at room temperature for 1 hour. This gave upon treatment N-((4-chloropyridin-2-yl)methylene) -2methylpropane-2-sulfinamide (365b) (25.9 g, 106 mmol, 100% yield), which was used as such in the next step;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (dd, J=5.3, 0.6 Hz, 1H), 8.48 (s, 1H), 8.13 (dd, J=2 ,1, 0.6 Hz, 1H), 7.76 (dd, J=5.3, 2.1 Hz, 1H), 1.22 (s, 9H).

Stage-2. Preparation of (+)-(S)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (365c).

Compound 365c was prepared according to the procedure described in step-2 of Scheme-220 from N((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (365b) (18.5 g, 76 mmol ) in methanol (300 ml) using NaBH ₄ (2.86 g, 76 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (120 g), eluted with 9:1 ethyl acetate/methanol in hexanes] (+)-(S)-N-((4-chloropyridine-2- yl)methyl)-2-methylpropane-2-sulfinamide (365c) (15.7 g, 84%) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (dd, J=5.3, 0.6 Hz, 1H), 7.58 (dd, J=2.1, 0.7 Hz, 1H ), 7.43 (dd, J=5.4, 2.1 Hz, 1H), 5.97 (t, J=6.3 Hz, 1H), 4.29 (dd, J=6.3, 3.3 Hz, 2H), 1.16 (s, 9H); optical rotation [a] _D = +45.4 (0.81, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (365d).

Compound 365d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (364a) (300 mg, 0.660 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloropyridine-2 -yl)methyl)-2methylpropane-2-sulfinamide (365c) (163 mg, 0.660 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (70 mg, 0.099 mmol) and solution K2CO3 (274 mg, 1.981 mmol) in water (0.5 ml) heating in

- 455 045626 argon atmosphere at 100°C for 3 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in

DCM 0% to 40%] ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran5-yl)methoxy)-4-fluorophenyl)acetate ( 365d) (355 mg, 100% yield) as a brown oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (dd, J=5.2, 0.8 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 8, 06 (dd, J=1.8, 0.9 Hz, 1H), 7.83-7.75 (m, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.05 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.96 (t, J=6.1 Hz, 1H), 5.27 (s, 2H), 4, 40-4.33 (m, 2H), 3.93-3.87 (m, 2H), 3.60 (s, 2H), 1.07 (s, 9H), 0.95 (t, J= 7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.62. MS (ESI+): 539.2 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (365e).

Compound 365e was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5 -yl)methoxy)-4fluorophenyl)acetate (365d) (355 mg, 0.659 mmol) in methanol (10 mL), using HCl (4 M in dioxane; 0.494 mL, 1.977 mmol) and stirring at room temperature for 30 min. This resulted in the production after treatment of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (365e) (270 mg, 94% yield ) as a yellow oil, which was used in the next step without further purification. MS (ESI+): 435.1 (M+1).

Stage-5. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (365f).

Compound 365f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4- fluorophenyl)acetate (365e) (270 mg, 0.621 mmol) in MeOH (12 ml), THF (12 ml), using 1N lithium hydroxide (2.486 ml, 2.486 mmol). This resulted in, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (365f) (162 mg, 64% yield), hydrochloride salt, as a pale yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 8.78 (dd, J=5.2, 0.8 Hz, 1H), 8.41 (s, 3H, D2O replaceable), 8.17 (d, J =2.2 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.98 (dd, J=5.3, 1.7 Hz, 1H), 7.87 (d , J=1.6 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.25 (dd, J=8.3, 6.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.31 (s, 2H), 4.32 (d, J=5.4 Hz, 2H), 3.57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.92; MS (ESI+): 407.1 (M+1); (ESI-): 405.1 (M-1); analysis calculation for C ₂ 3H1 _S FN2O44.35HCl 1.25H2O: C, 57.77; N, 4.82; Cl, 10.01; N, 5.86; observed: C, 57.46; N, 4.74; Cl, 10.18; N, 5.81.

Scheme-366

O Pd(dppf)CI ₂ CH ₂ C1;

'E COAS

K ₂ C0 ₃ Pd(PPh ₃ ) ₂ CI ₂

N 366b

Receipt

2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -methyl-1 H-indol-6-yl)methoxy)-4 methylphenyl)acetic acid (366d) .

Stage-1. Preparation of ethyl 2-(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indol-6-yl) methoxy)phenyl)acetate (366a).

Compound 366a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (358a) (1.05 g, 2.52 mmol) using bis(pinacolato)diboron (0.96 g, 3.78 mmol), potassium acetate (0.74 g, 7.57 mmol) and Pd(dppf )Cl ₂ -CH ₂ Cl ₂ (0.309 g, 0.378 mmol) in anhydrous dioxane (15 ml) under argon while heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH (9:1) in 0% to 10% hexanes], ethyl 2-(4-methyl2-((1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (366a) (450 mg, 39 % yield) as a yellow solid;

1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=1.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 7.37 (d, J =3.1 Hz, 1H),

- 456 045626

7.07 (d, J=7.5 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.73 (d, J=0.9 Hz, 1H), 6, 59 (d, J=1.2 Hz, 1H), 5.15 (s, 2H), 3.99 (m, 2H), 3.80 (s, 3H), 3.47 (s, 2H), 1.29 (s, 3H), 1.17 (s, 12H), 1.03 (t, J=7.1 Hz, 3H); MS (ESI+): 464.3 (M+1); MS (ESI+): 486.2 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-1 -methyl-1 H-indol-6-yl)methoxy)-4- methylphenyl)acetate (366b).

Compound 366b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (366a) (200 mg, 0.432 mmol) in dioxane (4 ml) using (+)-(S)-N-( (4-chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (137 mg, 0.518 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (45 mg, 0.065 mmol) and a solution of K2CO3 (179 mg, 1.295 mmol) in water (1.0 ml) heating under argon at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(2-((1,1dimethylethylsulfinamido )Methyl)-3-fluoropyridin-4-yl)-1-methyl-III-indol-6-yl)methoxy)-4methylphenyl)acetate (366b) (240 mg, 98% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (d, J=4.9 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.63 (dd , J=2.1, 1.2 Hz, 1H), 7.60-7.58 (m, 1H), 7.46 (d, J=3.2 Hz, 1H), 7.23 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.98 (s, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.35 (t, J=2.7 Hz, 1H), 5.24 (s, 2H), 4.44-4.37 (m, 2H), 4.10 (k, J=5.3 Hz, 2H), 3, 93 (s, 2H), 3.86 (s, 3H), 3.57 (s, 9H), 2.30 (s, 3H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 566.3 (M+1).

Stage-3. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (366c).

Compound 366c was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -1-methyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (366b) (240 mg, 0.42 mmol) in DCM (5 ml) using HCl (4 M in dioxane; 0.32 ml , 1.27 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0 to 70%], ethyl 2- (2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl1H-indol-6-yl)methoxy)-4-methylphenyl)acetate (366c) (40 mg, 20% yield) as a pale yellow oil; MS (ESI+): 462.2 (M+1).

Stage-4. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetic acid (366d).

Compound 366d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indole -6-yl)methoxy)-4-methylphenyl)acetate (366c) (40 mg, 0.09 mmol) in MeOH (4 ml), THF (4 ml), using lithium hydroxide monohydrate (29 mg, 0.69 mmol ) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with water in acetonitrile from 0% to 100%] 2-(2-((4-(2-(aminomethyl)-3 -fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (366d) (23 mg, 61% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (d, J=4.9 Hz, 1H), 7.69 (s, 1H), 7.50 (t, J=5.3 Hz, 1H), 7.44 (d, J=3.1 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H) , 6.94 (d, J=1.5 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.34 (t, J=2.8 Hz, 1H), 5 .25 (s, 2H), 3.96 (d, J=2.1 Hz, 2H), 3.85 (s, 3H), 3.60 (s, 2H), 2.28 (s, 3H) ; ¹⁹ F NMR (282 MHz, DMSO) δ -130.86; MS (ESI+): 434.2 (M+1); MS (ESI-): 432.1 (M-1); analysis calculation for: C25H24FN3O3-1.75H2O. C, 64.57; N, 5.96; N, 9.04; observed: C, 64.56; N, 5.62; N, 9.09.

Scheme-367

367b 367c

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (367c).

Stage-1. Preparation of ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1

- 457 045626 methyl-1 H-indol-6-yl)methoxy)-4-methylphenyl)acetate (3 67a).

Compound 367a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (366a) (230 mg, 0.50 mmol) in dioxane (4 ml) using (+)-(S)-N -((4chloropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (147 mg, 0.60 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (52 mg, 0.07 mmol) and a solution of K2CO3 (206 mg, 1.49 mmol) in water (1.0 ml) heating under argon at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(2-((1,1dimethylethylsulfinamido )methyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetate (367a) (266 mg, 98% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.63-8.53 (m, 1H), 8.48 (dd, J=5.3, 0.6 Hz, 1H), 7.84 ( s, 1H), 7.63 (s, 1H), 7.58 (dd, J=2.1, 0.6 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 7.44 (dd, J=5.4, 2.1 Hz, 1H), 7.30 (d, J=1.3 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H ), 6.98 (s, 1H), 5.24 (s, 2H), 4.36 (k, J=5.1 Hz, 2H), 3.95-3.87 (m, 2H), 3 .86 (s, 3H), 3.57 (s, 2H), 2.30 (s, 3H), 1.16 (s, 9H), 0.95 (t, J=7.1 Hz, 3H) ; MS (ESI+): 548.3 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)4-methylphenyl)acetate (367b).

Compound 367b was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((4-(2-(( 1,1 -dimethylethylsulfinamido)methyl)pyridin-4-yl)-1 - Methyl-1 P-indol-6-yl)methoxy)-4methylphenyl)acetate (367a) (266 mg, 0.49 mmol) in DCM (5 ml) using HCl (4 M in dioxane; 0.36 ml, 1 .46 mmol) and stirring at room temperature for 2 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0 to 70%], ethyl 2-(2 -((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6yl)methoxy)-4-methylphenyl)acetate (367b) (40 mg, 19% yield) as pale - yellow oil; MS (ESI+): 444.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4methylphenyl)acetic acid (367c).

Compound 367c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1 -methyl-1 H-indole-6 -yl)methoxy)-4-methylphenyl)acetate (367b) (40 mg, 0.09 mmol) in MeOH (4 ml), THF (4 ml), using lithium hydroxide monohydrate (30 mg, 0.72 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with water in acetonitrile from 0% to 100%] 2-(2-((4-(2(aminomethyl)pyridine-4 -yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetic acid (367c) (26 mg, 69% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.73 (dd, J=5.2, 1 ,6 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.49 (d, J=3.2 Hz, 1H), 7, 00 (d, J=7.5 Hz, 1H), 6.85 (d, J=1.5 Hz, 1H), 6.70 (d, J=3.1 Hz, 1H), 6.67- 6.61 (m, 1H), 5.27 (s, 2H), 4.07 (s, 2H), 3.86 (s, 3H), 3.39 (s, 2H), 2.25 (s , 3H); MS (ESI+): 416.2 (M+1); MS (ESI-): 414.1 (M-1); analysis calculation for: C25H25N ₃ O ₃ -2H2O. C, 66.50; N, 6.47; N, 9.31; detect: C, 66.95; N, 6.10; N, 9.21.

Scheme-368

(2S,4R)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2) Preparation of fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide ( 368c).

Stage-1. Preparation of tert-butyl 3-(5-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4fluoropyrrolidin-1 -yl)-2-oxoethyl)benzofuran-7-yl )benzylcarbamate (36 8b).

Compound 368b was prepared according to the procedure described in step-4 of Scheme-1 from 2-(7(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetic acid (273d) ( 50 mg, 0.13 mmol) in DMF (1 ml) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (368a) (43.2 mg, 0.16 mmol; prepared according to the procedure described by Altmann, Eva et al.; in international application PCT, 2012093101, July 12, 2012), DIPEA (0.09 ml, 0.52 mmol) and HATU (74 .8 mg, 0.20 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0 to 50% DMA80/DCM] tert-butyl 3-(5-(2-((2S,4R)-2 -((3chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate

- 458 045626 (368b) (60 mg, 72% yield) as a white solid; MS (ESI+): 538.1 and 540.1 (M-Boc+1), 660.3 (M+Na); MC (ESI-): 636.2 and 638.3 (M-1).

Stage-2. Preparation of (2S,4R)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide ( 368c).

Compound 368c was prepared according to the procedure described in step-5 of Scheme-1 from tert-butyl 3-(5-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4 -fluoropyrrolidin-1-yl)-2oxoethyl)benzofuran-7-yl)benzylcarbamate (368b) (60 mg, 0.09 mmol) in DCM (5 ml) using TFA (0.15 ml, 1.88 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (2S,4R)-1-(2- (7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4fluoropyrrolidine-2-carboxamide (368c) (35 mg, 69% yield), salt HCl, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.18 and 8.72 (2t, J=5.9 Hz, 1H), 8.46 (s, 3H), 8.06 (dd, J=2 ,3, 1.0 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.87 (td, J=6.3, 5.5, 3.0 Hz, 1H) , 7.63-7.49 (m, 3H), 7.49-7.27 (m, 3H), 7.19-6.96 (m, 2H), 5.53-5.15 (m, 1H), 4.52-4.24 (m, 3H), 4.24-3.94 (m, 3H), 3.93-3.63 (m, 3H), 2.75-2.53 ( m, 1H), 2.46-1.85 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.47; MS (ESI+): 538.2 (M+1); analysis calculation for: C ₂₉ H ₂₆ ClF ₂ N ₃ O ₃ -HCl-1.5H ₂ O. C, 57.91; H, 5.03; Cl, 11.79; N, 6.99; observed: C, 57.74; N, 5.08; Cl, 11.94; N, 7.07.

Scheme-369

Preparation of (S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)ethyl)-N-(3-chloro-2fluorobenzyl)pyrrolidine-2-carboxamide (369d).

Stage-1. Preparation of tert-butyl 3-(5-(2-hydroxyethyl)benzofuran-7-yl)benzylcarbamate (369a).

Compound 369a was prepared according to the procedure described in step-1 of Scheme-23 from 2-(7(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetic acid (273d) ( 0.2 g, 0.52 mmol) using N-methylmorpholine (0.07 ml, 0.63 mmol) in THF (8 ml), isobutyl chloroformate (0.08 ml, 0.63 mmol) and NaBH ₄ (0 .06 g, 1.57 mmol) in water (0.5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH=9:1 in hexane 0% to 100%] tert-butyl 3-(5-(2-hydroxyethyl )benzofuran-7-yl)benzylcarbamate (369a) (0.12 g, 62% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (d, J=2.2 Hz, 1H), 7.71 (dt, J=9.5, 1.7 Hz, 2H), 7 .52-7.41 (m, 3H), 7.32 (d, J=1.7 Hz, 1H), 7.27 (dt, J=7.7, 1.4 Hz, 1H), 6, 98 (d, J=2.2 Hz, 1H), 4.67 (t, J=5.2 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.67 ( td, J=7.0, 5.1 Hz, 2H), 2.86 (t, J=7.0 Hz, 2H), 1.40 (s, 9H); MS (ESI+): 390.2 (M+Na).

Stage-2. Preparation of 2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)ethyl methanesulfonate (369b).

To a stirred solution of tert-butyl 3-(5-(2-hydroxyethyl)benzofuran-7-yl)benzylcarbamate (369a) (110 mg, 0.30 mmol) in DCM (3 ml) was added methanesulfonyl chloride (0. 03 ml, 0.33 mmol), triethylamine (0.063 ml, 0.449 mmol) and stirred at 0°C for 30 min. The reaction mixture was diluted with DCM, washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc/MeOH=9:1 in hexane from 0% to 100%] to give 2-(7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)ethyl methanesulfonate (369b) (116 mg, 87% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=2.2 Hz, 1H), 7.77-7.69 (m, 2H), 7.58 (d, J=1, 7 Hz, 1H), 7.527.41 (m, 3H), 7.32-7.24 (m, 1H), 7.02 (d, J=2.2 Hz, 1H), 4.49 (t, J=6.8 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.18-3.14 (m, 2H), 3.13 (s, 3H), 1, 40 (s, 9H); MS (ESI+): 468.10 (M+Na).

Stage-3. Preparation of (S)-tert-butyl 3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1yl)ethyl)benzofuran-7-yl)benzylcarbamate (369c).

- 459 045626

Compound 369c was prepared according to the procedure described in step-2 of Scheme-152 from 2-(7(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)ethyl methanesulfonate (369b) ( 110 mg, 0.29 mmol), using (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (146 mg, 0.57 mmol), K2CO3 (118 mg, 0. 86 mmol) in DMF (2 ml) and stirring at 65°C for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes) (S)-tert -butyl 3-(5-(2-(2-((3-chloro-2fluorobenzyl)carbamoyl)pyrrolidin-1-yl)ethyl)benzofuran-7-yl)benzylcarbamate (369c) (35 mg, 20% yield) in as a white solid; MS (ESI+): 606.3 and 608.3 (M+1); MS (ESI-): 640.3 and 642.2 (M+Cl).

Stage-4. Preparation of (S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofurαn-5-yl)ethyl)-N-(3-chloro-2fluorobenzyl)pyrrolidine-2-carboxamide (369d).

Compound 369d was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1 -yl)ethyl)benzofuran-7yl)benzylcarbamate (369c) (30 mg, 0.05 mmol) in DCM (5 ml) using TFA (0.08 ml, 0.99 mmol). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%](S)-1-(2- (7-(3(aminomethyl)phenyl)benzofuran-5-yl)ethyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (369d) (9 mg, 36% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 9.41 (s, 1H), 8.48 (s, 3H), 8.09 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J=7.3 Hz, 1H), 7.64-7.45 (m, 5H), 7.36 (t, J =7.8 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 4.45 (t, J=6 .5 Hz, 2H), 4.41-4.25 (m, 1H), 4.13 (d, J=5.1 Hz, 2H), 3.76-3.62 (m, 1H), 3 .62-3.43 (m, 2H), 3.15-2.98 (m, 2H), 2.33-2.20 (m, 1H), 2.14-2.01 (m, 2H) , 1.98-1.80 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.07; MS (ESI+): 506.2, 508.2 (M+1).

Scheme-370

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-3-yl)acetic acid (370f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-3-carbaldehyde (370b).

Compound 370b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (1.053 g, 3.63 mmol) using 2-hydroxy-[1,1'-biphenyl ]-3carbaldehyde (370a) (0.72 g, 3.63 mmol; CAS No. 14562-10-8), K ₂ CO ₃ (1.506 g, 10.90 mmol) in DMF (20 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-5% ethyl acetate in hexanes), 2-((7-bromobenzofuran-5-yl)methoxy)-[1,1 '-biphenyl]-3-carbaldehyde (370b) (1.38 g, 93% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.30 (t, J=0.8 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.76 (dtd, J=9.4, 7.6, 1.4 Hz, 2H), 7.64-7.55 (m, 2H), 7.55-7.38 (m, 4H), 7.35 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.05 (dd, J=2.2, 0.8 Hz, 1H), 4.70 ( s, 2H); MS (ESI+): 429/431 (M+Na).

Stage-2. Preparation of 7-bromo-5-(((3 -(2-(methylsulfinyl)-2-(methylthio)vinyl)-[1,1'-biphenyl]-2yl)oxy)methyl)benzofuran (370c).

Compound 370c was prepared according to the procedure described in step-3 of Scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-3-carbaldehyde (370b) (2 g, 5 .01 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane (0.674 g, 5.42 mmol), Triton-B (40% methanol solution, 0.765 mL, 1.694 mmol) and reflux for 16 This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-40% EtOAc in hexane), 7-bromo-5-(((3-(2-(methylsulfinyl)-2 -(methylthio)vinyl)-[1,1'-biphenyl]2-yl)oxy)methyl)benzofuran (370c) (1.06 g, 61% yield) as an opaque oil;

- 460 045626

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 8.06 (ddd, J=7.7, 1.8, 0.6 Hz, 1H) , 7.86 (s, 1H),

7.62-7.54 (m, 2H), 7.53-7.42 (m, 4H), 7.36 (td, J=7.7, 0.5 Hz, 1H), 7.32 ( d, J=1.5 Hz, 1H), 7.20-7.14 (m, 1H),

7.02 (d, J=2.2 Hz, 1H), 4.62-4.39 (m, 2H), 2.73 (s, 3H), 2.28 (s, 3H); MS (ESI+): 513/515 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-3-yl)acetate (370d).

Compound 370d was prepared according to the procedure described in step-4 of Scheme-266 from 7bromo-5-(((3-(2-(methylsulfinyl)-2-(methylthio)vinyl)-[1,1'-biphenyl]- 2-yl)oxy)methyl)benzofuran (370c) (1.06 g, 2.064 mmol) in ethanol (20 ml) using HCl (4 M in 1,4-dioxane, 2.58 ml, 10.32 mmol) and reflux for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-5% ethyl acetate and hexanes), ethyl 2-(2-((7-bromobenzofuran -5-yl)methoxy)-[1,1'-biphenyl]-3-yl)acetate (370d) (0.59 g, 61% yield) as an opaque oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 7.61-7.53 (m, 2H), 7.52-7.40 (m , 3H), 7.36-7.27 (m, 3H), 7.22 (dd, J=8.3, 6.6 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.07 (dd, J=2.2, 0.7 Hz, 1H), 4.42 (s, 2H), 4.03 (k, 2H), 3.74 (s, 2H), 1.12 (t, J=7.1, 0.7 Hz, 3H); MS (ESI+): 465/467 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-3-yl)acetate (370e).

Compound 370e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-3-yl)acetate (370d) (100 mg, 0.215 mmol) in dioxane (4 ml) water (1 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (60 mg, 0.322 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (15.08 mg, 0.021 mmol), 3.3 M aq. K ₂ CO ₃ (0.195 ml, 0.645 mmol) heating under argon at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-5% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl )methoxy)-[1,1'-biphenyl]-3-yl)acetate (370e) (74 mg, 70% yield) as a clear, colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=2.2 Hz, 1H), 7.75-7.69 (m, 1H), 7.62 (dt, J=8, 2, 1.8 Hz, 3H), 7.49 (ddd, J=10.8, 6.6, 3.1 Hz, 3H), 7.44-7.37 (m, 2H), 7.33 (ddd, J=6.0, 4.3, 2.4 Hz, 3H), 7.27-7.18 (m, 1H), 7.14 (d, J=1.7 Hz, 1H), 7.01 (dd, J=2.2, 0.7 Hz, 1H), 4.48 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.83 (s , 2H), 3.75 (s, 2H), 1.15-0.97 (m, 3H); MS (ESI+): 492 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,G-biphenyl]-3yl)acetic acid (370f).

Compound 370f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'- biphenyl]-3-yl)acetate (370e) (74 mg, 0.151 mmol) in MeOH (3 ml) using 2 M aqueous lithium hydroxide (0.376 ml, 0.753 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-3-yl)acetic acid (370f) (57 mg, 82% yield), HCl salt, as a white solid substances after lyophilization.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.2 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.81 (dt, J=7.4, 1.7 Hz, 1H), 7.68-7.53 (m, 4H), 7.53-7.44 (m, 2H), 7.44-7.36 (m, 1H), 7.36-7.28 (m, 3H), 7.27-7.18 (m, 2H), 7.03 (d, J=2.2 Hz, 1H), 4.50 (s , 2H), 4.15 (s, 2H), 3.70 (s, 2H). Purity after HPLC: 99.4%; MS (ESI+): 464 (M+1), (ESI-): 462 (M-1); analysis calculation for C ₃₀ H ₂₅ NO ₄ -HCl-1.25H ₂ O: C, 68.96; N, 5.50; Cl, 6.79; N, 2.68; observed: C, 69.01; N, 5.56; Cl, 6.94; N, 2.82.

Scheme-371

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid

- 461 045626 acid (371c).

Stage-1. Preparation of ethyl 2-(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (371a) .

Compound 371a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d) (0.51 g , 1.222 mmol), using bis(pinacolato)diboron (0.466 g, 1.833 mmol), potassium acetate (0.360 g, 3.67 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.1 g, 0.122 mmol ) in anhydrous dioxane (5 ml) under nitrogen when heated at 100°C for 16 g. This gave, after work-up and purification by flash column chromatography, [silica gel (24 g), eluted with EtOAc in hexanes from 0% up to 10%] ethyl 2-(4-ethyl-2-((7-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (371a) (0.45 g, 79% yield) as a colorless oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.66 (d , J=1.8 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.97 (dd, J =2.3, 0.5 Hz, 1H), 6.75 (dd, J=7.6, 1.5 Hz, 1H), 5.16 (s, 2H), 3.99 (k, J= 7.1 Hz, 2H), 3.53 (s, 2H), 2.58 (k, J=7.6 Hz, 2H), 1.34 (s, 12H), 1.19 (t, 3H) , 1.05 (t, 3H); MS (ESI+): 487 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetate (371b).

Compound 371b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (371a) (209 mg, 0.45 mmol) in dioxane (4 ml), using (4-chloropyridin-2-yl)methanamine (74a) (96 mg, 0.675 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (31.6 mg, 0.045 mmol) and K ₂ CO ₃ solution (0.409 ml, 1.35 mmol) in water (1.0 ml) heating in a nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-8% MeOH in DCM] ethyl 2-(2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran -5-yl)methoxy)-4-ethylphenyl)acetate (371b) (38 mg) as a pale yellow oil, which was used as is in the following reaction; MS (ESI+): 445 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (371c).

Compound 371c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4- ethylphenyl)acetate (371b) (38 mg, 0.085 mmol) in MeOH (3 ml), THF (4 ml), using 2.0 M aq. LiOH (0.214 ml, 0.427 mmol). This resulted in the preparation, after work-up and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with water in acetonitrile from 0% to 60%] 2-(2-((7-(2-(aminomethyl)pyridinium- 4yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (371c) (14 mg, 39% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (d, J=5.3 Hz, 1H), 8.62-8.34 (m, 3H), 8.17 (d, J=2 .2 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.99 (dd, J=5.3, 1.7 Hz, 1H), 7.88 (d, J =1.5 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.16-7.06 (m, 2H), 6.98 (d, J=1.6 Hz , 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H), 5.28 (s, 2H), 4.31 (k, J=5.7, 5.3 Hz, 2H), 3.55 (s, 2H), 2.59 (k, J=7.7 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H); MS (ESI+): 417 (M+1), (ESI-): 415 (M-1).

Scheme-372

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran5-yl)methoxy)phenyl)acetic acid (372s).

Stage-1. Preparation of ethyl 2-(2-((7-iodo-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (372a).

Compound 372a was prepared according to the procedure described in step-1 of scheme-279 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (200 mg, 0.431 mmol) in ethanol (5 ml), using 1-methyl-1H-pyrazol-3-amine (46.0 mg, 0.474 mmol), sodium borohydride (32.6 mg, 0.862

- 462 045626 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with DMA80 in DCM), ethyl 2-(2-((7-iodo-2-(((1-methyl-1H-pyrazol- 3yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (372a) (165 mg, 70% yield) as a brown solid; MS (ESI+): 546.1 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (372b).

Compound 372b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl) benzofuran-5-yl)methoxy)phenyl)acetate (372a) (160 mg, 0.293 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (88 mg, 0.469 mmol), bis( triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (31 mg, 0.044 mmol) and a solution of K ₂ CO ₃ (122 mg, 0.880 mmol) in water (3 ml) heating in an N2 atmosphere at 100° C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)phenyl)-2-( ((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (372b) (45 mg, 29% yield) as a colorless gum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 (d, J=1.8 Hz, 1H), 7.72 (dt, J=7.6, 1.6 Hz, 1H), 7 .58 (d, J=1.7 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.48-7.35 (m, 2H), 7.32 (d, J=2.2 Hz, 1H), 7.22 (td, J=7.6, 1.8 Hz, 2H), 7.14-7.02 (m, 1H), 6.90 (td, J =7.4, 1.1 Hz, 1H), 6.73 (s, 1H), 5.78 (t, J=6.3 Hz, 1H), 5.51 (d, J=2.2 Hz , 1H), 5.21 (s, 2H), 4.38 (d, J=6.3 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.80 (s , 2H), 3.62 (s, 2H), 3.59 (s, 3H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 525.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (372s).

Compound 372c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazole-3 -yl)amino)methyl)benzofuran-5yl)methoxy)phenyl)acetate (372b) (45 mg, 0.086 mmol) in THF/MeOH (2.5 mL each), using lithium hydroxide monohydrate solution (7 mg, 0.257 mmol ) in water (0.5 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(3-(aminomethyl)phenyl)-2-(((1methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (372c) (30 mg , 70% yield), hydrochloric salt, in the form of a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 3H), 8.03 (s, 1H), 7.91 (tt, J=4.9, 4.1, 1.8 Hz, 1H), 7.67 (k, J=2.0 Hz, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.60-7.52 (m, 2H), 7, 28-7.19 (m, 2H), 7.20 (s, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.91 (dd, J=7.6, 0, 9 Hz, 1H), 6.91-6.84 (m, 1H), 5.77 (d, J=2.6 Hz, 1H), 5.24 (s, 2H), 4.55 (s, 2H), 4.19-4.08 (m, 2H), 3.59 (s, 2H), 2.54 (s, 3H); MS (ESI+): 497.2 (M+1), (ESI-): 495.2 (M-1); analysis calculation for C ₂ 9H ₂₇ ClFN ₃ O3-HCl-1.5H ₂ O: C, 59.70; N, 5.36; Cl, 12.15; N, 7.20; observed C, 59.62; N, 5.25; Cl, 11.96; N, 7.15.

Scheme-373 he

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (373b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetate (373a).

Compound 373a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (227c) (420 mg, 1.031 mmol) in dioxane (10 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (244 mg, 1.186 mmol), solution of K2CO3 (428 mg, 3.09 mmol) in water (2 ml), bis(triphenylphosphine)palladium(P) chloride (109 mg, 0.155 mmol) when heated at 100°C for 7 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with DMA80 in DCM 0% to 90%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetate (373a) (342 mg, 74% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J=1.7 Hz, 1H), 7.65-7.55 (m, 1H), 7.49-7.38 (m, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.30-7.19 (m, 2H), 7.10 (dd, J=8.2, 1.1 Hz, 1H ), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.45 (d, J=6.4 Hz, 1H), 5.21 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.62 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.69, -121.98; MS (ESI+): 452.2 (M+1).

- 463 045626

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (373b).

Compound 373b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl )acetate (373a) (330 mg, 0.731 mmol) in MeOH/THF (2/10 mL each), using a solution of lithium hydroxide monohydrate (70.0 mg, 2.92 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (150 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (373b) (210 mg, 68% yield), hydrochloride salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J=1.6 Hz, 1H), 7.71 (dd, J=7.8, 1.7 Hz, 1H), 7, 66 (d, J=6.9 Hz, 1H), 7.49-7.40 (m, 2H), 7.23 (t, J=7.9 Hz, 2H), 7.08 (d, J =8.0 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.45 (d, J=6.5 Hz, 1H), 5.25 (s , 2H), 4.18 (s, 2H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.58, -118.50; MS (ESI+) 420.10 (M+1), (ESI-) 418.10 (M-1); MS (ESI+): 424.10 (M+1), (ESI-): 422.10 (M-1); analysis calculation for C ₂₄ H ₁₉ F ₂ NO ₄ -HCl-0.75H ₂ O: C, 60.89; N, 4.58; Cl, 7.49; N, 2.96; observable; C, 60.82; N, 4.55; Cl, 7.19; N, 2.98.

Scheme-374

NaBH ₄

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetic acid (374f).

Stage-1. Preparation of methyl 7-iodo-2-phenylbenzofuran-5-carboxylate (374a).

Compound 374a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (6 g, 14.85 mmol) in pyridine (20 ml) using ethynylbenzene ( 1.52 g, 14.85 mmol) and copper(I) oxide (1.06 g, 7.43 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0-10% EtOAc in hexanes), methyl 7-iodo-2-phenylbenzofuran-5-carboxylate (374a) (1.6 g, 57%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (d, J=1.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.97-7, 91 (m, 2H), 7.70 (s, 1H), 7.61-7.41 (m, 3H), 3.89 (s, 3H).

Stage-2. Preparation of 7-iodo-2-phenylbenzofuran-5-carboxylic acid (374b).

Compound 374b was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-iodo-2-phenylbenzofuran-5-carboxylate (374a) (1.6 g, 4.23 mmol) in THF (10 ml) MeOH (10 ml) using a solution of lithium hydroxide monohydrate (355 g, 8.46 mmol) in water (2 ml). This resulted in 7-iodo-2-phenylbenzofuran-5-carboxylic acid (374b) (1.4 g, 91%) as a white solid upon treatment;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.23 (s, 1H), 8.14 (s, 1H), 7.93 (d, J=7.7 Hz, 2H), 7.62 ( d, J=1.2 Hz, 1H), 7.58-7.40 (m, 3H).

Stage-3. Preparation of (7-iodo-2-phenylbenzofuran-5-yl)methanol (374c).

Compound 374c was prepared according to the procedure described in step-1 of Scheme-23 from 7iodo-2-phenylbenzofuran-5-carboxylic acid (374b) (1.4 g, 3.84 mmol) using N-methylmorpholine (0.466 g , 4.61 mmol) in THF (50 ml), isobutyl chloroformate (0.63 g, 4.61 mmol) and NaBH ₄ (0.436 g, 11.53 mmol) in water (1 ml). This resulted in (7iodo-2-phenylbenzofuran-5-yl)methanol (374c) (1.04 g, 77%) as a white solid after workup and crystallization from ethyl acetate.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (d, J=1.5 Hz, 1H), 7.86 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.58-7.38 (m, 5H), 4.52 (s, 2H).

Stage-4. Preparation of ethyl 2-(2-((7-iodo-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate (374d).

- 464 045626

Compound 374d was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-phenylbenzofuran-5-yl)methanol (374c) (0.3 g, 0.857 mmol) in DCM (10 ml) using triphenylphosphine (0.247 g, 0.942 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.170 g, 0.942 mmol) and bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 0.346 g, 0.942 mmol) in DCM (10 ml). This resulted, after workup and purification by flash column chromatography (silica gel, eluted with EtOAc in 0% to 10% hexane), ethyl 2-(2-((7-iodo-2-phenylbenzofuran-5yl)methoxy)phenyl) acetate (374d) (0.206 g, 47% yield) as a colorless solid;

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93-7.90 (m, 1H), 7.89 (t, J=1.4 Hz, 1H), 7.70 (d, J=1, 5 Hz, 1H), 7.59 (dd, J=1.5, 0.8 Hz, 1H), 7.52-7.44 (m, 2H), 7.43-7.36 (m, 1H ), 7.25-7.19 (m, 2H), 7.11 (s, 1H), 7.00-6.91 (m, 2H), 5.12 (s, 2H), 4.14 ( k, J=7.1 Hz, 2H), 3.68 (d, J=2.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H); MS (ESI+): 535 (M+23), (ESI-): 511 (M-1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5yl)methoxy)phenyl)acetate (374e).

Compound 374e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate (374d) (200 mg, 0.390 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (80 mg, 0.429 mmol), K2CO3 solution (162 mg, 1.171 mmol) in water, bis(triphenylphosphine) palladium(P) chloride (27 mg, 0.039 mmol) when heated at 100°C for 8 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in 0% to 4% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate (374e) (146 mg) as a colorless oil; MS (ESI+) 492 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5yl)methoxy)phenyl)acetic acid (374f).

Compound 374f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate ( 374e) (146 mg, from previous step-5) in MeOH (3 ml), water (1 ml), using sodium hydroxide (47 mg, 1.171 mmol). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 100 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 60%] 2-(2-((7-(3(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetic acid (374f) (115 mg, 64% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=1.7 Hz, 1H), 8.04 (dt, J=7.7, 1.5 Hz, 1H), 8, 01-7.92 (m, 2H), 7.77 (d, J=1.6 Hz, 1H), 7.71-7.62 (m, 2H), 7.62-7.49 (m, 4H), 7.49-7.39 (m, 1H), 7.25 (t, J=7.6 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H), 6, 91 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.18 (s, 2H), 3.62 (s, 2H); MS (ESI+): 464 (M+1), (ESI-): 462 (M-1).

Scheme-375

C.I.

375b 375c

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (375c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (375a).

Compound 375a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (371a) (224 mg, 0.482 mmol) in dioxane (4 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (192 mg, 0.724 mmol), bis(triphenylphosphine)palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (34 mg, 0.048 mmol) and a solution of K2CO3 (0.439 ml, 1.447 mmol) in water (1.0 ml) heating in

- 465 045626 nitrogen atmosphere at 100°C for 16 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in

DCM 0% to 4%] ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-4-ethylphenyl )acetate (375a) (189 mg) as a pale yellow oil; MS (ESI+): 567 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-ethylphenyl)acetate (375b).

Compound 375b was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) benzofuran-5-yl)methoxy)-4ethylphenyl)acetate (375a) (189 mg, 0.334 mmol) in dioxane (4 ml), using HCl (4 M in dioxane; 0.250 ml, 1.001 mmol) and stirring at room temperature for 16 h. This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetate (375b), which was used as is without purification in the next step; MS (ESI+): 463 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (375c).

Compound 375c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -4-ethylphenyl)acetate (375b) (from previous step-2) in MeOH (3 ml) using 2.0 M aq. LiOH (0.649 ml, 1.297 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with water in acetonitrile from 0% to 60%] 2-(2-((7-(2-(aminomethyl)-3fluoropyridine -4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (375c) (26 mg, 23% yield), HCl salt, as a pale yellow solid after lyophilization.

^1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.0 Hz, 1H), 8.60-8.40 (m, 3H), 8.12 (d, J=2 .2 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.61 (s, 1H), 7. 18-7.04 (m, 2H), 6.98 (d, J=1.6 Hz, 1H), 6.76 (dd, J=7.5, 1.5 Hz, 1H), 5.27 (s, 2H), 4.47-4.27 (m, 2H), 3.55 (s, 2H), 2.57 (k, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.37; MS (ESI+): 435 (M+1), (ESI-): 433 (M-1); analysis calculation for C25H23FN2O44.35HCl4.75H2O: C, 58.28; N, 5.45; Cl, 9.29; N, 5.44; observed: C, 58.38; N, 5.16; Cl, 9.38; N, 5.40.

Scheme-376

Preparation of 7-(3-(aminomethyl)phenyl)-N-((trans)-2-((3-chloro-2fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide (376e).

Stage-1. Preparation of tert-butyl ((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate (376b).

Compound 376b was prepared according to the procedure described in step-4 of Scheme-1 from (trans)-2-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (376a) (0.46 g, 2.006 mmol; CAS No. 245115- 25-7) in DCM (10 ml) using (3-chloro-2-fluorophenyl)methanamine (0.336 g, 2.107 mmol), DIPEA (1.051 ml, 6.02 mmol) and HATU (0.915 g, 2.408 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 30% EtOAc in hexane), tert-butyl ((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl) carbamate (376b) as an opaque oil; MS (ESI+): 371/373 (M+1).

Stage-2. Preparation of (trans)-2-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (376c).

Compound 376c was prepared according to the procedure described in step-3 of scheme-305 from tert-butyl ((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate (376b) (from previous step-1) in methanol (10 ml) using HCl (4 M in dioxane; 10.03 ml, 40.1 mmol) and stirring at 40°C for 1 hour. This resulted in, after workup and purification by flash chromatography, 466 045626 on a column (silica gel, eluted with 0-10% MeOH in DCM) (trans)-2-amino-I-(3-chloro-2fluorobenzyl)cyclopentanecarboxamide (376c) (60 mg, 11% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.77 (t, J=5.8 Hz, 1H), 8.25 (s, 3H), 7.49 (ddd, J=8.0, 7 ,2, 1.7 Hz, 1H), 7.40-7.27 (m, 1H), 7.20 (td, J=7.8, 1.1 Hz, 1H), 4.35 (cd, J=15.2, 5.7 Hz, 2H), 3.70 (dt, J=7.4, 5.7 Hz, 1H), 2.912.76 (m, 1H), 2.08 (dt, J =11.5, 9.9, 4.9 Hz, 1H), 2.03-1.87 (m, 1H), 1.85-1.50 (m, 4H); MS (ESI+): 271/273 (M+1).

Stage-3. Preparation of 7-bromo-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide (376d).

Compound 376d was prepared according to the procedure described in step-4 of Scheme-1 from (trans)-2-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (376c) (60 mg, 0.222 mmol) in DCM (10 ml) using 7-bromobenzofuran-5-carboxylic acid (15a) (59 mg, 0.244 mmol), DIPEA (0.116 ml, 0.665 mmol) and HATU (101 mg, 0.266 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 30% EtOAc in hexane), 7bromo-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl )benzofuran-5-carboxamide (376d) (90 mg, 82% yield);

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (d, J=7.8 Hz, 1H), 8.41 (t, J=5.9 Hz, 1H), 8.20 (dd, J=6.0, 1.9 Hz, 2H), 8.05 (d, J=1.6 Hz, 1H), 7.41 (td, J=7.6, 1.7 Hz, 1H), 7.30-7.17 (m, 2H), 7.02 (td, J=7.9, 1.1 Hz, 1H), 4.544.19 (m, 3H), 2.76 (td, J= 7.7, 5.2 Hz, 1H), 2.09-1.85 (m, 2H), 1.83-1.55 (m, 4H); MS (ESI+): 493/495 (M+1); (ESI-): 491/493 (M-1).

Stage-4. Preparation of 7-(3-(aminomethyl)phenyl)-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide (376e).

Compound 376e was prepared according to the procedure described in step-3 of Scheme-1 from -bromoN-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide (376d) (77 mg, 0.156 mmol) in dioxane (2 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (32 mg, 0.172 mmol), a solution of K2CO3 (65 mg, 0.468 mmol) in water (1 ml), bis(triphenylphosphine)palladium(11) chloride (11 mg, 0.016 mmol) by heating at 100°C under argon for 16 hours in an oil bath. This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted with 0-60% MeCN in H ₂ O with 0.1% HCl) 7-(3-(aminomethyl)phenyl)-K ((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide (376e) (62 mg, 76% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (d, J=7.7 Hz, 1H), 8.53 (t, J=5.9 Hz, 1H), 8.38 (s, 3H), 8.22 (d, J=1.7 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.13 (d, J=1.7 Hz, 1H) , 8.08 (d, J=1.9 Hz, 1H), 7.97 (dt, J=7.6, 1.6 Hz, 1H), 7.66-7.52 (m, 2H), 7.37 (ddd, J=8.0, 7.1, 1.7 Hz, 1H), 7.30-7.21 (m, 1H), 7.17 (d, J=2.2 Hz, 1H), 6.95 (td, J=7.9, 1.1 Hz, 1H), 4.55-4.22 (m, 3H), 4.16 (k, J=5.5 Hz, 2H ), 2.90 (k, J=8.1 Hz, 1H), 2.12-1.85 (m, 2H), 1.851.52 (m, 4H); MS (ESI+): 520/522 (M+1), (ESI-): 518/520; analysis calculation for C ₂₉ H ₂₇ ClFN ₃ O ₃ -HCl-1.5H ₂ O: C, 59.70; N, 5.36; Cl, 12.15; N, 7.20; observed: C, 59.38; H, 5.09; Cl, 12.20; N, 7.13.

Scheme-377

377s

377d 377e

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)acetic acid (377e).

Stage-1. Preparation of methyl 2-benzyl-7-bromobenzofuran-5-carboxylate (377a).

Compound 377a was prepared according to the procedure described in step-1 of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (2.0 g, 6.45 mmol) in pyridine (17 ml), using prop-2-yne-1-467 045626 ylbenzene (0.825 g, 7.10 mmol) and copper(1) oxide (0.462 g, 3.23 mmol). This resulted in, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-3%

EtOAc in hexanes) methyl 2-benzyl-7-bromobenzofuran-5-carboxylate (377a) (0.93 g, 42% yield) as a white solid.

¹ H NMR (300 MHz, CDQ3) δ 8.11 (s, 2H), 7.41-7.27 (m, 5H), 6.43 (t, J=1.1 Hz, 1H), 4, 16 (d, J=1.1 Hz, 2H), 3.92 (s, 3H); MS (ESI+): 345/347 (M+1).

Stage-2. Preparation of (2-benzyl-7-bromobenzofuran-5-yl)methanol (377b).

Compound 377b was prepared according to the procedure described in step-2 of scheme-212 from methyl 2-benzyl-7-bromobenzofuran-5-carboxylate (377a) (0.93 g, 2.69 mmol) in DCM (10 ml) using 1 M DIBAL-H in DCM (6.74 mL, 6.74 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-20% EtOAc in hexane), (2-benzyl7-bromobenzofuran-5-yl)methanol (377b) (0.73 g, 85% yield ) as a pale yellow oil;

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43-7.26 (m, 8H), 6.34 (t, J=1.1 Hz, 1H), 4.70 (d, J=4, 9 Hz, 2H), 4.14 (d, J=1.1 Hz, 2H); MS (ESI+): 339/341 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((2-benzyl-7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (377c).

Compound 377c was prepared according to the procedure described in step-2 of Scheme-23 from (2benzyl-7-bromobenzofuran-5-yl)methanol (377b) (0.73 g, 2.302 mmol) in DCM (20 ml) using triphenylphosphine (0.905 g, 3.45 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.622 g, 3.45 mmol) and bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 1.268 g, 3.45 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 10% EtOAc in hexane), ethyl 2-(2-((2-benzyl-7-bromobenzofuran-5-yl)methoxy) phenyl)acetate (377c) (0.81 g, 73% yield) as a pale yellow oil;

¹ H NMR (300 MHz, DMSO-d6) δ 7.60 (d, J=1.5 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.40-7, 18 (m, 7H), 7.06 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.72 (d, J=0.9 Hz, 1H), 5.15 (s, 2H), 4.20 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI+): 501/503 (M+Na), (ESI-): 477/479 (M-1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5yl)methoxy)phenyl)acetate (377d).

Compound 377d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-benzyl-7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (377c) (85 mg, 0.177 mmol) in dioxane (4 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (37 mg, 0.195 mmol), a solution of K ₂ CO ₃ (74 mg, 0.532 mmol) in water (1 ml), bis( triphenylphosphine)palladium(P) chloride (13 mg, 0.018 mmol) by heating at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in 0% to 6% DCM] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -2-benzylbenzofuran-5yl)methoxy)phenyl)acetate (377d) (48 mg) as a colorless oil; MS (ESI+): 506 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5yl)methoxy)phenyl)acetic acid (377e).

Compound 377e was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)acetate ( 377d) (48 mg, from previous step-4) in MeOH (3 ml), water (1 ml), using sodium hydroxide (22 mg, 0.532 mmol). This resulted in the following workup and purification by reverse phase column chromatography [column C-18, 100 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 60%] 2-(2-((7-(3(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)acetic acid (377e) (41 mg, 48% yield), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 7.97-7.85 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.62-7.48 (m , 3H), 7.35 (d, J=4.4 Hz, 4H), 7.29-7.16 (m, 3H), 7.13-7.03 (m, 1H), 6.89 ( td, J=7.3, 1.1 Hz, 1H), 6.65 (s, 1H), 5.23 (s, 2H), 4.20 (s, 2H), 4.11 (s, 2H ), 3.58 (s, 2H); MS (ESI+): 478 (M+1), (ESI-): 476 (M-1); analysis calculation for C31H ₂ 7NO4-HCl-H ₂ O: C, 69.98; N, 5.68; N, 2.63; Cl, 6.66; observed: C, 69.81; N, 5.33; N, 2.65; Cl, 7.01.

- 468 045626

Scheme-378

Preparation of 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetic acid (378d).

Stage-1. Preparation of methyl 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)amino)methyl)phenyl)acetate (378a).

Compound 378a was prepared according to the procedure described in step-1 of scheme-279 from tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c) (104 mg, 0.307 mmol) in DCM (10 ml), using methyl 2-(2-formylphenyl) acetate (66 mg, 0.369 mmol; CAS No. 63969-83-5) and sodium borohydride (58 mg, 1.537 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-20% EtOAc in hexane) methyl 2-(2-(((7-(3(((tert-butoxycarbonyl)amino)methyl )phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate (378a) (117 mg) as a colorless oil; MS (ESI+) 501 (M+1).

Stage-2. Preparation of methyl 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)(methyl)amino)methyl)phenyl)acetate (378b).

To a solution of methyl 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)amino)methyl)phenyl)acetate (378a) (117 mg, from the previous step -1) methyl iodide (218 mg, 1.537 mmol), K2CO3 (85 mg, 0.615 mmol) were added to MeCN (10 ml) and heated at 40°C for 48 hours. The reaction mixture was cooled and evaporated to dryness. The residue was taken into water (25 ml) and extracted with EtOAc (3x25 ml). The combined organic layers were washed with H2O (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-20% EtOAc in hexanes) to give methyl 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetate (378b) (67 mg) as a colorless oil; MS (ESI+): 515 (M+1).

Stage-3. Preparation of 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)(methyl)amino)methyl)phenyl)acetic acid (378c).

Compound 378c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl )(methyl)amino)methyl)phenyl)acetate (378b) (67 mg, from previous step-2) in MeOH (3 ml), water (1 ml), using NaOH (36.9 mg, 0.922 mmol) This resulted to obtain after treatment 2-(2-(((7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetic acid (378c), which used as is in the next stage; MS (ESI+): 501 (M+1), (ESI-): 499 (M-1).

Stage-4. Preparation of 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetic acid (378d).

Compound 378d was prepared according to the procedure described in step-3 of scheme-305 from 2-(2(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)(methyl)amino )methyl)phenyl)acetic acid (378c) (from previous step-3) in dioxane (5 ml), using HCl (4 M in dioxane; 0.768 ml, 3.07 mmol) and stirring at 60°C for 1 h This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in _H2O with 0.1% HCl) 2-(2-(((7-(3 -(aminomethyl)phenyl)benzofuran-5yl)(methyl)amino)methyl)phenyl)acetic acid (378d) (50 mg, 41% yield), HCl salt, as a white solid;

Ή NMR (300 MHz, DMSO-d6+D2O) δ 7.94 (d, J=2.2 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=7.6 Hz , 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.23 (m, 3H), 7.14 (d , J=6.9 Hz, 1H), 7.05 (d, J=4.2 Hz, 2H), 6.90 (d, J=2.2 Hz, 1H), 4.65 (s, 2H ), 4.12 (t, J=5.6 Hz, 2H), 3.73 (s, 2H), 3.11 (s, 3H); MS (ESI+): 401 (M+1), (ESI-): 399 (M-1).

- 469 045626

Scheme-379

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (379c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (379a).

Compound 379a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (343a ) (141 mg, 0.299 mmol) in dioxane (5 ml), using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridin-2-yl) methyl) carbamate (123a) (150 mg, 0.449 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (32 mg, 0.045 mmol) and K ₂ CO ₃ solution (124 mg, 0.898 mmol) in water (0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(2-(((tert- butoxycarbonyl)amino)methyl)pyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (379a) (179 mg, 100% yield) as a dark oil; MS (ESI+): 599.3 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (379b).

Compound 379b was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3 -(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (379a) (175 mg, 0.292 mmol) in methanol (6 ml) using HCl (4 M in dioxane; 0.6 ml, 2.4 mmol ) and stirring at room temperature overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 80%] methyl 2-(2-((7-(2-(aminomethyl)pyridinium- 4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (379b) (91 mg, 64% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.95 (k, J=1.7 Hz, 1H), 8.66 (d, J=5.2 Hz, 1H), 7.96 (s, 1H), 7.93-7.84 (m, 2H), 7.80-7.70 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.98 (d , J=1.6 Hz, 1H), 6.81-6.67 (m, 1H), 5.31 (s, 2H), 3.92 (s, 2H), 3.61 (s, 2H) , 3.46 (s, 3H), 2.30 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.07. MS (ESI+): 485.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (379c).

Compound 379c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5- yl)methoxy)-4methylphenyl)acetate (379b) (89 mg, 0.184 mmol) in MeOH/THF (6 ml each), THF (6 ml), using a solution of lithium hydroxide (61 mg, 1.454 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (379c) (51 mg, 59% yield), HCl salt, as a white solid substances;

1H NMR (300 MHz, DMSO-d6) δ 8.98 (k, J=1.6 Hz, 1H), 8.81 (d, J=5.3 Hz, 1H), 8.61 (s, 3H ), 8.08 (d, J=1.7 Hz, 1H), 7.97 (t, J=2.7 Hz, 3H), 7.10 (d, J=7.5 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 6.74 (d, J=7.3 Hz, 1H), 5.33 (s, 2H), 4.32 (d, J=5 .5 Hz, 2H), 3.56 (d, J=2.4 Hz, 2H), 2.30 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 57.99. MS (ESI+): 471.1 (M+1); MS (ESI-): 469.1 (M-1); analysis calculation for C ₂₅ H ₂₁ F ₃ N ₂ O ₄ -1.25HCl-1.5H ₂ O: C, 55.29; N, 4.69; N, 5.16, Cl, 8.16; observed: C, 55.20; N, 4.71; N, 5.20, Cl, 8.08.

- 470 045626

Scheme-380

Preparation of (R)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (380e).

Stage-1. Preparation of (R)-tert-butyl (1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (380b).

To a solution of (R)-1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethanamine hydrochloride (380a) (200 mg, 0.686 mmol; CAS No. 1213120-39-8) in DCM (10 ml) was added Boc anhydride (449 mg, 2.058 mmol), Et ₃ N (208 mg, 2.058 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 ml), washed with H2O (2x25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with methanol in DCM 0% to 5%] to give the product (R)-tert-butyl (1-(4-bromopyridin-2-yl)-2,2, 2-trifluoroethyl)carbamate (380b) (120 mg, 49% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (d, J=5.3 Hz, 1H), 8.23 (d, J=10.0 Hz, 1H), 8.04 (d , J=1.9 Hz, 1H), 7.77 (dd, J=5.3, 1.8 Hz, 1H), 5.53 (p, J=8.7 Hz, 1H), 1.41 (s, 9H); optical rotation [a] _D = -65 (c = 0.04, MeOH).

Stage-2. Preparation of (R)-ethyl 2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (380c).

Compound 380c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (134 mg, 0.307 mmol) in dioxane (4 ml) using (R)-tert-butyl (1-(4-bromopyridin-2-yl)-2 ,2,2trifluoroethyl)carbamate (380b) (120 mg, 0.338 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (22 mg, 0.031 mmol) and K2CO3 solution (127 mg, 0.922 mmol) in water (1 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-15% EtOAc in hexane] (R)-ethyl 2-(2-((7-(2-(1-((tert- butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran5-yl)methoxy)phenyl)acetate (380c) (97 mg, 54.0% yield) as a pale green oil;

1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, 1H), 8.35-8.13 (m, 3H), 8.01 (dd, J=5.2, 1.7 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.32-7.19 (m, 2H), 7, 13 (dd, J=7.3, 1.7 Hz, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.60 (t, J=8.9 Hz , 1H), 5.27 (s, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.41 (s, 9H), 0.92 (t, J=7.1 Hz, 3H); MS (ESI+): 585 (M+1); optical rotation [a] _D = -40 (c = 0.015, MeOH).

Stage-3. Preparation of (R)-ethyl 2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (380d).

Compound 380d was prepared according to the procedure described in step-3 of scheme-305 from (R)ethyl 2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2, 2-Trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (380c) (97 mg, 0.166 mmol) in methanol (5 ml) using HCl (4 M in dioxane; 0.830 ml, 3.32 mmol) and stirring at 60°C for 1 hour. This gave, after work-up, (R)-ethyl 2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl) pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (380d) (80 mg) as a pale yellow oil; MS (ESI+): 485 (M+1).

Stage-4. Preparation of (R)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofurαn-5yl)methoxy)phenyl)acetic acid (380e).

- 471 045626

Compound 380e was prepared according to the procedure described in step-4 of Scheme-4 from (R)ethyl 2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridine-4 -yl)benzofuran-5-yl)methoxy)phenyl)acetate (380d) (80 mg, from previous step-4) in MeOH (4 ml), water (1 ml), using 1N aq. NaOH (0.498 ml, 0.498 mmol). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H ₂ O with 0.1% HCl) (R)-2-(2-((7- (2-(1-amino-2,2,2trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (380e) (65 mg, 86% yield), HCl salt, as pale -green solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.89 (d, J=5.2 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 8.13 (dd, J=5.2, 1.7 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.83 ( d, J=1.6 Hz, 1H), 7.30-7.18 (m, 2H), 7.17-7.07 (m, 2H), 6.92 (t, 1H), 5.84 (k, J=7.6 Hz, 1H), 5.31 (s, 2H), 3.61 (s, 2H); MS (ESI+): 457 (M+1), (ESI-): 455 (M1); analysis calculation for C ₂ 4Hi9F3N ₂ O4-1.15HC1-2H ₂ O: C, 53.94; N, 4.56; Cl, 7.63; N, 5.24; observed: C,

53.97; N, 4.30; Cl, 7.96; N, 5.17; optical rotation [a] _D = -2.62 (c = 0.305, MeOH).

Scheme-381

Preparation of (s)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (381e).

Stage-1. Preparation of (S)-tert-butyl (1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (381b).

Compound 381b was prepared according to the procedure described in step-1 of scheme-380 from (S)1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethanamine hydrochloride (381a) (200 mg, 0.686 mmol; CAS No. 1213859-26-7) in DCM (10 ml), using Boc anhydride (449 mg, 2.058 mmol), Et ₃ N (208 mg, 2.058 mmol) and stirring at room temperature for 16 hours. This resulted in the following treatment and purification by flash column chromatography (silica gel, 0-5% MeOH in DCM) (S)tert-butyl (1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (381b ) (70 mg, 29% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (d, J=5.3 Hz, 1H), 8.21 (d, J=10.0 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.77 (dd, J=5.3, 1.9 Hz, 1H), 5.66-5.34 (m, 1H), 1.41 (s, 9H ); optical rotation [a] _D = +36 (c = 0.05, MeOH).

Stage-2. Preparation of (S)-ethyl 2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (381c).

Compound 381c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (80 mg, 0.183 mmol) in dioxane (4 ml), using (S)-tert-butyl (1-(4-bromopyridin-2-yl)-2 ,2,2trifluoroethyl)carbamate (381b) (72 mg, 0.202 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (13 mg, 0.018 mmol) and K ₂ CO ₃ solution ( 76 mg, 0.550 mmol) in water (1 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-15% EtOAc in hexane] (S)-ethyl 2-(2-((7-(2-(1-((tert- butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (381c) as a pale green thick oil; MS (ESI+): 585 (M+1).

Stage-3. Preparation of (S)-ethyl 2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (381d).

Compound 381d was prepared according to the procedure described in step-3 of scheme-305 from (S)-472 045626 ethyl 2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2 ,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (381c) (from previous step-2) in methanol (5 ml), using HCl (4 M in dioxane; 0.458 ml, 1.834 mmol) and stirring at 60°C for 1 hour. This gave, after work-up, (S)-ethyl 2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl )pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (381d) (20 mg) as a pale yellow oil; MS (ESI+): 485 (M+1).

Stage-4. Preparation of (S)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (381e).

Compound 381e was prepared according to the procedure described in step-4 of Scheme-4 from (S)ethyl 2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridine-4 -yl)benzofuran-5-yl)methoxy)phenyl)acetate (381d) (20 mg, from previous step-3) in MeOH (4 ml), water (1 ml), using NaOH (22.00 mg, 0.550 mmol ). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H2O with 0.1% HCl) (S)-2-(2-((7-(2 -(1-amino-2,2,2trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (381e) (15 mg, 18% yield), HCl salt, as pale green solid matter;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.64 (s, 3H, D2O replaceable), 8.89 (d, J=5.2 Hz, 1H), 8.30 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 8.13 (dd, J=5.2, 1.7 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H ), 7.83 (d, J=1.7 Hz, 1H), 7.27-7.20 (m, 2H), 7.15-7.08 (m, 2H), 6.91 (td, J=8.2, 7.7, 1.1 Hz, 2H), 5.94-5.80 (m, 1H), 5.30 (s, 2H), 3.60 (s, 2H); MS (ESI+): 457 (M+1), (ESI-): 455 (M-1); optical rotation [a]D = +3.56 (c = 0.225, MeOH).

Scheme-382

382d 382е

382g 382h

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (382h).

Stage-1. Preparation of methyl 3-acetyl-5-bromo-4-(2-(tert-butoxy)-2-oxoethoxy)benzoate (382b)

Mixture of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (382a) (1.03 g, 3.77 mmol), tert-butyl 2-bromoacetate (1.1 g, 5.64 mmol; CAS No. 160753-84-4 ) and K2CO3 (1.26 g, 9.12 mmol) in acetone (30 ml) were refluxed overnight. The reaction mixture was cooled to room temperature and the solid was removed by filtration. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with 0% to 35% EtOAc in hexane] to give methyl 3-acetyl-5-bromo-4-(2-(tert- butoxy)-2-oxoethoxy)benzoate (382b) (1.39 g, 95% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.1 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 4.68 (s, 2H), 3.88 (s, 3H), 2.63 (s, 3H), 1.43 (s, 9H).

Stage-2. Preparation of 2-(2-acetyl-6-bromo-4-(methoxycarbonyl)phenoxy)acetic acid (382c).

Compound 382c was prepared according to the procedure described in step-5 of Scheme-1 from methyl 3-acetyl-5-bromo-4-(2-(tert-butoxy)-2-oxoethoxy)benzoate (382b) (1.38 g, 3.56 mmol) in DCM (20 ml) using TFA (10.98 ml, 143 mmol). This gave, after workup and trituration in hexanes, a residue of 2-(2-acetyl-6-bromo-4-(methoxycarbonyl)phenoxy)acetic acid (382c) (1.18 g, 100% yield) as a gray solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 2.63 (s, 3H).

Stage-3. Preparation of methyl 7-bromo-3-methylbenzofuran-5-carboxylate (382d)

A mixture of 2-(2-acetyl-6-bromo-4-(methoxycarbonyl)phenoxy)acetic acid (382c) (1.1 g, 3.32 mmol) and anhydrous NaOAc (1.090 g, 13.29 mmol) in Ac ₂ O (25 ml, 265 mmol) was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aq. NaHCO3 solution, saline, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with ethyl acetate in 0-35% hexanes] to give methyl 7-bromo-3-methylbenzofuran-5-carboxylate (382d) (424 mg, 47% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (d, J=1.6 Hz, 1H), 8.08 (d, J=1.5 Hz, 1H), 8.04 (d , J=1.4 Hz, 1H), 3.90 (s, 3H), 2.27 (d, J=1.3 Hz, 3H).

Stage-4. Preparation of (7-bromo-3-methylbenzofuran-5-yl)methanol (382e).

Compound 382e was prepared according to the procedure described in step-2 of Scheme-76 from methyl 7-bromo-3-methylbenzofuran-5-carboxylate (382d) (420 mg, 1.561 mmol) in THF (15 ml) using LiBH4 ( 1.8 ml, 7.20 mmol) and MeOH (0.27 ml, 6.67 mmol). This resulted in (7-bromo3-methylbenzofuran-5-yl)methanol (382e) (376 mg, 100% yield) as a white solid upon treatment;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.87 (d, J=1.4 Hz, 1H), 7.57-7.52 (m, 1H), 7.49 (dd, J= 1.4, 0.6 Hz, 1H), 5.33 (t, J=5.8 Hz, 1H), 4.58 (t, J=5.8, 0.7 Hz, 2H), 2, 20 (s, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate (382f).

Compound 382f was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-3-methylbenzofuran-5-yl)methanol (382e) (370 mg, 1.535 mmol) in DCM (20 ml) using triphenylphosphine ( 443 mg, 1.688 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (332 mg, 1.842 mmol) and (E)bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (620 mg, 1.688 mmol) in DCM (5 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((7-bromo-3-methylbenzofuran-5yl) methoxy)phenyl)acetate (382f) (299 mg, 48% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.93 (d, J=1.4 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.25 (ddd, J=14.1, 7.3, 1.7 Hz, 2H), 7.12-7.04 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.19 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.63 (s, 2H) , 2.22 (d, J=1.3 Hz, 3H), 1.07 (t, J=7.1 Hz, 3H).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5yl)methoxy)phenyl)acetate (382g).

Compound 382g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate (382f) (157 mg, 0.389 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (88 mg, 0.584 mmol), K ₂ CO ₃ (161 mg, 1.168 mmol) in water (0.5 ml) and bis (triphenylphosphine)palladium(P)chloride (41 mg, 0.058 mmol) in an Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3-methylbenzofuran-5yl)methoxy)phenyl)acetate (382g) (167 mg, 100% yield) as a dark oil. MS (ESI+): 430.2 (M+1).

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (382h).

Compound 382h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate ( 382g) (163 mg, 0.38 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (70 mg, 1.668 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (382h) (78 mg, 51% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.56 (s, 2H), 8.01 (s, 1H), 7.97-7.83 (m, 2H) , 7.74 (s, 1H), 7.67 (s, 1H), 7.63-7.49 (m, 2H), 7.34-7.17 (m, 2H), 7.11 (d , J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.62 (s , 2H), 2.27 (s, 3H); MS (ESI+): 402.2 (M+1); MS (ESI-): 400.2 (M-1); analysis calculation for C ₂₅ H ₂₃ NO ₄ -HCl-H ₂ O: C, 65.86; N, 5.75; Cl, 7.78; N, 3.07; observed: C, 66.12; N, 5.75; Cl, 7.61, N, 3.10.

Scheme-383

382f 383a ^383b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (383b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-474 045626 yl)methoxy)phenyl)acetate (383 a).

Compound 383a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate (382f) (139 mg, 0.345 mmol) in dioxane (5 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid (56a) (106 mg, 0.517 mmol), K ₂ CO ₃ (143 mg, 1.034 mmol) in water (0.5 ml) and bis(triphenylphosphine)palladium(P)chloride (36 mg, 0.052 mmol) under Ar atmosphere by heating at 100°C for 45 min in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-3-methylbenzofuran-5yl)methoxy)phenyl)acetate (383a) (154 mg, 100% yield) as a dark oil. MS (ESI+): 448.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (383b).

Compound 383b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl )acetate (383a) (154 mg, 0.344 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (79 mg, 1.883 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (383b) (85 mg, 59% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 2H), 7.89-7.77 (m, 2H), 7.73 (t, J=6.9 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.51-7.35 (m, 2H), 7.30-7.17 (m, 2H), 7.10 (d, J= 8.0 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.16 (s, 2H), 3.60 (s, 2H) , 2.26 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.51; MS (ESI+): 420.1 (M+1); MS (ESI-): 418.1 (M-1); analysis calculation for C ₂₅ H22FNO4-HCl'H2O: C, 63.36; N, 5.32; Cl, 7.48; N, 2.96; observed: C, 63.51; N, 5.38; Cl, 7.79, N, 3.28.

Scheme-384

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (384c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (384a).

Compound 384a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-4-fluorobenzofuran-5-yl)methanol (136b) (594 mg, 2.424 mmol) in DCM (75 ml) using triphenylphosphine ( 699 mg, 2.67 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (612 mg, 2.91 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2 -dicarboxylate (DCAD, 979 mg, 2.67 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5yl) methoxy)-4-methoxyphenyl)acetate (384a) (703 mg, 66% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=2.2 Hz, 1H), 7.70 (d, J=6.1 Hz, 1H), 7.28 (d, J =2.3 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8 ,3, 2.4 Hz, 1H), 5.20 (d, J=1.4 Hz, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.76 (s, 3H ), 3.48 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.53.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (384b).

Compound 384b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (384a) (150 mg, 0.343 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (78 mg, 0.515 mmol), K ₂ CO ₃ (142 mg, 1.029 mmol) in water (0.5 ml ) and bis(triphenylphosphine)palladium(P)chloride (36 mg, 0.051 mmol) in an Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-( aminomethyl)phenyl)-4-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (384b) (109 mg, 69% yield) as a colorless oil.

^1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=2.2 Hz, 1H), 7.82-7.75 (m, 1H), 7.72-7.62 (m , 2H), 7.46 (t, J=7.5 Hz, 1H), 7.42-7.36 (m, 1H), 7.21 (d, J=2.3 Hz, 1H), 7 .10 (d, J=8.3 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H) , 5.26 (s, 2H), 3.86 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.76 (s, 3H), 3.48 (s, 2H), 0.91 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -125.43. MS (ESI+): 464.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (384c).

Compound 384c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl )acetate (384b) (105 mg, 0.227 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (38 mg, 0.906 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (384c) (79 mg, 80% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.91-8.18 (m, 3H), 8.18-8.01 (m, 1H), 7.91 (s, 1H), 7.82 (t, J=4.6 Hz, 1H), 7.68 (d, J=6.7 Hz, 1H), 7.51 (d, J=4.6 Hz , 2H), 7.23-7.10 (m, 1H), 7.04 (d, J=8.3 Hz, 1h), 6.68 (s, 1H), 6.52-6.34 ( m, 1H), 5.22 (s, 2H), 4.05 (s, 2H), 3.69 (s, 3H), 3.39 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ 124.69; MS (ESI+): 436.1 (M+1); MS (ESI-): 434.2 (M-1); analysis calculation for C25H ₂₂ FNO ₅ -HCl-0.25H ₂ O: C, 63.03; N, 4.97; Cl, 7.44; N, 2.94; observed: C, 63.25; N, 4.82; Cl, 7.19; N, 2.92.

Scheme-385

385a

385b $385c 385d

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (385d).

Stage-1. Preparation of ethyl 2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (385a).

Compound 385a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (384a) ( 250 mg, 0.572 mmol), using bis(pinacolato)diboron (218 mg, 0.858 mmol), potassium acetate (168 mg, 1.715 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (70 mg, 0.086 mmol) in anhydrous dioxane (6 ml) under argon while heating at 95°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((4fluoro-7-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (385a) (189 mg, 68% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.3 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.49 (dd, J= 8.3, 2.4 Hz, 1H), 5.19 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.77 (s, 3H), 3.42 ( s, 2H), 1.33 (s, 12H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.86.

Stage-2. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (385b ).

Compound 385b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (385a) (185 mg, 0.382 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro- 3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (121 mg, 0.458 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (40 mg, 0.057 mmol) and K ₂ CO ₃ solution (158 mg,

- 476 045626

1.146 mmol) in water (0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 15% MeOH in DCM] ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido )Methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (385b) (224 mg, 100% yield) as a pale yellow oil. MS (ESI+): 587.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (385c).

Compound 385c was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -4-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (385b) (224 mg, 0.382 mmol) in MeOH (8 mL) using HCl (4 M in dioxane; 0.5 mL, 2.0 mmol) and stirring at room temperature for 1.5 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0 to 70%], ethyl 2-(2-( (7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (385c) (79 mg, 43% yield) as a pale yellow oil. MS (ESI+): 483.1 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (385d).

