EA045366B1 - QUINOLINE DERIVATIVES AS INHIBITORS OF α4β7 INTEGRIN - Google Patents

Description

The present disclosure generally relates to novel compounds having α4β7 integrin inhibitory activity, prodrugs of compounds having α4β7 integrin inhibitory activity, and methods for their use and preparation.

State of the art

Integrins are heterodimeric cell surface proteins involved in numerous cellular processes, including cell-cell and cell-extracellular matrix interactions. After binding to an extracellular ligand, integrins mediate signal transmission into the cell, which leads to the capture of the lymphocyte cell, its adhesion and infiltration into the tissue.

Integrins are heterodimeric proteins consisting of alpha and beta subunits. There are 18 known alpha subunits and 8 known beta subunits. Integrin α4β7 is expressed on the surface of lymphocytes and recognizes extracellular ligand mucosal addressing cell adhesion molecule-1 (MAdCAM-1). Integrin α4β7 controls the migration and retention of lymphocytes into intestinal tissues through its interaction with MAdCAM-1, which is expressed in venules in the intestinal mucosa and high endothelial venules (HEV) in gut-associated lymphoid tissues (GALT). ). Inhibition of the interactions of integrins with their respective ligands has been proposed as an effective treatment for various autoimmune and inflammatory diseases; The therapeutic effect of blocking the α4β7MAdCAM-1 interaction in inflammatory bowel disease (Crohn's disease and ulcerative colitis) has also been shown.

There is a need for improved α4β7 integrin antagonist molecules for the treatment of autoimmune and inflammatory diseases, including inflammatory bowel disease.

Short description

The present invention provides compounds that are α4β7 integrin inhibitors. The present invention also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and preparing the compounds. The compounds provided herein are suitable for the treatment of diseases, disorders or conditions mediated by α4β7 integrin. The present disclosure also provides compounds for use in therapy. In addition, the present invention provides compounds for use in a method of treating a disease, disorder or condition mediated by α4β7 integrin. The invention further provides uses of the compounds for the preparation of a medicament for the treatment of a disease, disorder or condition that is mediated by α4β7 integrin.

In one aspect, there is provided a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof

R ⁴ R ⁵

where L is selected from the bond, -O-, -O-C(O)-*, -NH-, -C(O)-N(H)-* and -N(H)-C(O)-*, where * denotes the place of attachment of L to R ¹ ;

R ¹ is selected from A ¹ , A ² , A ³ and A ⁴ ;

A ¹ is a 5-10 membered heteroaryl containing one to five heteroatoms independently selected from S, N and O; where A ¹ optionally contains one to three C(O) and where A ¹ is optionally substituted with one to six R ^a ;

A ² is C _6-10 aryl, optionally substituted with one to six R ^a ;

And ³ represents C _5-10 cycloalkyl or 5-14 membered heterocyclyl; wherein A ³ is optionally substituted with one to four groups independently selected from oxo and R ^a ; And

And ⁴ is -NR ^a1 R ^a2 ;

where each R ^a is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, -S(O) _m -C _1-6 alkyl, C _3-8 cycloalkyl, 3-6-membered heterocyclyl, C _6-10 aryl, 5-6-membered heteroaryl, -O-C _{3- 8} cycloalkyl, -O-(3-6 membered heterocyclyl), -O-C _1-4 alkylene-C _3-8 cycloalkyl and -O-phenyl;

- 1 045366 where each C ₃ - ₈ cycloalkyl, 3-6-membered heterocyclyl, C _6- 1oaryl, 5-6-membered heteroaryl, -O-C ₃ _ ₈ cycloalkyl, -O-(3-6-membered heterocyclyl) , -O-C ₁ _ ₄ alkylene-C ₃ _ ₈ cycloalkyl and -O-phenyl R ^a is independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl,

-NR ^a1 R ^a2 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy and _C1-6 haloalkoxy; and where each _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 haloalkoxy and _-S (O) _{m -C1_6} alkyl R ^a _optional substituted with one to three R ^a3 , where each R ^a3 is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , _C1-6 alkoxy, C _3-8 cycloalkyl and 3-6 membered heterocyclyl;

where each C _3-8 cycloalkyl and 3-6 membered heterocyclyl R ^a3 is optionally substituted with one to three R ^a4 ; and each R ^a4 is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxyl, _C1-6 haloalkoxy, _C3-8 cycloalkyl and 3-6 membered heterocyclyl;

each R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, cyano, hydroxyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-8haloalkyl, C1-8haloalkoxy, -NR ^b1 R ^b2 , -R ^b3 S(O)mR ^b4 , -S(O)mR ^b4 , -NR ^b1 S(O)nR ^b4 , -COOR ^b1 , -CONR ^b1 R ^b2 , -NR ^b1 COOR ^b2 , -NR ^b1 COR ^b4 , -R ^b3 NR ^b1 R ^b2 , -S(O)nNR ^b1 R ^b2 , C3-8 cycloalkyl, C ₆ - ₁₀ aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl;

where each _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C1-8 haloalkyl and _C1-8 haloalkoxy ^R2 , ^R3 , ^R4 , ^R5 and ^R6 are optional replaced by one or two R ^c ; wherein each R ^c is independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; where each C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^c is optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkyl , _C1-6 haloalkyl, _C1-4 alkoxy and _C3-6 cycloalkyl;

wherein each C ₆ - ₁₀ aryl and 5-6 membered heteroaryl R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently optionally substituted with one to five R ^b and where each C _3-8 cycloalkyl and 3-12 member heterocyclyl R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently optionally substituted with one to six groups independently selected from =CR ^b1 R ^b2 and R ^b ;

where each R ^b is independently selected from azido, cyano, halogen, hydroxyl, -NR ^a1 R ^a2 , C1-6 alkyl, C18 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6- member heterocyclyl; where each C3-6 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b is independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1- 4 alkyl, C _1-4 haloalkyl and C _1-4 alkoxy;

where each R ^b1 and R ^b2 are independently selected from H, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, C ₆ - ₁₀ aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl;

where each C _3-8 cycloalkyl, C ₆ - ₁₀ aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b1 and R ^b2 independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, - NR ^a1 R ^a2 , C _1-8 alkyl, C _1-8 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _{6-10 aryl} , 56-membered heteroaryl and 4-6-membered heterocyclyl; and wherein each C _1-8 alkyl and C _1-8 haloalkyl R ^b1 and R ^b2 is optionally substituted with one or two R ^b5 ;

where R ^b3 represents _C1-4 alkylene;

where R ^b4 is selected from C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; wherein each C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, C6-10aryl, 56-membered heteroaryl and said 4-6-membered heterocyclyl Rb ⁴ is optionally substituted with one to three Rb6 _; where each R ^b5 is independently selected from cyano, hydroxyl, C1-4 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and each C1-4 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b5 is optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and phenyl; and wherein each R ^b6 is independently selected from halogen, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein each C3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl R ^b6 is independently optionally substituted with one to three groups independently selected from halogen, cyano, -NR ^a1 R ^a2 , C1-4 alkyl, C _1-4 haloalkyl and C _1-4 alkoxy; or

R ² and R ³ , R ³ and R ⁴ or R ⁵ and R ⁶ together with the atoms to which they are attached form C6-10aryl, 5-6-membered heteroaryl, C3-6cycloalkyl or 5-6-membered heterocyclyl; wherein each C6-10 aryl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 5-6 member heterocyclyl group is independently optionally substituted with one to three groups independently selected from halogen, cyano, -NR ^a1 R ^a2 , C1-6 alkyl, _C1-6 alkoxyl , _C1-6 haloalkyl, C _3-8 cycloalkyl, 3-6-membered heterocyclyl, C _6-10 aryl, 5-6-membered heteroaryl, C _{1 . 4} alkylene-C ₃ . ₈ cycloalkyl, C ₁ . ₄ alkylene-C ₆ . ₁₀ aryl and C1- ₄ alkylene-(5-6 membered heteroaryl);

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halogen, hydroxyl, cyano, _C1-6 alkyl, _C1-6 alkoxyl, _C1-6 haloalkyl, _C1-6 haloalkoxy and - NR ^a1 R ^a2 ;

R ¹³ is selected from H, C _1-4 alkyl and C _1-4 haloalkyl; And

R ¹⁴ is selected from H, C1-6alkyl, -C1.4alkylene-NR ^a1 R ^a2 , -C1. ₄ alkylene-C(O)NR ^a1 R ^a2 , -C1- ₄ alkylene-O-C(O)- 2 045366

C1- ₄ alkyl, -C1-4alkylene-O-C(O)-O-C _1- 4alkyl, -C _1- 4alkylene-O-C(O)-C _1- 4alkylene-NR ^a1 R ^a2 , -C1- ₄ alkylene-OS _1-4 alkyl, C _3-8 cycloalkyl, -C ₁ _ ₄ alkylene-C ₃ _ ₈ cycloalkyl, 4-6-membered heterocyclyl and -C1- ₄ alkylene (4-6-membered heterocyclyl);

where each C _3-8 cycloalkyl, -C1. ₄ alkylene-C ₃ _ ₈ cycloalkyl, 4-6-membered heterocyclyl and -C1- ₄ alkylene-(4-6 membered heterocyclyl), R ¹⁴ optionally substituted with one to three groups independently selected from halogen, C _1-4 alkyl , C _1-4 alkoxy and C _1-4 haloalkyl; or

R ¹⁴ together with the N atom, which is attached to R ¹³ , forms a 5-membered heterocyclyl; wherein said 5-membered heterocyclyl is optionally substituted with one or two groups independently selected from halogen, C ₁ . ₆ alkyl, C ₁ . ₆ alkoxyl, C ₁ . ₆ haloalkyl and C ₆ - ₁₀ aryl; wherein said C ₆ - ₁₀ aryl is optionally substituted with one to three groups independently selected from halogen, C ₁ . ₆ alkyl, C ₁ . ₆ αlkoxyl and C ₁ . ₆ haloalkyl;

R ^a1 and R ^a2 are each independently selected from H, C ₁ . ₆ alkyl and C ₁ . ₆ haloalkyl;

m is selected from 0, 1 and 2 and n is selected from 1 and 2.

Detailed description Definitions and general parameters

The following description provides examples of methods, parameters, and the like. However, it should be understood that such description does not limit the scope of the present description, but is instead provided as a description of exemplary embodiments.

As used herein, the following words, phrases and symbols generally have the meanings set forth below unless the context in which they are used indicates otherwise.

A dash (-) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached via a carbon atom. The dash before or at the end of a chemical group is provided for convenience; chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn through a line in the structure indicates the point of attachment of the group. Unless required chemically or structurally, the order in which a chemical group is written or named does not indicate or imply a specific focus.

v ^0H

A wavy line in a chemical group, such as shown below, ' denotes the site of attachment, i.e. shows a broken link by which a group is connected to another described group.

The prefix C _u - _v indicates that the following group contains u to v carbon atoms. For example, _C1-8 alkyl means that the alkyl group has 1 to 8 carbon atoms.

Reference to an exemplary value or parameter herein includes (and describes) implementations that address the specified value or parameter as such. In specific embodiments, the term approximately includes the indicated amount ±10%. In other embodiments, the term approximately includes the indicated amount ±5%. In some other embodiments, the term approximately includes the indicated amount ±1%. In addition, the term about X includes a description of X. In addition, singular forms include references to the plural unless the context clearly indicates otherwise. Thus, for example, a reference to a compound includes a plurality of such compounds, and a reference to an assay includes a reference to one or more assays and equivalents known to those skilled in the art.

Alkyl refers to a straight or branched saturated hydrocarbon chain. As used herein _{, alkyl has 1-20 carbon atoms (i.e. C1.20 alkyl} ), 1-8 carbon atoms (i.e. _C1.8 αalkyl), _1-6 carbon atoms (i.e. C _1.6 alkyl) or 1-4 carbon atoms ( _i.e. C _1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl moiety containing a certain number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be included; thus, for example, butyl includes n-butyl (i.e. -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl (i.e. -CH ₂ CH(CH ₃ ) ₂ ) and tert-butyl (i.e. -C(CH ₃ ) ₃ ) and propyl includes n-propyl (i.e. -(CH ₂ ) ₂ CH ₃ ) and isopropyl (i.e. -CH(CH ₃ ) ₂ ).

Alkylene (including those that are part of other groups) refers to branched and unbranched bivalent alkyl groups. As used herein _, alkylene has 1-20 carbon atoms (i.e. _C1-20 alkylene), 1-8 carbon atoms (i.e. _C1.8 alkylene), 1-6 carbon atoms (i.e. C _1.6 alkylene) or 1-4 carbon atoms ( _{i.e. C1_4 alkylene} ). Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise stated, the definitions of propylene and butylene include all possible isomeric forms of the specified groups with the same number of carbon atoms. Thus, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

_Alkenyl refers to an aliphatic group containing at least one carbon double bond and having 2-20 carbon atoms (i.e. _{C2_20} alkenyl), 2-8 carbon atoms (i.e.

C ₂ - ₈ alkenyl), 2-6 carbon atoms (ie C ₂ - ₆ alkenyl) or 2-4 carbon atoms (ie C ₂ - ₄ alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

_Alkynyl refers to an aliphatic group containing at least one carbon-carbon triple bond and having 2-20 carbon atoms (i.e. _{C2_20} alkynyl), _2-8 carbon atoms (i.e. _{C2_8} alkynyl), 2-6 carbon atoms (i.e. C _{2_6} alkynyl) or _{2-4 carbon atoms (i.e. C 2_4 alkynyl )} . The term alkynyl also includes groups that have one triple bond and one double bond.

Alkoxy and alkoxy are used interchangeably and belong to the alkyl-O- group. Examples of alkoxy and alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Haloalkoxy refers to an alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by halogen.

Acyl refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl and benzoyl.

Aryl refers to an aromatic carbocyclic group containing one ring (eg, monocyclic) or multiple rings (eg, bicyclic or tricyclic), including fused systems. As used herein _{, aryl has 6-20 ring carbons (i.e., C6_20 aryl), 6-12 ring carbons (i.e., C6_12 aryl ) ,} or 6-10 ring carbons (i.e. C ₆ - ₁₀ aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl, as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

Azido belongs to the -N ₃ group.