Compound 385d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl )methoxy)-4-methoxyphenyl)acetate (385c) (75 mg, 0.155 mmol) in MeOH/THF (6 mL each), using lithium hydroxide monohydrate (50 mg, 1.192 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with water in acetonitrile from 0% to 100%] 2-(2-((7-(2-(aminomethyl)-3 -fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (385d) (42 mg, 60% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.63 (d, J=5.5 Hz, 4H), 8.20 (d, J=2.3 Hz, 1H ), 7.79 (t, J=5.3 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.3, 2.4 Hz, 1H ), 5.31 (s, 2H), 4.36 (d, J=5.5 Hz, 2H), 3.76 (s, 3H), 3.45 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.26, -128.47. MS (ESI+): 455.1 (M+1); MS (ESI-): 453.1 (M-1); analysis calculation for C ₂ 4H ₂ 0F ₂ N ₂ O5-HCl-2.5H ₂ O: C, 53.79; N, 4.89; Cl, 6.62; N, 5.23; observed: C, 53.73; N, 4.77; Cl, 6.83; N, 5.37.

Scheme-386

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (386c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (386a).

Compound 386a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-4-fluorobenzofuran-5-yl)methanol (136b) (0.98 g, 4.00 mmol) in DCM (35 ml) using triphenylphosphine (1.154 g, 4.40 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl) acetate (205a) (0.951 g, 4.80 mmol) and (E)bis(4-chlorobenzyl)diazen- 1,2-dicarboxylate (DCAD, 1.615 g, 4.40 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 50% EtOAc in hexane] ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5- yl)methoxy)-5fluorophenyl)acetate (386a) (1.65 g, 97% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, J=2.3 Hz, 1H), 7.70 (d, J=6.2 Hz, 1H), 7.28 (d, J =2.3 Hz, 1H), 7.21-7.07 (m, 3H), 5.19 (s, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz,

DMSO-d6) δ -123.58, -124.55.

- 477 045626

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetate (386b).

Compound 386b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (386a) (150 mg, 0.353 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (80 mg, 0.529 mmol), K2CO3 (146 mg, 1.058 mmol) in water (0.5 ml) and bis (triphenylphosphine)palladium(P)chloride (37 mg, 0.053 mmol) in an Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetate (386b) (127 mg, 80% yield) as a colorless oil;

1H NMR (300 MHz, DMSOO δ 8.17 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.67 (ddd, J=6, 7, 3.9, 2.1 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.42-7.36 (m, 1H), 7.22-7.17 (m, 2H), 7.12 (dd, J=8.8, 2.3 Hz, 2H), 5.25 (d, J=1.3 Hz, 2H), 3.87 (k, J= 7.1 Hz, 2H), 3.80 (s, 2H), 3.59 (s, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO -d6) δ -123.74, -125.46 MS (ESI+): 452.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (386c).

Compound 386c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl )acetate (386b) (123 mg, 0.272 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (60 mg, 1.430 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2(2-((7-(3- (aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (386c) (103 mg, 89% yield), HCl salt, as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 8.46 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.91 (s, 1H), 7.82 (dk, J=7.3, 3.0, 2.1 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.57- 7.44 (m, 2H), 7.20-7.08 (m, 2H), 7.08-6.96 (m, 2H), 5.21 (s, 2H), 4.05 (s, 2H), 3.50 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -123.66, -124.66; MS (ESI+): 424.1 (M+1); MS (ESI-): 422.1 (M-1); analysis calculation for ^^NO^HCr^O: C, 60.32; N, 4.64; Cl, 7.42; N, 2.93; observed: C, 60.08; N, 4.80; Cl, 7.32; N, 2.96.

Scheme-387

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (387b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetate (387a).

Compound 387a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (386a) (156 mg, 0.367 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (93 mg, 0.550 mmol), K2CO3 (152 mg, 1.101 mmol) in water (0 .5 ml) and bis(triphenylphosphine)palladium(11) chloride (39 mg, 0.055 mmol) in an Ar atmosphere by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-4fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (387a) (153 mg, 89% yield) as a colorless oil; MS (ESI+): 470.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (387b).

Compound 387b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)- 5-fluorophenyl)acetate (387a) (153 mg, 0.326 mmol) in MeOH/THF (6 mL each), using a solution of lithium hydroxide monohydrate (61 mg, 1.454 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (387b) (57 mg, 40% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 8.84 (s, 2H), 8.06 (d, J=2.3 Hz, 1H), 7.70- 7.54 (m, 2H), 7.50 (d, J=6.7 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.15 (d, J=2 .3 Hz, 1H), 7.13-7.08 (m, 1H), 7.08-6.97 (m, 2H), 5.20

- 478 045626 (s, 2H), 4.10 (s, 2H), 3.48 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -118.49, -123.53, -123.60; MS (ESI+): 442.1 (M+1), MS (ESI-): 440.1 (M-1); analysis calculation for C24H^3^E4-HC1-0.75H2O: C, 58.66; N, 4.21; Cl, 7.22;

N, 2.85; observed: C, 58.74; N, 4.24; Cl, 7.38; N, 2.97.

Scheme-388

2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5 -yl)methoxy)-5 Preparation of fluorophenyl)acetic acid (388d).

Stage-1. Preparation of ethyl 2-(5-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl) acetate (388a).

Compound 388a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (386a) ( 630 mg, 1.482 mmol) using bis(pinacolato)diboron (564 mg, 2.222 mmol), potassium acetate (436 mg, 4.44 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (181 mg, 0.222 mmol) in anhydrous dioxane (12 ml) under argon while heating at 95°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(5fluoro-2-((4-fluoro-7-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (388a) (596 mg, 85% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.3 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.19 (dd, J=9.8, 4.8 Hz, 1H), 7.11 (cd, J=4.2, 3.8, 1.7 Hz, 3H), 5.17 (d, J=1.2 Hz , 2H), 3.95 (k, 2H), 3.53 (s, 2H), 1.33 (s, 12H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -118.98, -123.68.

Stage-2. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (388b ).

Compound 388b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (388a) (252 mg, 0.534 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro -3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (184 mg, 0.694 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (40 mg , 0.057 mmol) and a solution of K2CO3 (221 mg, 1.601 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 15% MeOH in DCM] ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido )methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetate (388b) (307 mg, 100% yield) as a dark oil, used in the next step without further purification . MS (ESI+): 575.2 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetate (388c).

Compound 388c was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetate (388b) (307 mg, 0.534 mmol) in MeOH (8 mL) using HCl (4 M in dioxane; 0.6 mL, 2.40 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0 to 100%], a mixture of methyl and ethyl 2-(2- ((7-(2-(aminomethyl)-3-fluoropyridin-4yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (388c) as a colorless oil. MS (ESI+): 471.1 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetic acid (388d).

- 479 045626

Compound 388d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl )methoxy)-5-fluorophenyl)acetate (388c) (138 mg, 0.293 mmol) in MeOH (6 ml), using lithium hydroxide monohydrate (71 mg, 1.692 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with water in acetonitrile (with 0.1% HCl) from 0% to 100%] 2-(2-((7-(2 -(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (388d) (91 mg, 70% yield), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.63 (d, J=5.7 Hz, 4H), 8.20 (d, J=2.3 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.73 (d, J=6.6 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H) , 7.20 (dd, J=8.7, 4.7 Hz, 1H), 7.16-7.05 (m, 2H), 5.30 (s, 2H), 4.37 (s, 2H ), 3.56 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.24, -123.56, -128.49; MS (ESI+): 443.1 (M+1); MS (ESI-): 441.1 (M-1); analysis calculation for C ₂₃ H ₁₇ F ₃ N ₂ O ₄ -HCl-0.5H ₂ O: C, 56.62; N, 3.93; Cl, 7.27; N, 5.74; observed: C, 56.53; N, 3.81; Cl, 7.25; N, 5.79.

Scheme-389

^386a 389a

389b 389с

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (389c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (389a).

Compound 389a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (386a) (240 mg, 0.564 mmol) in dioxane (5 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methylcarbamate (123a) (264 mg, 0.790 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (59 mg, 0.085 mmol) and a solution of K ₂ CO ₃ (234 mg, 1.693 mmol) in water ( 0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0% to 70%] ethyl 2-(2-((7-(2-((( tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetate (389a) (288 mg, 92% yield) as a dark oil. MS (ESI+): 553.2 (M+1).

Stage-2. Preparation of methyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methox and)-5-fluorophenyl) acetate (389b).

Compound 389b was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4 -fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetate (389a) (288 mg, 0.521 mmol) in MeOH (6 mL) using HCl (4 M in dioxane; 1 mL, 4.0 mmol) and stirring at room temperature temperature overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM 0% to 100%] methyl 2-(2-((7-(2-(aminomethyl)pyridinium- 4-yl)-4-fluorobenzofuran-5yl)methoxy)-5-fluorophenyl)acetate (389b) (229 mg, 100% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI+): 439.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (389c).

Compound 389c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy )-5-fluorophenyl)acetate (389b) ((229 mg, 0.506 mmol) in MeOH (6 ml), using lithium hydroxide monohydrate (111 mg, 2.65 mmol) in water (2 ml). This resulted in treatment and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7-(2(aminomethyl) pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (389c)

- 480 045626 (132 mg, 62% yield), HCl salt, in the form of a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.81 (d, J=5.4 Hz, 1H), 8.70 (s, 3H), 8.26 (d, J=2.3 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.04 (dd, J=5.4, 1.7 Hz, 1H), 7.98 (d, J=6.7 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.21 (dd, J=8.8, 4.7 Hz, 1H), 7.17-7.01 (m , 2H), 5.30 (s, 2H), 4.34 (d, J=5.2 Hz, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ 121.10, -123.60; MS (ESI+): 425.1 (M+1); MS (ESI-): 423.1 (M-1); analysis calculation for C23H1 ₈ F2N ₂ O4-2HCl-H2O: C, 53.61; N, 4.30; Cl, 13.76; N, 5.44; observed: C, 53.54; N, 4.13; Cl, 13.45; N, 5.43.

Scheme-390

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (390c).

Stage-1. Preparation of ethyl 2-(4-ethyl-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl) acetate (390a).

Compound 390a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (469e) ( 350 mg, 0.804 mmol) using bis(pinacolato)diboron (306 mg, 1.206 mmol), potassium acetate (237 mg, 2.412 mmol) and PdCl ₂ (dppf)CH ₂ Cl ₂ (66 mg, 0.080 mmol) in anhydrous dioxane (5 ml) under nitrogen atmosphere when heated at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane 0 to 5%] ethyl 2-(4-ethyl-2-((2-fluoro-7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (390a) (326 mg, 84% yield) as an opaque oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.75 (s, 1H), 7.63 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.35 (d, J=6.4 Hz, 1H), 5.15 (s, 2H), 3.99 (k, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.58 (k, J=7.7 Hz, 2H), 1.19-1.13 (m, 15H) , 1.05 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -111.75; MS (ESI+): 505.2 (M+Na).

Stage-2. Preparation of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate ( 390b).

Compound 390b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-ethyl-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (390a) (156 mg, 0.323 mmol) in dioxane (4 ml) using (+)-(S)-N-((4chloropyridine-2 -yl)methyl)-2-methylpropane-2-sulfinamide (365c) (88 mg, 0.356 mmol), PdCl ₂ (PPh3) ₂ (23 mg, 0.032 mmol) and K ₂ CO ₃ solution (134 mg, 0.970 mmol) in water (0.3 ml) was heated under a nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM 0% to 3%] (S)-ethyl 2-(2-((7(2-((1.1 -dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetate (390b) (111 mg, 61% yield) as an orange oil; MS (ESI+): 567.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (390c).

Compound 390c was prepared from (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl )acetate (390b) (111 mg, 0.196 mmol) in THF (4 mL), using 4 M HCl in dioxane (0.147 mL, 0.588 mmol) and stirring at room temperature for 16 h. A solution of 2.0 M LiOH (0.378 ml, 0.757 mmol) was added and stirred at 40°C for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 100 g, eluted with acetonitrile in water (with 0.1 % HCl) from 0% to 60%] 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid

- 481 045626 (390c) (11 mg, 17% yield) in the form of a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.3 Hz, 1H), 8.37 (s, 3H, D2O replaceable), 7.98 (s, 1H), 7 .90 (d, 1H), 7.79 (d, 2H), 7.12 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.76 (d, J= 7.9, 1.4 Hz, 1H), 6.50 (d, 1H), 5.26 (s, 2H),

4.37-4.26 (m, 2H), 3.54 (s, 2H), 2.60 (k, 2H), 1.18 (t, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.21; LC, 2.069 min, 98.3%; MS (ESI+): 435.2 (M+1); (ESI-): 433.1 (M-1).

Scheme-391

^391e 391f

Preparation of 2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5 -yl)methoxy)-[1,1'-biphenyl]-4yl)acetic acid (391f).

Stage-1. Preparation of ethyl 2-(3-methoxy-[1,1'-biphenyl]-4-yl)acetate (391b).

Compound 391b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-methoxyphenyl)acetate (391a) (0.95 g, 3.48 mmol; CAS No. 1261570-38- 0) in dioxane (8 ml), using phenylboronic acid (0.467 g, 3.83 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.244 g, 0.348 mmol) and solution K2CO3 (1.442 g, 10.43 mmol) in water (2 ml) heat under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 5% ethyl acetate in hexane), ethyl 2-(3-methoxy-[1,1'-biphenyl]-4-yl)acetate (391b) (0.67 g, 71% yield) as a clear, colorless thick oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.69 (d, 2H), 7.47 (tq, J=6.8, 0.9 Hz, 2H), 7.42-7.33 ( m, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.24-7.16 (m, 2H), 4.07 (k, 2H), 3.85 (s, 3H ), 3.61 (s, 2H), 1.19 (t, J=7.1, 0.8 Hz, 3H); MS (ESI+): 293 (M+Na).

Stage-2. Preparation of ethyl 2-(3-hydroxy-[1,1'-biphenyl]-4-yl)acetate (391c).

Compound 391c was prepared according to the procedure described in step-5 of Scheme-257 from ethyl 2-(3-methoxy-[1,1'-biphenyl]-4-yl)acetate (391b) (0.67 g, 2.479 mmol) in dichloromethane (10 ml) using boron tribromide (4.96 ml, 4.96 mmol, 1 M solution in DCM). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-10% EtOAc in hexanes), ethyl 2-(3-hydroxy-[1,1'-biphenyl]-4-yl)acetate (391c ) (0.46 g, 72% yield) as a pale yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 7.63-7.51 (m, 2H), 7.45 (dd, J=8.5, 6.7 Hz , 2H), 7.40-7.29 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4 .08 (k, J=7.1 Hz, 2H), 3.58 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); MS (ESI+): 257 (M+1).

Stage-3. Preparation of ethyl 2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl)acetate (391d).

Compound 391d was prepared according to the procedure described in step-2 of Scheme-23 from (7bromobenzofuran-5-yl)methanol (23a) (0.448 g, 1.974 mmol) in DCM (10 ml) using triphenylphosphine (0.941 g, 3 .59 mmol), ethyl 2-(3-hydroxy-[1,1'-biphenyl]-4-yl)acetate (391c) (0.46 g, 1.795 mmol) and (E)bis(4-chlorobenzyl)diazene -1,2-dicarboxylate (DCAD, 1.318 g, 3.59 mmol) in DCM (25 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 10% EtOAc in hexane), ethyl 2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1, 1'-Biphenyl]4-yl)acetate (391d) (0.69 g, 83% yield) as a pale green solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.52-7.44 ( m, 2H), 7.41-7.34 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.7, 1.6 Hz , 1H), 7.13 (d, J=2.2 Hz, 1H), 5.31 (s, 2H), 4.03 (k, J=7.1 Hz, 2H), 3.67 (s , 2H), 1.09 (t, J=7.1 Hz, 3H); MS (ESI+): 487/489 (M+Na).

Stage-4. Preparation of ethyl 2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetate (391e).

Compound 391e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2-482 045626 (3-((7-bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4- yl)acetate (391d) (135 mg, 0.290 mmol) in dioxane (4 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (66 mg, 0.319 mmol), bis(triphenylphosphine) palladium(P ) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (20 mg, 0.029 mmol) and a solution of K ₂ CO ₃ (120 mg, 0.870 mmol) in water (1 ml) heating in an N2 atmosphere at 100 ° C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with MeOH in DCM 0% to 5%), ethyl 2-(3-((7-(3-(aminomethyl)-2fluorophenyl)benzofuran-5 -yl)methoxy)-[1,1'-biphenyl]-4-yl)acetate (391e) (65 mg) as a clear pale yellow oil; MS (ESI+): 510 (M+1).

Stage-5. Preparation of 2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetic acid (391f).

Compound 391f was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1, 1'-Biphenyl]-4-yl)acetate (391e) (65 mg, from previous step-4) in MeOH (3 ml), using a solution of sodium hydroxide (23 mg, 0.58 mmol) in water (1 ml) . This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(3-((7- (3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl)acetic acid (391 f) (50 mg, 36% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.74-7.61 (m, 4H), 7.52 (d, J=1.6 Hz, 1H), 7.50-7.41 (m, 3H), 7.41-7.33 (m, 2H), 7. 31 (d, J=7.8 Hz, 1H), 7.20 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.40 (s, 2H), 4.18 (s, 2H), 3.62 (s, 2H); MS (ESI+): 482 (M+1), (ESI-): 480 (M-1); analysis calculation for C ₃₀ H ₂₄ FNO ₄ -HCl-2H ₂ O: C, 65.04; N, 5.28; Cl, 6.40; N, 2.53: observed: C, 65.04; N, 5.00; Cl, 6.74; N, 2.61.

Scheme-392

Preparation of 2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)acetic acid (392g).

Stage-1. Preparation of 7-hydroxybenzofuran-6-carbaldehyde (392b).

Compound 392b was prepared according to the procedure described in step-1 of scheme-266 from benzofuran-7-ol (392a) (500 mg, 3.73 mmol; CAS No. 4790-81-2) using MgCl ₂ (532 mg, 5.59 mmol), Et ₃ N (1.975 ml, 14.17 mmol), paraformaldehyde (2.239 g, 74.6 mmol) in anhydrous MeCN (25 ml) This resulted after work-up and purification by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate and hexanes) 7-hydroxybenzofuran-6-carbaldehyde (392b) (133 mg, 22.00% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.27 (d, J=0.5 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H ), 7.55 (d, J=8.2 Hz, 1H), 7.24 (dd, J=8.2, 0.5 Hz, 1H), 7.06 (d, J=2.1 Hz , 1H).

Stage-2. Preparation of 7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-carbaldehyde (392c).

Compound 392c was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (125 mg, 0.771 mmol) using 7-hydroxybenzofuran-6carbaldehyde (392b) (224 mg, 0.771 mmol) and K ₂ CO ₃ (320 mg, 2.313 mmol) in DMF (5 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with EtOAc in hexane) 7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-carbaldehyde (392c) (255 mg , 89%) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 10.34 (d, J=0.8 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.14 (d, J =2.2 Hz, 1H),

- 483 045626

7.82 (d, J=1.5 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7, 44 (dd, J=8.2, 0.8 Hz, 1H), 7.13 (dd,

J=5.5, 2.2 Hz, 2H), 5.72 (s, 2H).

Stage-3. Preparation of (E)-7-bromo-5-(((6-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-7yl)oxy)methyl)benzofuran (392d).

Compound 392d was prepared according to the procedure described in step-3 of Scheme-266 from 7((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-carbaldehyde (392c) (250 mg, 0.674 mmol) using methyl(methylsulfinylmethyl )sulfan (134 mg, 1.078 mmol), Triton-B (40% methanol solution) (0.153 ml, 0.337 mmol) in THF (10 ml) when heated at 70°C for 12 hours. This resulted in the following treatment and Purification by flash column chromatography (silica gel, 24 g, eluted with 0-40% EtOAc in hexane) (E)-7-bromo-5-(((6-(2-(methylsulfinyl)-2-(methylthio)vinyl )benzofuran-7yl)oxy)methyl)benzofuran (392d) (322 mg, 100% yield) as yellow syrup; MS (ESI+): 477.0, 479.9 (M, M+2).

Stage-4. Preparation of ethyl 2-(7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-yl)acetate (392e).

Compound 392e was prepared according to the procedure described in step-4 of scheme-266 from (E)7-bromo-5-(((6-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-7-yl )oxy)methyl)benzofuran (392d) (322 mg, 0.674 mmol) in ethanol (20 ml), using HCl (4 M in 1,4-dioxane, 0.674 ml, 2.70 mmol) and reflux for 12 hours This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate and hexanes), ethyl 2-(7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6- yl)acetate (392e) (135 mg, 47% yield) as a thick syrup;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.75 (d , J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.14-7.07 (m, 2H), 6.99 (d, J=2.2 Hz, 1H), 5.45 (s, 2H), 3.99 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.09 (t, J=7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6yl)acetate (392f).

Compound 392f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-yl)acetate (392e) (125 mg, 0.291 mmol) in dioxane (8 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (68 mg, 0.364 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (31 mg, 0.044 mmol) and K2CO3 (121 mg, 0.894 mmol) in water (2 ml) heating under N2 at 100°C for 12 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA80 in DCM 0% to 90%), ethyl 2-(7-((7-(3-(aminomethyl)phenyl)benzofuran -5yl)methoxy)benzofuran-6-yl)acetate (392f) (70 mg, 53% yield) as an oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.70 (dt, J=9.1, 1.7 Hz, 2H), 7.59 (d, J=1.7 Hz, 1H), 7.46 ( t, J=7.6 Hz, 1H), 7.42-7.37 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.10 (d, J=7 .9 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 5.53 (s, 2H), 3, 93 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.71 (s, 2H), 1.01 (t, J=7.1 Hz, 3H; MS (ESI +): 456.1 (M+1).

Stage-6. Preparation of 2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6yl)acetic acid (392g).

Compound 392g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)acetate (392f) (68 mg, 0.149 mmol) in THF (10 ml), MeOH (2 ml), using a solution of lithium hydroxide (14 mg, 0.597 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(7-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)acetic acid (392g) (52 mg, 81% yield), hydrochloride salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 8.50 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.06 ( d, J=2.2 Hz, 1H), 7.99 (s, 1H), 7.97-7.87 (m, 1H), 7.80 (s, 1H), 7.68 (d, J =1.7 Hz, 1H), 7.65-7.50 (m, 2H), 7.30 (d, J=7.9 Hz, 1H), 7.19-7.04 (m, 2H) , 6.99 (d, J=2.2 Hz, 1H), 5.52 (s, 2H), 4.14 (s, 2H), 3.68 (s, 2H); MS (ESI+): 428.10 (M+1), (ESI-): 426.10 (M-1); analysis calculation for C ₂₆ H ₂₁ NO ₅ -HCl-1.25H ₂ O: C, 64.20; N, 5.08; Cl, 7.29; N, 2.88; observed: C, 64.27; N, 5.17; Cl, 7.35; N, 2.89.

- 484 045626

Scheme-393

Preparation of 2-(3-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4yl)acetic acid (393d).

Stage-1. Preparation of ethyl 2-(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5yl)methoxy)-[1,1'-biphenyl] - 4-yl)acetate (393a).

Compound 393a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl) acetate (391d) (328 mg, 0.705 mmol), using bis(pinacolato)diboron (268 mg, 1.057 mmol), potassium acetate (208 mg, 2.115 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (58 mg, 0.070 mmol) in anhydrous dioxane (5 ml) under argon while heating at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexane from 0 to 10%] ethyl 2-(3-((7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-[1,1' -biphenyl]-4-yl)acetate (393a) (331 mg, 92% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.07 (d, J=2.2 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.76-7, 65 (m, 3H), 7.537.43 (m, 2H), 7.42-7.33 (m, 2H), 7.30 (d, J=7.8 Hz, 1H), 7.20 (dd , J=7.7, 1.6 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 5.31 (s, 2H), 4.02 (k, J=7, 1 Hz, 2H), 3.63 (s, 2H), 1.34 (s, 12H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI+): 535 (M+Na).

Stage-2. Preparation of ethyl 2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl )acetate (393b).

Compound 393b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4yl)acetate (393a) (145 mg, 0.283 mmol) in dioxane (4 ml) using tert-butyl (4-chloropyridin-2yl)methylcarbamate (271a) (76 mg, 0.311 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (20 mg, 0.028 mmol) and K ₂ CO ₃ solution (117 mg, 0.849 mmol) in water (1 ml) heating in an argon atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-30% EtOAc in hexane] ethyl 2-(3-((7-(2-(((tert-butoxycarbonyl) amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetate (393b) (35 mg) as a pale yellow oil; MS (ESI+): 593 (M+1).

Stage-3. Preparation of methyl 2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl )acetate (393c).

Compound 393c was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran- 5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetate (393b) (35 mg, from previous step-2) in MeOH (5 ml) using HCl (4 M in dioxane; 1.415 ml , 5.66 mmol) and stirring at 60°C for 1 hour. This resulted in the preparation after treatment of methyl 2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridine-4 -yl)benzofuran-5yl)methoxy)-[1,1'-biphenyl]-4-yl)acetate (393c); MS (ESI+): 479 (M+1).

Stage-4. Preparation of 2-(3-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetic acid (393 d).

Compound 393 d was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran -5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetate (393c) (from previous step-3) in MeOH (3 ml), using NaOH (34.0 mg, 0.849 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted with 0-60% MeCN in _H2O with 0.1% HCl) 2-(3-((7-(2(aminomethyl) pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl)acetic acid (393d) (10 mg, 8% yield), HCl salt, as pale green solid matter;

1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.48-8.32 (m, 3H), 8.18 (d, J=2, 2 Hz, 1H), 8.07

- 485 045626 (s, 1H), 7.99 (dd, J=5.0, 1.7 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.86 (d , J=1.6 Hz, 1H), 7.71-7.64 (m, 2H), 7.46 (dt,

J=8.4, 6.7 Hz, 2H), 7.42-7.28 (m, 3H), 7.21 (dd, J=7.6, 1.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 5.42 (s, 2H), 4.414.27 (m, 2H), 3.65 (s, 2H); MS (ESI+): 465 (M+1), 463 (M-1).

Scheme-394

Preparation of 2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetic acid (394с ).

Stage-1. Preparation of (S)-ethyl 2-(3-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-[1,1'- biphenyl]-4-yl)acetate (394a).

Compound 394a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4yl)acetate (393a) (202 mg, 0.394 mmol) in dioxane (4 ml) using (+)-(S)-N-( (4-chloro-3-fluoropyridin2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (115 mg, 0.434 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (28 mg, 0.039 mmol) and a solution of K ₂ CO ₃ (163 mg, 1.183 mmol) in water (1 ml) heating in an argon atmosphere at 100 ° C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-4% MeOH in DCM] (8)-ethyl 2-(3-((7-(2-((1 ,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4yl)acetate (394a) (100 mg) as a pale yellow oil; MS (ESI+) 615 (M+1).

Stage-2. Preparation of methyl 2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-[1,1'-biphenyl]-4-yl)acetate (394b) .

Compound 394b was prepared according to the procedure described in step-3 of scheme-305 from (S)ethyl 2-(3-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridine-4 -yl)benzofuran-5-yl)methoxy)[1,1'-biphenyl]-4-yl)acetate (394a) (100 mg, from previous step-1) in MeOH (4 ml) using HCl (4 M in dioxane; 1.971 ml, 7.88 mmol) and stirring at 60°C for 1 hour. This resulted in the preparation after treatment of methyl 2-(3-((7-(2-(aminomethyl)-3-fluoropyridine-4 -yl)benzofuran-5-yl)methoxy)-[1,1'biphenyl]-4-yl)acetate (394b); MS (ESI+): 497 (M+1).

Stage-3. Preparation of 2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)[1,1'-biphenyl]-4-yl)acetic acid (394с ).

Compound 394c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy )-[1,1'-biphenyl]-4-yl)acetate (394b) (from previous step-2) in MeOH (3 ml), using NaOH (47 mg, 1.183 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted with 0-60% MeCN in H ₂ O with 0.1% HCl) 2-(3-((7-(2- (aminomethyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1'-biphenyl]-4-yl)acetic acid (394c) (60 mg, 32% yield) HCl as pale green solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.0 Hz, 1H), 8.57-8.39 (m, 3H), 8.12 (d, J=2 .2 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.72-7.63 (m, 3H ), 7.47 (dt, J=8.3, 6.6 Hz, 2H), 7.41-7.33 (m, 2H), 7.31 (d, J=7.8 Hz, 1H) , 7.21 (dd, J=7.7, 1.6 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 5.41 (s, 2H), 4.40 ( g, J=4.7 Hz, 2H), 3.63 (s, 2H); MS (ESI+) 483 (M+1), 481 (M-1); Analysis calculation for C29H2 ₃ FN2O4-1.15HCl-H2O: C, 64.21; N, 4.86; Cl, 7.52; N, 5.16; observed: C, 64.34; N, 4.85; Cl, 7.40; N, 5.18.

- 486 045626

Scheme-395

395b 395c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetic acid (395c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-cyclopentylphenyl)acetate (395a).

Compound 395a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5 -yl)methoxy)phenyl)acetate (182b) (202 mg, 0.394 mmol) in PhMe (10 ml), using cyclopentylboronic acid (84 mg, 0.740 mmol), Pd(OAc) ₂ (8.31 mg, 0.037 mmol) , P(Cy) ₃ (20.76 mg, 0.074 mmol) and a solution of K2CO3 (169 mg, 1.221 mmol) in water (1 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-15% EtOAc in hexane] ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate (395a) (57 mg) as a colorless oil; MS (ESI+): 606 (M+Na).

Stage-2. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyclopentylphenyl)acetate (395b).

Compound 395b was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4cyclopentylphenyl)acetate (395a) (57 mg, from previous step-1) in MeOH (5 ml) using HCl (4 M in dioxane; 0.463 ml, 1.850 mmol) and stirring at 40°C for 1 h This gave, after treatment, methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyclopentylphenyl)acetate (395b); MC (ESI+) 470 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4cyclopentylphenyl)acetic acid (395c).

Compound 395c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate (395b) (from previous step-2) in MeOH (3 ml), using NaOH (44 mg, 1.11 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted with 0-60% MeCN in H2O with 0.1% HCl) 2-(2-((7-(3-(aminomethyl )phenyl)benzofuran-5yl)methoxy)-4-cyclopentylphenyl)acetic acid (395c) (20 mg, 12% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.93 (dt, J=7.6, 1.5 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.60 ( t, J=7.6 Hz, 1H), 7.56-7.50 (m, 1H), 7.12-7.03 (m, 2H), 6.99 (d, J=1.6 Hz , 1H), 6.79 (dd, J=7.4, 1.6 Hz, 1H), 5.26 (s, 2H), 4.14 (s, 2H), 3.53 (s, 2H) , 2.94 (t, J=8.1 Hz, 1H), 1.98 (s, 2H), 1.75 (dd, J=5.4, 2.7 Hz, 2H), 1.69- 1.49 (m, 4H); MS (ESI+): 456 (M+1), 454 (M-1).

- 487 045626

Scheme-396

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-III-pyrazol-4yl)phenyl)acetic acid (396e).

Stage-1. Preparation of ethyl 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396a).

Compound 396a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-bromo-2-methoxyphenyl)acetate (391a) (406 mg, 1.486 mmol) in dioxane (8 ml) using 1- methyl 4(4,4,5,5-tetraαmethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (340 mg, 1.634 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd( PPh ₃ ) ₂ Cl ₂ ) (104 mg, 0.149 mmol) and a solution of K ₂ CO ₃ (616 mg, 4.46 mmol) in water (2 ml) heating under N2 at 100°C for 16 hours in an oil bath . This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 40% ethyl acetate in hexane), ethyl 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4yl)phenyl )acetate (396a) (250 mg, 61% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=0.8 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.21-7.04 (m, 3H), 4.06 (k, J=7.1 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.54 (s, 2H), 1 .17 (t, J=7.1 Hz, 3H); MS (ESI+): 275 (M+1).

Stage-2. Preparation of ethyl 2-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396b).

Compound 396b was prepared according to the procedure described in step-5 of Scheme-257 from ethyl 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396a) (243 mg , 0.886 mmol) in dichloromethane (10 ml), using boron tribromide (1.772 ml, 1.772 mmol, 1 M solution in DCM). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 50% hexane), ethyl 2-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl )phenyl)acetateα (396b) (81 mg, 35% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.99 (s, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.07 ( d, J=7.6 Hz, 1H), 6.97-6.86 (m, 2H), 4.05 (k, 2H), 3.85 (s, 3H), 3.51 (s, 2H ), 1.17 (t, J=7.1, 0.7 Hz, 3H); MS (ESI+): 261 (M+1), (ESI-): 259 (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl )acetate (396c).

Compound 396c was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (121 mg, 0.342 mmol) in DCM (10 ml) using triphenylphosphine (163 mg, 0.622 mmol), ethyl 2-(2-hydroxy-4-(1-methyl-1H-pyrazol-4yl)phenyl) acetate (396b) (81 mg, 0.311 mmol) and (E)- bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 229 mg, 0.622 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 50% EtOAc in hexane), ethyl 2-(2-((7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl )benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4yl)phenyl)acetate (396c) (138 mg) as a pale yellow oil; MS (ESI+) 596 (M+1).

Stage-4. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl1 H-pyrazol-4-yl)phenyl)acetate (396d).

Compound 396d was prepared according to the procedure described in step-3 of scheme-305 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4-(1-methyl-1Hpyrazol-4-yl)phenyl)acetate (396c) (138 mg, from previous step-3) in MeOH (4 ml) using HCl (4 M in dioxane; 0.778 ml, 3.11 mmol) and stirring at 60°C for 1 hour. This resulted in the preparation after treatment of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4 -(1-methyl-1Hpyrazol-4-yl)phenyl)acetate (396d); MS (ESI+): 482 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1Hpyrazol-4-yl)phenyl)acetic acid (396e).

- 488 045626

Compound 396e was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1- methyl 1H-pyrazol-4-yl)phenyl)acetate (396d) (from previous step-4) in MeOH (3 ml), using a solution of sodium hydroxide (25 mg, 0.622 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2(2-((7-(3 - (aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-4-(1 -methyl-1 H-pyrazol-4-yl)phenyl)acetic acid (396e) (80 mg, 55% yield), HCl salt, in as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.44-8.22 (m, 3H), 8.15 (s, 1H), 8.11 (d, J=2.2 Hz, 1H), 8 .00 (d, J=1.7 Hz, 1H), 7.94 (dt, J=7.6, 1.6 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H) , 7.80 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7 .57-7.51 (m, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.14-7, 05 (m, 2H), 5.33 (s, 2H), 4.15 (k, J=5.8 Hz, 2H), 3.86 (s, 3H), 3.57 (s, 2H); MS (ESI+): 468 (M+1), 466 (M-1); analysis calculation for C2 ₈ Н25КзО44.5НС1-ЗН2О: С, 58.36; N, 5.68; Cl, 9.23; N, 7.29; observed: C, 58.20; N, 5.48; Cl, 9.32; N, 7.26.

Scheme-397

397с 397d 397е

Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2'-fluoro-4'-methoxy-[1,1'biphenyl]-4-yl)acetic acid acids (397e).

Stage-1. Preparation of methyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (397b).

Compound 397b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.920 g, 2.60 mmol) in DCM (20 ml), using triphenylphosphine (1.241 g, 4.73 mmol), methyl 2-(4-bromo-2-hydroxyphenyl) acetate (397a) (0.58 g, 2.367 mmol) and (E)-bis(4-chlorobenzyl) )diazene-1,2-dicarboxylate (DCAD, 1.738 g, 4.73 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 20% hexanes), methyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (397b) (1.08 g, 79% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.2 Hz, 1H), 7.81-7.66 (m, 3H), 7.58-7.43 (m , 3H), 7.35 (d, J=1.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.20 (d, J=8.0 Hz, 1H), 7 .12 (dd, J=8.0, 1.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.63 (s, 2H), 3.45 (s, 3H), 1.39 (s, 9H); MS (ESI+): 602/604 (M+Na).

Stage-2. Preparation of methyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-2'-fluoro-4'-methoxy-[1,1'- biphenyl]-4-yl)acetate (397c).

Compound 397c was prepared according to the procedure described in step-3 of Scheme-1 from methyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5-yl)methoxy)phenyl)acetate (397b) (200 mg, 0.345 mmol) in dioxane (4 ml), using (2-fluoro-4-methoxyphenyl)boronic acid (59 mg, 0.345 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (24 mg, 0.034 mmol) and a solution of K2CO3 (143 mg, 1.034 mmol) in water (1 ml) heating in an N2 atmosphere at 100 ° C for 16 hours in an oil bath. This resulted, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 20% ethyl acetate in hexane), methyl 2-(3((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl )benzofuran-5-yl)methoxy)-2'-fluoro-4'-methoxy-[1,1'biphenyl]-4-yl)acetate (397c) (120 mg) as a clear, colorless oil; MS (ESI+) 648 (M+Na).

Stage-3. Preparation of methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2'-fluoro-4'methoxy-[1,1'-biphenyl]-4-yl) acetate (3 97d).

- 489 045626

Compound 397d was prepared according to the procedure described in step-3 of scheme-305 from methyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-2'-fluoro-4'methoxy-[1,1'-biphenyl]-4-yl)acetate (397c) (120 mg, from previous step-2) in MeOH (5 ml) using HCl (4 M in dioxane; 0.861 ml, 3.45 mmol) and stirring at 40°C for 1 hour. This gave, after treatment, methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-2'-fluoro-4'methoxy-[1,1'-biphenyl]-4-yl)acetate (397d); MS (ESI+): 526 (M+1).

Stage-4. Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2'-fluoro-4'-methoxy[1,1'-biphenyl]-4-yl)acetic acid acids (397e).

Compound 397e was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2'-fluoro- 4'-methoxy-[1,1'-biphenyl]-4-yl)acetate (397d) (from previous step-3) in MeOH (3 ml), using a solution of sodium hydroxide (41 mg, 1.034 mmol) in water ( 1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2(3-((7-(3- (aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid (397e) (76 mg, 43% yield) , HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.94 (dt , J=7.6, 1.5 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.53 (dt, J=7.7, 1.5 Hz, 1H), 7.46 (dd, J=9.3, 8.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.22 (t, J=1.4 Hz, 1H), 7.11-7.01 (m, 2H), 6, 93 (dd, J=12.9, 2.5 Hz, 1H), 6.90-6.84 (m, 1H), 5.33 (s, 2H), 4.14 (s, 2H), 3 .81 (s, 3H), 3.63 (s, 2H); MS (ESI+): 512 (M+1), 511 (M-1); analysis calculation for C ₃₁ H ₂₆ FNO ₅ -HCl-1.25H ₂ O: C, 65.26; N, 5.21; Cl, 6.21; N, 2.46; observed: C, 65.26; H, 5.03; Cl: 6.19; N, 2.62.

Scheme-398

F

Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro-[1,1'-biphenyl]-4yl)acetic acid (398c).

Stage-1. Preparation of methyl 2-(3-((7'-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)-4'-fluoro-[1,1'-biphenyl]-4 -yl)acetate (398a).

Compound 398a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5-yl)methoxy)phenyl)acetate (397b) (193 mg, 0.332 mmol) in dioxane (4 ml), using 4-fluorophenylboronic acid (56 mg, 0.399 mmol; CAS No. 1765-93-1), bis(triphenylphosphine ) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (23 mg, 0.033 mmol) and a solution of K ₂ CO ₃ (138 mg, 0.997 mmol) in water (1 ml) heating in an atmosphere of N ₂ at 100° C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with ethyl acetate in 0% to 20% hexane), methyl 2(3-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro-[1,1'-biphenyl]4-yl)acetate (398a) (140 mg) as a clear, colorless oil; MS (ESI+): 618 (M+Na).

Stage-2. Preparation of methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro-[1,1'biphenyl]-4-yl)acetate (398b).

Compound 398b was prepared according to the procedure described in step-3 of scheme-305 from methyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)-4'-fluoro-[1,1'biphenyl]-4-yl)acetate (398a) (140 mg, from previous step-1) in MeOH (4 ml) using HCl (4 M in dioxane; 0.831 ml, 3.32 mmol) and stirring at 40°C for 1 hour. This resulted in

- 490 045626 after treatment with methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro-[1,1'-biphenyl]4-yl)acetate (398b); MC (ESI+): 496 (M+1).

Stage-3. Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro-[1,1'biphenyl]-4-yl)acetic acid (398c).

Compound 398c was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro- [1,1'-biphenyl]-4-yl)acetate (398b) (from previous step-2) in MeOH (3 ml), using a solution of sodium hydroxide (40 mg, 0.997 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(3-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid (398c) (41 mg, 26% yield), HCl salt , as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (t, J=1.6 Hz, 1H), 7.94 (dt, J=7.6, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.77-7.67 (m, 3H), 7.61 (t, J =7.6 Hz, 1H), 7.54 (dt, J=7.9, 1.6 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H), 7.34-7 .24 (m, 3H), 7.19 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.39 (s, 2H), 4.15 (s, 2H), 3.63 (s, 2H). ¹⁹ F NMR (300 MHz, DMSO-d6) δ -115.49; MS (ESI+): 482 (M+1), 480 (M-1); analysis calculation for C30H24FNO4-HCl-H2O: C, 67.23; N, 5.08; Cl, 6.61; N, 2.61; observed: C, 66.94; N, 4.91; Cl, 7.09; N, 2.69.

Scheme-399

399с 399d

Preparation of 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl)acetic acid (399d).

Stage-1. Preparation of methyl 2-(1-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)naphthalene-2-yl)acetate (399b).

Compound 399b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (426 mg, 1.206 mmol) in DCM (20 ml) using triphenylphosphine (431 mg, 1.644 mmol) methyl 2-(1-hydroxynaphthalene-2-yl)acetate (399a) (237 mg, 1.096 mmol; CAS No. 888739-82-0) and (E)-bis(4- chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 604 mg, 1.644 mmol). This resulted, after workup and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 20% hexanes), methyl 2-(1((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl )benzofuran-5-yl)methoxy)naphthalene-2-yl)acetate (399b) (75 mg) as a colorless oil; MS (ESI+) 574 (M+Na).

Stage-2. Preparation of methyl 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2yl)acetate (399c).

Compound 399c was prepared according to the procedure described in step-3 of scheme-305 from methyl 2-(1-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)naphthalene-2yl)acetate (399b) (75 mg, from previous step-1) in MeOH (5 ml), using HCl (4 M in dioxane; 1.096 ml, 4.38 mmol) and stirring at 40°C in for 1 hour. This resulted in the production, after treatment, of methyl 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl)acetate (399c); MS (ESI+): 452 (M+1).

Stage-3. Preparation of 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2yl)acetic acid (399d).

Compound 399d was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl) acetate (399c) (from previous step-2) in MeOH (3 ml), using a solution of sodium hydroxide (132 mg, 3.29 mmol) in water (1 ml). This resulted in, after work-up and purification by reverse phase chromatography,

- 491 045626 column [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(1-((7-(3(aminomethyl)phenyl)benzofuran-5- yl)methoxy)naphthalene-2-yl)acetic acid (399d) (18 mg, 4% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.19-8.07 (m, 2H), 8.05-8.00 (m, 1H), 8.00-7.87 (m, 3H) , 7.79-7.67 (m, 2H), 7.67-7.51 (m, 4H), 7.47 (dd, J=8.4, 2.5 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 5.17 (s, 2H), 4.16 (s, 2H), 3.84 (s, 2H); MS (ESI+): 438 (M+1), 436 (M-1).

Scheme-400

400d 400e

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-1-yl)acetic acid (400e).

Stage-1. Preparation of methyl 2-(2-hydroxynaphthalene-1-yl)acetate (400b).

Compound 400b was prepared according to the procedure described in step-3 of Scheme-305 from naphtho[2,1-b]furan-2(1H)-one (400a) (170 mg, 0.923 mmol; CAS No. 4352-63- 0) in MeOH (10 ml), using HCl (4 M in dioxane; 2.307 ml, 9.23 mmol) and stirring at 60°C for 1 hour. This resulted in the preparation after workup of methyl 2-(2-hydroxynaphthalene- 1-yl)acetate (400b) (200 mg, 100% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 7.78 (td, J=7.2, 6.6, 1.2 Hz, 2H), 7.71 ( d, J=8.8 Hz, 1H), 7.44 (ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.28 (ddd, J=8.0, 6, 8, 1.0 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 4.03 (s, 2H), 3.59 (s, 3H).

Stage-2. Preparation of methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)naphthalene-1-yl)acetate (400c).

Compound 400c was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (345 mg, 0.977 mmol) in DCM (15 ml) using triphenylphosphine (349 mg, 1.332 mmol) methyl 2-(2-hydroxynaphthalene-1-yl)acetate (400b) (192 mg, 0.888 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2- dicarboxylate (DCAD, 489 mg, 1.332 mmol). This resulted, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 20% hexanes), methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)benzofuran-5-yl)methoxy)naphthalene-1-yl)acetate (400c) as a colorless oil; MS (ESI+) 574 (M+Na).

Stage-3. Preparation of methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-1yl)acetate (400d).

Compound 400d was prepared according to the procedure described in step-3 of scheme-305 from methyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)naphthalene-1yl)acetate (400c) (from previous step-2) in MeOH (5 ml), using HCl (4 M in dioxane; 1.110 ml, 4.44 mmol) and stirring at 40°C for 1 hour This gave, after treatment, methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-1-yl)acetate (400d); MC (ESI+) 452 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-1yl)acetic acid (400e).

Compound 400e was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-1-yl) acetate (400d) (from previous step-3) in MeOH (3 ml), using a solution of sodium hydroxide (107 mg, 2.66 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(2-((7- (3-492 045626 (aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-1-yl)acetic acid (400e) (53 mg, 14% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.97-7.84 (m, 4H), 7.81 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.64-7.46 (m, 4H) , 7.37 (ddd, J=8.0, 6.8, 1.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.44 (s, 2H), 4.14 (s, 2H), 4.08 (s, 2H); MS (ESI+): 438 (M+1), 436 (M-1); analysis calculation for C28H23NO4-HCl-1.25H ₂ O: C, 67.74; N, 5.38; Cl, 7.14; N, 2.82; observed: C, 67.54; N, 5.31; Cl, 7.20; N,2.93.

Scheme-401, CO ₂ Me

CO ₂ Me

PPh ₃ , DCAD

CO ₂ Me

Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl)acetic acid (401e).

Stage-1. Preparation of methyl 2-(3-hydroxynaphthalene-2-yl)acetate (401b).

Compound 401b was prepared according to the procedure described in step-3 of Scheme-305 from naphtho[2,3-b]furan-2(3H)-one (401a) (100 mg, 0.543 mmol; CAS No. 4420-43- 3) in MeOH (10 ml), using HCl (4 M in dioxane; 1.357 ml, 5.43 mmol) and stirring at 60°C for 1 hour. This resulted in the preparation after workup of methyl 2-(3-hydroxynaphthalene- 2-yl)acetate (401b) (114 mg, 97% yield) as a purple solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 7.76-7.61 (m, 3H), 7.36 (ddd, J=8.1, 6.8 , 1.4 Hz, 1H), 7.25 (ddd, J=8.1, 6.8, 1.3 Hz, 1H), 7.12 (s, 1H), 3.74 (s, 2H) , 3.61 (s, 3H).

Stage-2. Preparation of methyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)methoxy)naphthalene-2-yl)acetate (401c).

Compound 401c was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (205 mg, 0.580 mmol) in DCM (20 ml) using triphenylphosphine (207 mg, 0.791 mmol), methyl 2-(3-hydroxynaphthalene-2-yl)acetate (401b) (114 mg, 0.527 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2 -dicarboxylate (DCAD, 290 mg, 0.791 mmol). This resulted, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0% to 20% hexanes), methyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl)acetate (401c) (108 mg) as a colorless oil; MS (ESI+) 574 (M+Na).

Stage-3. Preparation of methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2yl)acetate (401d).

Compound 401d was prepared according to the procedure described in step-3 of scheme-305 from methyl 2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl) methoxy)naphthalene-2yl)acetate (401c) (108 mg, from previous step-2) in MeOH (5 ml), using HCl (4 M in dioxane; 0.659 ml, 2.64 mmol) and stirring at 40°C in for 1 hour. This gave, after treatment, methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl)acetate (401d); MS (ESI+) 452 (M+1).

Stage-4. Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2yl)acetic acid (401e).

Compound 401e was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl) acetate (401 d) (from previous step-3) in MeOH (3 ml), using a solution of sodium hydroxide (63 mg, 1.582 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with ACN in water (with 0.1% HCl) from 0% to 60%] 2-(3-((7- (3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalene-2-yl)acetic acid (401e) (49 mg, 21% yield), HCl salt, as a pale yellow solid.

- 493 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 (d, J=2.2 Hz, 1H), 8.02 (d, J=1.7 Hz, 1H), 7.96 (dt, J=7.5, 1.5 Hz,

1H), 7.85-7.80 (m, 2H), 7.80-7.75 (m, 2H), 7.71 (d, J=1.7 Hz, 1H), 7.61 (t , J=7.7 Hz, 1H), 7.53 (dt, J=7.5, 1.4

Hz, 1H), 7.50-7.40 (m, 2H), 7.35 (ddd, J=8.0, 6.9, 1.3 Hz, 1H), 7.08 (d, J= 2.2 Hz, 1H), 5.40 (s, 2H), 4.15 (s, 2H),

3.77 (s, 2H); MS (ESI+): 438 (M+1), 436 (M-1); analysis calculation for C ₂₈ H ₂₃ NO ₄ -HCl-1.5H ₂ O: C, 67.13; N, 5.43; Cl, 7.08; N, 2.80; observed: C, 67.24; N, 5.24; Cl, 7.18; N, 2.90.

Scheme-402

402e 402f (+)-isomer

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (402f).

Stage-1. Preparation of (S)-N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2sulfinamide (402b).

Compound 402b was prepared according to the procedure described in Step-1 of Scheme-258 from 1-(3bromo-2-fluorophenyl)-2-fluoroethanone (402a) (250 mg, 1.064 mmol; CAS No. 1646556-83-3; prepared in accordance with the method described by Belanger, David B. et al., int. patent application, 2015009977, January 22, 2015) and (S)-2-methylpropane-2-sulfinamide (258 mg, 2.127 mmol) in tetrahydrofuran (15 ml) using tetraethoxytitanium (728 mg, 3.19 mmol) by heating at 65°C for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in hexanes from 0 to 10%) (8)-L-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2methylpropane-2-sulfinamide (402b) (80 mg) as a yellow oil; MS (ESI+): 360/362 (M+Na).

Stage-2. Preparation of (+)-(S)-N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2sulfinamide (402c).

Compound 402c was prepared according to the procedure described in step-2 of Scheme-258 from (S)N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (402b ) (80 mg, from previous step-1) in tetrahydrofuran (5 ml), using sodium borohydride (80 mg, 2.127 mmol). This resulted in (+)-(S)-N-(1-(3-bromo-2-fluorophenyl) )-2-fluoroethyl)-2methylpropane-2-sulfinamide (402c) (53 mg, 15% yield) as an orange oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.67 (dtd, J=8.2, 6.8, 1.4 Hz, 1H), 7.57 (dtd, J=15.9, 7, 2, 6.5, 1.6 Hz, 1H), 7.21 (tt, J=7.8, 1.6 Hz, 1H), 6.01 (dd, J=58.3, 8.1 Hz , 1H), 4.94-4.77 (m, 1H), 4.77-4.41 (m, 2H), 1.10 (d, J=5.4 Hz, 9H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.79, -218.57; MS (ESI+) 340/342 (M+1); optical rotation [a] _D = +24 (c = 0.025, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (402d) .

Compound 402d was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (75 mg, 0.171 mmol) in dioxane (4 ml) using (+)-(S)-N-(1-(3-bromo-2-fluorophenyl )-2-fluoroethyl)-2- 494 045626 methylpropane-2-sulfinamide (402c) (53 mg, 0.156 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (11 mg, 0.016 mmol) and K ₂ CO ₃ solution (65 mg, 0.467 mmol) in water (1 ml) under a nitrogen atmosphere while heating at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-40% EtOAc in hexane), ethyl 2-(2-((7-(3-(1-((S)1,1 -dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (402d) (53 mg) as a colorless oil; MS (ESI+): 570 (M+1).

Stage-4. Preparation of methyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (402e).

Compound 402e was prepared according to the procedure described in step-10 of scheme-257 from ethyl 2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinαamido)-2-fluoroethyl) -2-fluorophenyl)benzofurαn-5yl)methoxy)phenyl)acetate (402d) (53 mg, from previous step-3) in MeOH (5 ml) using HCl (4 M in 1,4-dioxane, 0.389 ml, 1.558 mmol) when heated at 40°C for 1 hour. This resulted in the preparation after treatment of methyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl) methoxy)phenyl)acetate (402e); MS (ESI+) 452 (M+1).

Stage-5. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (402f).

Compound 402f was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl )methoxy)phenyl)acetate (402e) (from previous step-4) in MeOH (3 ml), using a solution of NaOH (18.69 mg, 0.467 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in _H2O with 0.1% HCl) (+)-2-(2-((7- (3-(1-amino-2-fluoroethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (402f) (31 mg, 46% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.80-7.69 (m, 2H), 7.537.45 (m, 2H), 7.28-7.18 (m, 2H), 7.14-7.04 (m, 2H), 6.91 (td, J=7 .4, 1.1 Hz, 1H), 5.27 (s, 2H), 5.07-4.89 (m, 2H), 4.83-4.74 (m, 1H), 3.58 ( s, 2H); MS (ESI+): 438 (M+1), 436 (M-1); analysis calculation for C25H21F2NO4-1.15HCl-2H2O: C, 58.26; N, 5.11; Cl, 7.91; N, 2.72; observed: C, 58.52; N, 4.85; Cl, 7.76; N,

2.73; optical rotation [a] _D = +3.02 (c = 0.265, MeOH).

Scheme-403

Preparation of (-)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (403e).

Stage-1. Preparation of (R)-N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpronan-2sulfinamide (403a).

Compound 403a was prepared according to the procedure described in Step-1 of Scheme-258 from 1-(3bromo-2-fluorophenyl)-2-fluoroethanone (402a) (729 mg, 3.10 mmol; CAS No. 1646556-83-3 ; prepared in accordance with the method described by Belanger, David B. et al.; int. patent application, 2015009977, January 22, 2015) and (R)-2-methylpropan-2-sulfinamide (752 mg, 6. 20 mmol) in tetrahydrofuran (15 ml) using tetraethoxytitanium (2123 mg, 9.31 mmol) by heating at 65°C for 16 hours. This resulted in 495 045626 after work-up and purification by flash column chromatography (silica gel, eluted with ethyl acetate in 0 to 10% hexanes) (R)-N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2methylpropane-2-sulfinamide (403a) as a yellow oil; MS (ESI+): 360/362 (M+Na).

Stage-2. Preparation of (R)-N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (403b).

Compound 403b was prepared according to the procedure described in step-2 of Scheme-258 from (R)N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (403a ) (from previous step-1) in tetrahydrofuran (15 ml) using sodium borohydride (235 mg, 6.20 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with ethyl acetate in 0 to 40% hexanes), (R)-N-(1-(3-bromo-2-fluorophenyl)-2- fluoroethyl)-2methylpropane-2-sulfinamide (403b) (202 mg, 19% yield) as an orange oil;

¹ H NMR (300 MHz, DMSO-d6) δ 7.67 (dtd, J=8.1, 6.7, 1.3 Hz, 1H), 7.57 (ddd, J=15.8, 8, 3, 6.6, 1.6 Hz, 1H), 7.21 (tdd, J=7.8, 1.9, 1.0 Hz, 1H), 6.01 (dd, J=58.4, 8.0 Hz, 1H), 4.86 (dt, J=14.7, 6.6 Hz, 1H), 4.77-4.40 (m, 2H), 1.10 (dd, J=5 .5, 0.7 Hz, 9H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.78, -218.58; MS (ESI+): 340/342 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfunamudo)-2-fluoroethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (403c) .

Compound 403c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-5-yl)methoxy)phenyl)acetate (59a) (130 mg, 0.297 mmol) in dioxane (4 ml) using (R)-N-(1-(3-bromo-2-fluorophenyl)-2- fluoroethyl)-2methylpropane-2-sulfinamide (403b) (92 mg, 0.270 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (19 mg, 0.027 mmol) and a solution of K ₂ CO ₃ (112 mg, 0.811 mmol) in water ( 1 ml) in a nitrogen atmosphere when heated at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-20% EtOAc in hexane), ethyl 2-(2-((7-(3-(1((R)-1,1 -dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (403c) (103 mg) as a colorless oil; MS (ESI+) 592 (M+Na).

Stage-4. Preparation of methyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (403d).

Compound 403d was prepared according to the procedure described in step-10 of Scheme-257 from ethyl 2-(2-((7-(3-(1-(R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)- 2-Fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (403c) (103 mg, from previous step-3) in MeOH (5 ml) using HCl (4 M in 1,4-dioxane, 0.676 ml, 2. 70 mmol) when heated at 40°C for 1 hour. This resulted in the preparation after treatment of methyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl )methoxy)phenyl)acetate (403d); MC (ESI+) 452 (M+1).

Stage-5. Preparation of (-)-2-(2-((7-(3 -(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (403e).

Compound 403e was prepared according to the procedure described in step-4 of Scheme-4 from methyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl )methoxy)phenyl)acetate (403d) (from previous step-4) in MeOH (3 ml), using a solution of NaOH (32 mg, 0.811 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in _H2O with 0.1% HCl) (-)-2-(2-((7- (3-(1-amino-2-fluoroethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (403e) (73 mg, 62% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.75 (dtd, J =12.4, 7.5, 1.7 Hz, 2H), 7.55-7.43 (m, 2H), 7.29-7.18 (m, 2H), 7.14-7.03 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 5.09-4.87 (m, 2H), 4, 86-4.71 (m, 1H), 3.58 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO46) δ -118.21, -223.44; MS (ESI+): 438 (M+1), (ESI-): 436 (M-1); analysis calculation for C ₂₅ H ₂ 1F ₂ NO4-HCl-1.75H ₂ O: C, 59.41; H, 5.09; Cl, 7.01; N, 2.77; observed: C, 59.46; N, 4.93; Cl, 7.12; N, 2.76; optical rotation [a] _D = -1.724 (c = 0.58, MeOH).

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Scheme-404

Preparation of 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetic acid (404c).

Stage-1. Preparation of methyl 2-(2-((((benzyloxy)carbonyl)(7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate (404a).

To a solution of methyl 2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)amino)methyl)phenyl)acetate (378a) (320 mg, 0.64 mmol) in DCM (10 ml) was added 30% CBz-Cl in PhMe (0.757 ml, 1.279 mmol) and iodine (3.24 mg, 0.013 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 ml), washed with saturated Na ₂ S ₂ O ₃ (25 ml), H2O (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo to give methyl 2-(2-((((benzyloxy)carbonyl )(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5yl)amino)methyl)phenyl)acetate (404a) (175 mg) as a colorless oil.

Stage-2. Preparation of methyl 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetate (404b).

Compound 404b was prepared according to the procedure described in step-3 of scheme-305 from methyl 2-(2-((((benzyloxy)carbonyl)(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl )benzofuran-5yl)amino)methyl)phenyl)acetate (404a) (175 mg, from previous step-1) in methanol (5 ml), using HCl (4 M in dioxane; 0.160 ml, 0.639 mmol) and stirring at 40 °C for 1 hour. This resulted in the production after treatment of methyl 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetate ( 404b).

Stage-3. Preparation of 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetic acid (404c).

Compound 404c was prepared according to the procedure described in step-4 of scheme-4 from methyl 2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino )methyl)phenyl)acetate (404b) (from previous step-2) in MeOH (3 ml), water (1 ml), using NaOH (26 mg, 0.639 mmol). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, 0-60% MeCN in H2O with 0.1% HCl) 2-(2-(((7-(3-(aminomethyl )phenyl)benzofuran-5yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetic acid (404c) (85 mg, 26% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (t, J=1.6 Hz, 1H), 7.94 (dt , J=7.6, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.77-7.67 (m, 3H), 7.61 (t, J=7.6 Hz, 1H), 7.54 (dt, J=7.9, 1.6 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H), 7.34- 7.24 (m, 3H), 7.19 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.39 (s , 2H), 4.15 (s, 2H), 3.63 (s, 2H); MS (ESI+): 521 (M+1), 519 (M-1).

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Scheme-405

Preparation of 2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (405e).

Stage-1. Preparation of (+)-(S)-N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2yl)methyl)-2-methylpropane-2-sulfinamide (405a).

Compound 405a was prepared according to the procedure described in step-3 of Scheme-1 from (7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (2.5 g, 9.12 mmol) in dioxane (50 ml) using (+)-(S)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2 -methylpropane-2-sulfinamide (220c) (2.90 g, 10.94 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.960 g, 1.368 mmol) and K2CO3 solution (3.78 g, 27.4 mmol) in water (6 ml) heat under N2 at 100°C for 11.5 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 9:1 ethyl acetate/methanol in hexanes (1:0 to 1:2)] (+)-(S)-N-((3- fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2methylpropan-2-sulfinamide (405a) (1.51 g, 44%) as yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (dd, J=4.9, 0.7 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.74 (dd, J=1.7, 0.8 Hz, 1H), 7.65 (t, J=5.3 Hz, 1H), 7.42 (s, 1H), 7.06 (d, J= 2.2 Hz, 1H), 5.85 (t, J=5.8 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.64 (d, J=5, 7 Hz, 2H), 4.40 (dd, J=5.8, 2.1 Hz, 2H), 1.11 (s, 9H); optical rotation [a]D = +35.56 (c = 0.315, MeOH).

Stage-2. Preparation of (+)-(S)-ethyl 2-(4-cyano-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy )phenyl)acetate (405b).

Compound 405b was prepared according to the procedure described in step-2 of Scheme-23 from (+)(S)-N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2 -yl)methyl)-2-methylpropane-2sulfinamide (405a) (440 mg, 1.170 mmol) in DCM (12 ml) using triphenylphosphine (460 mg, 1.754 mmol), ethyl 2-(4-cyano-2-hydroxyphenyl) acetate (257f) (240 mg, 1.170 mmol) and a solution of (E)-bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 644 mg, 1.754 mmol) in DCM (12 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 9:1 ethyl acetate/methanol in hexanes (1:0 to 1:1)] (+)-(S)-ethyl 2-( 4-cyano-2-((7-(2((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (405b) (594 mg, 90 %) in the form of a yellow resin;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=4.9 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.86 (d , J=1.6 Hz, 1H), 7.67 (t, J=5.2 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.52 (s, 1H ), 7.47-7.39 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 5.86 (t, J=5.7 Hz, 1H), 5.32 (s, 2H), 4.41 (dd, J=5.9, 2.0 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.72 (s, 2H) , 1.11 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 564.20 (M+1); optical rotation [a] _D = +25.12 (c = 0.43, MeOH).

Stage-3. Preparation of (S)-ethyl 2-(4-(aminomethyl)-2-((7-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl )acetate (405c).

Compound 405c was prepared according to the procedure described in step-2 of Scheme-256 from (+)(S)-ethyl 2-(4-cyano-2-((7-(2-((1,1-dimethylethylsulfinamido) methyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (405b) (500 mg, 0.887 mmol) in methanol (25 ml), using nickel(II) chloride hexahydrate (52.7 mg, 0.222 mmol) and sodium borohydride (201 mg, 5.32 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.192 ml, 1.774 mmol) to quench. This resulted in, after workup, purification by flash column chromatography [silica gel, eluted with chloroform/DMA80 (1:0 to 0:1)] (S)-ethyl 2-(4-(aminomethyl)-2-((7 -(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (405c) (124 mg, 25%). MS (ESI+): 568.20 (M+1).

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Stage-4. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)phenyl)acetate (405d).

To a solution of (s)-ethyl 2-(4-(aminomethyl)-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (405c) (120 mg, 0.211 mmol) in tetrahydrofuran (4 ml) was added 3N aq. HCl (0.211 mL, 0.634 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(4(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridine -4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (405d), which was used as is in the next step.

Stage-5. Preparation of 2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (405e).

Compound 405e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran- 5-yl)methoxy)phenyl)acetate (405d) (0.211 mmol, from previous step-4) in MeOH (5 ml), using a solution of lithium hydroxide monohydrate (72.3 mg, 1.688 mmol) in water (5 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted (1:0 to 0:1) MeCN in H ₂ O with 0.1% HCl) 2-(4-( aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (405e) (59 mg, 16% in 3 steps), HCl salt , as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.67-8.54 (m, 4H), 8.47 (s, 3H), 8.13 (d, J=2.2 Hz, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.42 (d, J=1 .6 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.02 (dd, J=7.7 , 1.5 Hz, 1H), 5.29 (s, 2H), 4.45-4.30 (m, 2H), 4.03-3.94 (m, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.35; MS (ESI+): 436.10 (M+1); MS (ESI-): 434.10 (M-1); analysis calculation for

C ₂ 4H ₂₂ FN3O4-3.0HCl-2.75H ₂ O: C, 48.50; N, 5.17; N, 7.07; detect: C, 48.71; N, 5.55; N, 6.53.

Scheme-406

Preparation of 2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (406e).

Stage-1. Preparation of (+)-(R,Z)-ethyl 2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (406a).

Compound 406a was prepared according to the procedure described in step-1 of Scheme-258 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (1,2 g, 2.58 mmol) and (R)-2methylpropane-2-sulfinamide (0.394 g, 3.23 mmol) in tetrahydrofuran (15 ml), using tetraethoxytitanium (1.084 ml, 5.17 mmol) and refluxing at for 14 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with ethyl acetate in hexanes (1:0 to 2:1)] (+)-(R,Z)-ethyl 2-( 2-((2-(((tert-butylsulfinyl)imino)methyl)7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (406a) (965 mg, 66%) as a yellow gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 7.96 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.85 ( d, J=1.5 Hz, 1H), 7.30-7.18 (m, 2H), 7.07 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td , J=7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.15-3.94 (m, 2H),

3.63 (s, 2H), 1.21 (s, 9H), 1.09 (t, J=7.1 Hz, 3H); optical rotation [a]D = +61.76 (c = 0.34, MeOH).

Stage-2. Preparation of (-)-(R)-ethyl 2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (406b).

Compound 406b was prepared according to the procedure described in step-2 of Scheme-258 from (+)(R,Z)-ethyl 2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7 -iodobenzofuran-5-yl)methoxy)phenyl)acetate (406a) (0.92 g, 1.621 mmol) in tetrahydrofuran (25 ml) using sodium borohydride (0.125 g, 3.24 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (-)-(R)-ethyl 2-(2- ((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (406b) (722 mg, 78%) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.69 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.30-7, 17 (m, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.97-6.86 (m, 2H), 5.99 (t, J=5.7 Hz, 1H ), 5.13 (s, 2H), 4.48-4.23 (m, 2H), 4.02 (k, J=7.1 Hz,

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2H), 3.61 (s, 2H), 1.15 (s, 9H), 1.08 (t, J=7.1 Hz, 3H); MS (ESI+): 570.00 (M+1); optical rotation [a]D = -10.34 (c = 0.29, MeOH).

Stage-3. Preparation of (-)-(R)-ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((1,1dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 406c).

Compound 406c was prepared according to the procedure described in step-3 of Scheme-1 from (-)-(R)ethyl 2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran- 5-yl)methoxy)phenyl)acetate (406b) (500 mg, 0.878 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (247 mg, 1.317 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (123 mg, 0.176 mmol) and a solution of K ₂ CO ₃ (364 mg, 2.63 mmol) in water (1.8 ml) under nitrogen atmosphere when heated at 100 ° C for 3 hours in an oil bath . This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 4:1)] (-)-(R)-ethyl 2-(2-((7- (3(aminomethyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (406c) (340 mg, 71%) as a colorless gum;

1H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.78-7.72 (m, 1H), 7.63 (d, J=1.6 Hz, 1H), 7 .54 (d, J=1.7 Hz, 1H), 7.49-7.36 (m, 2H), 7.29-7.17 (m, 2H), 7.14-7.05 (m , 1H), 6.93-6.87 (m, 1H), 6.86 (s, 1H), 5.97 (t, J=5.4 Hz, 1H), 5.22 (s, 2H) , 4.35 (d, J=5.6 Hz, 3H), 3.93 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.62 (s, 2H) , 1.15 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 549.20 (M+1); optical rotation [a] _D = -21.33 (c = 0.15, MeOH).

Stage-4. Preparation of ethyl 2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (406d).

Compound 406d was prepared according to the procedure described in step-10 of Scheme-257 from (-)(R)-ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((1, 1-Dimethylethylsulfinamido)methyl)benzofuran-5yl)methoxy)phenyl)acetate (406c) (310 mg, 0.565 mmol) in THF (5 ml) using 3N aq. HCl (0.565 ml, 1.695 mmol) and stirring at room temperature for 3 hours. This resulted in the preparation after workup of ethyl 2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (406d), which was used as is in the next step without further purification.

Stage-5. Preparation of 2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (406e).

Compound 406e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl )acetate (406d) (0.565 mmol, from previous step-4) in MeOH/THF (10 ml each), using a solution of lithium hydroxide monohydrate (194 mg, 4.52 mmol) in water (10 ml) and stirring at room temperature for 15 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18, 100 g, eluted with MeCN in H ₂ O with 0.1% HCl (1:0 to 0:1)] 2-(2-((2-(aminomethyl)-7(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (406e) (115 mg, 81%), HCl salt, as white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.67 (s, 6H), 8.20-8.17 (m, 1H), 7.98 (dt, J=7.3, 1.8 Hz , 1H), 7.76 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.62-7.51 (m, 2H), 7 .23 (s, 1H), 7.21 (s, 1H), 7.11-7.05 (m, 2H), 6.94-6.87 (m, 1H), 5.27 (s, 2H ), 4.31 (s, 2H), 4.16 (s, 2H), 3.60 (s, 2H); MS (ESI+): 417.10 (M+1); MS (ESI-): 415.20 (M-1); analysis calculation for C ₂ 5H ₂ 4N2O4 1.95HCl 1.5H2O: C, 58.35; N, 5.67; Cl, 13.43; N, 5.44; observed: C, 58.27; N, 5.37; N, 5.33; Cl, 13.13.

Scheme-407

407c 407d

Preparation of 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetic acid (407d).

Stage-1. Preparation of 7-bromobenzofuran-5-carbonyl azide (407a)

Diphenylphosphoryl azide (0.461 ml, 2.074 mmol) was added to a suspension of 7-bromobenzofuran-5carboxylic acid (15a) (500 mg, 2.074 mmol), TEA (0.289 ml, 2.074 mmol) in THF (40 ml), stirred at room temperature temperature for 18 hours. The reaction mixture was concentrated in vacuo to form 7-bromobenzofuran-5-carbonyl azide (407a), which was used as is in the next step.