Cyano or carbonitrile belongs to the -CN group.

Cycloalkyl refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged and spiro ring systems. The term cycloalkyl includes cycloalkenyl groups (ie, a cyclic group having at least one double bond). As used herein _{, cycloalkyl has 3-20 ring carbons (i.e., C3_20 cycloalkyl} ), 3-12 ring carbons (i.e. _{, C3_12 cycloalkyl} ), 3-10 ring carbons (ie C ₃ - ₁₀ cycloalkyl), 3-8 carbon atoms in the ring (ie C ₃ - ₈ cycloalkyl) or 3-6 carbon atoms in the ring (ie C ₃ - ₆ cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems containing one aromatic ring and one non-aromatic ring, but not completely aromatic ring systems.

Bridging refers to a ring condensation in which non-adjacent ring atoms are joined through a bivalent substituent such as an alkylenyl or heteroalkylenyl group or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

The term fused refers to a ring that is connected to an adjacent ring.

Spiro refers to a ring substituent that is connected by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane and 4-benzyl-4-methylpiperidine, wherein said cyclopentane and piperidine, respectively, are spiro substituents.

Spiro also refers to the bicyclic moiety, where the two rings are connected through one common atom. Spiro compounds can be completely carbocyclic or heterocyclic. Examples of spiro groups include 5-oxa-8-azaspiro[3.5]nonane, 7-oxa-4-azaspiro[2.5]octane and 5λ ² azaspiro[2.4]heptane.

Halogen or halo includes fluorine, chlorine, bromine and iodine. Haloalkyl refers to a straight or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen. For example, when a residue is substituted with more than one halogen atom, it may be named using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (di) or three (tri) halogen groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

The term heterocyclyl or heterocycle as used herein refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic system of multiple rings having at least one heteroatom in the ring (i.e., at least one heteroatom in the ring selected from O, N, S, S(O), S(O) ₂ and N-oxide groups). Unless otherwise specified, a heterocyclyl group has from 3 to about 20 ring atoms, for example from 3 to 12 ring atoms,

- 4 045366 for example from 3 to 10 atoms in a ring, for example from 5 to 10 atoms in a ring or for example from 5 to 6 atoms in a ring. Thus, the term includes saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms, independently selected from the group consisting of O, N, S, S(O), S(O) ₂ and N-oxide in the ring. Rings from a system consisting of several fused rings (for example, bicyclic heterocyclyl) can be connected to each other using fused, spiro- and bridging bonds, if valence requirements allow it. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, 1,1 dioxide tetrahydro-2H-thiopyran, quinuclidine, N-bromopyrrolidine, N-chloropiperidine and the like. Heterocycles include spirocycles, such as, for example, aza- or oxospiroheptanes. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems containing one aromatic ring and one non-aromatic ring, but not completely aromatic ring systems. Examples include dihydroquinolines, e.g. 3,4-dihydroquinoline, dihydroisoquinolines, e.g. 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g. isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindoline]-3'one and the like. Additional examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxa7,9-diazabicyclo[3.3 .1]nonanyl and hexahydropyrazino[2.1-c][1,4]oxazinyl.

Hydroxyl and hydroxy are used interchangeably and refer to -OH. Oxo belongs to the group (=O) or (O). In the case of the existence of tautomeric forms of a compound, hydroxyl and oxo groups are interchangeable.

Heteroaryl refers to an aromatic group, including groups having an aromatic tautomer or resonance structure, containing one ring, several rings or several fused rings, with at least one heteroatom in the ring, i.e. one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said nitrogen or sulfur atoms may be oxidized. Thus, the term includes rings containing one or more O, N, S, S(O), S(O) ₂ and N-oxide groups in the ring. The term includes rings containing one or more OC(O) groups on the ring. As used herein, heteroaryl contains from 5 to 20 ring atoms (i.e., 5 to 20 membered heteroaryl), from 5 to 12 ring atoms (i.e., 5 to 12 membered heteroaryl), or from 5 to 10 ring atoms (ie, 5-10 membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, and oxidized forms of the heteroatoms. Examples of heteroaryl groups include pyridin2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not include or overlap with aryl as defined above.

Sulfonyl refers to the group -S(O) ₂ R, where R represents alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When the graphical representation of a group ends with a nitrogen atom with a single bond, the group is a -NH group unless otherwise noted. Likewise, unless otherwise stated, hydrogen atom(s) are assumed and considered to be present where necessary, based on the knowledge of one skilled in the art, to fill valence or provide stability.

Some common alternative chemical names may be used. For example, a divalent group such as a divalent alkyl group, a divalent aryl group, etc. may also be referred to as an alkylene group or alkylenyl group, an arylene group or an arylenyl group, respectively. In addition, unless explicitly stated otherwise, when combinations of groups are referred to herein as a single moiety, such as arylalkyl, the last mentioned group contains the atom at which the moiety is attached to the rest of the molecule.

The terms optional or optional mean that the subsequently described event or circumstance may or may not occur, and that the description includes cases in which the specified event or circumstance has occurred and cases in which it has not. Also, the term optionally substituted refers to any one or more hydrogen atoms at a specified atom or group, which may or may not be substituted by a non-hydrogen moiety.

The term substituted means that any one or more hydrogen atoms on the designated atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valency of the designated atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylic acid ester, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or

- 5 045366 Similar undefined structures obtained by defining substituents with additional substituents added ad infinitum (for example, a substituted aryl containing a substituted alkyl which is itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not included in this document. Unless otherwise stated, the maximum number of sequential substitutions in the compounds described herein is three. For example, successive substitutions of substituted aryl groups by two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryl. Likewise, the above definitions do not include unacceptable substitution variations (eg, methyl substituted with 5 fluorines, or heteroaryl groups having two adjacent oxygen atoms on the ring). Such unacceptable substitution variations are well known to one skilled in the art. When used to modify a chemical group, the term substituted may describe other chemical groups as defined herein. For example, the term substituted aryl includes, but is not limited to, alkylaryl. Unless otherwise indicated, when a group is described as optionally substituted, any substituents on the group are themselves unsubstituted.

In some embodiments, the term substituted alkyl refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In further embodiments, substituted cycloalkyl refers to a cycloalkyl group having one or more substituents, including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxyl; substituted heterocyclyl refers to a heterocyclyl group having one or more substituents, including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo and hydroxyl; substituted aryl refers to an aryl group having one or more substituents, including halogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano; substituted heteroaryl refers to a heteroaryl group having one or more substituents, including halogen, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano, and substituted sulfonyl refers to a -S(O)2R group, in which R is substituted by one or more substituents, including alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other embodiments, one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

Some of the compounds exist in the form of tautomeric isomers. Tautomeric isomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imido acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compounds include both an amide tautomer and an imido acid tautomer. Thus, amide-containing compounds are understood to include their imido-acid tautomers. Likewise, imido acid-containing compounds are meant to include their amide tautomers.

Any formula or structure given herein is also intended to represent the unlabeled forms and isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), ^3H (tritium), ^PS , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Various isotopically labeled compounds according to the present invention, for example compounds in which radioactive isotopes are included, such as ^3H , ^13C and ^14C . Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetics studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including assays distribution of drug or substrate into tissue, or during radioactive treatment of patients.

The description also includes compounds according to the present description in which from 1 to n hydrogen atoms attached to the carbon atom are replaced by deuterium, where n represents the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound herein when administered to a mammal, particularly a human. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Labeled or deuterium-substituted therapeutic compounds according to the present description

- 6 045366 may have improved DMPK (drug metabolism and pharmacokinetics) distribution, metabolism and excretion (ADME) properties. Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits associated with greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and/or improved therapeutic index. The ¹⁸ F labeled compound may be useful for PET or SPECT studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by following the procedures described in the Schemes or in the Examples and Preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is considered as a substituent in the compound according to the present description.

The concentration of such a heavier isotope, in particular deuterium, can be determined using an isotope enrichment factor. In the compounds herein, any atom not specifically designated as a particular isotope is any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as H or hydrogen, the position is considered to contain hydrogen with the isotopic composition of a natural isotope. Accordingly, in the compounds herein, any atom specifically designated deuterium (D) is intended to denote deuterium.

In many cases, the compounds described herein are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or groups similar thereto.

The term pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines , trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, mono-, di- and tri-cycloalkylamines, mono-, di- and tri-arylamines or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

Salts, such as TFA salts, can be converted to free bases/acids or other pharmaceutically acceptable salts.

As used herein, the term pharmaceutically acceptable carrier or pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional vehicle or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional active ingredients may also be included in these compositions.

Treatment or treat is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (eg, reducing one or more symptoms caused by the disease or condition and/or reducing the severity of the disease or condition); b) slowing or stopping the development of one or more clinical symptoms associated with a disease or condition (eg, stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and/or preventing or slowing the spread (eg, metastasis) of a disease or condition) ; and/or c) alleviation of the disease, that is, providing regression of clinical symptoms (for example, improving the condition of the disease, providing partial or complete remission of the disease or condition, increasing the effect of another drug, delaying the progression of the disease, improving quality of life and/or prolongation of survival period.

Prevention or prevent means any treatment of a disease or condition that prevents clinical symptoms of the disease or condition from developing. In some embodiments, the compounds may be administered to a subject (including a human) who has an increased risk or family history of a disease or condition.

Subject refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein may be suitable for use in human and/or veterinary medicine. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

The term therapeutically effective amount or effective amount of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof means an amount sufficient to provide treatment when administered to a subject to provide a therapeutic effect, such as improving symptoms or slowing the progression of a disease. For example, a therapeutically effective amount may be an amount sufficient to reduce a symptom of a disease or condition responsive to inhibition of α4β7 integrin activity. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the body weight and age of the subject, the severity of the disease or condition and the route of administration, and can be readily determined by one of ordinary skill in the art.

The term inhibition indicates a decrease in the initial level of biological activity or process. Inhibition of the activity of α4β7 integrin or variants thereof refers to a decrease in the activity of α4β7 integrin as a direct or indirect response to the presence of a compound of this application relative to the activity of α4β7 integrin in the absence of a compound of this application. α4β7 inhibition refers to a decrease in the activity of α4β7 integrin as a direct or indirect response to the presence of a compound described herein relative to the activity of α4β7 integrin in the absence of the compound described herein. In some embodiments, inhibition of α4β7 integrin activity can be compared in the same subject before treatment or with other subjects not receiving treatment.

Connections

Provided herein are compounds that function as α4β7 integrin inhibitors. In one aspect, there is provided a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof

R ⁴ R ⁵

R ¹³ )=O

R ⁷ R ⁸ 'n OR ¹⁴ r ¹ -l—(у—( o

WR ^{12 N} pT ^R9

R ¹¹ R ¹⁰ (I);

where R ¹ , R ² , R ³ , R 4 , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , ^{R 14 and} L are as defined above.

In another aspect, compounds of formula (II) or pharmaceutically acceptable salts thereof are provided:

R ⁴ R ⁵

Rl3)=O

R ⁷ R ⁸ N OR ¹⁴

R ¹ -L— ^{3 n} >a ⁹

R ¹¹ R ¹⁰ (II);

where L is selected from the bond, -O-, -O-C(O)-*, -NH-, -C(O)-N(H)-* and -N(H)-C(O)-*; where * denotes the place of attachment of L to R ¹ ;

R ¹ is selected from A ¹ , A ² and A ³ ;

A ¹ is a 5-10 membered heteroaryl containing one to five heteroatoms independently selected from S, N and O; where A ¹ optionally contains one to three C(O); and where A ¹ is optionally substituted with one to six R ^a ;

A ² is C ₆ - ₁₀ aryl, optionally substituted with one to six R ^a ; And

- 8 045366

A ³ represents C-^cycloalkyl or 5-14-membered heterocyclyl; wherein A ³ is optionally substituted with one to four groups independently selected from oxo and R ^a ; and wherein each R ^a is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C ₁ . ₆ haloalkyl, C ₁ . ₆ haloalkoxyl, -S(O) _m -C _1-6 αlkyl, C _3-8 cycloalkyl, 3-6-membered heterocyclyl, C ₆ - ₁₀ aryl, 5-6-membered heteroaryl, -O-C ₃ - ₈ cycloalkyl , -O-(3-6-membered heterocyclyl), -O-C ₁ _ ₄ alkylene-C ₃ . ₈ cycloalkyl and -O-phenyl;

where each C ₃ - ₈ cycloalkyl, 3-6-membered heterocyclyl, C ₆ - ₁₀ aryl, 5-6-membered heteroaryl, -O-C ₃ - ₈ cycloalkyl, -O-(3-6-membered heterocyclyl), - O-C ₁ _ ₄ alkylene-C ₃ _ ₈ cycloalkyl and -O-phenyl R ^a is independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ alkoxy and C ₁ . ₆ haloalkoxy; and where each C ₁ . ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ . ₆ alkoxyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ haloalkoxy and -S(O) _m -C ₁ . _{The 6} alkyl R ^a is optionally substituted with one to three R ^a3 , where each R ^a3 is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C ₁ . ₆ alkoxyl, C _3-8 cycloalkyl and 3-6 membered heterocyclyl;

where each C ₃ . ₈ cycloalkyl and 3-6 membered heterocyclyl R ^a3 is optionally substituted with one to three R ^a4 ; and each R ^a4 is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C ₁ - ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ αlkoxylα, C ₁ . ₆ haloalkoxy, C _3-8 cycloalkyl and 3-6 membered heterocyclyl;

each R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, cyano, hydroxyl, C1.6alkyl, C2-6alkenyl, C2-6alkynyl, C1.6alkoxy, C1-8haloalkyl, C1.8haloalkoxy, -NR ^b1 R ^b2 , -R ^b3 S(O)mR ^b4 , -S(O)mR ^b4 , -NR ^b1 S(O)nR ^b4 , -COOR ^b1 , -CONR ^b1 R ^b2 , -NR ^b1 COOR ^b2 , -NR ^b1 COR ^b4 , -R ^b3 NR ^b1 R ^b2 , -S(O)nNR ^b1 R ^b2 , C3-12 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl;

where each C ₁ . ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ . ₆ alkoxyl, C ₁ . ₈ haloalkyl and C1. ₈ haloalkoxy R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are optionally substituted with one or two R ^c ; where each R ^c is independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkoxyl, C3.8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; where each C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^c is optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1_ ₄ alkyl, C ₁ . ₆ haloalkyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

wherein each C _6-10 aryl and 5-6 membered heteroaryl R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently optionally substituted with one to five R ^b ; and wherein each C _3-8 cycloalkyl and 3-12 membered heterocyclyl R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently optionally substituted with one to six groups independently selected from =CR ^b1 R ^b2 and R ^b ;

where each R ^b is independently selected from azido, cyano, halogen, hydroxyl, -NR ^a1 R ^a2 , C1.6alkyl, C1-8haloalkyl, C1.6alkoxy, C3-6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl and 4- 6-membered heterocyclyl; where each C3-6 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b is independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1- 4 alkyl, C _1-4 haloalkyl and C _1-4 alkoxy;

where each R ^b1 and R ^b2 is independently selected from H, C _1-8 alkyl, C ₁ . ₈ haloalkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl;

where each C _3-8 cycloalkyl, C ₆ - ₁₀ aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b1 and R ^b2 independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, - NR ^a1 R ^a2 , C _1-8 alkyl, C ₁ . ₈ haloalkyl, C ₁ . ₆ αlkoxyα, C _3-6 cycloalkyl, C ₆ - ₁₀ aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and wherein each C _1-8 alkyl and C _1-8 haloalkyl R ^b1 and R ^b2 is optionally substituted with one or two R ^b5 ;

where R ^b3 represents C _1-4 alkylene;

where R ^b4 is selected from C1-4alkyl, C1-4haloalkyl, C3.6cycloalkyl, C6-10aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; wherein each C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl and said 4-6 membered heterocyclyl R ^b4 is optionally substituted with one to three Rb6 _; where each R ^b5 is independently selected from cyano, hydroxyl, C1-4 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and each C1-4 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b5 is optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and phenyl; and wherein each R ^b6 is independently selected from halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C 3-6 cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein each C3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl R ^b6 is independently optionally substituted with one to three groups independently selected from halogen, cyano, -NR ^a1 R ^a2 , C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy; or

R ² and R ³ , R ³ and R ⁴ or R ⁵ and R ⁶ together with the atoms to which they are attached form C6-10aryl, 5-6-membered heteroaryl, C3-6cycloalkyl or 5-6-membered heterocyclyl; wherein each C6-10 aryl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 5-6 member heterocyclyl is independently optionally substituted with one to three groups independently selected from halogen, cyano, -NR ^a1 R ^a2 , C1_ ₆ alkyl, C ₁ . ₆ alkoxyl,

- 9 045366

C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl,

C _1-4 alkylene-C _3-8 cycloalkyl, C _1-4 alkylene-C _6-10 aryl and C _1-4 alkylene-(5-6-membered heteroaryl);

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl,

C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and -NR ^a1 R ^a2 ;

R ¹³ is selected from H, C _1-4 alkyl and C _1-4 haloalkyl and

R ¹⁴ is selected from H, C1-6alkyl, -C1-4alkylene-NR ^a1 R ^a2 , -C1-4alkylene-C(O)NR ^a1 R ^a2 , -C1-4alkylene-O-C(O)C1-4alkyl, - C1-4alkylene-O-C(O)-O-C1-4alkyl, -C1-4alkylene-O-C(O)-C1-4alkylene-NR ^a1 R ^a2 , -C1-4alkylene-OS _1-4 alkyl, C _3-8 cycloalkyl, -C _1-4 alkylene-C _3-8 cycloalkyl, 4-6 membered heterocyclyl and -C _1-4 alkylene (4-6 membered heterocyclyl);

where C _3-8 cycloalkyl, -C _1-4 alkylene-C _3-8 cycloalkyl, 4-6-membered heterocyclyl and -C _1-4 alkylene-(4-6-membered heterocyclyl) R ¹⁴ is optionally substituted with one to three groups, regardless selected from halogen, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 haloalkyl; or

R ¹⁴ together with the N atom, which is attached to R ¹³ , forms a 5-membered heterocyclyl; wherein said 5-membered heterocyclyl is optionally substituted with one or two groups independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _6-10 aryl; wherein said C _6-10 aryl is optionally substituted with one to three groups independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl;

each R ^a1 and R ^a2 is independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; m is selected from 0, 1 and 2; and n is selected from 1 and 2.

In another aspect, compounds of formula (IIa) or pharmaceutically acceptable salts thereof are provided.

where R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ¹⁴ , R ^{b 1} and R ^{b 2} are as defined above in formula (I), (II) or other parts herein.

In another aspect, compounds of formula (IIb) or pharmaceutically acceptable salts thereof are provided:

where R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ¹⁴ and R ^b are as defined above in formula (I), (II) or other parts herein. X ¹ selected from CR ^x1 and N; and X ² is selected from CR ^x1 R ^x2 , NR ^x2 , O and S(O)2. R ^x1 selected from H and R ^b ; and R ^x2 is selected from H, C1-4alkyl and _{C1-4haloalkyl} . p is selected from 0, 1 and 2. q is selected from 0, 1, 2, 3 and 4.

In another aspect, compounds of formula (II) or pharmaceutically acceptable salts thereof are provided.

where R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ¹⁴ and R ^b4 are as defined above in formula (I), (II) or other parts herein.

In another aspect, compounds of formula (IId) or pharmaceutically acceptable salts thereof are provided.

- 10 045366

Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are each independently selected from CR ^y and N. R ^y is selected from H and R ^a . R ^a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁴ are as defined above in formula (I), (II) or other parts herein.

In another aspect, compounds of formula (IIe) or pharmaceutically acceptable salts thereof are provided.

where R ^a , R ² , R ⁴ , R ⁶ and R ¹⁴ are as defined above in formula (I), (II) or other parts herein, and is selected from 0, 1, 2, 3, 4 and 5.

In another aspect, compounds of formula (IIf) or pharmaceutically acceptable salts thereof are provided.

wherein R ^y is independently selected from H and R ^a , R ^a , R ² , R ⁴ , R ⁶ and R ¹⁴ as defined above in formula (I), (II) or other parts herein.

In another aspect, compounds of formula (IIg) or pharmaceutically acceptable salts thereof are provided.

where R ^a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁴ are as defined above in formula (I), (II) or other parts of this document. Y ³ , Y ⁴ and Y ⁵ are as defined above in formula (IId) or elsewhere herein. Each R ^y is independently selected from H and R ^a .

In another aspect, compounds of formula (IIh) or pharmaceutically acceptable salts thereof are provided.

where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁴ are as defined above in formula (I), (II) or other parts herein. Each R ^y is independently as defined above in formula (IId) or other parts herein.

In another aspect, compounds of formula (IIi) or pharmaceutically acceptable salts thereof are provided.

- 11 045366 where R ^a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁴ are as defined above in formula (I), (II) or other parts of this document, r is selected from 0, 1 , 2, 3, 4, 5 and 6.

In some embodiments of formula (I) or (II), L is a bond. In some embodiments, L is -O-. In some embodiments, L is C(O)-N(H)-*.

In some embodiments of Formula (I), (II), (IIa), (IIb) or (IIc), R ¹ is selected from phenyl, naphthyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, isoxazolyl, triazolyl, pyrazolyl, benzothiazolyl, pyridinonyl, quinolinonyl, isoquinolinonyl, quinazolindionyl, pyrazinonyl, pyrimidinonyl, pyrimidinedionyl, pyridazinonyl, quinazolinonyl, benzofuranyl, tetrahydrocyclopenta[b]pyridinonyl, naphthyridinonyl, chromanyl, isochromanyl and chromenonyl. Each R ¹ is independently optionally substituted with one to four R ^a . In some embodiments, R ¹ is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, isoxazolyl, pyridinonyl, quinolinonyl, quinazolinedionyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, quinazolinonyl, benzofuranyl, and chromonyl, and each R ¹ is independently optionally substituted with one to four ^Ra .

In some embodiments of formula (I) or (II), R^L- is selected from

Each R1-L- is optionally substituted with one to four R ^a . In some embodiments, each R ^a is independently selected from halogen, cyano, hydroxyl, NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl , -O-C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-(3-6 membered heterocyclyl) and phenyl. In some embodiments, each R ^a is independently selected from F, Cl, CN, OH, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3.

In some embodiments of formula (I) or (II), R^L- is selected from

- 12 045366

Each R1-L- is optionally substituted with one to four R ^a . In some embodiments, each R ^a is independently selected from halogen, cyano, hydroxyl, NR ^a1 R ^a2 , C1-4alkyl, C1.4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, -O-C3.6cycloalkyl, and phenyl. In some embodiments, each Ra ^is independently selected from F, Cl, CN, OH, -NH2, _-CH3 , _-CH2F , _-CHF2 , _-CF3 , -OCH3 _, and -OCF3.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

Each R ¹ is optionally replaced by one to four R ^a .

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

- 13 045366

Each R ¹ is optionally replaced by one to four R ^a .

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

each R ¹ is optionally replaced by one to four R ^a . In some embodiments, each R ^a is independently selected from halogen, CN, -OH, NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl and phenyl. In some embodiments, each R ^a is independently selected from F, Cl, OH, CN, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

each R ¹ is optionally replaced by one to four R ^a . In some embodiments, each R ^a is independently selected from halogen, CN, -OH, NR ^a1 R ^a2 , C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1. 4haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl and phenyl. In some embodiments, each R ^a is independently selected from F, Cl, OH, CN, -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -CH ₂ F, -CHF ₂ , - CF ₃ , -OCH3 and -OCF3. In some embodiments, each R ^a is independently selected from F, Cl, -N(CH3)2, -CH3, -OCH3, and -CF3.

In some embodiments of formula (I), (II), (IIa), (IIb) or (IIc), R ¹ is ^o , optionally substituted with one to three ^Ra . In some embodiments, each R ^a is independently selected from F, Cl, -N(CH ₃ ) ₂ , -CH3, -OCH3 and -CF3. In some embodiments, R ¹ is substituted with -CH3.

In some embodiments of formula (I), (II), (IIa), (IIb) or (IIc), R ¹ is substituted with one to three R ^a independently selected from halogen, CN, OH, NR ^a1 R ^a2 , C1-4alkyl , C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy and C3-6cycloalkyl. In some embodiments, each R ^a is independently selected from F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CN , -CH2CH2CN, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2F, -CHF2, - CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3,

-OCH2CH2F, -OCH2CHF2, -OCH2CF3, -SO2CH3, -SO2CH2CH3, ’cyclopropyl,

- 14 045366 cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -O-cyclopropyl, -O-CH2-cyclopropyl, -O-cyclobutyl, -O-CH2cyclobutyl, -O-cyclopentyl, -O-CH2cyclopentyl, -O-cyclohexyl,

-O-CH2cyclohexyl and -O-phenyl. In some embodiments, each R ^a is independently selected from

F, Cl, CN, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -CH2OCH2CH3 and -OCF3.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

- 15 045366

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R ¹ is selected from

- 16 045366

In some embodiments, R ¹ is

In some embodiments of Formula (I), (II), (IIa), (IIb) or (IIc), R ¹ -L- is -OC(O)-NR ^a1 R ^a2 . In some embodiments, R ^a1 and R ^a2 are each independently selected from H and C1-4 alkyl. In some embodiments, R ^a1 and R ^a2 are each independently selected from H, CH3, -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , and -C(CH ₃ ) ₃ . In some embodiments, R ^a1 and R ^a2 are each independently selected from H, CH3, and -CH2CH3. In some embodiments, both R ^a1 and R ^a2 are CH3. In some embodiments, R1-L- is -OC(O)-N(CH ₃ ) ₂ .

In some embodiments of formula (I) or (II), R ² and R ³ form C ₃ . ₆ cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl. In some embodiments, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains one or two Ns. In some embodiments, C ₃ . ₆ cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are substituted with one or two groups independently selected from halogen, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl and C1. ₄ alkylenephenyls. In some embodiments, C ₃ . _6- cycloalkyl, 5-6-membered heterocyclyl, phenyl or 5-6-membered heteroaryl is substituted with one or two groups independently selected from Cl, -CH ₃ , cyclopropyl and -CH ₂ -phenyl.

In some embodiments of formula (I) or (II), R ³ and R ⁴ form C ₃ . ₆ cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl. In some embodiments, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains one or two Ns. In some embodiments, C ₃ . ₆ cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are substituted with one or two groups independently selected from halogen, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl and C ₁ . ₄ alkylenephenyls. In some embodiments, C ₃ . _6- cycloalkyl, 5-6-membered heterocyclyl, phenyl or 5-6-membered heteroaryl are substituted with one or two groups independently selected from Cl, -CH3, cyclopropyl and -CH2-phenyl.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIg), (IIh), or (IIi), each R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from H, halogen, CN, OH, -NR ^b1 R ^b2 , C1.6alkyl, C1.6alkoxy, C1.6haloalkyl and C1.6haloalkoxy. In some embodiments, R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are each independently selected from H, halogen, CN, OH, -NR ^b1 R ^b2 , C1.4alkyl, C1. ₄ alkoxyl, C1. ₄ haloalkyl and C1. ₄ haloalkoxy. In some embodiments, R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are each independently selected from H, F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, CD3, -CH2F, -CHF2, -CF3, -OCH3 and -OCF3. In some embodiments, R ² and R ⁶ are each independently selected from H, halogen, CN, OH, -NR ^b1 R ^b2 , C1.4alkyl, C1. ₄ alkoxyl, C1. ₄ haloalkyl and C1. ₄ haloalkoxy. In some embodiments, each R ² and R ⁶ is independently selected from F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, both R ² and R ⁶ are F. In some embodiments, R ⁶ is -CH3. In some embodiments, R ³ and R ⁵ are each independently selected from H, C1.6alkyl, C1.6alkoxy, C1.6haloalkyl, C1.6haloalkoxy, and C3.6cycloalkyl. In some embodiments, R ³ and R ⁵ are each independently selected from H, C1.4alkyl, C1. ₄ alkoxyl, C ₁ . ₄ haloalkyl and C1. ₄ haloalkoxy. In some embodiments, R ³ and R ⁵ are each independently selected from H, F, -NH2, -CH3, -CH2F, -CHF2, -CF3, and -OCH3. In some embodiments, both ^R3 and ^R5 are H.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIg), (IIh) or (IIi), R ² is F and R ⁶ is -CH ₃ .