Stage-2. Preparation of methyl 2-(1-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate (407b)

A suspension of 7-bromobenzofuran-5-carbonyl azide (407a) (2.074 mmol, from previous step-1) in toluene (60 ml) was refluxed for 0.5 h. The reaction mixture was cooled to room temperature and triethylamine (0.442 ml) was added , 3.17 mmol), methyl 2(pyrrolidin-2-yl)acetate hydrochloride (120 mg, 0.635 mmol; CAS No. 1263378-78-4) and refluxed for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (120 ml), washed with water (75 ml), brine (75 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give methyl 2-(1-((7bromobenzofuran-5-yl)carbamoyl)pyrrolidin-2-yl )acetate (407b) (241 mg, 30% yield in 2 steps) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H), 7.72 (dd, J=2.0, 0.5 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 4.30-4.16 (m, 1H ), 3.59 (s, 3H), 3.53-3.25 (m, 2H), 2.79 (dd, J=15.3, 4.0 Hz, 1H), 2.39 (dd, J=15.3, 9.5 Hz, 1H), 2.13-1.57 (m, 4H); MS (ESI+): 381.00 and 382.00 (M+1).

Stage-3. Preparation of methyl 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)carbamoyl)pyrrolidin-2-yl)acetate (407c).

Compound 407c was prepared according to the procedure described in step-3 of Scheme-1 from methyl 2-(1-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate (407b) (235 mg, 0.616 mmol) in dioxane (12 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (173 mg, 0.925 mmol), solution of K2CO3 (256 mg, 1.849 mmol) in water (1.2 ml), Pd( PPh ₃ ) ₂ Cl ₂ (87 mg, 0.123 mmol) and heating under nitrogen at 100°C for 3 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (from 1:0 to 4:1)] methyl 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate (407c) (66 mg, 26 % yield) as a white solid; MS (ESI+): 408.20 (M+1).

Stage-4. Preparation of 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2yl)acetic acid (407d).

Compound 407d was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl) acetate (407c) (63 mg, 0.155 mmol) in MeOH/THF (4 mL each), using a solution of lithium hydroxide monohydrate (40 mg, 0.928 mmol) in water (4 mL) and stirring at room temperature for 19 hours. This gave, after work-up and purification by reverse-phase column chromatography [C18, 100 g, eluted with MeCN in H ₂ O with 0.1% HCl (1:0 to 0:1)] 2-(1-( (7-(3-(aminomethyl)phenyl)benzofuran-5yl)carbamoyl)pyrrolidin-2-yl)acetic acid (407d) (10 mg, 16%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.31 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.93-7 .90 (m, 1H), 7.84 (dt, J=7.5, 1.6 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.63-7.50 (m, 2H), 7.00 (d, J=2.2 Hz, 1H), 4.30-4.18 (m, 1H ), 4.18-4.06 (m, 2H), 3.57-3.45 (m, 2H), 2.79 (dd, J=15.7, 3.6 Hz, 1H), 2, 29 (dd, J=15.6, 9.8 Hz, 1H), 2.10-1.65 (m, 4H); MS (ESI+): 394.10 (M+1); MS (ESI-): 392.15 (M-1).

Scheme-408

Preparation of (R)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1yl)acetic acid (408e).

Stage-1. Preparation of ((R)-tert-butyl 2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1carboxylate (408a).

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Compound 408a was prepared according to the procedure described in step-4 of Scheme-1 from 7-bromobenzofuran-5-amine hydrochloride (216b) (240 mg, 0.966 mmol) in DMF (12 ml) using (R)-1(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (260 mg, 1.207 mmol), DIPEA (0.673 ml, 3.86 mmol) and HATU (551 mg, 1.449 mmol) and stirring at room temperature for 19 hours. This resulted in treatment and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] ((R)-tert-butyl 2-((7-bromobenzofuran-5yl)carbamoyl)pyrrolidine-1 -carboxylate (408a) (342 mg, 87%) as a colorless gum;

^1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.96-7.89 (m, 1H), 7.84-7.77 (m, 1H), 7.11-7.06 (m, 1H), 4.31-4.12 (m, 1H), 3.50-3.27 (m, 2H ), 2.29-2.06 (m, 1H), 1.95-1.72 (m, 3H), 1.40 (s, 3H), 1.27 (s, 6H); MS (ESI-): 406.90 (M-1).

Stage-2. Preparation of (R)-N-(7-bromobenzofuran-5-yl)pyrrolidin-2-carboxamide (408b).

Compound 408b was prepared according to the procedure described in step-5 of Scheme-1 from ((R)tert-butyl 2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (408a) (330 mg , 0.806 mmol) using TFA (0.621 ml, 8.06 mmol) in DCM (15 ml) This resulted in (R)-N-(7-bromobenzofuran-5-yl)pyrrolidin-2-carboxamide ( 408b), which was used as is in the next stage.

Stage-3. Preparation of (R)-ethyl 2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408c).

Compound 408c was prepared according to the procedure described in Step-1 of Scheme-382 (R)-N(7-bromobenzofuran-5-yl)pyrrolidin-2-carboxamide (408b) (249 mg, 0.806 mmol), ethyl 2-bromoacetate (0.134 ml, 1.209 mmol), K ₂ CO ₃ (557 mg, 4.03 mmol) in DMF (8 ml) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography, [ silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] (R)-ethyl 2-(2((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408c) (234 mg, 74% in two stages) in the form of a colorless resin;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 4.11 (k, J=7.1 Hz, 2H) , 3.72-3.44 (m, 3H), 3.24-3.09 (m, 1H), 2.78-2.59 (m, 1H), 2.30-2.06 (m, 1H), 1.96-1.67 (m, 3H), 1.19 (t, J=7.1 Hz, 3H); MS (ESI+): 395.00 (M+1).

Stage-4. Preparation of (R)-ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl)carbamoyl)pyrrolidin-1-yl)acetate (408d).

Compound 408d was prepared according to the procedure described in step-3 of Scheme-1 from (R)ethyl 2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408c) ( 220 mg, 0.557 mmol) in dioxane (10 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (156 mg, 0.835 mmol), K ₂ CO ₃ (231 mg, 1.670 mmol) in water (1 ml) and bis(triphenylphosphine)palladium(P) chloride (78 mg, 0.111 mmol) under nitrogen atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 9:1)] (R)-ethyl 2-(2-((7-(3(aminomethyl )phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408d) (97 mg, 41%) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.79-7.76 (m, 1H), 7.72-7.65 (m, 2H), 7.47 (t, J=7.5 Hz, 1H), 7.43-7 .36 (m, 1H), 7.03 (d, J=2.2 Hz, 1H), 4.11 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3 .74-3.44 (m, 3H), 3.26-3.13 (m, 1H), 2.79-2.62 (m, 1H), 2.30-2.09 (m, 1H) , 1.98-1.64 (m, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI+): 422.100 (M+1).

Stage-5. Preparation of (R)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin1-yl)acetic acid (408e).

Compound 408e was prepared according to the procedure described in step-6 of Scheme-1 from (R)ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidine-1 -yl)acetate (408d) (90 mg, 0.214 mmol) in MeOH/THF (5 mL each), using a solution of lithium hydroxide monohydrate (54.9 mg, 1.281 mmol) in water (5 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted (1:0 to 0:1) ACN in water (with 0.1% HCl)] (R)2-(2 -((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetic acid (408e) (14 mg, 17%), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.51 (s, 3H), 8.09 (d, J=2.2 Hz, 1H), 8.01 ( d, J=2.0 Hz, 1H), 7.92 (s, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.64-7.56 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 4.50 (s, 1H), 4.43-4.02 (m, 4H) , 3.72 (s, 2H), 2.67-2.56 (m, 1H), 2.20-2.03 (m, 2H), 1.96 (s, 1H); MS (ESI+): 394.20 (M+1); MS (ESI-): 392.10 (M-1).

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Scheme-409

409d 409e 409f

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetic acid (409f).

Stage-1. Preparation of 6-(hydroxymethyl)-2-methylbenzofuran-4-ol (409b).

Compound 409b was prepared according to the procedure described in step-1 of scheme-115 from methyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (409a) (2.4 g, 11.64 mmol; CAS No. 314725-17-2 ) in THF (40 ml), using lithium aluminum hydride (0.663 g, 17.46 mmol) and stirring at RT for 21 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate ( 1:0 to 1:1)] 6-(hydroxymethyl)-2methylbenzofuran-4-ol (409b) (1.40 g, 68%) as a yellow solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.66 (s, 1H), 6.87-6.84 (m, 1H), 6.55-6.52 (m, 1H), 6. 51-6.49 (m, 1H), 5.12 (t, J=5.8 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 2.38 (d, J =1.2 Hz, 3H); MS (ESI+): 201.20 (M+1).

Stage-2. Preparation of 6-(hydroxymethyl)-2-methylbenzofuran-4-yl trifluoromethanesulfonate (409c).

Compound 409c was prepared according to the procedure described in step-2 of scheme-115 from 6(hydroxymethyl)-2-methylbenzofuran-4-ol (409b) (1.37 g, 7.69 mmol) in DMF (25 ml), using 1,1,1trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.80 g, 7.69 mmol), triethylamine (2.143 ml, 15.38 mmol) and stirring at RT for 16 hours. This resulted to obtain, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 4:1)] 6-(hydroxymethyl)-2-methylbenzofuran-4-yl trifluoromethanesulfonate (409c) (1.747 g , 73%) as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.62-7.56 (m, 1H), 7.28 (d, J=1.0 Hz, 1H), 6.66 (t, J=1 .2 Hz, 1H), 5.50 (s, 1H), 4.62 (s, 2H), 2.48 (d, J=1.2 Hz, 3H); MS (ESI-): 309.80 (M-1).

Stage-3. Preparation of ethyl 2-(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6yl)methoxy)phenyl)acetate (409d).

Compound 409d was prepared according to the procedure described in step-2 of Scheme-23 from 6(hydroxymethyl)-2-methylbenzofuran-4-yl trifluoromethanesulfonate (409c) (1.7 g, 5.48 mmol) in DCM (40 ml ), using triphenylphosphine (2.156 g, 8.22 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (1.481 g, 8.22 mmol) and (E)-bis(4-chlorobenzyl)diazen-1, 2-dicarboxylate (DCAD, 3.02 g, 8.22 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 5:1)] ethyl 2-(2-((2-methyl-4(((trifluoromethyl) sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (409d) (2.09 g, 81%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (t, J=1.0 Hz, 1H), 7.42 (d, J=1.1 Hz, 1H), 7.31-7, 18 (m, 2H), 7.097.01 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.74-6.67 (m, 1H), 5 .26 (s, 2H), 4.04-3.96 (m, 2H), 3.65 (s, 2H), 2.50 (d, J=1.0 Hz, 3H), 1.08 ( t, J=7.1 Hz, 3H); MS (ESI+): 473.00 (M+1).

Stage-4. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6yl)methoxy)phenyl)acetate (409e).

Compound 409e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (409d) (600 mg, 1.270 mmol) in dioxane (12 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (391 mg, 1.905 mmol), sodium bicarbonate solution (320 mg, 3.81 mmol) in water (1.2 ml), Pd(PPh ₃ ) ₂ Cl ₂ (267 mg, 0.381 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted in, after work-up and flash purification -column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 19:1)] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2methylbenzofuran-6-yl) methoxy)phenyl)acetate (409e) (208 mg, 37%) as a brown gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.63-7.50 (m, 2H), 7.37 (td, J=7.4, 2.0 Hz, 1H), 7.32-7 .17 (m, 4H), 7.117.07 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.44 (dt, J=2.3, 1 ,1 Hz, 1H), 5.23 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.63 (s, 2H), 2.45 (d, J=1.1 Hz, 3H), 1.92 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ESI+): 448.20 (M+1).

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Stage-5. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6yl)methoxy)phenyl)acetic acid (409f).

Compound 409f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl )acetate (409e) (180 mg, 0.402 mmol) in THF/MeOH (8 mL each), using a solution of lithium hydroxide monohydrate (101 mg, 2.413 mmol) in water (8 mL) and stirring at room temperature for 19 h This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-(( 4-(3-(aminomethyl)-2fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetic acid (409f) (128 mg, 70%), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.67-7.64 (m, 1H), 7.64-7.54 (m, 2H), 7.40 (t, J=7.7 Hz , 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.93 -6.87 (m, 1H), 6.58-6.54 (m, 1H), 5.27 (s, 2H), 4.16 (s, 2H), 3.58 (s, 2H), 2.46 (d, J=1.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-06) δ -118.94; MS (ESI+): 420.10 (M+1); MS (ESI-): 418.10 (M-1); analysis calculation for C ₂₅ H ₂₂ FNO ₄ -1.0HCl: C, 65.86; N, 5.08; N, 3.07; Cl, 7.78; observed: C, 65.42; N, 4.80; N, 3.15; Cl, 7.89.

Scheme-410

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4(aminomethyl)phenyl)acetic acid (410d).

Stage-1. Preparation of (-)-ethyl 2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl )acetate (410a).

Compound 410a was prepared according to the procedure described in step-2 of Scheme-23 from (-)(R)-N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl )ethyl)-2-methylpropane-2-sulfinamide (269f) (547 mg, 1.403 mmol) in DCM (12 ml), using triphenylphosphine (460 mg, 1.754 mmol), ethyl 2-(4cyano-2-hydroxyphenyl) acetate ( 257f) (240 mg, 1.170 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 644 mg, 1.754 mmol) in DCM (12 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 9:1 ethyl acetate/methanol in hexanes (1:0 to 1:1)] (-)-ethyl 2-(4-cyano- 2-((7-(3-(1-((R)-1,1dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (410a) (661 mg) as a white solid substances; MS (ESI+): 577.20 (M+1); optical rotation [a] _D = -3.12 (c = 0.685, MeOH).

Stage-2. Preparation of (-)-ethyl 2-(4-(aminomethyl)-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5 -yl)methoxy )phenyl)acetate (410b).

Compound 410b was prepared according to the procedure described in step-2 of Scheme-256 from (-)ethyl 2-(4-cyano-2-((7-(3-(1-((R)-1,1- dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (410a) (420 mg, 0.728 mmol) in methanol (22 ml), using nickel (II) chloride hexahydrate (43 mg, 0.182 mmol) and sodium borohydride (165 mg, 4.37 mmol) using N1(2-aminoethyl)ethane-1,2-diamine (0.157 mL, 1.457 mmol) to quench. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 6:1)] (-)-ethyl 2-(4-(aminomethyl)-2-(( 7-(3-(1-((R)-1,1dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (410b) (128 mg) as a white solid; MS (ESI+): 581.30 (M+1); optical rotation [a] _D = -2.20 (c = 0.27, MeOH).

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Stage-3. Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4(aminomethyl)phenyl)acetate (410c).

Compound 410c was prepared according to the procedure described in step-4 of scheme-405 from (-)ethyl 2-(4-(aminomethyl)-2-((7-(3-(1-((R)-1, 1-Dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (410b) (120 mg, 0.207 mmol) in tetrahydrofuran (4 ml) using 3N aq. HCl (0.207 ml, 0.620 mmol) and stirring at room temperature for 3 hours. This resulted in the preparation after workup of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran- 5-yl)methoxy)-4(aminomethyl)phenyl)acetate (410c), which was used as is in the next step. MS (ESI+): 477.10 (M+1).

Stage-4. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4(aminomethyl)phenyl)acetic acid (410d).

Compound 410d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)- 4-(aminomethyl)phenyl)acetate (410c) (0.099 g, 0.207 mmol) in MeOH (5 ml), using a solution of lithium hydroxide monohydrate (0.071 g, 1.656 mmol) in water (5 ml) and stirring at room temperature for 20 hours This resulted in, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted (1:0 to 0:1) MeCN in H ₂ O with 0.1% HCl) (+) -2-(2-((7-(3-(1-amino-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)acetic acid (410d) (43 mg, 13% per 4 stages), HCl salt, as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.01 (s, 3H), 8.46 (s, 3H), 8.13-8.10 (m, 2H ), 8.04-7.90 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.66 -7.60 (m, 2H), 7.42 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.07 (d, J= 2.2 Hz, 1H), 7.02 (dd, J=7.7, 1.5 Hz, 1H), 5.28 (s, 2H), 4.98-4.72 (m, 3H), 4.07-3.93 (m, 2H), 3.60 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -222.72; MS (ESI+): 449.10 (M+1); MS (ESI-): 447.10 (M1); analysis calculation for C ₂₆ H ₂₅ FN ₂ O ₄ -1.85HCl-3H ₂ O: C, 54.79; N, 5.81; N, 4.91; Cl, 11.51; observed: C,

54.41; N, 5.64; N, 4.71; Cl, 11.15; optical rotation [a] _D = +20.69 (c = 0.145, MeOH).

Scheme-411

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (411e).

Stage-1. Preparation of tert-butyl 2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a).

Compound 411a was prepared according to the procedure described in step-3 of Scheme-1 from (7bromobenzofuran-5-yl)methanol (23a) (4.1 g, 18.06 mmol) in dioxane (150 ml) using tert-butyl 2fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (6.34 g, 18.06 mmol), potassium carbonate solution (7.49 g, 54.2 mmol) in water (15 ml), Pd(PPh ₃ ) ₂ Cl ₂ (1.901 g, 2.71 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted in the following treatment and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 35% ethyl acetate in hexanes) tert-butyl 2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a) ( 3.14 g, 47% yield) as a light brown gummy solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.99 (d, J=2.2 Hz, 1H), 7.65 (dd, J=1.7, 0.9 Hz, 1H), 7, 52-7.24 (m, 4H), 7.01 (d, J=2.2 Hz, 1H), 5.28 (t, J=5.8 Hz, 1H), 4.68-4.58 (m, 2H), 4.26 (d, J=6.1 Hz, 2H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.94.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (411b).

Compound 411b was prepared according to the procedure described in step-2 of Scheme-23 from tert-505 045626 butyl 2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a) (434 mg, 1.170 mmol) in DCM (12 ml) using triphenylphosphine (460 mg, 1.754 mmol), ethyl 2-(4-cyano-2hydroxyphenyl) acetate (257f) (240 mg, 1.170 mmol) and solution of (E)-bis(4- chlorobenzyl)diazene-1,2dicarboxylate (DCAD, 644 mg, 1.754 mmol) in DCM (12 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 30% ethyl acetate in hexanes), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl )-2-fluorophenyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (411b) (527 mg, 81% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.63 (d , J=1.3 Hz, 1H), 7.54-7.29 (m, 7H), 7.07 (d, J=2.2 Hz, 1H), 5.30 (s, 2H), 4 .26 (d, J=6.1 Hz, 2H), 3.88 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.41 (s, 9H), 0 .94 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.79; MS (ESI+): 581.20 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (411c).

Compound 411c was prepared according to the procedure described in step-1 of Scheme-238 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5- yl)methoxy)-4cyanophenyl)acetate (411b) (200 mg, 0.358 mmol) in THF (9 ml) and water (0.8 ml), using acetamide (127 mg, 2.148 mmol), palladium(P) chloride (19 mg, 0.107 mmol) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in 0 to 5% DCM), ethyl 2-(2-( (7-(3(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetate (411c) (130 mg, 63.0%) as a white solid ;

1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.2 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J=1.6 Hz, 1H ), 7.63 (d, 1H), 7.55-7.26 (m, 8H), 7.06 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4 .26 (d, J=6.1 Hz, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.41 (s, 9H), 0 .96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -120.70; MS (ESI+): 599.20 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetate (411d).

Compound 411d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5- yl)methoxy)-4carbamoylphenyl)acetate (411c) (120 mg, 0.208 mmol) in DCM (8 ml) using TFA (0.309 ml, 4.16 mmol). This resulted in the production of ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (411d) upon treatment, which was used as is in the next step . MS (ESI+): 477.20 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (411e).

Compound 411e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl )acetate (411d) (0.208 mmol, from previous step-4) in THF/methanol (5 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (0.071 g, 1.664 mmol) in water (5 ml) and stirring at room temperature for 15 hours. This resulted in the following work-up and purification by reverse-phase column chromatography [C-18 column, eluted with water (with 0.1% W^/acetonitrile (1:0 to 0:1) )] 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetic acid (411e) (56 mg, 60% in 2 stages), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.48 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 8.00 (s , 1H), 7.84 (d, J=1.6 Hz, 1H), 7.69 (t, J=7.4 Hz, 2H), 7.61 (d, J=1.6 Hz, 1H ), 7.49 (s, 1H), 7.47-7.35 (m, 3H), 7.29 (d, J=7.8 Hz, 1H), 7.07 (d, J=2, 2 Hz, 1H), 5.32 (s, 2H), 4.23-4.12 (m, 2H), 3.63 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 118.26; MS (ESI+): 449.10 (M+1); analysis calculation for C ₂₅ H ₂₁ FN ₂ O ₄ -HCl-2H ₂ O: C, 57.64; H, 5.03; N, 5.38; Cl, 6.81; observed: C, 57.38; N, 4.84; N, 5.31; Cl, 6.55.

Scheme-412

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (412b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-506 045626 cyanophenyl)acetate (412a).

Compound 412a was prepared according to the procedure described in step-4 of Scheme-405 from (-)ethyl 2-(4-cyano-2-((7-(3-(1-((R)-1,1- dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (410a) (88 mg, 0.153 mmol) in THF (4 ml) using 3N aq. HCl (0.153 ml, 0.458 mmol) and stirring at room temperature for 4 hours. This resulted in the preparation after workup of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran- 5-yl)methoxy)-4cyanophenyl)acetate (412a), which was used as is in the next step. MS (ESI+): 473.20 (M+1).

Stage-2. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (412b).

Compound 412b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)- 4-cyanophenyl)acetate (412a) (0.153 mmol; from previous step-1) in MeOH/THF (4 ml each), using a solution of lithium hydroxide monohydrate (0.052 g, 1.224 mmol) in water (4 ml) and stirring at room temperature for 16 hours. This resulted in, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] ( +)-2-(2-((7(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (412b), HCl salt, (30 mg , 44% yield in 2 steps) HCl as a white solid.

1H NMR (300 MHz, DMSO-06) δ 8.12 (d, J=2.2 Hz, 1H), 8.05-8.02 (m, 1H), 7.97 (dt, J=7, 3, 1.7 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.68-7.56 (m, 4H), 7.48-7.38 (m, 2H ), 7.08 (d, J=2.2 Hz, 1H), 5.35 (s, 2H), 4.94-4.69 (m, 3H), 3.69 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -222.51; MS (ESI+): 445.10 (M+1); analysis calculation for C26H21FN ₂ O4-HCl-1.75H2O: C, 60.94; N, 5.02; N, 5.47; detect: C, 61.00; N, 4.96; N, 5.45; optical rotation [a] _D = +16.521 (c = 0.115, MeOH).

Scheme-413

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (413m) and 2-(2-((7-(3-( aminomethyl)phenyl)-4-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (413n).

Stage-1. Preparation of methyl 3-bromo-4-hydroxy-2-methylbenzoate (413a) and methyl 5-bromo-4-hydroxy2-methylbenzoate (413b).

Bromine (2.116 g, 13.24 mmol) was added to a solution of methyl 4-hydroxy-2-methylbenzoate (2.0 g, 12.04 mmol; CAS No. 57556-31-7) in DCM (10 mL) at 0°C. in DCM (5 ml) dropwise over 1 hour. The resulting mixture was stirred at rt for 2 hours, quenched with ice (30 g). The organic layer was separated, washed with H2O (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-10% EtOAc in hexanes) to give an unseparable 1:1 mixture of methyl 5-bromo-4-hydroxy-2methylbenzoate (413b) and methyl 3-bromo- 4-Hydroxy-2-methylbenzoate (413a) (2.90 g, 98% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) 11.28-10.81 (m, 2H), 7.97 (d, J=1.0 Hz, 1H), 7.68 (dd, J=8, 6, 1.0 Hz, 1H),

- 507 045626

6.94-6.76 (m, 2H), 3.77 (dd, J=3.2, 1.0 Hz, 6H), 2.59 (s, 3H), 2.43 (s, 3H) . LC-MC: t=2.38-2.41 min; MS (ESI-): 243/245.

Stage-2. Preparation of methyl 3-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413c) and methyl 5-bromo4-(2,2-diethoxyethoxy)-2-methylbenzoate (413d).

Compounds 413c and 413d were prepared according to the procedure described in step-1 of scheme-382 from a mixture containing methyl 3-bromo-4-hydroxy-2-methylbenzoate (413a) and methyl 5-bromo-4-hydroxy-2methylbenzoate (413b ) (2.90 g, 11.83 mmol; from Step-1 previously described), bromoacetaldehyde diethyl acetal (3.50 g, 17.75 mmol), K ₂ CO ₃ (3.27 g, 23.67 mmol) in DMF (10 ml) when heated at 80°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane from 0% to 15%] as an inseparable 1:1,2 mixture of methyl 3bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413c) and methyl 5-bromo-4-(2,2-diethoxyethoxy)-2methylbenzoate (413d) (3.08 g , 72.1% yield) as a clear, colorless oil: 1H NMR (300 MHz, DMSO-d ₆ , pure compound 413d) δ 8.01 (s, 1H), 7.15 (s, 1H), 4, 85 (t, J=5.3 Hz, 1H), 4.10 (d, J=5.3 Hz, 2H), 3.79 (s, 3H), 3.78-3.55 (m, 4H ), 2.51 (s, 3H), 1.15 (t, J=7.0 Hz, 6H); MS (ESI+): 383/385.

Stage-3. Preparation of methyl 7-bromo-6-methylbenzofuran-5-carboxylate (413e) and methyl 7-bromo-4methylbenzofuran-5-carboxylate (413f).

Compounds 413e and 413f were prepared according to the procedure described in step-2 of Scheme-390 from a mixture containing methyl 3-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413c) and methyl 5-bromo- 4-(2,2diethoxyethoxy)-2-methylbenzoate (413d) (3.08 g, 8.53 mmol; from Step-2 previously described) in anhydrous PhMe (30 ml) using Amberlyst 15 (0.869 g, 8.53 mmol) when heated at 130°C for 16 hours while removing water using a Dean-Stark apparatus. This resulted, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0% to 11% EtOAc in hexanes], of an inseparable 1:1.8 mixture of methyl 7-bromo-6-methylbenzofuran-5-carboxylate ( 413e) and methyl 7-bromo-4-methylbenzofuran-5-carboxylate (413f (0.59 g, 26% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ; mixture 1:1.8) δ 8.21 (d, J=2.1 Hz, 0.65H), 8.16 (d, J=2.2 Hz, 0.35Н), 8.11 (d, J=4.0 Hz, 0.35Н), 7.98 (s, 0.65Н), 7.37 (dd, J=2.3, 1.2 Hz , 0.65H), 7.16 (dd, J=2.2, 1.3 Hz, 0.35H), 3.86 (s, 1.05H), 3.85 (3, 1.95H), 2.69 (s, 1.95H), 2.65 (s, 0.35H).

Stage-4. Preparation of (7-bromo-6-methylbenzofuran-5-yl)methanol (413g) and (7-bromo-4methylbenzofuran-5-yl)methanol (413h).

Compounds 413g and 413h were prepared according to the procedure described in step-2 of Scheme-212 from a mixture containing methyl 7-bromo-6-methylbenzofuran-5-carboxylate (413e) and methyl 7-bromo-4methylbenzofuran-5-carboxylate ( 413f) (0.47 g, 1.747 mmol) in DCM (10 ml) using 1 M DIBAL-H in DCM (4.02 ml, 4.02 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0-20% EtOAc in hexane), an inseparable 1:1.8 mixture of (7-bromo-6-methylbenzofuran-5-yl)methanol (413g) and ( 7-bromo-4-methylbenzofuran-5-yl)methanol (413h) (0.38 g, 90% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ for pure compound 413h) δ 8.06 (d, J=2.2 Hz, 1H), 7.52 (s, 1H), 7.18 (dd, J=2 ,3, 0.6 Hz, 1H), 5.22 (t, J=5.4 Hz, 1H), 4.57 (d, J=5.0 Hz, 2H), 2.39 (s, 3H ).

Stage-5. Preparation of ethyl 2-(2-((7-bromo-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413i) and ethyl 2-(2-((7-bromo-4-methylbenzofuran-5-yl) methoxy)phenyl)acetate (413j).

Compounds 413i and 413j were prepared according to the procedure described in step-2 of Scheme-23 from a mixture containing (7-bromo-6-methylbenzofuran-5-yl)methanol (413g) and (7-bromo-4-methylbenzofuran- 5yl)methanol (413h) (380 mg, 1.576 mmol) in DCM (10 ml), using triphenylphosphine (827 mg, 3.15 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (369 mg, 2.049 mmol ) and (E)-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 1158 mg, 3.15 mmol). This resulted, after work-up and purification by flash column chromatography (silica gel, eluted with EtOAc in hexane from 0% to 15%) of an inseparable 1:1.8 mixture of ethyl 2-(2-((7-bromo-6-methylbenzofuran -5-yl)methoxy)phenyl)acetate (413i) and ethyl 2-(2-((7-bromo-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413j) (500 mg, 1.240 mmol, 79 % yield) in the form of a colorless oil, which solidified when left in air;

1H NMR (300 MHz, DMSO-d ₆ for pure compound 413j) δ 8.08 (d, J=2.2 Hz, 1H), 7.73 (s, 1H), 7.29 (dd, J=8 ,8, 7.1 Hz, 1H), 7.25-7.19 (m, 1H), 7.19-7.13 (m, 1H), 7.06 (dd, J=2.3, 1 .6 Hz, 1H), 6.93 (dd, J=7.9, 6.8 Hz, 1H), 5.19 (s, 2H), 3.91 (k, J=7.1 Hz, 2H ), 3.57 (s, 2H), 1.03-0.99 (m, 3H). LC-MS: t=2.97 min; MS (ESI+): 425/427 (M+Na).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5yl)methoxy)phenyl)acetate (413k) and ethyl 2-(2-((7-(3-(aminomethyl) )phenyl)-4-methylbenzofuran-5yl)methoxy)phenyl)acetate (413l).

Compounds 413k and 413l were prepared according to the procedure described in step-3 of Scheme-1 from a mixture containing ethyl 2-(2-((7-bromo-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413i ) and ethyl 2-(2((7-bromo-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413j) (290 mg, 0.719 mmol) in dioxane (4 ml), using 3-(aminomethyl) hydrochloride phenylboronic acid (6c) (162 mg, 0.863 mmol), K ₂ CO ₃ (298

- 508 045626 mg, 2.157 mmol) in water (1 ml) and bis(triphenylphosphine) palladium(P) chloride (51 mg, 0.072 mmol) in an Ar atmosphere when heated at 100 ° C for 16 hours in an oil bath. This resulted in a non-separable mixture of compounds 413k and 413l (272 mg) as a whitish colorless oil (272 mg); MS (ESI+): 430 (M+1).

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (413m) and 2-(2-((7-(3-(aminomethyl) phenyl)-4-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (413n).

Compounds 413m and 413n were prepared according to the procedure described in step-4 of Scheme-4 from a mixture containing ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5yl)methoxy) phenyl)acetate (413k) and ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5yl)methoxy)phenyl)acetate (413l) (272 mg, from previous step-6) in MeOH (4 ml) using NaOH (86 mg, 2.157 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography (C18 100 g, eluted with 0-60% MeCN in H2O with 0.1% HCl) 2(2-((7-(3-(aminomethyl)phenyl )-6-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (413t) (12 mg, 0.030 mmol, 4% yield), HCl salt, as a white solid: 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.63-7.49 (m, 3H), 7.41 (dt, J=6, 9, 1.8 Hz, 1H), 7.31-7.14 (m, 3H), 6.97 (d, J=2.2 Hz, 1H), 6.92 (td, J=7.4 , 1.2 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H), 2.24 (s, 3H); MS (ESI+): 402 (M+1), (ESI-): 400 (M-1) and 2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5yl)methoxy )phenyl)acetic acid (413n) (40 mg, 14% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.3 Hz, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.93 (dt, J =7.9, 1.5 Hz, 1H), 7.70 (s, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50 (dt, J=7.7, 1.5 Hz, 1H), 7.32-7.14 (m, 4H), 6.92 (td, J=7.3, 1.2 Hz, 1H), 5.24 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 2.54 (s, 3H); MS (ESI+): 402 (M+1) (ESI-): 400 (M-1).

Scheme-414

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (414b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (414a).

Compound 414a was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5- yl)methoxy)-4cyanophenyl)acetate (411b) (200 mg, 0.358 mmol) in DCM (10 ml) using TFA (0.532 ml, 7.16 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (414a), which was used as is in the next step . MS (ESI+): 459.15 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (414b).

Compound 414b was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl) acetate (414a) (0.358 mmol; from previous step-1) in MeOH/THF (5 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (123 mg, 2.86 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1) ] 2-(2-((7-(3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (414b) (74 mg, 48% yield) (74 mg, 48%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 3H), 8.07 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.77-7.63 (m, 2H), 7.60 (d, J=1.4 Hz, 1H), 7.49-7.31 (m, 4H), 7.07 (d , J=2.2 Hz, 1H), 5.34 (s, 2H), 4.17 (s, 2H), 3.68 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO4) δ -118.46; MS (ESI+): 446.20 (M+1); MS (ESI-): 431.10 (M-1); analysis calculation for C25H ₁₉ FN ₂ O ₄ -HCl-1.25H ₂ O: C, 61.35; N, 4.63; N, 5.72; observed: C, 61.22; N, 4.47; N, 5.60.

- 509 045626

Scheme-415

CH ₃

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (415e).

Stage-1. Preparation of 5-(chloromethyl)-7-iodo-2-(methoxymethyl)benzofuran (415a).

Compound 415a was prepared according to the procedure described in step-4 of Scheme-257 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (1.0 g, 3.14 mmol) in DCM ( 10 ml), to which SOCl ₂ (0.748 g, 6.28 mmol) was added at 0°C. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 1-2% EtOAc in n-heptane), 5(chloromethyl)-7-iodo-2-(methoxymethyl)benzofuran (415a) (0.90 g, 85.71%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.79 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.08 (s, 1H), 4.85 (s, 2H), 4.56 (s, 2H), 3.34 (s, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (415b).

Compound 415b was prepared according to the procedure described in step-6 of scheme-257 from 5(chloromethyl)-7-iodo-2-(methoxymethyl)benzofuran (415a) (0.5 g, 1.48 mmol) using ethyl 2 -(2hydroxy-4-methylphenyl)acetate (269d) (0.431 g, 2.22 mmol), Cs ₂ CO ₃ (0.482 g, 1.48 mmol) in DMSO (5 ml) and stirring at room temperature for 24 hours This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 1-3% EtOAc in nheptane), ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl) methoxy)-4-methylphenyl)acetate (415b) (0.5 g, 68.49%) as an off-white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.73 (s, 1H), 7.66 (s, 1H), 7.09 (d, J=7.0 Hz, 2H), 6.92 (s, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.12 (s, 2H), 4.56 (s, 2H), 4.07-3.94 (m, 2H), 3.55 (s, 2H), 3.35 (s, 3H), 2.29 (s, 3H), 1.07 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (415c).

Compound 415c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (415b ) (0.5 g, 1.01 mmol) in acetonitrile (12.5 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzylcarbamate ( 3b) (0.505 g, 1.51 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.070 g, 0.10 mmol) and a solution of Na ₂ CO ₃ (0.32 g, 3.03 mmol) in water (4 ml) and heating in a nitrogen atmosphere at 90°C for 2 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 1-3% EtOAc in n-heptane), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (415c) (0.30 g, 513%) as an off-white semi-solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78-7.65 (m, 3H), 7.58-7.43 (m, 3H), 7.31 (d, J=7.6 Hz , 1H), 7.09 (d, J=7.5 Hz, 1H), 6.98 (d, J=9.7 Hz, 2H), 6.73 (d, J=7.5 Hz, 1H ), 5.20 (s, 2H), 4.57 (s, 2H), 4.23 (d, J=6.3 Hz, 2H), 3.90 (k, J=7.2 Hz, 2H ), 3.56 (s, 2H), 3.33 (s, 3H), 2.30 (s, 3H), 1.39 (s, 9H), 0.96 (t, J=7.1 Hz , 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5

- 510 045626 yl)methoxy)-4-methylphenyl)acetate (415d).

Compound 415d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran -5-yl)methoxy)-4methylphenyl)acetate (415c) (150 mg, 0.261 mmol) in DCM (10 ml) using TFA (0.388 ml, 5.23 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (415d), which was used as is at the next stage. MS (ESI+): 474.20 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)4-methylphenyl)acetic acid (415e).

Compound 415e was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4 -methylphenyl)acetate (415d) (0.262 mmol; from previous step-4) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (90 mg, 2.095 mmol) in water (5 ml) and stirring at room temperature temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2- (2-((7(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (415e) (33 mg, 28%), HCl salt, in as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.45 (s, 3H), 7.96 (t, J=1.5 Hz, 1H), 7.92 ( dt, J=7.3, 1.7 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7, 61-7.52 (m, 2H), 7.09 (d, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J=1.6 Hz, 1H ), 6.72 (ddd, J=7.5, 1.5, 0.8 Hz, 1H), 5.23 (s, 2H), 4.58 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 3.33 (s, 3H), 2.29 (s, 3H); MS (ESI+): 446.20 (M+1); MS (ESI-): 444.10 (M-1); analysis calculation for C ₂₇ H ₂₇ NO ₅ -HCl-H ₂ O: C, 64.86; N, 6.05; N, 2.80; detect: C, 64.48; N, 5.85; N, 2.82.

Scheme-416

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (416d).

Stage-1. Preparation of tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7yl)benzylcarbamate (416a).

Compound 416a was prepared according to the procedure described in step-3 of Scheme-1 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (4.0 g, 12.57 mmol) in dioxane (75 ml) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (4.42 g, 12.57 mmol ), a solution of potassium carbonate (5.21 g, 37.7 mmol) in water (9 ml), Pd(PPh ₃ ) ₂ Cl ₂ (1.324 g, 1.886 mmol) and heating under nitrogen at 100°C for 3 This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 50% ethyl acetate in hexanes), tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-2-( methoxymethyl)benzofuran-7yl)benzylcarbamate (416a) (3.54 g, 68% yield) as a light brown tarry solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.61 (d, J=1.6 Hz, 1H), 7.53-7.23 (m, 5H), 6.96 (s, 1H), 5.27 (t, J=5.7 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 4.50 (s, 2H), 4.26 (d, J=6 .0 Hz, 2H), 3.28 (s, 3H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.16.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate ( 416b).

Compound 416b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (416a) (875 mg , 2.105 mmol) in DCM (20 ml) using triphenylphosphine (690 mg, 2.63 mmol), ethyl 2-(4-cyano-2hydroxyphenyl) acetate (257f) (360 mg, 1.754 mmol) and solution (E)- bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 966 mg, 2.63 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 0 to 30% ethyl acetate in hexanes), ethyl 2-(2-((7-(3-(((tert -butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (416b) (1.41 g) as an off-white waxy solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.52-7.29 (m, 6H), 7.01 (s, 1H), 5.29 (s, 2H), 4.52 (s, 2H), 4.26 (d, J =6.1 Hz, 2H), 3.88 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 3.29 (s, 3H), 1.41 (s, 9H ), 0.95 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (416c).

Compound 416c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-( methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (416b) (230 mg, 0.382 mmol) in DCM (15 ml) using TFA (0.567 ml, 7.63 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (416c), which used as is in the next stage. MS (ESI+): 503.20 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetic acid (416d).

Compound 416d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)-4-cyanophenyl)acetate (416c) (0.382 mmol, from previous step-3) in THF/methanol (7 ml, 1:1 each), using lithium hydroxide monohydrate solution (128 mg, 3.06 mmol) in water (7 ml) and stirring at room temperature for 20 hours. This resulted in the following work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (with 0.1% HCl)/acetonitrile (from 1 :0 to 0:1)] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (416d) (54 mg, 30% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 3H), 7.79 (d, J=1.6 Hz, 1H), 7.75-7.62 (m, 2H), 7 .59 (d, J=1.4 Hz, 1H), 7.48-7.29 (m, 4H), 7.02 (s, 1H), 5.33 (s, 2H), 4.52 ( s, 2H), 4.17 (s, 2H), 3.68 (s, 2H), 3.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.72; MS (ESI+): 475.20 (M+1); analysis calculation for C27H23FN2O5-HCM,75H2O: C, 59.78; N, 5.11; N, 5.16; Cl, 6.54; observed: C, 59.58; N, 4.73; N, 4.94; Cl, 6.83.

Scheme-417

Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (417e).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-methoxyphenyl)acetate (417a).

Compound 417a was prepared according to the procedure described in step-1 of scheme-224 from ethyl 2-(4-bromo-2-methoxyphenyl) acetate (391a) (3.5 g, 12.81 mmol) in dioxane (52.5 ml), using acetamide (1.53 g, 25.90 mmol), (Note: acetamide was dried over P ₂ O ₅ before use), Cs ₂ CO ₃ (12.52 g 38.42 mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-PHOS) (2.74 g, 5.74 mmol), Pd ₂ (dba) ₃ (1.76 g, 1.92 mmol) on heating at 105-110°C for 6 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 25% EtOAc in n-heptane), ethyl 2-(4-acetamido-2-methoxyphenyl) acetate (417a) (2.5 g, 78%) as a yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 4.04 (k, J=7.1, Hz, 2H), 3.70 (s, 3H), 3.50 (s, 2H), 2.01 (s, 3H), 1.17 (t, J=7.1, Hz, 3H); MS (ESI+): 252.1 (M+1); (ESI-) 250.1 (M-1).

- 512 045626

Stage-2. Preparation of ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b).

Compound 417b was prepared according to the procedure described in step-5 of scheme-257 from ethyl 2-(4-acetamido-2-methoxyphenyl)acetate (417a) (350 mg, 1.39 mmol) in dichloromethane (7 ml), using boron tribromide (0.6 ml, 1.395 g, 5.57 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 25% EtOAc in n-heptane), ethyl 2(4-acetamido-2-hydroxyphenyl)acetate (417b) (240 mg, 73%) as oily mass.

^1H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.50 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 6.97 ( d, J=8.2 Hz, 1H), 6.83 (dd, J=8.2, 2.1 Hz, 1H), 4.04 (k, J=7.1 Hz, 2H), 3, 45 (s, 2H), 2.01 (s, 3H), 1.27-1.11 (t, 3H).

Stage-3. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (417c) .

Compound 417c was prepared according to the procedure described in step-6 of scheme-257 from tert-butyl 3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (309d) (0.45 g, 1. 08 mmol), using ethyl 2-(4-acetamido-2-hydroxyphenyl) acetate (417b) (0.385 g, 1.62 mmol), Cs ₂ CO ₃ (0.351 g, 1.08 mmol) in DMSO (4, 5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 70-75% EtOAc in n-heptane), ethyl 2-(4-acetamido-2 -((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (417c) (0.3 g, 46%) in the form of a thick syrup;

1H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.67 (d, J=1.6 Hz, 1H ), 7.57-7.41 (m, 4H), 7.30 (d, J=7.8 Hz, 1H), 7.16-7.03 (m, 2H), 6.99 (s, 1H), 5.16 (s, 2H), 4.57 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.55 (s, 3H), 3.33 (s, 2H), 2.03 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H). MS (ESI+): 617.2 (M+1), (ESI-): 615.2 (M-1).

Stage-4. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (417d).

Compound 417d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2- (methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (417c) (250 mg, 0.405 mmol) in DCM (15 ml) using TFA (0.602 ml, 8.11 mmol). This gave, upon treatment, ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (417d), which was used at the next stage without additional purification; MS (ESI+): 517.20 (M+1).

Stage-5. Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (417e).

Compound 417e was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)phenyl)acetate (417d) (0.381 mmol; from previous step-4) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (131 mg, 3.05 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1) ] 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (417e) (32 mg, 17% yield ), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.99-7.91 (m, 2H), 7.73 (d, J=1.6 Hz, 1H), 7 .63 (d, J=1.8 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.56-7.49 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.2, 1.8 Hz, 1H), 7.00 (s, 1H), 5.19 (s, 2H), 4, 58 (s, 2H), 4.14 (s, 2H), 3.52 (s, 2H), 3.33 (s, 3H), 2.03 (s, 3H); MS (ESI+): 489.20 (M+1); MS (ESI-): 487.15 (M-1); analysis calculation for €28^8^06-^1^20: C, 58.08; N, 6.09; N, 4.84; Cl, 6.12; observed: C, 58.19; N, 5.89; N, 4.88; Cl, 6.37.

Scheme-418

Preparation of (S)-1H-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-1H-(3-chloro-2-513 045626 fluorobenzyl)pyrrolidine-1,2-dicarboxamide (418c).

Stage-1. Preparation of tert-butyl 3-(5-(azidocarbonyl)benzofuran-7-yl)benzylcarbamate (418a).

Compound 418a was prepared according to the procedure described in step-1 of scheme-143 from 7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (130c) (1 g, 2.72 mmol) in toluene (15 ml) using triethylamine (0.379 µl, 2.72 mmol), diphenylphosphorazidate (0.607 ml, 2.72 mmol) and stirred at room temperature for 25 hours. This gave, after workup and purification via flash column chromatography (silica gel, 4 g, eluted with DCM) tert-butyl 3-(5-(azidocarbonyl)benzofuran-7-yl)benzylcarbamate (418a) (0.8 g, 75% yield);

^1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J=1.8 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.79-7.68 (m, 2H), 7.47 (k, J=1.1 Hz, 1H), 7.36 (t, J=1.2 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 5.76 (s, 1H), 4.24 (d, J=6.2 Hz, 2H), 1.41 ( s, 9H).

Stage-2. Preparation of (S)-tert-butyl 3-(5-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1carboxamido)benzofuran-7-yl)benzylcarbamate (418b)

A solution of tert-butyl 3-(5-(azidocarbonyl)benzofuran-7-yl)benzylcarbamate (418a) (80 mg, 0.204 mmol) in toluene (10 ml) was refluxed for 1.5 h, cooled to room temperature and add a solution of (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (52 mg, 0.204 mmol) in THF (5 ml), triethylamine (0.057 ml, 0.408 mmol) and stir at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM from 0% to 50%] to give (S)-tert-butyl 3- (5-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1carboxamido)benzofuran-7-yl)benzylcarbamate (418b) (117 mg, 0.188 mmol, 92% yield);

1H NMR (300 MHz, DMSO-d6) δ 8.49 (t, J=6.0 Hz, 1H), 8.34 (s, 1H), 7.98 (d, J=2.2 Hz, 1H ), 7.85 (d, J=2.1 Hz, 1H), 7.72-7.62 (m, 3H), 7.53-7.21 (m, 5H), 7.20-7, 06 (m, 1H), 6.99 (d, J=2.2 Hz, 1H), 4.44-4.29 (m, 3H), 4.22 (d, J=6.2 Hz, 2H ), 3.74-3.58 (m, 1H), 3.50 (k, J=8.5, 7.9 Hz, 1H), 2.19-2.03 (m, 1H), 2, 03-1.79 (m, 3H), 1.40 (s, 9H); MS (ESI+): 643.2 (M+Na).

Stage-3. Preparation of (S)-1H-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2fluorobenzyl)pyrrolidine-1,2-dicarboxamide (418c).

Compound 418c was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 3-(5-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxamido) benzofuran-7yl)benzylcarbamate (418b) (117 mg, 0.188 mmol) in DCM (3 ml) using TFA (0.290 ml, 3.77 mmol). This resulted in, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-Nl-(7- (3(aminomethyl)phenyl)benzofuran-5-yl)-1H-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide (418c) (45 mg, 46% yield), HCl salt, as white solid matter;

1H NMR (300 MHz, DMSO-d6) δ 8.52 (t, J=5.9 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 3H, D2O replaceable), 8, 01 (d, J=2.2 Hz, 1H), 7.92 (s, 1H), 7.85-7.78 (m, 2H), 7.74 (d, J=2.1 Hz, 1H ), 7.60 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.47-7.41 (m, 1H), 7.39 -7.29 (m, 1H), 7.14-7.06 (m, 1H), 7.01 (d, J=2.2 Hz, 1H), 4.44-4.24 (m, 3H ), 4.14 (s, 2H), 3.66 (dt, J=11.1, 5.7 Hz, 1H), 3.55-3.44 (m, 1H), 2.14 (dd, J=11.3, 7.6 Hz, 1H), 2.01-1.80 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.77. MS (ESI+): 521.2 (M+1); (ESI-): 519.1 (M-1), 555.1 (M+Cl); analysis calculation for C ₂₈ H ₂₆ ClFN ₄ O ₃ -HCl-2H ₂ O: C, 56.67; N, 5.26; Cl, 11.95; N, 9.44; observed: C, 56.67; N, 5.08; Cl, 11.95; N, 9.34.

Scheme-419

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (419c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-514 045626 methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (419a).

Compound 419a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (257g) (1 .2 g, 2.52 mmol) in acetonitrile (24 ml) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) ( 1.0 g, 3.02 mmol), a solution of Na ₂ CO ₃ (0.668 g, 6.31 mmol) in water (1.2 ml), Pd(PPh ₃ ) ₂ Cl ₂ (0.265 g, 0.378 mmol) and heating under nitrogen at 90°C for 4 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 40% ethyl acetate in hexanes), ethyl 2-(2-((7-(3- (((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5yl)methoxy)-4-cyanophenyl)acetate (419a) (550 mg, 40%) as an oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.75-7.68 (m, 2H), 7.61 (d, J=1.4 Hz, 1H), 7.56 (d, J= 1.6 Hz, 1H), 7.547.37 (m, 4H), 7.29 (d, J=7.7 Hz, 1H), 6.67 (d, J=1.2 Hz, 1H), 5 .27 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 2 .48 (s, 3H), 1.39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): (553.2); (ESI-): (M-1).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4cyanophenyl)acetate (419b).

Compound 419b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5- yl)methoxy)-4cyanophenyl)acetate (419a) (320 mg, 0.577 mmol) in DCM (15 ml) using TFA (0.857 ml, 11.54 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran5-yl)methoxy)-4-cyanophenyl)acetate (419b), which was used in the next step without additional cleaning; MS (ESI+): 455.20 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (419c).

Compound 419c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl) acetate (419b) (0.577 mmol; from previous step-3) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (198 mg, 4.62 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-( 2-((7-(3(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (419c) (11 mg, 4%), HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO- _d6 , D2O substitution) δ 7.95-7.88 (m, 2H), 7.62-7.55 (m, 3H), 7.53-7.48 (m , 2H), 7.44 (d, J=7.7 Hz, 1H), 7.39 (dd, J=7.7, 1.4 Hz, 1H), 6.67 (d, J=1, 2 Hz, 1H), 5.30 (s, 2H), 4.13 (s, 2H), 3.67 (s, 2H), 2.48 (d, J=1.0 Hz, 3H); MS (ESI+): 427.10 (M+1).

Scheme-420

CH ₃

420d 420e

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (420e).

Stage-1. Preparation of tert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane (420a).

To a solution of (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (76b) (11.5

- 515 045626 g, 27.49 mmol) in DMAc (396 ml), cooled to 0°C, was added PCl ₅ (8.58 g, 41.21 mmol) and stirred for 1 hour at 0°C. The reaction mixture was poured into ice water (200 ml), made alkaline with a saturated aqueous solution of NaHCO ₃ (200 ml). The aqueous layer was extracted with ethyl acetate (2x200 ml). The combined organic layer was washed with brine (100 ml), dried, concentrated in vacuo. The resulting residue was purified by flash column chromatography (5% EtOAc in n-heptane) to give tert-butyl((5-(chloromethyl)-7-iodobenzofuran-2yl)methoxy)dimethylsilane (420a) (6.0 g, 75 %) in the form of a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, J=1.7 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 6.85 (s, 1H), 4.71 (s, 2H), 4.70 (s, 2H), 0.76 (s, 9H), 0.00 (s, 6H).

Stage-2. Preparation of ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (420b).

Compound 420b was prepared according to the procedure described in step-6 of Scheme-257 from tert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane (420a) (1.09 g, 3.379 mmol) using ethyl 2-(2-hydroxy-4-methylphenyl) acetate (269d) (0.78 g, 4.01 mmol) Cs ₂ CO ₃ (2.20 g, 6.75 mmol) in DMSO (21 ml) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 15% EtOAc in n-heptane), ethyl 2-(2-((2-(hydroxymethyl) )-7-iodobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (420b) (1.0 g, 65.53%) as a yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J=1.4 Hz, 1H), 7.63 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.91 (s, 2H), 6.73 (d, J=7.5 Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 5.11 (s, 2H), 4.60 (d, J=5.9 Hz, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.55 (s, 2H), 2.29 (s, 3H), 1.08 (t, J=7.1 Hz, 3H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (420c).

Compound 420c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (420b) (1.0 g, 2.08 mmol) in acetonitrile (25 ml) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzylcarbamate (3b) ( 1.03 g, 3.12 mmol), solution of Na ₂ CO ₃ (0.66 g, 6.24 mmol) in water (1.2 ml), Pd(PPh ₃ ) ₂ Cl ₂ (0.14 g, 0.20 mmol) and heating under nitrogen at 90°C overnight. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 40% ethyl acetate in heptane), ethyl ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) -2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (420c) (570 mg, 49%) as a yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.82-7.68 (m, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.54-7.43 (m, 3H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.51 (t, J=5.9 Hz, 1H), 5.19 (s, 2H), 4.60 (d, J=5.9 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.56 (s, 2H) , 2.30 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (420d).

Compound 420d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran -5-yl)methoxy)-4methylphenyl)acetate (420c) (390 mg, 0.697 mmol) in DCM (15 ml) using TFA (1.035 ml, 13.94 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (420d), which was used for next stage without additional purification; MS (ESI+): 460.20 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)4-methylphenyl)acetic acid (420e).

Compound 420e was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4 -methylphenyl)acetate (420d) (0.680 mmol; from previous step-4) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (233 mg, 5.44 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (420e) (69 mg, 24%), HCl salt , as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.45 (s, 3H), 7.99 (d, J=1.6 Hz, 1H), 7.94 (dt , J=7.3, 1.7 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.63-7.52 (m, 3H), 7.09 (d, J=7.5 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.85 (s, 1H), 6.77-6.68 (m, 1H), 5, 55 (s, 1H), 5.22 (s, 2H), 4.61 (s, 2H), 4.14 (d, J=5.8 Hz, 2H), 3.54 (s, 2H), 2.29 (s, 3H); MS (ESI+): 432.20 (M+1); MS (ESI-): 430.15 (M-1); analysis calculation for C ₂ 6H ₂₅ NO ₅ -HCl-H ₂ O: C, 63.09; N, 5.91; N, 2.83; Cl, 7.09; observed: C, 63.00; N, 5.79; N, 2.88; Cl, 7.09.

- 516 045626

Scheme-421

Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (421e).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (421a).

Compound 421a was prepared according to the procedure described in step-6 of Scheme-257 from tert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane (420a) (0.215 g, 0.492 mmol) using ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (0.13 g, 0.55 mmol), Cs ₂ CO ₃ (0.24 g, 0.736 mmol) in DMSO (2 ml) and stirring at room temperature overnight. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 25% EtOAc in n-heptane), ethyl 2-(4-acetamido-2-((2-(((tert-butyldimethylsilyl)oxy)methyl )-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (421a) 0.24 g, 0.736 mmol (0.12 g, 38%) as a dark brown oil;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7. 10 (s, 2H), 6.96 (s, 1H), 5.07 (s, 2H), 4.83 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.03 (s, 3H), 1.07 (t, J=7.1 Hz, 3H), 0.90 (s, 9H), 0.13 (s, 6H ).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (421b).

Compound 421b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-acetamido-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5yl)methoxy) phenyl)acetate (421a) (0.12 g, 0.22 mmol) in acetonitrile (3 ml), using tert-butyl 3(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)benzylcarbamate (3b) (0.09 g, 0.34 mmol), solution of Na ₂ CO ₃ (0.07 g, 0.68 mmol) in water (2 ml), Pd(PPh ₃ ) ₂ Cl ₂ ( 0.016 g, 0.022 mmol) and heating under nitrogen at 90°C for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 50% ethyl acetate in hexanes), ethyl 2-(4-acetamido- 2((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (421b) (101 mg , 93%) as a light brown oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.94 (s, 1H), 7.74 (s, 2H), 7.65 (s, 1H), 7.53 (s, 1H), 7 .46 (d, J=7.9 Hz, 2H), 7.30 (d, J=7.4 Hz, 1H), 7.09 (d, J=3.8 Hz, 2H), 6.88 (s, 1H), 5.15 (s, 2H), 4.83 (s, 2H), 4.23 (d, J=6.3 Hz, 2H), 3.91 (k, J=7, 1 Hz, 2H), 3.55 (s, 3H), 2.03 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H), 0 .89 (s, 9H), 0.10 (s, 6H).

Stage-3. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (421c) .

To a solution of ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl) methoxy)phenyl)acetate (421b) (90 mg, 0.126 mmol) in

- 517 045626

THF (10 ml) was added at 0°C TBAF (1M in THF) (0.157 ml, 0.157 mmol) and left to warm to RT for 1.5 hours. The reaction mixture was diluted with saturated NH4Cl solution (20 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine, dried, filtered and evaporated to dryness. The resulting crude product was purified by flash column chromatography [silica gel, 4 g, eluted with ethyl acetate/MeOH (9:1) in 0 to 50% hexanes] to give ethyl 2-(4-acetamido-2-((7-(3- (((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (421c) (61 mg, 81% yield) as a clear oil; MS (ESI+): 625.25 (M+Na).

Stage-4. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (421d).

Compound 421d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2- (Hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (421c) (55 mg, 0.091 mmol) in DCM (7 ml) using TFA (0.136 ml, 1.825 mmol). This gave, upon treatment, ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (421d), which was used at the next stage without additional purification; MS (ESI+): 503.20 (M+1).

Stage-5. Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (421e).

Compound 421e was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl) methoxy)phenyl)acetate (421d) (0.084 mmol; from previous step-4) in MeOH/THF (3 ml each), using a solution of lithium hydroxide monohydrate (29 mg, 0.627 mmol) in water (3 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2 -(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (421e) (12 mg, 30%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.33 (s, 3H), 8.00-7.98 (m, 1H), 7.96 (dt, J =7.5, 1.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.63-7.56 (m, 2H), 7.55-7.50 ( m, 2H), 7.11 (d, J=8.2 Hz, 1H), 7.04 (dd, J=8.1, 1.8 Hz, 1H), 6.84 (s, 1H), 5.53 (t, J=5.9 Hz, 1H), 5.18 (s, 2H), 4.61 (d, J=5.7 Hz, 2H), 4.14 (s, 2H), 3.52 (s, 2H), 2.03 (s, 3H); MS (ESI+): 475.20 (M+1); MS (ESI-): 473.20 (M-1).

Scheme-422

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (422e).

Stage-1. Preparation of ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5yl)methoxy)-4-cyanophenyl)acetate (422a).

Compound 422a was prepared according to the procedure described in step-6 of scheme-257 from tert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane (420a) (4.0 g, 9.16 mmol ), using ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (2.82 g, 13.74 mmol), Cs ₂ CO ₃ (8.95 g, 27.48 mmol) in DMSO (40 ml) and stirring at room temperature for 18 hours. This resulted in

- 518 045626 after treatment and purification by flash column chromatography (silica gel, eluted with 15%

EtOAc in n-heptane) ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5yl)methoxy)-4-cyanophenyl)acetate (422a) (1.0 g , 13.36%) as a light yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.58 (d, J=1.5 Hz, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.35- 7.26 (m, 2H), 6.85 (s, 1H), 5.08 (s, 2H), 4.70 (s, 2H), 3.88 (k, J=7.1 Hz, 2H ), 3.58 (s, 2H), 0.92 (t, J=7.1 Hz, 3H), 0.76 (s, 9H), 0.00 (s, 6H); MS (ESI+): 605.5 (M+1), (ESI-): 604.5 (M-1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4- cyanophenyl)acetate (422b).

Compound 422b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)- 4-cyanophenyl)acetate (422a) (1.0 g, 1.65 mmol) in acetonitrile (25 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolane-2 -yl)benzylcarbamate (3b) (1.03 g, 3.12 mmol), solution of Na ₂ CO ₃ (0.66 g, 6.24 mmol) in water (5 ml), Pd(PPh ₃ ) ₂ Cl ₂ (0.14 g, 0.20 mmol) and heating under nitrogen at 90°C overnight. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 40% ethyl acetate in n-heptane), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) -2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (422b) (620 mg, 54.86%) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.77-7.69 (m, 2H), 7.64 (dd, J=8.1, 1.5 Hz, 2H), 7.55-7, 40 (m, 4H), 7.30 (d, J=7.6 Hz, 1H), 6.90 (s, 1H), 5.29 (s, 2H), 4.83 (s, 2H), 4.25-4.16 (m, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.38 (s, 9H), 0.93 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 6H).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (422c).

Compound 422c was prepared according to the procedure described in step-3 of scheme-421 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((( tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (422b) (220 mg, 0.321 mmol) in THF (10 ml), using TBAF (1M in THF) (0.402 ml, 0.402 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 4 g, eluted with 0 to 50% ethyl acetate in hexanes), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl) amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (422c) (151 mg, 82% yield) as a colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 7.79-7.67 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.62 (d, J=1, 3 Hz, 1H), 7.527.38 (m, 5H), 7.30 (d, J=7.7 Hz, 1H), 6.85 (d, J=0.8 Hz, 1H), 5.51 (t, J=5.7 Hz, 1H), 5.29 (s, 2H), 4.60 (d, J=5.3 Hz, 2H), 4.23 (d, J=6.2 Hz , 2H), 3.90 (k, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.38 (s, 9H), 0.94 (t, J=7.1 Hz , 3H); MS (ESI+): 593.20 (M+Na).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (422d).

Compound 422d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran -5-yl)methoxy)-4cyanophenyl)acetate (422c) (130 mg, 0.228 mmol) in DCM (7 ml) using TFA (0.338 ml, 4.56 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (422d), which was used for next stage without additional purification; MS (ESI+): 471.20 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)4-cyanophenyl)acetic acid (422e).

Compound 422e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4 -cyanophenyl)acetate (422d) (0.228 mmol; from previous step-4) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (69 mg, 1.6 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7-(3(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (422e) (41 mg, 41%), HCl salt , as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.99-7.97 (m, 1H), 7.94 (dt, J=7.7, 1.5 Hz, 1H), 7.69 (d , J=1.6 Hz, 1H), 7.64-7.50 (m, 4H), 7.47-7.37 (m, 2H), 6.86 (s, 1H), 5.53 ( t, J=5.8 Hz, 1H), 5.33 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.14 (s, 2H), 3.68 ( s, 2H); MS (ESI+): 443.10 (M+1); analysis calculation for C26H ₂₂ N ₂ O ₅ -HCl-0.9H ₂ O: C, 63.07; N, 5.05; N, 5.66; Cl, 7.16; observed: C, 63.12; N, 4.85; N, 5.50; Cl, 6.97.

- 519 045626

Scheme-423

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (423 sec).

Stage-1. Preparation of ethyl 2-(2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (423a).

Compound 423a was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-methylbenzofuran-5-yl)methanol (257c) (1.5 g, 5.21 mmol) in DCM (40 ml) using triphenylphosphine (1.775 g, 6.77 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (1.315 g, 6.77 mmol) and (E)bis(4-chlorobenzyl)diazen- 1,2-dicarboxylate (DCAD, 2.485 g, 6.77 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0% to 8% EtOAc in hexane), ethyl 2-(2-((7-iodo-2-methylbenzofuran-5-yl)methoxy) -4methylphenyl)acetate (423a) (1.85 g, 77% yield).

1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=1.5 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.07 (d, 1H ), 6.91 (d, J=1.4 Hz, 1H), 6.76-6.70 (m, 2H), 5.09 (s, 2H), 4.01 (k, J=7, 1 Hz, 2H), 3.55 (s, 2H), 2.48 (d, J=1.1 Hz, 3H), 2.29 (s, 3H), 1.08 (t, J=7, 1 Hz, 3H); MS: 487.00 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4methylphenyl)acetate (423b).

Compound 423b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (423a) (1 .8 g, 3.88 mmol) in dioxane (25 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (1.09 g, 5.82 mmol), K ₂ CO ₃ (1.607 g, 11. 63 mmol) in water (4 ml) and bis(triphenylphosphine) palladium(P) chloride (0.408 g, 0.582 mmol) in an argon atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 0-5% MeOH in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5 -yl)methoxy)-4methylphenyl)acetate (423b) (1.05 g, 61% yield) as a yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.81-7.77 (m, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.52-7.34 (m, 3H), 7.08 (d, J=7.5 Hz, 1H), 6.96-6.94 (m, 1H ), 6.72 (ddd, J=7.4, 1.6, 0.8 Hz, 1H), 6.67-6.63 (m, 1H), 5.18 (s, 2H), 3, 92 (k, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.56 (s, 2H), 2.47 (d, J=1.1 Hz, 3H), 2, 29 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 444.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (423c).

Compound 423c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl) acetate (423b) (500 mg, 1.127 mmol) in MeOH (10 ml), using a solution of lithium hydroxide monohydrate (386 mg, 9.02 mmol) in water (10 ml) and stirred for 16 hours. This resulted in the following treatment and purification by reverse phase column chromatography (C18 100 g, eluted with 0-60% MeCN in H2O with 0.1% HCl) 2-(2-((7-(3-(aminomethyl)phenyl)-2- methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (423 c) (408 mg, 87%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.99-7.94 (m, 1H), 7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.61 (d , J=1.5 Hz, 1H), 7.60-7.47 (m, 3H), 7.08 (d, J=7.5 Hz, 1H), 6.93 (d, J=1, 6 Hz, 1H), 6.75-6.69 (m, 1H), 6.67 (d, J=1.2 Hz, 1H), 5.20 (s, 2H), 4.13 (s, 2H), 3.53 (s, 2H), 2.49 (s, 3H), 2.28 (s, 3H); MS (ESI+): 416.20 (M+1); MS (ESI-): 414.20 (M-1); analysis calculation for C ₂₆ H ₂₅ NO ₄ -HCl-0.5H ₂ O: C, 67.75; N, 5.90; N, 3.04; Cl, 7.69; observed: C, 67.66; N, 6.04; N, 3.01; Cl, 7.53.

- 520 045626

422b

Scheme-424

424b

424d

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (424d).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tertbutyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4- carbamoylphenyl)acetate (424a).

Compound 424a was prepared according to the procedure described in step-1 of scheme-238 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl )oxy)methyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (422b) (300 mg, 0.438 mmol) in THF (15 ml) and water (1.2 ml), using acetamide (155 mg, 2.63 mmol), palladium(II) chloride (23 mg, 0.131 mmol) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with methanol in DCM from 0 to 5%) ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5 -yl)methoxy)-4-carbamoylphenyl)acetate (424a) (76 mg, 25% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.80-7.71 (m, 2H), 7.66 (d, J=1.6 Hz, 1H), 7.64-7.63 (m, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.51-7.39 (m, 3H), 7.37 (s, 1H) , 7.32-7.31 (m, 1H), 7.30-7.27 (m, 1H), 6.90-6.89 (m, 1H), 5.27 (s, 2H), 4 .83 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 1 .39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 6H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (424b).

Compound 424b was prepared according to the procedure described in step-3 of scheme-421 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((( tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (424a) (70 mg, 0.100 mmol) in THF (10 ml) using TBAF (33 mg, 0.124 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 4 g, eluted with 0 to 50% methanol in dichloromethane) ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino )methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (424b) (58 mg, 99% yield) as a colorless oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.79-7.69 (m, 2H), 7.65 (d, J=1.6 Hz, 1H) , 7.63-7.62 (m, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.49-7.42 (m, 3H), 7.37 (s, 1H ), 7.31 (s, 1H), 7.28 (s, 1H), 6.85-6.83 (m, 1H), 5.50 (t, J=5.9 Hz, 1H), 5 .26 (d, J=1.6 Hz, 2H), 4.60 (d, J=6.0 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.67 (s, 2H), 1.39 (s, 9H), 1.02-0.93 (m, 3H); MS: 611.20 (M+Na).

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)-4-carbamoylphenyl)acetate (424c).

Compound 424c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran -5-yl)methoxy)-4carbamoylphenyl)acetate (424b) (52 mg, 0.088 mmol) in DCM (7 mL) using TFA (0.131 mL, 1.767 mmol). This resulted in the production after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (424c) (92 mg) , which was used as is in the next step without further purification; MS (ESI+): 489.10 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)- 521 045626

4-carbamoylphenyl)acetic acid (424d).

Compound 424d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4 -carbamoylphenyl)acetate (424c) (0.08 mmol; from previous step-3) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (27 mg, 0.640 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (424d) (3 mg, 7%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.02-7.93 (m, 3H), 7.69 (s, 1H), 7.66-7.55 (m, 3H), 7.54 -7.47 (m, 1H), 7.44 (d, J=7.9 Hz, 1H), 6.85 (s, 1H), 7.35 (s, 1H), 7.28 (d, J=7.6 Hz, 1H), 5.51 (t, J=5.8 Hz, 1H), 5.30 (s, 2H), 4.64-4.58 (m, 2H), 4, 14 (s, 2H), 3.62 (s, 2H); MS (ESI+): 461.10 (M+1).

Scheme-425 o

NHBoc

DCM, Br ₂ °C.12h

_H3C

H;

H ₃

Pd(PPh ₃ ) ₂ CI ₂ ,

425e

425f

2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5 Preparation of yl)methoxy)phenyl)acetic acid (425f).

Stage-1. Preparation of methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran5-carboxylate (425a).

Compound 425a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a) (3.0 g, 9.49 mmol) in acetonitrile (60 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (3.79 g, 11.38 mmol), Na ₂ CO ₃ solution (3.01 g, 28.47 mmol) in water (6.0 ml), Pd(PPh ₃ ) ₂ Cl ₂ (1.33 g, 1.89 mmol) and heating under nitrogen at 90°C for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 40% ethyl acetate in n-heptane), methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) -2-methylbenzofuran-5-carboxylate (425a) (2.1 g, 56%) as an oil;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.26-8.11 (m, 1H), 8.04-7.90 (m, 1H), 7.82-7.65 (m, 2H ), 7.49 (dd, J=13.2, 6.4 Hz, 2H), 7.41-7.25 (m, 1H), 6.80 (td, J=6.1, 1.2 Hz, 1H), 4.37-4.09 (m, 2H), 3.88 (s, 3H), 2.50 (s, 3H), 1.39 (s, 9H).

Stage-2. Preparation of methyl 3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2methylbenzofuran-5-carboxylate (425b).

To a solution of methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5carboxylate (425a) (10.0 g, 25.28 mmol) in DCM (300 ml) was added at room temperature Br ₂ (4.04 g, 25.28 mmol) and heated at 50°C for 12 hours.

The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium thiosulfate (300 ml) and extracted with DCM (2x500 ml). The combined organic extracts were washed with brine (500 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0 to 40% ethyl acetate in n-heptane) to give methyl 3-bromo-7-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran -5-carboxylate (425b) (4.0 g, 34%) as an oil;

- 522 045626 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (d, J=1.7 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7, 74 (d, J=7.7 Hz, 1H),

7.68 (s, 1H), 7.51 (t, J=7.5 Hz, 2H), 7.35 (d, J=7.7 Hz, 1H), 4.24 (d, J=6 ,2 Hz, 2H), 3.92 (s, 3H), 2.53 (s, 3H),

1.40 (s, 9H).

Stage-3. Preparation of tert-butyl 3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7yl)benzylcarbamate (425c).

Compound 425c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate ( 425b) (10.0 g, 25.28 mmol) in THF (160 ml) using LiBH ₄ (4.04 g, 25.28 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 40% EtOAc in n-heptane] tert-butyl 3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl) benzylcarbamate (425c) (3.3 g, 87%) as an oil;

1H NMR (300 MHz, DMSO- _d6 ) δ 7.76-7.61 (m, 2H), 7.57-7.43 (m, 3H), 7.41-7.36 (m, 1H) , 7.30 (d, J=7.6 Hz, 1H), 5.35 (t, J=5.8 Hz, 1H), 4.66 (d, J=5.6 Hz, 2H), 4 .22 (d, J=6.2 Hz, 2H), 2.52 (s, 3H), 1.40 (s, 9H).

Stage-4. Preparation of ethyl 2-(2-((3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2methylbenzofuran-5-yl)methoxy)phenyl)acetate (425d).

Compound 425d was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzylcarbamate (425c) (3.3 g, 7.39 mmol) in DCM (75 ml) using triphenylphosphine (2.52 g, 9.61 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.732 g, 9.61 mmol) and solution ( E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 3.53 g, 9.61 mmol) in DCM (60 ml). This resulted, after workup and purification by flash column chromatography (silica gel, eluted with 0 to 20% ethyl acetate in hexanes), ethyl 2-(2-((3bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl) Phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (425d) (3.40 g, 76% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78-7.65 (m, 2H), 7.57 (d, J=1.7 Hz, 1H), 7.54-7.42 (m , 3H), 7.34-7.28 (m, 1H), 7.28-7.19 (m, 2H), 7.12 (dd, J=8.0, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.93 (k , J=7.1 Hz, 2H), 3.62 (s, 2H), 2.51-2.49 (m, 3H), 1.39 (s, 9H), 0.97 (t, J= 7.1 Hz, 3H).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (425e).

Compound 425e was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2- methylbenzofuran-5yl)methoxy)phenyl)acetate (425d) (250 mg, 0.411 mmol) in DCM (10 ml) using TFA (0.61 ml, 8.22 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2methylbenzofuran-5-yl)methoxy)phenyl)acetate (425e), which was used as is in the following stages; MS (ESI+): 509.10 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (425f).

Compound 425f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy) phenyl)acetate (425e) (0.411 mmol, from previous step-5) in THF/methanol (7 ml each), using a solution of lithium hydroxide monohydrate (141 mg, 3.29 mmol) in water (7 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1) ] 2-(2-((7-(3(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (425f) (91 mg, 46%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 3H), 7.98-7.93 (m, 1H), 7.90 (dt, J=7.4, 1.7 Hz , 1H), 7.66 (d, J=1.7 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.57-7.53 (m, 2H), 7 .24 (s, 1H), 7.21 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.14 (s, 2H), 3.60 (s, 2H), 2.52 (s, 3H); MS (ESI+): 480.10 (M+1); MS (ESI-): 478.05 (M-1); analysis calculation for C2 ₅ H22BrNO4-HCl-H2O: C, 56.14; N, 4.71; N, 2.62; Cl, 6.63; observed: C, 56.17; N, 4.67; N, 2.58; Cl, 6.49.

- 523 045626

Scheme-426

Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (426c).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-((7-iodo-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (426a).

Compound 426a was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-methylbenzofuran-5-yl)methanol (257c) (486 mg, 1.686 mmol) in DCM (20 ml) using triphenylphosphine ( 575 mg, 2.192 mmol), ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (400 mg, 1.686 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD , 805 mg, 2.192 mmol) in DCM (15 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes), ethyl 2-(4-acetamido-2-((7-iodo-2methylbenzofuran-5- yl)methoxy)phenyl)acetate (426a) (472 mg, 55% yield).

^1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.38 (s, 1H), 7.11-7.09 (m, 2H), 6.73 (d, J=1.2 Hz, 1H), 5.05 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.48 (d, J=1.3 Hz, 3H), 2.02 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); MS (ESI+): 508.00 (M+1).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (426b).

Compound 426b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-acetamido-2-((7-iodo-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (426a) (450 mg , 0.887 mmol) in dioxane (15 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (249 mg, 1.331 mmol), K ₂ CO ₃ (368 mg, 2.66 mmol) in water (4 ml) and bis(triphenylphosphine)palladium(P) chloride (93 mg, 0.133 mmol) under nitrogen atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 12% methanol in dichloromethane), ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl) phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (426b) (258 mg, 60% yield) as a light yellow oil.

1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.80 (s, 1H), 7.75-7.70 (m, 1H), 7.54 (d, 1H) , 7.49-7.34 (m, 4H), 7.14-7.05 (m, 2H), 6.65 (d, J=1.2 Hz, 1H), 5.14 (s, 2H ), 3.93 (k, J=7.2 Hz, 2H), 3.82 (s, 2H), 3.55 (s, 2H), 2.48 (d, 3H), 2.03 (s , 3H), 1.00 (t, J=7.1 Hz, 3H); MS (ESI+): 487.20 (M+1).

Stage-3. Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (426c).

Compound 426c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl )acetate (426b) (240 mg, 0.493 mmol) in MeOH (10 ml), using a solution of lithium hydroxide monohydrate (169 mg, 3.95 mmol) in water (10 ml) and stirred for 16 hours. This gave after workup and purification by reverse phase column chromatography (C-18, eluted with 0-100% MeCN in H ₂ O with 0.1% HCl) 2-(4-acetamido-2-((7-(3-( aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (426c) (157 mg, 69%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6, D2O substitution) δ 10.00 (s, 1H), 7.98-7.88 (m, 2H), 7.62-7.54 (m, 2H), 7.537 .46 (m, 3H), 7.10 (d, J=8.2 Hz, 1H), 7.02 (dd, J=8.0, 1.8 Hz, 1H), 6.65 (d, J=1.2 Hz, 1H), 5.16 (s, 2H), 4.13 (s, 2H), 3.51 (s, 2H), 2.46 (d, J=1.1 Hz, 3H), 2.02 (s, 3H); MS (ESI+): 459.20 (M+1); MS (ESI-): 457.15 (M-1); analysis calculation for O^iNiOs-HCl-USHiO: C, 62.67; N, 5.75; N, 5.41; Cl, 6.85; observed: C, 62.86; N, 5.58; N, 5.28; Cl, 6.79.

- 524 045626

Scheme-427

427a ^427b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (427b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetate (427a).

Compound 427a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d) (400 mg, 0.959 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (295 mg, 1.438 mmol), K ₂ CO ₃ (397 mg, 2.88 mmol) in water (0.5 ml) and bis(triphenylphosphine) palladium(P) chloride (101 mg, 0.144 mmol) under nitrogen atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA80 in DCM 0% to 30%), ethyl 2-(2-((7-(3-(aminomethyl)-2- fluorophenyl)benzofuran5-yl)methoxy)-4,5-dimethylphenyl)acetate (427a) (232 mg, 52% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.03 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.59 (td, J=7.4, 1.9 Hz, 1H), 7.45 (td, J=7.4, 1.9 Hz, 1H), 7.41-7.39 (m, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.94 (d, J=2.7 Hz, 2H), 5.17 (s , 2H), 3.90 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.53 (s, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 0.98 (t, J=7.1 Hz, 3H). 19F NMR (282 MHz, DMSO-d6) δ -121.77; MS: 362.20 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (427b).

Compound 427b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5- dimethylphenyl)acetate (427a) (210 mg, 0.455 mmol) in THF/MeOH (10 ml each), using a solution of lithium hydroxide monohydrate (117 mg, 2.73 mmol) in water (10 ml) and stirred for 16 h This gave, after work-up and purification by reverse phase column chromatography (C-18, eluted with 0-100% MeCN in H2O with 0.1% HCl) 2-(2-((7-(3-(aminomethyl )-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (427b) (91 mg, 46%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 3H), 8.05 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H ), 7.73 (td, J=7.4, 1.7 Hz, 1H), 7.67 (td, J=7.5, 1.7 Hz, 1H), 7.47 (s, 1H) , 7.42 (t, J=7.7 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.95 (s, 1H), 6.92 (s, 1H) , 5.20 (s, 2H), 4.16 (s, 2H), 3.49 (s, 2H), 2.19 (s, 3H), 2.12 (s, 3H); ¹⁹ F NMR (282

MHz, DMSO-d6) δ -118.49; MS (ESI+): 434.20 (M+1); MS (ESI-): 432.20 (M-1); analysis calculation for C26H24FNO4-HCl-0.75H2O: C, 64.59; N, 5.53; N, 2.90; Cl, 7.33; observed: C, 64.93; N, 5.31; N, 2.81; Cl, 6.99.

Scheme-428

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5 Preparation of dimethylphenyl)acetic acid (428c).

Stage-1. Preparation of ethyl 2-(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate ( 428a).

Compound 428a was prepared according to the procedure described in step-1 of scheme-59 from ethyl

- 525 045626

2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d) (1.00 g, 2.396 mmol), using bis(pinacolato)diboron (0.913 g, 3. 59 mmol), potassium acetate (0.706 g, 7.19 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ (0.196 g, 0.240 mmol) in anhydrous dioxane (25 ml) under nitrogen atmosphere while heating at 90°C in This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0 to 12% EtOAc in hexane] ethyl 2-(4,5-dimethyl-2-((7 -(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (428a) (939 mg, 84% yield) as a light brown oil .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.64 (d , J=1.9 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 5.11 (s , 2H), 4.07-3.94 (m, 2H), 3.50 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.34 (s, 12H), 1.05 (t, J=7.1 Hz, 3H); MS: (ESI+): 487.20 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetate (428b).

Compound 428b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (428a) (450 mg, 0.969 mmol) in dioxane (10 ml), using (4-chloropyridin-2yl)methanamine (74a) (138 mg, 0.969 mmol ), K ₂ CO ₃ (402 mg, 2.91 mmol) in water (1 ml) and bis(triphenylphosphine) palladium(P) chloride (102 mg, 0.145 mmol) under nitrogen when heated at 100°C for 16 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with ethyl acetate in hexanes (0 to 100%) then dichloromethane/DMA 80 (0 to 25%)] ethyl 2-(2-((7- (2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)-4,5-dimethylphenyl)acetate (428b) (50 mg, 12% yield).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.62 (d, J=5.2 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.97 (s , 1H), 7.79 (d, J=1.6 Hz, 1H), 7.78-7.71 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 6 .96 (s, 1H), 6.94 (s, 1H), 5.21 (s, 2H), 4.00-3.85 (m, 4H), 3.55 (s, 2H), 2. 20 (s, 3H), 2.13 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 445.15 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (428c).

Compound 428c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5 -dimethylphenyl)acetate (428b) (45 mg, 0.101 mmol) in THF/methanol (5 ml each), using a solution of lithium hydroxide monohydrate (26.0 mg, 0.607 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2 -(2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetic acid (428c) (21 mg, 50%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6, D2O replacement) δ 8.75 (dd, J=5.3, 0.8 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H) , 8.037.98 (m, 1H), 7.96 (dd, J=5.3, 1.8 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.76 ( d, J=1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.94 (s, 1H), 6.90 (s, 1H), 5.20 ( s, 2H), 4.29 (s, 2H), 3.49 (s, 2H), 2.16 (s, 3H), 2.10 (s, 3H); MS (ESI+): 417.15 (M+1); MS (ESI-): 415.20 (M-1).

Scheme-429

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (429c).

Stage-1. Preparation of ethyl 2-(4-carbamoyl-2-((7-iodo-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (429a).

Compound 429a was prepared according to the procedure described in step-1 of scheme-238 from ethyl

- 526 045626

2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (257g) (500 mg, 1.052 mmol) in THF (20 ml) and water (1.5 ml), using acetamide (373 mg, 6.31 mmol), palladium(II) chloride (56.0 mg, 0.316 mmol) and stirring at room temperature for 16 hours. This resulted in, after workup and flash purification, Column chromatography (silica gel, 24 g, eluted with methanol in DCM from 0 to 6%] ethyl 2-(4-carbamoyl-2-((7-iodo-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (429a) ( 468 mg, 90% yield) as an off-white solid.

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.98 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.60-7.53 (m, 2H) , 7.45 (dd, J=7.7, 1.5 Hz, 1H), 7.39 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.75 ( d, J=1.2 Hz, 1H), 5.17 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.48 ( d, 3H), 1.08 (t, J=7.1 Hz, 3H); MS: 516.00 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4carbamoylphenyl)acetate (429b).

Compound 429b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-carbamoyl-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (429a) ( 450 mg, 0.912 mmol) in dioxane (20 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (256 mg, 1.368 mmol), K2CO3 (378 mg, 2.74 mmol) in water (4 ml) and bis(triphenylphosphine)palladium(P) chloride (96 mg, 0.137 mmol) under nitrogen by heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 10% methanol in dichloromethane), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2methylbenzofuran -5-yl)methoxy)-4-carbamoylphenyl)acetate (429b) (262 mg, 61% yield).

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.99 (s, 1H), 7.81-7.78 (m, 1H), 7.75-7.70 (m, 1H), 7. 62 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.51-7.35 (m, 5H), 7.29 (d, J =7.8 Hz, 1H), 6.66 (d, J=1.2 Hz, 1H), 5.26 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.67 (s, 2H), 2.48 (d, J=1.1 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); MS: 473.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (429c).

Compound 429c was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl) acetate (429b) (250 mg, 0.529 mmol) in THF/MeOH (10 ml each), using a solution of lithium hydroxide monohydrate (136 mg, 3.17 mmol) in water (10 ml) and stirred for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, chromatography with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7- (3-(aminomethyl)phenyl)-2-methylbenzofuran-5yl)methoxy)-4-carbamoylphenyl)acetic acid (429c) (151 mg, 64%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 , D2O substitution) δ 7.94-7.87 (m, 2H), 7.61-7.55 (m, 3H), 7.53-7.47 (m , 2H), 7.42 (dd, J=7.7, 1.5 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 6.65 (d, J=1, 3 Hz, 1H), 5.27 (s, 2H), 4.12 (s, 2H), 3.62 (s, 2H), 2.46 (d, J=1.0 Hz, 3H); MS (ESI+): 445.15 (M+1); analysis calculation for C2 ₆ H24^O5-1.45HCM,5H2O: C, 59.55; N, 5.47; Cl, 9.80; N, 5.34; observed: C, 59.42; N, 5.53; Cl, 9.59; N, 5.37.

Scheme-430

(+)-isomer

430b 430c

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (430c).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4, 5-dimethylphenyl)acetate (430a).

Compound 430a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (428a) (430 mg, 0.926 mmol) in dioxane (15 ml) using (+)-(S)-N-((4-chloro-527 045626

3-fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (294 mg, 1.111 mmol), bis(triphenylphosphine)palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (97 mg, 0.139 mmol) and a solution of K ₂ CO ₃ (384 mg, 2.78 mmol) in water (1.2 ml) heating under N2 at 100°C for 16 hours in an oil bath. This resulted in (+)-(S)-ethyl 2-(2-((7-(2- ((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetate (430a) (448 mg, 85% yield); MS: 567.30 (M+1); optical rotation [a] _D = +36.667 (c = 0.06, MeOH).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4,5-dimethylphenyl)acetate (430b).

To a solution of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-4 ,5-dimethylphenyl)acetate (430a) (420 mg, 0.741 mmol) in tetrahydrofuran (15 ml) was added conc. HCl (0.741 mL, 2.223 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran -5-yl)methoxy)-4,5-dimethylphenyl)acetate (430b); MC (ESI+): 463.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (430c).

Compound 430c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -4,5-dimethylphenyl)acetate (430b) (0.741 mmol, from previous step-2) in MeOH/THF (7 ml each), using a solution of lithium hydroxide monohydrate (254 mg, 5.93 mmol) in water (7 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, eluted (1:0 to 0:1) MeCN in H ₂ O with 0.1% HCl) 2-(2-((7- (2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5dimethylphenyl)acetic acid (430c) (83 mg, 26%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.61-8.51 (m, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7, 60 (d, J=1.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.95 (s, 1H), 6.92 (s, 1H), 5, 22 (s, 2H), 4.44-4.31 (m, 2H), 3.49 (s, 2H), 2.19 (s, 3H), 2.12 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.43; MS (ESI+): 435.20 (M+1); MS (ESI-): 433.10 (M-1); analysis calculation for C2 ₅ H23FN2O4-HCl-1.25H2O: C, 60.85; N, 5.41; N, 5.68; Cl, 7.18; observed: C, 60.63; N, 5.15; N, 5.65; Cl, 6.94.

Scheme-431 CI

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5yl)methoxy)phenyl)acetic acid (431c).

Stage-1. Preparation of (-)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy )phenyl)acetate (431a).

Compound 431a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (310a) (100 mg, 0.221 mmol) in dioxane (4 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)-2methylpropan-2-sulfinamide (220c) (64 mg, 0.243 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (16 mg, 0.022 mmol) and a solution of K ₂ CO ₃ (92 mg, 0.663 mmol) in water (1.0 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0-5% MeOH in DCM] (-)-(S)-ethyl 2-(2-((7-(2 -((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate (431a) as a pale yellow oil; MS (ESI+): 555

- 528 045626 (M+1); optical rotation [a]D = -8.00 (c = 0.05, MeOH).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5yl)methoxy)phenyl)acetate (431b).

To a solution of (-)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzo[b]thiophen-5-yl) methoxy)phenyl)acetate (431a) (81 mg; from previous step-1) in MeOH (2 ml) was added 4 M HCl in dioxane (0.553 ml, 2.211 mmol) at room temperature and stirred for 1 hour. The reaction mixture was concentrated to dryness and purified by flash column chromatography (silica gel, 12 g, eluted with 0-8% MeOH in DCM) to give ethyl 2-(2((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo [B]thiophen-5-yl)methoxy)phenyl)acetate (431B) (55 mg) as a pale yellow oil; MS (ESI+): 451.00 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5yl)methoxy)phenyl)acetic acid (431c).

Compound 431c was prepared according to the procedure described in step-4 of Scheme-4 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophene-5- yl)methoxy)phenyl)acetate (431b) (55 mg, from previous step-2) in MeOH (3 ml) water (1 ml), using NaOH (44 mg, 1.105 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with water in acetonitrile from 0% to 60%] 2-(2-((7-(2-(aminomethyl)-3fluoropyridine -4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetic acid (431c) (15 mg, 16% yield), HCl salt, as a pale green solid;

'11 NMR (300 MHz, DMSO-d ₆ ) δ 8.66 (d, J=5.0 Hz, 1H), 8.50 (d, J=5.9 Hz, 3H), 8.13 (d , J=1.5 Hz, 1H), 7.90 (d, J=5.5 Hz, 1H), 7.83 (t, J=5.3 Hz, 1H), 7.64-7.54 (m, 2H), 7.29-7.19 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.47-4.33 (m, 2H), 3.59 (s, 2H); MS (ESI+): 423 (M+1), (ESI-): 422 (M1).

Scheme-432

Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (432c).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (432a).

Compound 432a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a) (352 mg, 0.948 mmol) in DCM (8 ml) using triphenylphosphine (249 mg, 0.948 mmol), ethyl 2-(4-acetamido-2hydroxyphenyl)acetate (417b) (150 mg, 0.632 mmol) and (E)-bis(4-chlorobenzyl)diazen-1 ,2-dicarboxylate (DCAD, 348 mg, 0.948 mmol) in DCM (8 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1) then hexanes/10% methanol in ethyl acetate (1:1)] ethyl 2-( 4-acetamido-2-((7-(3-(((tertbutoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (432a) (309 mg) as light brown resins; MS (ESI+): 613.20 (M+1).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (432b).

Compound 432b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl) benzofuran-5yl)methoxy)phenyl)acetate (432a) (290 mg, 0.491 mmol) in DCM (15 ml) using TFA (0.729 ml, 9.82 mmol). This resulted in the preparation, after treatment, of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-529 045626 fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (432b), which was used as is in the next stage. MS (ESI+): 491.20 (M+1).

Stage-3. Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (432c).

Compound 432c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl )acetate (432b) (0.491 mmol; from previous step-2) in THF/MeOH (10 ml each), using a solution of lithium hydroxide monohydrate (0.168 g, 3.93 mmol) in water (10 ml) and stirred for 21 hours This gave, after work-up and purification by reverse phase chromatography on a [C-18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(4 -acetamido-2-((7-(3-(aminomethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (432c) (45 mg, 17%) HCl salt, as an off-white solid ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H), 9.99 (s, 1H), 8.46 (s, 3H), 8.06 (d, J=2, 2 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.74-7.63 (m, 2H), 7.49 (d, J=1.8 Hz, 1H) , 7.48-7.38 (m, 2H), 7.14-7.02 (m, 3H), 5.19 (s, 2H), 4.25-4.07 (m, 2H), 3 .51 (s, 2H), 2.03 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.20; MS (ESI+): 463.10 (M+1); MS (ESI-): 461.15 (M-1); analysis calculation for C26H23FN2O5-HCl-2.25H2O: C, 57.89; N, 5.32; N, 5.19;

Cl, 6.57; observed: C, 57.81; N, 5.27; N, 5.07; Cl, 6.30.

Scheme-433

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4 Preparation of cyanophenyl)acetic acid (433c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (433a).

Compound 433a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl ((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate (271b) (518 mg, 1.462 mmol) in DCM (15 ml) using triphenylphosphine (575 mg, 2.193 mmol), ethyl 2-(4-cyano-2hydroxyphenyl) acetate (257f (300 mg, 1.462 mmol) and solution of (E)-bis( 4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 805 mg, 2.193 mmol) in DCM (15 ml) This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (from 1: 0 to 1:1)] ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate ( 433a) (332 mg, 42%) as a light pink gum;

1H NMR (300 MHz, DMSO-d6) δ 8.65-8.62 (m, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.85-7.78 (m, 2H), 7.77-7.74 (m, 1H), 7.69-7.68 (m, 1H), 7.64-7.63 (m, 1H), 7.56-7.35 ( m, 3H), 7.12 (d, J=2.2 Hz, 1H), 5.32 (s, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.89 ( k, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.39 (s, 9H), 0.91 (t, J=7.1 Hz, 3H); MS (ESI+): 542.20 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (433b).

Compound 433b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5 -yl)methoxy)-4cyanophenyl)acetate (433a) (110 mg, 0.203 mmol) in DCM (10 ml) using TFA (0.302 ml, 4.06 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (433b), which was used as is in the following stages; MS (ESI+): 442.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (433c).

Compound 433c was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2-530 045626 (2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)- 4-cyanophenyl)acetate (433b) (0.203 mmol; from previous step-2) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (0.070 g, 1.624 mmol) in water (6 ml) and stirring at room temperature for 19 hours. This resulted in, after work-up and purification by reverse phase column chromatography [C-18 column eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetic acid (433c) (51 mg, 61%), HCl salt, in as an off-white solid;

^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.80-8.77 (m, 1H), 8.43 (s, 3H), 8.18 (d, J=2.2 Hz, 1H) , 8.08-8.03 (m, 1H), 7.98 (dd, J=5.3, 1.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 7.497.39 (m, 2H), 7.13 (d, J=2 .2 Hz, 1H), 5.37 (s, 2H), 4.39-4.24 (m, 2H), 3.70 (s, 2H); MS (ESI+): 414.10 (M+1); analysis calculation for C24H^3O4-1.75HC1-2.5H2O: C, 55.19; N, 4.97; N, 8.05; Cl, 11.88; observed: C, 54.88; N, 4.67; N, 7.91; Cl, 11.92.

Scheme-434

Preparation of (+)-2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (434c).

Stage-1. Preparation of (+)-ethyl 2-(4-acetamido-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl )acetate (434a).

Compound 434a was prepared according to the procedure described in step-2 of Scheme-23 from (-)(R)-N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl )ethyl)-2-methylpropane-2-sulfinamide (269f (260 mg, 0.668 mmol) in DCM (8 ml), using triphenylphosphine (219 mg, 0.835 mmol), ethyl 2-(4acetamido-2-hydroxyphenyl)acetate (417b ) (132 mg, 0.556 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene 1,2-dicarboxylate (DCAD, 306 mg, 0.835 mmol) in DCM (8 ml). flash column chromatography [silica gel, 25 g, eluted with hexanes/ethyl acetate (1:0 to 2:1), then hexanes/10% methanol in ethyl acetate (1:1)] (+)-ethyl 2-(4acetamido- 2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (434a) (150 mg, 44%) in as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.94 (s, 1H), 7.87- 7.80 (m, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H), 7.56-7.47 (m , 3H), 7.14-7.07 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 6.04 (d, J=8.2 Hz, 1H), 5 .18 (s, 2H), 4.79-4.47 (m, 3H), 3.91 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.03 ( s, 3H), 1.14 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -216.97; MS (ESI+): 609.20 (M+1); optical rotation [a] _D = +1.9 (c = 0.21, MeOH).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (434b).

Compound 434b was prepared according to the procedure described in step-4 of scheme-405 from (+)ethyl 2-(4-acetamido-2-((7-(3-(1-((R)-1,1- dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (434a) (140 mg, 0.230 mmol) in THF (7 ml) using 3N aq. HCl (0.230 ml, 0.690 mmol) and stirring at room temperature for 3 hours. This resulted in the preparation after workup of ethyl 2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl) phenyl)benzofuran-5yl)methoxy)phenyl)acetate (434b), which was used as is in the next step. MS (ESI+):

- 531 045626

505.20 (M+1).

Stage-3. Preparation of (+)-2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (434c).

Compound 434c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (434b) (0.23 mmol; from previous step-2) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (0.079 g, 1.840 mmol) in water (5 ml) and stirring at room temperature for 19 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1) ] (+)-2-(4acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (434c) (38 mg, 35 %), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.89 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.10- 8.05 (m, 1H), 8.00 (dt, J=7.1, 1.8 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.67-7 .60 (m, 3H), 7.53 (d, J=1.9 Hz, 1H), 7.13-7.01 (m, 3H), 5.21 (s, 2H), 4.97- 4.66 (m, 3H), 3.53 (s, 2H), 2.03 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -222.45; MS (ESI+): 477.15 (M+1); MS (ESI-): 475.10 (M-1); analysis calculation for C27H ₂₅ FN ₂ O ₅ -HC1-2.25H ₂ O: C, 58.59; N, 5.55; N, 5.06; Cl, 6.41; observed: C, 58.54; N, 5.51; N, 5.01; Cl, 6.58; optical rotation [a] _D = +11.11 (c = 0.27, MeOH).

Scheme-435

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (435b).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (435a).

To a solution of (+)-(S)-ethyl 2-(4-cyano-2-((7-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin4-yl)benzofuran-5-yl) methoxy)phenyl)acetate (405b) (215 mg, 0.381 mmol) in tetrahydrofuran (10 ml) was added 3N aq. HCl (0.381 mL, 1.144 mmol) at room temperature and stirred for 5 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(2-(aminomethyl)-3fluoropyridin-4-yl)benzofuran- 5-yl)methoxy)-4-cyanophenyl)acetate (435a), which was used as is in the next step. MS (ESI+): 460.20 (M+1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5 -yl)methoxy)-4cyanophenyl)acetic acid (435b).

Compound 435b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -4-cyanophenyl)acetate (435a) (0.381 mmol, from previous step-1) in THF/MeOH (8 ml each), using a solution of lithium hydroxide monohydrate (0.131 g, 3.05 mmol) in water (12 ml) . This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted (1:0 to 0:1) MeCN in H ₂ O with 0.1% HCl) 2-(2-( (7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (435b) (112 mg, 68%), HCl salt, as a white solid ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=5.0 Hz, 1H), 8.60-8.49 (m, 3H), 8.13 (d, J=2 .2 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.62-7.59 (m, 2H ), 7.48-7.37 (m, 2H), 7.12 (d, J=2.2 Hz, 1H), 5.36 (s, 2H), 4.44-4.30 (m, 2H), 3.68 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.40; MS (ESI+): 432.10 (M+1); analysis calculation for C ₂₄ H ₁₈ FN ₃ O ₄ -1.5HC1-2.0R ₂ O: C, 55.21; N, 4.54; N, 8.05; Cl, 10.18; observed: C, 54.97; N, 4.33; N, 7.93; Cl, 10.32.

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Scheme-436

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (436c).

Stage-1. Preparation of ethyl 2-(4-carbamoyl-2-((7-(3-(1-((R)-1,1-dimethylethylsulfunamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (436a ).

Compound 436a was prepared according to the procedure described in step-1 of scheme-238 from (-)ethyl 2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfonamido )-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (410a) (200 mg, 0.347 mmol) in THF (9 ml) and water (0.8 ml), using acetamide (123 mg, 2.081 mmol ), palladium(II) chloride (19 mg, 0.104 mmol) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 9:1 EtOAc/MeOH in hexanes from 0 to 50%) ethyl 2-(4-carbamoyl-2-((7-(3-(1-((R)-1,1-dimethylethylsulfunamido)-2-fluoroethyl)phenyl)benzofuran-5yl)methoxy )phenyl)acetate (436a) (73 mg, 35%) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.86- 7.81 (m, 1H), 7.74-7.72 (m, 1H), 7.64-7.62 (m, 1H), 7.62-7.60 (m, 1H), 7. 54 (s, 1H), 7.52 (s, 1H), 7.48-7.43 (m, 1H), 7.39 (s, 1H), 7.30 (d, J=7.8 Hz , 1H), 7.07 (d, J=2.2 Hz, 1H), 6.05 (d, J=8.2 Hz, 1H), 5.29 (s, 2H), 4.80-4 .43 (m, 3H), 3.91 (k, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.13 (s, 9H), 0.95 (t, J= 7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -217.01; MS (ESI+): 595.20 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetate (436b).

To a solution of ethyl 2-(4-carbamoyl-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinαamido)-2fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 436a) (65 mg, 0.109 mmol) in THF (4 ml) was added 3N aq. HCl (0.109 mL, 0.328 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(3-(1-amino-2fluoroethyl)phenyl)benzofuran-5 -yl)methoxy)-4-carbamoylphenyl)acetate (436b), which was used as is in the next step. MS (ESI+): 491.20 (M+1).

Stage-3. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (436c).

Compound 436c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)- 4-Carbamoylphenyl)acetate (436b) (0.109 mmol, from previous step-2) in THF/MeOH (3 ml each), using a solution of lithium hydroxide monohydrate (37 mg, 0.872 mmol) in water (3 ml). This gave, after work-up and purification by reverse phase column chromatography (C18, 100 g, eluted (1:0 to 0:1) MeCN in H2O with 0.1% HCl) (+)-2-(2 -((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (436c) (18 mg, 36%), HCl salt, as a yellow solid substances;

1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.88 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.08-8 .03 (m, 1H), 8.02-7.94 (m, 2H), 7.78 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.63 (d, J=7.3 Hz, 3H), 7.45 (dd, J=7.8, 1.5 Hz, 1H), 7.37 (s, 1H), 7. 30 (d, J=7.8 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.33 (s, 2H), 4.97-4.68 (m, 3H ), 3.65 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -222.61; MS (ESI+): 463.15 (M+1); optical rotation [a] _D = +7.75 (c = 0.155, MeOH).

- 533 045626

Scheme-437

2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5 Preparation of yl)methoxy)phenyl)acetic acid (437c).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (437a).

Compound 437a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl ((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate (271b) (269 mg , 0.759 mmol) in DCM (9 ml) using triphenylphosphine (249 mg, 0.948 mmol), ethyl 2-(4-acetamido-2hydroxyphenyl)acetate (417b) (150 mg, 0.632 mmol) and solution of (E)-bis( 4-chlorobenzyl)diazene-1,2dicarboxylate (DCAD, 348 mg, 0.948 mmol) in DCM (9 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] ethyl 2-(4-acetamido-2-((7- (2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (437a) (178 mg, 49%) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.63 (dd, J=5.2, 0.8 Hz, 1H), 8.12 (d, J=2 .2 Hz, 1H), 7.83 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.77 (dd, J=5.2, 1.7 Hz, 1H ), 7.70 (d, J=1.6 Hz, 1H), 7.54-7.42 (m, 2H), 7.167.02 (m, 3H), 5.19 (s, 2H), 4 .32 (d, J=6.1 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.03 (s, 3H), 1 .40 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 574.20 (M+1).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (437b).

Compound 437b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl )benzofuran-5yl)methoxy)phenyl)acetate (437a) (165 mg, 0.288 mmol) in DCM (15 ml) using TFA (0.427 ml, 5.75 mmol). This resulted in the preparation, after treatment, of ethyl 2-(4-acetamido-2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (437b), which was used as is at the next stage. MS (ESI+): 474.20 (M+1).

Stage-3. Preparation of 2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (437c).

Compound 437c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy )phenyl)acetate (437b) (0.288 mmol; from previous step-2) in THF/MeOH (6 ml each), using a solution of lithium hydroxide monohydrate (99 mg, 2.304 mmol) in water (6 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(4- acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (437c) (61 mg, 48%), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.78 (d, J=5.3 Hz, 1H), 8.47 (s, 3H), 8.17 ( d, J=2.2 Hz, 1H), 8.13-8.07 (m, 1H), 8.01 (dd, J=5.3, 1.7 Hz, 1H), 7.88 (d , J=1.5 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.54 (d,

J=1.9 Hz, 1H), 7.14-7.01 (m, 3H), 5.23 (s, 2H), 4.37-4.26 (m, 2H), 3.54 (s , 2H), 2.03 (s, 3H); MS (ESI+):

446.20 (M+1); MS (ESI-): 444.10 (M-1); analysis calculation for ^^N^^HCl^Q: C, 52.45; N, 5.46; N, 7.34; Cl, 12.39; observed: C, 52.43; N, 5.44; N, 7.23; Cl, 12.18.

- 534 045626

Scheme-438

Preparation of 2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (438c).

Stage-1. Preparation of (+)-(S)-ethyl 2-(4-acetamido-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)3-fluoropyridin-4-yl)benzofuran-5-yl) methoxy)phenyl)acetate (438a).

Compound 438a was prepared according to the procedure described in step-2 of Scheme-23 from (+)(S)-N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2 -yl)methyl)-2-methylpropane-2sulfinamide (405a) (286 mg, 0.759 mmol) in DCM (9 ml)/THF (3.5 ml) using triphenylphosphine (249 mg, 0.948 mmol), ethyl 2-( 4-acetamido-2-hydroxyphenyl)acetate (417b) (150 mg, 0.632 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 348 mg, 0.948 mmol) in DCM ( 9 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with a 9:1 mixture of ethyl acetate and methanol in hexanes (1:0 to 0:1)] (+)-(S)-ethyl 2- (4-acetamido2-((7-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (438a) (85 mg, 23%) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.68 (t, J=5.2 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.16-6.98 (m, 3H), 5.86 (t, J=5.8 Hz, 1H), 5.18 (s, 2H), 4, 43-4.38 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.55 (s, 2H), 2.03 (s, 3H), 1.11 (s , 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -127.79; MS (ESI+): 596.20 (M+1); optical rotation

[a] _D = +36.67 (c = 0.24, MeOH).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran5-yl)methoxy)phenyl)acetate (438b).

To a solution of (+)-(S)-ethyl 2-(4-acetamido-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl) methoxy)phenyl)acetate (438a) (80 mg, 0.134 mmol) in tetrahydrofuran (5 ml) was added 3N aq. HCl (0.134 mL, 0.403 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(4-acetamido-2-((7(2-(aminomethyl)-3-fluoropyridine-4 -yl)benzofuran-5-yl)methoxy)phenyl)acetate (438b), which was used as is in the next step. MS (ESI+): 492.10 (M+1).

Stage-3. Preparation of 2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (438c).

Compound 438c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5- yl)methoxy)phenyl)acetate (438b) (0.134 mmol, from previous step-2) in MeOH/THF (4 ml each), using a solution of lithium hydroxide monohydrate (46 mg, 1.072 mmol) in water (4 ml). This gave, after work-up and purification by reverse phase column chromatography [C18, 100 g, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(4-acetamido -2-((7-(2-(aminomethyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (438c) (72 mg, 94%), HCl salt, as a white solid dogo substances;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.57-8.49 (m, 3H), 8.12 (d, J=2.2 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7, 61-7.59 (m, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.16-7.00 (m, 3H), 5.21 (s, 2H), 4 .46-4.26 (m, 2H), 3.52 (s, 2H), 2.03 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.15; MS (ESI+): 464.15 (M+1); MS (ESI-): 462.15 (M-1); analysis calculation for C ₂₅ H ₂₂ FN ₃ O ₅ -1.5HCl-3H ₂ O: C, 52.48; N, 5.20; N, 7.34; Cl, 9.29; observed: C, 52.56; N, 5.02; N, 7.31; Cl, 8.98.

- 535 045626

Scheme-439

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4carbamoylphenyl)acetic acid (439c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate ( 439a).

Compound 439a was prepared according to the procedure described in step-1 of scheme-238 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-( methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (416b) (300 mg, 0.498 mmol) in THF (9 ml) and water (0.8 ml), using acetamide (176 mg, 2.99 mmol) , palladium(P) chloride (27 mg, 0.149 mmol) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 9:1 EtOAc/MeOH in hexanes from 0 to 60%) ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4- carbamoylphenyl)acetate (439a) (214 mg, 69%) as an off-white waxy oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.99 (s, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.62 (d, 1H), 7.55- 7.25 (m, 8H), 7.00 (s, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 4.26 (d, J=6.1 Hz, 2H ), 3.89 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 3.29 (s, 3H), 1.41 (s, 9H), 0.96 (t , J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.72.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-carbamoylphenyl)acetate (439b).

Compound 439b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-( methoxymethyl)benzofuran-5yl)methoxy)-4-carbamoylphenyl)acetate (439a) (180 mg, 0.290 mmol) in DCM (15 ml) using TFA (0.431 ml, 5.80 mmol). This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate (439b), which used as is in the next stage. MS (ESI+): 521.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-carbamoylphenyl)acetic acid (439c).

Compound 439c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)-4carbamoylphenyl)acetate (439b) (0.29 mmol, from previous step-2) in THF/MeOH (6 ml each), using a solution of lithium hydroxide monohydrate (0.099 g, 2.320 mmol) in water (6 ml) . This gave, after work-up and purification by reverse phase chromatography on a [C18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7- (3-(aminomethyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetic acid (439c) (80 mg, 56%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.45 (s, 3H), 7.99 (s, 1H), 7.80 (d, J=1.6 Hz , 1H), 7.747.63 (m, 2H), 7.61 (d, J=1.5 Hz, 1H), 7.49-7.41 (m, 3H), 7.37 (s, 1H) , 7.29 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 5.30 (s, 2H), 4.52 (s, 2H), 4.18 (s, 2H), 3.62 (s, 2H), 3.29 (s, 3H); MS (ESI+): 493.10 (M+1); analysis calculation for C^FNO^HCl^HO: C, 55.62; N, 5.53; N, 4.81; Cl, 6.08; observed: C, 55.89; N, 5.15; N, 4.72; Cl, 6.15.

- 536 045626

Scheme-440

440b 440c

Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (440c).

Stage-1. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl) acetate (440a).

Compound 440a was prepared according to the procedure described in step-2 of Scheme-256 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2- (methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (416b) (400 mg, 0.664 mmol) in methanol (20 ml), using nickel(II) chloride hexahydrate (39 mg, 0.166 mmol) and sodium borohydride ( 151 mg, 3.98 mmol) using N1-(2-aminoethyl)ethane-1,2-diamine (0.143 mL, 1.327 mmol) to quench. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 9:1)] ethyl 2-(4-(aminomethyl)-2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (440a) (166 mg) as a colorless gum; MS (ESI+): 607.30 (M+1).

Stage-2. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (440b).

Compound 440b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2- fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (440a) (150 mg, 0.247 mmol) in DCM (12 ml) using TFA (0.367 ml, 4.94 mmol). This resulted in the preparation after treatment of ethyl 2-(4(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (440b) , which was used as is in the next stage. MS (ESI+): 507.20 (M+1).

Stage-3. Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (440c).

Compound 440c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran -5yl)methoxy)phenyl)acetate (440b) (0.247 mmol, from previous step-2) in THF/MeOH (6 ml each), using a solution of lithium hydroxide monohydrate (85 mg, 1.976 mmol) in water (6 ml) stirred at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (440c) (88 mg, 75 %), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 6H), 7.81 (d, J=1.6 Hz, 1H), 7.75-7.61 (m, 2H), 7.51-7.38 (m, 3H), 7.24 (d, J=7.7 Hz, 1H), 7.04-6.99 (m, 2H), 5.26 (s, 2H) , 4.52 (s, 2H), 4.17 (s, 2H), 3.99 (s, 2H), 3.58 (s, 2H), 3.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.70; MS (ESI+): 479.20 (M+1); MS (ESI-): 477.20 (M-1); analysis calculation for CjHyFNO^HCl^SHO: С, 54.37; N, 5.75; N, 4.70; Cl, 11.89; observed: C, 54.24; N, 5.70; N, 4.76; Cl, 11.94.

- 537 045626

Scheme-441

Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (441c).

Stage-1. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 441a).

Compound 441a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (416a) (360 mg , 0.867 mmol) in DCM (9 ml)/THF (3.5 ml), using triphenylphosphine (257 mg, 0.980 mmol), ethyl 2-(4acetamido-2-hydroxyphenyl) acetate (417b) (155 mg, 0.653 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene 1,2-dicarboxylate (DCAD, 360 mg, 0.980 mmol) in DCM (9 ml). This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 50% 9:1 ethyl acetate/methanol in hexanes), ethyl 2-(4-acetamido-2-((7-(3-(( (tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (441a) (195 mg, 47%) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.55-7.27 (m, 6H) , 7.10 (s, 2H), 7.00 (s, 1H), 5.15 (s, 2H), 4.52 (s, 2H), 4.26 (d, J=6.4 Hz, 2H), 3.89 (k, J=7.0 Hz, 2H), 3.54 (s, 2H), 3.29 (s, 3H), 2.03 (s, 3H), 1.41 ( s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 657.25 (M+Na).

Stage-2. Preparation of ethyl 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (441b).

Compound 441b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl) -2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (441a) (100 mg, 0.158 mmol) in DCM (10 ml) using TFA (0.234 ml, 3.15 mmol). This resulted in the preparation after treatment of ethyl 2-(4-acetamido2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (441b), which was used as is in the next stage. MS (ESI+): 535.20 (M+1).

Stage-3. Preparation of 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (441c).

Compound 441c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl )methoxy)phenyl)acetate (441b) (0.158 mmol, from previous step-2) in THF/methanol (4 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (54 mg, 1.264 mmol) in water (4 ml) and stirring at room temperature for 17.5 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (with 0.1% HCl)/acetonitrile (from 1 :0 to 0:1)] 2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid ( 441c) (72 mg, 90%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.16 (s, 1H), 9.97 (s, 1H), 8.44 (s, 3H), 7.79 (d, J=1.6 Hz, 1H), 7.747.61 (m, 2H), 7.49 (d, J=1.8 Hz, 1H), 7.47-7.39 (m, 2H), 7.15-7.03 (m, 2H), 7.00 (s, 1H), 5.18 (s, 2H), 4.52 (s, 2H), 4.23-4.10 (m, 2H), 3.50 ( s, 2H), 3.29 (s, 3H), 2.03 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.48; MS (ESI+): 507.20 (M+1); MS (ESI-): 505.20 (M-1); analysis calculation for CaHiFNO^HCl-^HO: C, 57.19; N, 5.66; N, 4.76; Cl, 6.03; observed: C, 57.04; N, 5.22; N, 4.71; Cl, 5.89.

- 538 045626

Scheme-442

442с 442d (-)-isomer

Preparation of (-)-2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (442d).

Stage-1. Preparation of (+)-(R,Z)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1((tert-butylsulfinyl)imino) ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (442a).

Compound 442a was prepared according to the procedure described in step-1 of Scheme-258 from ethyl 2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (252b) (500 mg, 0.897 mmol) and (R)-2-methylnponan-2-sulfinamide (137 mg, 1.121 mmol) in tetrahydrofuran (10 ml), using tetraethoxytitanium (0.376 ml, 1.793 mmol) and reflux for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] (+)-(R ,Z)-ethyl 2-(2-((7-(3(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5yl)methoxy )phenyl)acetate (442a) (391 mg, 66%) as a yellow gum;

^1H NMR (300 MHz, DMSO-d6) δ 7.92-7.78 (m, 4H), 7.78-7.76 (m, 1H), 7.54-7.40 (m, 2H) , 7.36-7.19 (m, 3H), 7.14-7.09 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.73 (s, 3H), 1.38 (s, 9H), 1.26 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); optical rotation [a] _D = +48.00 (c = 0.3, MeOH).

Stage-2. Preparation of (-)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((R)1,1-dimethylethylsulfinamido)ethyl)benzofuran -5-yl)methoxy)phenyl)acetate (442b).

Compound 442b was prepared according to the procedure described in step-2 of scheme-258 from (+)(R,Z)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (442a) (350 mg, 0.530 mmol) in tetrahydrofuran (12 ml) using sodium borohydride ( 41 mg, 1.059 mmol) and stirring at room temperature for 10 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (-)-ethyl 2-(2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-( 1 -((R)-1,1 dimethylethylsulfinamido)ethyl)benzofuran- 5-yl)methoxy)phenyl)acetate (442b) (215 mg, 61%) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.55-7.40 (m, 3H), 7.31-7.17 (m, 3H), 7.10 (d, J=8.1 Hz, 1H), 6.94-6 .83 (m, 2H), 5.92 (d, J=8.0 Hz, 1H), 5.22 (s, 2H), 4.674.45 (m, 1H), 4.23 (d, J= 6.3 Hz, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.56 (d, J=6.9 Hz, 3H), 1 .38 (s, 9H), 1.14 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 685.20 (M+Na); optical rotation [a]D= -26.67 (c=0.06, MeOH).

Stage-3. Preparation of ethyl 2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (442c).

Compound 442c was prepared according to the procedure described in step-5 of Scheme-1 from (-)ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2- (1-(R)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (442b) (200 mg, 0.302 mmol) in DCM (15 mL), using TFA (0.448 mL, 6 .03 mmol) and stirring at room temperature for 19 hours. This resulted in the preparation after treatment of ethyl 2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl) methoxy)phenyl)acetate (442c), which was used as is in the next step. MS (ESI+): 459.20 (M+1).

Stage-4. Preparation of (-)-2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (442d).

Compound 442d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy) phenyl)acetate (442c) (0.302 mmol, from previous step-3) in MeOH/THF (6 ml; 1:1) using hydroxide monohydrate solution

- 539 045626 lithium (0.103 g, 2.416 mmol) in water (6 ml) and stirring at room temperature for 20 hours.

This gave, after work-up and purification by reverse phase column chromatography [C18, 100 g, eluted with acetonitrile in H ₂ O with 0.1% HCl (1:0 to 0:1)] (-)-2- (2-((2-(1aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (442d) (40 mg,

31%), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.96-8.70 (m, 3H), 8.52 (s, 3H), 8.27-8.11 (m, 1H), 7. 99 (dt, J=7.4, 1.7 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.28-7.19 (m, 2H), 7.11-7.06 (m, 2H), 6.90 (td, J=7.4 , 1.1 Hz, 1H), 5.27 (s, 2H), 4.82-4.65 (m, 1H), 4.23-4.08 (m, 2H), 3.59 (s, 2H), 1.66 (d, J=6.8 Hz, 3H); MS (ESI+): 431.10 (M+1); MS (ESI-): 429.20 (M-1); analysis calculation for

C26H2 ₆ N2O4-HCl-0.5CF3COOH-3.0H2O: C, 56.10; N, 5.84; N, 4.85; Cl, 6.13; observed: C, 56.22; N, 5.89; N, 4.61; Cl, 6.09; chiral HPLC 89.06% ee; [method: ethanol/heptane 90:10 [0.1% DEA in heptane: 0.1% DEA in ethanol], temperature: 15°C, UV detection: = 242 nm; flow rate: 1 ml/min; analysis time: 70 min; compound (452d) (Rt=45.273 min, 5.47%) compound (442d) (Rt=51.833 min; 94.53%)]; optical rotation [a] _D = -8.0 (c = 0.05, MeOH).

Scheme-443

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetic acid (443i).

Stage-1. Preparation of methyl 7-bromobenzo[b]thiophene-5-carboxylate (443b).

To a stirred solution of methyl benzo[b]thiophene-5-carboxylateα (443a) (1.00 g, 5.20 mmol) in AcOH (20.0 mL) was added sodium acetate (1.70 g, 20.71 mL) at room temperature mmol), Br ₂ (1.66 g, 10.38 mmol) and stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with EtOAc (2x100 ml). The combined organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by flash column chromatography (silica gel, eluted with 1% EtOAc in n-heptane) to give methyl 7-bromobenzo[b]thiophene-5-carboxylateα (443b ) (0.80 g, 57%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.26 (d, J=1.6 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.11 (s, 1H), 7.95 (dd, J=8.5, 1.6 Hz, 1H), 3.86 (s, 3H).

Stage-2. Preparation of 7-bromobenzo[b]thiophene-5-carboxylic acid (443c).

Compound 443c was prepared according to the procedure described in step-6 of Scheme-1 from methyl 7-bromobenzo[b]thiophene-5-carboxylate (443b) (2.20 g, 8.11 mmol) in THF/MeOH (6 .6 ml each) using a solution of LiOH (0.680 g, 16.20 mmol) in water (6.6 ml). This resulted in 7bromobenzo[b]thiophene-5-carboxylic acid (443c) (2.00 g, 96%) as an off-white solid upon treatment;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 8.00 ( d, J=8.5 Hz, 1H).

Stage-3. Preparation of (7-bromobenzo[b]thiophen-5-yl)methanol (443d).

Compound 443d was prepared according to the procedure described in step-1 of Scheme-23 from 7bromobenzo[b]thiophene-5-carboxylic acid (443c) (2.00 g, 7.77 mmol) using N-methylmorpholine (0.868 g , 8.55 mmol) in THF (20 ml), isobutyl chloroformate (1.168 g, 8.55 mmol) and NaBH4 (0.441 g, 11.65 mmol). This resulted in, after work-up and purification by flash chromatography,

- 540 045626 column (silica gel, eluted with 2-4% EtOAc in n-heptane) (7-bromobenzo[b]thiophen-5-yl)methanol (443d) (1.10 g, 58%) as an off-white solid substances;

1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=8.3 Hz, 2H), 7.74 (s, 1H), 7.46-7.37 (m, 1H), 5 .40 (t, J=5.8

Hz, 1H), 4.67 (d, J=5.8 Hz, 2H).

Stage-4. Preparation of 7-bromo-5-(chloromethyl)benzo[b]thiophene (443e).

Compound 443e was prepared according to the procedure described in step-4 of scheme-257 from (7bromobenzo[b]thiophen-5-yl)methanol (443d) (3.0 g, 12.34 mmol) in DCM (30 ml), using SOCl ₂ (2.93 g, 24.62 mmol), DMF (0.5 ml) and stirred the reaction at room temperature for 2 hours. This resulted in the following work-up and purification by flash column chromatography (silica gel, eluted with 1-2% EtOAc in n-heptane) 7-bromo-5-(chloromethyl)benzo[b]thiophene (443e) (2.90 g, 90%) as an off-white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.15-7.92 (m, 2H), 7.89-7.78 (m, 1H), 7.60-7.42 (m, 1H ), 4.98 (s, 2H).

Stage-5. Preparation of ethyl 2-(2-((7-bromobenzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate (443f).

Compound 443f was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(chloromethyl)benzo[b]thiophene (443e) (1.0 g, 3.82 mmol) using ethyl 2-( 2-Hydroxy-4methylphenyl)acetate (269d) (1.85 g, 9.55 mmol) in DMF (20 ml), using K2CO3 (0.792 g, 5.73 mmol) and stirring at room temperature for 24 h. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 1-3% EtOAc in nheptane), ethyl 2-(2-((7-bromobenzo[b]thiophen-5-yl)methoxy)-4- methylphenyl)acetate (443f) (1.14 g, 71%) as an off-white solid;

1H NMR (300 MHz, chloroform-d) δ 7.84-7.60 (m, 2H), 7.42 (dd, J=8.4, 1.7 Hz, 1H), 7.19 (s, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.76-6.66 (m, 2H), 5.13 (d, J=5.9 Hz, 2H), 4, 02 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.27 (s, 3H), 1.08 (t, J=7.1 Hz, 3H).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen5-yl)methoxy)-4-methylphenyl)acetate (443g).

Compound 443g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate (443f) (1 .0 g, 2.38 mmol) in acetonitrile (25 ml) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) ( 1.18 g, 3.57 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.167 g, 0.237 mmol) and a solution of Na ₂ CO ₃ (0.756 g, 7.14 mmol) in water (8 ml) and heating in nitrogen atmosphere at 90°C for 2 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 1-3% EtOAc in n-heptane), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino) methyl)phenyl)benzo[b]thiophen-5yl)methoxy)-4-methylphenyl)acetate (443g) (1.0 g, 77%) as an off-white semi-solid;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=8.3 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.53-7 .43 (m, 5H), 7.31 (d, J=4.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.94 (s, 1H), 6 .77-6.68 (m, 1H), 5.19 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.84 (k, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.28 (s, 3H), 1.37 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Stage-7. Preparation of 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5yl)methoxy)-4-methylphenyl)acetic acid (443h).

Compound 443h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophene-5- yl)methoxy)-4methylphenyl)acetate (443g) (0.9 g, 1.64 mmol) in MeOH/THF (4.5 ml, 1:1 each), using lithium hydroxide monohydrate solution (0.173 g, 4. 12 mmol) in water (4.5 ml) and stirring at room temperature for 2 hours. This gave, after workup, 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetic acid (443h) (0.7 g, 82%) as an off-white solid;

1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.98 (s, 1H), 7.82 (s , 1H), 7.577.41 (m, 5H), 7.31 (t, J=4.6 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.92 (s , 1H), 6.71 (d, J=7.5 Hz, 1H), 5.21 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.50 (s , 2H), 2.27 (s, 3H), 1.38 (s, 9H).

Stage-8. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4methylphenyl)acetic acid (443i).

Compound 443i was prepared according to the procedure described in step-10 of Scheme-257 from 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophene-5- yl)methoxy)-4methylphenyl)acetic acid (443h) (0.7 g, 1.35 mmol) in 1,4-dioxane (35 ml), using a solution of 1,4dioxane.HC1 (28%, 3.5 ml) and stirred for 4 hours at room temperature. This gave, after work-up and purification by reverse phase chromatography on a [C18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7- (3(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetic acid (443i) (22 mg), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.77 (s , 1H), 7.67-7.49 (m, 4H), 7.07 (d, J=7.5 Hz, 1H), 6.92 (s, 1H), 6.71 (d, J= 7.5 Hz, 1H), 5.22 (s, 2H), 4.14 (s, 2H), 3.48 (s, 2H), 2.27 (s, 3H); MS (ESI+): 418.10 (M+1); MS (ESI-): 416.10 (M-1).

- 541 045626

Scheme-444

CH ₃

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (444c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate ( 444a).

Compound 444a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (416a) (513 mg , 1.236 mmol) in DCM (10 ml) using triphenylphosphine (405 mg, 1.545 mmol), ethyl 2-(2-hydroxy-4methylphenyl) acetate (269d) (200 mg, 1.03 mmol) and solution (E)- bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 567 mg, 1.545 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 3:1 to 1:1)] ethyl 2-(2-((7-( 3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (444a) (413 mg, 68%) as colorless gum ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.72 (d, J=1.6 Hz, 1H), 7.56-7.27 (m, 5H), 7.08 (d, J=7 .5 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J=1.4 Hz, 1H), 6.75-6.69 (m, 1H), 5.19 (s , 2H), 4.52 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.88 (k, J=7.1 Hz, 2H), 3.55 (s , 2H), 3.29 (s, 3H), 2.30 (s, 3H), 1.41 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.01; MS (ESI+): 614.20 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (444b).

Compound 444b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-( methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (444a) (395 mg, 0.668 mmol) in DCM (20 ml) using TFA (0.992 ml, 13.35 mmol). This resulted in the preparation after treatment of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (444b), which was used as is in the next stage. MS (ESI+): 492.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (444c).

Compound 444c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy )-4-methylphenyl)acetate (444b) (0.668 mmol, from previous step-2) in THF/methanol (10 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (0.229 g, 5.34 mmol) in water (10 ml) and stirring at room temperature for 14 hours. This resulted in the following work-up and purification by reverse phase column chromatography [column C-18, eluted with water (with 0.1% HCl)/acetonitrile (from 1: 0 to 0:1)] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (444c) ( 165 mg, 53%), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (s, 3H), 7.78 (d, J=1.6 Hz, 1H), 7.73 (td, J=7.4, 1 .7 Hz, 1H), 7.66 (td, J=7.5, 1.7 Hz, 1H), 7.49-7.37 (m, 2H), 7.08 (d, J=7, 5 Hz, 1H), 7.00 (s, 1H), 6.95-6.93 (m, 1H), 6.74-6.70 (m, 1H), 5.22 (s, 2H), 4.52 (s, 2H), 4.16 (s, 2H), 3.52 (s, 2H), 3.29 (s, 3H), 2.28 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.73; MS (ESI+): 464.20 (M+1); MS (ESI-): 462.20 (M-1); analysis calculation for C ₂₇ H ₂₆ FNO ₅ -HCl-H ₂ O: C, 62.61; N, 5.64; N, 2.70; Cl, 6.84; observed: C, 62.31; N, 5.53; N, 2.86; Cl, 7.08.

- 542 045626

Scheme-445

Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (445c).

Stage-1. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (445a).

Compound 445a was prepared according to the procedure described in step-2 of Scheme-256 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl) benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (309e) (300 mg, 0.513 mmol) in methanol (15 ml), using nickel(II) chloride hexahydrate (31 mg, 0.128 mmol) and sodium borohydride (116 mg, 3.08 mmol) using N1-(2aminoethyl)ethane-1,2-diamine (0.111 mL, 1.026 mmol) to quench. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)], ethyl 2-(4-(aminomethyl)-2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (445a) (117 mg); MS (ESI+): 589.30 (M+1).

Stage-2. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (445b).

Compound 445b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)- 2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (445a) (110 mg, 0.187 mmol) in DCM (10 mL) using TFA (0.278 mL, 3.74 mmol). This resulted in the preparation, upon treatment, of ethyl 2-(4-(aminomethyl)-2-((7-(3(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (445b), which was used as is in the next stage. MS (ESI+): 489.20 (M+1).

Stage-3. Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran5-yl)methoxy)phenyl)acetic acid (445c).

Compound 445c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5- yl)methoxy)phenyl)acetate (445b) (0.187 mmol, from previous step-2) in THF/MeOH (4 ml each), using a solution of lithium hydroxide monohydrate (0.064 g, 1.496 mmol) in water (6 ml) was stirred at room temperature for 19 hours. This gave, after work-up and purification by reverse phase column chromatography [C18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2 -(4(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (445c) (53 mg, 24% in three stage), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 6H), 8.02-7.99 (m, 1H), 7.93 (dt, J=7.4, 1.7 Hz , 1H), 7.74 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.63-7.53 (m, 2H), 7 .40 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.056.96 (m, 2H), 5.27 (s, 2H), 4 .59 (s, 2H), 4.14 (s, 2H), 4.00 (s, 2H), 3.60 (s, 2H), 3.33 (s, 3H); MS (ESI+): 461.20 (M+1); MS (ESI-): 460.20 (M-1); analysis calculation for C2 ₇ H28N2O5-2.0HCl-2.6H2O: C, 55.88; N, 6.11; N, 4.83; Cl, 12.22; observed: C, 55.84; N, 5.84; N, 4.79; Cl, 12.00.

- 543 045626

Scheme-446

Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (446c).

Stage-1. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (446a).

Compound 446a was prepared according to the procedure described in step-2 of Scheme-256 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl) benzofuran-5-yl)methoxy)-4cyanophenyl)acetate (422c) (320 mg, 0.561 mmol) in methanol (15 ml), using nickel(II) chloride hexahydrate (33 mg, 0.140 mmol) and sodium borohydride (127 mg, 3.36 mmol) using N1-(2aminoethyl)ethane-1,2-diamine (0.111 mL, 1.026 mmol) to quench. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)] ethyl 2-(4-(aminomethyl)-2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (446a) (84 mg) as a colorless gum.

Stage-2. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (446b).

Compound 446b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)- 2-(Hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (446a) (80 mg, 0.139 mmol) in DCM (10 ml), using TFA (0.207 ml, 2.78 mmol) and stirring at room temperature for 20 h. This resulted in the preparation, after treatment, of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (446b) , which was used as is in the next stage.

Stage-3. Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (446c).

Compound 446c was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5yl) methoxy)phenyl)acetate (446b) (0.139 mmol, from previous step-2) in THF/MeOH (4 ml each), using a solution of lithium hydroxide monohydrate (0.048 g, 1.112 mmol) in water (6 ml) was stirred at room temperature for 19 hours. This gave, after work-up and purification by reverse phase column chromatography [C18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-( 4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (446c) (32 mg, 52%), HCl salt , as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.27 (s, 1H), 8.44 (s, 6H), 8.04-8.02 (m, 1H), 7.95 (dt, J =7.4, 1.7 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 7.62-7 .51 (m, 2H), 7.39 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.01 (dd, J=7, 7, 1.5 Hz, 1H), 6.85 (s, 1H), 5.56 (t, J=5.9 Hz, 1H), 5.26 (s, 2H), 4.62 (d, J=5.7 Hz, 2H), 4.14 (s, 2H), 4.00 (s, 2H), 3.60 (s, 2H); MS (ESI+): 447.10 (M+1); MS (ESI-): 445.10 (M-1); analysis calculation for C26H26N2O5-2HCl-1.5H2O: C, 57.15; N, 5.72; N, 5.13; Cl, 12.98; observed: C, 57.12; N, 5.44; N, 5.13; Cl, 12.74.

- 544 045626

Scheme-447

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetic acid (447d).

Stage-1. Preparation of ethyl 2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindol-6-yl)methoxy)-4- methoxyphenyl)acetate (447a).

Compound 447a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate (356a) (0.85 g, 1.85 mmol) using bis(pinacolato)diboron (0.70 g, 2.77 mmol), potassium acetate (0.54 g, 5.54 mmol) and Pd(dppf )Cl ₂ DCM (0.23 g, 0.28 mmol) in anhydrous dioxane (15 ml) under argon while heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/methanol (9:1) in 0% to 10% hexanes], ethyl 2-(2-((1-isopropyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III-indol-6-yl)methoxy)-4methoxyphenyl)acetate (447a) (0.7 g, 75% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.70 (d, J=1.4 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.47 (d , J=1.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.76 (dd, J=3.1, 0.7 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.4 Hz, 1H), 5.17 (s, 2H), 4.76 (p, J= 6.6 Hz, 1H), 4.00 (k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.51 (s, 2H), 1.45 (d, J= 6.7 Hz, 6H), 1.32 (s, 12H), 1.05 (t, J=7.1 Hz, 3H); MS (ESI+): 508.2 (M+1); 530.2 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate ( 447b).

Compound 447b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (447a) (350 mg, 0.69 mmol) in dioxane (4 ml) using (+)-(S)-N-( (4chloropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (204 mg, 0.83 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) ( 73 mg, 0.10 mmol) and a solution of K2CO3 (286 mg, 2.07 mmol) in water (1 ml) heating under nitrogen at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(2-((1,1dimethylethylsulfinamido )methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (447b) (300 mg, 74% yield) as a yellow oil; MS (ESI+): 592.3 (M+1).

Stage-3. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methoxyphenyl)acetate (447c).

Compound 447c was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1- isopropyl-1H-indol-6-yl)methoxy)4-methoxyphenyl)acetate (447b) (300 mg, 0.51 mmol) in DCM (5 mL) using HCl (4 M in dioxane; 0.380 mL, 1.52 mmol) and stirring at room temperature for 1 hour. Purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0-70%] gave ethyl 2-(2-((4-(2- (aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (447c) (170 mg, 69% yield) as a pale yellow oil; MS (ESI+): 488.3 (M+1).

Stage-4. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)4-methoxyphenyl)acetic acid (447d).

Compound 447d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indole-6- yl)methoxy)-4-methoxyphenyl)acetate (447c) (170 mg, 0.35 mmol) in MeOH/THF (4 ml each), using a solution of lithium hydroxide (117 mg, 2.79 mmol) in water (1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(2-545 045626 (aminomethyl)pyridinium- 4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetic acid (447d) (105 mg, 66% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (d, J=5.1 Hz, 1H), 8.13-8.07 (m, 1H), 7.72 (d, J=3 .5 Hz, 2H), 7.64 (d, J=3.3 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.74-6.70 (m, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.40 (dd, J=8.2, 2.4 Hz , 1H), 5.27 (s, 2H), 4.83 (p, J=6.6 Hz, 1H), 4.05 (s, 2H), 3.70 (s, 3H), 3.36 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); MS (ESI+): 460.2 (M+1); MS (ESI-): 458.2 (M-1); analysis calculation for C^Hj^O^O: C, 67.91; N, 6.54; N, 8.80; detect: C, 68.04; N, 6.46; N, 8.80.

Scheme-448

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetic acid (448c).

Stage-1. Preparation of ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl )acetate (448a).

Compound 448a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (447a) (350 mg, 0.69 mmol) in dioxane (4 ml) using (+)-(S)-N-( (4-chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (219 mg, 0.83 mmol), bis(triphenylphosphine) palladium(11) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (73 mg, 0.10 mmol) and a solution of K ₂ CO ₃ (286 mg, 2.07 mmol) in water (1 ml) heating under nitrogen at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(2-((1,1dimethylethylsulfinamido )Methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (448a) (300 mg, 71% yield) as a yellow oil; MS (ESI+): 610.3 (M+1); 622.3 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methoxyphenyl)acetate (448b).

Compound 448b was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)- 1-Isopropyl-1H-indol-6yl)methoxy)-4-methoxyphenyl)acetate (448a) (300 mg, 0.49 mmol) in DCM (5 mL) using HCl (4 M in dioxane; 0.37 mL, 1.48 mmol) and stirring at room temperature for 1 hour. Purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0-70%] gave ethyl 2-(2-((4- (2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4methoxyphenyl)acetate (448b) (240 mg, 96% yield) as pale yellow oils;

1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=4.9 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.74 (s, 1H ), 7.48 (t, J=5.3 Hz, 1H), 7.21 (t, J=1.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.3, 2.4 Hz, 1H), 6.36 (t, J=3.0 Hz, 1H ), 5.25 (s, 2H), 4.82 (p, J=6.7 Hz, 1H), 3.95-3.92 (m, 2H), 3.91-3.86 (m, 2H), 3.54 (s, 2H), 3.17 (s, 3H), 1.50 (d, J=6.7 Hz, 6H), 0.97 (t, J=7.1 Hz, 3H); MS (ESI+): 506.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-methoxyphenyl)acetic acid (448c).

Compound 448c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indole -6-yl)methoxy)-4methoxyphenyl)acetate (448b) (170 mg, 0.35 mmol) in MeOH/THF (4 ml each), using a solution of lithium hydroxide (159 mg, 3.80 mmol) in water ( 1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(2-(aminomethyl)-3 -fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-546 045626 methoxyphenyl)acetic acid (448c) (135 mg, 60% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (d, J=5.0 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.51 (t, J=5.3 Hz, 1H), 7.27 (t, J=1.3 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H) , 6.68 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.4 Hz, 1H), 6.37 (t, J=2.9 Hz, 1H), 5.26 (s, 2H), 4.82 (g, J=6.6 Hz, 1H), 3.98 (d, J=2.1 Hz, 2H), 3.73 (s, 3H), 3.47 (s, 2H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ -130.79; MS (ESI+): 478.2 (M+1); MS (ESI-): 476.2 (M-1); analysis calculation for C ₂₇ H ₂₈ FN ₃ O ₄ -0.5H ₂ O: C, 66.65; N, 6.01; N, 8.64; detect: C, 66.45; N, 5.96; N, 8.57.

Scheme-449

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4fluorophenyl)acetic acid (449c).

Stage-1. Preparation of ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate (449a).

Compound 449a was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-isopropyl-1H-indol-6-yl)methanol (109d) (1.56 g, 5.82 mmol) in THF using triphenylphosphine (1.68 g, 6.40 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl) acetate (260d) (1.27 g, 6.40 mmol) and DIAD (1.24 ml, 6.40 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with EtOAc/methanol (9:1) in 0% to 30% hexane] ethyl 2-(2-((4-bromo-1- isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate (449a) (1 g, 38% yield) as a pale yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.66-7.63 (m, 2H), 7.28 (d, J=1.1 Hz, 1H), 7.24 (dd, J=8 ,4, 6.9 Hz, 1H), 7.02 (dd, J=11.4, 2.5 Hz, 1H), 6.73 (td, J=8.5, 2.5 Hz, 1H) , 6.42 (dd, J=3.3, 0.8 Hz, 1H), 5.20 (s, 2H), 4.75 (g, J=6.6 Hz, 1H), 4.02 ( k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.47 (d, J=6.6 Hz, 6H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI+): 449.1 (M+1); MS (ESI-): 447.0 (M-1).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4fluorophenyl)acetate (449b).

Compound 449b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate ( 449a) (150 mg, 0.34 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (82 mg, 0.44 mmol), bis(triphenylphosphine)palladium(P ) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (35.2 mg, 0.05 mmol) and a solution of K ₂ CO ₃ (139 mg, 1.00 mmol) in water (1.0 ml) heating in an argon atmosphere at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)1 -isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate (449b) (110 mg, 69% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (s, 1H), 7.61-7.56 (m, 2H), 7.48 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.4 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.23 (dd, J=8.3, 6.9 Hz, 1H ), 7.16 (d, J=1.3 Hz, 1H), 7.05 (dd, J=11.4, 2.6 Hz, 1H), 6.72 (td, J=8.4, 2.5 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 4.80 (p, J=6.6 Hz, 1H), 3 .90 (k, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.60 (s, 2H), 1.49 (d, J=6.6 Hz, 6H), 0 .97 (t, J=7.1 Hz, 3H); MS (ESI+): 475.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4fluorophenyl)acetic acid (449c).