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from H, -NR ^b1 R ^b2 , -NR ^b1 S(O)nR ^b4 and 3-8-membered heterocyclyl. In some embodiments, said 3-8 membered heterocyclyl R ⁴ contains one or two heteroatoms or groups independently selected from S, N, O and S(O) 2 .

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is -NR ^b1 R ^b2 . In some embodiments, R ^b1 and R ^b2 are each independently selected from H,

- 17 045366

C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, phenyl and 3-8 membered heterocyclyl. In some embodiments, the 3-8 membered heterocyclyl contains one or two atoms independently selected from N and O. In some embodiments, R ^b1 is selected from H, C1-4alkyl, and C1_6haloalkyl. In some embodiments, R ^b1 is selected from H and CH3. In some embodiments, R ^b2 is selected from C16alkyl, C1-8haloalkyl, C3_6cycloalkyl, C3_6cycloalkyl, and 4-6 membered heterocyclyl. In some embodiments, R ^b2 is selected from _{C1_6} alkyl, _{C1_6 haloalkyl} , _C3-6 cycloalkyl, and 4-6 membered heterocyclyl. In some embodiments, R ^b1 is H and R ^b2 is selected from C1_6alkyl, C1-8haloalkyl, C3-6cycloalkyl, and 5-6 membered heterocyclyl. In some embodiments, R ^b1 is H and R ^b2 is C1_ ₆ haloalkyl. In some embodiments, R ^b2 is -C1_5alkylene-CF3. In some embodiments, R ^b2 is selected from -methyleneCF3, -ethylene- _CF3 , -propylene- _CF3 , -butylene- _CF3, and -pentylene- _CF3 . In some embodiments, R ^b2 is -C1_5alkylene-CF3 substituted with one or two R ^b5 . In some embodiments, each R ^b5 is independently selected from hydroxyl, C1-4 alkoxy, C _3-6 cycloalkyl, phenyl, and 4-6 membered heterocyclyl. In some embodiments, each R ^b5 is independently selected from C3-6 cycloalkyl, 4-6 membered heterocyclyl, and phenyl. Each C3-6cycloalkyl, 4-6 membered heterocyclyl and phenyl R ^b5 is optionally substituted with one to three groups independently selected from halogen, hydroxyl, cyano, -NR ^b1 R ^b2 , C1-4 alkyl, C _1-4 alkoxy and C _{1- 4} haloalkyl. In some embodiments, R ^b5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuran, and phenyl; and each R ^b5 is optionally substituted with one group selected from F, Cl, CN, -CH3, -CH2F, -CHF2 and -CF3. In some embodiments, R ^b5 is phenyl. In some embodiments, R ^b5 is phenyl substituted with one to two groups independently selected from F, Cl, CN, CH3, -CH ₂ F, -CHF ₂ and -CF ₃ . In some embodiments, R ^b5 is phenyl substituted with one to two groups independently selected from F, Cl, CN, and -CF3. In some embodiments, R ^b5 is unsubstituted phenyl.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

- 18 045366

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is

constitutes

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is a 3-8 membered heterocyclyl, optionally substituted with one -three R ^b ; and each R ^b is independently selected from halogen, hydroxyl, cyano, -NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy and C _1-4 haloalkyl. In some embodiments, each ^R4 is optionally substituted with one or two groups independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2, and -CF3.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is a 3-8 membered spiro-, fused or bridged heterocyclyl. In some embodiments, R ⁴ is selected from azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, piperidinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydropyridinyl, tetrahydropyridinyl, 1,1-dioxide-thiomorpho linyl and quinuclidinyl; and each R ⁴ is optionally substituted with one or three R ^b . In some embodiments, R ⁴ is selected from morpholinyl, piperidinyl, tetrahydropyranyl, and pyrrolidinyl; each R ⁴ is optionally substituted with one to three R ^b . In some embodiments, each R ^b is independently selected from halogen, hydroxyl, cyano, -NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy, and C _1-4 haloalkyl. In some embodiments, each R ^b is independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2, and -CF3.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is spirocyclyl, optionally substituted with one to three R ^b . In some embodiments, R ⁴ is azaspiroheptanil. In some embodiments, R ⁴ is azaspiro[3.3]heptanyl. In some embodiments, R ⁴ is azaspiro[2.4]heptanyl. In some embodiments, each R ^b is independently selected from halogen, hydroxyl, cyano, NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy, and C _1-4 haloalkyl. In some embodiments, each R ^b is independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2, and -CF3.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is a fused or bridged heterocyclyl, optionally substituted with one -three R ^b . In some embodiments, each R ⁴ is independently selected from azabicyclo[3.1.0]hexanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, and oxaazabicyclo[2.2.2]octanyl; each R ⁴ is optionally substituted with one to three R ^b . Each R ^b is independently selected from halogen, hydroxyl, cyano, NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy and C _1-4 haloalkyl. In some embodiments, each R ^b is independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2, and -CF3.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

- 19 045366 and each R ⁴ is optionally substituted by one to three groups independently selected from halogen,

OH, CN, -NR ^a1 R ^a2 , C _1-4 alkyl, C _1-4 alkoxy and C _1-4 haloalkyl.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

and each R ⁴ is optionally substituted with one to three groups independently selected from F, Cl, OH, CN, NH2, -CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, C3-6Cycloalkyl and -CH2C3-6Cycloalkyl.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

- 20 045366

In some embodiments, R ⁴ is ^CF3

In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is -NHS(O)2R ^b4 . In some embodiments, R ^b4 is selected from C1.4alkyl, C1-4haloalkyl, C3.6cycloalkyl, and phenyl. In some embodiments, R ^b4 is selected from -CH3, -CH2F,

-CHF2, -CF ₃ and phenyl. In some embodiments, the phenyl is optionally substituted with pyridinyl, which is optionally substituted with one or two groups independently selected from halogen and C ₁₄ alkyl. In some embodiments, the pyridinyl is optionally substituted with one or two groups independently selected from F and -CH ₃ .

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R ⁴ is selected from

In some embodiments of formula (IIb), X ¹ is CH or N. In some embodiments, X ¹ is N. In some embodiments, X 2 is selected from CH 2 , NR ^x 2 , O, and S(O) 2 . In some embodiments, X ¹ is N and X2 is O. In some embodiments, X ¹ is N and X2 is CH2. In some embodiments, X ¹ is N and X ² is S(O)2. In some embodiments, each R ^b is independently selected from F, OH, -CH3, -CH( _CH3 )2, -CH2F, -CHF2, and _-CF3 .

In some embodiments of formula (IIb), p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 1. In some embodiments, q is 2.

In some embodiments of formula (IId), Y ¹ , Y ² , Y ³ , Y ^{4 ,} and Y ⁵ are CR ^y . In some embodiments, at least one of Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ is N. In some embodiments, Y ¹ is N; and Y ⁵ represents N; and Y ² , Y ³ , Y ⁴ and Y ⁵ represent CR ^y . In some embodiments, Y ² is N; and Y ¹ , Y ³ , Y ⁴ and Y ⁵ represent CR ^y . In some embodiments, Y ³ is N; and Y ¹ , Y ² , Y ⁴ and Y ⁵ represent CR ^y . In some embodiments, Y ¹ and Y ⁵ are N; and Y ¹ , Y ² and Y ³ represent CR ^y .

In some embodiments of formula (IId), (IIf), (IIg) or (IIh), each R ^y is independently selected from H, halogen, hydroxyl, -NR ^a1 R ^a2 , C1-4alkyl, C1.4alkoxy and C1-4haloalkyl . In some embodiments, each R ^y is independently selected from H, F, Cl, CN, OH, -NH2, -N(CH3) ₂ , _-CH3 , _{-CH2CH3 ,} -CH(CH3)2, -C( CH3)3, -CH2CN, -CH2CH2CN, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, - CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -SO2CH3, -SO2CH2CH3,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -O-cyclopropyl, -O-CH2-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclobutyl, -O-cyclopentyl, -O-CH2cyclopentyl, -O-cyclohexyl, -O- CH2-cyclohexyl and -O-phenyl. In some embodiments, each R ^y is independently selected from H, F, Cl, OH, CN, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -CH2OCH2CH3, and -OCF3. In some embodiments, each R ^y is independently selected from H, F, -CH3, -CH ₂ F, -CHF ₂ , -CF3, -OCH3, -CH2OCH2CH3, and -OCF3.

In some embodiments of formula (IIe), u is selected from 1, 2, and 3. In some embodiments, u is 3.

In some embodiments of formula (IIg), Y ³ , Y ⁴ and Y ⁵ are independently selected from CR ^y and N; where each R ^y is independently selected from H and R ^a . In some embodiments, Y ³ is N; and Y ⁴ and Y ⁵ represent CR ^y . In some embodiments, Y ⁵ is N; and Y ³ and Y ⁴

- 21 045366 represent CR ^y . In some embodiments, each R ^y is independently selected from H, F, Cl,

CN, -NH2, -N(CH3) ₂ , -CH ₃ , -CH2F, -CHF2, -CF ₃ and -OCH ₃ . In some embodiments, each R ^x1 is independently selected from H, F, Cl, -NH2, -N(CH ₃ ) ₂ , -CH ₃ , -CF ₃ , -OCH _{3 ,} and -OCF ₃ .

In some embodiments of formula (IIi), r is selected from 1, 2, and 3. In some embodiments, r is 3.

In some embodiments of formula (I) or (II), R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from H, F, Cl, CN, -NH2, -N(CH3)2, -CH3 , -CH2F, -ChF2, -CF3, -OCH3 and -OCF3. In some embodiments, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each selected from H, F, CN, -N(CH3) ₂ , -CH _{3 ,} and -CF ₃ . In some embodiments, each R7-R ¹¹ is selected from H, F, and -N(CH3)2. In some embodiments, R7 to R ¹¹ are H. In some embodiments, R ⁷ is selected from H, F, CN, -N(CH3) ₂ , -CH2 and -CF ₃ . In some embodiments, R ⁷ is F. In some embodiments, R ⁸ is selected from H, F, CN, -N(CH3)2, -CH3, and -CF3. In some embodiments, R ⁸ is F. In some embodiments, R ¹⁰ is selected from H, F, CN, -N(CH3) ₂ , -CH ₃ and -CF ₃ . In some embodiments, R ¹⁰ is F or -N(CH3)2. In some embodiments, R ¹¹ is -CH3.

In some embodiments of Formula (I), R ¹² is H. In some embodiments, R ¹² is -CH ₃ .

In some embodiments of formula (I), R ¹³ is H. In some embodiments, R ¹³ is -CH ₃ .

In some embodiments of formula (I), R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ are each H.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIe), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi) R ¹⁴ selected from C1-6alkyl, C3-8cycloalkyl and 4-6 membered heterocyclyl. In some embodiments, each C3-8 cycloalkyl and 4-6 membered heterocyclyl R ¹⁴ is optionally substituted with one to three groups independently selected from halogen, C1-4 alkyl, and C _1-4 haloalkyl. In some embodiments, R ¹⁴ is selected from -C1-4αalkylene-NR ^a1 R ^a2 , -C1-4αalkylene-C(O)NR ^a1 R ^a2 , -C1-4alkylene-O-C(O)-C1-4alkyl, -C1 -4alkylene-O-C(O)-O-C1-4alkyl, -C1-4alkylene-O-C(O)-C1-4alkylene-NR ^a1 R ^a2 and -C1-4alkylene-O-C _1-4 alkyl. In some embodiments, when introduced into a biological system, the esters provided herein generate active ingredients, wherein R ¹⁴ is hydrogen, as a result of chemical reaction(s), enzyme-catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). reactions).

In some embodiments of formula (I), (II), (IIa), (IIb), (IIe), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi) R ¹⁴ selected from H, methyl, ethyl, propyl, butyl, -CH ₂ C(O)N(Ch ₃ ) ₂ , -(Ch ₂ ) ₂ N(Ch ₂ CH ₃ ) ₂ , -CH2-OC(O)CH3, -(CH2)2-O-C(O)CH3, -CH2-O-C(O)C(CH)3, -(CH2)2-O-C(O)C(CH)3, -CH2- O-C(O)-O-CH3, -CH(CH3)-O-C(O)-O-CH3, -CH2-O-C(O)-O-CH2CH3, -CH2-O-C(O )-O-CH(CH3)2, -CH2-O-C(O)-O-C(CH3)3, Ar ~ Λ

-(CH2)2C(O)CH3, .

In some embodiments, R ¹⁴ is selected from H, -CH ₂ -O-C(O)C(CH) ₃ , -CH(CH ₃ )-O-C(O)-O-CH ₃ , X

Ό.-Χ ⁴

In some embodiments, R ¹⁴ together with the N atom attached to R ¹³ forms a 5-membered heterocyclyl. In some embodiments, said 5-membered heterocyclyl is substituted with one or two groups independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C _{6-10 aryl} . In some embodiments, said 5-membered heterocyclyl is substituted with one or two groups independently selected from CH ₃ , CH 2 CH 3 , -OCH ₃ , -OCH ₂ CH ₃ and phenyl. In some embodiments, said 5-membered heterocyclyl is substituted with phenyl, and the phenyl is optionally substituted with one to three groups independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, and C _1-6 haloalkyl _.

In some embodiments, R ¹⁴ is H.

In some embodiments, R ¹⁴ is CH3 or CH2CH3. In some embodiments, R ¹⁴ is CH3. In some embodiments, R ¹⁴ is CH2CH3.

In some embodiments, the compound of the present invention is selected from Examples 1-354.

In some embodiments, a compound of the present invention is selected from Examples 355-406. In some embodiments, a compound of the present invention is selected from Examples 407-496.

In some embodiments, a compound of the present invention is selected from

- 22 045366

In another aspect, compounds of formula (J) or pharmaceutically acceptable salts thereof are provided:

- 23 045366

or pharmaceutically acceptable salts thereof, wherein

L is selected from the bond, -O-, -O-C(O)-*, -NH-, -C(O)-N(H)-* and -N(H)-C(O)-*; where * denotes the place of attachment of L to R ¹ ;

R ¹ is selected from A ¹ , A ² , A ³ and A ⁴ ;

A ¹ is a 5-10 membered heteroaryl containing one to five heteroatoms independently selected from S, N and O; where A ¹ optionally contains one to three C(O); and where A ¹ is optionally substituted with one to six R ^a ;

A ² is C _6-10 aryl, optionally substituted with one to six R ^a ;

And ³ represents C _5-10 cycloalkyl or 5-14 membered heterocyclyl; wherein A ³ is optionally substituted with one to four groups independently selected from oxo and R ^a ; And

And ⁴ is -NR ^a1 R ^a2 ;

where each R ^a is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, -S(O) _m -C _1-6 alkyl, C _3-8 cycloalkyl, 3-6-membered heterocyclyl, C _6-10 aryl, 5-6-membered heteroaryl, -O-C _{3- 8} cycloalkyl, -O-(36-membered heterocyclyl), -O-C _1-4 alkylene-C _3-8 cycloalkyl and -O-phenyl;

where each C _3-8 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, -O-C _3-8 cycloalkyl, -O-(3-6 membered heterocyclyl), - O-C _1-4 alkylene-C _3-8 cycloalkyl and -O-phenyl R ^a is independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy; and where each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and -S(O) _m -C _1-6 alkyl R ^a is optionally substituted with one to three R ^a3 , where each R ^a3 is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C _1-6 alkoxyl, C _3-8 cycloalkyl and 3-6 membered heterocyclyl;

where each C _3-8 cycloalkyl and 3-6 membered heterocyclyl R ^a3 is optionally substituted with one to three R ^a4 ; and each R ^a4 is independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-8 cycloalkyl and 3 -6-membered heterocyclyl;

each R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, cyano, hydroxyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-8haloalkyl, C1-8haloalkoxy, -NR ^b1 R ^b2 , -R ^b3 S(O)mR ^b4 , -S(O)mR ^b4 , -NR ^b1 S(O)nR ^b4 , -COOR ^b1 , -CONR ^b1 R ^b2 , -NR ^b1 COOR ^b2 , -NR ^b1 COR ^b4 , -R ^b3 NR ^b1 R ^b2 , -S(O)nNR ^b1 R ^b2 , C3-12 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl;

where each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-8 haloalkyl and C _1-8 haloalkoxy R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is optionally substituted with one or two R ^c ; wherein each R ^c is independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; where each C3-8 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^c is optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1-4 alkyl, C _1-6 haloalkyl, C1-4 alkoxy and C3-6 cycloalkyl;

wherein each C6-10 aryl and 5-6 membered heteroaryl R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently optionally substituted with one to five R ^b ; and wherein each C3-8 cycloalkyl and 3-12 membered heterocyclyl R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently optionally substituted with one to six groups independently selected from =CR ^b1 R ^b2 and R ^b ;

where each R ^b is independently selected from azido, cyano, halogen, hydroxyl, -NR ^a1 R ^a2 , C1-6 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4- 6-membered heterocyclyl; where each C3-6 cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b is independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1- 4 alkyl, C _1-4 haloalkyl and C _1-4 alkoxy;

where each R ^b1 and R ^b2 is independently selected from H, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl;

where each C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b1 and R ^b2 independently optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, - NR ^a1 R ^a2 , C _1-8 alkyl, C _1-8 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _6-10 aryl, 56-membered heteroaryl and 4-6-membered heterocyclyl; and wherein each C _1-8 alkyl and C _1-8 haloalkyl R ^b1 and R ^b2 is optionally substituted with one or two R ^b5 ;

where R ^b3 represents C _1-4 alkylene;

- 24 045366 where R ^b4 is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; where each C _1-4 alkyl, C _1-4 haloalkyl, C ₃ - ₈ cycloalkyl, C _6-10 aryl, 56-membered heteroaryl and said 4-6 membered heterocyclyl R ^b4 is optionally substituted by one to three

^Rb6 ;

where each R ^b5 is independently selected from cyano, hydroxyl, C1_4 alkoxyl, C3-8 cycloalkyl, C610 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and each C1_4alkoxyl, C3-8cycloalkyl, C6-10aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl R ^b5 is optionally substituted with one to three groups independently selected from halogen, cyano, hydroxyl, -NR ^a1 R ^a2 , C1_4alkyl , C ₁ - ₄ haloalkyl, C1_ ₄ alkoxy and phenyl; and wherein each R ^b6 is independently selected from halogen, cyano, C1_4alkyl, C1_4haloalkyl, C1_4alkoxy, C3-6cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein each C3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl R ^b6 is independently optionally substituted with one to three groups independently selected from halogen, cyano, -NR ^a1 R ^a2 , C 1_4 alkyl, C ₁ - ₄ haloalkyl and C1_ ₄ alkoxy; or

R ² and R ³ , R ³ and R ⁴ or R ⁵ and R ⁶ together with the atoms to which they are attached form C6-10aryl, 5-6-membered heteroaryl, C3-6cycloalkyl or 5-6-membered heterocyclyl; where each C6-10 aryl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 5-6 membered heterocyclyl is independently optionally substituted with one to three groups independently selected from halogen, cyano, -NR ^a1 R ^a2 , C1_ ₆ alkyl, C ₁ _ ₆ alkoxyl, C ₁ _ ₆ haloalkyl, C ₃ - ₈ cycloalkyl, 3-6-membered heterocyclyl, C ₆ - ₁₀ aryl, 5-6-membered heteroaryl, C ₁ _ ₄ alkylene-C ₃ _ ₈ cycloalkyl, C ₁ _ ₄ alkylene-C ₆ - ₁₀ aryl and C ₁ - ₄ alkylene-(5-6-membered heteroaryl);

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halogen, hydroxyl, cyano, C ₁ _ ₆ alkyl, C ₁ _ ₆ alkoxyl, C ₁ _ ₆ haloalkyl, C ₁ _ ₆ haloalkoxy and -NR ^a1 R ^a2 ;

R ¹³ is selected from H, _{C1_4} alkyl and _{C1_4} haloalkyl;

R ¹⁵ is selected from H, C1-10alkyl, C1-10haloalkyl, C3-10cycloalkyl, 3-14 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -C1_4alkylene-NR ^a1 R ^a2 , -C1_ ₄ alkylene-C (O)NR ^a1 R ^a2 and -L1-R ¹⁶ ;

where L ¹ is selected from -C1-4alkylene-, -C1-4alkylene-O-, -C1-4alkylene-C(O)-, -C1-4alkylene-O-C(O)-, -C1-4alkylene-O- C(O)-C1-4alkylene-, -C1-4alkylene-C(O)-O-, -C1_4alkylene-C(O)-O-C1_4alkylene, -C1-4alkylene-O-C(O)O-, - C1_4alkylene-O-C(O)-O-C1_4alkylene-, -C1_4alkylene-NR ^a1 C(O)-O- and -C1_ ₄ alkylene-OC(O)-NR ^a1 -; and where R ¹⁶ is selected from C ₁ - ₆ alkyl, C ₁ - ₆ haloalkyl, C ₃ - ₁₀ cycloalkyl, 3-14 membered heterocyclyl, C ₆ - ₁₀ aryl and 5-10 membered heteroaryl;

where each C ₃ - ₁₀ cycloalkyl, 3-14 membered heterocyclyl, C ₆ - ₁₀ aryl and 5-10 membered heteroaryl R ¹⁵ and R ¹⁶ is optionally substituted with one to four groups independently selected from halogen, hydroxyl, -COOR ^b7 , -NR ^a1 R ^a2 , -S(O)2R ^a5 , C1_ ₄ alkyl, C1_ ₄ alkoxyl, C1_ ₄ haloalkyl, C1_ ₄ haloalkoxy and -C _{1_ 4} alkylene-NR ^a1 R ^a2 .

each R ^a1 and R ^a2 are independently selected from H, C ₁ - ₆ alkyl and C ₁ - ₆ haloalkyl;

R ^a5 is C _{1_6} alkyl _;

R ^b7 is independently selected from H and C ₁ _ ₆ alkyl;

m is selected from 0, 1 and 2 and n is selected from 1 and 2.

In some embodiments of formula (J) or a pharmaceutically acceptable salt thereof, said compound has formula (Ja)

R ⁴ R ⁵

where each Y ¹ , Y ² , Y ³ and Y ⁴ are independently selected from CR ^y and N; where each R ^y is independently selected from H and R ^a ; and where R ^z is selected from H, C ₁ - ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C ₁ - ₆ haloalkyl, C ₃ - ₈ cycloalkyl and 36-membered heterocyclyl.

In some embodiments of formula (J) or (Ja) or a pharmaceutically acceptable salt thereof, said compound has formula (Jb)

- 25 045366 where each Y ² and Y ⁴ is independently selected from CR ^y and N. Each R ^y is independently selected from H and R ^a . R ^z is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl and 3-6 membered heterocyclyl. X ¹ is selected from CR ^x1 and N. X ² is selected from CR ^x1 R ^x2 , NR ^x2 , O and S(O) ₂ . R ^x1 selected from H and R ^b ; and R ^x2 is selected from H, C _1-4 alkyl and C _1-4 haloalkyl; q is selected from 0, 1, 2 and 3 and r is selected from 0, 1 and 2.

In some embodiments of formula (J) or (Ja) or a pharmaceutically acceptable salt thereof, said compound has formula (Jc)

where R ^z is selected from H, C _1-6 αlkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl and 3-6 membered heterocyclyl and where r is selected from 0, 1, 2 and 3.

In some embodiments of formula (J), (Ja), (Jb) or (Jc) or a pharmaceutically acceptable salt thereof, the compound has formula (Jd)

(Jd);

where R ^z is selected from H, -CH3, -CD3-CH2F, -CHF2, -CF3 and -CH2CH3; X ¹ is selected from CR ^x1 and N. X ² is selected from CR ^x1 R ^x2 , NR ^x2 , O and S(O)2. R ^x1 is selected from H and R ^b and R ^x2 is selected from H, C _1-4 alkyl and C _1-4 haloalkyl; q is selected from 0, 1, 2 and 3 and r is selected from 0, 1, 2 and 3.

In some embodiments of formula (J), (Ja), (Jb), (Jc) or (Jd) or a pharmaceutically acceptable salt thereof, the compound has formula (Je)

where X ¹ is selected from CR ^x1 and N. X ² is selected from CR ^x1 R ^x2 , NR ^x2 , O and S(O)2. R ^x1 is selected from H and R ^b and R ^x2 is selected from H, C1-4alkyl and _{C1-4haloalkyl} ; q is selected from 0, 1, 2 and 3.

In some embodiments of formula (J) or (Ja) or a pharmaceutically acceptable salt thereof, said compound has formula (Jf)

- 26 045366 where each Y ¹ and Y ⁴ is independently selected from CR ^y and N. Each R ^y is independently selected from H and R ^a . R ^z is selected from H, -CH ₃ , -CD ₃ , -CH2F, -CHF2, -CF ₃ and -CH ₂ CH ₃ . X ¹ selected from CR ^x1 and N. X2 selected from CR ^x1 R ^x 2, NR ^x 2,

O and S(O) ₂ . R ^x1 is selected from H and R ^b and R ^x 2 is selected from H, C _1-4 alkyl and C 1_ ₄ haloalkyl; q selected from 0, 1, 2 and 3

and r is selected from 0, 1 and 2.

In some embodiments of formula (J) or a pharmaceutically acceptable salt thereof, said compound has formula (Jg)

where each Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from CR ^y1 R ^y2 , NR ^z1 and O; where each R ^y1 and R ^y2 is independently selected from H and R ^a and where each R ^z and R ^z1 is independently selected from H, C ₁ - ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl,

C ₁ _ ₆ haloalkyl, C _3-8 cycloalkyl and 3-6 membered heterocyclyl.

In some embodiments of formula (I) or (J) or a pharmaceutically acceptable salt thereof, R ¹ is selected from

where each R ¹ is replaced by one to four R ^a . In some embodiments, R ^a is C1-4 alkyl. In some embodiments, R ^a is -CH3. In some embodiments, R ¹ is selected

In some embodiments of formula (I) or (J) or a pharmaceutically acceptable salt thereof, R ¹ is selected from

each R ¹ is optionally replaced by one to four R ^a . In some embodiments, each R ^a is independently selected from halogen, CN, -OH, NR ^a1 R ^a2 , _{C1_4} alkyl, _{C1_4} alkoxy, _{C1-4 haloalkyl} ,

- 27 045366

C _1-4 haloalkoxy, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl and phenyl. In some embodiments, each R ^a is independently selected from F, Cl, OH, CN, -NH2, -NH(CH ₃ ), -N(CH ₃ )2, -CH ₃ , -CH2F, -CHF2, -CF ₃ ,

-OCH3 and -OCF ₃ . In some embodiments, each R ^a is independently selected from -N(CH ₃ ) ₂ , -CH ₃ ,

-OCH3 and -CF3.

In some embodiments of formula (I) or (J), R ¹ is selected from /

—N

In some embodiments, R ¹ is ^{/ 0}

In some embodiments of formula (I) or (J) or a pharmaceutically acceptable salt thereof

R ¹ represents ⁰ · substituted with one or two R ^a . Each R ^a is independently selected from C1 ₄ alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _3-6 cycloalkyl. In some embodiments, R ¹ is ⁰

In some embodiments, formula (J), (Ja) or (Jc) or pharmaceutically acceptable salts thereof, ^R3 and ^R5 are H.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, each R ² and R ⁶ is independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl and 3-7 membered heterocyclyl. In some embodiments, each R ² and R ⁶ is independently selected from F, Cl, -CH3, -CD3, -CH2CH3, -OCH3, _-OCH2CH3 , -CH2F, -CHF2, _-CF3 , -CH2CH2F, -CH2CHF2, - CH2CF3, -NH2 and -N(CH ₃ ) ₂ . In some embodiments, R ² and R ⁶ are each independently selected from F, Cl, and -CH3. In some embodiments, R ² is F and R ⁶ is -CH3. In some embodiments, R ² and R ⁶ are each independently selected from F and Cl. In some embodiments, R ² and R ⁶ are F.