Compound 449c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy) -4-fluorophenyl)acetate (449b) (110 mg, 0.23 mmol) in MeOH (4 ml), THF (4 ml), using a solution of lithium hydroxide (78 mg, 1.85 mmol) in water (1 ml) . This gave, after work-up and purification by reverse phase chromatography on a [C18 (50 g) column, eluted with ACN in water from 0% to 100%] 2-(2-((4-(3(aminomethyl)phenyl)- 1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetic acid (449c) (70

- 547 045626 mg, 68% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.12 (t, J=1.8 Hz, 1H), 7.76 (dt, J=7.8, 1.4 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=3.2 Hz, 1H), 7.47-7.39 (m, 2H), 7.29 (dt, J=7.6, 1.4 Hz, 1H), 7.09 (dd, J=8.3, 7.1 Hz, 1H), 6.88 (dd, J=11.5, 2.5 Hz, 1H), 6.66-6 .55 (m, 2H), 5.28 (s, 2H), 4.81 (hept, J=6.5 Hz, 1H), 3.97 (s, 2H), 3.38 (s, 2H) , 1.50 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -115.20; MS (ESI-): 445.2 (M-1); analysis calculation for C ₂₇ H ₂₇ FN ₂ O ₃ -0.5H ₂ O: C, 71.19; N, 6.20; N, 6.15; detect: C, 71.04; N, 6.29; N, 6.12.

Scheme-450 he

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4fluorophenyl)acetic acid (450b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)-4-fluorophenyl)acetate (450a).

Compound 450a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate ( 449a) (150 mg, 0.34 mmol) in dioxane (5 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (89 mg, 0.44 mmol), bis(triphenylphosphine) palladium(P ) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (35 mg, 0.05 mmol) and a solution of K2CO3 (139 mg, 1.00 mmol) in water (1.0 ml) heating in an argon atmosphere at 90 ° C in for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with DMA80 in DCM 0% to 50%], ethyl 2-(2-((4-(3-(aminomethyl)-2fluorophenyl) -1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate (450a) (130 mg, 79% yield) as yellow syrup;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.60-7.57 (m, 1H), 7.56-7.53 (m, 2H), 7.37 (td, J=7.4, 2.0 Hz, 1H), 7.307.19 (m, 2H), 7.10 (t, J=1.3 Hz, 1H), 7.05 (dd, J=11.4, 2.5 Hz, 1H), 6.72 (td, J=8.5, 2.5 Hz, 1H), 6.31-6.26 (m, 1H), 5.25 (s, 2H), 4.80 (p , J=6.7 Hz, 1H), 3.89 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.59 (s, 2H), 1.49 (d , J=6.6 Hz, 6H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.71, 122.60; MS (ESI+): 493.2 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)4-fluorophenyl)acetic acid (450b).

Compound 450b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl )methoxy)-4-fluorophenyl)acetate (450a) (130 mg, 0.26 mmol) in MeOH (4 ml), THF (4 ml), using a solution of lithium hydroxide (89 mg, 2.11 mmol) in water ( 1 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water from 0% to 100%] 2-(2-((4-(3-(aminomethyl)2- fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetic acid (450b) (105 mg, 86% yield) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.66 (d, J=3.1 Hz, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.53-7, 41 (m, 2H), 7.307.16 (m, 3H), 6.98 (dd, J=11.4, 2.5 Hz, 1H), 6.68 (td, J=8.5, 2, 5 Hz, 1H), 6.32 (dd, J=3.3, 1.9 Hz, 1H), 5.27 (s, 2H), 4.81 (g, J=6.6 Hz, 1H) , 3.88 (s, 2H), 3.49 (s, 2H), 1.48 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ 113.77, 121.06; MS (ESI+): 465.2 (M+1); MS (ESI-): 463.2 (M-1); analysis calculation for C27H26F2N2O3O.25H2O: C, 69.14; N, 5.70; N, 5.97; detect: C, 69.33; N, 5.66; N, 5.67.

Scheme-451

BocHN^ C TFA Η ₂ Ν _χ Preparation CN CH ₂ NH ₂ A NiCI ₂ V fl LI] BocHN^ A. J N 433a 451a ch ₂ nh ₂ ch ₂ nh ₂ 1 0 1 0 451b 451c 2-(4-(aminomethyl)-2-((7-(2 -(aminomethyl)pyridin-4-yl)benzofuran-5-

- 548 045626 yl)methoxy)phenyl)acetic acid (451c).

Stage-1. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (451a ).

Compound 451a was prepared according to the procedure described in step-2 of Scheme-256 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran- 5-yl)methoxy)-4cyanophenyl)acetate (433a) (350 mg, 0.646 mmol) in methanol (20 ml), using nickel(II) chloride hexahydrate (38 mg, 0.162 mmol) and sodium borohydride (147 mg, 3. 88 mmol) using N1-(2aminoethyl)ethane-1,2-diamine (0.140 mL, 1.292 mmol) to quench. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 4:1)] ethyl 2-(4-(aminomethyl)-2-((7-(2 -(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)phenyl)acetate (451a) (83 mg) as a colorless gum.

Stage-2. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (451b).

Compound 451b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridine-4 -yl)benzofuran-5yl)methoxy)phenyl)acetate (451a) (83 mg, 0.152 mmol) in DCM (8 ml), using TFA (0.226 ml, 3.04 mmol) and stirring at room temperature for 22 h. This resulted in the preparation, after treatment, of ethyl 2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (451b), which was used as is at the next stage. MS (ESI+): 446.20 (M+1).

Stage-3. Preparation of 2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (451c).

Compound 451c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl) methoxy)phenyl)acetate (451b) (0.068 g, 0.152 mmol) in THF/MeOH (4 ml each), using a solution of lithium hydroxide monohydrate (0.052 g, 1.216 mmol) in water (4 ml) was stirred at room temperature for 17 hours This gave, after work-up and purification by reverse phase chromatography on a [C18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(4-( aminomethyl)-2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (451c) (38 mg, 14% in 3 steps), HCl salt, in as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J=5.3 Hz, 1H), 8.51 (2s, 6H), 8.18 (d, J=2.2 Hz, 1H), 8.14-8.12 (m, 1H), 8.02 (dd, J=5.3, 1.7 Hz, 1H), 7.93-7.82 (m, 2H), 7 .43 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.02 (dd, J=7.6, 1.5 Hz, 1H), 5.30 (s, 2H), 4.37-4.26 (m, 2H), 4.04-3.93 (m, 2H ), 3.60 (s, 2H); MS (ESI+): 418.10 (M+1); MS (ESI-): 416.10 (M-1); analysis calculation for C ₂ 4H ₂ 3N3O4-2.75HCl*3H2O: C, 50.41; N, 5.60; N, 7.35; Cl, 17.05; observed: C, 50.07; N, 5.53; N, 7.22; Cl, 17.01.

Scheme-452

Preparation of 2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (452d).

- 549 045626

Stage-1. Preparation of (-)-(S,Z)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1((tert-butylsulfinyl)imino) ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (452a).

Compound 452a was prepared according to the procedure described in step-1 of Scheme-258 from ethyl 2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran- 5yl)methoxy)phenyl)acetate (252b) (500 mg, 0.897 mmol) and (S)-2-methylpropane-2-sulfinamide (136 mg, 1.121 mmol) in tetrahydrofuran (10 ml), using tetraethoxytitanium (0.376 ml, 1.793 mmol) and reflux for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] (-)-(S ,Z)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tertbutylsulfinyl)imino)ethyl)benzofuran-5-yl) methoxy)phenyl)acetate (452a) (319 mg, 64%) as a yellow gum;

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.92-7.74 (m, 5H), 7.52-7.39 (m, 2H), 7.34-7.20 (m, 3H ), 7.15-7.07 (m, 1H), 6.96-6.88 (m, 1H), 5.27 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.73 (s, 3H), 1.38 (s, 9H), 1.26 ( s, 9H), 0.97 (t, J=7.1 Hz, 3H); optical rotation [a] _D = -45.13 (c = 0.195, MeOH).

Stage-2. Preparation of (+)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((S)1,1-dimethylethylsulfinamido)ethyl)benzofuran -5-yl)methoxy)phenyl)acetate (452b).

Compound 452b was prepared according to the procedure described in step-2 of scheme-258 from (-)(S,Z)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl) phenyl)-2-(1-((tertbutylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (452a) (300 mg, 0.454 mmol) in tetrahydrofuran (10 ml) using sodium borohydride (35 mg , 0.908 mmol) and stirring at room temperature for 18 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (+)-ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((S)-1,1dimethylethylsulfinamido)ethyl)benzofuran-5 -yl)methoxy)phenyl)acetate (452b) (160 mg, 53%) as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.87 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.56-7.40 (m, 3H), 7.33-7.24 (m, 2H), 7.21 (dd, J=6.2 Hz, 1H), 7.11 (d , J=8.1 Hz, 1H), 6.94-6.85 (m, 2H), 5.91 (d, J=8.1 Hz, 1H), 5.22 (s, 2H), 4 ,64-4.48 (m, 1H), 4.23 (d, J=6.2 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.56 (d, J=6.9 Hz, 3H), 1.38 (s, 9H), 1.14 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); optical rotation [a] _D = +14.4 (c = 0.125, MeOH).

Stage-3. Preparation of ethyl 2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (452c).

Compound 452c was prepared according to the procedure described in step-5 of Scheme-1 from (+)ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2- (1-((S)-1,1dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (452b) (150 mg, 0.226 mmol) in DCM (12 mL), using TFA (0.336 mL, 4. 53 mmol) and stirring at room temperature for 18 hours. This resulted in the preparation after workup of ethyl 2-(2-((2-(1-aminoethyl)-7-(3(aminomethyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (452c), which was used as is in the next step. MS (eSi+): 459.2o (M+1).

Stage-4. Preparation of 2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (452d).

Compound 452d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy) phenyl)acetate (452c) (0.226 mmol, from previous step-3) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (77 mg, 1.808 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18, 100 g, eluted with MeCN in H ₂ O with 0.1% HCl (1:0 to 0:1)] 2 -(2-((2-(1-aminoethyl)-7(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (452d) (20 mg, 21%), HCl salt, in as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 12.21 (s, 1H), 8.92-8.82 (m, 3H), 8.66-8.48 (m, 3H), 8.22 -8.19 (m, 1H), 7.98 (dt, J=7.3, 1.8 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.70 ( d, J=1.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.23 (s, 1H), 7.21 (s, 1H), 7.11-7.05 (m, 2H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.86-4.61 (m, 1H), 4, 27-4.06 (m, 2H), 3.59 (s, 2H), 1.66 (d, J=6.9 Hz, 3H); MS (ESI+): 431.20 (M+1); MS (ESI-): 429.15 (M-1).

- 550 045626

Scheme-453

(+)-isomer

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5 yl)methoxy)-4-methylphenyl)acetic acid (453d).

Stage-1. Preparation of (+)-(S)-N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7yl)pyridin-2-yl)methyl)-2-methylpropan-2- sulfinamide (453a).

Compound 453a was prepared according to the procedure described in step-3 of Scheme-1 from (2 (methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran -5-yl)methanol (278a) (1.5 g, 4.71 mmol) in dioxane (25 ml) using (+)-(S)-N-((4-chloro-3-fluoroniridine-2- yl)methyl)-2methylpropane-2-sulfinamide (220c) (1.248 g, 4.71 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.496 g, 0.707 mmol) and solution of K2CO3 (1.955 g, 14.14 mmol) in water (3 ml) heating under argon at 100°C for 18 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:2)] (+)-(S)-N-((3- fluoro-4-(5-(hydroxymethyl)-2(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (453a) (517 mg, 26%) as brown resins;

^1H NMR (300 MHz, DMSO-d6) δ 8.50 (dd, J=4.9, 0.7 Hz, 1H), 7.71-7.69 (m, 1H), 7.63 (dd , J=5.6, 4.9 Hz, 1H), 7.39 (t, J=1.4 Hz, 1H), 7.00 (s, 1H), 5.83 (t, J=5, 8 Hz, 1H), 5.31 (t, J=5.7 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.51 (s, 2H), 4.40 (dd, J=5.8, 2.1 Hz, 2H), 3.29 (s, 3H), 1.11 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.27;

MS (ESI+): 421.10 (M+1); optical rotation [a] _D = +35.56 (c = 0.045, MeOH).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl )methoxy)-4-methylphenyl)acetate (453b).

Compound 453b was prepared according to the procedure described in step-2 of Scheme-23 from (+)(S)-N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7 -yl)pyridin-2-yl)methyl)-2methylpropan-2-sulfinamide (453a) (476 mg, 1.133 mmol) in DCM (10 ml), using triphenylphosphine (405 mg, 1.545 mmol), ethyl 2-(2- Hydroxy-4-methylphenyl)acetate (269d) (200 mg, 1.030 mmol) and (E)-bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 567 mg, 1.545 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (+)-(S)-ethyl 2-(2- ((7-(2-((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (453b) (215 mg, 35 %) in the form of a colorless resin;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=5.0 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.65 (t , J=5.2 Hz, 1H), 7.50 (s, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.04 (s, 1H), 6.98-6 .95 (m, 1H), 6.75-6.71 (m, 1H), 5.84 (t, J=5.7 Hz, 1H), 5.21 (s, 2H), 4.52 ( s, 2H), 4.43-4.39 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 3.30 (s, 3H ), 2.30 (s, 3H), 1.11 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -128.11; MS (ESI+): 597.20 (M+1); optical rotation [a] _D = +34.78 (c = 0.115, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (453c).

Compound 453c was prepared according to the procedure described in step-3 of scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (453b) (205 mg, 0.344 mmol) in THF (7 ml) using HCl (3 M aq. ; 0.344 ml, 1.031 mmol) and stirring at room temperature for 2 hours. This resulted in the preparation after workup of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin4-yl)-2-( methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (453c), which was used as is in the next step. MS (ESI+): 493.20 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran - 551 045626

5-yl)methoxy)-4-methylphenyl)acetic acid (453d).

Compound 453 d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran -5-yl)methoxy)-4methylphenyl)acetate (453c) (0.344 mmol; from previous step-3) in MeOH (7 ml), THF (7 ml), using lithium hydroxide solution (0.118 g, 2.75 mmol) in water (7 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 up to 0:1)] 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid ( 453d) (81 mg, 51%), HCl salt, as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.0 Hz, 1H), 8.60-8.53 (m, 3H), 7.87 (d, J=1 .6 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.59-7.57 (m, 1H), 7.08 (d, J=7.6 Hz, 1H ), 7.05 (s, 1H), 6.94 (s, 1H), 6.75-6.70 (m, 1H), 5.24 (s, 2H), 4.54 (s, 2H) , 4.42-4.32 (m, 2H), 3.52 (s, 2H), 3.30 (s, 3H), 2.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.62; MS (ESI+): 465.10 (M+1); MS (ESI-): 463.10 (M-1); analysis calculation for C26H25FN2O5-1.25HCl-1.75H2O: C, 57.66; N, 5.54; N, 5.17; Cl, 8.18; observed: C, 57.68; N, 5.40; N, 5.12; Cl, 8.19.

Scheme-454

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (454d).

Stage-1. Preparation of tert-butyl ((4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7yl)pyridin-2-yl)methyl)carbamate (454a).

Compound 454a was prepared according to the procedure described in step-3 of Scheme-1 from (2(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran -5-yl)methanol (278a) (1241 mg, 3.90 mmol) in dioxane (20 ml), using tert-butyl ((4-chloropyridin-2-yl)methyl)carbamate (271a) (885 mg, 3 .65 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (384 mg, 0.547 mmol) and a solution of K ₂ CO ₃ (1512 mg, 10.94 mmol) in water (2 .4 ml) heating in a nitrogen atmosphere at 100°C for 18 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/methanol (1:0 to 19:1)] tert-butyl ((4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7 -yl)pyridin-2-yl)methyl)carbamate (454a) (941 mg) as a brown gum; MS (ESI+): 399.20 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (454b).

Compound 454b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl ((4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate (454a) (900 mg, 2.259 mmol) in DCM (20 mL) using triphenylphosphine (889 mg, 3.39 mmol), ethyl 2-(2hydroxy-4-methylphenyl) acetate (269d) (570 mg, 2.94 mmol) and (E)-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 1244 mg, 3.39 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)], ethyl 2-(2-((7-(2-( ((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (454b) (374 mg, 19% in two steps) as colorless resins;

1H NMR (300 MHz, DMSO-d6) δ 8.64 (dd, J=5.2, 0.8 Hz, 1H), 7.85-7.52 (m, 4H), 7.45 (t, J=6.0 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.04 (s, 1H), 6.96 (s, 1H), 6.73 (d, J=7.4 Hz, 1H), 5.21 (s, 2H), 4.59 (s, 2H), 4.33 (d, J=6.1 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.56 (s, 2H), 3.34 (s, 3H), 2.30 (s, 3H), 1.39 (s, 9H), 0.95 ( t, J=7.1 Hz, 3H); MS (ESI+): 447.20 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (454c).

Compound 454c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2

- 552 045626 (2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (454b ) (360 mg, 0.626 mmol) in DCM (25 ml), using TFA (0.931 ml, 12.53 mmol) and stirring at room temperature for 20 hours. This resulted in ethyl 2-(2-(( 7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (454c), which was used as is in the next step. MS (ESI+): 475.20 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (454d).

Compound 454d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)-4-methylphenyl)acetate (454c) (0.626 mmol; from previous step-3) in MeOH (10 ml), THF (10 ml), using a solution of lithium hydroxide (214 mg, 5.01 mmol) in water ( 10 ml) and stirring at room temperature for 19 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (454d) ( 161 mg, 58%), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.3 Hz, 1H), 8.54 (s, 3H), 8.06-8.04 (m, 1H), 7.99 (dd, J=5.3, 1.7 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H ), 7.09 (d, J=7.5 Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 6.73 (d, J=7.5 Hz, 1H ), 5.25 (s, 2H), 4.61 (s, 2H), 4.41-4.20 (m, 2H), 3.55 (s, 2H), 3.34 (s, 3H) , 2.29 (s, 3H); MS (ESI+): 447.20 (M+1); MS (ESI-): 445.20 (M-1); analysis calculation for C ₂₆ H ₂₆ N ₂ O ₅ -1.25HCl-1.75H ₂ O: C, 59.64; N, 5.92; N, 5.35; Cl, 8.46; observed: C, 59.67; N, 5.70; N, 5.30; Cl, 8.67.

Scheme-455

Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)4-methylphenyl)acetic acid (455c ).

Stage-1. Preparation of (+)-ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy )-4-methylphenyl)acetate (455a).

Compound 455a was prepared according to the procedure described in step-2 of Scheme-23 from (+)(R)-N-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran -7-yl)phenyl)ethyl)-2-methylpropane-2sulfinamide (278b) (1.0 g, 2.307 mmol) in DCM (20 ml) using triphenylphosphine (0.907 g, 3.46 mmol), ethyl 2-( 2-Hydroxy-4-methylphenyl)acetate (269d) (0.582 g, 3.00 mmol) and solution of (E)-bis(4chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.270 g, 3.46 mmol) in DCM (20 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with ethyl acetate in hexanes (1:0 to 1:1)] (+)-ethyl 2-(2-((7-(3-( 1-((R)-1,1dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (455a) (556 mg, 40%) as a white solid substances;

^1H NMR (300 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.85-7.77 (m, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.55-7.50 (m, 2H), 7.09 (d, J=7.5 Hz, 1H), 6.99 (s , 1H), 6.97 (s, 1H), 6.75-6.70 (m, 1H), 6.02 (d, J=8.1 Hz, 1H), 5.21 (s, 2H) , 4.78-4.46 (m, 5H), 3.90 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 3.32 (s, 3H), 2, 30 (s, 3H), 1.14 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d6) δ -217.17; MS (ESI+): 632.30 (M+Na); optical rotation [a] _D = +4.66 (c = 0.815, MeOH).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetate (455b).

To a stirred solution of (+)-ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2

- 553 045626 fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (455a) (470 mg, 0.771 mmol) in THF (15 ml) was added 3N aq. HCl (0.771 mL, 2.312 mmol) at room temperature and stirred for 3 hours. The reaction mixture was concentrated in vacuo to dryness to give ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl )-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (455b), which was used as is in the next step. MS (ESI+): 506.20 (M+1).

Stage-3. Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (455c) .

Compound 455c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5 -yl)methoxy)-4-methylphenyl)acetate (455b) (0.771 mmol; from previous step-2) in THF/MeOH (10 ml each), using a solution of lithium hydroxide monohydrate (0.264 g, 6.17 mmol) in water (10 ml). This resulted in, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] (+)-2-(2 -((7-(3-(1-amino-2-fluoroethyl)phenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (455c) (168 mg, 57%), HCl salt, as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.97 (td, J=4.4, 1.7 Hz, 1H), 7.73 (d, J=1 .6 Hz, 1H), 7.687.59 (m, 3H), 7.09 (d, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.96-6.94 (m , 1H), 6.72 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 5.23 (s, 2H), 4.99-4.72 (m, 3H), 4.58 (s, 2H), 3.54 (s, 2H), 3.33 (s, 3H), 2.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 222.70; MS (ESI+): 478.20 (M+1); MS (ESI-): 476.20 (M-1); analysis calculation for C2sH28FNO5-0.95HCi-1.75H2O: C, 61.86; N, 6.02; N, 2.58; Cl, 6.19; observed: C, 61.91; N, 5.71; N, 2.53; Cl, 6.07; optical rotation [a]D = +14.58 (c = 0.48, MeOH).

Scheme-456

Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (456c).

Stage-1. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (456a).

Compound 456a was prepared according to the procedure described in step-2 of Scheme-256 from ethyl 2-(2-((7-(3-((tert-butoxycarbonylamino)methyl)-2-fluorophenyl)benzofuran-5-yl) methoxy)-4cyanophenyl)acetate (411b) (310 mg, 0.555 mmol) in methanol, using nickel(N) chloride hexahydrate (33 mg, 0.139 mmol) and sodium borohydride (126 mg, 3.33 mmol), using 1H to quench -(2aminoethyl)ethane-1,2-diamine (0.12 ml, 1.110 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 4:1)], ethyl 2-(4-(aminomethyl)-2-((7-(3 -(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (456a) (141 mg) as a white solid; MS (ESI+): 563.30 (M+1).

Stage-2. Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (456b).

Compound 456b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2- fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (456a) (135 mg, 0.240 mmol) in DCM (8 ml), using TFA (0.356 ml, 4.80 mmol) and stirring at room temperature for 20 hours. This resulted in the preparation after treatment of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (456b), which was used as is in next stage; MS (ESI+): 463.20 (M+1).

- 554 045626

Stage-3. Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (456c).

Compound 456c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy )phenyl)acetate (456b) (0.111 g, 0.240 mmol) in THF/MeOH (5 ml each), using a solution of lithium hydroxide monohydrate (0.082 g, 1.920 mmol) in water (5 ml) was stirred at room temperature for 20 This gave, after work-up and purification by reverse-phase column chromatography [C18, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(4-(aminomethyl )-2-((7-(3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (456c) (69 mg, 30% in 3 steps), HCl salt, as white solid matter;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (s, 1H), 8.57 (s, 3H), 8.50 (s, 3H), 8.07 (d, J=2, 2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.75-7.64 (m, 2H), 7.49 (s, 1H), 7.47-7, 38 (m, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.04-6.98 (m, 1H ), 5.27 (s, 2H), 4.17 (s, 2H), 3.99 (s, 2H), 3.58 (s, 2H); MS (ESI+): 435.10 (M+1); MS (ESI-): 433.20 (M-1); analysis calculation for C^FNiO^HCM^HiO: C, 56.66; N, 5.23; N, 5.29; Cl, 13.38; observed: C, 56.69; N, 4.98; N, 5.16; Cl, 12.84.

Scheme-457

2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5 Preparation of yl)methoxy)phenyl)acetic acid (457c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (457a).

Compound 457a was prepared according to the procedure described in step-2 of Scheme-23 from ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl) benzofuran-5yl)methoxy)phenyl)acetate (138b) (300 mg, 0.550 mmol) in DCM (8 ml), using triphenylphosphine (216 mg, 0.825 mmol), phenol (67.3 mg, 0.715 mmol) and solution (E )-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 303 mg, 0.825 mmol) in DCM (8 ml). This gave, after work-up and purification by flash column chromatography [silica gel, eluted with ethyl acetate in hexanes (1:0 to 3:1)] ethyl 2-(2-((7-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)-2(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (457a) (202 mg, 59%) as a colorless gum;

1H NMR (300 MHz, DMSO-d6) δ 7.75-7.67 (m, 3H), 7.55 (d, J=1.7 Hz, 1H), 7.51-7.38 (m, 2H), 7.35-7.19 (m, 5H), 7.13-7.05 (m, 4H), 7.01-6.94 (m, 1H), 6.94-6.88 ( m, 1H), 5.30 (s, 2H), 5.22 (s, 2H), 4.22 (d, J=6.3 Hz,

2H), 3.91 (k, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (457b).

Compound 457b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(phenoxymethyl)benzofuran -5yl)methoxy)phenyl)acetate (457a) (190 mg, 0.306 mmol) in DCM (15 ml), using TFA (0.454 ml, 6.11 mmol) and stirring at room temperature for 18 hours. This gave after treatment with ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (457b), which was used as is in the next step; MS (ESI+): 522.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (457c).

Compound 457c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl )acetate (457b) (0.306 mmol; from previous step-2) in THF/MeOH (5 ml each), using a solution of lithium hydroxide monohydrate (105 mg, 2.448 mmol) in water (5 ml). This led to the obtaining, after treatment and purification by - 555 045626 using reverse phase chromatography on a column [C18 column, eluted with water (with 0.1%

HC1)/acetonitrile (from 1:0 to 0:1)] 2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (457c ) (20 mg, 13%), HCl salt, as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 3H), 7.97-7.94 (m, 1H), 7.91 (dt, J=7.4, 1.7 Hz , 1H), 7.75 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.62-7.51 (m, 2H), 7 ,36-7.28 (m, 2H), 7.22 (d, J=7.4 Hz, 2H), 7.13 (s, 1H), 7.12-7.04 (m, 3H), 7.02-6.95 (m, 1H), 6.94-6.85 (m, 1H), 5.32 (s, 2H), 5.26 (s, 2H), 4.12 (s, 2H), 3.59 (s, 2H); MS (ESI+): 494.15 (M+1); MS (ESI-): 492.20 (M-1).

Scheme-458

309e 458a 458b

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4cyanophenyl)acetic acid (458b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (458a).

Compound 458a was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran -5-yl)methoxy)-4cyanophenyl)acetate (309e) (0.250 g, 0.427 mmol) in DCM (7.5 ml) using TFA (7.5 ml). This resulted in the production after treatment of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl)acetate (458a) (0.1 g , 48%) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.91-7.80 (m, 2H), 7.69 (s, 1H), 7.63 (s, 1H), 7.55 (d, J =8.5 Hz, 2H), 7.46 (dd, J=12.7, 5.6 Hz, 3H), 7.02 (s, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 4.02 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.73 (s, 2H), 3.33 (s, 3H), 0 .96 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)4-cyanophenyl)acetic acid (458b).

Compound 458b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4 -cyanophenyl)acetate (458a) (0.1 g, 0.206 mmol) in THF/MeOH (7.5 ml each), using a solution of lithium hydroxide monohydrate (0.0173 g, 0.412 mmol) in water (7.5 ml ) was stirred at room temperature for 2 hours. This resulted in the preparation after workup of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-cyanophenyl) acetic acid (458b) (0.015 g, 17%), HCl salt, as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.72 (d, J=6.0 Hz, 2H), 7.60-7.53 (m, 1H), 7.50 (s, 1H), 7.48-7.42 (m, 1H), 7.36 (s, 2H), 7.02 (s, 1H), 5.34 (s, 2H), 4.58 (s, 2H), 4.09 (s, 2H), 3.58 (s, 2H), 3.33 (s, 3H) .

- 556 045626

Scheme-459 he is about

CN

DCM, Br ₂ °C. 12h

BUT

459g

459h

PdCI ₂ (PPh ₃ ) ₂ .

N39CO3

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (459h).

Stage-1. Preparation of methyl 7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459a).

Compound 459a was prepared according to the procedure described in step-3 of Scheme-1 from methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a) (10 g, 31.63 mmol) in acetonitrile (60 ml) using ( 3-cyanophenyl)boronic acid (5.57 g, 37.96 mmol), solution of Na ₂ CO ₃ (310.5 g, 94.90 mmol) in water (20.0 ml), Pd(PPh ₃ ) ₂ Cl ₂ (4.44 g, 6.32 mmol) and heating under nitrogen at 90°C for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 40% ethyl acetate in n-heptane) methyl 7-(3-cyanophenyl)-2-methylbenzofuran-5carboxylate (459a) (6.0 g, 65%) as an oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.34-8.27 (m, 1H), 8.24-8.19 (m, 2H), 8.04 (d, J=1.7 Hz, 1H), 7.97-7.90 (m, 1H), 7.82-7.71 (m, 1H), 6.91-6.74 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3H).

Stage-2. Preparation of methyl 3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459b).

Compound 459b was prepared according to the procedure described in step-2 of scheme-425 from methyl 7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459a) (1.0 g, 3.43 mmol) in DCM ( 30 ml) using Br ₂ (540 mg, 3.43 mmol) by heating at 50°C for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 to 40% ethyl acetate in n-heptane) methyl 3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459b) (1.2 g, 34%) as an off-white solid;

^1H NMR (300 MHz, chloroform-d) δ 8.16-8.05 (m, 3H), 7.99 (ddd, J=7.8, 1.9, 1.3 Hz, 1H), 7 .65 (dt, J=7.7, 1.4 Hz, 1H), 7.56 (td, J=7.7, 0.6 Hz, 1H), 3.92 (s, 3H), 2, 48 (s, 3H).

Stage-3. Preparation of 3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzonitrile (459c).

Compound 459c was prepared according to the procedure described in step-2 of Scheme-76 from methyl 3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459b) (1.0 g, 2.70 mmol ) in THF (30 ml) using LiBH ₄ (0.472 g, 21.60 mmol) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with 40% EtOAc in n-heptane] 3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7yl)benzonitrile (459c) (0.6 g, 65%) as an off-white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.30-8.23 (m, 1H), 8.25-8.12 (m, 1H), 7.91 (dt, J=7.8, 1.3 Hz, 1H), 7.76 (td, J=7.8, 0.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 5.37 (t, J=5.8 Hz, 1H), 4.68 (d, J=5.6 Hz,

- 557 045626

2H), 2.50 (s, 3H).

Stage-4. Preparation of 3-(3-bromo-5-(chloromethyl)-2-methylbenzofuran-7-yl)benzonitrile (459d).

Compound 459d was prepared according to the procedure described in step-4 of scheme-257 from 3-(3bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzonitrile (459c) (3.2 g, 9.35 mmol ) in DCM (64 ml) using SOCl ₂ (2.22 g, 18.70 mmol) and stirred the reaction at 0°C for 2 hours. This resulted in, after workup and purification by flash column chromatography (silica gel , eluted with 10% EtOAc in n-heptane) 3-(3-bromo-5-(chloromethyl)-2-methylbenzofuran-7-yl)benzonitrile (459d) (3.2 g, 95%) as an off-white solid substances;

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.33-8.26 (m, 1H), 8.26-8.16 (m, 1H), 7.97-7.88 (m, 1H ), 7.83-7.71 (m, 2H), 7.63-7.56 (m, 1H), 4.97 (s, 2H), 2.52 (s, 3H).

Stage-5. Preparation of ethyl 2-(2-((3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (459e).

Compound 459e was prepared according to the procedure described in step-6 of Scheme-257 from 3-(3bromo-5-(chloromethyl)-2-methylbenzofuran-7-yl)benzonitrile (459d) (3.2 g, 8.87 mmol), using ethyl 2(2-hydroxyphenyl)acetate (23b) (1.59 g, 8.87 mmol) in DMF (32 ml), using Cs ₂ CO ₃ (2.89 g, 8.87 mmol) and stirring at room temperature for 12 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 20% EtOAc in nheptane), ethyl 2-(2-((3-bromo-7-(3- cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (459e) (3.2 g, 72%) as an off-white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.30 (t, J=1.7 Hz, 1H), 8.23 (dt, J=8.0, 1.4 Hz, 1H), 7, 93 (dt, J=7.8, 1.4 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.33-7.19 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.96-6 .85 (m, 1H), 5.28 (s, 2H), 3.96 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.52 (s, 3H) , 1.00 (t, J=7.1 Hz, 3H).

Stage-6. Preparation of ethyl 2-(2-((7-(3-cyanophenyl)-3-(furan-3-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (459f).

Compound 459f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate ( 459e) (504 mg, 1 mmol) in 1,4-dioxane (20 ml), using furan-3-ylboronic acid (168 mg, 1,500 mmol), solution of K2CO3 (415 mg, 3.00 mmol) in water (20 .0 ml), Pd(PPh ₃ ) ₂ Cl ₂ (140 mg, 0.2 mmol) and heating under nitrogen at 100°C for 16 hours. This resulted in, after work-up and purification by flash column chromatography [silica gel , eluted with hexanes/ethyl acetate (1:0 to 9:1)] ethyl 2-(2-((7(3-cyanophenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy )phenyl)acetate (459f) (368 mg, 75%) as a yellow gum;

^1H NMR (300 MHz, DMSO-d6) δ 8.35-8.31 (m, 1H), 8.29-8.25 (m, 1H), 8.19-8.17 (m, 1H) , 7.95-7.88 (m, 2H), 7.82 (d, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.67-7.65 (m, 1H ), 7.30-7.17 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.95 (dd, J=1.8, 0.9 Hz, 1H) , 6.93-6.86 (m, 1H), 5.27 (s, 2H), 3.88 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2, 61 (s, 3H), 0.94 (t, J=7.1 Hz, 3H).

Stage-7. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetate (459g).

Compound 459g was prepared according to the procedure described in step-2 of Scheme-256 from ethyl 2-(2-((7-(3-cyanophenyl)-3-(furan-3-yl)-2-methylbenzofuran-5- yl)methoxy)phenyl)acetate (459f) (350 mg, 0.712 mmol) in methanol (20 ml), using nickel(N) chloride hexahydrate (42 mg, 0.178 mmol) and sodium borohydride (162 mg, 4.27 mmol) using K1-(2-aminoethyl)ethane-1,2-diamine (0.154 mL, 1.424 mmol) to quench.

This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 9:1)] ethyl 2-(2-((7-(3(aminomethyl)phenyl)- 3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (459g) (31 mg) as a light yellow solid; MS (ESI+): 496.20 (M+1).

Stage-8. Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-3 -(furan-3-yl)-2-methylbenzofuran-5yl)methoxy)phenyl)acetic acid (459h).

Compound 459h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5 -yl)methoxy)phenyl)acetate (459g) (29 mg, 0.059 mmol) in THF/methanol (3 ml each), using a solution of lithium hydroxide monohydrate (15 mg, 0.351 mmol) in water (3 ml) and stirring at room temperature for 17 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1) ] 2-(2-((7-(3(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetic acid (459h) (12 mg, 44 %), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO- _d6 ) δ 12.20 (s, 1H), 8.32 (s, 3H), 8.20-8.17 (m, 1H), 7.99-7, 96 (m, 1H), 7.967.92 (m, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.82-7.80 (m, 1H), 7.66-7 .50 (m, 3H), 7.29-7.18 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.95 (dd, J=1.8, 0 .9 Hz, 1H), 6.93-6.87 (m, 1H), 5.28 (s, 2H), 4.15 (s, 2H), 3.60 (s, 2H), 2.60 (s, 3H); MS

- 558 045626 (ESI+): 468.10 (M+1); MS (ESI-): 466.10 (M-1).

Scheme-460

Preparation of (+)-2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (460d).

Stage-1. Preparation of (+)-ethyl 2-(2-((2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-7iodobenzofuran-5-yl)methoxy)phenyl)acetate (460a).

To a solution of (+)-(R,Z)-ethyl 2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5yl)methoxy)phenyl)acetate (406a) (1 .4 g, 2.467 mmol) in toluene (30 ml), cooled to -8°C, add phenylmagnesium bromide (2.467 ml, 2.467 mmol), stir at -8°C for 2 hours and leave to warm to room temperature over 14 hours The reaction mixture was quenched with saturated aq. NH ₄ Cl (60 ml), water (30 ml) and extracted with ethyl acetate (120 ml). The organic layer was washed with brine (60 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give (+)-ethyl 2-(2-((2-(((R)-1 ,1dimethylethylsulfinamido)(phenyl)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (460a) (717 mg, 45%) as a colorless gum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.68 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.59-7 .50 (m, 2H), 7.447.29 (m, 3H), 7.28-7.16 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.90 ( td, J=7.4, 1.1 Hz, 1H), 6.85 (d, J=0.8 Hz, 1H), 6.32 (d, J=6.5 Hz, 1H), 5, 78 (d, J=6.4 Hz, 1H), 5.11 (s, 2H), 4.10-3.89 (m, 2H), 3.59 (s, 2H), 1.18 (s , 9H), 1.06 (t, J=7.1 Hz, 3H); MS (ESI+): 646.10 (M+1); optical rotation [ab = +5.52 (c = 0.905, MeOH).

Stage-2. Preparation of (-)-ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((R)-1,1dimethylethylsulfinamido)(phenyl)methyl)benzofuran-5-yl)methoxy)phenyl )acetate (460b).

Compound 460b was prepared according to the procedure described in step-3 of Scheme-1 from (+)ethyl 2-(2-((2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-7 -iodobenzofuran-5yl)methoxy)phenyl)acetate (460a) (480 mg, 0.744 mmol) in dioxane (20 ml), using 3(aminomethyl)phenylboronic acid hydrochloride (6c) (209 mg, 1.115 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (104 mg, 0.149 mmol) and a solution of K2CO3 (308 mg, 2.231 mmol) in water (2 ml) under a nitrogen atmosphere while heating at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 9:1)] (-)-ethyl 2(2-((7-(3-(aminomethyl)phenyl )-2-(((r)-1,1-dimethylethylsulfinamido)(phenyl)methyl)benzofuran-5yl)methoxy)phenyl)acetate (460b) (301 mg, 65%) as a colorless gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.81-7.79 (m, 1H), 7.73-7.68 (m, 1H), 7.61 (d, J=1.7 Hz , 1H), 7.55 (dt, J=5.6, 1.7 Hz, 3H), 7.47-7.18 (m, 7H), 7.11-7.07 (m, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 6.38 (d, J=6.8 Hz, 1H ), 5.78 (d, J=6.7 Hz, 1H), 5.20 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.79 (s, 2H ), 3.61 (s, 2H), 1.15 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 625.30 (M+1); optical rotation [ab= -12.17 (c=0.115, MeOH).

Stage-3. Preparation of ethyl 2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5yl)methoxy)phenyl)acetate (460c).

Compound 460c was prepared according to the procedure described in step-10 of scheme-257, from (-)ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((R)-1, 1-Dimethylethylsulfinamido)(phenyl)methyl)benzofuran-5yl)methoxy)phenyl)acetate (460b) (280 mg, 0.448 mmol) in THF (5 ml) using 3N aq. HCl (0.448 ml, 1.344 mmol) and stirring at room temperature for 4 hours. This gave, upon workup, ethyl 2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl) phenyl)benzofuran-5yl)methoxy)phenyl)acetate (460c), which was used as is in the next step.

Stage-4. Preparation of (+)-2-(2-((2-(amino(phenyl)methyl)-7-(3(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (460d).

- 559 045626

Compound 460d was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl) methoxy)phenyl)acetate (460c) (0.448 mmol, from previous step-3) in MeOH/THF (5 ml each), using a solution of lithium hydroxide monohydrate (123 mg, 2.87 mmol) in water (5 ml) and stirring at room temperature for 18 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] (+)-2-(2-((2(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (460d) as a white solid colors (129 mg, 59%), HCl salts;

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.60 (s, 3H), 8.66 (s, 3H), 8.18 (s, 1H), 7.98-7.87 (m, 1H), 7.79-7.67 (m, 4H), 7.56 (d, J=4.8 Hz, 2H), 7.52-7.39 (m, 3H), 7.27-7 .16 (m, 2H), 7.10-7.03 (m, 1H), 6.97 (s, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 5.99 (s, 1H), 5.26 (s, 2H), 4.15 (s, 2H), 3.59 (s, 2H); MS (ESI-): 491.20 (M-1); analysis calculation for Сз^^О^НСШО: С, 63.81; N, 5.53; N, 4.80; Cl, 12.15; observed: C, 63.89; N, 5.29; N, 4.71; Cl, 12.02; optical rotation [a] _D = +16.07 (c = 0.56, MeOH).

Scheme-461

409d 461a

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6yl)methoxy)phenyl)acetic acid (461c).

Stage-1. Preparation of ethyl 2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2methylbenzofuran-6-yl)methoxy)phenyl)acetate (461a).

Compound 461a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl) acetate (409d) (515 mg, 1.090 mmol) in dioxane (10 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridin-2- yl)methylcarbamate (123a) (546 mg, 1.635 mmol), sodium bicarbonate solution (275 mg, 3.27 mmol) in water (1 ml), Pd(PPh ₃ ) ₂ Cl ₂ (230 mg, 0.327 mmol) and heat under a nitrogen atmosphere at 100°C for 3.5 hours. This resulted in, after work-up and double purification by flash column chromatography (silica gel, 24 g, eluted with 0-5% methanol in DCM), (silica gel, 24 g, eluted 0-50%, ethyl acetate in hexanes) ethyl 2-(2-((4-(2-(((tertbutoxycarbonyl)amino)methyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl) acetate (461a) (404 mg, 70% yield) as a yellowish solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.60 (dd, J=5.0, 0.9 Hz, 1H), 7.66 (t, J=1.1 Hz, 1H), 7, 58-7.51 (m, 3H), 7.49 (d, J=1.3 Hz, 1H), 7.29-7.19 (m, 2H), 7.11-7.07 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.77-6.74 (m, 1H), 5.25 (s, 2H), 4.31 (d , J=6.1 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.48 (d, J=1.0 Hz, 3H ), 1.41 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 531.30 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6yl)methoxy)phenyl)acetate (461b).

Compound 461b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2- methylbenzofuran-6yl)methoxy)phenyl)acetate (461a) (390 mg, 0.735 mmol) in DCM (25 ml) using TFA (0.566 ml, 7.35 mmol). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in 0% to 10% DCM] ethyl 2-(2-((4-(2(aminomethyl)pyridine-4 -yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate (461b) (290 mg, 92% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (d, J=5.1 Hz, 1H), 8.08 (s, 3H), 7.80 (s, 1H), 7.72- 7.67 (m, 2H), 7.54 (s, 1H), 7.30-7.20 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.95 -6.87 (m, 2H), 5.27 (s, 2H), 4.29 (s, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.51 (s, 3H), 1.02 (t, J=7.1 Hz, 3H); MS (ESI+): 431.15 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6yl)methoxy)phenyl)acetic acid (461c).

- 560 045626

Compound 461c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl )acetate (461b) (280 mg, 0.650 mmol) in THF/MeOH (8 mL each), using a solution of lithium hydroxide monohydrate (109 mg, 2.60 mmol) in water (8 mL) and stirring at room temperature for 18 hours This resulted in, after work-up and purification by reverse phase column chromatography (C-18 column, 50 g, eluted with 0 to 100% acetonitrile in 0.1% HCl/water) 2-(2-(( 4-(2(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetic acid (461c) (125 mg, 48% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (dd, J=5.2, 0.8 Hz, 1H), 8.47 (s, 3H), 7.85-7.82 ( m, 1H), 7.75-7.70 (m, 2H), 7.59 (d, J=1.3 Hz, 1H), 7.27-7.19 (m, 2H), 7.09 -7.04 (m, 1H), 6.94 (t, J=1.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.29 ( s, 2H), 4.36-4.21 (m, 2H), 3.60 (s, 2H), 2.50 (s, 3H); Analysis calculation for C ₂ 4H ₂₂ N ₂ O4-1.75HCl-H ₂ O: C, 59.52; N, 5.36; Cl, 12.81; N, 5.78; observed: C, 59.51; N, 5.21; Cl, 12.45; N, 5.83.

Scheme-462

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (462c).

Stage-1. Preparation of ethyl 2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (462a).

Compound 462a was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (2.00 g, 6.29 mmol) in DCM ( 60 ml), using triphenylphosphine (1.786 g, 6.81 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl) acetate (205a) (1.038 g, 5.24 mmol) and solution of (E)-bis(4 -chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.501 g, 6.81 mmol) in DCM (60 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 20% ethyl acetate in hexanes), ethyl 2-(5-fluoro-2-((7-iodo2-(methoxymethyl)benzofuran -5-yl)methoxy)phenyl)acetate (462a) (2.18 g, 84% yield) as a clear oil that solidified on standing.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.73 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.16-7, 04 (m, 4H), 5.12 (s, 2H), 4.59-4.52 (m, 2H), 4.03 (cd, J=7.1, 0.6 Hz, 2H), 3 .63 (s, 2H), 3.33 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -123.93; MS (ESI+): 521.00 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetate (462b).

Compound 462b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (462a ) (400 mg, 0.803 mmol) in dioxane (15 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (226 mg, 1.204 mmol), solution of potassium carbonate (333 mg, 2.408 mmol) in water (1.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (113 mg, 0.161 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted in, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0 to 5% methanol in DCM) ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5fluorophenyl) acetate (462b) (70 mg, 19% yield);

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (d, J=1.8 Hz, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7, 64 (d, J=1.6 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.43- 7.37 (m, 1H), 7.17-7.03 (m, 3H), 6.98 (s, 1H), 5.21 (s, 2H), 4.57 (s, 2H), 3 .94 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.64 (s, 2H), 3.32 (s, 3H), 0.99 (t, J= 7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.07; MS (ESI+): 478.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)5-fluorophenyl)acetic acid (462c).

Compound 462c was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2

- 561 045626 (2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (462b) (66 mg, 0.138 mmol) in THF /methanol (5 ml each) using a solution of lithium hydroxide monohydrate (36 mg, 0.829 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This resulted in, after work-up and purification by reverse phase chromatography on a column [column C-18, eluted with water (0.1% HCl)/acetonitrile from 0 to 70%] 2-(2-((7-(3(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5 -yl)methoxy)-5-fluorophenyl)acetic acid (462c) (30 mg, 48% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 3H), 7.95 (d, J=1.7 Hz, 1H), 7.93-7.87 (m, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.65-7.51 (m, 3H), 7.15-7.05 (m, 3H), 7.00 (s, 1H) , 5.23 (s, 2H), 4.58 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H), 3.32 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.07; MS (ESI+): 450.2 (M+1); analysis calculation for C26H24FNO5-HCl-H2O: C, 61.97; N, 5.40; Cl, 7.04; N, 2.78; observed: C, 62.00; N, 5.27; Cl, 6.91; N, 2.84.

Scheme-463

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (463b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetate (463a).

Compound 463a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (462a ) (400 mg, 0.803 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (136 mg, 0.803 mmol), solution of potassium carbonate (333 mg, 2.408 mmol) in water (1.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (113 mg, 0.161 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted in, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 7% methanol in DCM) ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy)- 5-fluorophenyl)acetate (463a) (127 mg, 32% yield) as a brown oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=1.7 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.44 (t, J=6.5 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.15-7.07 (m, 3H), 6, 99 (s, 1H), 5.19 (s, 2H), 4.51 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.63 (s, 2H), 3.32 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 121.95, -124.03; MS (ESI+): 496.10 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetic acid (463b).

Compound 463b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy )-5-fluorophenyl)acetate (463 a) (120 mg, 0.242 mmol) in THF/methanol (5 ml each), using a solution of lithium hydroxide monohydrate (62 mg, 1.453 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This resulted, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile from 0 to 70%] 2-(2- ((7-(3(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (463b) (84 mg, 74% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 3H), 7.77 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H), 7 .47-7.38 (m, 2H), 7.15-7.02 (m, 3H), 7.00 (s, 1H), 5.22 (s, 2H), 4.52 (s, 2H ), 4.17 (s, 2H), 3.59 (s, 2H), 3.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.68, -124.03; MS (ESI+): 468.10 (M+1); analysis calculation for C2 ₆ H ₂ 3F ₂ NO5-HCl-1.25H ₂ O C, 59.32; N, 5.07; Cl, 6.73; N, 2.66; observed: C, 59.55; N, 4.93; N, 2.74; Cl, 6.81.

- 562 045626

Scheme-464 ci

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (464d).

Stage-1. Preparation of ethyl 2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (464a) .

Compound 464a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e) (4.0 g , 9.54 mmol), using bis(pinacolato)diboron (3.63 g, 14.31 mmol), potassium acetate (2.81 g, 28.6 mmol) and Pd(dppf)Cl ₂ -DCM (0.779 g . ethyl acetate in hexanes) ethyl 2-(4-methoxy-2-((7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (464a) (3.61 g, 81% yield);

1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.65 (d, J =1.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.68 (d, J=2 .4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.16 (s, 2H), 3.99 (k, J=7.1 Hz, 2H ), 3.74 (s, 3H), 3.50 (s, 2H), 1.34 (s, 12H), 1.10-1.00 (m, 3H).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4- methoxyphenyl)acetate (464b).

Compound 464b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (464a) (1.00 g, 2.144 mmol) in dioxane (30 ml) using (+)-(S)-N-((4-chloro -3-fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (0.681 g, 2.57 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.226 g, 0.322 mmol) and a solution of K2CO3 (0.889 g, 6.43 mmol) in water (3 ml) heating under nitrogen at 90°C for 3 hours in an oil bath. This resulted in (+)-(S)-ethyl 2-(2-((7-( 2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (464b) (689 mg, 57% yield) as a light brown resin solid matter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=4.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.67 (t, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.16-7.02 (m, 2H), 6, 70 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.86 (t, J=5.8 Hz, 1H), 5.24 (s, 2H), 4.41 (dd, J=5.9, 2.0 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.74 (s , 3H), 3.53 (s, 2H), 1.11 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -127.99; MS (ESI+): 569.20 (M+1); optical rotation [a] _D = +28.27 (c = 0.375, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (464c).

Compound 464c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3- fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (464b) (650 mg, 1.143 mmol) in THF (15 ml) using HCl (3 M aq; 1.143 ml, 3.43 mmol ) and stirring at room temperature for 2 hours. This resulted in the preparation after treatment of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4 -methoxyphenyl)acetate (464c) which was used as is in the next step;

1H NMR (300 MHz, DMSO-06) δ 8.68-8.52 (m, 5H), 8.12 (d, J=2.2 Hz, 1H), 7.88 (d, J=1, 6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.16-7.07 (m, 2H) , 6.69 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.25 (s, 2H), 3.91 ( k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.53 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz,

- 563 045626

DMSO-d ₆ ) δ -128.55; MS (ESI+): 465.15 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (464d).

Compound 464d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -4-methoxyphenyl)acetate (464c) (1.143 mmol; from previous step-3) in MeOH/THF (10 ml each), using a solution of lithium hydroxide (392 mg, 9.14 mmol) in water (10 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7 -(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (464d) (353 mg, 71%), HCl salt, as a yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.66-8.59 (m, 4H), 8.12 (d, J=2.2 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.61-7.58 (m, 1H), 7.15-7 .06 (m, 2H), 6.68 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.27 (s, 2H), 4.44-4.24 (m, 2H), 3.73 (s, 3H), 3.50 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 128.40; MS (ESI+): 437.10 (M+1); MS (ESI-): 435.10 (M-1); analysis calculation for C ₂₄ H ₂₁ FN ₂ O ₅ -1.1HCl-1.25H ₂ O: C, 57.76; N, 4.97; N, 5.61; Cl, 7.81; observed: C, 57.56; H, 5.09; N, 5.64; Cl, 7.95.

Scheme-465

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (465b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (465a).

Compound 465a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e) (300 mg, 0.716 mmol ) in dioxane (5 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (220 mg, 1.073 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (75 mg, 0.107 mmol) and a solution of K2CO3 (297 mg, 2.147 mmol) in water (0.5 ml) heating under nitrogen at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 5% methanol in DCM), ethyl 2-(2-((7-(3-(aminomethyl)-2fluorophenyl)benzofuran -5-yl)methoxy)-4-methoxyphenyl)acetate (465a) (138 mg, 42% yield) as a clear oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.63-7 .56 (m, 1H), 7.45 (td, J=7.4, 1.9 Hz, 1H), 7.40 (s, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H) , 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.22 (s, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.83 ( s, 2H), 3.74 (s, 3H), 3.52 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.75; MS (ESI+): 464.10 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (465b).

Compound 465b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl )acetate (465a) (125 mg, 0.270 mmol) in MeOH/THF (5 mL each), using a solution of lithium hydroxide (69 mg, 1.618 mmol) in water (5 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2((7- (3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (465b) (104 mg, 89% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.03 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.75-7.62 (m, 2H), 7.47-7.45 (m, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.10 (d , J=8.3 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.48 (dd, J =8.3, 2.4 Hz, 1H), 5.25 (s, 2H), 4.17 (s, 2H), 3.73 (s, 3H), 3.49 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.42; MS (ESI+): 436.10 (M+1); analysis calculation for C ₂ 5H ₂₂ FNO5-HCl-0.75H ₂ O: C, 61.86; H, 5.09; Cl, 7.30; N, 2.89; observed: C, 61.53; N, 5.23; N, 2.92; Cl, 7.62.

- 564 045626

Scheme-466

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (466c).

Stage-1. Preparation of ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (466a).

Compound 466a was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (2.00 g, 6.29 mmol) in DCM ( 60 ml), using triphenylphosphine (1.786 g, 6.81 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl) acetate (303d) (1.101 g, 5.24 mmol) and solution of (E)-bis(4 -chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.501 g, 6.81 mmol) in DCM (60 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 20% ethyl acetate in hexanes), ethyl 2-(2-((7-iodo-2(methoxymethyl)benzofuran-5-yl )methoxy)-4-methoxyphenyl)acetate (466a) (2.24 g, 84% yield) as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.73 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.11 (d , J=8.3 Hz, 1H), 7.07 (s, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2, 4 Hz, 1H), 5.13 (s, 2H), 4.56 (s, 2H), 4.07-3.94 (m, 2H), 3.74 (s, 3H), 3.52 ( s, 2H), 3.33 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); MS (ESI+): 511.00 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (466b).

Compound 466b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (466a ) (500 mg, 0.980 mmol) in dioxane (15 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (275 mg, 1.470 mmol), potassium carbonate solution (406 mg, 2.94 mmol) in water (1.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (138 mg, 0.196 mmol) and heating under nitrogen at 100°C for 3 hours. This gave, after work-up and purification by flash chromatography on a column (silica gel, 24 g, eluted with 0 to 10% methanol in DCM) ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4 -methoxyphenyl)acetate (466b) (375 mg, 78% yield) as a brown oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (d, J=1.9 Hz, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7 .65 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.99 (s, 1H), 6.69 (d, J=2.4 Hz , 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.76 (s, 2H), 5.22 (s, 2H), 4.57 (s, 2H) , 3.92 (k, J=7.1 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.54 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 490.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)4-methoxyphenyl)acetic acid (466c).

Compound 466c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)- 4-methoxyphenyl)acetate (466b) (350 mg, 0.715 mmol) in THF/methanol (5 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (184 mg, 4.29 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This resulted in, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0 :1)] 2-(2-((7-(3(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (466c) (175 mg, 53, 0% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 8.72 (s, 3H), 7.99-7.96 (m, 1H), 7.95-7.88 (m, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.62-7.54 (m, 2H), 7.11 (d, J= 8.3 Hz, 1H), 7.00 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.25 (s, 2H), 4.58 (s, 2H), 4.12 (s, 2H), 3.73 (s, 3H), 3.51 (s, 2H), 3. 33 (s, 3H); MS (ESI+): 462.10 (M+1); MS (ESI-): 460.20 (M-1); analysis calculation for C ₂₇ H ₂₇ NO ₆ -HCl-0.5H ₂ O: C, 63.97; N, 5.77; N, 2.76; Cl, 6.99; observed: C, 63.90; N, 5.65; N, 2.74; Cl, 6.84.

- 565 045626

Scheme-467

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (467b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (467a).

Compound 467a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (466a ) (500 mg, 0.980 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (166 mg, 0.980 mmol), potassium carbonate solution (406 mg, 2.94 mmol) in water (1.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (138 mg, 0.196 mmol) and heating under nitrogen at 100°C for 3 hours. This gave, after work-up and purification by flash chromatography on a column (silica gel, 24 g, eluted with 0 to 7% methanol in DCM) ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl) methoxy)-4-methoxyphenyl)acetate (467a) (227 mg, 46% yield) as a brown oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (d, J=1.7 Hz, 1H), 7.63-7.54 (m, 1H), 7.44 (td, J=7 ,4, 1.9 Hz, 1H), 7.39 (t, J=1.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.10 (d, J =8.3 Hz, 1H), 6.98 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz , 1H), 5.21 (s, 2H), 4.52 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.74 (s, 3H), 3.52 (s, 2H), 3.29 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.97; MS (ESI+): 508.20 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (467b).

Compound 467b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)-4methoxyphenyl)acetate (467a) (200 mg, 0.394 mmol) in THF/methanol (5 ml each), using a solution of lithium hydroxide monohydrate (101 mg, 2.364 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% PS1)/acetonitrile (1:0 to 0:1)] 2-( 2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (467b) (76 mg, 40% yield), HCl salt , as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.87 (s, 3P), 7.78 (d, J=1.6 Hz, 1P), 7.73-7.61 (m, 2H), 7.51-7.37 (m, 2H), 7.10 (d, J=8.3 Hz, 1P), 7.00 (s, 1P), 6.67 (d, J=2.4 Hz , 1P), 6.48 (dd, J=8.3, 2.4 Hz, 1P), 5.24 (s, 2H), 4.52 (s, 2H), 4.17 (s, 2H) , 3.73 (s, 3P), 3.49 (s, 2H), 3.29 (s, 3P); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -118.66; MS (ESI+): 480.20 (M+1); MS (ESI-): 478.20 (M-1); analysis calculation for C2 ₇ P ₂₆ FNO _b · PCl · 0.5 P ₂ O: C, 61.77; N, 5.38; N, 2.67; Cl, 6.75; observed: C, 61.67; N, 5.37; N, 2.64; Cl, 6.66.

- 566 045626

Scheme-468

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3yl)phenyl)acetic acid (468h).

Stage-1. Preparation of 3-(furan-3-yl)-2-hydroxybenzaldehyde (468b).

Compound 468b was prepared according to the procedure described in step-3 of Scheme-1 from 3bromo-2-hydroxybenzaldehyde (468a) (1.0 g, 4.97 mmol; CAS No. 1829-34-1) in dioxane (15 ml ), using furan-3-ylboronic acid (0.835 g, 7.46 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.349 g, 0.497 mmol) and 3.3 M aq. K2CO3 (4.52 mL, 14.92 mmol) Heat under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-1% EtOAc in hexane) 3(furan-3-yl)-2-hydroxybenzaldehyde (468b) (0.69 g, 74% yield) as a clear yellow oil that solidified after drying under vacuum;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 10.06 (s, 1H), 8.25 (dd, J=1.6, 0.8 Hz, 1H) , 7.98 (dd, J=7.7, 1.7 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 7.73 (dd, J=7.7, 1 .7 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.09 (dd, J=2.0, 0.9 Hz, 1H).

Stage-3. Preparation of 7-bromo-5-(chloromethyl)benzofuran (468c).

Compound 468c was prepared according to the procedure described in step-4 of scheme-257 from (7bromobenzofuran-5-yl)methanol (23a) (5.00 g, 22.02 mmol) in DCM (100 ml) using SOCl ₂ ( 3.21 ml, 44.0 mmol), DMF (0.3 ml) and stirred the reaction at room temperature for δ h. This resulted in the preparation after treatment of 7-bromo-5-(chloromethyl)benzofuran (468с) (4 .88 g, 90% yield) as an off-white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J =1.6 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 4.88 (s, 2H).

Stage-3. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)benzaldehyde (468d).

Compound 468d was prepared according to the procedure described in step-2 of Scheme-152 from 3(furan-3-yl)-2-hydroxybenzaldehyde (468b) (0.69 g, 3.67 mmol) using 7-bromo- 5(chloromethyl)benzofuran (468c) (0.9 g, 3.67 mmol) and K2CO3 (1.52 g, 11.0 mmol) in DMF (20 ml) and stirring at room temperature for 16 hours. This resulted to be obtained after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-5% EtOAc in hexane) 2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl )benzaldehyde (468d) (0.82 g, 56% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.19 (d, J=0.8 Hz, 1H), 8.23-8.09 (m, 2H), 7.95 (dd, J=7, 7, 1.8 Hz, 1H), 7.82 (t, J=1.7 Hz, 1H), 7.76-7.63 (m, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.39 (td, J=7.7, 0.8 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.02 (dd, J=1 ,9, 0.8 Hz, 1H), 4.99 (s, 2H); MS (ESI+): 397/399 (M+1).

Stage-4. Preparation of 7-bromo-5-((2-(furan-3-yl)-6-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (468e).

Compound 468e was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)benzaldehyde (468d) (0.82 g, 2.064 mmol) in THF (20 ml), using methyl(methylsulfinylmethyl)sulfane (0.410 g, 3.30 mmol), Triton-B (40 wt.% in methanol) (0.432 g, 1.032 mmol) when heating at 70°C in over a period of 16 hours. This resulted in, after workup 567 045626 and purification by flash column chromatography (silica gel, 24 g, eluted 0-40%

EtOAc in hexane) 7-bromo-5-((2-(furan-3-yl)-6-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (468e) (0.67 g , 65% yield) as a pale yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.2 Hz, 1H), 8.11 (dt, J=1.6, 0.9 Hz, 1H), 7, 97 (dd, J=8.0, 1.6 Hz, 1H), 7.85 (s, 1H), 7.82-7.77 (m, 1H), 7.73-7.64 (m, 2H), 7.59 (d, J=1.4 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.10 (dd, J=2.2, 0.9 Hz, 1H), 7.00 (dd, J=1.9, 0.9 Hz, 1H), 4.83-4.71 (m, 2H), 2.71 (d, J=0.9 Hz , 3H), 2.28 (d, J=0.9 Hz, 3H); MS (ESI+): 503/505 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate (468f).

Compound 468f was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((2-(furan-3-yl)-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy )methyl)benzofuran (468e) (0.67 g, 1.331 mmol) in EtOH (20 ml), using 4 M HCl in dioxane (1.664 ml, 6.65 mmol) by heating at 80 °C for 16 h. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-5% EtOAc in hexane) ethyl 2-(2-((7bromobenzofuran-5-yl)methoxy)-3-(furan-3- yl)phenyl)acetate (468f) (474 mg, 78% yield) as a colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.1 Hz, 1H), 8.08-8.02 (m, 1H), 7.77 (t, J=1 .7 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.58-7.49 (m, 2H), 7.26 (dd, J=7.6, 1, 9 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 6.94 (dd, J=1.9, 0.8 Hz, 1H), 4.74 (s, 2H), 4.04 (k, J=7.1 Hz, 2H), 3.73 (s, 2H), 1.11 (t, J= 7.1 Hz, 3H); MS (ESI+): 455/457 (M+1).

Stage-6. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3yl)phenyl)acetate (468g).

Compound 468g was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate (468f ) (109 mg, 0.239 mmol) in dioxane (4 ml)/water (1 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (67 mg, 0.359 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (17 mg, 0.024 mmol) and 3.3 M aq. K ₂ CO ₃ (0.218 ml, 0.718 mmol) heating under N ₂ at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel 12 g, eluted with methanol in 0% to 6% DCM), ethyl 2-(2-((7-(3(aminomethyl)phenyl)benzofuran-5 -yl)methoxy)-3-(furan-3-yl)phenyl)acetate (468g) (81 mg, 70% yield) as a colorless oil, which was used as is in the following reaction; MS (ESI+): 482 (M+1).

Stage-7. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3yl)phenyl)acetic acid (468h).

Compound 468h was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3 -yl)phenyl)acetate (468g) (81 mg, 0.168 mmol) in MeOH (3 ml) using 2 M aqueous lithium hydroxide (0.421 ml, 0.841 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with 0-60% MeCN in H2O with 0.1% HCl] 2-(2-((7-(3(aminomethyl )phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetic acid (468h) (70 mg, 92% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.12 (d, J=2.2 Hz, 1H), 8.09 (dd, J=1.6, 0.8 Hz, 1H), 7, 97 (d, J=1.8 Hz, 1H), 7.90 (dt, J=7.6, 1.6 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.587.49 (m, 3H), 7.27 (dd, J=7 .6, 1.9 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.99 (dd, J =1.9, 0.8 Hz, 1H), 4.82 (s, 2H), 4.15 (s, 2H), 3.70 (s, 2H); MS (ESI+): 454 (M+1), (ESI-): 452 (M-1); analysis calculation for C ₂ 8H ₂ 3NO ₅ -HCl-1.5H ₂ O: C, 65.05; H, 5.26; Cl, 6.86; N, 2.71; observed: C, 65.11; N, 5.21; Cl, 6.99; N, 2.78.

- 568 045626

Scheme-469

469f 469g

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (469g).

Stage-1. Preparation of (2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (469b).

Compound 469b was prepared according to the procedure described in step-3 of scheme-266 from 4ethyl-2-methoxybenzaldehyde (469a) (1.82 g, 11.08 mmol; CAS No. 142224-35-9) in THF (20 ml) using methyl(methylsulfinylmethyl)sulfane (2.203 g, 17.73 mmol), Triton-B (40% methanol solution; 2.317 g, 5.54 mmol) by heating at 70°C for 16 h. This resulted in treatment and purification by flash column chromatography (silica gel, 24 g, eluted with 0-40% EtOAc in hexane) (2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (469b ) (2.66 g, 89% yield) as a pale yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.01 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 6.95 (d, J=1.6 Hz , 1H), 6.93-6.83 (m, 1H), 3.84 (s, 3H), 2.71 (s, 3H), 2.64 (k, J=7.6 Hz, 2H) , 2.28 (s, 3H), 1.22 (t, J=7.6 Hz, 3H); MS (ESI+): 271 (M+1).

Stage-2. Preparation of ethyl 2-(4-ethyl-2-methoxyphenyl) acetate (469c).

Compound 469c was prepared according to the procedure described in step-4 of scheme-266 from (2-(4ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (469b) (2.66 g, 9. 84 mmol) in ethanol (20 ml) using 4 M HCl in dioxane (12.30 ml, 49.2 mmol) by heating at 80°C for 16 h. This resulted in, after work-up and purification by flash chromatography on a column (silica gel, 24 g, eluted with 0-2% EtOAc in hexane) ethyl 2-(4-ethyl-2-methoxyphenyl) acetate (469c) (1.61 g, 74% yield) as a colorless liquid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.06 (d, J=7.5 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.73 (dd , J=7.5, 1.6 Hz, 1H), 4.05 (k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.51 (s, 2H), 2 .58 (k, J=7.6 Hz, 2H), 1.22-1.13 (m, 6H); MS (ESI+): 245 (M+Na).

Stage-3. Preparation of ethyl 2-(4-ethyl-2-hydroxyphenyl)acetate (469d).

Compound 469d was prepared according to the procedure described in step-5 of scheme-257 from ethyl 2-(4-ethyl-2-methoxyphenyl) acetate (469c) (1.61 g, 7.24 mmol) in dichloromethane (15 ml) , using boron tribromide (14.49 ml, 14.49 mmol; 1 M solution in DCM) and stirring at 0°C for 2 hours. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with 0 -10% EtOAc in hexane) to give the product ethyl 2-(4-ethyl-2-hydroxyphenyl) acetate (469d) (472 mg, 2.266 mmol, 31% yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.62 (d, J=1.7 Hz , 1H), 6.58 (dd, J=7.6, 1.7 Hz, 1H), 4.05 (k, J=7.1 Hz, 2H), 3.48 (s, 2H), 2 .49-2.43 (m, 2H), 1.15 (dt, J=10.4, 7.3 Hz, 6H); MS (ESI+): 209 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (469e).

Compound 469e was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-fluorobenzofuran-5-yl)methanol (227b) (555 mg, 2.266 mmol) in DCM (20 ml) using triphenylphosphine ( 892 mg, 3.40 mmol), ethyl 2-(4-ethyl-2-hydroxyphenyl) acetate (469d) (472 mg, 2.266 mmol) and solution of (E)-bis(4-chlorobenzyl)diazen-1,2- dicarboxylate (DCAD, 1248 mg, 3.40 mmol) in DCM (20 ml).

- 569 045626

This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 5% ethyl acetate in hexanes), ethyl 2-(2-((7-bromo-2-fluorobenzofuran5-yl)methoxy) -4-ethylphenyl)acetate (469e) (575 mg, 58% yield) as a pale yellow oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H), 6.54 ( d, J=6.4 Hz, 1H), 5.16 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.58 ( k, J=7.7 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSOd6) δ -110.50; MS (ESI+): 435/437 (M+1).

Stage-5. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetate (469f).

Compound 469f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (469e) (100 mg, 0.230 mmol) in dioxane (4 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (52 mg, 0.276 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (16 mg, 0.023 mmol) and a solution of K ₂ CO ₃ (0.209 ml, 0.689 mmol) in water (1 ml) heating under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-6% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2- fluorobenzofuran5-yl)methoxy)-4-ethylphenyl)acetate (469f) (55 mg, 52% yield) as a clear, colorless oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.76 (s, 1H), 7.68-7.59 (m, 2H), 7.56 (d, J=1.8 Hz, 1H), 7.51-7.37 (m, 2H), 7.10 (dd, J=7.8, 2.0 Hz, 1H), 6.99 (d, J=1.8 Hz, 1H), 6 .75 (d, 1H), 6.44 (dd, J=6.5, 1.6 Hz, 1H), 5.21 (s, 2H), 3.91 (k, J=7.2, 1 .9 Hz, 2H), 3.81 (s, 2H), 3.57 (s, 2H), 2.59 (k, J=7.6 Hz, 2H), 1.18 (t, 3H), 0.98 (t, J=7.9, 7.5, 2.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.77; MS (ESI+): 462 (M+1).

Stage-6. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (469g).

Compound 469g was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl )acetate (469f) (55 mg, 0.119 mmol) in THF (3 ml) and H ₂ O (1 ml), using a solution of 2.0 M aq. LiOH (0.596 ml, 1.192 mmol). This gave, after work-up and purification by reverse phase column chromatography [C18 column, 100 g, eluted with 0-60% MeCN in H ₂ O with 0.1% HCl] 2-(2-((7-(3 -(aminomethyl)phenyl)2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetic acid (469g) (31 mg, 60% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (s, 3H), 7.96 (d, J=1.5 Hz, 1H), 7.85 (m, 1H), 7.69 ( d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.62-7.54 (m, 2H), 7.11 (d, J=7 .6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H), 6.45 (d, J =6.4 Hz, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 2.58 (k, J=7.6 Hz, 2H ), 1.18 (t, J=7.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.61; MS (ESI+): 434 (M+1), (ESI-): 432 (M-1); analysis calculation for C ₂₆ H^O4-HC1-2H ₂ O ₂ : C, 61.72; N, 5.78; Cl, 7.01; N, 2.77; observed: C, 61.60; N, 5.63; Cl, 7.40; N, 2.89.