In some embodiments, formula (J), (Ja), (Jb), (Jc), (Jd), (Je) or (Jf) or pharmaceutical formulations thereof

JVWW of the commercially acceptable salt R ⁴ is ¹ -substituted with one to three R ^b . In some embodiments, each Rb is independently selected from C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, and C _1-4 haloalkoxy. In some embodiments, each Rb is independently selected from -CH ₃ , -CF3 and -OCF3. In some embodiments, each Rb is -CF3. In some embodiments, R ⁴ is ι

In some embodiments of formula (Ja) or (Jb), Y ² is N. In some embodiments of formula (Ja) or (Jb), Y ² is N and Y ⁴ is CH. In some embodiments, formulas (Ja) Y ¹ , Y ³ and Y ⁴ are CR ^y . In some embodiments, (Ja) at least one of Y ¹ , Y 2 , Y ^{3 ,} or Y ⁴ is N. In some embodiments, Y ⁴ is CH. In some embodiments, formulas (Ja) Y ¹ , Y 2 , Y ³ , and Y ⁴ are CR ^y .

In some embodiments of formula (Jf), Y ¹ is N. In some embodiments, Y ⁴ is N. In some embodiments, both Y ¹ and Y ⁴ are N.

In some embodiments, formula (Ja), (Jb), (Jc), (Jd), or (Jf) or pharmaceutically

- 28 045366 acceptable salt R ^z represents -CH ₃ .

In some embodiments of formula (Jb), (Jd), (Je) or (Jf or a pharmaceutically acceptable salt thereof, X ¹ is N.

In some embodiments of formula (Jb), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, X ² is O. In some embodiments, X ¹ is N and X ² is O.

In some embodiments of formula (Jb), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, q is 1.

In some embodiments of formula (Jb), (Jd), (Je), or (Jf), each R ^b is independently selected from C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, and C1-4haloalkoxy. In some embodiments, R ^b is C1-4haloalkyl. In some embodiments, R ^b is independently selected from -CH2F, -CHF2, and -CF3. In some embodiments, R ^b is CF3.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, R ¹⁵ is selected from H, C1_6alkyl, C1_6haloalkyl, C3-8cycloalkyl , 4-10 membered heterocyclyl and C6-10 aryl. In some embodiments, R ¹⁵ is selected from H, C1_ ₆ alkyl, and phenyl; and the phenyl is optionally substituted with one _to three groups independently selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl and C _1-4 haloalkoxy. In some embodiments, R ¹⁵ is selected from H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl, and phenyl. In some embodiments, R ¹⁵ is selected from H, methyl, ethyl, and phenyl. In some embodiments, R ¹⁵ is H. In some embodiments, R ¹⁵ is methyl. In some embodiments, R ¹⁵ is ethyl. In some embodiments, R ¹⁵ is phenyl. In some embodiments, R ¹⁵ is phenyl substituted with one group selected from F, -CH3, -CF3, -OCF3, and -(CH2)2N(CH2CH3)2. In some embodiments, R ¹⁵ is -CH2CH ₂ N(CH ₂ CH ₃ ) ₂ .

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, R ¹⁵ is -L1-R ¹⁶ . In some embodiments, L ¹ is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2-O-C(O)-C1-4alkyl, and -CH2-O-C(O)-O-C1 -4alkyl. In some embodiments, R ¹⁶ is selected from _-CH2CH3 , -CH( _CH3 ) ₂ , -C( _CH3 ) ₃ , _-CH2CH2CH3 , phenyl, _pyridinyl , _imidazolyl , tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl. The phenyl, pyridinyl, imidazolyl, tetrahydrofuranyl, morpholinyl and tetrahydropyranyl R ¹⁶ are each optionally substituted with one or two groups independently selected from F, -CH ₃ , -CH ₂ CH ₃ , hydroxyl and -COOH.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, R ¹⁵ is selected from H, -CH ₃ , -CH ₂ CH ₃

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je) or (Jf) or a pharmaceutically acceptable salt thereof, R ¹⁵ is selected from H, -CH3 and -CH2CH3. In some embodiments, R ¹⁵ is H. In some embodiments, R ¹⁵ is -CH2CH ₃ .

In some embodiments of formula (Jg) or a pharmaceutically acceptable salt thereof, Z ¹ is O. In some embodiments, Z ² is O. In some embodiments, Z ³ is O. In some embodiments, Z ⁴ is is O. In some embodiments, Z ¹ is NR ^z1 . In some embodiments, Z ² is NR ^z1 . In some embodiments, Z ³ is NR ^z1 . In some embodiments, Z ⁴ is NR ^z1 . In some embodiments, R ^z1 is selected from H,

-CH ₃ and -CH ₂ CH ₃ . In some embodiments, R ^z1 is H.

In some embodiments of formula (Jg) or a pharmaceutically acceptable salt thereof, R ^z is -CH ₃ .

In some embodiments of formula (Jg) or its pharmaceutically acceptable salts, ^R3 and ^R5 are H.

In some embodiments of formula (Jg) or a pharmaceutically acceptable salt thereof, each R ² and R ⁶ is independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxyl, C1-4 haloalkyl, C14 haloalkoxy, C3-6 cycloalkyl, and 3-7 membered heterocyclyl . In some embodiments, each R ² and R ⁶ is independently selected from F, Cl, -CH3, -CD3, -CH2CH3, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -NH ₂ and -K(CH ₃ ) ₂ . In some embodiments, R ² and R ⁶ are each independently selected from F, Cl, and -CH3. In some embodiments, R ² is F and R ⁶ is -CH3. In some embodiments, R ² and R ⁶ are each independently selected from F and Cl. In some embodiments, R ² and R ⁶ are F.

In some embodiments of formula (Jg) or a pharmaceutically acceptable salt thereof, R ⁴ is ¹ · substituted with one to three R ^b . In some embodiments, each R ^b is independently selected from C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy. In some embodiments, each R ^b is independently selected from -CH3, _-CF3 , and _-OCF3 . In some embodiments, each R ^b is -CF ₃ . In some embodiments, R ⁴ is

ABOUT,

JjL ^С|=3

In some embodiments of formula (Jg) or a pharmaceutically acceptable salt thereof, R ¹⁵ is selected from H, -CH3, -CH2CH3, and -CH2CH2CH3. In some embodiments, R ¹⁵ is H. In some embodiments, R ¹⁵ is -CH3. In some embodiments, R ¹⁵ is -CH ₂ CH ₃ . In some embodiments, R ¹⁵ is -CH2CH2CH3.

In some embodiments, a compound of the present invention is selected from

- 30 045366

- 31 045366

- 32 045366

In some embodiments, a compound of the present invention is selected from

Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium or D atom, in which n represents the number of hydrogen atoms in a molecule. As is known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may enhance metabolic stability and, therefore, may be suitable for increasing the half-life of the compounds described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, when administered to a mammal. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized using methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

In some embodiments, a compound of the present invention contains one to six deuterium atoms ( ^2H or D). In some embodiments, one of R ² , R ³ , R ⁴ , R ⁵ , or R ⁶ contains one to six D. In some embodiments, R ⁶ contains one to six D. In some embodiments, R ⁶ is CD ₃ .

Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein are also provided. Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms and other materials that are suitable for use in the preparation of a pharmaceutical composition suitable for pharmaceutical use in animals or humans. Pharmaceutically acceptable salts or physiologically acceptable salts include, for example, inorganic acid salts and organic acid salts. In addition, when the compounds described herein are prepared as an acid addition salt, the free base can be prepared by making the acid salt solution alkaline. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic techniques that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

The solvate is formed by the interaction of a solvent and a compound. Also provided are solvates of salts of the compounds described herein. Hydrates of the compounds described herein are also provided.

A prodrug is a biologically inactive derivative of a drug that, when introduced into the human body, is converted into the biologically active parent drug.

- 33 045366 herbal agent according to certain chemical or enzymatic pathways.

Some embodiments provide optical isomers, racemates, or other mixtures of the compounds described herein, or pharmaceutically acceptable salts or mixtures thereof. In these situations, the single enantiomer or diastereomer, that is, the optically active form, can be obtained by asymmetric synthesis or resolution of the racemate. The separation of racemates can be carried out, for example, by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, chiral high pressure liquid chromatography (HPLC). In addition, Z- and E-forms (or cis- and trans-forms) of the hydroxyamidine compounds described herein are also provided. In particular, the Z- and E-forms are included even though only one designation is given for both carbon-carbon double bonds as well as the hydroxyamidine bond.

Where chirality is not specified but is present, it is understood that such embodiment refers either to a particular diastereomeric or enantiomerically enriched form; or to a racemic or scalemic mixture of such compound(s).

Enantiomers are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. A mixture of enantiomers in a ratio other than 1:1 is a scalemic mixture.

Diastereoisomers are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of each other.

Atropisomers are stereoisomers resulting from hindered rotation around a single bond, where the hindrance to rotation around said bond is strong enough to permit isolation of individual stereoisomers.

Some embodiments provide atropisomers of the compounds described herein or pharmaceutically acceptable salts thereof.

Compositions provided herein that include a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or individual diastereomers or diastereomeric mixtures. All such isomeric forms of said compounds are expressly included herein in the same manner as if each isomeric form had been specifically and individually identified.

Specific embodiments also provide chelates, non-covalent complexes, and mixtures thereof of the compounds described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof. A chelate is formed by coordinating a compound with a metal ion at two (or more) points. A non-covalent complex is formed by the interaction of a compound and another molecule, where no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also called ionic bonds).

Therapeutic uses of the compounds

The methods described herein can be applied to cell populations in vivo or ex vivo. In vivo means in a living individual, that is, in an animal or a human being. In this context, the methods described herein can be used therapeutically in an individual. Ex vivo means outside the living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from individuals. Such samples can be prepared by methods well known in the art. Examples of body fluid samples include blood, cerebrospinal fluid, urine, and saliva. Examples of tissue samples include tumors and tumor biopsies. In this context, the present invention can be used for various purposes, including therapeutic and experimental purposes. For example, the present invention can be used ex vivo to determine the optimal regimen and/or dosage for administration of an α4β7 integrin inhibitor for a given target, cell type, individual, and other parameters. Information obtained from such use can be used for experimental purposes or in the clinic to establish protocols for in vivo treatment. Other ex vivo applications for which the present invention may be suitable are described below or will be apparent to those skilled in the art. Selected compounds may be further characterized to study safety or dosage tolerance in humans or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

In some embodiments, compounds described herein, for example, compounds of formula (I), (II), (IIa), (IIb), (IIe), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or deuterated analogue thereof can be used for the treatment of subjects who have or are suspected of having diseases, disorders or conditions (also collectively referred to as indications) that meet or 34 045366 will presumably respond to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit excessive or destructive immune responses or the growth or proliferation of a cell, such as a cancer cell, or to inhibit immunosuppression.

In some embodiments, compounds described herein, for example, compounds of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf) or a pharmaceutically acceptable salt, stereoisomer, the mixture of stereoisomers, tautomer or deuterated analogue can be used to treat subjects who have or are suspected of having diseases, disorders or conditions (also collectively referred to as indications) that respond or are expected to respond to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit excessive or destructive immune responses or the growth or proliferation of a cell, such as a cancer cell, or to inhibit immunosuppression.

Methods

In some embodiments, the present invention provides a compound described herein suitable for use as an α4β7 integrin inhibitor. In some embodiments, the present invention provides a method of treating an inflammatory disease or condition, comprising administering a compound described herein.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein and at least one additional therapeutic agent and at least one pharmaceutically acceptable excipient.

The present invention provides a compound described herein for use in therapy.

In another embodiment, the present invention provides a compound described herein for use in the preparation of a medicament for treating a disease or condition described herein.

In some embodiments, a compound described herein is provided that is suitable for treating a disease or condition in a patient that is treatable by inhibiting α4β7 integrin. Diseases or conditions that can be treated with the compounds described herein include solid tumor, diabetes, inflammatory disease, graft-versus-host disease, primary sclerosing cholangitis, HIV, autoimmune disease, inflammatory bowel disease (IBD), alcoholic hepatitis, systemic lupus erythematosus (SLE) and lupus nephritis.

In some embodiments, a compound described herein is provided that is suitable for treating an inflammatory disease or condition in a patient that is mediated, at least in part, by α4β7 integrin.

Administration refers to the delivery of one or more therapeutic agents to a patient. In some embodiments, said administration is a monotherapy, wherein the compound described herein is the only active ingredient administered to the patient in need of therapy. In another embodiment of the invention, the administration is co-administration such that two or more therapeutic agents are delivered together during a course of treatment. In some embodiments, two or more therapeutic agents may be formulated together in a single dosage form or combination dosage unit, or formulated separately and subsequently combined into a combination dosage unit, as is typically the case for intravenous or oral administration as a mono- or dual-layer tablets or capsules.

In some embodiments, a compound described herein is administered to a human patient in need thereof in an effective amount, for example, from about 0.1 to about 1000 mg per dose of the compound. In some embodiments, the effective amount is from about 0.1 to about 400 mg per dose. In some embodiments, the effective amount is from about 0.1 to about 300 mg per dose. In some embodiments, the effective amount is from about 0.1 to about 200 mg per dose. In some embodiments, the effective amount is from about 1 to about 100 mg per dose. In other embodiments, the effective amount is about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18

- 35045366 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg or about 300 mg per dose.

In some embodiments, a compound described herein and at least one additional therapeutic agent are administered to a human patient in need thereof, an effective amount of each agent independently ranging from about 0.1 to about 1000 mg per dose of the compound or composition per dose per compound. In some embodiments, the effective amount for combination treatment of a compound described herein and an additional compound, independently, is from about 0.1 to about 200 mg per compound per dose. In some embodiments, the effective amount for combination treatment of a compound described herein and an additional compound is independently from about 1 mg to about 100 mg per compound per dose. In other embodiments, the effective amount for combination treatment of a compound described herein and an additional compound is for each component about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg , about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 200, or about 500 mg of each per dose.

In some embodiments, a dose of a compound described herein and/or a combination of a dose of a compound described herein and/or a dose of an additional therapeutic agent is administered once daily, twice daily, or three times daily. In yet another embodiment, a dose of a compound described herein and/or a dose of an additional therapeutic agent is administered as a loading dose of about 0.1 to about 1000 mg per compound on the first day and every day or on alternate days, or weekly on for up to a month, followed by a regular schedule of administration of a compound described herein and/or one or more additional therapeutic agents or therapies. The maintenance dose may be from about 0.1 to about 1000 mg once daily, twice daily, three times daily, or weekly for each component of a multidrug regimen. A qualified caregiver or prescriber will be aware of which dosing regimen is best for a particular patient or medical condition and will make appropriate decisions about the treatment regimen for that patient. Thus, in another embodiment, a skilled healthcare professional may tailor the dosage regimen of a compound described herein and/or additional therapeutic agent(s) described herein to the specific needs of a patient. Thus, it should be understood that the dose amount of a compound described herein and the amount of additional therapeutic agent dose actually administered will generally be determined by the physician in light of the relevant circumstances, including the condition(s) being treated, the route of administration chosen, the actual compound (eg, salt or free base) and its relative potency, the age, body weight and response of the individual patient, the severity of the patient's symptoms, and the like.

Co-administration may also include administration of component drugs, for example, one or more of the compounds described herein and one or more additional (eg, second, third, fourth or fifth) therapeutic agents. Such a combination of one or more compounds described herein and one or more additional therapeutic agents may be administered simultaneously or sequentially (one after the other) for a reasonable period of time of each administration (for example, from about 1 minute to 24 hours) depending on the pharmacokinetic and/or pharmacodynamic properties of each agent or combination. Co-administration may also include fixed combination exposure, in which the agents of the treatment regimen may be combined in a fixed dose or combination dosage medium, eg, solid, liquid or aerosol. In some embodiments, a kit for administering a drug or drug components may be used.

Thus, some embodiments of the present invention provide a method of treating a disease or condition mediated, at least in part, by α4β7 integrin, comprising administering therapeutically effective amounts of formulations of one or more compounds described herein and one or more additional therapeutic agents, including, for example, using a kit for a patient in need. It should be understood that a qualified healthcare professional will administer or direct the administration of a therapeutically effective amount of any compound(s) or combinations of compounds of the present invention.

Intravenous administration is the administration of substances directly into a vein or intravenously. Compared to other routes of administration, the intravenous (IV) route is a faster way to deliver fluids and medications throughout the body. An infusion pump can allow precise control of the flow rate and total amount of drug delivered. However, in cases where changing the flow rate will not have a major effect or where pumps are not available, the IV is often left to flow by simply placing the bag above the patient's level and using a clamp to control the speed. As an alternative, a rapid infuser can be used if the patient requires a high flow rate and the IV device is large enough in diameter to accommodate it. This is either an inflatable cuff placed around a fluid bag to force fluid into the patient, or a similar electrical device that can also heat the fluid being infused. When a patient only needs medications at certain times, an intermittent infusion is used, which does not require additional fluid. This can be done using the same methods as for an IV (pump or gravity drip), but after the full dose of medication has been administered, the tubing is disconnected from the IV device. Some medications are also given by intravenous injection or bolus injection, which means a syringe is attached to an IV device and the medication is injected directly (slowly if doing so may irritate the vein or cause the effect to occur too quickly). Once the drug is introduced into the fluid stream in the IV tubing, it must be ensured that it flows from the tubing to the patient. This is usually achieved by ensuring normal fluid flow and thus transferring the drug into the bloodstream; however, a second injection of liquid is sometimes used as a post-injection wash to get the drug into the bloodstream more quickly. Thus, in some embodiments, a compound(s) or combination of compounds described herein can be administered by intravenous administration alone or in combination with the administration of certain components of a treatment regimen by oral or parenteral routes.

Oral administration is a route of administration in which a substance is administered through the mouth, and includes buccal, sublabial and sublingual administration, as well as enteral and respiratory administration, unless it is administered, for example, through tubes so that the drug is not present in direct contact with any of the mucous membranes of the oral cavity. A typical form for oral administration of therapeutic agents includes the use of tablets or capsules. Thus, in some embodiments, a compound(s) or combination of compounds described herein may be administered orally, alone or in combination with certain components of a treatment regimen via the IV or parenteral route.

Pharmaceutical compounds

The compounds described herein can be administered in a pharmaceutical formulation. The pharmaceutical formulations/compositions provided by the present invention contain, in addition to the carrier, a compound described herein or a combination of compounds described herein, optionally in combination with an additional therapeutic agent.

Pharmaceutical formulations/compositions provided by the present invention may also be intended for administration by injection and include aqueous solutions, oily suspensions, emulsions (with sesame oil, corn oil, cottonseed oil or peanut oil), as well as elixirs, mannitol, dextrose or sterile aqueous solution and similar pharmaceutical carriers. Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerin, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Proper fluidity can be maintained, for example, by a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and/or by surfactants. Prevention of the action of microorganisms can be achieved by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.

Sterile injection solutions are prepared by incorporating the component compound(s) in the required quantity in a suitable diluent with various other ingredients listed above or as required, followed by filter sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the necessary other ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization methods, which produce a powder of the active ingredient(s), as well as any additional desired ingredient, from its previously sterilized filtered solution.

In the manufacture of pharmaceutical compositions that contain a compound described herein in combination with an additional agent/therapy suitable for the purpose, or a pharmaceutically acceptable salt thereof, the active ingredient is usually diluted with an excipient and/or enclosed or mixed with such a carrier that can be in the form of a capsule, sachet, paper or other container. In the case where the excipient serves as a diluent, it may be a solid, semi-solid or liquid material (as described above) that acts

- 37 045366 as a filler, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid form), ointments containing, for example, more than 20% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The compositions may further include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavors.

The compositions of the present invention can be formulated to provide rapid, sustained or sustained release of the active ingredient following administration to a patient using procedures known in the art. In some embodiments, sustained release formulations are used. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or polymer matrix formulations containing the drug.

In some embodiments, the compositions are preferably formulated in a unit dosage form. The term dosage unit or combination dosage unit refers to physically discrete units that are suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of one or more active materials (e.g., a compound described herein, optionally in combination with an additional therapeutic agent calculated to produce the desired effect, in combination with a suitable pharmaceutical excipient, for example, in a tablet, capsule, ampoule or vial for injection. It should be understood, however, that the amount of each active agent actually administered is usually determined by the physician in in the light of relevant circumstances, including the condition being treated, the chosen route of administration, the specific compounds administered and their relative potency, the age, body weight and response of the particular patient, the severity of the patient's symptoms, and the like.

To prepare solid compositions such as tablets, the main active ingredient(s) can be mixed with a pharmaceutical excipient to form a solid composition before being formulated into a dosage form containing a homogeneous mixture of the compound of the present invention. Where these compositions are referred to as homogeneous before dosage forming, it is intended that the active ingredient(s) may be uniformly distributed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms, such as tablets, pills and capsules.

Tablets or pills containing a compound of the present invention described herein, optionally in combination with a second agent, may be coated or otherwise formulated into a dosage form providing the benefit of long-acting or protection against acidic conditions of the stomach. For example, a tablet or pill may comprise an inner dosage element and an outer dosage element, the latter being encased above the former. In some embodiments, the inner dosage element may contain a compound described herein and the outer dosage element may contain a second or additional therapeutic agent, or vice versa. Alternatively, the combination dosage unit may be configured in an adjacent manner, as in a capsule or tablet, where one part or half of the tablet or capsule is filled with a compound composition described herein, while the other part or half of the tablet or capsule contains additional therapeutic agent.

Various materials can be used for such enteric layers or coatings, such as a number of polymer acids and mixtures of polymer acids with substances such as shellac, cetyl alcohol and cellulose acetate. One skilled in the art will know the techniques and materials used to prepare the dosages of the compositions described herein.

A sustained release formulation or extended release formulation is a formulation designed to slowly release a therapeutic agent into the body over an extended period of time, whereas an immediate release formulation is a formulation designed to rapidly release a therapeutic agent into the body over a shortened period of time. . In some cases, the immediate release formulation may be coated such that the therapeutic agent is released only after reaching the desired target in the body (eg, the stomach). One skilled in the art is capable of developing the sustained release formulations described herein.

- 38,045,366 connections without unnecessary experiments. Thus, in some embodiments, a compound(s) or combination of compounds described herein may be administered via sustained release formulations alone or in combination with the administration of certain components of a treatment regimen via the oral, intravenous, or parenteral route.

The lyophilized formulation can also be used to administer a compound described herein, alone or in combination with an additional therapeutic agent. One skilled in the art will know how to prepare and use lyophilized drug formulations suitable for lyophilization.

The spray-dried formulation can also be used to administer a compound described herein, alone or in combination with an additional therapeutic agent. One skilled in the art will know how to make and use spray-dried drug formulations suitable for spray drying. Other known methods for preparing the compounds may also be used to prepare the compound or combination of compounds described herein.

The compounds disclosed herein are suitable for the treatment of diseases or conditions mediated, at least in part, by α4β7 integrin. Non-limiting examples of diseases or conditions mediated at least in part by α4β7 integrin include, but are not limited to, acne, acid-induced lung injury, Addison's disease, adrenal hyperplasia, adrenal insufficiency, adult-onset Still's disease, respiratory distress syndrome adults (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergies, allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angiourotic edema, angiofibroma, anhydrotic ectodermic dysplasia -ill, a disease of the membrane with an antigenantic complex, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascitis, ascitis, ascitis, ascitis, ascite pergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrinopathies, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid diseases, autoimmune inflammatory diseases, pain in back, bacillary anthracite infection, Bechet's disease, bee sting inflammation, Behçet's syndrome, Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP), asthma, burns, bursitis, cardiac hypertrophy, digital tunnel syndrome , Castleman's disease, catabolic diseases, cataracts, celiac disease, cerebral aneurysm, inflammation caused by a chemical irritant, chorioretinitis, cholestasis, chronic atypical neutrophilic dermatosis with lipodystrophy and fever (CANDLE syndrome), chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, organ transplant complications, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulcer, disease Crohn's, cryopyrin-related periodic syndromes, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of interleukin-1 receptor antagonist (DIRA), dermatitis, endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermos bullosa, erythema multiforme, erythroblastemia, esophagitis, familial polyamyloid neuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth restriction, fibromyalgia, fistolizing Crohn's disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glom regular disease, glomerular nephritis, glomerulonephritis, plant protein enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, bile duct disease, bile duct disease, bile duct disease, diffuse toxic goiter, growth plate injury, Guillain's syndrome -Barre, bowel disease, hair loss, Hashimoto's thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic arthropathy, Henoch's Schonlein disease, hepatitis, hereditary periodic fever syndrome, hereditary connective tissue disorders, herpes zoster and herpes simplex, hidradenitis suppurativa (HS), hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane syndrome, hyperactive inflammatory response, hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with relapsing fever (HIDS), hypersensitivity pneumonitis , formation of hypertropic bones, hypoplastic and others

- 39 045366 anemia, hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathy, immune complex nephritis, immune thrombocytopenic purpura y (ITP), pigment incontinence syndrome (IP, Bloch-Siemens syndrome), infectious mononucleosis, infectious diseases, including viral diseases such as AIDS (HIV infection), hepatitis A, B, C, D and E, herpes; inflammation, inflammation of the central nervous system, inflammatory bowel disease (IBD), inflammatory disease of the lower respiratory tract, including bronchitis or chronic obstructive pulmonary disease, inflammatory disease of the upper respiratory tract, including the nose and sinuses, such as rhinitis or sinusitis, inflammatory disease of the respiratory tract, inflammatory ischemic an event such as stroke or cardiac arrest, inflammatory lung disease, inflammatory myopathy such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, interstitial cystitis, interstitial lung disease, iritis, inflammation caused by irritation, ischemia/reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney damage caused by parasitic infections, kidney transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, deafness, amyloidosis), mucositis, multiple organ involvement syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis, neonatal multisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, asthma, caused by non-allergens, obesity, allergic eye diseases, optic neuritis, organ transplant rejection, Osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, congenital pachyonychia, Paget's disease, Paget's disease of bone, pancreatitis, Parkinson's disease , pediatric rheumatology, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), whooping cough, PFAPA (periodic fever, aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritants, Pneumocystis pneumonia, pneumonia, pneumonitis, inflammation caused by poison ivy/urushiol oil, polyarthritis, polychondria, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis, pouchitis ileitis , reperfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress diseases, lung diseases, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum , pyogenic granuloma, retrolental fibroplasia, pyogenic sterile arthritis, Raynaud's syndrome, Raynaud's syndrome, Reiter's syndrome, reactive arthritis, kidney disease, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal disease, retrolental fibroplasia, Raynaud's syndrome, rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler's syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sickle cell anemia, disease caused by silicon dioxide (silicosis), Sjogren's syndrome, skin diseases, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathy, sports injuries, sprains and sprains, syndrome Stevens-Johnson (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mastocytosis (SMCD), systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendinitis , tenosinovitis, thrombocytopenia, thyroiditis, thyroiditis, tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, periodic syndrome (TRAPS), tumor necrosis factor receptor (TNF) associated, type 1 diabetes, diabetes Type 2, complications from type 1 or 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis and Wippel's disease.

In additional embodiments, methods are provided for alleviating a symptom of a disease or disorder mediated at least in part by α4β7 integrin. In some embodiments, the methods include identifying a mammal having a symptom of a disease or disorder mediated at least in part by α4β7 integrin,

- 40 045366 and providing the specified mammal with an amount of a compound described herein effective to improve (ie, reduce the severity of) the symptom.