Scheme-470

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (470b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)-4-ethylphenyl)acetate (470a).

Compound 470a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (469e) (100 mg, 0.230 mmol) in dioxane (4 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (57 mg, 0.276 mmol), bis(triphenylphosphine) palladium(H) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (16 mg, 0.023 mmol) and a solution of K ₂ CO ₃ (0.209 ml, 0.689 mmol) in water (1 ml) heating under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-3% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl) -2fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (470a) (38 mg, 34.5% yield) as a colorless oil; MS (ESI+): 480 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (470b).

Compound 470b was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2-570 045626 (2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy )-4-ethylphenyl)acetate (470a) (38 mg, 0.079 mmol) in THF (3 ml) and H2O (1 ml), using a solution of 2.0 M aq. LiOH (0.198 ml, 0.396 mmol) and stirring at 40°C for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, 100 g, eluted with 0-60% MeCN in H2O with 0.1% HCl) 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4ethylphenyl)acetic acid (470b) (20 mg, 56 % yield), HCl salt, as a white solid;

Ή NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.64 (s, 3H), 7.82-7.70 (m, 2H), 7.67 (td, J= 7.4, 1.8 Hz, 1H), 7.54-7.38 (m, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.97 (d, J=1 .5 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H), 6.45 (d, J=6.4 Hz, 1H), 5.23 (s, 2H ), 4.17 (s, 2H), 3.53 (s, 2H), 2.58 (k, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H ). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.63, -118.62; MS (ESI+): 452 (M+1), (ESI-): 450 (M-1).

Scheme-471

471a

471с 471d

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (471d).

Stage-1. Preparation of ethyl 2-(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzofuran-5-yl)methoxy) phenyl)acetate (471a).

Compound 471a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate ( 466a) (1.01 g, 1.979 mmol) using bis(pinacolato)diboron (0.754 g, 2.97 mmol), potassium acetate (0.583 g, 5.94 mmol) and Pd(dppf)Cl ₂ -DCM (0.242 g, 0.297 mmol) in anhydrous dioxane (20 ml) under nitrogen atmosphere by heating at 90°C for 18 hours. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (from 1:0 up to 2:1)] ethyl 2-(4methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5yl )methoxy)phenyl)acetate (471a) (1.05 g) as a brown gum; MS (ESI+): 533.20 (M+Na).

Stage-2. Preparation of (+)-(8)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl )methoxy)-4-methoxyphenyl)acetate (471b).

Compound 471b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (471a) (500 mg, 0.980 mmol) in dioxane (20 ml) using (+)-(8)-N-((4 -chloro3-fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (311 mg, 1.176 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) ( 103 mg, 0.147 mmol) and a solution of K ₂ CO ₃ (406 mg, 2.94 mmol) in water (2.4 ml) heating under nitrogen at 100°C for 19 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:2)] (+)-(8)-ethyl 2-(2- ((7-(2-((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (471b) (113 mg, 20 % for 2 stages) in the form of a light yellow resin;

1H NMR (300 MHz, DM8O-d6) δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.65 (t, J =5.2 Hz, 1H), 7.50 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.04 (s, 1H), 6.70 (d, J =2.4 Hz, 1H), 6.49 (dd, J=8.2, 2.4 Hz, 1H), 5.84 (t, J=5.7 Hz, 1H), 5.23 (s , 2H), 4.52 (s, 2H), 4.44-4.36 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.74 (s, 3H) , 3.53 (s, 2H),

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3.30 (s, 3H), 1.11 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.10; MS (ESI+):

613.30 (M+1); optical rotation [a] _D = +26.67 (c = 0.09, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (471 sec).

Compound 471c was prepared according to the procedure described in step-3 of scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (471b) (105 mg, 0.171 mmol) in THF (5 ml) using HCl (3 M aq. ; 0.171 ml, 0.514 mmol) and stirring at room temperature for 3 hours. This resulted in the preparation after workup of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin4-yl)-2-( methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (471c), which was used as is in the next step. MS (ESI+): 509.20 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran5-yl)methoxy)-4-methoxyphenyl)acetic acid (471d).

Compound 471d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran- 5-yl)methoxy)-4methoxyphenyl)acetate (471c) (0.171 mmol; from previous step-3) in MeOH/THF (3 ml each), using a solution of lithium hydroxide (59 mg, 1.368 mmol) in water (3 ml ). This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (with 0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7 -(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (471d) (36 mg, 44% in 2 steps), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (d, J=5.0 Hz, 1H), 8.62-8.54 (m, 3H), 7.87 (d, J=1 .6 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.58 (t, J=1.4 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.05 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.26 (s, 2H), 4.54 (s, 2H), 4.44-4.25 (m, 2H), 3.73 (s, 3H), 3.49 (s, 2H), 3 ,30 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.61; MS (ESI+): 481.20 (M+1); MS (ESI ^- ): 479.20 (M-1); analysis calculation for C ₂₆ H ₂₅ FN ₂ O ₆ 4.15HCH,25H ₂ O: C, 57.31; N, 5.30; Cl, 7.48; F, 3.49; N, 5.14; observed: C, 57.32; N, 5.07; N, 5.15; Cl, 7.52.

Scheme-472

472a 472b

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (472b).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (472a).

Compound 472a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (471a) (510 mg, 0.999 mmol) in dioxane (20 ml), using (4-chloropyridin-2yl)methanamine (74a) (171 mg, 1.199 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (140 mg, 0.200 mmol) and a solution of K2CO3 (414 mg, 3.00 mmol) in water (2.4 ml) heating in a nitrogen atmosphere at 100°C for 19 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with dichloromethane/DMA 80 (1:0 to 3:1)] ethyl 2-(2-((7-(2-(aminomethyl)pyridine -4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (472a) (104 mg) as a light yellow gum; MS (ESI+): 613.30 (M+1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (472b).

Compound 472b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl )methoxy)-4methoxyphenyl)acetate (472a) (100 mg, 0.204 mmol) in MeOH/THF (3 mL each), using a solution of lithium hydroxide (52 mg, 1.223 mmol) in water (3 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2-((7 -(2-(aminomethyl)pyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (472b) (12 mg, 3% in 2 steps), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.85-8.74 (m, 1H), 8.42 (s, 3H), 8.02 (s, 1H), 7.97 (dd, J =5.2, 1.7 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.12 (d , J=8.3 Hz, 1H), 7.05 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2, 4 Hz, 1H), 5.27 (s, 2H), 4.61 (s, 2H), 4.35-4.27 (m, 2H), 3.73 (s, 3H), 3.51 ( s, 2H), 3.34 (s,

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3H); MS (ESI+): 463.20 (M+1); MS (ESI-): 461.10 (M-1).

Scheme-473

Preparation of 2-(2-((7-(3 -(aminomethyl)phenyl)-6-fluorobenzofuran-5 -yl)methoxy)phenyl)acetic acid (473e).

Stage-1. Preparation of (7-bromo-6-fluorobenzofuran-5-yl)methanol (473b).

Compound 473b was prepared according to the procedure described in step-1 of Scheme-23 from 7bromo-6-fluorobenzofuran-5-carboxylic acid (473a) (200 mg, 0.772 mmol) using Nmethylmorpholine (0.102 ml, 0.927 mmol) in THF (6 ml), isobutyl chloroformate (0.122 ml, 0.927 mmol) and NaBH ₄ (88 mg, 2.316 mmol) in water (2 ml). This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 50% EtOAc in hexane] (7-bromo-6-fluorobenzofuran-5-yl)methanol (473b) ( 179 mg, 95% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.12 (d, J=2.2 Hz, 1H), 7.71 (dt, J=6.9, 0.9 Hz, 1H), 7, 12 (d, J=2.2 Hz, 1H), 5.39 (t, J=5.7 Hz, 1H), 4.63 (ddd, J=5.8, 1.6, 0.8 Hz , 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.17.

Stage-2. Preparation of ethyl 2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c).

Compound 473c was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-6-fluorobenzofuran-5-yl)methanol (473b) (175 mg, 0.714 mmol) in DCM (8 ml) using triphenylphosphine (206 mg, 0.786 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (167 mg, 0.928 mmol) and (E)-bis(4chlorobenzyl) diazene-1,2-dicarboxylate (DIAD, 288 mg, 0.786 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane from 0-50%] ethyl 2-(2-((7-bromo6 -fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473 s) (244 mg, 84% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (d, J=2.2 Hz, 1H), 7.81 (d, J=6.7 Hz, 1H), 7.31-7, 03 (m, 4H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.23 (t, J=0.9 Hz, 2H), 3.95 (k, J =7.1 Hz, 2H), 3.57 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d6) δ -119.47.

Stage-3. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetate (473d).

Compound 473d was prepared according to the procedure described in step-3 of scheme-1 ethyl 2-(2((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c) (240 mg, 0.589 mmol) in dioxane (5 ml), using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (133 mg, 0.884 mmol), Pd(Ph ₃ ) ₂ Cl ₂ (62 mg, 0.088 mmol) and K ₂ CO ₃ solution (244 mg, 1.768 mmol) in water (0.5 ml) in an Ar atmosphere when heated at 100°C for 3 hours. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0-50%]ethyl 2-(2-((7-(3(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473d) (255 mg, 100% yield) as yellow oil, which was used in the next step without further purification. MS (ESI+): 434.1 (M+1).

Stage-4. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (473e).

Compound 473e was prepared according to the procedure described in step-6 of Scheme-1, ethyl 2-(2((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473d ) (255 mg, 0.588 mmol) in MeOH/THF (6 mL), using a solution of lithium hydroxide (99 mg, 2.353 mmol) in water (2 mL). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3-(aminomethyl)phenyl)6-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (473e) (77 mg, 32% yield), HCl salt, as a white solid.

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1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.00 (d, J=2.2 Hz, 1H), 7.78 (d, J=6.8 Hz, 1H ), 7.73 (s, 1H),

7.66-7.48 (m, 3H), 7.23-7.12 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.99 (d, J= 2.3 Hz, 1H), 6.86 (td, J=7.3, 1.1 Hz,

1H), 5.21 (s, 2H), 4.05 (s, 2H), 3.50 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.50; MS (ESI+): 406.1 (M+1); MS (ESI-): 404.1 (M-1); analysis calculation for: SzNoRKO^NSY^SCHO: C, 62.07; N, 5.10; Cl, 7.63;

N, 3.02; observed: C, 62.02; N, 5.12; Cl, 7.87, N, 3.20.

Scheme-474 nh ₂ HCl 6c

K ₂ CO ₃

Pd(PPh ₃ ) ₂ CI ₂

DIAD. PPh

DCM

2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5

Preparation of fluorophenyl)acetic acid (474c).

Stage-1. Preparation of ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate (474a).

Compound 474a was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-isopropyl-1H-indol-6-yl)methanol (109d) (0.62 g, 2.312 mmol) in toluene (20 ml) using triphenylphosphine (1.213 g, 4.62 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl) acetate (205a) (0.458 g, 2.312 mmol) and DIAD (0.935 g, 4.62 mmol). This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with 0-5% EtOAc in hexanes], ethyl 2-(2-((4bromo-1-isopropyl-1H-indol-6-yl )methoxy)-5-fluorophenyl)acetate (474a) (0.58 g, 56% yield) as a pale yellow oil.

1H NMR (300 MHz, DMSO-d6) δ 7.69-7.60 (m, 2H), 7.28 (d, J=0.8 Hz, 1H), 7.17-7.04 (m, 3H), 6.42 (d, J=3.2 Hz, 1H), 5.16 (s, 2H), 4.75 (hept, J=6.7 Hz, 1H), 4.02 (k, 2H), 3.64 (s, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.07 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.07; MS (ESI+): 448/450.

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5fluorophenyl)acetate (474b).

Compound 474b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate ( 474a) (104 mg, 0.232 mmol) in dioxane (4 ml)/water (1 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (65 mg, 0.348 mmol), bis(triphenylphosphine)palladium (P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (16 mg, 0.023 mmol) and 3.3 M aq. K ₂ CO ₃ (0.211 ml, 0.696 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-6% MeOH in DCM), ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1isopropyl- 1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate (474b) (72 mg, 65% yield) as a colorless oil; MS (ESI+) 475 (M+1).

Stage-3. Preparation of 2-(2-((4-(3 -(aminomethyl)phenyl)-1-isopropyl-1 H-indol-6-yl)methoxy)-5fluorophenyl)acetic acid (474c).

Compound 474c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy) -5-fluorophenyl)acetate (474b) (72 mg, 0.152 mmol) in MeOH (3 ml), using 2 M aqueous lithium hydroxide (0.379 ml, 0.759 mmol) and stirring at room temperature for 16 hours. This resulted in obtained after workup and purification by reverse phase chromatography on a [C18 (100 g) column, eluted with 060% MeCN in H ₂ O] 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl- 1H-indol-6-yl)methoxy)-5fluorophenyl)acetic acid (474c) (54 mg, 80% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (d, J=1.8 Hz, 1H), 7.76-7.69 (m, 1H), 7.62 (s, 1H), 7.59 (d, J=3.3 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.43-7.36 (m, 1H), 7.32 (d , J=1.3 Hz, 1H), 7.00 (dtt, J=20.0, 8.5, 3.9 Hz, 3H), 6.65 (d, J=3.3 Hz, 1H) , 5.24 (s, 2H), 4.81 (hept, J=6.9 Hz, 1H), 4.06 (s, 2H), 3.50 (s, 2H), 1.51 (s, 3H), 1.48 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.84; MS (ESI+): 447 (M+1), (ESI-): 445 (M-1); analysis calculation for: C27H27FN2O3-0.65HCl«1.25H2O. C, 65.81; N, 6.17; Cl, 4.68; N, 5.69; observed: C, 66.19; N, 6.05; Cl, 4.67; N, 5.73.

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Scheme-475

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-III-indol-6-yl)methoxy)-5methoxyphenyl)acetic acid (475g).

Stage-1. Preparation of 2-(3-methoxyphenyl)-1-morpholinoethanethione (475b).

Compound 475b was prepared according to the procedure described in Step-1 of Scheme-265 from 1-(2hydroxy-5-methoxyphenyl)ethanone (475a) (2 g, 12.04 mmol; CAS No. 705-15-7) in N- methyl-2-pyrrolidinone (6 ml), using sulfur powder (0.772 g, 24.07 mmol), morpholine (2.097 g, 24.07 mmol) by heating at 130°C for 16 hours. This resulted in the following workup and purification: via flash column chromatography (silica gel, 24 g, eluted with 0-30% ethyl acetate and hexanes) 2-(3-methoxyphenyl)-1-morpholinoethanethione (475b) (1.30 g, 40% yield) as a red semi-solid ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 6.79 (d, J=3.0 Hz, 1H), 6.75 (d, J=8.7 Hz , 1H), 6.67 (dd, J=8.7, 3.0 Hz, 1H), 4.28-4.18 (m, 2H), 4.10 (s, 2H), 3.68- 3.61 (m, 7H), 3.45-3.36 (m, 2H); MS (ESI+) 268 (M+1).

Stage-2. Preparation of 2-(2-hydroxy-5-methoxyphenyl)acetic acid (475c).

Compound 475c was prepared according to the procedure described in step-2 of scheme-265 from 2-(3methoxyphenyl)-1-morpholinoethanethione (475b) (1.30 g, 4.86 mmol) in ethanol (20 ml) using 4 M aq. NaOH (3.65 ml, 14.59 mmol) and reflux for 16 hours. This resulted in 2-(2-hydroxy-5-methoxyphenyl)acetic acid (475c) (0.87 g, 98% yield) as a black semi-solid, which was used in the next step without further purification.

Stage-3. Preparation of ethyl 2-(2-hydroxy-5-methoxyphenyl)acetate (475d).

Compound 475d was prepared according to the procedure described in step-3 of scheme-265 from 2-(2hydroxy-5-methoxyphenyl)acetic acid (475c) (0.87 g, 4.78 mmol) in ethanol (20 ml) using sulfuric acid (1 ml) and reflux for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 020% ethyl acetate in hexanes), ethyl 2-(2-hydroxy -5-methoxyphenyl)acetate (475d) (0.49 g, 49% yield) as an orange oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 6.77-6.60 (m, 3H), 4.06 (k, J=7.1 Hz, 2H), 3.65 (s, 3H), 3.51 (s, 2H), 1.17 (t, J=7.1 Hz, 3H); MS (ESI+): 211 (M+1).

Stage-4. Preparation of ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5methoxyphenyl)acetate (475e).

Compound 475e was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-isopropyl-1H-indol-6-yl)methanol (109d) (0.688 g, 2.56 mmol) in toluene (5 ml), using triphenylphosphine (1.223 g, 4.66 mmol), ethyl 2-(2-hydroxy-5-methoxyphenyl) acetate (475d) (0.49 g, 2.331 mmol) and DIAD (0.943 g, 4.66 mmol ) in toluene (20 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with 0-10% EtOAc in hexanes], ethyl 2-( 2-((4-bromo-1-isopropyl-Shindol-6-yl)methoxy)-5-methoxyphenyl)acetate (475e) (455 mg, 42% yield) as an orange oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.68-7.59 (m, 2H), 7.28 (d, J=1.1 Hz, 1H), 7.01 (d, J=8 .8 Hz, 1H), 6.85 (d, J=3.1 Hz, 1H), 6.80 (dd, J=8.8, 3.1 Hz, 1H), 6.41 (d, J =3.2 Hz, 1H), 5.11 (s, 2H), 4.75 (hept, J=6.7 Hz, 1H),

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4.03 (k, 2H), 3.69 (s, 3H), 3.61 (s, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.09 (t , J=7.1, 0.7 Hz, 3H); MS (ESI+):

482/484 (M+Na).

Stage-5. Preparation of ethyl 2-(2-((4-(3-(αmunomethyl)-2-fluorophenyl)-1-isopronul-1H-undol-6yl)methoxy)-5-methoxyphenyl)acetate (475f).

Compound 475f was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate ( 475e) (100 mg, 0.217 mmol) in dioxane (4 ml), water (1 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (66.9 mg, 0.326 mmol), bis(triphenylphosphine )palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (15 mg, 0.022 mmol) and 3.3 M aq. K ₂ CO ₃ (0.197 ml, 0.652 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-6% MeOH in DCM), ethyl 2-(2-((4-(3(aminomethyl)-2-fluorophenyl)-1- isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate (475f) (73 mg, 67% yield) as a clear, colorless oil; MS (ESI+): 505 (M+1).

Stage-6. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)5-methoxyphenyl)acetic acid (475g).

Compound 475g was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl) methoxy)-5-methoxyphenyl)acetate (475f) (73 mg, 0.145 mmol) in MeOH (3 ml) using 2.0 M aq. LiOH (0.362 ml, 0.723 mmol) and stirring at room temperature for 16 hours. This gave after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with 0-60% MeCN in H2O] 2 -(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5methoxyphenyl)acetic acid (475g) (42 mg, 61% yield) , HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.51 (dd, J=11.6, 2.5 Hz, 2H), 7.42 (td, J=7 ,4, 1.8 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.00 (d, J =8.8 Hz, 1H), 6.81 (d, J=3.1 Hz, 1H), 6.75 (dd, J=8.8, 3.1 Hz, 1H), 6.31 (d , J=2.7 Hz, 1H), 5.18 (s, 2H), 4.80 (hept, J=6.6 Hz, 1H), 3.86 (s, 2H), 3.68 (s , 3H), 3.52 (s, 2H), 1.49 (s, 3H), 1.47 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -121.45; MS (ESI+): 477 (M+1), (ESI-): 475 (M-1); analysis calculation for C2sH29FN2O ₄ -H2O: C, 66.78; N, 6.41; N, 5.56; detect: C, 66.87; N, 6.16; N, 5.62.

Scheme-476

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetic acid (476f).

Stage-1. Preparation of 2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxybenzaldehyde (476b).

Compound 476b was prepared according to the procedure described in step-2 of Scheme-152 from 7bromo-5-(bromomethyl)benzofuran (152a) (2.0 g, 8.15 mmol) using 2-hydroxy-3-methoxybenzaldehyde ( 476a) (1.239 g, 8.15 mmol; CAS No. 148-53-8), K ₂ CO ₃ (3.38 g, 24.44 mmol) in DMF (20 ml) and stirring at room temperature for 4 hours This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-10% EtOAc in hexane) 2((7-bromobenzofuran-5-yl)methoxy)-3-methoxybenzaldehyde (476b) (2.32 g, 79% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.16 (d, J=0.6 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.44 (dd, J=6.4, 3.3 Hz, 1H), 7.26- 7.21 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H); MS (ESI+): 383/385 (M+Na).

Stage-2. Preparation of 7-bromo-5-((2-methoxy-6-(2-(methylsulfinyl)-2(methylthio)vinyl)phenoxy)methyl)benzofuran (476c).

Compound 476c was prepared according to the procedure described in step-3 of scheme-266 from 2-((7bromobenzofuran-5-yl)methoxy)-3-methoxybenzaldehyde (476b) (2.32 g, 6.42 mmol) in THF ( 20 mL), using methyl(methylsulfinylmethyl)sulfane (1.277 g, 10.28 mmol), Triton-B (40% methanol solution; 1.451 mL, 3.21 mmol) and reflux for 16 h This gave, after work-up and purification by flash column chromatography (silica gel 24 g, eluted with 0-40% EtOAc in hexane) 7-bromo-5-((2-methoxy-6-(2-(methylsulfinyl)- 2(methylthio)vinyl)phenoxy)methyl)benzofuran (476c) (2.00 g, 67% yield) as a pale yellow oil.

1H NMR (300 MHz, DMSO-d6) δ 8.12 (d, J=2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=1.5 Hz, 1H ), 7.66-7.58 (m, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.14-5.00 (m, 2H), 3.90 (s, 3H), 2.64 (s, 3H), 2.13 (s, 3H); MS (ESI+): 467/469 (M+1).

Stage-3. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d).

Compound 476d was prepared according to the procedure described in step-4 of scheme-266 from 7bromo-5-((2-methoxy-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (476c ) (2.00 g, 4.28 mmol) in ethanol (20 mL) using HCl (4 M in 1,4-dioxane, 5.35 mL, 21.40 mmol) and reflux for 16 h This gave, after work-up and purification by flash column chromatography (silica gel 24 g, eluted with ethyl acetate and hexanes), ethyl 2-(2((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d ) (0.74 g, 41% yield) as a clear, colorless oil.

^1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=2.1 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.9 Hz, 1H), 7.03 (s, 1H) , 6.83 (dd, J=5.9, 3.2 Hz, 1H), 5.01 (s, 2H), 3.97 (k, J=7.1 Hz, 2H), 3.86 ( s, 3H), 3.58 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); MS (ESI+): 419/421 (M+1).

Stage-4. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetate (476e).

Compound 476e was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d) (109 mg, 0.260 mmol ) in dioxane (4 ml), water (1 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (59 mg, 0.312 mmol), bis(triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (18 mg, 0.026 mmol) and 3.3 M aq. K2CO3 (0.236 ml, 0.780 mmol) heating under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-6% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5yl )methoxy)-3-methoxyphenyl)acetate (476e) (92 mg, 79% yield) as a clear, colorless oil; MS (ESI+): 446 (M+1).

Stage-5. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetic acid (476f).

Compound 476f was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate ( 476e) (92 mg, 0.207 mmol) in MeOH (3 ml) using 2.0 M aq. LiOH (0.516 ml, 1.033 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with 0-60% MeCN in H ₂ O with 0.1% HCl] 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetic acid (476f) (68 mg, 79% yield) , HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 7.97 (d, J=1.7 Hz, 1H ), 7.91 (dt, J=7.4, 1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.66-7.52 (m, 3H) , 7.08 (d, J=2.2 Hz, 1H), 7.06-6.99 (m, 2H), 6.84 (dd, J=6.0, 3.2 Hz, 1H), 5.09 (s, 2H), 4.15 (s, 2H), 3.87 (s, 3H), 3.54 (s, 2H); MS (ESI+): 418 (M+1), (ESI-): 416 (M-1); analysis calculation for C^^NOs-HCM^^: C, 61.85; N, 5.71; Cl, 7.30; N, 2.89; observed: C, 62.03; N, 5.48; Cl, 7.35; N, 2.98.

Scheme-477

2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4 Preparation of fluorophenyl)acetic acid (477c).

- 577 045626

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (477a).

Compound 477a was prepared according to the procedure described in step-2 of Scheme-23 from (7iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (2.00 g, 6.29 mmol) in DCM ( 60 ml), using triphenylphosphine (1.786 g, 6.81 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl) acetate (260d) (1.038 g, 5.24 mmol) and solution of (E)-bis(4 -chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.501 g, 6.81 mmol) in DCM (60 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 25% ethyl acetate in hexanes), ethyl 2-(4-fluoro-2-((7-iodo-2(methoxymethyl)benzofuran -5-yl)methoxy)phenyl)acetate (477a) (2.15 g, 82% yield) as a clear oil that solidified to a white solid on standing.

^1H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.08 (s, 1H), 7.00 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J =8.5, 2.5 Hz, 1H), 5.15 (s, 2H), 4.56 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.33 (s, 3H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.64; MS: 521.00 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (477b).

Compound 477b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 477a) (400 mg, 0.803 mmol) in dioxane (15 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (226 mg, 1.204 mmol), potassium carbonate solution (333 mg, 2.408 mmol) in water (1.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (113 mg, 0.161 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted in the preparation after work-up and purification by flash chromatography on column (silica gel, 12 g, eluted with 0 to 5% methanol in DCM) ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4fluorophenyl )acetate (477b) (176 mg, 46% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.80-7.77 (m, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7.65 (d , J=1.6 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.42-7.36 (m, 1H), 7.24 (dd, J=8.3, 6.9 Hz, 1H), 7.04 (dd, J=11.3, 2.5 Hz, 1H), 6.99 ( s, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.24 (s, 2H), 4.57 (s, 2H), 3.92 (k, J =7.1 Hz, 2H), 3.81 (s, 2H), 3.60 (s, 2H), 3.33 (s, 3H), 0.97 (t, J=7.1 Hz, 3H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.65; MS: 478.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)4-fluorophenyl)acetic acid (477c).

Compound 477c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)- 4-fluorophenyl)acetate (477b) (160 mg, 0.335 mmol) in THF/methanol (5 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (86 mg, 2.010 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile 0 to 70%] 2-(2 -((7-(3(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (477c) (137 mg, 91% yield), HCl salt, as white solid.

1H NMR (300 MHz, DMSO-d6) δ 7.98-7.94 (m, 1H), 7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.61-7.52 (m, 2H), 7.24 (dd, J=8.4 , 6.9 Hz, 1H), 7.05-6.97 (m, 2H), 6.73 (td, J=8.5, 2.5 Hz, 1H), 5.27 (s, 2H) , 4.58 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H), 3.33 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 113.00; MS (ESI+): 450.20 (M+1); analysis calculation for C ₂₆ H ₂₄ FNO ₅ -HCl-1.5H ₂ O: C, 60.88; N, 5.50; N, 2.73; Cl, 6.91; observed: C, 60.72; N, 5.36; N, 2.72; Cl, 6.95.

Scheme-478

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (478b).

- 578 045626

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl) acetate (478a).

Compound 478a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate ( 477a) (400 mg, 0.803 mmol) in dioxane (15 ml), using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (136 mg, 0.803 mmol), potassium carbonate solution (333 mg, 2.408 mmol) in water (1.8 ml), Pd(PPh ₃ ) ₂ Cl ₂ (113 mg, 0.161 mmol) and heating under nitrogen at 100°C for 3 hours. This resulted in the preparation after work-up and purification by flash chromatography on column (silica gel, 12 g, eluted with 0 to 5% methanol in DCM) ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2(methoxymethyl)benzofuran-5-yl)methoxy) -4-fluorophenyl)acetate (478a) (260 mg, 65% yield) as a brown oil.

^1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=1.7 Hz, 1H), 7.64-7.56 (m, 1H), 7.44 (td, J=7 ,3, 1.9 Hz, 1H), 7.39 (t, J=1.3 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (dd, J =8.4, 6.9 Hz, 1H), 7.04 (dd, J=11.3, 2.5 Hz, 1H), 6.99 (s, 1H), 6.74 (td, J= 8.5, 2.5 Hz, 1H), 5.23 (s, 2H), 4.52 (s, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.83 ( s, 2H), 3.58 (s, 2H), 3.29 (s, 3H), 1.99 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.65, -121.98; MS (ESI+): 496.15 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (478b).

Compound 478b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy )-4-fluorophenyl)acetate (478a) (245 mg, 0.494 mmol) in THF/methanol (5 ml, 1:1 each), using a solution of lithium hydroxide monohydrate (127 mg, 2.97 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This resulted in, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile from 0 to 70%] 2-(2-((7-(3(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (478b) (138 mg, 60% yield ), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.78 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H), 7.48-7.38 (m , 2H), 7.24 (dd, J=8.4, 6.9 Hz, 1H), 7.05-6.97 (m, 2H), 6.73 (td, J=8.5, 2 .5 Hz, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 4.17 (s, 2H), 3.55 (s, 2H), 3.29 (s, 3H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -113.00, -118.72; MS (ESI+): 468.10 (M+1); analysis calculation for C26H ₂₃ F ₂ NO ₅ -HCl-0.25H ₂ O: C, 61.42; N, 4.86; N, 2.75; Cl, 6.97; observed: C, 61.45; N, 4.96; N, 2.71; Cl, 6.85.

Scheme-479

Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (479d).

Stage-1. Preparation of ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (479a).

Compound 479a was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a) (1.00 g, 2.69 mmol) in DCM (30 ml) using triphenylphosphine (0.835 g, 3.18 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl) acetate (182a) (0.634 g, 2.448 mmol) and solution (E)- bis(4-chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 1.168 g, 3.18 mmol) in DCM (30 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 80 g, eluted with 0 to 25% ethyl acetate in hexanes), ethyl 2-(4bromo-2-((7-(3-(((tert-butoxycarbonyl)amino )Methyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (479a) (760 mg, 51% yield) as a light brown oil;

- 579 045626

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.53-7, 44 (m, 2H), 7.437.27 (m, 4H), 7.19 (d, J=8.0 Hz, 1H), 7.12 (dd, J=8.0, 1.8 Hz, 1H ), 7.06 (d, J=2.2 Hz, 1H), 5.26 (s, 2H), 4.26 (d,

J=6.1 Hz, 2H), 3.88 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.41 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz,

DMSO-d ₆ ) δ -120.76.

Stage-2. Preparation of ethyl 2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (479b).

Compound 479b was prepared according to the procedure described in step-1 of scheme-262 from ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl) benzofuran-5yl)methoxy)phenyl)acetate (479a) (400 mg, 0.653 mmol) in toluene (15 ml), using tributyl(1ethoxyvinyl)stannane (0.291 ml, 0.816 mmol) and Pd(PPh ₃ ) ₄ (75 mg, 0.065 mmol) and reflux for 24 hours under nitrogen followed by hydrolysis using 3N aq. HCl (0.653 ml, 1.959 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 35% ethyl acetate in hexanes), ethyl 2-(4acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino )Methyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (479b) (170 mg, 45% yield) as a clear oil;

1H NMR (300 MHz, DMSO-06) δ 8.05 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.63 (d, J =1.6 Hz, 1H), 7.58 (dd, J=7.7, 1.5 Hz, 1H), 7.53-7.28 (m, 6H), 7.06 (d, J= 2.2 Hz, 1H), 5.32 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3 .71 (s, 2H), 2.59 (s, 3H), 1.41 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSOd ₆ ) δ -120.72.

Stage-3. Preparation of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetate (479c).

Compound 479c was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl) benzofuran-5yl)methoxy)phenyl)acetate (479b) (160 mg, 0.278 mmol) in DCM (10 ml) using TFA (0.413 ml, 5.56 mmol). This resulted in the preparation, after treatment, of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)-2fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (479c), which was used as is in the following stages. MS (ESI+): 476.10 (M+1).

Stage-4. Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5yl)methoxy)phenyl)acetic acid (479d).

Compound 479d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy) phenyl)acetate (479c) (132 mg, 0.278 mmol) in THF/MeOH (5 mL each), using a solution of lithium hydroxide monohydrate (95 mg, 2.224 mmol) in water (5 mL) and stirring at room temperature for 16 h. This resulted in the preparation, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile 0 to 50%] 2-(4-acetyl-2-( (7-(3-(aminomethyl)2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (479d) (67 mg, 54% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.75-7.63 (m, 2H), 7.61-7.55 (m, 2H), 7.51-7.49 (m, 1H), 7.48-7.36 ( m, 2H), 7.06 (d, J=2.2 Hz, 1H), 5.36 (s, 2H), 4.17 (s, 2H), 3.67 (s, 2H), 2, 57 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.35; MS (ESI+): 448.20 (M+1); analysis calculation for C ₂₆ H ₂₂ FNO ₅ -HCM,25H ₂ O: C, 61.66; N, 5.08; Cl, 7.00; N, 2.77; observed: C, 61.56; N, 5.16; Cl, 7.00; N, 2.81.

Scheme-480

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)-580 045626 acetic acid (480c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (480a).

Compound 480a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-fluorobenzofuran-5-yl)methanol (227b) (1.42 g, 5.79 mmol) in DCM (60 ml) using triphenylphosphine (1.672 g, 6.37 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl) acetate (303d) (1.462 g, 6.95 mmol) and (E)-bis(4-chlorobenzyl) solution diazene-1,2-dicarboxylate (DCAD, 2.341 g, 6.37 mmol) in DCM (60 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 20% ethyl acetate in hexanes), ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5yl)methoxy)- 4-methoxyphenyl)acetate (480a) (1.75 g, 69% yield) as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 6.54 (d, J=6.4 Hz, 1H), 6.49 (dd, J= 8.3, 2.4 Hz, 1H), 5.16 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.54 ( s, 2H), 1.09 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -110.46.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (480b).

Compound 480b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (480a) (200 mg, 0.457 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (103 mg, 0.549 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (48 mg, 0.069 mmol) and a solution of K2CO3 (190 mg, 1.372 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3-(aminomethyl)phenyl)2 -fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (480b) (90 mg, 43% yield) as a clear oil.

^1H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J=2.2 Hz, 1H), 7.66 (dt, J=8.0, 1.9 Hz, 1H), 7, 61 (d, J=1.7 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.45- 7.39 (m, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8 ,3, 2.4 Hz, 1H), 6.44 (d, J=6.4 Hz, 1H), 5.22 (s, 2H), 3.93 (k, J=7.1 Hz, 2H ), 3.83 (s, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.00 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.73. MS (ESI+): 464.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (480c).

Compound 480c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl )acetate (480b) (89 mg, 0.192 mmol) in THF/MeOH (3 ml each) using a solution of 1.0 M aq. LiOH (0.576 ml, 0.576 mmol). This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (480c) ( 22 mg, 26% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 2H, D2O replaceable), 7.94 (s, 1H), 7.85 (dt, J=6.9, 2.0 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.62-7.56 (m, 3H), 7.11 (d, J=8.3 Hz, 1H), 6, 66 (d, J=2.4 Hz, 1H), 6.56-6.37 (m, 2H), 5.24 (s, 2H), 4.14 (s, 2H), 3.73 (s , 3H), 3.51 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.56. MS (ESI+): 436.1 (M+1); (ESI-): 434.2 (M-1).

Scheme-481

481a 481b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (481b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (481a).

Compound 481a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (480a) (200 mg, 0.457 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (94 mg, 0.457 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd( PPh ₃ ) ₂ Cl ₂ ) (48 mg, 0.069 mmol) and a solution of K2CO3 (190 mg, 1.372 mmol) in water (0.5 ml) heating under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with DMA80 in DCM 0% to 50%), ethyl 2-(2-((7-(3(aminomethyl)-2 -fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (481a) (80 mg,

36% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J=1.7 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 7.46 (td, J=7.3, 1.9 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.11 ( d, J=8.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 6, 45 (d, J=6.4 Hz, 1H), 5.20 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.85 (s, 2H), 3, 74 (s, 3H), 3.53 (s, 2H), 0.99 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.68, -121.86. MS (ESI+): 482.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (481b).

Compound 481b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)- 4-methoxyphenyl)acetate (481a) (79 mg, 0.164 mmol) in THF/MeOH (2.5 ml each) using a solution of 1.0 M aq. LiOH (0.492 ml, 0.492 mmol). This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (481b ) (35 mg, 47% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 3H, D2O replaceable), 7.78-7.61 (m, 3H), 7.51-7.38 (m, 2H), 7.11 (d, J=8.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.51-6.40 (m, 2H), 5.24 (s , 2H), 4.22-4.12 (m, 2H), 3.73 (s, 3H), 3.49 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.89, -118.52. MS (ESI+): 454.1 (M+1); (ESI-): 452.2 (M-1); analysis calculation for C ₂₅ H ₂₁ F ₂ NO ₅ -1.5HCl-2H ₂ O: C, 55.18; N, 4.91; N, 2.57; observed: C, 54.94; N, 5.11; N, 2.63.

Scheme-482

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (482b).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (482a).

Compound 482a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (464a) (1.00 g, 2.144 mmol) in dioxane (25 ml) using (4-chloropyridin-2-yl)methanamine (74a) (0.306 g, 2.144 mmol), bis(triphenylphosphine) palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (0.226 g, 0.322 mmol) and a solution of K ₂ CO ₃ (0.889 g, 6.43 mmol) in water ( 2.5 ml) heating in a nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes, then 0 to 40% DMA80 in DCM), ethyl 2-(2-((7-(2 -(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (482a) (526 mg, 55% yield) as a yellow semi-solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.62 (dd, J=5.3, 0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7, 98-7.96 (m, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.77-7.71 (m, 2H), 7.14-7.08 (m, 2H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.25 (s, 2H), 3, 97-3.87 (m, 4H), 3.74 (s, 3H), 3.55 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ESI+): 447.20 (M+1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (482b).

Compound 482b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl )acetate (482a) (500 mg, 1.120 mmol) in THF/MeOH (8 mL each), using a solution of lithium hydroxide monohydrate (288 mg, 6.72 mmol) in water (8 mL) and stirring at room temperature for 16 hours This gave, after work-up and purification by reverse phase column chromatography [C18 column, eluted with water (0.1% HCl)/acetonitrile (1:0 to 0:1)] 2-(2- ((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (482b) (254 mg, 54%), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (dd, J=5.3, 0.8 Hz, 1H), 8.49 (s, 3H), 8.17 (d, J= 2.2 Hz, 1H), 8.098.08 (m, 1H), 8.00 (dd, J=5.3, 1.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.17-7.04 (m, 2H), 6.67 (d, J=2.4 Hz, 1H), 6, 49 (dd, J=8.3, 2.4 Hz, 1H), 5.28 (s, 2H), 4.36-4.27 (m, 2H), 3.73 (s, 3H), 3 .52 (s, 2H);

- 582 045626

MS (ESI+): 419.10 (M+1); MS (ESI-): 417.20 (M-1); analysis calculation for C^NzOs^I^HCHJSHzO: C,

56.11; N, 5.35; N, 5.45; Cl, 12.08; observed: C, 56.30; N, 5.29; N, 5.51; Cl, 11.94.

Scheme-483

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (483c).

Stage-1. Preparation of ethyl 2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (483a).

Compound 483a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (480a) ( 1.15 g, 2.63 mmol) using bis(pinacolato)diboron (1.002 g, 3.95 mmol), potassium acetate (0.774 g, 7.89 mmol) and Pd(dppf)Cl ₂ DCM (0.215 g, 0.263 mmol) in anhydrous dioxane (35 ml) under argon while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(2-((2fluoro-7-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (483a) (1.10 g, 86% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.75 (d, J=1.9 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.10 (d , J=8.3 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 6.35 (d, J=6.4 Hz, 1H), 5.15 (s, 2H), 4.06-3.91 (m, 2H), 3.74 (s, 3H), 3.51 (s, 2H), 1.34 (s, 12H), 1.06 (t, J=7.1 Hz, 3H).

Stage-2. Preparation of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl )acetate (483b).

Compound 483b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (483a) (260 mg, 0.537 mmol) in dioxane (10 ml) using (+)-(S)-N-((4-chloro- 3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (142 mg, 0.537 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (57 mg, 0.081 mmol) and K ₂ CO ₃ solution (223 mg, 1.611 mmol) in water (1 ml) heating in a nitrogen atmosphere at 100°C for 15 hours in an oil bath. This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with CAN in water (with 0.1% HCl) from 0% to 100%] (S)-ethyl 2-(2 -((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (483b) (165 mg, 52 % yield) in the form of a brown resin;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (d, J=4.9 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (t, J=5.2 Hz, 1H), 7.53-7.50 (m, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.54-6.45 (m, 2H), 5.86 (t, J=5.8 Hz, 1H), 5.23 (s, 2H), 4.41 (dd, J =5.8, 2.1 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.11 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ESI+): 587.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (483c).

To a stirred solution of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4 -methoxyphenyl)acetate (483b) (165 mg, 0.281 mmol) in THF (5 ml), add hydrochloric acid (4 M in 1-4-dioxane, 0.141 ml, 0.563 mmol), stir at room temperature for 30 min and concentrate under vacuum until dry. The resulting residue was dissolved in THF (5 ml), acetonitrile (1 ml) and water (1 ml) and lithium hydroxide monohydrate (59.0 mg, 1.406 mmol) was added. The reaction mixture was stirred for 48 h at room temperature and concentrated to remove THF and acetonitrile. The reaction mixture was diluted with water (2 ml) and acidified to pH 4 using 1 M HCl. The separated solid was decanted and purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to give 2-(2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4 -methoxyphenyl)acetic acid

- 583 045626 (483c) (79 mg, 62% yield), HCl salt, in the form of a pale yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, J=4.9 Hz, 1H), 8.54 (s, 3H, D2O replaceable), 7.83 (d, J=1, 6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.58 (d, J=1.4 Hz, 1H), 7.11 (d, J=8.3 Hz , 1H), 6.67 (d, J=2.4 Hz, 1H), 6.53-6.46 (m, 2H), 5.26 (s, 2H), 4.39 (d, J= 6.0 Hz, 2H), 3.73 (s, 3H), 3.50 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -111.19, 128.49. MS (ESI+): 455.1 (M+1); (ESI-): 453.1 (M-1); analysis calculation for C ₂₄ H ₂₀ F ₂ N ₂ O ₅ -1.2HCl-H ₂ O: C, 55.84; N, 4.53; Cl, 8.24; F, 7.36; N, 5.43; observed: C, 55.72; N, 4.53; Cl, 8.10; N, 5.29.

Scheme-484

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (484c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (484a).

Compound 484a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-4-fluorobenzofuran-5-yl)methanol (136b) (792 mg, 3.23 mmol) in DCM (35 ml) using triphenylphosphine (1017 mg, 3.88 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl) acetate (260d) (705 mg, 3.56 mmol) and (E)-bis(4-chlorobenzyl) diazene-1 solution ,2-dicarboxylate (DCAD, 1424 mg, 3.88 mmol) in DCM (15 ml) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography (silica gel, 40 g , eluted with 0 to 50% ethyl acetate in hexanes) ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (484a) (1.07 g, 78% yield ) as a pale yellow oil that hardened on standing;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.22 (d, J=2.2 Hz, 1H), 7.72 (d, J=6.2 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.26-7.20 (m, 1H), 7.12 (dd, J=11.2, 2.5 Hz, 1H), 6.77 (td, J =8.5, 2.5 Hz, 1H), 5.22 (d, J=1.4 Hz, 2H), 3.95 (k, J=7.1 Hz, 2H), 3.54 (s , 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.54, -124.37.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetate (484b).

Compound 484b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (484a) (153 mg, 0.360 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (81 mg, 0.540 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (37.9 mg, 0.054 mmol) and a solution of K2CO3 (149 mg, 1.079 mmol) in water (0.5 ml) heated under argon at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetate (484b) (117 mg, 72% yield) as a dark oil. MS (ESI+): 452.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (484c).

Compound 484c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl )acetate (484b) (117 mg, 0.259 mmol) in THF/MeOH (6 mL each), using a solution of LiOH (65 mg, 1.549 mmol) in water (2 mL) and stirring at room temperature overnight. This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)-4fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (484c) (98 mg, 0.231 mmol, 89% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.39 (s, 2H), 8.19 (d, J=2.2 Hz, 1H), 7.97 (d , J=1.8 Hz, 1H), 7.89 (dt, J=7.4, 1.7 Hz, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.64 -7.50 (m, 2H), 7.30-7.19 (m, 2H), 7.13 (dd, J=11.3,

- 584 045626

2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H), 3.51 ( s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ

-112.88, -124.44; MS (ESI+): 424.1 (M+1); MS (ESI-): 422.1 (M-1); analysis calculation for

C24Hi9F2NO4-HC1-1.75HiO: C, 58.66; N, 4.82; Cl, 7.21; N, 2.85; observed: C, 58.67; N, 4.38; Cl, 6.88; N,

2.83.

Scheme-485

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (485b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (485a).

Compound 485a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (484a) (150 mg, 0.353 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (89 mg, 0.529 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (37 mg, 0.053 mmol) and a solution of K ₂ CO ₃ (146 mg, 1.058 mmol) in water (0.5 ml) heating in an argon atmosphere at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 70%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-4-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (485a) (125 mg, 75% yield) as a pale yellow oil. MS (ESI+): 470.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (485b).

Compound 485b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)- 4-Fluorophenyl)acetate (485a) (125 mg, 0.266 mmol) in THF/MeOH (6 mL each), using a solution of LiOH (75 mg, 1.787 mmol) in water (2 mL) and stirring at room temperature overnight . This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (485b ) (98 mg, 83% yield), HCl salt, as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.18 (s, 1H), 8.60 (s, 3H), 8.15 (d, J=2.3 Hz, 1H), 7.79 -7.62 (m, 2H), 7.59 (d, J=6.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.32-7.18 ( m, 2H), 7.13 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.32 (s , 2H), 4.17 (s, 2H), 3.50 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -112.89, -118.53, -123.30; MS (ESI+): 442.1 (M+1); MS (ESI-): 440.1 (M-1); analysis calculation for Ci^i^NO^HCl: C, 60.32; N, 4.01; Cl, 7.42; N, 2.93; observed: C, 59.98; N, 3.88; Cl, 7.40; N, 3.17.

Scheme-486

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (486c).

- 585 045626

Stage-1. Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (486a).

Compound 486a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (2 g, 6.78 mmol) in DCM (70 ml) using triphenylphosphine (1.956 g, 7.46 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (1.612 g, 8.13 mmol) and (E)-bis(4-chlorobenzyl) solution diazene-1,2-dicarboxylate (DCAD, 2.74 g, 7.46 mmol) in DCM (70 ml) and stirring at room temperature for 1 hour. This resulted in, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 20% ethyl acetate in hexanes) ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetate (486a) (2, 3 g, 71% yield) as a white solid;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.97 (k, J=1.6 Hz, 1H), 7.93-7.60 (m, 2H), 7.26 (dd, J=8 ,3, 6.9 Hz, 1H), 7.02 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H) , 5.26 (s, 2H), 4.01 (k, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J=7.1 Hz, 3H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.24, -112.61.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (486b).

Compound 486b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (486a ) (220 mg, 0.463 mmol) in dioxane (8 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (104 mg, 0.556 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.069 mmol) and a solution of K2CO3 (192 mg, 1.389 mmol) in water (0.8 ml) heating under argon at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (486b) (192 mg, 83% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.89 (k, J=1.6 Hz, 1H), 7.84-7.79 (m, 1H), 7.78-7.75 (m , 1H), 7.75 (s, 2H), 7.54-7.41 (m, 2H), 7.26 (dd, J=8.4, 6.9 Hz, 1H), 7.06 ( dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.4, 2.5 Hz, 1H), 5.32 (s, 2H), 3.91 (k , J=7.1 Hz, 2H), 3.82 (s, 2H), 3.61 (s, 2H), 0.96 (t, J=7.1 Hz, 3h); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.08, -112.60; MS (ESI+): 502.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)4-fluorophenyl)acetic acid (486c).

Compound 486c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)- 4-fluorophenyl)acetate (486b) (0.192 g, 0.383 mmol) in THF (2 ml), acetonitrile (1 ml) and water (1 ml), using lithium hydroxide monohydrate (0.048 g, 1.149 mmol) and stirring at room temperature during the night. This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid ( 486c) (135 mg, 75% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.18 (s, 1H, D2O replaceable), 8.91 (k, J=1.6 Hz, 1H), 8.41 (s, 3H, D2O replaceable ), 7.98 (s, 1H), 7.91 (dt, J=6.9, 2.0 Hz, 1H), 7.85 (s, 1H), 7.81-7.78 (m, 1H), 7.67-7.55 (m, 2H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.3, 2, 5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.35 (s, 2H), 4.14 (s, 2H), 3.57 (s, 2H);

1H NMR (300 MHz, DMSO-d ₆ /D ₂ O) δ 8.72 (d, J=1.9 Hz, 1H), 7.94-7.85 (m, 2H), 7.80 (s , 1H), 7.73 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H ), 7.21 (dd, J=8.4, 6.9 Hz, 1H), 6.96 (dd, J=11.2, 2.5 Hz, 1H), 6.72 (td, J= 8.5, 2.5 Hz, 1H), 5.29 (s, 2H), 4.11 (s, 3H), 3.54 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -57.99, -112.97. MS (ESI+): 474.1 (M+1); (ESI-): 472.1 (M-1); LC, 2.18 min, 99.83%; analysis calculation for C ₂₅ H ₁₉ F ₄ NO ₄ -HCl-0.25H ₂ O: C, 58.37; N, 4.02; Cl, 6.89; N, 2.72; observed: C, 58.47; N, 3.80; Cl, 7.06; N, 2.82.

Scheme-487

^40ba 487a 487b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (487b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (487a).

Compound 487a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2-586 045626 (2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl) acetate (486a) (220 mg, 0.463 mmol) in dioxane (8 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (114 mg, 0.556 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.069 mmol) and a solution of K2CO3 (192 mg, 1.389 mmol) in water (0.5 ml) heating under argon at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (487a) (158 mg, 66% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.86 (k, J=1.6 Hz, 1H), 7.87-7.80 (m, 1H), 7.68-7.57 (m , 2H), 7.48 (td, J=7.4, 1.9 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.25 (dd, J=8, 3, 6.9 Hz, 1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.31 (s, 2H), 3.94-3.79 (m, 4H), 3.59 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.09, -112.59, -121.93; MS (ESI+): 520.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (487b).

Compound 487b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl) methoxy)-4-fluorophenyl)acetate (487a) (0.158 g, 0.304 mmol) in THF (2 ml), acetonitrile (1 ml), water (1 ml), using lithium hydroxide monohydrate (0.038 g, 0.912 mmol) and stirring at room temperature overnight. This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl) acetic acid (487b) (121 mg, 81% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.88 (k, J=1.7 Hz, 1H), 7.97-7.88 (m, 1H), 7.77-7.67 (m , 2H), 7.67-7.63 (m, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.35 (s, 2H ), 4.19 (s, 2H), 3.55 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.01, -112.91, -118.55. MS (ESI+): 492.1 (M+1); (ESI-): 490.1 (M-1); analysis calculation for C ₂₅ H ₁₈ F ₅ NO ₄ -HCl: C, 56.88; N, 3.63; Cl, 6.72; N, 2.65; observed: C, 56.87; N, 3.48; Cl, 7.01; N, 2.78.

Scheme-488

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (488c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (488a).

Compound 488a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (2 g, 6.78 mmol) in DCM (70 ml) using triphenylphosphine (1.956 g, 7.46 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1.710 g, 8.13 mmol) and (E)-bis(4-chlorobenzyl) solution diazene-1,2-dicarboxylate (DCAD, 2.74 g, 7.46 mmol) in DCM (70 ml) and stirring at room temperature for 1 hour. This resulted in, after work-up and purification by flash column chromatography (silica gel, 120 g, eluted with 0 to 20% ethyl acetate in hexanes) ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (488a) (1.738 g , 53% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.96 (k, J=1.6 Hz, 1H), 7.85-7.72 (m, 2H), 7.12 (d, J=8, 3 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.24 (s, 2H) , 4.01 (k, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.07 (t, J=7.1 Hz, 3H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.25.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (488b).

- 587 045626

Compound 488b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (488a ) (225 mg, 0.462 mmol) in dioxane (8 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (104 mg, 0.554 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.069 mmol) and a solution of K ₂ CO ₃ (191 mg, 1.385 mmol) in water (0.8 ml) heating in an argon atmosphere at 100 ° C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (488b) (135 mg, 57% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.89 (k, J=1.7 Hz, 1H), 7.87-7.63 (m, 4H), 7.54-7.38 (m , 2H), 7.12 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2, 4 Hz, 1H), 5.30 (s, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.75 (s, 3H), 3 .55 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.08; MS (ESI+): 514.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)4-methoxyphenyl)acetic acid (488c).

Compound 488c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)- 4-methoxyphenyl)acetate (488b) (0.132 g, 0.257 mmol) in THF (1.54 ml), acetonitrile (0.77 ml), using 1N aq. lithium hydroxide monohydrate solution (0.771 mL, 0.771 mmol) and stirring at room temperature overnight. This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (488c ) (117 mg, 94% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H, D2O replaceable), 8.91 (k, J=1.6 Hz, 1H), 8.37 (s, 3H, D2O replaceable ), 7.98 (d, J=1.8 Hz, 1H), 7.91 (dt, J=7.2, 1.8 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.68-7.54 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.32 (s, 2H), 4.15 (s, 2H), 3.74 ( s, 3H), 3.51 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.10. MS (ESI+): 486.1 (M+1); (ESI-): 484.1 (M-1); analysis calculation for C ₂₆ H ₂₂ F ₃ NO ₅ -HCl-H ₂ O: C, 57.84; N, 4.67; Cl, 6.57; N, 2.59; observed: C, 58.06; N, 4.41; Cl, 6.59; N, 2.73.

Scheme-489

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (489b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (489a).

Compound 489a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (488a ) (225 mg, 0.462 mmol) in dioxane (8 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (114 mg, 0.556 mmol), Pd(PPh ₃ ) ₂ Cl ₂ ( 49 mg, 0.069 mmol) and a solution of K ₂ CO ₃ (191 mg, 1.385 mmol) in water (0.5 ml) heating in an argon atmosphere at 100 ° C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (489a) (140 mg, 57% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.85 (t, J=1.8 Hz, 1H), 7.84 (s, 1H), 7.62 (d, J=11.9 Hz, 2H), 7.54-7.43 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6, 71 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.29 (s, 2H), 3.96-3.82 (m, 4H), 3.75 (s, 3H), 3.53 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO d6) δ 58.10, -121.91; MS (ESI+): 532.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (489b).

Compound 489b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl) methoxy)-4methoxyphenyl)acetate (489a) (0.137 g, 0.258 mmol) in THF (1.55 ml), acetonitrile (0.773 ml), using 1N aq. lithium hydroxide monohydrate solution (0.773 mL, 0.773 mmol) and stirring at room temperature overnight. This resulted in the following treatment and purification by

- 588 045626 reverse phase chromatography on a column [column C18, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acids (489b) (115 mg, 89% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.87 (k, J=1.7 Hz, 1H), 7.92 (s, 1H), 7.76-7.66 (m, 2H) , 7.66 (s, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.32 (s, 2H), 4.19 (s, 2H), 3.74 ( s, 3H), 3.49 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.02, -118.53. MS (ESI+): 504.1 (M+1); (ESI-): 502.1 (M-1); analysis calculation for C26H21F4NO5-HCl: C, 57.84; N, 4.11; Cl, 6.57; N, 2.59; observed: C, 57.47; N, 4.02; Cl, 6.53; N, 2.61.

Scheme-490

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (490c).

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy )phenyl)acetate (490a).

Compound 490a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate ( 486a) (1.5 g, 3.16 mmol) using bis(pinacolato)diboron (1.202 g, 4.73 mmol), potassium acetate (0.929 g, 9.47 mmol) and Pd(dppf)Cl ₂ -DCM (0.258 g, 0.316 mmol) in anhydrous dioxane (50 ml) under argon while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2(4-fluoro-2-((7-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (490a) (1.46 g, 89% yield) as a clear oil ;

1H NMR (300 MHz, DMSO-d6) δ 8.86 (k, J=1.6 Hz, 1H), 7.93 (dd, J=1.9, 1.0 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.25 (dd, J=8.3, 6.9 Hz, 1H), 7.05 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.26 (s, 2H), 3.99 (k, J=7.0 Hz, 2H), 3, 57 (s, 2H), 1.35 (s, 12H), 1.03 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -57.99, 112.64.

Stage-2. Preparation of (+)-(8)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl )methoxy)-4-fluorophenyl)acetate (490b).

Compound 490b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (490a) (280 mg, 0.536 mmol) in dioxane (10 ml) using (+)-(S)-N-((4 -chloro3-fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (142 mg, 0.536 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (56 mg, 0.080 mmol) and K ₂ CO solution ₃ (222 mg, 1.608 mmol) in water (1 ml) heating under nitrogen at 100°C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)(S)-ethyl 2-(2-((7-( 2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (490b) (282 mg, 84% yield ) as brown butter;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (k, J=1.6 Hz, 1H), 8.56 (d, J=4.9 Hz, 1H), 7.94 (s, 1H), 7.74-7.68 (m, 2H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.06 (dd, J=11.3, 2, 5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.92-5.79 (m, 1H), 5.34 (s, 2H), 4, 42 (dd, J=5.8, 2.0 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.11 (s, 9H ), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 625.1 (M+1). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.07, -112.54, -128.19; optical rotation [a] _D = +24 (c = 0.1, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)-4-fluorophenyl)acetic acid (490c).

- 589 045626

To a stirred solution of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5 -yl)methoxy)-4-fluorophenyl)acetate (490b) (280 mg, 0.448 mmol) in THF (7.5 ml), add hydrochloric acid (4 M in 1-4-dioxane, 0.224 ml, 0.897 mmol), stir at room temperature for 30 min and concentrated in vacuo to dryness. The resulting residue was dissolved in THF (5 ml), acetonitrile (2.5 ml) and water (2.5 ml) and lithium hydroxide monohydrate (105 mg, 2.501 mmol) was added. The reaction mixture was stirred for 21 h at room temperature and concentrated to remove THF and acetonitrile. The reaction mixture was diluted with water (2 ml) and acidified to pH 4 using 1 M HCl. The separated solid was decanted and purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to give 2-(2-((7(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy )-4fluorophenyl)acetic acid (490c) (51 mg, 23% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.18 (s, 1H, D2O replaceable), 8.95 (k, J=1.6 Hz, 1H), 8.67 (d, J=5, 0 Hz, 1H), 8.52 (s, 3H, D2O replaceable), 8.12-7.95 (m, 1H), 7.83 (t, J=5.3 Hz, 1H), 7.78 (s, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.04 (dd, J=11.3, 2.5 Hz, 1H), 6.76 ( td, J=8.5, 2.5 Hz, 1H), 5.37 (s, 2H), 4.39 (s, 2H), 3.56 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.02, -112.91, -128.49. MS (ESI+): 493.1 (M+1); (ESI-): 491.1 (M-1); analysis calculation for C ₂₄ H ₁₇ F ₅ N ₂ O ₄ -HCl-0.5H ₂ O: C, 53.59; N, 3.56; Cl, 6.59; N, 5.21; observed: C, 53.53; N, 3.43; Cl, 6.62; N, 5.30.

Scheme-491

(+)-isomer

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (491b).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)3-(trifluoromethyl)benzofuran-5-yl)methoxy )-4-fluorophenyl)acetate (491a).

Compound 491a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (490a) (280 mg, 0.536 mmol) in dioxane (10 ml) using (+)-(S)-N-((4chloropyridine -2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (132 mg, 0.536 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (56 mg, 0.080 mmol) and K2CO3 solution (222 mg, 1.608 mmol ) in water (1 ml) heating in a nitrogen atmosphere at 100°C for 6 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)(S)-ethyl 2-(2-((7-( 2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)-4-fluorophenyl)acetate (491a) (235 mg, 72% yield) as brown oils;

1H NMR (300 MHz, DMSO-d6) δ 8.94 (k, J=1.6 Hz, 1H), 8.68 (dd, J=5.2, 0.8 Hz, 1H), 8.01 (s, 1H), 7.937.84 (m, 2H), 7.78 (dd, J=5.2, 1.7 Hz, 1H), 7.26 (dd, J=8.3, 6.9 Hz, 1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.96 (t , J=6.0 Hz, 1H), 5.34 (s, 2H), 4.38 (dd, J=6.1, 4.1 Hz, 2H), 3.92-3.86 (m, 2H), 3.61 (s, 2H), 1.17 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ESI+): 607.2 (M+1); optical rotation [a] _D = +10 (c = 0.15, MeOH).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (491b).

To a stirred solution of (+)-(S)-ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl) methoxy)-4fluorophenyl)acetate (491a) (231 mg, 0.381 mmol) in THF (6 ml), add hydrochloric acid (4 M in 1-4-dioxane, 0.190 ml, 0.762 mmol), stir at room temperature for 30 min and concentrated under vacuum to dryness. The resulting residue was dissolved in THF (4 ml), acetonitrile (2 ml) and water (2 ml) and lithium hydroxide monohydrate (84 mg, 1.999 mmol) was added. The reaction mixture was stirred for 21 h at room temperature and concentrated to remove THF and acetonitrile. The reaction mixture was diluted with water (2 ml) and acidified to pH 4 using 1 M HCl. The separated solid was decanted and purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to obtain 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)- 4fluorophenyl)acetic acid (491b) (93 mg, 52% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.98 (k, J=1.6 Hz, 1H), 8.81 (dd, J=5.3, 0.8 Hz, 1H), 8.48 (s, 3H), 8.04

- 590 045626 (dd, J=1.7, 0.8 Hz, 1H), 7.99-7.90 (m, 3H), 7.26 (dd, J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td,

J=8.5, 2.5 Hz, 1H), 5.37 (s, 2H), 4.32 (d, J=5.7 Hz, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -57.80, 112.92. MS (ESI+): 475.1 (M+1); (ESI-): 473.1 (M-1); analysis calculation for C ₂₄ H ₁₈ F ₄ N ₂ O ₄ -1.25HCl-1.5H ₂ O:

C, 52.70; N, 4.10; Cl, 8.10; N, 5.12; observed: C, 52.50; N, 3.92; Cl, 8.50; N, 5.06.

Scheme-492

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (492b).

Stage-1. Preparation of (S)-ethyl 2-(2-((7-(2-(( 1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate ( 492a).

Compound 492a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetate (483a) (260 mg, 0.537 mmol) in dioxane (10 ml) using (+)-(S)-N-((4chloropyridine-2- yl)methyl)-2-methylpropane-2-sulfinamide (365c) (132 mg, 0.537 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (57 mg, 0.081 mmol) and a solution of K2CO3 (223 mg, 1.611 mmol) in water (1 ml) heating in an argon atmosphere at 100°C for 15 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (S)-ethyl 2-(2-((7-(2-( (1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methoxyphenyl)acetate (492a) (168 mg, 55% yield) as a brown oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.76 (dd, J=22.9, 5.3 Hz, 1H), 8.36 (s, 1H), 8.03 (d, J=31 ,6 Hz, 1H), 7.93-7.81 (m, 1H), 7.78-7.69 (m, 2H), 7.12 (dd, J=8.3, 1.9 Hz, 1H), 6.68 (t, J=2.0 Hz, 1H), 6.56-6.43 (m, 2H), 5.24 (s, 2H), 4.37 (dd, J=29 ,3, 4.9 Hz, 2H), 3.93 (cd, J=7.1, 3.9 Hz, 2H), 3.74 (s, 3H), 3.55 (d, J=1, 7 Hz, 2H), 1.18 (s, 9H), 1.02-0.93 (m, 3H); MS (ESI+): 569.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (492b).

To a stirred solution of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl) acetate (492a) (168 mg, 0.295 mmol) in THF (5 ml), add hydrochloric acid (4 M in 1-4-dioxane, 0.148 ml, 0.591 mmol), stir at room temperature for 30 min and concentrate in vacuo to dryness The resulting residue was dissolved in THF (5 ml), acetonitrile (1 ml) and water (1 ml) and lithium hydroxide monohydrate (62 mg, 1.477 mmol) was added. The reaction mixture was stirred for 48 h at room temperature and concentrated to remove THF and acetonitrile. The reaction mixture was diluted with water (2 ml) and acidified to pH 4 using 1 M HCl. The separated solid was decanted and purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to obtain 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid acids (492b) (77 mg, 60% yield), HCl salt, as a pale yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.79 (dd, J=5.2, 0.8 Hz, 1H), 8.39 (s, 3H, D2O replaceable), 7.98 (s, 1H), 7.90 (dd, J=5.2, 1.7 Hz, 1H), 7.79-7.74 (m, 2H), 7.12 (d, J=8.3 Hz, 1H ), 6.66 (d, J=2.4 Hz, 1H), 6.53-6.45 (m, 2H), 5.26 (s, 2H), 4.32 (d, J=5, 7 Hz, 2H), 3.73 (s, 3H), 3.51 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -111.16. MS (ESI+): 437.1 (M+1); (ESI-): 435.1 (M-1); analysis calculation for C24H ₂ 1FN ₂ O5-1.75HCl-2H ₂ O: C, 53.75; H, 5.03; Cl, 11.57; N, 5.22; observed, 53.83; N, 4.80; Cl, 11.84; N, 5.19.

Scheme-493 he

^493a 493b

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5methoxyphenyl)acetic acid (493b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-591 045626 methoxyphenyl)acetate (493a).

Compound 493a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-III-indol-6-yl)methoxy)-5-methoxyphenyl)acetate ( 475e) (100 mg, 0.217 mmol) in dioxane (4 ml), water (1 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (61 mg, 0.326 mmol), bis(triphenylphosphine)palladium (P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (15 mg, 0.022 mmol) and 3.3 M aq. K2CO3 (0.197 ml, 0.652 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-6% MeOH in DCM), ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1isopropyl- 1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate (493a) (83 mg, 79% yield) as a colorless oil; MS (ESI+): 487 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5methoxyphenyl)acetic acid (493b).

Compound 493b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)- 5-methoxyphenyl)acetate (493a) (83 mg, 0.171 mmol) in MeOH (3 ml) using 2.0 M aq. LiOH (0.426 ml, 0.853 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with 0-60% MeCN in H2O] 2 -(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetic acid (493b) (60 mg, 77% yield) free base as a white solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.56 (d, J=3.3 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.30 (d , J=7.6 Hz, 1H), 6.88 (d, J=8.9 Hz, 1H), 6.70 (d, J=3.1 Hz, 1H), 6.66-6.57 (m, 2H), 5.20 (s, 2H), 4.81 (p, J=6.6 Hz, 1H), 3.98 (s, 2H), 3.66 (s, 3H), 3 .36 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); MS (ESI+): 459 (M+1), (ESI-): 457 (M-1).

Scheme-494 he

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5fluorophenyl)acetic acid (494b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6yl)methoxy)-5-fluorophenyl)acetate (494a).

Compound 494a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate ( 474a) (110 mg, 0.245 mmol) in dioxane (4 ml)/water (1 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (76 mg, 0.368 mmol), bis( triphenylphosphine)palladium(P) chloride (Pd(PPh ₃ ) ₂ Cl ₂ ) (17 mg, 0.025 mmol) and 3.3 M aq. K2CO3 (0.223 ml, 0.736 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-3% MeOH in DCM), ethyl 2-(2-((4-(3(aminomethyl)-2-fluorophenyl)-1- isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate (494a) (86 mg, 71% yield) as a colorless oil; MS (ESI+): 493 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)5-fluorophenyl)acetic acid (494b).

Compound 494b was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl) methoxy)-5-fluorophenyl)acetate (494a) (86 mg, 0.175 mmol) in MeOH (3 ml), using a 2 M aqueous solution of lithium hydroxide (0.436 ml, 0.873 mmol) and stirring at room temperature for 16 h This gave, after work-up and purification by reverse phase column chromatography [C18 (100 g), eluted with 0-60% MeCN in H2O] 2-(2-((4-(3-(aminomethyl)-2- fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)5-fluorophenyl)acetic acid (494b) (63 mg, 78% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.70 (s, 1H), 7.58-7.46 (m, 2H), 7.40 (td, J=7.3, 1.9 Hz , 1H), 7.26 (t, J=7.6 Hz, 1H), 7.15 (s, 1H), 7.08-6.97 (m, 2H), 6.95-6.85 ( m, 1H), 6.28 (t, J=2.6 Hz, 1H), 5.19 (s, 2H), 4.83 (p, J=6.6 Hz, 1H), 3.83 ( s, 2H), 3.34 (s, 2H), 1.47 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -122.06, 124.61; MS (ESI+): 465 (M+1), (ESI-): 463 (M-1).

- 592 045626

Scheme-495

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1 H-indol-6-yl)methoxy)-4fluorophenyl)acetic acid (495d).

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indol-6-yl)methoxy )phenyl)acetate (495a).

Compound 495a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-isopropyl-1P-indol-6-yl)methoxy)-4-fluorophenyl)acetate (449a) (0.7 g, 1.56 mmol) using bis(pinacolato)diboron (0.60 g, 2.34 mmol), potassium acetate (0.46 g, 4.68 mmol) and Pd(dppf )Cl ₂ -DCM (0.19 g, 0.23 mmol) in anhydrous dioxane (15 ml) under nitrogen while heating at 100°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel, 24 g, eluted with EtOAc/MeOH=9:1 in 0% to 10% hexane] ethyl 2-(4-fluoro-2-((1isopropyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (495a) (0.6 g, 78 % yield) as a yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.70 (d, J=1.3 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.46 (d , J=1.4 Hz, 1H), 7.23 (dd, J=8.3, 6.9 Hz, 1H), 7.03 (dd, J=11.4, 2.6 Hz, 1H) , 6.78-6.66 (m, 2H), 5.19 (s, 2H), 4.76 (p, J=6.6 Hz, 1H), 4.00 (k, J=7.1 Hz, 2H), 3.57 (s, 2H), 1.45 (d, J=6.6 Hz, 6H), 1.33 (s, 12H), 1.04 (t, J=7.1 Hz, 3H); MS (ESI+): 496.2 (M+1).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-1-isopropyl-1H-indol-6- yl)methoxy)-4-fluorophenyl)acetate (495b).

Compound 495b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1P-indol-6yl)methoxy)phenyl)acetate (495a) (300 mg, 0.61 mmol) in dioxane (4 ml) using (+)-(S)-N- ((4-chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (192 mg, 0.73 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (32 mg, 0.045 mmol) and a solution of K2CO3 (251 mg, 1.82 mmol) in water (1 ml) heating under nitrogen at 90°C for 3 hours in an oil bath. This resulted in (+)(S)-ethyl 2-(2-((4-(2 -((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1Nindol-6-yl)methoxy)-4-fluorophenyl)acetate (495b) (300 mg, 83% yield) as a yellow oil; MS (ESI+) 598.3 (M+1); optical rotation [a] _D = +22 (c = 0.1, MeOH).

Stage-3. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-fluorophenyl)acetate (495c).

Compound 495c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((4-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-1-isopropyl-1Nindol-6-yl)methoxy)-4-fluorophenyl)acetate (495b) (300 mg, 0.50 mmol) in DCM (4 ml) using 4 M HCl in dioxane (0.38 ml, 1.51 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM from 0- 70%] ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1isopropyl-1P-indol-6-yl)methoxy)-4-fluorophenyl)acetate (495c) (200 mg, 81% yield) as a pale yellow oil; MS (ESI+): 494.2 (M+1).

Stage-4. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-fluorophenyl)acetic acid (495d).

Compound 495d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indole -6-yl)methoxy)-4-fluorophenyl)acetate (495c) (200 mg, 0.41 mmol) in THF/MeOH (8 ml each) using lithium hydroxide monohydrate solution

- 593 045626 (136 mg, 3.24 mmol) in water (2 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [column C-18, 50 d, eluted with acetonitrile in water 0-100%] 2-(2-((4-(2-(aminomethyl)-3fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4 -fluorophenyl)acetic acid (495d) (140 mg, 74% yield) as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=4.9 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J=3.3 Hz, 1H ), 7.51 (t, J=5.4 Hz, 1H), 7.26 (s, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.00 (dd, J =11.6, 2.5 Hz, 1H), 6.70 (td, J=8.6, 2.5 Hz, 1H), 6.37 (t, J=2.9 Hz, 1H), 5 .28 (s, 2H), 4.83 (p, J=6.7 Hz, 1H), 3.97 (s, 2H), 3.52 (s, 2H), 1.49 (d, J= 6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -113.44, -130.73; MS (ESI+): 466.20 (M+1); (ESI-): 464.20 (M-1).

Scheme-496

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4fluorophenyl)acetic acid (496c).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)1-isopropyl-1H-indol-6-yl) methoxy)-4-fluorophenyl)acetate (496a).

Compound 496a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (495a) (300 mg, 0.61 mmol) in dioxane (4 ml) using (+)-(S)-N- ((4chloropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (179 mg, 0.73 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (64 mg, 0.09 mmol) and solution K ₂ CO ₃ (251 mg, 1.82 mmol) in water (1 ml) heating under nitrogen at 90°C for 3 hours in an oil bath. This resulted in (+)(S)-ethyl 2-(2-((4-(2 -((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)-4-fluorophenyl)acetate (496a) (300 mg, 85% yield) as yellow oil; MS (ESI+): 580.3 (M+1); optical rotation [a] _D = +21 (c = 0.1, MeOH).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-4-fluorophenyl)acetate (496b).

Compound 496b was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((4-(2-(( 1,1-dimethylethylsulfinamido)methyl)pyridine- 4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)-4-fluorophenyl)acetate (496a) (300 mg, 0.52 mmol) in DCM (5 ml) using 4 M HCl in dioxane ( 0.39 ml, 1.55 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80/DCM from 0-70% ]ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1Nindol-6-yl)methoxy)-4-fluorophenyl)acetate (496b) (200 mg, 81 % yield) as a pale yellow oil; MS (ESI+): 476.2 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)4-fluorophenyl)acetic acid (496c).

Compound 496c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl )methoxy)-4-fluorophenyl)acetate (496b) (200 mg, 0.42 mmol) in THF/MeOH (8 ml each), using a solution of lithium hydroxide monohydrate (141 mg, 3.36 mmol) in water (2 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column (50 g), eluted with 0-100% acetonitrile in water] 2-(2 -((4-(2-(aminomethyl)pyridin-4-yl)-1isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetic acid (496c) (140 mg, 74% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 7.74 (d, J=7.9 Hz, 2H ), 7.65 (d, J=3.3 Hz, 1H), 7.55 (s, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.90 (dd, J =11.5, 2.5 Hz, 1H), 6.73 (d, J=3.3 Hz, 1H), 6.62

- 594 045626 (td, J=8.3, 2.4 Hz, 1H), 5.30 (s, 2H), 4.83 (p, J=6.6 Hz, 1H), 4.06 (s , 2H), 3.38 (s, 2H), 1.51 (d, J=6.6 Hz, 6H);

¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -114.91; MS (ESI+): 448.20 (M+1); (ESI-): 446.15 (M-1).

Scheme-497

Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5fluorophenyl)acetic acid (497d).

Stage-1. Preparation of ethyl 2-(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indol-6-yl)methoxy )phenyl)acetate (497a).

Compound 497a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate (474a) (0.57 g, 1.271 mmol) using bis(pinacolato)diboron (0.484 g, 1.907 mmol), potassium acetate (0.374 g, 3.81 mmol) and Pd(dppf)Cl ₂ DCM (0.104 g, 0.127 mmol) in anhydrous dioxane (5 ml) under nitrogen while heating at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with ethyl acetate in hexanes 0- 6%) ethyl 2-(5-fluoro-2-((1-isopropyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl )methoxy)phenyl)acetate (497a) (471 mg, 75% yield) as a pale yellow oil;

Ή NMR (300 MHz, DMSO-d ₆ ) δ 7.68 (d, J=1.4 Hz, 1H), 7.53 (dd, J=3.2, 0.8 Hz, 1H), 7, 45 (t, J=1.1 Hz, 1H), 7.17-7.01 (m, 3H), 6.76 (d, J=3.2 Hz, 1H), 5.16 (s, 2H ), 4.85-4.67 (m, 1H), 4.01 (cd, J=7.1, 0.8 Hz, 2H), 3.62 (s, 2H), 1.46 (s, 3H), 1.44 (s, 3H), 1.33 (s, 12H), 1.06 (d, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.26; LC-MC: t=3.23 min; MS (ESI+): 496 (M+1).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)1-isopropyl-1H-indol-6-yl) methoxy)-5-fluorophenyl)acetate (497b).

Compound 497b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (497a) (224 mg, 0.452 mmol) in dioxane (4 ml) using (+)-(S)-N-(( 4chloropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (145 mg, 0.588 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (32 mg, 0.045 mmol) and 3.3 M aq. K ₂ CO ₃ (0.411 ml, 1.357 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This resulted in (+)-(S)-ethyl 2-(2((4-(2-( (1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5fluorophenyl)acetate (497b) (255 mg, 97% yield) as an orange oil; MS (ESI+) 580 (M+1); optical rotation [a] _D = +40 (c = 0.01, MeOH).

Stage-3. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-III-indol-6yl)methoxy)-5-fluorophenyl)acetate (497c).

Compound 497c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((4-(2-(( 1,1-dimethylethylsulfinamido)methyl)pyridine- 4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)-5-fluorophenyl)acetate (497b) (255 mg, 0.440 mmol) in DCM (4 ml), using 4 M HCl in dioxane (0.275 ml , 1.100 mmol) and stirring at room temperature for 3 hours. This resulted in the preparation after treatment of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indole -6yl)methoxy)-5-fluorophenyl)acetate (497c) (148 mg, 71% yield) as a yellow semi-solid; MS (ESI+): 476 (M+1).

Stage-4. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)5-fluorophenyl)acetic acid (497d).

Compound 497d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indole-6- yl)methoxy)-5-fluorophenyl)acetate (497c)

- 595 045626 (148 mg, 0.311 mmol) in MeOH (3 ml), using a solution of 2.0 M aq. LiOH (0.778 ml, 1.556 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography (C-18 column, 100 g, eluted with acetonitrile in water 0-60% ) 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-5-fluorophenyl)acetic acid (497d) (50 mg, 36 % yield) free base as a pale yellow solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.58 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.79-7.73 (m, 1H), 7.71 (s, 1H), 7.65 (d, J=3.3 Hz, 1H), 7.56 (s, 1H), 7.02-6.86 (m, 3H), 6.73 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 4.91-4.75 (m, 1H), 4.08 (s, 2H), 3.41 (s, 2H), 1.52 (s, 3H), 1.50 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -125.21; MS (ESI+): 448 (M+1), (ESI-): 446 (M-1); analysis calculation for C ₂₆ H ₂₆ FN ₃ O ₃ -0.75H ₂ O: C, 67.74; N, 6.01; N, 9.11; detect: C, 67.54; N, 5.99; N, 9.13.

Scheme-498

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (498c).

Stage-1. Preparation of ethyl 2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy )phenyl)acetate (498a).

Compound 498a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate ( 488a) (0.9 g, 1.847 mmol) using bis(pinacolato)diboron (0.704 g, 2.77 mmol), potassium acetate (0.544 g, 5.54 mmol) and Pd(dppf)Cl ₂ -DCM (0.151 g, 0.185 mmol) in anhydrous dioxane (50 ml) under argon while heating at 90°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2(4-methoxy-2-((7-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (498a) (797 mg, 81% yield) as a clear oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.85 (k, J=1.7 Hz, 1H), 7.93 (dd, J=2.0, 1.0 Hz, 1H), 7, 82 (d, J=1.8 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.49 ( dd, J=8.3, 2.4 Hz, 1H), 5.24 (s, 2H), 4.05-3.97 (m, 2H), 3.75 (s, 3H), 3.51 (s, 2H), 1.35 (s, 12H), 1.04 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -57.99.

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl )methoxy)-4-methoxyphenyl)acetate (498b).

Compound 498b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (498a) (265 mg, 0.496 mmol) in dioxane (10 ml) using (+)-(S)-N-((4 -chloro3-fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (131 mg, 0.496 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (52.2 mg, 0.074 mmol) and K solution ₂ CO ₃ (206 mg, 1.488 mmol) in water (1 ml) heating under nitrogen at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)-(S)-ethyl 2-(2-((7- (2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (498b) (203 mg, 64% yield) as brown oil.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.95-8.87 (m, 1H), 8.55 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.66-7.64 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.72 (d, J=2.4 Hz , 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.84 (k, J=6.3 Hz, 1H), 5.31 (s, 2H), 4 .42 (dd, J=5.9, 2.0 Hz, 2H), 3.92-3.85 (m, 2H), 3.75 (s, 3H), 3.54 (s, 2H), 1.11 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -58.08, -128.17; MS (ESI+): 637.2 (M+1); optical rotation [a] _D = +25.10 (c = 0.255, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran - 596 045626

5-yl)methoxy)-4-methoxyphenyl)acetic acid (498c).

To a stirred solution of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5 -yl)methoxy)-4-methoxyphenyl)acetate (498b) (200 mg, 0.314 mmol) in THF (5.25 ml), add hydrochloric acid (4 M in 1-4-dioxane, 0.157 ml, 0.628 mmol), stir at room temperature for 30 min and concentrated in vacuo to dryness. The resulting residue was dissolved in THF (3.5 ml), acetonitrile (1.75 ml) and water (1.75 ml) and lithium hydroxide monohydrate (73 mg, 1.75 mmol) was added. The reaction mixture was stirred for 21 h at room temperature and concentrated to remove THF and acetonitrile. The reaction mixture was diluted with water (2 ml) and acidified to pH 4 using 1 M HCl. The separated solid was decanted and purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to give 2-(2-((7(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy )-4methoxyphenyl)acetic acid (498c) (22 mg, 14% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.94 (d, J=1.8 Hz, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.01 (s, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.78 (s, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.3 Hz, 1H), 5.34 (s, 2H), 4.39 (s, 2H), 3, 74 (s, 3H), 3.50 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.03, -128.47; MS (ESI+): 505.1 (M+1); (ESI-): 503.1 (M-1); analysis calculation for C25H ₂₀ F ₄ N ₂ O ₅ -HCl-1.75H ₂ O: C, 52.46; N, 4.31; Cl, 6.19; N, 4.89; observed: C, 52.52; N, 4.00; Cl, 6.36; N, 5.16.

Scheme-499

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4methoxyphenyl)acetic acid (499b).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)3-(trifluoromethyl)benzofuran-5-yl)methoxy )-4-methoxyphenyl)acetate (499a).

Compound 499a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (498a) (265 mg, 0.496 mmol) in dioxane (10 ml) using (+)-(S)-N-((4chloropyridine -2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (122 mg, 0.496 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (52.2 mg, 0.074 mmol) and K ₂ CO ₃ solution ( 206 mg, 1.488 mmol) in water (1 ml) heating under nitrogen at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)(S)-ethyl 2-(2-((7-( 2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)-4-methoxyphenyl)acetate (499a) (147 mg, 48% yield) as brown oils

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.93 (d, J=1.7 Hz, 1H), 8.68 (dd, J=5.2, 0.8 Hz, 1H), 8, 04-7.98 (m, 1H), 7.92-7.83 (m, 2H), 7.78 (dd, J=5.2, 1.8 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.95 ( t, J=5.9 Hz, 1H), 5.31 (s, 2H), 4.38 (dd, J=6.1, 4.2 Hz, 2H), 3.92-3.86 (m , 2H), 3.74 (s, 3H), 3.55 (s, 2H), 1.07 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -58.05; MS (ESI+): 619.2 (M+1); optical rotation [a] _D = +16.84 (c = 0.095, MeOH).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3 -(trifluoromethyl)benzofuran-5yl)methoxy)-4-methoxyphenyl)acetic acid (499b).

To a stirred solution of (+)-(S)-ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl) methoxy)-4methoxyphenyl)acetate (499a) (140 mg, 0.226 mmol) in THF (3.75 ml) added hydrochloric acid (4.0 M in 1-4-dioxane, 0.113 ml, 0.453 mmol), stirred at room temperature for 30 min and concentrated under vacuum until dry. The resulting residue was dissolved in THF (2.5 ml), acetonitrile (1.25 ml) and water (1.25 ml) and lithium hydroxide monohydrate (52.5 mg, 1.25 mmol) was added. The reaction mixture was stirred for 21 h at room temperature and concentrated to remove THF and acetonitrile. The reaction mixture was diluted with water (2 ml) and acidified to pH 4 using 1 M HCl. The separated solid was decanted and purified by reverse phase column chromatography [C-18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] to give 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)-4- methoxyphenyl)acetic acid (499b) (67 mg, 61% yield), HCl salt, as a pale yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 8.43 (s, 3H, D2O replaceable), 8 .03

- 597 045626 (s, 1H), 7.96 (d, J=5.2 Hz, 3H), 7.13 (d, J=8.2 Hz, 1H), 6.69 (d, J=2 .3 Hz, 1H), 6.55-6.44 (m, 1H), 5.35 (s, 2H),

4.32 (d, J=5.7 Hz, 2H), 3.74 (s, 3H), 3.52 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.00; MS (ESI+): 487.1 (M+1); (ESI-): 485.1 (M-1); analysis calculation for Qs^iFs^Os-UHCI^O: C, 50.45; N, 4.83; Cl, 8.94; N,

4.71; observed: C, 50.32; N, 4.63; Cl, 8.70; N, 4.38.

F·

Vg 154d

Scheme-500

Pd(PPh ₃ ) ₂ CI ₂ h ₂ n o

F3C

500b 500c

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (500c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetate (500a).

Compound 500a was prepared according to the procedure described in step-2 of Scheme-23, from (7bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (1 g, 3.39 mmol) in DCM (35 ml ), using triphenylphosphine (0.978 g, 3.73 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl) acetate (205a) (0.806 g, 4.07 mmol) and a solution of (E)-bis(4-chlorobenzyl) )diazene-1,2-dicarboxylate (DCAD, 1.369 g, 3.73 mmol) in DCM (35 ml) and stirring at room temperature for 1 hour. This resulted in, after workup and purification by flash column chromatography, ( silica gel, 40 g, eluted with 0 to 20% ethyl acetate in hexanes) ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetate (500a) (1.16 g, 72.0% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.97 (k, J=1.6 Hz, 1H), 7.79 (s, 2H), 7.23-6.98 (m, 3H), 5.23 (s, 2H), 4.02 (k, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.23, -123.71.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetate (500b).

Compound 500b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (500a ) (225 mg, 0.473 mmol) in dioxane (8 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (106 mg, 0.568 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49.8 mg, 0.071 mmol) and a solution of K2CO3 (196 mg, 1.420 mmol) in water (0.8 ml) heated under argon at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)phenyl) -3(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (500b) (135 mg, 57% yield) as a clear oil.

^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.97-8.82 (m, 1H), 7.81 (s, 1H), 7.75 (d, J=6.4 Hz, 2H) , 7.70 (d, J=7.2 Hz, 1H), 7.52-7.41 (m, 2H), 7.18-7.08 (m, 3H), 5.28 (s, 2H ), 3.91 (t, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.65 (s, 2H), 0.97 (t, J=7.1 Hz, 3H ); MS (ESI+): 502.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)5-fluorophenyl)acetic acid (500c).

Compound 500c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)- 5-fluorophenyl)acetate (500b) (0.13 g, 0.259 mmol) in THF (1.6 ml), acetonitrile (0.8 ml), using 1N aq. lithium hydroxide monohydrate solution (0.8 ml, 0.8 mmol) and stirring at room temperature for 24 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0. 1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid ( 500c) (85 mg, 69% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.91 (s, 1H), 8.00 (s, 1H), 7.95-7.86 (m, 1H), 7.83 (s, 1H ), 7.81 (s, 1H), 7.67-7.55 (m, 2H), 7.18-7.01 (m, 3H), 5.31 (s, 2H), 4.14 ( s, 2H), 3.62 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -

- 598 045626

57.98, -123.90; MS (ESI+): 474.1 (M+1); (ESI-): 472.1 (M-1); analysis calculation for

C ₂₅ H ₁₉ F ₄ NO ₄ -HCl-0.5H ₂ O: C, 57.87; N, 4.08; Cl, 6.83; N, 2.70; observed: C, 58.06; N, 3.96; Cl, 6.62; N, 2.72.

Scheme-501

332a 501a

501e 501f

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (501f).

Stage-1. Preparation of 1-tert-butyl 6-methyl 4-bromo-2-(trifluoromethyl)-1H-indole-1,6-dicarboxylate (501a).

To a suspension of methyl 4-bromo-2-(trifluoromethyl)-1H-indole-6-carboxylate (332a) (1.05 g, 3.26 mmol) and (Boc)2O (1.067 g, 4.89 mmol) in DCM (20 ml) at room temperature, DMAP (0.040 g, 0.326 mmol) was added, stirred for 1 hour at room temperature and quenched with saturated aq. NH ₄ Cl (25 ml). The organic layer was separated, washed with brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g column, eluted with 0-3% EtOAc in hexane) to give l-tert-butyl 6methyl 4-bromo-2-(trifluoromethyl)-1H-indole-1,6 -dicarboxylate (501a) (1.31 g, 95% yield) as a white solid.

^1H NMR (300 MHz, DMSO-d6) δ 8.86-8.76 (m, 1H), 8.00 (dt, J=43.0, 0.9 Hz, 1H), 7.51 (d , J=36.8 Hz, 1H), 3.93 (s, 3H), 1.65 (s, 9H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -57.51.

Stage-2. Preparation of tert-butyl 4-bromo-6-(hydroxymethyl)-2-(trifluoromethyl)-1H-indole-1carboxylate (501b).

Compound 501b was prepared according to the procedure described in step-2 of Scheme-212 from l-tert-butyl 6-methyl 4-bromo-2-(trifluoromethyl)-1H-indole-1,6-dicarboxylate (501a) (1.31 g, 3.10 mmol) in DCM (15 ml) using 1 M DIBAL-H in DCM (7.76 ml, 7.76 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted with 0-15% EtOAc in Hexane) tert-butyl 4-bromo-6-(hydroxymethyl)-2-(trifluoromethyl)-1H- indole-1-carboxylate (501b) (0.89 g, 73% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 8.19 (d, 1H), 7.52 (d, 1H), 7.38 (d, 1H), 5.50 (t, J=5.8 Hz , 1H), 4.65 (d, J=5.7 Hz, 2H), 1.64 (s, 9H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -57.06; MS (ESI-): 292/294 (M-Vos-1).

Stage-3. Preparation of tert-butyl 4-bromo-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2(trifluoromethyl)-1H-indole-1-carboxylate (501c).

Compound 501c was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 4-bromo-6-(hydroxymethyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate (501b) (0.89 g , 2.258 mmol) in toluene (20 ml) using triphenylphosphine (1.184 g, 4.52 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.407 g, 2.258 mmol) and DIAD (0.913 g, 4. 52 mmol) in toluene (5 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 24 g column, eluted with EtOAc in 0% to 5% hexanes), tert-butyl 4-bromo-6-((2-(2-ethoxy- 2oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate (501c) (0.84 g, 67% yield) as a colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J=12.4 Hz, 1H), 7.61 (dd, J=44.2, 1.2 Hz, 1H), 7.42 (d, J=34.6 Hz, 1H), 7.31-7.20 (m, 2H), 7.09 (dd, J=8.3, 1.1 Hz, 1H), 6.93 ( td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.02 (cd, J=7.1, 1.1 Hz, 2H), 3.64 (s , 2H), 1.63 (s, 9H), 1.07 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -57.18; MS (ESI-): 454/456 (M-Vos-1).

- 599 045626

Stage-4. Preparation of tert-butyl 4-(3-(aminomethyl)-2-fluorophenyl)-6-((2-(2-ethoxy-2oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate ( 501d).

Compound 501d was prepared according to the procedure described in step-3 of Scheme-1 from tert-butyl 4-bromo-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H -indole-1-carboxylate (501c) (193 mg, 0.347 mmol) in dioxane (4 ml), using 3-(aminomethyl)-2fluorophenylboronic acid hydrochloride (56a) (107 mg, 0.520 mmol), solution of 1.27 M aq . K ₃ PO ₄ (0.546 ml, 0.694 mmol) in water, Pd ₂ (dba) ₃ (32 mg, 0.035 mmol), XPhos (33 mg, 0.069 mmol) and heating under nitrogen at 100 °C for 16 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with MeOH in DCM from 0-3%] tert-butyl 4-(3(aminomethyl)-2-fluorophenyl)-6-((2 -(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1carboxylate (501d) (220 mg, 106% yield) as a pale yellow oil.

1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.61 (td, J=7.1, 2.3 Hz, 1H), 7.47 (t, J=1, 1 Hz, 1H), 7.36 (dt, J=9.3, 6.3 Hz, 2H), 7.31-7.18 (m, 2H), 7.17-7.09 (m, 2H ), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 3.963.76 (m, 4H), 3.62 (s, 2H), 1 .64 (s, 9H), 0.95 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -56.88, 122.89; MS (ESI+): 601 (M+1).

Stage-5. Preparation of methyl 2-(2-((4-(3-(αminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (501e).

To a solution of tert-butyl 4-(3-(aminomethyl)-2-fluorophenyl)-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)2-(trifluoromethyl)-1H-indole-1- carboxylate (501d) (220 mg, 0.366 mmol) in MeOH (5 ml), add NaOMe (25 wt.% in MeOH) (0.251 ml, 1.099 mmol), stir at room temperature for 16 h and evaporate to dryness to obtain methyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (501e) (134 mg, 75% yield) as a pale yellow oil, which was used in the next step without further purification; MS (ESI+): 487 (M+1), (ESI-): 485 (M-1).

Stage-6. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (501f).

Compound 501f was prepared according to the procedure described in step-6 of Scheme-1 from methyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (501e) (134 mg, 0.275 mmol) in MeOH (3 ml) using 2.0 M aq. LiOH (0.413 ml, 0.826 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with 0-60% acetonitrile in water] 2 -(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (501f) (50 mg, 38% yield), lithium salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ +D ₂ O) δ 7.83 (s, 1H), 7.59-7.49 (m, 1H), 7.49-7.41 (m, 1H) , 7.35 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.10 (t, J= 7.7 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.84 (dd, J=14.4, 6.9 Hz, 2H), 5.30 (s, 2H), 3.89 (s, 2H), 3.39 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.88, -121.66; MS (ESI+): 472 (M+1), (ESI-): 471 (M-1).

Scheme-502 o

DCAD, РРК DCM

NH ₂ HCI

K ₂ C0 ₃

Pd(PPh ₃ ) ₂ CI ₂

Receipt

502b 502c

2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3 fluorophenyl)acetic acid (502c).

Stage-1. Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a).

Compound 502a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromobenzofuran-5-yl)methanol (23a) (699 mg, 3.08 mmol) in DCM (8 ml) using triphenylphosphine (801 mg, 3.05 mmol), ethyl 2-(3-fluoro-2-hydroxyphenyl) acetate (604 mg, 3.05 mmol; CAS No. 1261451-84-6) and a solution of (E)-bis(4-chlorobenzyl)diazen- 1,2-dicarboxylate (DCAD, 1.15 g, 3.13 mmol) in DCM (2 ml) and stirring at room temperature for 1 hour. This resulted in the following treatment:

- 600 045626 and purification by flash column chromatography (silica gel, 24 g, eluted with 0 to 50% ethyl acetate in hexanes) ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a) (633 mg,

51% yield) as a colorless oil;

1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.3 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.62 (d, J =1.5 Hz, 1H), 7.23 (ddd, J=11.8, 6.1, 3.8 Hz, 1H), 7.16-7.06 (m, 3H), 5.20- 5.05 (m, 2H), 3.98 (k, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -129.82.

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetate (502b).

Compound 502b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a) (150 mg, 0.368 mmol ) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (93 mg, 0.553 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (39 mg, 0.055 mmol) and solution of K ₂ CO ₃ (153 mg, 1.105 mmol) in water (0.5 ml) heating in an argon atmosphere at 100 ° C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, 12 g, eluted with DMA80 in DCM 0% to 70%], ethyl 2-(2-((7-(3-(aminomethyl)-2- fluorophenyl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetate (502b) (149 mg, 90% yield) as a yellow oil. MS (ESI+): 452.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetic acid (502c).

Compound 502c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl )acetate (502b) (149 mg, 0.330 mmol) in THF/acetonitrile (6 mL each), using a solution of lithium hydroxide monohydrate (82 mg, 1.954 mmol) in water (2 mL) and stirring at room temperature overnight. This resulted in the following workup and purification by reverse phase column chromatography [C18 column, 50 g, eluted with 0.1% aq. HCl in water and acetonitrile from 0% to 100%] 2-(2-((7-(3(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetic acid (502c) ( 79 mg, 57% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 2H), 8.11-8.02 (m, 1H), 7.82 (s, 1H), 7.77-7.58 ( m, 2H), 7.527.35 (m, 2H), 7.28-7.14 (m, 1H), 7.14-6.98 (m, 3H), 5.17 (s, 2H), 4 .17 (s, 2H), 3.61 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -118.58, -129.89. MS (ESI+): 424.1 (M+1); MS (ESI-): 422.1 (M-1); analysis calculation for C24H19F2NO4-1.1HCl-1.25H2O: C, 59.31; N, 4.69; Cl, 8.02; N, 2.88; observed: C, 59.32; N, 4.59; Cl, 7.94; N, 3.06.

Scheme-503

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (503c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (503 a) .

Compound 503a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (484a) ( 177 mg, 0.416 mmol) in dioxane (5 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2yl)methyl) carbamate (123a) (145 mg, 0.434 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (44 mg, 0.062 mmol) and a solution of K ₂ CO ₃ (173 mg, 1.249 mmol) in water (0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with DMA80 in DCM 0% to 70%), ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino )methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (503a) (193 mg, 84% yield) as a dark oil; MS (ESI+): 553.2 (M+1).

- 601 045626

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (503b).

Compound 503b was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4 -fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetate (503a) (193 mg, 0.349 mmol) in ethanol (6 ml), using 4 M HCl in dioxane (0.873 ml, 3.49 mmol) and stirring at room temperature during the night. This resulted in ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetate (503b) (127 mg, 80% yield) as a yellow solid. MS (ESI+): 453.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (503c).

Compound 503c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy) -4-fluorophenyl)acetate (503b) (127 mg, 0.281 mmol) in MeOH/THF (6 mL each), using a solution of LiOH (78 mg, 1.859 mmol) in water (2 mL) and stirring at room temperature for nights. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (with 0.1% HCl) from 0% to 100%] 2-(2-(( 7-(2-(aminomethyl)pyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (503c) (78 mg, 66% yield), HCl salt, as a white solid .

^1H NMR (300 MHz, DMSO-d6) δ 8.80 (d, J=5.4 Hz, 1H), 8.66 (s, 3H), 8.31-8.21 (m, 1H), 8.16 (s, 1H), 8.07-7.92 (m, 2H), 7.31-7.21 (m, 2H), 7.14 (dd, J=11.2, 2.5 Hz, 1H), 6.77 (td, J=8.4, 2.4 Hz, 1H), 5.34 (s, 2H), 4.33 (d, J=5.6 Hz, 2H), 3.54 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.82, -121.04. MS (ESI+): 425.1 (M+1); MS (ESI-): 423.1 (M-1); analysis calculation for C2 ₃ Hi ₈ F2N2O4-1.9HC1-2H2O: C, 52.15; N, 4.55; Cl, 12.72; N, 5.29; observed: C, 52.50; N, 4.26; Cl, 12.88; N, 5.45.

Scheme-504

504b 504c

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetic acid (504c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (504a).

Compound 504a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a) (163 mg, 0. 4 mmol) in dioxane (5 ml) using tert-butyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate (123a) (169 mg, 0.506 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (42 mg, 0.06 mmol) and a solution of K ₂ CO ₃ (166 mg, 1.201 mmol) in water (0.5 ml) heating in an argon atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with DMA80 in DCM 0% to 70%), ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino )methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (504a) (214 mg, 100% yield) as a dark oil; MS (ESI+): 535.2 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetate (504b).

Compound 504b was prepared according to the procedure described in step-3 of Scheme-305 from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran- 5-yl)methoxy)-3fluorophenyl)acetate (504a) (214 mg, 0.4 mmol) in ethanol (6 ml), using 4 M HCl in dioxane (1.0 ml, 4 mmol) and stirring at room temperature in for 72 hours. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted

- 602 045626

DMA80 in DCM from 0-90%]ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetate (504b) (70 mg, 40% yield) in the form of a colorless oil. MS (ESI+): 435.1 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetic acid (504c).

Compound 504c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3- fluorophenyl)acetate (504b) (70 mg, 0.161 mmol) in MeOH/THF (6 mL each), using a solution of LiOH (65 mg, 1.549 mmol) in water (2 mL) and stirring at room temperature overnight. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (with 0.1% HCl) from 0% to 100%] 2-(2-(( 7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)-3-fluorophenyl)acetic acid (504c) (45 mg, 69% yield), HCl salt, as a white solid.

Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.80 (d, J=5.3 Hz, 1H), 8.61 (s, 3H), 8.19 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.30- 7.18 (m, 1H), 7.18-6.99 (m, 3H), 5.21 (s, 2H), 4.33 (s, 2H), 3.64 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -129.81. MS (ESI+): 407.1 (M+1); MS (ESI-): 405.2 (M-1); analysis calculation for C ₂₃ H ₁₉ FN ₂ O ₄ -1.9HCl4.5H ₂ O: C, 54.95; N, 4.79; Cl, 13.40; N, 5.57; observed: C, 54.86; N, 4.56; Cl, 13.21; N, 5.60.

Scheme-505

Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (505d).

Stage-1. Preparation of (+)-(S)-ethyl 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy )phenyl)acetate (505a).

Compound 505a was prepared according to the procedure described in step-2 of Scheme-23 from (+)(S)-N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2 -yl)methyl)-2-methylpronan-2sulfinamide (405a) (900 mg, 2.391 mmol) in DCM (30 ml), using triphenylphosphine (776 mg, 2.96 mmol), ethyl 2-(4-bromo-2- hydroxyphenyl)acetate (182a) (590 mg, 2.277 mmol) and a solution of (E)-bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD, 1087 mg, 2.96 mmol) in DCM (30 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 80 g, eluted with 0 to 50% ethyl acetate in hexanes) (+)-(S)-ethyl 2-(4-bromo-2-((7 -(2-((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (505a) (710 mg, 51% yield) as a pale yellowish resin;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (dd, J=4.9, 0.7 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7, 85 (d, J=1.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.52 (k, J=1.6 Hz, 1H), 7.35 (d, J =1.8 Hz, 1H), 7.23-7.05 (m, 3H), 5.84 (t, J=5.8 Hz, 1H), 5.28 (s, 2H), 4.41 (dd, J=5.8, 2.1 Hz, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.11 (s, 9H) , 0.96 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.02; MS (ESI+): 617.20; optical rotation [a] _D = +19.78 (c = 0.445, MeOH).

Stage-2. Preparation of (S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (505b).

Compound 505b was prepared according to the procedure described in step-1 of scheme-262 from (+)(S)-ethyl 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl )-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (505a) (650 mg, 1.053 mmol) in toluene (15 ml), using tributyl(1ethoxyvinyl)stannane (0.469 ml, 1.316 mmol) and Pd(PPh ₃ ) ₄ (122 mg, 0.105 mmol) and reflux for 24 hours under nitrogen followed by hydrolysis using 3N aq. HCl (1.053 ml, 3.16 mmol). This gave, after work-up and purification by flash column chromatography (silica gel, 24 g, eluted from 0% to 50% to 100% in 9:1 ethyl acetate/methanol in hexanes) (S)-ethyl 2-( 4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (505b) (32 mg, 5% ); MS (ESI+): 581.20 (M+1).

Stage-3. Preparation of ethyl 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (505c).

To a solution of (S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)phenyl) acetate (505b) (30 mg, 0.052 mmol) in tetrahydrofuran (5 ml) was added 3N HCl (0.052 ml, 0.155 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(4- acetyl 2-((7-(2-(aminomethyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (505c), which was used as is in the next step without further purification.

Stage-4. Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (505d).

Compound 505d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl )methoxy)phenyl)acetate (505c) (25 mg, 0.052 mmol) in THF/MeOH (5 ml each), using a solution of lithium hydroxide monohydrate (18 mg, 0.416 mmol) in water (5 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile from 0 to 50%] 2-(4-acetyl- 2-((7-(2(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (505d) (4 mg, 19% yield), HCl salt, as white solid matter;

^1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.0 Hz, 1H), 8.43 (s, 3H), 8.13-8.09 (m, 1H), 7.94 (s, 1H), 7.81 (t, J=5.5 Hz, 1H), 7.65-7.53 (m, 3H), 7.39 (d, J=7.5 Hz , 1H), 7.12-7.10 (m, 1H), 5.38 (s, 2H), 4.45-4.34 (m, 2H), 3.68 (s, 2H), 2, 57 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.28; MS (ESI+): 449.15 (M+1).

Scheme-506

Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (506e).

Stage-1. Preparation of tert-butyl 3-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7yl)benzylcarbamate (506a).

Compound 506a was prepared according to the procedure described in step-3 of Scheme-1 from (7bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (1.0 g, 3.39 mmol) in dioxane ( 30 ml), using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (1.129 g, 3.39 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (357 mg, 0.508 mmol) and a solution of K2CO3 (1.405 g, 10.17 mmol) in water (3 ml) heating under nitrogen at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with 0 to 35% ethyl acetate in hexanes] to give tert-butyl 3-(5-(hydroxymethyl)-3 -(trifluoromethyl)benzofuran-7yl)benzylcarbamate (506a) (1.05 g, 74% yield) as a light brown resinous substance.

1H NMR (300 MHz, DMSO-d6) δ 8.83 (k, J=1.6 Hz, 1H), 7.77-7.66 (m, 2H), 7.65 (s, 1H), 7 .59 (s, 1H), 7.47 (dk, J=12.6, 7.0, 6.2 Hz, 2H), 7.40-7.23 (m, 1H), 5.40 (t , J=5.7 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 1.40 (s, 9H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.10; MS (ESI+): 444.1 (M+Na).

Stage-2. Preparation of ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (506b) .

Compound 506b was prepared according to the procedure described in step-2 of Scheme-23 from tert-butyl 3-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)benzylcarbamate (506a) (550 mg, 1.305 mmol) in DCM (20 ml) using triphenylphosphine (445 mg, 1.697 mmol), ethyl 2-(4-bromo-2hydroxyphenyl) acetate (182a) (338 mg, 1.305 mmol) and (E)-bis(4-chlorobenzyl) solution diazene-1,2dicarboxylate (DCAD, 623 mg, 1.697 mmol) in DCM (20 ml). This resulted after workup and purification by flash column chromatography (silica gel, 40 g, eluted with 0 to 25% ethyl acetate in hexanes) to give ethyl 2-(4-bromo-2-((7-(3-( ((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (506b) (695 mg, 80% yield) as a light brown oil.

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.95-8.78 (m, 1H), 7.78 (s, 1H), 7.75-7.68 (m, 3H), 7. 57-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.24-7.10 (m, 2H), 5.33 (s, 2H), 4.23 ( d, J=6.2 Hz, 2H), 3.89 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.39 (s, 9H), 0.93 ( t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d6) δ -58.07.

Stage-3. Preparation of ethyl 2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (506c) .

Compound 506c was prepared according to the procedure described in step-1 of Scheme-262 from ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3- (trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (506b) (570 mg, 0.860 mmol) in toluene (20 ml), using tributyl(1ethoxyvinyl)stannane (0.383 ml, 1.075 mmol) and Pd(PPh ₃ ) ₄ ( 99 mg, 0.086 mmol) and reflux for 24 hours under nitrogen followed by hydrolysis using 3N aq. HCl (0.86 ml, 2.58 mmol). This resulted in after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with ethyl acetate in 0% to 35% hexanes) to give ethyl 2-(4-acetyl-2-((7-(3-(( (tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (506c) (290 mg, 5% yield) as a clear oil.

1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.83 (s, 1H), 7.78-7.71 (m, 3H), 7.68-7.32 ( m, 6H), 5.40 (s, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.72 ( s, 2H), 2.59 (s, 3H), 1.39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO) δ -58.08.

Stage-4. Preparation of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran5-yl)methoxy)phenyl)acetate (506d).

Compound 506d was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3- (trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetate (506c) (270 mg, 0.432 mmol) in DCM (6.5 ml) using TFA (0.665 ml, 8.63 mmol). This resulted in the production after treatment of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (506d) (225 mg , 99% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (k, J=1.7 Hz, 1H), 8.25 (s, 2H), 7.97 (s, 1H), 7.91 ( d, J=7.5 Hz, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.66-7.58 (m, 2H), 7.41 (d, J =7.7 Hz, 1H), 7.26-7.16 (m, 2H), 5.42 (s, 2H), 4.16 (d, J=5.9 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.74 (s, 2H), 2.59 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.06; MS (ESI+): 526.2 (M+1).

Stage-5. Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (506e).

Compound 506e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl )methoxy)phenyl)acetate (506d) (220 mg, 0.419 mmol) in THF (2.5 ml), acetonitrile (1.25 ml) using 1N aq. lithium hydroxide monohydrate solution (1.25 ml, 1.25 mmol) and stirred the reaction mixture for 24 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0. 1% HCl)/acetonitrile from 0 to 100%] to give 2-(4acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acids (506e) (167 mg, 80% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.92 (s, 1H), 8.02 (s, 1H), 7.96-7.80 (m, 3H), 7.68-7.54 (m, 4H), 7.41 (d, J=7.6 Hz, 1H), 5.43 (s, 2H), 4.14 (s, 2H), 3.70 (s, 2H), 2 .51 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -58.01; MS (ESI+): 498.2 (M+1).

- 605 045626

Scheme-507

DIPEA 507e 507f

Preparation of (S)-1H-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N1-(3-chloro-2fluorobenzyl)pyrrolidine-1,2-dicarboxamide (507f).

Stage-1. Preparation of 2-(3-chloro-2-fluorophenyl)acetyl azide (507b)

Diphenylphosphoryl azide (1.182 ml, 5.30 mmol) was added to a suspension of 2-(3-chloro-2fluorophenyl)acetic acid (507a) (1 g, 5.30 mmol), TEA (0.739 ml, 5.30 mmol) in toluene ( 15 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, then purified by flash column chromatography on silica gel (4 g, DCM) to give 2-(3-chloro-2-fluorophenyl)acetyl azide (507b) ( 1.1 g, 97% yield).

Ή NMR (300 MHz, DMSO- _d6 ) δ 7.57-7.50 (m, 1H), 7.37-7.31 (m, 1H), 7.22-7.18 (m, 1H) , 3.92 (s, 2H).

Stage-2. Preparation of (S)-tert-butyl 1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2carboxylate (507c)

A suspension of 2-(3-chloro-2-fluorophenyl)acetyl azide (507b) (1.1 g, 5.15 mmol) in toluene (20 ml) was refluxed for 1.5 h. The reaction mixture was cooled to room temperature and add triethylamine (1.436 ml, 10.30 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (882 mg, 5.15 mmol) in THF (10 ml) followed by stirring at RT for 1.5 The mixture was concentrated and the resulting residue was purified by chromatography [silica gel, (40 g), eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give (S)-tert-butyl 1-(( 3-chloro-2fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylate (507c) (1.45 g, 4.06 mmol, 79% yield) as a pale yellow oil.

^1H NMR (300 MHz, DMSO-d6) δ 7.44 (t, J=7.5 Hz, 1H), 7.29 (k, J=6.8, 6.3 Hz, 1H), 7, 17 (t, J=7.8 Hz, 1H), 6.89 (t, J=5.9 Hz, 1H), 4.37-4.18 (m, 2H), 4.13 (dd, J =8.7, 2.9 Hz, 1H), 3.45-3.32 (m, 2H), 2.19-2.03 (m, 1H), 1.94-1.67 (m, 3H ), 1.36 (d, J=1.1 Hz, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -122.15; MS (ESI+): 379.1 (M+Na).

Stage-3. Preparation of (S)-1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid (507d).

Compound 507d was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylate (507c) (1.42 g, 3.98 mmol) in DCM (30 ml) using TFA (4.60 ml, 59.7 mmol). This resulted in (S)-1((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid (507d) (1.19 g, 99% yield) being treated as a clear foam, which was used as is at the next stage. MS (ESI+): 301.1 (M+1).

Stage-4. Preparation of (S)-tert-butyl 3-(5-(1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2carboxamido)benzofuran-7-yl)benzylcarbamate (507e).

Compound 507e was prepared according to the procedure described in step-4 of Scheme-1 from (S)-1((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid (507d) (80 mg, 0.266 mmol ) in DMF (1 ml), using tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c) (90 mg, 0.266 mmol), DIPEA (0.185 ml, 1.064 mmol) and HATU (152 mg, 0.399 mmol). This resulted in, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with 0 to 50% ethyl acetate/hexane], giving (S)-tert-butyl 3-(5-(1-((3- chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2carboxamido)benzofuran-7-yl)benzylcarbamate (507e) (22 mg, 13% yield) as a light brown gum. MS (ESI+): 643.2 (M+Na).

Stage-5. Preparation of (S)-N2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N 1 -(3-chloro-2fluorobenzyl)pyrrolidine-1,2-dicarboxamide (507f).

Compound 507f was prepared according to the procedure described in step-5 of Scheme-1 from (S)tert-butyl 3-(5-(1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxamido) benzofuran-7yl)benzylcarbamate (507e) (21 mg, 0.034 mmol) in DCM (0.6 ml) using TFA (0.052 ml, 0.676 mmol). This resulted in, after workup and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] (S)-1H-(7-( 3- 606 045626 (aminomethyl)phenyl)benzofuran-5-yl)-N 1 -(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide (507f) (9 mg, 51% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 8.28 (s, 3H, D2O replaceable), 8.04 (t, J=1.6 Hz, 1H), 7 .92-7.85 (m, 2H), 7.85-7.74 (m, 2H), 7.58 (dt, J=15.5, 7.7 Hz, 2H), 7.42 (t , J=7.6 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 7.04 (t, J =1.7 Hz, 1H), 6.99 (t, J=5.9 Hz, 1H, D2O replaceable), 4.53-4.04 (m, 5H), 3.63-3.36 (m , 2H), 2.21-1.88 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -122.16; MS (ESI+): 521.2 (M+1); (ESI-): 519.1 (M-1), 555.1 (M+Cl).

Scheme-508

476d _508a 508b

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetic acid (508b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetate (508a).

Compound 508a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d) (160 mg, 0.382 mmol ) in dioxane (4 ml), water (1 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (118 mg, 0.572 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (27 mg, 0.038 mmol) and 3.3 M aq. K ₂ CO ₃ (0.347 ml, 1.145 mmol) heating under N2 at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, 12 g, eluted with 0-3% MeOH in DCM), ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl) benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (508a) (127 mg, 72% yield) as a colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 8.03 (t, J=1.7 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.67-7.55 (m, 1H), 7.507.38 (m, 2H), 7.31 (t, J=7.7 Hz, 1H), 7.13-7.00 (m, 3H), 6.82 (t, J=4.3 Hz, 1H), 5.06 (s, 2H), 3.97-3.88 (m, 2H), 3.86 (s, 3H), 3.84 (s, 2H), 3.58 (s, 2H), 1.01 (d, J=7.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO4) δ -121.88; LCMC: t=2.16 min; MS (ESI+): 464 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetic acid (508b).

Compound 508b was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl) acetate (508a) (127 mg, 0.274 mmol) in MeOH (3 ml) using 2.0 M aq. LiOH (0.685 ml, 1.370 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (100 g), eluted with 0-60% MeCN in H ₂ O with 0.1% HCl] 2-(2-((7-(3 -(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetic acid (508b) (60 mg, 50 % yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.62 (s, 2H), 8.06 (d, J=2.1 Hz, 1H), 7.80 (s, 1H), 7.76- 7.60 (m, 2H), 7.52-7.36 (m, 2H), 7.08 (d, J=2.1 Hz, 1H), 7.06-6.97 (m, 2H) , 6.83 (dd, J=6.5, 2.7 Hz, 1H), 5.07 (s, 2H), 4.18 (s, 2H), 3.86 (s, 3H), 3, 54 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -118.58; MS (ESI+): 436 (M+1), (ESI-): 434 (M-1); analysis calculation for C ₂₅ H ₂₂ FNO ₅ -1.1HCl-H ₂ O: C, 60.84; N, 5.13; Cl, 7.90; N, 2.84; observed: C, 61.09; N, 4.94; Cl, 7.78; N, 3.15.

Scheme-509

C.I.

(+)-isomer

- 607 045626

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (509d).

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl) acetate (509a).

Compound 509a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (484a) ( 299 mg, 0.703 mmol) using bis(pinacolato)diboron (268 mg, 1.055 mmol), potassium acetate (207 mg, 2.109 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (86 mg, 0.105 mmol) in anhydrous dioxane (12 ml) under argon while heating at 95°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(4fluoro-2-((4-fluoro-7-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (509a) (265 mg, 80% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.14 (d, J=2.3 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.23 (dd, J=8.4, 6.9 Hz, 1H), 7.16-7.06 (m, 2H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.26 -5.13 (m, 2H), 3.91 (k, J=7.1 Hz, 2H), 3.48 (s, 2H), 1.33 (s, 12H), 0.95 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d ₆ ) δ -112.65, -118.76.

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy) -4-fluorophenyl)acetate (509b).

Compound 509b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (509a) (262 mg, 0.555 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro -3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (191 mg, 0.721 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (58 mg, 0.083 mmol) and K2CO3 solution (230 mg, 1.664 mmol) in water (0.5 ml) heating under nitrogen at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in DCM 0% to 15%] (+)-(S)-ethyl 2-(2-((7- (2-(( 1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran5-yl)methoxy)-4-fluorophenyl)acetate (509b) (319 mg, 100% yield) as dark oil; MS (ESI+): 575.2 (M+1); optical rotation [a] _D = +18.56 (c = 0.485, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (509c).

Compound 509c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3- fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (509b) (310 mg, 0.539 mmol) in ethanol (8 ml), using 4 M HCl in dioxane (0.8 ml, 3.20 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80/DCM from 0-100%] ethyl 2 -(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (509c) (143 mg, 56% yield) in in the form of a pale yellow oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=4.9 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.67 (d , J=6.6 Hz, 1H), 7.59 (t, J=5.3 Hz, 1H), 7.30-7.19 (m, 2H), 7.15 (dd, J=11, 4, 2.5 Hz, 1H), 6.76 (td, J=9.7, 9.0, 2.4 Hz, 1H), 5.29 (s, 2H), 3.94 (s, 2H ), 3.84 (k, J=7.1 Hz, 2H), 3.53 (s, 2H), 0.90 (t, J=7.7, 6.5 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.55, -121.74, -130.73. MS (ESI+): 471.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (509d).

Compound 509d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl )methoxy)-4-fluorophenyl)acetate (509c) (14θ mg, 0.298 mmol) in MeOH/THF (3 mL each), using LiOH (60 mg, 1.430 mmol) in water (2 mL) and stirring at room temperature during the night. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (with 0.1% HCl) from 0% to 100%] 2-(2-(( 7-(2-(aminomethyl)-3fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (509d) (89 mg, 68% yield), HCl salt, as white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 12.06 (s, 1H), 8.84-8.48 (m, 4H), 8.29-8.11 (m, 1H), 7.91 -7.66 (m, 2H), 7.31-7.19 (m, 2H), 7.14 (dd, J=11.4, 2.5 Hz, 1H), 6.77 (td, J =8.4, 2.4 Hz, 1H), 5.34 (s, 2H), 4.36 (d, J=5.9 Hz, 2H), 3.51 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.87, -121.02, -128.52; MS (ESI+): 443.1 (M+1); MS (ESI-): 441.1 (M-1).

- 608 045626

Scheme-510 ci

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetic acid (510d).

Stage-1. Preparation of ethyl 2-(3-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (510a) .

Compound 510a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a) (338 mg, 0.830 mmol), using bis(pinacolato)diboron (316 mg, 1.245 mmol), potassium acetate (244 mg, 2.490 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (102 mg, 0.124 mmol) in anhydrous dioxane (12 ml) in an argon atmosphere while heating at 95°C overnight. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 40% EtOAc in hexane] ethyl 2-(3-fluoro-2-((7-(4,4 ,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (510a) (305 mg, 81% yield) as a clear oil.

^1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.23 (ddd, J=11.7, 6.1, 3.8 Hz, 1H), 7.08 (td, J=3.3, 2.4 Hz , 2H), 6.99 (d, J=2.2 Hz, 1H), 5.11 (s, 2H), 4.00 (k, J=7.1 Hz, 2H), 3.63 (s , 2H), 1.34 (s, 12H), 1.09 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -129.76.

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3- fluorophenyl)acetate (510b).

Compound 510b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(3-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (510a) (300 mg, 0.660 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (227 mg, 0.858 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (70 mg, 0.099 mmol) and K2CO3 solution (274 mg, 1.981 mmol) in water (0.5 ml) heating in a nitrogen atmosphere at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 15% methanol in DCM] (+)-(S)-ethyl 2-(2-((7-(2 -((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetate (510b) (368 mg, 100% yield) as a dark oil; MS (ESI+): 557.2 (M+1); optical rotation [a] _D = +18.69 (c = 0.76, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5yl)methoxy)-3-fluorophenyl)acetate (510c).

Compound 510c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3- fluoropyridin-4-yl)benzofuran-5yl)methoxy)-3-fluorophenyl)acetate (510b) (360 mg, 0.647 mmol) in ethanol (8 ml), using 4 M HCl in dioxane (0.8 ml, 3.20 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80/DCM from 0-100%] ethyl 2-(2 -((7-(2-(aminomethyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (510c) (180 mg, 62% yield) as a pale yellow oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=5.0 Hz, 1H), 8.15-8.06 (m, 1H), 7.86 (s, 1H), 7.62 (t, J=5.3 Hz, 1H), 7.54 (s, 1H), 7.30-7.16 (m, 1H), 7.16-7.01 (m, 3H) , 5.20 (s, 2H), 4.02 (s, 2H), 3.94 (k, 2H), 3.66 (s, 2H), 1.01 (t, J=7.1, 1 ,1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -129.75, -130.33. MS (ESI+): 553.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3fluorophenyl)acetic acid (510d).

Compound 510d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy) -3-fluorophenyl)acetate (510c) (175

- 609 045626 mg, 0.387 mmol) in MeOH/THF (3 ml each), using LiOH (83 mg, 1.978 mmol) in water (2 ml) and stirring at room temperature overnight. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (with 0.1% HCl) from 0% to 100%] 2-(2-(( 7-(2-(aminomethyl)-3-fluoropyridin-4yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetic acid (510d) (115 mg, 70% yield), HCl salt, as a white solid ;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (s, 3H), 8.56 (d, J=5.0 Hz, 1H), 8.12-8.03 (m, 1H) , 7.85 (s, 1H), 7.73 (t, J=5.3 Hz, 1H), 7.54 (s, 1H), 7.22-7.10 (m, 1H), 7, 10-6.95 (m, 3H), 5.13 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 3.55 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.52, -129.88. MS (ESI+): 425.1 (M+1); MS (ESI-): 423.1 (M-1).

Scheme-511

Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (511e).

Stage-1. Preparation of (+)-(S)-N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2methylpropan-2-sulfinamide (511a).

Compound 511a was prepared according to the procedure described in step-3 of Scheme-1 from (7(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (269e) (1.5 g, 5.47 mmol) in dioxane (60 ml) using (+)-(S)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropan-2 -sulfinamide (365c) (1.620 g, 6.57 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.576 g, 0.821 mmol) and potassium carbonate solution (2.269 g, 16.42 mmol) in water (7 ml) heating in a nitrogen atmosphere at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), eluted with 0% to 7% methanol in DCM] (+)-(S)-N-((4-(5-( hydroxymethyl)benzofuran-7-yl)pyridin2-yl)methyl)-2-methylpropane-2-sulfinamide (511a) (875 mg, 45% yield) as an off-white tar-like solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.63 (dd, J=5.2, 0.8 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 8, 04-8.03 (m, 1H), 7.78 (dd, J=5.2, 1.8 Hz, 1H), 7.72-7.69 (m, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.98 (t, J=6.1 Hz, 1H), 5.31 (t, J= 5.7 Hz, 1H), 4.65 (dt, J=5.7, 0.7 Hz, 2H), 4.45-4.28 (m, 2H), 1.19 (s, 9H); MS (ESI+): 359.10 (M+1); optical rotation [a] _D = +32.77 (c = 0.47, MeOH).

Stage-2. Preparation of (+)-(S)-ethyl 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (511b).

Compound 511b was prepared according to the procedure described in step-2 of Scheme-23 from (+)(S)-N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl )-2-methylpropane-2-sulfinamide (511a) (750 mg, 2.092 mmol) in DCM (25 ml), using triphenylphosphine (713 mg, 2.72 mmol), ethyl 2-(4bromo-2-hydroxyphenyl) acetate ( 182a) (542 mg, 2.092 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazen-1,2dicarboxylate (DCAD, 999 mg, 2.72 mmol) in DCM (25 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with 0 to 5% methanol in DCM) (+)-(S)-ethyl 2-(4-bromo-2 -((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)phenyl)acetate (511b) (906 mg, 72% yield) as a clear oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (dd, J=5.2, 0.8 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 8, 07-8.04 (m, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.78 (dd, J=5.3, 1.8 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.15-7 .10 (m, 2H), 5.96 (t, J=6.1 Hz, 1H), 5.28 (s, 2H), 4.47-4.28 (m, 2H), 3.95- 3.86 (m, 2H), 3.61 (s, 2H), 1.18 (s, 9H), 0.94 (t, J=7.1 Hz, 3H); MS (ESI+): 599.10 (M+1); optical rotation [a] _D = +18.6 (c = 0.5, MeOH).

Stage-3. Preparation of (+)-(S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (511c).

Compound 511c was prepared according to the procedure described in step-1 of scheme-262 from (+)(S)-ethyl 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl )pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (511b) (800 mg, 1.334 mmol) in toluene (25 ml), using tributyl(1ethoxyvinyl)stannane (0.594 ml, 1.668 mmol) and Pd(PPh ₃ ) ₄ (154 mg, 0.133 mmol) and reflux for 24 hours under nitrogen followed by hydrolysis using 3N aq. HCl (1.334 ml, 4.00 mmol). This resulted in (+)-(S)-ethyl 2-(4-acetyl2-((7-(2- ((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (511c) (211 mg, 28% yield) as a clear oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (d, J=5.2 Hz, 1H), 8.14-8.10 (m, 1H), 8.07 (s, 1H) , 7.84 (s, 1H), 7.81-7.74 (m, 2H), 7.62 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7, 40 (d, J=7.7 Hz, 1H), 7.12-7.10 (m, 1H), 5.95 (t, J=6.1 Hz, 1H), 5.35 (s, 2H ), 4.48-4.25 (m, 2H), 3.99-3.85 (m, 2H), 3.73 (s, 2H), 2.58 (s, 3H), 1.18 ( s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 563.30 (M+1); optical rotation [ab = +25 (c = 0.04, MeOH).

Stage-4. Preparation of ethyl 2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetate (511d).

To a solution of (+)-(S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)phenyl )acetate (511c) (195 mg, 0.347 mmol) in tetrahydrofuran (10 ml) was added 3N HCl (0.347 ml, 1.040 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(4 -acetyl-2-((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (511d) (232 mg) which was used in the next step without further purification; MS (ESI+): 459.20 (M+1); (ESI-) 457.20 (M-1).

Stage-5. Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5yl)methoxy)phenyl)acetic acid (511e).

Compound 511e was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy) phenyl)acetate (511d) (159 mg, 0.347 mmol) in THF/MeOH (5 mL each), using a solution of lithium hydroxide monohydrate (119 mg, 2.78 mmol) in water (5 mL) and stirring at room temperature in over a period of 16 hours. This resulted, after work-up and purification by reverse phase column chromatography [C-18 column, eluted with water (0.1% HCl)/acetonitrile from 0 to 50%] 2-(4-acetyl-2 -((7-(2(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (511e) (84 mg, 56% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (d, J=5.2 Hz, 1H), 8.37 (s, 3H), 8.17 (s, 1H), 8.06 ( s, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.63-7.56 (m, 2H ), 7.41 (d, J=7.6 Hz, 1H), 7.12 (s, 1H), 5.39 (s, 2H), 4.38-4.26 (m, 2H), 3 .70 (s, 2H), 2.57 (s, 3H); MS (ESI+): 431.10 (M+1).

Scheme-512

365c O

Pd(dppf)CI ₂ CH ₂ CI ₂ KOAc

K ₂ CO ₃ Pd(PPh ₃ ) ₂ CI ₂

512b O

Receipt

2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3 methoxyphenyl)acetic acid (512d).

Stage-1. Preparation of ethyl 2-(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (512a) .

- 611 045626

Compound 512a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d) (600 mg, 1.431 mmol), using bis(pinacolato)diboron (545 mg, 2.147 mmol), potassium acetate (421 mg, 4.29 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (117 mg, 0.143 mmol) in anhydrous dioxane (5 ml) under argon while heating at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexane 0 to 15%] ethyl 2-(3-methoxy-2-((7-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (512a) (670 mg, 100% yield) as a colorless oil;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (t, J=1.7 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.69 (d , J=1.7 Hz, 1H), 7.06-7.00 (m, 2H), 6.98 (t, J=1.7 Hz, 1H), 6.82 (dd, J=5, 6, 3.6 Hz, 1H), 5.00 (s, 2H), 3.99 (k, J=7.1 Hz, 2H), 3.87 (s, 3H), 3.57 (s, 2H), 1.35 (s, 12H), 1.12-1.05 (m, 3H); MS (ESI+): 489 (M+Na).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (512b).

Compound 512b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (512a) (325 mg, 0.697 mmol) in dioxane (4 ml) using (+)-(S)-N-((4-chloropyridine-2 -yl)methyl)-2methylpropan-2-sulfinamide (365c) (189 mg, 0.767 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.070 mmol) and 3.3 M aq. K2CO3 (0.634 ml, 2.091 mmol) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 3% methanol in DCM] (+)-(S)-ethyl 2-(2-((7- (2-((1,1dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (512b) (273 mg, 71% yield) as an orange oil; MS (ESI+) 551 (M+1); optical rotation [a] _D = +24 (c = 0.05, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetate (512c).

Compound 512c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridine- 4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetate (512b) (273 mg, 0.496 mmol) in ethanol (4 ml), using 4 M HCl in dioxane (0.372 ml, 1.487 mmol) and stirring at room temperature for 1 hour. This resulted in the preparation, after treatment, of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetate (512c) ( 200 mg, 90% yield) as a pale orange oil, which was used as is in the following reaction; MS (ESI+) 447 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetic acid (512d).

Compound 512d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl )acetate (512c) (200 mg, 0.448 mmol) in ethanol (3 ml) using 2.0 M aq. LiOH (1.12 ml, 2.24 mmol) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 100 g, eluted with acetonitrile in water (with 0.1% HCl) from 0-60%] 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetic acid (512d ) (145 mg, 77% yield), HCl salt, as a pale green solid;

1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.65-8.29 (m, 3H), 8.17 (d, J=2, 0 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7 .13 (d, J=2.0 Hz, 1H), 7.04 (d, J=3.5 Hz, 2H), 6.916.78 (m, 1H), 5.11 (s, 2H), 4 .32 (k, J=5.2 Hz, 2H), 3.87 (s, 3H), 3.55 (s, 2H); MS (ESI+): 419 (M+1), (ESI-): 417 (M-1).

- 612 045626

Scheme-513

513b 513c

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1 H-indol-6-yl)methoxy)-5fluorophenyl)acetic acid (513c).

Stage-1. Preparation of (S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-1-isopropyl-1H-indol-6-yl)methoxy) -5-fluorophenyl)acetate (513a).

Compound 513a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-indol-6yl)methoxy)phenyl)acetate (497a) (270 mg, 0.545 mmol) in dioxane (4 ml) using (+)-(S)-N-( (4-chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (188 mg, 0.709 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (38.3 mg, 0.055 mmol) and 3.3 M aq. K2CO3 (0.495 ml, 1.635 mmol) under nitrogen atmosphere was heated at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in DCM 0% to 3%] (S)-ethyl 2(2-((4-(2-(((1.1 -dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1 H-indol-6yl)methoxy)-5-fluorophenyl)acetate (513a) (407 mg, 125% yield) as an orange oil; MS (ESI+) 598 (M+1).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-5-fluorophenyl)acetate (513b).

Compound 513b was prepared according to the procedure described in step-3 of Scheme-305 from (S)ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridine-4 -yl)-1-isopropyl-1 H-indol-6yl)methoxy)-5-fluorophenyl)acetate (513a) (407 mg, 0.681 mmol), 4 M HCl in dioxane (0.426 ml, 1.7 mmol) in dioxane (4 ml) and water (1 ml) and stirring at room temperature for 1 hour. This resulted in the preparation after workup of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl )-1-isopropyl-Shindol-6-yl)methoxy)-5-fluorophenyl)acetate (513b) as a pale orange oil, which was used as is in the following reaction; MS (ESI+): 505 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6yl)methoxy)-5-fluorophenyl)acetic acid (513c).

Compound 513c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indole -6-yl)methoxy)-5-fluorophenyl)acetate (513b) (176 mg, 0.357 mmol) in MeOH (5 ml), using a 2.0 M aqueous solution of lithium hydroxide (0.892 ml, 1.783 mmol) and stirring at room temperature for 16 hours. This resulted, after work-up and purification by reverse phase column chromatography [C18 column, 50 g, eluted with acetonitrile in water 0-60%] 2-(2-((4-(2 -(aminomethyl)-3-fluoropyridin-4-yl)-1isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetic acid (513c) (17 mg, 10% yield) free base as a white solid substances;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (d, J=4.9 Hz, 1H), 7.78 (s, 1H), 7.70-7.56 (m, 1H), 7.51 (t, J=5.4 Hz, 1H), 7.25 (s, 1H), 7.11-7.00 (m, 2H), 7.00-6.74 (m, 1H) , 6.36 (s, 1H), 5.22 (s, 2H), 4.98-4.73 (m, 1H), 3.94 (s, 2H), 3.44 (s, 2H), 1.47 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.42, -130.91; MS (ESI+): 466.1 (M+1), (ESI-): 464.1 (M-1).

- 613 045626

Scheme-514

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (514d).

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzofuran-5-yl)methoxy) phenyl)acetate (514a).

Compound 514a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (477a) (1.2 g, 2.408 mmol) using bis(pinacolato)diboron (1.835 g, 7.22 mmol), potassium acetate (0.709 g, 7.22 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.295 g, 0.361 mmol) in anhydrous dioxane (25 ml) under argon by heating at 100°C for 16 hours. This resulted after work-up and purification by flash column chromatography (silica gel, eluted with EtOAc in hexane from 0 to 25%) ethyl 2-(4-fluoro2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran- 5yl)methoxy)phenyl)acetate (514a) (1.05 g, 87% yield) as a brown gum; MS (ESI+): 521 (M+Na).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl )methoxy)-4-fluorophenyl)acetate (514b).

Compound 514b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (514a) (450 mg, 0.903 mmol) in dioxane (20 ml) using (+)-(S)-N-((4 -chloro3-fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (287 mg, 1.084 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (95 mg, 0.135 mmol) and K ₂ CO solution ₃ (374 mg, 2.71 mmol) in water (2.4 ml) under nitrogen was heated at 100°C for 15 hours in an oil bath. This resulted in (+)-(S)-ethyl 2-(2-(( 7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (514b) (215 mg, 40% yield) in the form of a colorless resin;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (s, 1H), 7.65 (t, J=5.2 Hz, 1H), 7.50 (s, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.09-7.00 (m, 2H), 6.78-6.70 (m , 1H), 5.84 (t, J=5.7 Hz, 1H), 5.25 (s, 2H), 4.52 (s, 2H), 4.40 (d, J=5.8 Hz , 2H), 3.90 (k, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.62, -128.12; MS (ESI+) 601.2 (M+1); optical rotation [a] _D = +28.57 (c = 0.105, MeOH).

Stage-3. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (514c).

Compound 514c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (514b) (205 mg, 0.341 mmol) in THF (10 ml) using 3 M aq. HCl (0.341 ml, 1.024 mmol) and stir at room temperature in

- 614 045626 for 6 hours. This led to the production after treatment of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy) -4-fluorophenyl)acetate (514c), which was used as is in the following reaction; MS (ESI+) 497.2 (M+1).

Stage-4. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran5-yl)methoxy)-4-fluorophenyl)acetic acid (514d).

Compound 514d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5 -yl)methoxy)-4fluorophenyl)acetate (514c) (0.341 mmol) in THF (6 ml) and MeOH (6 ml), using a solution of LiOH (117 mg, 2.73 mmol) in water (6 ml) and stirring at room temperature for 19 hours. This resulted in, after work-up and purification by reverse phase column chromatography [C-18 column, 100 g, eluted with acetonitrile in water (with 0.1% HCl) from 0-100%] 2 -(2-((7-(2-(aminomethyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (514d) (49 mg, 31 % yield in two stages), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.61-8.43 (m, 3H), 7.88 (s, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.10-6.95 (m, 2H), 6.81-6.62 (m, 1H), 5.29 (s, 2H), 4.54 (s, 2H), 4.44-4, 31 (m, 2H), 3.56 (s, 2H), 3.30 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.98, -128.63; MS (ESI+) 469.1 (M+1); Analysis calculation for C ₂ 5H ₂₂ F ₂ N ₂ O5-HCl-0.5H ₂ O: C, 58.43; N, 4.71; Cl, 6.90; N, 5.45; observed: C, 58.37; N, 4.72; Cl, 7.14; N, 5.44.

Scheme-515

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (515c).

Stage-1. Preparation of (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4- fluorophenyl)acetate (515a).

Compound 515a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (514a) (495 mg, 0.993 mmol) in dioxane (20 ml) using (+)-(S)-N-((4chloropyridine -2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (294 mg, 1.192 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (105 mg, 0.149 mmol) and K2CO3 solution (412 mg, 2. 98 mmol) in water (2.4 ml) under nitrogen atmosphere was heated at 100°C for 13 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (ratio 1:0 to 1:1)] (S)-ethyl 2-(2-((7-(2 -((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (515a) (135 mg, 23% yield) as colorless resins;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.79-7.73 (m, 2H), 7.68 (s, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.10-6.99 (m, 2H), 6.79-6.70 (m, 1H) , 5.95 (t, J=6.1 Hz, 1H), 5.25 (s, 2H), 4.58 (s, 2H), 4.46-4.27 (m, 2H), 3, 91 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 3.32 (s, 3H), 1.17 (s, 9H), 0.98-0.92 (m , 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.61; MS (ESI+): 583.2 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (515b).

Compound 515b was prepared according to the procedure described in step-3 of Scheme-305 from (S)ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl) -2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (515a) (130 mg, 0.223 mmol) in THF (10 ml) using 3 M aq. HCl (0.223 ml, 0.669 mmol) and stirring at room temperature for 6 hours. This resulted in

- 615 045626 obtaining after treatment ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetate (515b), which was used as is in the following reaction; MS (ESI+): 479.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (515c).

Compound 515c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl) methoxy)-4-fluorophenyl)acetate (515b) (0.223 mmol) in THF (4 ml) and MeOH (4 ml), using a solution of aq. LiOH (76 mg, 1.784 mmol) in water (4 ml) and stirring at room temperature for 19 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 100 g, eluted with acetonitrile in water (with 0.1% HCl) from 0-100%] 2-(2-((7-(2-(aminomethyl)pyridin-4yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)- 4-fluorophenyl)acetic acid (515c) (49 mg, 31% yield in two steps), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.2 Hz, 1H), 8.43 (s, 3H), 8.02 (s, 1H), 7.97 ( d, J=5.4 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.06 ( s, 1H), 7.02 (dd, J=11.6, 2.5 Hz, 1H), 6.78-6.70 (m, 1H), 5.29 (s, 2H), 4.61 (s, 2H), 4.39-4.19 (m, 2H), 3.57 (s, 2H), 3.34 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 112.95; MS (ESI+) 451.1 (M+1); Analysis calculation for C ₂₅ H ₂₃ FN ₂ O ₅ -1.45HCl-H ₂ O: C, 57.60; N, 5.11; Cl, 9.86; N, 5.37; observed: C, 57.46; N, 5.10; Cl, 9.60; N, 5.36.

Scheme-516

516b 516c

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (516c).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetate (516b).

Compound 516b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c) (150 mg, 0.368 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (93 mg, 0.553 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (38.8 mg, 0.055 mmol) and a solution of K2CO3 (153 mg, 1.105 mmol) in water (0.5 ml) under Ar atmosphere by heating at 100°C for 3 hours. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 070%]ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (516b ) (101 mg, 61% yield) as a colorless oil, which was used in the next step without further purification.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.09-7.99 (m, 1H), 7.85 (d, J=6.8 Hz, 1H), 7.65 (t, J=7 .4 Hz, 1H), 7.43 (t, J=7.0 Hz, 1H), 7.37-7.13 (m, 4H), 7.10-7.03 (m, 1H), 6 .93 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 3.93 (k, J=7.1 Hz, 2H), 3.83 (s, 2H), 3 .60 (s, 2H), 1.00 (t, J=7.6, 6.5 Hz, 3H). MS (ESI+): 452.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (516c).

Compound 516c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl )acetate (516b) (98 mg, 0.217 mmol) in acetonitrile/THF (6 ml), using a solution of lithium hydroxide (72 mg, 1.716 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (3(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (516c) (70 mg, 76% yield), HCl salt, as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.93 (d, J=6.8 Hz, 1H), 7.79 (t, J=7.4 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.46 (t, 1H), 7.33-7.19 (m, 2H), 7.15 (d, J=8 ,0 Hz, 1H), 7.07 (s, 1H), 6.93 (t, J=7.5 Hz, 1H), 5.28 (s, 2H), 4.18 (s, 2H), 3.57 (s, 2H), ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -117.07, -125.48; MS (ESI+): 424.1 (M+1); MS (ESI-): 422.1 (M-1); analysis calculation for C^H^NOp C, 60.32; N, 4.64; Cl, 7.42; N, 2.93; observed: C, 60.06; N, 4.49; Cl, 7.46; N, 3.04.

- 616 045626

Scheme-517

Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (517d).

Stage-1. Preparation of ethyl 2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (517b).

Compound 517b was prepared according to the procedure described in step-2 of Scheme-23 from (4bromo-1-(trifluoromethyl)-1H-indol-6-yl)methanol (517a) (0.4 g, 1.360 mmol) using triphenylphosphine (0.464 g, 1.768 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.319 g, 1.768 mmol) and DIAD (0.358 mg, 1.768 mmol) in THF (15 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 40 g, eluted with EtOAc/MeOH (9:1) in 0% to 40% hexanes), ethyl 2-(2-((4-bromo-1- (trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (517b) (0.4 g, 65% yield) as a pale yellow oil;

1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, J=3.7 Hz, 1H), 7.75 (s, 1H), 7.60 (s, 1H), 7.31-7 .19 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.79 (d, J=3, 7 Hz, 1H), 5.25 (s, 2H), 4.07-3.94 (m, 2H), 3.63 (s, 2H), 1.06 (td, J=7.1, 1 ,1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -55.23; MS (ESI+): 479 (M+Na).

Stage-2. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (517c).

Compound 517c was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (517b ) (200 mg, 0.438 mmol) in dioxane (5 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (79 mg, 0.526 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (46.2 mg, 0.066 mmol) and a solution of K2CO3 (182 mg, 1.315 mmol) in water (1 ml) heating under nitrogen at 90°C for 4 hours. This resulted in, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 0-50%] ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1 H-indol-6-yl)methoxy )phenyl)acetate (517c) (212 mg, 71% yield) as a pale yellow oil.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 (d, J=3.8 Hz, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.51 -7.42 (m, 3H), 7.42-7.34 (m, 1H), 7.30-7.18 (m, 2H), 7.12 (d, J=8.1 Hz, 1H ), 6.95-6.85 (m, 2H), 5.30 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3 .63 (s, 2H), 1.03-0.88 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO4) δ -55.14; MS (ESI+): 483.10 (M+1).

Stage-3. Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (517d).

Compound 517d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy )phenyl)acetate (517c) (150 mg, 0.311 mmol) in THF/MeOH (6 mL each), using a solution of LiOH (104 mg, 2.487 mmol) in water (2 mL) and stirring at room temperature for 16 h This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with acetonitrile in water from 0-100%] 2-(2-((4-(3-(aminomethyl)phenyl) -1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (517d) (105 mg, 74% yield) free base as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.83 (d, J=3.7 Hz, 1H), 7.77-7.66 (m, 3H), 7 .47 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.09 (t, J=6.9 Hz, 2H), 7.00 -6.93 (m, 2H), 6.80 (t, J=7.3 Hz, 1H), 5.32 (s, 2H), 3.98 (s, 2H), 3.38 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -55.10; MS (ESI+): 455.2 (M+1), (ESI-): 453.10 (M-1); analysis calculation for С^^з^Оз'О^НО: С, 64.17; N, 4.85; N, 5.99; detect: C, 63.92; N, 4.75; N, 6.00.

- 617 045626

Scheme-518

Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (518b).

Stage-1. Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (518a).

Compound 518a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (517b) (200 mg, 0.438 mmol) in dioxane (5 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117 mg, 0.57 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (46.2 mg, 0.066 mmol) and a solution of K ₂ CO ₃ (182 mg, 1.315 mmol) in water (1 ml) was heated under nitrogen at 90°C for 3 hours. This resulted in the following treatment and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM from 050%] ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H- indol-6yl)methoxy)phenyl)acetate (518a) (180 mg, 82% yield) as yellow syrup; ¹⁹ F NMR (282 MHz, DMSOd ₆ ) δ -55.09, -122.64; MS (ESI+): 501.20 (M+1).

Stage-2. Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (518b).

Compound 518b was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((4-(3 -(aminomethyl)-2-fluorophenyl)-1 -(trifluoromethyl)-1 H-indole-6 -yl)methoxy)phenyl)acetate (518a) (180 mg, 0.360 mmol) in THF/MeOH (8 mL each), using a solution of LiOH (121 mg, 2.88 mmol) in water (2 mL) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with acetonitrile in water from 0-100%] 2-(2-((4-(3 -(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (518b) (135 mg, 79% yield) free base as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.82-7.75 (m, 2H), 7.59-7.50 (m, 2H), 7.43 (t, J=7.5 Hz , 1H), 7.30 (t, J=7.5 Hz, 1H), 7.24-7.15 (m, 2H), 7.06 (d, J=8.4 Hz, 1H), 6 .88 (t, J=7.4 Hz, 1H), 6.67-6.63 (m, 1H), 5.32 (s, 2H), 3.87 (s, 2H), 3.53 ( s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -55.05, -121.11; MS (ESI+): 473.1 (M+1), (ESI): 471.1 (M-1); analysis calculation for C ₂₅ H ₂₀ F ₄ N ₂ O ₃ -0.5H ₂ O: C, 62.37; N, 4.40; N, 5.82; detect: C, 62.33; N, 4.32; N, 5.89.

Scheme-519

519b 519c

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (519c).

Stage-1. Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-6fluorobenzofuran-5-yl)methoxy)phenyl)acetate (519a).

Compound 519a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c) (154 mg, 0.378 mmol) in dioxane (5 ml) using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate

- 618 045626 (123a) (171 mg, 0.512 mmol), solution of K ₂ CO ₃ (157 mg, 1.134 mmol) in water (0.5 ml), bis(triphenylphosphine) palladium(P) chloride (39.8 mg, 0.057 mmol) and heating in a nitrogen atmosphere at

100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with methanol in 0% to 15% DCM] ethyl 2-(2-((7-(2-(((tert- butoxycarbonyl)amino)methyl)pyridin-4-yl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetate (519a) (202 mg, 100% yield) as a dark oil; MS (ESI+): 535.20 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetate (519b).

Compound 519b was prepared according to the procedure described in step-5 of Scheme-1 from ethyl 2(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-6- fluorobenzofuran-5yl)methoxy)phenyl)acetate (519a) (202 mg, 0.378 mmol) in ethanol (6 ml), using 4 M HCl (0.945 ml, 3.78 mmol) in dioxane, followed by stirring at room temperature for 36 h. This resulted in the preparation after treatment of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6fluorobenzofuran-5-yl)methoxy)phenyl)acetate (519b) (164 mg, 100 % yield), HCl salt, as a brown solid, which was used as is in the next step-3; MS (ESI+): 435.15 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (519c).

Compound 519c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy) phenyl)acetate (519b) (164 mg, 0.377 mmol) in THF (3 ml) and acetonitrile (3 ml), using a solution of lithium hydroxide monohydrate (72 mg, 1.716 mmol) in water (2 ml). This gave, after work-up and purification by reverse phase column chromatography [C18 (50 g), eluted with ACN in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7- (2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (519c) (48 mg, 31% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J=5.2 Hz, 1H), 8.63 (s, 3H), 8.12 (s, 1H), 8.01- 7.86 (m, 2H), 7.79 (d, J=5.2 Hz, 1H), 7.32-7.18 (m, 2H), 7.15 (d, J=8.1 Hz , 1H), 7.10 (s, 1H), 6.93 (t, J=7.3 Hz, 1H), 5.29 (s, 2H), 4.40-4.23 (m, 2H) , 3.56 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -127.48; MS (ESI+): 407.1 (M+1); MS (ESI-): 405.1 (M-1); analysis calculation for C ₂₃ H ₁₉ FN ₂ O ₄ -1.75HCl-2.5H ₂ O: C, 53.61; N, 5.04; Cl, 12.04; N, 5.44; observed: C, 53.53; N, 4.86; Cl, 11.89; N, 5.42.

Scheme-520

Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (520c).

Stage-1. Preparation of ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (520a).

Compound 520a was prepared according to the procedure described in step-2 of Scheme-23 from (7bromo-2-fluorobenzofuran-5-yl)methanol (227b) (1.3 g, 5.31 mmol) in DCM (60 ml) using triphenylphosphine (1.531 g, 5.84 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl) acetate (260d) (1.262 g, 6.37 mmol) and (E)-bis(4-chlorobenzyl) solution diαzene-1,2-dicarboxylate (DCAD, 2.143 g, 5.84 mmol) in DCM (30 ml). This gave, after work-up and purification by flash column chromatography (silica gel, 80 g, eluted with ethyl acetate in 0 to 25% hexanes), ethyl 2-(2-((7-bromo-2-fluorobenzofuran5-yl)methoxy) -4-fluorophenyl)acetate (520a) (1.44 g, 63.8% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (s, 1H), 7.58 (s, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.00 ( dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.4, 2.4 Hz, 1H), 6.54 (d, J=6.4, 1, 1 Hz, 1H), 5.18 (s, 2H), 4.03 (k, 2H), 3.60 (s, 2H), 1.08 (t, J=7.1, 1.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -110.37, -110.39; MS (ESI+): 448.9 (M+1).

Stage-2. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-619 045626 fluorophenyl)acetate (520b).

Compound 520b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (520a) (220 mg , 0.475 mmol) in dioxane (8 ml), using (3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (107 mg, 0.570 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (50.0 mg, 0.071 mmol ) and a solution of K ₂ CO ₃ (197 mg, 1.425 mmol) in water (0.8 ml) was heated under argon at 100°C for 4 hours. This gave, after work-up and purification by flash column chromatography, [ silica gel (24 g), eluted with DMA80 in DCM from 050%]ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate ( 520b) (197 mg, 92% yield) as a clear oil;

Ή NMR (300 MHz, DMSO- _d6 ) δ 7.76 (s, 1H), 7.67-7.59 (m, 2H), 7.55 (s, 1H), 7.45 (dt, J =14.3, 7.5 Hz, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6 .74 (td, J=8.5, 2.6 Hz, 1H), 6.44 (d, J=6.4 Hz, 1H), 5.24 (s, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.60 (s, 2H), 0.99 (t, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 111.64, -112.65; MS (ESI+): 452.20 (M+1).

Stage-3. Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (520c).

Compound 520c was prepared according to the procedure described in step-6 of scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl) acetate (520b) (195 mg, 0.432 mmol) in THF (2.60 ml) and acetonitrile (1.3 ml) using 1N aq. LiOH (1.296 ml, 1.296 mmol) and stirring at room temperature for 35 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluted with acetonitrile in water (0.1% HCl ) from 0-100%] 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (520c) (101 mg, 55% yield ), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H, D2O replaceable), 8.40 (s, 3H, D2O replaceable), 7.94 (s, 1H), 7.85 (dd , J=7.2, 2.3 Hz, 1H), 7.68 (s, 1H), 7.65-7.54 (m, 3H), 7.25 (t, J=7.6 Hz, 1H), 7.01 (dd, J=11.2, 2.5 Hz, 1H), 6.74 (td, J=8.6, 2.5 Hz, 1H), 6.45 (d, J =6.4 Hz, 1H), 5.27 (s, 2H), 4.14 (s, 2H), 3.57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.46, -112.93; MS (ESI+): 424.1 (M+1), (ESI-): 422.1 (M-1); analysis calculation for C ₂₄ H ₁₉ F ₂ NO ₄ -HCbH ₂ O: C, 60.32; N, 4.64; Cl, 7.42; N, 2.93; observed: C, 60.41; N, 4.62; Cl, 7.28; N, 2.92.

Scheme-521

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (521b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (521a).

Compound 521a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (520a) (202 mg , 0.475 mmol) in dioxane (8 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117 mg, 0.570 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (50.0 mg , 0.071 mmol) and a solution of K ₂ CO ₃ (197 mg, 1.425 mmol) in water (0.8 ml) was heated under argon at 100°C for 4 hours. This resulted in, after workup and purification by flash chromatography on a column [silica gel (24 g), eluted with DMA80 in DCM from 0-50%] ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy )-4fluorophenyl)acetate (521a) (220 mg, 99% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.64-7.60 (m, 2H), 7.45 (t, J=7.4 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.10-6.95 (m, 1H), 6.74 (td , J=8.5, 2.4 Hz, 1H), 6.52-6.38 (m, 1H), 5.23 (s, 2H), 3.95-3.86 (m, 2H), 3.84 (s, 2H), 3.59 (s, 2H), 0.98 (td, J=7.1, 1.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 111.61, -112.65, -122.02; MS (ESI+): 470.1 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (521b).

Compound 521b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4 -fluorophenyl)acetate (521 a) (217 mg, 0.462 mmol) in THF (2.8 ml) and acetonitrile (1.4 ml) using 1N aq. LiOH (1.387 ml, 1.387 mmol) and stirring at room temperature for 35 hours. This gave, after work-up and purification by reverse phase column chromatography, [C18 (50 g), eluting with acetonitrile in water (0 .1% HCl) from 0-100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (521b) (101 mg, 55% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 7.77-7.62 (m, 3H), 7.47 (s, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.01 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2, 5 Hz, 1H), 6.46 (d, J=6.5, 1.1 Hz, 1H), 5.27 (s, 2H), 4.15 (s, 2H), 3.55 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.51, -113.03, -118.73; MS (ESI+): 442.1 (M+1), (ESI-): 440.1 (M-1); analysis calculation for C ₂₄ H ₁₈ F ₃ NO ₄ -0.85HCl-H ₂ O: C, 58.78; N, 4.29; Cl, 6.14; N, 2.86; observed: C, 59.07; N, 4.39; Cl, 6.42; N, 2.85.

Scheme-522

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (522c).

Stage-1. Preparation of ethyl 2-(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl) acetate (522a).

Compound 522a was prepared according to the procedure described in step-1 of Scheme-59 from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (520a) ( 0.84 g, 1.975 mmol) using bis(pinacolato)diboron (0.752 g, 2.96 mmol), potassium acetate (0.582 g, 5.93 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (0.161 g . up to 40%] ethyl 2-(4-fluoro2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy )phenyl)acetate (522a) as a colorless oil;

¹ H NMR (300 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.61 (s, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.02 ( dd, J=10.3, 2.1 Hz, 1H), 6.74 (td, J=8.4 Hz, 1H), 6.36 (d, J=6.3 Hz, 1H), 5, 17 (s, 2H), 4.00 (k, J=7.1 Hz, 2n), 3.57 (s, 2n), 1.34 (s, 12H), 1.05 (t, J=7 ,1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.63, -112.69.

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy) -4-fluorophenyl)acetate (522b).

Compound 522b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (522a) (220 mg, 0.466 mmol) in dioxane (10 ml) using (+)-(S)-N-((4-chloro3 -fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (123 mg, 0.466 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.070 mmol) and K2CO3 solution (193 mg, 1.397 mmol) in water (1 ml) under nitrogen atmosphere was heated at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)-(S)-ethyl 2(2-((7-(2-( (1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (522b) (160 mg, 60% yield) as a brown oil; MS (ESI+) 575.2 (M+1); optical rotation [a] _D = +18.46 (c = 0.065, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetic acid (522c).

Compound 522c was prepared according to the procedure described in step-2 of scheme-499 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (522b) (155 mg, 0.27 mmol) in THF (4.50 ml) using 4 M HCl in 1, 4dioxane (0.135 ml, 0.539 mmol) and stirring at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum until dry. The resulting residue was dissolved in THF (3.0 ml) and acetonitrile (1.5 ml), 1N aq. was added. LiOH (1.5 ml, 1.5 mmol) and stirred at room

- 621 045626 temperature for 48 hours. This resulted in the following work-up and purification by reverse phase column chromatography [column C-18, 50 g, eluted with acetonitrile in water (with

0.1% HCl) from 0% to 100%] 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl )acetic acid (522c) (43 mg, 36% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, J=5.0 Hz, 1H), 8.59-8.49 (m, 3H, D2O replaceable), 7.86-7, 76 (m, 2H), 7.58 (s, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.02 (dd, J=11.5, 2.5 Hz, 1H ), 6.74 (td, J=8.5, 2.5 Hz, 1H), 6.51 (d, J=6.3 Hz, 1H), 5.29 (s, 2H), 4.51 -4.20 (m, 2H), 3.56 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -111.11, -112.90, 128.53; MS (ESI+): 443.1 (M+1); (ESI-): 441.1 (M-1); analysis calculation for C ₂₃ H ₁₇ F ₃ N ₂ O ₄ -HCl-1.5H ₂ O: C, 54.61; N, 4.18; Cl, 7.01; N, 5.54; observed: C, 54.87; N, 4.17; Cl, 6.94; N, 5.50.

Scheme-523

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (523b).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)2-fluorobenzofuran-5-yl)methoxy)-4 -fluorophenyl)acetate (523a).

Compound 523a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (522a) (220 mg, 0.466 mmol) in dioxane (10 ml) using (+)-(S)-N-((4chloropyridine-2 -yl)methyl)-2-methylpropane-2-sulfinamide (365c) (115 mg, 0.466 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.070 mmol) and K ₂ CO ₃ solution (193 mg, 1.397 mmol) in water (1 ml) under nitrogen atmosphere was heated at 100°C for 4 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)-(S)-ethyl 2(2-((7-(2-( (1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetate (523a) (140 mg, 54% yield) as a brown oil; MS (ESI+) 557.2 (M+1); optical rotation [a] _D = +27.69 (c = 0.065, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (523b).

Compound 523b was prepared according to the procedure described in step-2 of Scheme-499 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridine- 4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-fluorophenyl)acetate (523a) (135 mg, 0.243 mmol) in THF (3.75 ml), using 4 M HCl in 1,4dioxane, (0.121 ml , 0.485 mmol) and stirring at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum until dry. The resulting residue was dissolved in THF (2.5 ml) and acetonitrile (1.25 ml), 1N aq. was added. LiOH (1.25 ml, 1.250 mmol) and stirred at room temperature for 48 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (c 0.1% HCl) from 0% to 100%] 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4fluorophenyl)acetic acid (523b) (53 mg, 52% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=5.3 Hz, 1H), 8.47 (s, 3H, D2O exchangeable), 8.00 (s, 1H), 7 .90 (d, J=5.3 Hz, 1H), 7.77 (d, J=8.6 Hz, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.01 (dd, J=U,3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.29 (s, 2H), 4.44-4.21 (m, 2H), 3.57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -111.05, -112.94; MS (ESI+): 425.1 (M+1); (ESI-): 423.1 (M-1); analysis calculation for C ₂₃ H ₁₈ F ₂ N ₂ O ₄ -1.5HCl-1.75H ₂ O: C, 54.10; N, 4.54; Cl, 10.41; N, 5.49; observed: C, 53.72; N, 4.32; Cl, 10.77; N, 5.49.

Scheme-524

- 622 045626

Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (524b).

Stage-1. Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (524a).

Compound 524a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (299a) (200 mg, 0.475 mmol) in dioxane (8 ml), using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117 mg, 0.570 mmol), K ₂ CO ₃ solution (197 mg, 1.424 mmol) in water (0.8 ml), bis(triphenylphosphine) palladium(P) chloride (50.0 mg, 0.071 mmol) by heating at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 50%] ethyl 2-(2-((7-(3-(aminomethyl)-2 -fluorophenyl)-2fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (524a) (125 mg, 57% yield) as a clear oil;

^1H NMR (300 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.45 (t, J=7.3 Hz, 1H), 7.41 (s, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.45 (d, J=6.5 Hz, 1H), 5.19 (s, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.56 (s, 2H), 2.30 (s, 3H), 0.98 (t, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.72, -122.00; MS (ESI+): 466.2 (M+1).

Stage-2. Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (524b).

Compound 524b was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)- 4-methylphenyl)acetate (524a) (120 mg, 0.258 mmol) in acetonitrile/THF (0.45/0.90 ml) using 1N lithium hydroxide monohydrate solution (0.773 ml, 0.773 mmol) and stirred the reaction mixture at room temperature for 35 hours. This resulted in, after work-up and purification by reverse phase column chromatography [column C-18, 50 g, eluted with acetonitrile in water (containing 0.1% aq. HCl) from 0 to 100%] 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (524b) (90 mg, 80% yield), hydrochloride salt , as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.77-7.61 (m, 3H), 7.49-7.40 (m, 2H), 7.08 (d, J=7.5 Hz , 1H), 6.94 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.45 (d, J=6.4 Hz, 1H), 5.22 (s , 2H), 4.17 (s, 2H), 3.52 (s, 2H), 2.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.62, -118.60; MS (ESI+): 438.10 (M+1), (ESI-): 436.10 (M-1); analysis calculation for C ₂₅ H ₂₁ F ₂ NO ₄ -HCl-H ₂ O: C, 61.04; N, 4.92; Cl, 7.21; F, 7.72; N, 2.85; observed: C, 61.05; N, 4.78; Cl, 7.19; N, 2.93.

Scheme-525

525b (3 525с

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (525c).

Stage-1. Preparation of ethyl 2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate (525a).

Compound 525a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (299a) ( 1 g, 2.374 mmol) using bis(pinacolato)diboron (0.904 g, 3.56 mmol), potassium acetate (0.699 g, 7.12 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.194 g, 0.237 mmol) in anhydrous dioxane (35 ml) under argon while heating at 90°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane from 0 to 40%] ethyl 2-(2-((2-fluoro-7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4 -methylphenyl)acetate (525a) in the form

- 623 045626 colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (s, 1H), 7.61 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.93 ( s, 1H), 6.72 (d,

J=7.5 Hz, 1H), 6.38-6.33 (m, 1H), 5.13 (s, 2H), 3.99 (k, J=6.7 Hz, 2H), 3, 53 (s, 2H), 2.29 (s, 3H), 1.34 (s, 12H),

1.05 (t, 3H); ¹⁹ F NMR (282 MHz, DMSO4) δ -111.72.

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy) -4-methylphenyl)acetate (525b).

Compound 525b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (525a) (220 mg, 0.470 mmol) in dioxane (10 ml) using (+)-(S)-N-((4-chloro- 3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (124 mg, 0.470 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49.5 mg, 0.070 mmol) and K2CO3 solution (195 mg , 1.409 mmol) in water (1.0 ml) under nitrogen atmosphere was heated at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)-(S)-ethyl 2(2-((7-(2-( (1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetate (525b) (230 mg, 86% yield) as a brown oil; MS (ESI+) 571.2 (M+1); optical rotation [a] _D = +21.33 (c = 0.075, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (525c).

Compound 525c was prepared according to the procedure described in step-2 of Scheme-499 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-2-fluorobenzofuran-5 yl)methoxy)-4-methylphenyl)acetate (525b) (225 mg, 0.394 mmol) in THF (4 ml) using 4 M HCl in 1,4dioxane (0.197 ml, 0.789 mmol) and stirring at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum until dry. The resulting residue was dissolved in THF (4 ml) and acetonitrile (2 ml), 1N aq. was added. LiOH (2.0 mL, 2,000 mmol) and stirred at room temperature for 48 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (c 0.1% HCl) from 0% to 100%] 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methylphenyl )acetic acid (525c) (53 mg, 31% yield), HCl salt, as a white solid;

1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.0 Hz, 1H), 8.57 (s, 3H, D2O replaceable), 7.86-7.75 (m, 2H ), 7.59 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J=7.5 Hz, 1H ), 6.51 (d, J=6.4 Hz, 1H), 5.24 (s, 2H), 4.44-4.31 (m, 2H), 3.52 (s, 2H), 2 .29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -111.19, -128.53; MS (ESI+): 439.1 (M+1); (ESI-): 437.1 (M-1); analysis calculation for C ₂ 4H ₂ oF ₂ N ₂ O4-HCl-H ₂ O: C, 58.48; N, 4.70; Cl, 7.19; N, 5.68; observed: C, 58.18; N, 4.57; Cl, 6.91; N, 5.67.

Scheme-526

O

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (526b).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)2-fluorobenzofuran-5-yl)methoxy)-4 -methylphenyl)acetate (526a).

Compound 526a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)-4methylphenyl)acetate (525a) (220 mg, 0.470 mmol) in dioxane (10 ml) using (+)-(S)-N-((4chloropyridine-2- yl)methyl)-2-methylpropane-2-sulfinamide (365c) (116 mg, 0.470 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49.5 mg, 0.070 mmol) and K ₂ CO ₃ solution (195 mg, 1.409 mmol) in water (1 ml) under nitrogen atmosphere was heated at 100°C for 4 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0% to 30%] (+)-(S)-ethyl 2(2-((7-(2-( (1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetate (526a) (120 mg, 46% yield) as a brown oil; MS (ESI+): 553.2 (M+1); optical rotation [a] _D = +57.14 (c = 0.035, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4methylphenyl)acetic acid (526b).

Compound 526b was prepared according to the procedure described in step-2 of scheme-499, from (+)

- 624 045626 (S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methylphenyl) acetate (526a) (115 mg, 0.208 mmol) in THF (3.30 ml) using 4 M HCl in 1,4-dioxane (0.104 ml, 0.416 mmol) and stirring at room temperature for 30 min. The reaction mixture was concentrated under vacuum until dry. The resulting residue was dissolved in THF (2.2 ml) and acetonitrile (1.1 ml), 1N aq. was added. LiOH (1.1 ml, 1.100 mmol) and stirred at room temperature for 48 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (c 0.1% HCl) from 0% to 100%] 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5yl)methoxy)-4-methylphenyl)acetic acid (526b) (35 mg, 40% yield), as a white solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.3 Hz, 1H), 8.48 (s, 3H, D2O replaceable), 8.01 (s, 1H), 7 .91 (d, J=5.3 Hz, 1H), 7.78 (d, J=4.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.25 (s, 2H), 4.38 -4.23 (m, 2H), 3.55 (s, 2H), 2.29 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ 111.18; MS (ESI+): 421.1 (M+1); (ESI-): 419.1 (M-1); analysis calculation for C ₂₄ H ₂₁ FN ₂ O ₄ -1.65HCl-1.5H ₂ O: C, 56.79; H, 5.09; Cl, 11.52; N, 5.52; observed: C, 56.45; N, 4.99; Cl, 11.25; N, 5.64.

Scheme-527

512a 527a ^D

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetic acid (527b).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3- methoxyphenyl)acetate (527a).

Compound 527a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (512a) (407 mg, 0.873 mmol) in dioxane (4 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (254 mg, 0.960 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (61.3 mg, 0.087 mmol) and K ₂ CO ₃ solution (362.1 mg, 2.62 mmol) in water (0.8 ml) heating under nitrogen at 100°C for 16 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [(silica gel 12 g, eluted with MeOH in DCM 0% to 3%)] (+)-(S)-ethyl 2-(2((7-(2- ((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetate (527a) (412 mg, 83% yield) as an orange oil; MS (ESI+) 569.2 (M+1); optical rotation [a] _D = +36.19 (c = 0.105, MeOH).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3methoxyphenyl)acetic acid (527b).

Compound 527b was prepared according to the procedure described in step-2 of scheme-499 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)benzofuran-5yl)methoxy)-3-methoxyphenyl)acetate (527a) (412 mg, 0.725 mmol) in EtOH (4 ml), using 4 M HCl in dioxane (0.543 ml, 2.174 mmol) and stirring at room temperature for 16 hours. To this reaction mixture was added EtOH (3 ml), 2.0 M lithium hydroxide monohydrate solution (1.545 ml, 3.09 mmol) and stirred at room temperature for 16 hours. This resulted in obtained after treatment and purification by reverse phase column chromatography [column C-18, 100 g, eluted with acetonitrile in water (containing 0.1% aq. HCl) from 0% to 60%] 2-(2-(( 7-(2-(aminomethyl)-3fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetic acid (527b) (119 mg, 44% yield), HCl salt, as a yellow solid ;

1H NMR (300 MHz, DMSO- _d6 ) δ 8.73-8.49 (m, 4H, 3H D2O replaceable), 8.12 (s, 1H), 7.90 (s, 1H), 7.81 (t, J=5.5 Hz, 1H), 7.60 (s, 1H), 7.13 (s, 1H), 7.09-6.96 (m, 2H), 6.91-6, 77 (m, 1H), 5.09 (s, 2H), 4.48-4.30 (m, 2H), 3.86 (s, 3H), 3.54 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -128.56; MS (ESI+): 437.1 (M+1); (ESI-): 435.1 (M-1); analysis calculation for C ₂₄ H ₂ 1FN ₂ O5-1.3HCl-H ₂ O: C, 57.44; N, 4.88; Cl, 9.18; N, 5.58; observed: C, 57.22; N, 4.68; Cl, 9.18; N, 5.62.

- 625 045626

Scheme-528 ci

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetic acid (528c).

Stage-1. Preparation of ethyl 2-(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzofuran-5-yl)methoxy) phenyl)acetate (528a).

Compound 528a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (462a) (1.2 g, 2.408 mmol) using bis(pinacolato)diboron (1.835 g, 7.22 mmol), potassium acetate (0.709 g, 7.22 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.295 g, 0.361 mmol) in anhydrous dioxane (25 ml) under argon when heated at 100°C for 62 hours. This resulted after work-up and purification by flash column chromatography (silica gel, eluted with EtOAc in hexane from 0 to 33%) ethyl 2-(5-fluoro2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran- 5yl)methoxy)phenyl)acetate (528a) (898 mg, 75% yield) as a brown gum;

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (d, J=1.9 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.16-7, 03 (m, 3H), 6.91 (s, 1H), 5.14 (s, 2H), 4.55 (s, 2H), 4.07-3.96 (m, 2H), 3.61 (s, 2H), 3.33 (s, 3H), 1.34 (s, 12H), 1.10-1.01 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -124.05; MS (ESI+): 521.20 (M+Na).

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl )methoxy)-5-fluorophenyl)acetate (528b).

Compound 528b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (528a) (420 mg, 0.843 mmol) in dioxane (18 ml) using (+)-(S)-N-((4 -chloro3-fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (268 mg, 1.011 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (89 mg, 0.126 mmol) and K ₂ CO solution ₃ (349 mg, 2.53 mmol) in water (2.2 ml) under nitrogen was heated at 100°C for 20 hours in an oil bath. This gave, after work-up and purification by flash column chromatography (silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1 ratio)] (+)-(S)-ethyl 2-(2-(( 7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (528b) (250 mg, 49% yield) in the form of a colorless resin;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.65 (t, J=5.2 Hz, 1H), 7.49 (s, 1H), 7.16-7.06 (m, 3H), 7.04 (s, 1H), 5.84 (t, J=5 .7 Hz, 1H), 5.22 (s, 2H), 4.52 (s, 2H), 4.44-4.36 (m, 2H), 3.92 (k, J=7.1 Hz , 2H), 3.64 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -123.94, -128.08; MS (ESI+): 601.2 (M+1); optical rotation [ab = +24.24 (c = 0.165, MeOH).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran5-yl)methoxy)-5-fluorophenyl)acetic acid (528c).

Compound 528c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (528b) (245 mg, 0.408 mmol) in THF (10 ml) using 3 M aq. HCl (0.408 ml, 1.224 mmol) and stirring at room temperature for 5 hours. The reaction mixture was concentrated in vacuo to dryness. The resulting residue was dissolved in THF (7 ml) and MeOH (7 ml), a solution of LiOH (140 mg, 3.26 mmol) in water (7 ml) was added and stirred at room temperature for 20 hours. This resulted in the following workup: and purification by reverse phase column chromatography [column C-18, eluted with acetonitrile in water (with 0.1% HCl) from 0% to 100%] 2-(2-((7-(2-(aminomethyl)- 3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (528c) (77 mg, 40% yield

- 626 045626 two stages), HCl salt, in the form of a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.72-8.59 (m, 4H), 7.86 (s, 1H), 7.78 (t, J=5.3 Hz, 1H), 7.57 (s, 1H),

7.16-7.01 (m, 4H), 5.24 (s, 2H), 4.54 (s, 2H), 4.42-4.30 (m, 2H), 3.60 (s, 2H), 3.30 (s, 3H); ¹⁹ F NMR (282 MHz,

DMSO-d ₆ ) δ -123.98, -128.59; MS (ESI+): 469.1 (M+1).

Scheme-529

529b

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5fluorophenyl)acetic acid (529b).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)2-(methoxymethyl)benzofuran-5-yl)methoxy )-5-fluorophenyl)acetate (529a).

Compound 529a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)benzofuran-5yl)methoxy)phenyl)acetate (528a) (440 mg, 0.883 mmol) in dioxane (20 ml) using (+)-(S)-N-((4chloropyridine -2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (261 mg, 1.06 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (93 mg, 0.132 mmol) and K ₂ CO ₃ solution ( 366 mg, 2.65 mmol) in water (2.4 ml) under nitrogen atmosphere was heated at 100°C for 16 hours in an oil bath. This gave, after workup and purification by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate from 0% to 33%] (+)-(S)-ethyl 2-(2-((7-(2- ((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (529a) (278 mg, 54% yield) as a colorless gum ;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.79-7.74 (m, 2H), 7.68 (d, J=1.7 Hz, 1H), 7.16-7.07 (m, 3H), 7.04 (s, 1H), 5.94 (t, J=6.2 Hz , 1H), 5.22 (s, 2H), 4.58 (s, 2H), 4.46-4.26 (m, 2H), 3.93 (k, J=7.1 Hz, 2H) , 3.65 (s, 2H), 3.33 (s, 3H), 1.17 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz,

DMSO) δ -123.97, MS (ESI+) 583.3 (M+1); optical rotation [a] _D = +20.69 (c = 0.145, MeOH).

Stage-2. Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)-5-fluorophenyl)acetic acid (529b).

Compound 529b was prepared according to the procedure described in step-2 of Scheme-499 from (+)(S)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridine- 4-yl)-2-(methoxymethyl)benzofuran5-yl)methoxy)-5-fluorophenyl)acetate (529a) (250 mg, 0.429 mmol) in THF (10.0 mL) using 3 M HCl (0.429 mL, 0 ,1.287 mmol) and stirring at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum until dry. The resulting residue was dissolved in THF (7 ml) and methanol (7.0 ml) and 1N aq. was added. LiOH (147 mg, 3.43 mmol) and stirred at room temperature for 12 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water (c 0.1% HCl) from 0% to 100%] 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5fluorophenyl )acetic acid (529b) (73 mg, 38% yield), HCl salt, as a yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.3 Hz, 1H), 8.53 (s, 3H), 8.06 (s, 1H), 7.99 ( d, J=5.4 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.19-7.01 (m, 4H), 5.26 (s, 2H ), 4.61 (s, 2H), 4.35-4.25 (m, 2H), 3.62 (s, 2H), 3.34 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -124.00; MS (ESI+): 451.15 (M+1); (ESI-): 449.20 (M-1).

- 627 045626

Scheme-530

Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetic acid (530c).

Stage-1. Preparation of (+)-(S)-ethyl 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran -5-yl)methoxy)phenyl)acetate (530a).

Compound 530a was prepared according to the procedure described in step-2 of Scheme-23 from (+)(S)-N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7 -yl)pyridin-2-yl)methyl)-2methylpropan-2-sulfinamide (453a) (1.05 g, 2.497 mmol) in DCM (30 ml) using triphenylphosphine (0.851 g, 3.25 mmol), ethyl 2 -(4-bromo-2-hydroxyphenyl)acetate (182a) (0.647 g, 2.497 mmol) and (E)-bis(4chlorobenzyl)diazen-1,2-dicarboxylate (DCAD) (1.192 g, 3.25 mmol) in DCM (10 ml). This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with ethyl acetate/methanol (9:1) in 0% to 50% hexanes] (+)-(S)-ethyl 2-( 4-bromo-2-((7-(2-((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (530a) (1 .33 g, 81%);

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (s, 1H), 7.65 (t, J=5.3 Hz, 1H), 7.50 (s, 1H), 7.34 (s, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.05 (s, 1H), 5.84 (t, J=5.8 Hz, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 4.46- 4.34 (m, 2H), 3.90 (k, J=7.1 Hz, 2H), 3.60 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H ), 0.96 (t, J=7.1 Hz, 3H); MS (ESI+): 662.1 (M+1); optical rotation [a] _D = +22.35 (c = 0.68, MeOH).

Stage-2. Preparation of (+)-(S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran -5-yl)methoxy)phenyl)acetate (530b).

Compound 530b was prepared from (+)-(S)-ethyl 2-(4-bromo-2-((7-(2-((1,1dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-( methoxymethyl)benzofuran-5yl)methoxy)phenyl)acetate (530a) (1.3 g, 1.965 mmol) in toluene (10 ml), using tributyl(1ethoxyvinyl)stannane (0.875 ml, 2.456 mmol), Pd(PPh ₃ ) ₄ (0.227 g, 0.196 mmol) when heated at 120°C for 22 hours. This gave, after work-up and purification by flash column chromatography [silica gel, 40 g, eluted with ethyl acetate/methanol (9:1) in hexanes from 0% up to 50%] (+)-(S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2 (methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (530b) (485 mg, 40%) as a colorless oil;

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (d, J=4.9 Hz, 1H), 7.84 (s, 1H), 7.65 (t, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.05 (s, 1H), 5.84 (t, J=5.8 Hz, 1H), 5.33 (s, 2H), 4.52 (s, 2H), 4.43- 4.38 (m, 2H), 3.92 (k, J=7.1 Hz, 2H), 3.71 (s, 2H), 3.30 (s, 3H), 2.58 (s, 3H ), 1.11 (s, 9H), 1.00-0.93 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.05; MS (ESI+): 625.25 (M+1); optical rotation [a]D = +8 (c = 0.1, MeOH).

Stage-3. Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (530c).

Compound 530c was prepared according to the procedure described in step-2 of Scheme-499 from (+)(S)-ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido) methyl)-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (530b) (450 mg, 0.720 mmol) in THF (15 ml) using 3 M HCl (0.720 ml, 2.161 mmol) and stirring at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to dryness. The resulting residue was dissolved in THF

- 628 045626 (7 ml) and methanol (7 ml), a solution of LiOH (247 mg, 5.76 mmol) in water (7 ml) was added and stirred at room temperature for 16 hours. This resulted in the following workup and purification: by reverse phase column chromatography [column C-18, eluted with acetonitrile in water (with 0.1% HCl) from 0% to 40%] 2-(4-acetyl-2-((7-(2-(aminomethyl )-3-fluoropyridin-4-yl)-2(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (530c) (259 mg, 73% yield), HCl salt, as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=5.0 Hz, 1H), 8.53 (t, J=5.9 Hz, 3H, D2O replaceable), 7.90 (s, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.64-7.55 (m, 3H), 7.39 (d, J=7.6 Hz, 1H) , 7.05 (s, 1H), 5.36 (s, 2H), 4.54 (s, 2H), 4.44-4.31 (m, 2H), 3.67 (s, 2H), 3.30 (s, 3H), 2.57 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.57; MS (ESI+): 493.1 (M+1); (ESI-).

Scheme-531

C.I.

473s

Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (531c).

Stage-1. Preparation of ethyl 2-(2-((6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzofuran-5-yl)methoxy)phenyl)acetate (531a) .

Compound 531a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c) (314 mg, 0.771 mmol) using bis(pinacolato)diboron (294 g, 1.157 mmol), potassium acetate (227 mg, 2.313 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (94 mg, 0.116 mmol) in anhydrous dioxane ( 12 ml) under argon when heated at 95°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexane 0 to 40%] ethyl 2 -(2-((6-fluoro-7-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (531a) (181 mg , 52%) in the form of colorless oil;

^1H NMR (300 MHz, DMSO-d6) δ 8.10-8.03 (m, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.32-7.18 (m , 2H), 7.13 (d, J=8.2 Hz, 1H), 7.00-6.96 (m, 1H), 6.92 (t, J=7.4 Hz, 1H), 5 .17 (s, 2H), 3.96 (k, J=6.9 Hz, 2H), 3.57 (s, 2H), 1.35 (s, 12H), 1.03 (t, J= 7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -111.29.

Stage-2. Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (531b).

Compound 531b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (531a) (178 mg, 0.392 mmol) in dioxane (5 ml) using (+)-(S)-N-((4-chloro-3 -fluoropyridin-2-yl)methyl)2-methylpropan-2-sulfinamide (220c) (156 mg, 0.588 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (41 mg, 0.059 mmol) and K ₂ CO ₃ solution (162 mg, 1.175 mmol) in water (0.5 ml) under nitrogen atmosphere was heated at 100°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with 0% to 15% methanol/DCM] ethyl 2-(2-((7-(2-((1,1dimethylethylsulfinamido) methyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (531b) (218 mg, 100% yield) as a yellow oil; MS (ESI+): 557.2 (M+1).

Stage-3. Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5yl)methoxy)phenyl)acetic acid (531c).

Compound 531c was prepared according to the procedure described in step-2 of scheme-499 from ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl) -6-fluorobenzofuran-5yl)methoxy)phenyl)acetate (531b) (218 mg, 0.392 mmol), in ethanol (6 ml), using 4 M HCl in dioxane (1 ml, 4.0 mmol) and stirring at room temperature for 1 hour. The reaction mixture was concentrated under vacuum until dry. The resulting residue was dissolved in THF (3 ml) and methanol (3 ml),

- 629 045626 a solution of LiOH (153 mg, 3.65 mmol) in water (2 ml) was added and stirred at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [column C- 18, eluted with acetonitrile in water (with 0.1% HCl) from 0% to

100%] 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (531c) (11 mg, 7 % yield), HCl salt, as a white-yellow solid;

1H NMR (300 MHz, DMSO-d ₆ ) δ 12.21 (s, 1H), 8.75-8.55 (m, 4H), 8.12 (d, J=2.2 Hz, 1H), 8.01 (d, J=6.9 Hz, 1H), 7.82 (t, J=5.1 Hz, 1H), 7.32-7.19 (m, 2H), 7.19-7 .06 (m, 2H), 6.93 (t, J=7.3 Hz, 1H), 5.30 (s, 2H), 4.39 (d, J=5.9 Hz, 2H), 3 .57 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -124.79, -126.55; MS (ESI+): 425.1 (M+1); MS (ESI-): 423.1 (M-1).

Receipt

Scheme 532

2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (532d).

Stage-1. Preparation of ethyl 2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)1H-indol-6-yl)methoxy) phenyl)acetate (532a).

Compound 532a was prepared according to the procedure described in step-1 of scheme-59 from ethyl 2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate ( 517b) (0.72 g, 1.578 mmol) using bis(pinacolato)diboron (0.601 g, 2.367 mmol), potassium acetate (0.465 g, 4.73 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (0.193 g, 0.237 mmol) in anhydrous dioxane (15 ml) under argon while heating at 100°C for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc/MeOH ( 9:1) in hexane from 0 to 10%] ethyl 2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl )-1H-indol-6yl)methoxy)phenyl)acetate (532a) (0.76 g, 96% yield) as a yellow solid;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 (s, 1H), 7.79 (d, J=3.6 Hz, 1H), 7.70 (s, 1H), 7.30 -7.19 (m, 2H), 7.10 (s, 1H), 7.08-7.05 (m, 1H), 6.91 (t, J=7.4 Hz, 1H), 5, 24 (s, 2H), 4.03-3.94 (m, 2H), 3.60 (s, 2H), 1.34 (s, 12H), 1.03 (t, J=7.1, 1.2 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -54.99.

Stage-2. Preparation of (+)-(S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)1-(trifluoromethyl)-1H-indole-6- yl)methoxy)phenyl)acetate (532b).

Compound 532b was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (532a) (0.38 g, 0.755 mmol) in dioxane (6 ml) using (+)-(S)-N-(( 4chloropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (365c) (0.186 g, 0.755 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.079 g, 0.113 mmol) and K2CO3 solution (0.313 g, 2.265 mmol) in water (2.0 ml) under nitrogen atmosphere was heated at 90°C for 3 hours in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0% to 50%] (+)-(S)-ethyl 2(2-((4-(2-( (1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (532b) (0.4 g, 90% yield) as yellow oil ; ¹⁹ F NMR (282 MHz, DMSO) δ - 630 045626

55.10; MS (ESI+): 588.2 (M+1); optical rotation [α]ρ = +19.05 (c=0.21, MeOH).

Stage-3. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (532c).

Compound 532c was prepared according to the procedure described in step-3 of Scheme-305 from (+)(S)-ethyl 2-(2-((4-(2-(( 1,1-dimethylethylsulfinamido)methyl)pyridine- 4-yl)-1-(trifluoromethyl)-1 H-indol-6yl)methoxy)phenyl)acetate (532b) (0.4 g, 0.681 mmol) in DCM (5 ml), using 4 M HCl in dioxane (0.511 ml, 2.042 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80/DCM from 0-70%] ethyl 2 -(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1Nindol-6-yl)methoxy)phenyl)acetate (532c) (0.3 g, 91% yield ) as a pale yellow oil; MS (ESI+): 484.2 (M+1).

Stage-4. Preparation of 2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (532d).

Compound 532d was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indole-6 -yl)methoxy)phenyl)acetate (532c) (0.3 g, 0.620 mmol) in MeOH/THF (3 ml each), using a solution of LiOH hydrate (0.208 g, 4.96 mmol) in water (2 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [C-18 column, 50 g, eluted with acetonitrile in water from 0-100%] 2-(2-( (4-(2-(aminomethyl)pyridin-4-yl)-1(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (532d) (0.08 g, 28% yield) free base as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J=3.7 Hz, 1H), 7.82 (s, 2H), 7.70 (d, J=5.2 Hz, 1H), 7.12 (dt, J=7.6, 3.8 Hz, 2H), 7, 05 (d, J=3.8 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 5.34 ( s, 2H), 4.07 (s, 2H), 3.43 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -55.06; MS (ESI+): 456.15 (M+1); (ESI-): 454.10 (M-1).

Scheme 533

(+)-isomer

533b _533с

Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (533c).

Stage-1. Preparation of (+)-(S)-ethyl 2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol- 6-yl)methoxy)phenyl)αcetαtα (533a).

Compound 533a was prepared according to the procedure described in step-3 of Scheme-1 from ethyl 2(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetate (532a) (0.38 g, 0.755 mmol) in dioxane (6 ml) using (+)-(S)-N-( (4-chloro-3fluoropyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide (220c) (0.200 g, 0.755 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.079 g, 0.113 mmol) and K2CO3 solution (0.313 g, 2.265 mmol) in water (2.0 ml) heating under argon at 90°C for 3 hours in an oil bath. This resulted in (+)-(S)ethyl 2-(2-((4-(2) -((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1Nindol-6-yl)methoxy)phenyl)acetate (533a) (0.4 g, 87% yield ) as a yellow oil; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -55.06, -128.45; MS (ESI+): 606.2 (M+1); (ESI-): 604.2 (M-1); optical rotation [ab = +27.41 (c = 0.27, MeOH).

Stage-2. Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1Nindol-6-yl)methoxy)phenyl)acetate (533b).

Compound 533b was prepared according to the procedure described in step-3 of scheme-305 from (+)(S)-ethyl 2-(2-((4-(2-(( 1,1-dimethylethylsulfinamido)methyl)-3 -fluoropyridin-4-yl)-1 -(trifluoromethyl)-1H

- 631 045626 indol-6-yl)methoxy)phenyl)acetate (533a) (0.4 g, 0.660 mmol) in DCM (5 ml), using 4 M HCl in dioxanes (0.495 ml, 1.981 mmol) and stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80/DCM 0 to 70%] ethyl 2-(2-((4-( 2-(Aminomethyl)-3-fluoropyridin-4-yl)-1(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate (533b) (0.3 g, 91% yield) as pale yellow oil; MS (ESI+): 502.15 (M+1).

Stage-3. Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6yl)methoxy)phenyl)acetic acid (533c).

Compound 533c was prepared according to the procedure described in step-6 of Scheme-1 from ethyl 2(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 -(trifluoromethyl)-1H -indol-6-yl)methoxy)phenyl)acetate (533b) (0.3 g, 0.598 mmol) in MeOH/THF (3 mL each), using a solution of LiOH hydrate (0.201 g, 4.79 mmol) in water (2 ml) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse phase column chromatography [column C-18, 50 g, eluted with acetonitrile in water from 0-100%] 2- (2-((4-(2-(aminomethyl)-3-fluoropyridin4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (533c) (0.1 g, 35% yield) free base as a white solid;

^1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H, D2O replaceable), 8.61 (d, J=4.9 Hz, 1H), 8.51 (s, 3H, D2O replaceable ), 7.93 (d, J=4.0 Hz, 2H), 7.69 (t, J=5.3 Hz, 1H), 7.56 (s, 1H), 7.24 (t, J =8.8 Hz, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.77 (t, J=3 .5 Hz, 1H), 5.35 (s, 2H), 4.37 (s, 2H), 3.59 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -55.06, -128.60, MS (ESI+): 474.15 (M+1); (ESI-): 472.10 (M-1).

Example 534

The IC ₅₀ value of a compound (ie, the concentration of a compound that inhibits 50% of the enzyme activity) was calculated according to the procedure described in US Pat. No. 6,653,340 B1, eg, column 74 (incorporated by reference).

Specifically, the compounds were dissolved in DMSO stock solution to obtain 10.0 or 100 mM. A portion of this stock solution was added to the assay buffer in a final volume of 50 μL. The control included only buffer and enzyme solutions to which DMSO was added. The substrate was added to the reaction wells immediately or after incubation at room temperature. Reaction rates were measured spectrophotometrically by the formation of a product with absorbance at 405 nm within 600 sec. The background absorbance at 690 nm was measured and subtracted from the absorbance at 405 nm for each well.

The reaction rate for the enzyme alone was compared with the rate of the enzyme in the presence of the inhibitor and the percentage of inhibition was calculated as shown below:

Inhibition percentage = [Speed without inhibitor - Speed with inhibitor) / (Speed without inhibitor)] x 100

Factor D esterolytic assay:

To measure factor D activity and inhibition of factor D activity, a conventional esterolytic assay was used (Kam, S.M.; McRae, B.J.; Harper, J.W.; Niemann, M.A.; Volanakis, J.E.; Powers, J.C. Human complement proteins D, C2 , and In Active site mapping with peptide thioester substrates. J Biol. Chem. 1987, 262, 3444-3451). Z-Lys-SBzl, 1.29 mM was used for this analysis (Kim, S.; Narayana, S. V. L; Volanakis, J. E. Mutational analysis of the substrate binding site of human complement Factor D. Biochemistry. 1994, 33, 14393-14399 ) as a substrate for factor D (104 mM). Hydrolysis of this compound by factor D releases a free sulfhydryl group, which then reacts with 5,5'-dithiobis(2-nitrobenzoic acid), creating a rich yellow color (Habeeb, A. F. S. A. Reaction of protein sulfhydryl groups with Ellman's Reagent. Methods in Enzymol. 1976, 25, 457-464). Assays were performed in 96-well microtiter plates and hydrolysis rates were monitored at 405 nm on a Biotek Synergy H1 plate reader. Hydrolysis rates were presented as changes in mU/min. The assay was performed in 100 mM HEPES, 500 mM NaCl, pH 7.5, containing 10% DMSO in a final volume of 50 μl per well.

The IC50, the concentration of a compound that inhibits 50% of the enzyme activity, was calculated. The compounds in the examples were tested at least three times. In the table below, three plus symbols (+++) are used to indicate compounds with an IC ₅₀ value of less than 1 micromole per liter; two plus symbols (++) indicate compounds with an IC50 value between 1 and 10 micromoles per liter; and a single plus (+) symbol indicates compounds with an IC ₅₀ value greater than 10 micromoles per liter.

- 632 045626

Table 1

Measured Ki value (IC ₅₀ ) for connections

Three (+++) is used to denote compounds with an IC50 value less than 1 micromolar concentration; two (++) show compounds with IC50 values between 1 and 10 micromolar concentrations; one (+) shows compounds with an IC ₅₀ value greater than 10 micromolar concentration.

Compound IC50 16i +++ 17s + 18f +++ 19c +++ 20th + 21d +++ 23rd +++ 25s ++ 26d +++ 27f + 28d +++ 29d ++ 30d + 31f +++ 32h +++ 33f +++ 34f +++ 35f ++

- 633 045626

Compound ICso 53d +++ 124g +++ 54d + 55g +++ 56c +++ 57c +++ 59d +++ 60c +++ 142d +++ 61f ++ 62c +++ 58b +++ 125c + 63c +++ 64f +++ 65c +++ 66c +++ 67c +++

Compound IC50 92b +++

Compound IC50 Compound IC50 68c +++ 158c ++ 70a +++ 146g ++ 72c +++ 82f +++ 73c +++ 83h +++ 143g + 147c +++ 144d +++ 84f +++ 74c +++ 85d ++ 156b +++ 85c +++ 75c +++ 93h +++ 76f +++ 86b +++ 77c +++ 87c + 78c +++ 88b +++ 145c +++ 128g +++ 79c +++ 89c +++ 126h +++ 160e +++ 80e +++ 129e +++ 81d + 161e +++ 127b +++ 91h +++ Compound IC50 Compound IC50 108f +++ 131b +++

- 634 045626

94c +++ 187f +++ 95c +++ 109g +++ 96e +++ 165f +++ 97b +++ 110c +++ 98e +++ 111b +++ 130g +++ 166d +++ 99b +++ 112c +++ 159f ++ 113c +++ 100c ++ 114j +++ 162e +++ 115f +++ 103d +++ 167e +++ 163d +++ 116f +++ 164e +++ 118c +++ 104e +++ 119e +++ 105c +++ 120c +++ 106c ++ 121b +++ 107f +++ 122b +++

132b +++ 123d +++ 133c +++ 134b +++ 135c +++ 136e +++ 137b +++ 138f +++ 139c +++ 140c +++ 141c +++ 148e +++ 149b +++ 150b +++ 151c +++ 168c +++ 153b +++

Compound IC50 188b +++ 154g +++ 155c +++ 204e + 169f +++ 43d +++ 69e +++ 170b +++ 189c +++ 171c +++

Compound IC50 176c ++ 178g +++ 179b +++ 180e +++ 181d +++ 182d +++ 200e +++ 183c + 184c ++ 185c +++

Compound IC50 198b +++ 201b +++ 199f +++ 202c +++ 203c +++ 222f +++ 206c +++ 211c +++ 210c +++ 218f +

- 635 045626

172b +++ 186c +++ 214f +++ 152d +++ 191h +++ 207c +++ 173b +++ 192e +++ 208d +++ 174c +++ 193c ++ 209c +++ 190c +++ 194d +++ 223 e +++ 117b +++ 195d +++ 205d +++ 175c +++ 196d +++ 215h +++ 177f +++ 197c +++ 217e +++

Compound IC ₅ 0 Compound IC ₅ 0 Compound IC ₅ 0 224c +++ 238c +++ 12c +++ 237b +++ 234f +++ 22a +++ 225h +++ 98f +++ 256c +++ 212e +++ 235b +++ 24b +++ 213b +++ 239c +++ 38f +++ 211e +++ 98g +++ 101c +++ 226c +++ 240d +++ 251c ++ 227e +++ 241c +++ 252d +++ 228e +++ 242b +++ 255c ++ 229b +++ 243 d + 253f +++ 219c +++ 244c ++ 90d +++ 220g +++ 245g +++ 254c +++ 221c +++ 250f ++ 216d + 246b +++ 230e ++ 247b +++ 231c +++ 248c +++ 232c +++ 249f +++ 233c +++ 236d +++

Compound ICso Compound ICso Compound ICso

- 636 045626

334d ++ 261c +++ 377e +++ 329b +++ 262c +++ 270c +++ 330c +++ 263c +++ 271e +++ 258f +++ 431c +++ 272e +++ 259e +++ 310c +++ 309h +++ 331c +++ 361c +++ 380e + 260g +++ 407d + 406e +++ 409f +++ 339c +++ 405e +++ 267h +++ 303g +++ 451c +++ 332e +++ 341e +++ 456c +++ 335d + 376e +++ 410d +++ 350e +++ 336c +++ 273g +++ 408e + 338c +++ 411e +++ 337b +++ 362e +++ 412b +++ 340e ++ 264c +++ 436c +++ 360c +++ 351f +++ 390c +++ 268h +++ 374f +++ 257k +++ 461c +++ 269h +++ 414b +++

Compound IC50 Compound ICso Compound ICso 432c +++ 328f +++ 442d +++ 274g +++ 278e +++ 444c +++ 391f +++ 277e +++ 404c +++ 282f +++ 372c +++ 445c +++ 378d +++ 439c +++ 397e +++ 381e + 440c +++ 398c +++ 314f +++ 458b +++ 283c +++ 435b +++ 413m +++ 446c +++ 434c +++ 396e +++ 423 s +++ 275e ++ 413n +++ 284f +++ 276f +++ 321f +++ 400e +++

- 637 045626

433c +++ 279c +++ 452d +++ 308h +++ 443i +++ 453d +++ 437c +++ 441c +++ 429c +++ 438c +++ 415e +++ 417e +++ 393d +++ 280c +++ 421e +++ 394c +++ 281c +++ 399d +++ 416d +++ 420e +++ 401e +++

Compound IC50 Compound IC50 Compound IC50 454d +++ 322c +++ 318c +++ 419c +++ 322d +++ 316b +++ 402f +++ 287c +++ 293c +++ 457c +++ 288f +++ 379c +++ 395c +++ 320c +++ 426c +++ 455c +++ 324c +++ 427b +++ 403e +++ 289d +++ 294f +++ 286g +++ 290c +++ 295c +++ 285e +++ 291g +++ 296c +++ 342e +++ 333g +++ 313c +++ 326g ++ 347b +++ 312b +++ 327d +++ 319c +++ 297c +++ 422e +++ 325a +++ 428c +++ 424d +++ 292f +++ 311b + 343e +++ 349b +++ 307f +++ 323c +++ 348b +++ 298f +++ 345b +++ 317f +++ 315f +++ 346c +++ 425f +++ 383b +++

Compound IC50 382h +++ 368c +++ 369d +++ 299c +++

Compound ICso 459h +++ 460d +++ 467b +++ 356c +++

Compound IC50 385d +++ 386c +++ 387b +++ 344f +++

- 638 045626

373b +++ 301b +++ 300c +++ 306f +++ 266g +++ 265g +++ 430c +++ 352c +++ 353b +++ 482b +++ 354c +++ 464d +++ 465b +++ 302f +++

384c +++ 466c +++ 392g +++ 357b +++ 355c +++ 370f +++ 305d +++ 363b +++ 364d +++ 304b +++ 375c +++ 371c +++ 358c +++ 359b +++

365f +++ 471d +++ 472b +++ 462c +++ 463b +++ 389c +++ 388d +++ 366d +++ 367c +++ 477c +++ 478b +++ 447d +++ 448c +++ 473e +++

Compound IC50 480c +++ 481b +++ 449c +++ 450b +++ 468h +++ 469g +++ 470b +++ 479d +++ 474c +++ 475g +++ 476f +++ 486c +++ 487b +++ 488c +++ 489b +++ 490c +++ 491b +++ 483c +++

Compound IC50 492b +++ 484c +++ 485b +++ 493b +++ 494b +++ 418c +++ 497d +++ 496c +++ 495d +++ 498c +++ 499b +++ 500c +++ 501f +++ 502c +++ 503c +++ 504c +++ 505d +++ 506e +++

Compound IC50 507f ++ 508b +++ 509d +++ 510d +++ 511e +++ 512d +++ 513c +++ 514d +++ 515c +++ 520c +++ 521b +++ 522c +++ 523b +++ 527b +++ 524b +++ 525c +++ 526b +++ 517d +++

-639 045626

Compound IC50 518b +++ 516s +++ 519c +++ 530s +++ 529b +++ 528d +++ 531s +++ 532d +++ 533s +++

Incorporation by reference

All US patents and published US and PCT patent applications cited herein are hereby incorporated by reference.

Equivalents

The above written description is considered sufficient to enable one skilled in the art to practice the present invention. The present invention should not be limited in scope by the examples, since these examples are intended as the sole illustration of one aspect of the invention, and other functionally equivalent embodiments are within the scope of the present invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and are within the scope of the appended claims. The advantages and objects of the invention are not necessarily covered by every embodiment of the present invention.

Claims (20)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I); where the ring CE) represents (C ₆ -Ciu)aryl, heteroaryl, (C ₃ -C1 ₂ )cycloalkyl or heterocycloalkyl; the CD ring is furyl; the CD ring is (C ₆ -Ciu)aryl or heteroaryl; R ^a , independently for each case, is selected from the group consisting of halogen, cyano, hydroxy, -NH ₂ , -NHC(O)CH ₃ , -C(O)NH ₂ , (C ₃ -C1 ₂ )cycloalkyl, ( C1- _C6 )alkyl, hydroxy(C1- _C6 )alkyl and amino( _CrC6 )alkyl _; R ^b , independently for each case, is selected from the group consisting of halogen, (C1-C ₆ )alkyl, halogen(C1-C ₆ )alkyl, hydroxy(C1-C ₆ )alkyl, (C1-C ₆ )alkoxy( C1- _C6 )alkyl, (hydroxy)halogen(C1- _C6 )alkyl, hydroxy(( _C3 - _C12 )cycloalkyl)(C1- _C6 )alkyl, (heterocycloalkyl)(C1- _C6 )alkyl, heteroaryl (C1-C ₆ )alkyl, (C ₃ -C1 ₂ )cycloalkyl, -C(O)((C1-C ₆ )alkyl) and -(Ci-C ₆ )anKHneH-NR ^J R ^k ; R ^{c is} , independently for each case, selected from the group consisting of halogen, -OH and (C1- _C6 )alkyl; R ¹ is selected from the group consisting of -NH ₂ , -CH ₂ COOH, -CH(MH(CO)((C1-C ₆ )alkyl))COOH, -CH(CN(CO)((C1-C ₆ ) aryl(C1- _C6 )alkyl))COOH, -CH(CHC(O)(( _C3 - _C12 )cycloalkyl))COOH, -CH(CN(CO)((C1- _C6 )aryl-substituted ( _C3 - _C12 )cycloalkyl)COOH and -COCH( _CH2 (optionally substituted ( _C6- C1o)aryl)); η is 0, 1 or 2; w is 0, 1 or 2; p is 0, 1 or 2; J represents -C(O)-, -ΝΗ- or -CH ₂ -; K represents -C(O)-, -ΝΗ- or -O-; -640045626 where at least one of J and K is -C(O)- or -CH2-; L is selected from the group consisting of bonds, -CH2-, -CH2CH2-, -CHR ² -, -C(O)- and -C(=NR ^L )-; where RL represents H; or wherein RL and the present R ^c together with intermediate atoms form a substituted or unsubstituted heteroaryl ring containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R ² is (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or halogen(C ₁ -C ₆ )alkyl; Rj and ^Rk are each independently selected from the group consisting of H, (C ₁ -C ₆ )alkyl, amino(C ₁ -C ₆ )alkyl, (heterocycloalkyl)(C ₁ -C ₆ )alkyl and optionally substituted heterocycloalkyl; U represents N or CR ³ ; R ³ represents H, halogen or (C ₁ -C ₆ )alkoxy; And V represents N or CH; where heteroaryl refers to a monocyclic, bicyclic or polycyclic aromatic group containing in total from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; heterocycloalkyl refers to a monocyclic, bicyclic or polycyclic non-aromatic ring system containing in the aggregate from 3 to 12 atoms, including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and when the group is substituted, said one or more substituents are independently selected from the group consisting of halogen and (C ₁ -C ₆ )alkyl. 2. A compound according to claim 1, having the structure of formula (Ia): R ¹ J—К w^z Г А ' ^Y (la); where W represents N, CH or CR ^c ; X represents N, CH or CR ^c ; Y is N, CH or CR ^c ; And Z represents N, CH or CR ^c ; in this case, ring A, ring B, ring C, R ^a , R ^b , R ^c , R ¹ , U, V, J, K, L, p and m are as defined in paragraph 1. 3. A compound according to claim 1 or 2, characterized in that the CD ring is phenyl, thiophenyl or pyridinyl. 4. A compound according to any one of claims 2, 3, having the structure of formula (Ib): in this case, ring B, R ^a , R ^b , R ¹ , U, V, J, K, L, W, X, Y, Z, p and m are as defined in paragraphs 1 and 2. 5. A compound according to any one of claims 1-4, characterized in that p is equal to 0. 6. A compound according to any one of claims 1 to 5, characterized in that R ¹ represents -CH2COOH. 7. A connection according to any one of claims 1 to 6, characterized in that -J-K- is selected from the group consisting of -C(O)-NH-, -NH-C(O)- and -CH2O-. 8. A compound according to any one of claims 1 to 7, characterized in that -J-K- represents -CH2O-. 9. A compound according to any one of claims 1 to 8, characterized in that U represents CH. 10. A compound according to any one of claims 1 to 9, characterized in that V represents CH. 11. A compound according to any one of claims 2 to 8, having the structure of formula (Ic): where ring B, R ^a , R ^b , R ¹ , J, K, L, W, X, Y, Z, p and m are as indicated in paragraphs 1 and 2. - 641 045626 12. The connection according to any one of claims 1-11, characterized in that m is equal to 0. 13. A compound according to any one of claims 2 to 12, characterized in that at least one of W, X, Y and Z is CR ^c . 14. The compound according to claim 13, characterized in that Z represents CR ^c . 15. A compound according to any one of claims 13, 14, characterized in that R ^c is a halogen, for example a fluoride. 16. A compound according to any one of claims 2 to 13, characterized in that at least one of W, X, Y and Z is N. 17. A compound according to claim 16, characterized in that Y is N. 18. A compound according to any one of claims 1 to 17, characterized in that L represents -CH2-. 19. The compound according to claim 1, selected from the following table: and about. ΞΤ I ^O ^\ ) gУЧ оА/ ⁰ NH _S оч Ζ о IX th / \ о ΣΕ ⁰ ΣΕ GO g / -p Xu o o ΣΕ I Oh oh hpps g Cd X <xr°Y F Z Y th ζ 1 ( ° / €>Q /=° ΪΖ ο ΣΕ I rj Z -/ -п Ф' Х сНН O o I ΣΕ Ζ 1.../ -η 0^4 cPq ο ο X O o bе ζ O X ¹ ΣΕ rj I { π ο 4 0 ο ΣΕ o o / \ \ £ Chh-° / ^g Ο Co / 2 GC X - 642 045626 φΑ· F., X 0 H ₂ M^. V F h ₂ n^^ Il N 4 gA I O Q>° O ho^ [ί NHj jO l X> a : ' 0 ⁱ Y A A ^,nh ₂ a rA ΑΎ Qr Ά XA e ' F I □ nh ₂ nh ₂ c+ wА H ₃ C^ a Έ О £еА ^с о h ₂ n .,0 ” h ₂ n A ) ch I I oh oh / H + A X ° % ⁰ A JL^H ₂ ^H 2 ^N [Γ 0 N.H. - 643 045626 ZE Ζ 4>q o o I MM ° n _g “% Tsk _SNZ “% CHGG^. .,%« ° ίγ4- h ₂ n h.j0 ° ^ΗΤΓ ^ξοΗ .,% ° ° ⁿ 2 *% ° nh ₂ L^SIZ CG“ y - 644 045626 €0 ^g % _Н UJk^ ^NH 2 »НХ ^Г %„ m ° Η2Ν^Λ^Ν h ₂ n^XJ ⁿ ,s _ -,.jO ° I C Q->° O 4,.,° / T ^z 1 ¹ X X s s^° o 4.^ ^w / T ¹ X ~°hhrMR L? ° fL F^k ° ri NH^ - 645 045626 - 646 045626 - 647 045626 - 648 045626 _st NL nh ₂ A SG S A O % I -ST ° Ί A? C0 ₂ H H ₂ N^ g j) O-.A' ZE ( ^Ο /Αί - CO ₂ H) 0 and H ₃ C NH CN /A A^ i GA- V X ^r V o HN F 5 ^J h ₂ n^. s ^Η 2 ^Ν χχΑί s X I X h ₂ n^ s: 0 l JI ° - 649 045626 - 650 045626 - 651 045626 о <о>° о ^Ш / ] Z О I LL? Н _: ,С'' b^ Π ^0Η o ^Η0 γγ·ρ4 κ,ΑΛ'Μ γ ^Η o o €У^° ZI o =( 4s^o / ζ gch I ZE Ζ / and )=□ IZ About ZE O Yq OO Z OvJ γο -I O^CH Ul/Ch Ζ o T \ to 2 \ lO 0 hj t α Lo f I ο ΖΕ ~ сЧ5 o o=^ o ZE \ ο 0 y4Ч) 4.0 i. } ζ Λί X I m Z ^g ЪЧ=л° 12 о I ^σ 4 0^0 ? °\ 0 I Z rJ Z / ° 7 C>-Q )=о IZ o I / ΛΎΛ ζ ==( E ^- ο ¹⁴ ο ο ζ yJ^W 4.0 о w° / ζ сч X . = ζ θ ^Η 2 ^Ν ^Χγ 20. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of: - 652 045626 cor iS ^HJ W ГГгГ A '<2.......° ^x i h ₂ nXX 21. Connection according to item 20 or ei is 22. Connection according to item 20 or is 23. Connection according to item 20 or it goes by itself 24. The connection according to item 20 or it goes by itself 25. The connection according to item 20 or it goes by itself about XJ ''ST''? _Y ^OH W φ _Η ^{0 0} Y°H ⁰ Ai ⁰ _and h ₂ n ^{% U} o pharmaceutically acceptable salt, wherein the compound is representing , about bAJ k^OH F^X. o d J |^N nh ₂ o pharmaceutically acceptable salt, and the compound is - Λ bAJ % ^he /L o h ₂ n^ _n J o pharmaceutically acceptable salt, and the compound is - F ₃ C Дь ДПр° ⁰ h ₂ n^ _n J o pharmaceutically acceptable salt, wherein the compound is - 653 045626 26. The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein the compound is 27. A pharmaceutical composition containing a compound according to any one of claims 1 to 26 or a practically acceptable salt thereof and a pharmaceutically acceptable carrier. 28. The use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease or condition characterized by aberrant activity of the complement system, wherein said disease or condition characterized by aberrant activity of the complement system is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense sediment disease, cold agglutinin disease, catastrophic antiphospholipid syndrome associated with antineutrophil cytoplasmic antibodies (ANCA) vasculitis (AAV), IgA nephropathy, age-related macular degeneration (AMD), systemic lupus erythematosus, autoimmune hemolytic anemia with warm agglutinin syndrome and focal segmental glomerulosclerosis. 29. Use according to claim 28, wherein said disease or condition characterized by aberrant activity of the complement system is paroxysmal nocturnal hemoglobinuria.