In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is an inflammatory disease or LPS-induced endotoxin shock. In some embodiments, the disease is an autoimmune disease. In specific embodiments, the disease or condition is selected from systemic lupus erythematosus (SLE), myesthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis , Sjogren's syndrome, autoimmune hemolytic anemia, asthma or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, reactive arthritis, single-joint arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile rheumatoid arthritis with systemic onset, juvenile rheumatoid arthritis, gouty arthritis or psoriatic arthritis arthritis. In other embodiments, the disease is inflammation. In other embodiments, the disease is an excessive or destructive immune response, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is inflammatory bowel disease (IBD). As used herein, the term inflammatory bowel disease or IBD is a general term describing inflammatory diseases of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated with the compounds, compositions and methods described herein include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudosembrane colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet's disease, gastroduodenal Crohn's disease, nausea, ileitis, ileocolitis, Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcers, diverticulitis, pouchitis ileitis, proctitis and chronic diarrhea.

Treatment or prevention of IBD also includes improving or reducing one or more IBD symptoms. As used herein, the term IBD symptoms refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite and other more serious complications such as dehydration, anemia and exhaustion. A number of such symptoms can be analyzed quantitatively (eg, weight loss, fever, anemia, etc.). Some symptoms are easily determined by a blood test (such as anemia) or a test that detects the presence of blood (such as rectal bleeding). The term wherein said symptoms are reduced refers to a qualitative or quantitative reduction in detectable symptoms, including, but not limited to, a detectable effect on the rate of recovery from illness (eg, rate of weight gain). Diagnosis is usually determined by endoscopic observation of the mucosa and pathological examination of endoscopic biopsy specimens.

The course of IBD varies and is often associated with periods of intermittent remission and exacerbation of the disease. Various methods have been described to characterize disease activity and severity of IBD, as well as response to treatment in patients with IBD. Treatment in accordance with the present methods is generally applicable to a subject having IBD of any level or degree of disease activity.

In some embodiments, the disease or condition treated by administration of a compound and composition described herein includes acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, bone cancer pain and pain due to endometriosis, BRAF-resistant melanoma, brain glioma or pituitary adenoma, burns, bursitis, anal cancer, endocrine cancer, kidney or ureter cancer (eg, renal cell carcinoma and renal pelvis carcinoma), penile cancer, small intestinal cancer, thyroid cancer, urethral cancer, blood cancers such as acute myeloid leukemia, tongue cancers, cervical carcinoma, endometrial carcinoma, fallopian tube carcinoma, renal pelvis carcinoma, carcinoma vaginal or vulvar carcinoma, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classic Bartter's syndrome, cold conjunctivitis, coronary heart disease, cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infections, gout, gynecological tumors, uterine sarcoma, fallopian tube carcinoma, headache, hemophilic arthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin's disease, Huntington's syndrome, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile rheumatoid arthritis with systemic onset, juvenile rheumatoid arthritis, low back and neck pain, lymphocytic lymphomas, myofascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory diseases, neuropathic pain, vulvar carcinoma, Parkinson's disease, childhood tumor, pulmonary fibrosis, rectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, solid tumors in children, spinal axis tumors, dislocations and sprains, stomach cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, surgical or dental procedures, symptoms associated with influenza or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcomas, uveitis, vasculitis, viral infections, viral infections (eg, influenza) and wound healing.

Criteria suitable for assessing disease activity in patients with ulcerative colitis can be found, for example, in Truelove et al. (1955) Br Med J 2:1041–1048. Using these criteria, disease activity can be characterized in a subject having IBD as moderate disease activity or severe disease activity. Subjects who do not meet all criteria for severe disease activity and who exceed the criteria for moderate disease activity are classified as having moderate disease activity.

The treatments described herein can also be applied at any time during the course of the disease. In some embodiments, the methods are applied to a subject having IBD during a period of remission (ie, inactive disease). In such embodiments, the present methods provide the benefit of prolonging the time period of remission (eg, prolonging the period of inactive disease) or preventing, reducing, or delaying the onset of active disease. In other embodiments, the methods may be applied to a subject having IBD during a period of active disease. Such methods provide the benefit of shortening the duration of active disease, reducing or improving one or more symptoms of IBD, or treating IBD.

Measures to determine the effectiveness of IBD treatment in clinical practice have been described and include, for example, the following: symptom control; closure of the fistula; the required degree of corticosteroid therapy; and improving quality of life. Health-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess quality of life in a subject with IBD. . (See Guyatt et al. (1989) Gastroenterology 96:804-810.) In some embodiments, the disease or condition is an immune-mediated liver injury, disease or condition.

In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is alcoholic hepatitis. Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver failure that develops in patients with chronic and active alcohol abuse. (See Akriviadis E et al., Ann Gastroenterol. Apr-Jun 2016; 29(2): 236-237). Alcoholic hepatitis can cause cirrhosis and fibrosis of liver cells. Glucocorticoids (eg, prednisolone) and phosphodiesterase inhibitors (eg, pentoxifylline) may be used to treat alcoholic hepatitis. The compounds provided herein may be used as stand-alone treatments or in combination with existing treatments for alcoholic hepatitis.

In one aspect, the present invention provides methods for treating or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. this document.

In some embodiments, the disease or condition mediated at least in part by the α4β7 integrin is systemic lupus erythematosus (SLE), lupus nephritis, lupus or other autoimmune disorder, or a symptom of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth ulcers, swollen lymph nodes, sensitivity to sunlight, skin rash, headaches, numbness, tingling, seizures, vision problems, personality changes , abdominal pain, nausea, vomiting, abnormal heart rhythms, hemoptysis and difficulty breathing, uneven skin color and Raynaud's phenomenon.

Combination therapy

Also provided are methods of treatment in which a patient is administered a compound described herein in combination with one or more additional active agents or therapy.

Thus, in some embodiments of the invention, a method of treating diseases or

- 42 045366 conditions mediated, at least in part, by α4β7 integrin and/or diseases or symptoms that accompany or are aggravated or initiated by diseases or conditions mediated, at least in part, by α4β7 integrin, for example an allergic disorder and/or an autoimmune and/ or an inflammatory disease and/or an acute inflammatory response, involves administering to a patient in need thereof an effective amount of a compound described herein, optionally in combination with an additional agent (eg, a second, third, fourth or fifth active agent) that may be useful for the treatment of diseases or conditions mediated at least in part by α4β7 integrin, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory response occurring or concomitant with diseases or conditions mediated at least in part , α4β7 integrin. Treatment with a second, third, fourth or fifth active agent may be administered before, simultaneously with, or after treatment with a compound described herein. In some embodiments, a compound described herein is combined with another active agent in a single dosage form. Suitable therapeutic agents that may be used in combination with a compound described herein include, but are not limited to, the therapeutic agents provided herein or a combination containing at least one therapeutic agent provided herein.

Provided herein are methods of treatment in which a compound described herein is administered in combination with an agent for treating an inflammatory disease or condition. Examples of agents for treating an inflammatory disease or condition that may be used in combination with the compounds described herein include alpha-fetoprotein modulators; adenosine A3 receptor antagonist; adrenomedullin ligands; AKT1 gene inhibitors; antibiotics; antifungal drugs; ASK1 inhibitors; ATPase inhibitors; beta-adrenergic receptor antagonists; BTK inhibitors; calcineurin inhibitors; modulators of carbohydrate metabolism; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists; CXC chemokine ligand inhibitors; CHST15 gene inhibitors; collagen modulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics; eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; F10 ATP synthase modulators; agonists or modulators of farnesoid X receptors (FXR and NHR14); fecal microbiota transplantation (FMT); fractalin ligand inhibitors; free fatty acid receptor 2 antagonists; GATA 3 transcription factor inhibitors; glucagon-like peptide 2 agonists; glucocorticoid agonists; glucocorticoid receptor modulators; guanylate cyclase receptor agonists; HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLA class II antigen modulators; hypoxia-inducible factor-1 stimulator; ICAM1 gene inhibitors; IL-1 beta ligand antagonists; IL-12 antagonists; IL-13 antagonists; IL-18 antagonists; IL-22 agonists; IL-23 antagonists; IL-23A inhibitors; IL-6 antagonists; IL-7 receptor antagonists; IL-8 receptor antagonists; alpha4/beta-1 integrin antagonists; alpha-4/beta-7 integrin antagonists; integrin antagonists; interleukin ligand inhibitors; interleukin 17A receptor antagonists; interleukin-1-beta ligands; interleukin-1-like receptor 2 inhibitors; IL-6 receptor modulators; JAK tyrosine kinase inhibitors; Jak1 tyrosine kinase inhibitors; Jak3 tyrosine kinase inhibitors; lactoferrin stimulants; LanC-like protein 2 modulators; leukocyte elastate inhibitors; leukocyte proteinase 3 inhibitors; MAdCAM inhibitors; melanin-concentrating hormone antagonist (MCH-1); melanocortin agonists; metalloprotease inhibitors 9; microbiome-targeted therapeutics; natriuretic peptide receptor C agonists; neuregulin-4 ligands; NLPR3 inhibitors; NKG2 D antagonists that activate the NK receptor; nuclear factor kappa B inhibitors; opioid receptor antagonists; OX40 ligand inhibitors; oxidoreductase inhibitors; P2X7 purinoceptor inhibitors; PDE 4 inhibitors; Pellino homologue 1 inhibitors; alpha/delta PPAR agonists; PPAR gamma agonists; fimH protein inhibitors; P-selective glycoprotein ligand-1 inhibitors; Ret tyrosine kinase receptor inhibitors; RIP-1 kinase inhibitors; RIP-2 kinase inhibitors; RNA polymerase inhibitors; sphingosine-1-phosphate phosphatase 1 stimulators; sphingosine 1phosphate receptor-1 agonists; sphingosine-1-phosphate receptor-5 agonists; sphingosine-1phosphate receptor-1 antagonists; sphingosine 1-phosphate receptor-1 modulators; stem cell antigen-1 inhibitors; superoxide dismutase modulators; SYK inhibitors; tissue transglutaminase inhibitor; TLR-3 antagonists; TLR-4 antagonists; Toll-like receptor 8 (TLR8) inhibitors; TLR-9 agonists;

TNF alpha ligand inhibitors; TNF ligand inhibitors; TNF alpha ligand modulators; TNF antagonists; TPL-2 inhibitors; tumor necrosis factor ligand modulators 14; tumor necrosis factor ligand inhibitors 15; Tyk2 tyrosine kinase inhibitors; IL-1 receptor type I antagonists; vanilloid VR1 agonists; and zonulin inhibitors and combinations thereof.

- 43 045366

Adenosine A3 receptor antagonists include PBF-677. Adrenomedullin ligands include adrenomedullin.

Antibiotics include ciprofloxacin, clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, and tosufloxacin.

ASK1 inhibitors include GS-4997.

Alpha-fetoprotein modulators include ACT-101.

Anti-CD28 inhibitors include JNJ-3133 and abatacept.

Beta-adrenergic antagonists include NM-001.

BTK inhibitors include GS-4059.

Calcineurin inhibitors: include tacrolimus and cyclosporine.

Modulators of carbohydrate metabolism include ASD-003.

Cathepsin S inhibitors include VBY-129.

CCR9 chemokine antagonists include CCX-507.

CD233 modulators include GSK-2831781.

CD29 modulators include PF-06687234.

CD3 antagonists include NI-0401.

CD4 antagonists include IT-1208.

CD40 ligand inhibitors include SAR-441344 and letolizumab.

CD40 gene inhibitors include NJA-730.

CD40 ligand receptor antagonists include FFP-104, BI-655064.

The chaperonin-binding immunoglobulin protein includes IRL-201805.

CXC chemokine ligand inhibitors include LY-3041658.

Inhibitors of the CHST15 gene include STNM-01.

Collagen modulators include ECCS-50 (DCCT-10).

COT protein kinase inhibitors include GS-4875.

CSF-1 antagonists include JNJ-40346527 (PRV-6527) and SNDX-6352.

CX3CR1 chemokine modulators include E-6130.

Ecobiotics include SER-287.

Eotaxin ligand inhibitors include bertilimumab.

EP4 prostanoid receptor agonists include KAG-308.

F1F0 ATP synthase modulators include LYC-30937 EC.

Fractalkine ligand inhibitors include ketmolimab (E-6011).

Free fatty acid receptor 2 antagonists include GLPG-0974.

GATA 3 transcription factor inhibitors include SB-012.

Glucagon-like peptide 2 agonists include teduglutide and apraglutide.

Glucocorticoid receptor agonists include budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate.

Glucocorticoid receptor modulators/TNF ligand inhibitors include ABBV-3373.

Guanylate cyclase receptor agonists include dolcanatide.

HIF prolyl hydroxylase inhibitors include DS-1093 and AKB-4924.

HIF prolyl hydroxylase-2 inhibitors/hypoxia-inducible factor-1 stimulators include GB-004.

Histone deacetylase inhibitors include givinostat.

Histone deacetylase-6 inhibitors include CKD-506.

HLA class II antigen modulators include HLA class II protein modulators.

Inhibitors of the ICAM1 gene include alicaforsen.

IL-12 antagonists include ustekinumab (IL12/IL23).

IL-13 antagonists include tralokinumab.

IL-18 antagonists include GSK-1070806.

IL-22 antagonists include RG-7880.

IL-23 antagonists include tildrakizumab, rizankizumab (BI-655066), mirikizumab (LY3074828), brazicumab (AMG-139) and PTG-200.

IL-23A inhibitors include guselkumab.

IL-6 antagonists include olokizumab.

IL-7 receptor antagonists include OSE-127.

IL-8 receptor antagonists include clotrimazole.

Alpha-4/beta-1 integrin antagonists include natalizumab.

Alpha-4/beta-7 integrin antagonists include etrolizumab (a4b7/aEb7), vedolizumab, carotegast methyl, TRK-170 (a4b7/a4b1), PN-10943, and PTG-100.

Integrin antagonists include E-6007.

Interleukin ligand inhibitors include bimekizumab (IL-17A/IL-17F).

Interleukin 17A receptor antagonists include brodalumab.

- 44 045366

Interleukin-1 beta ligands include K(D)PT.

Interleukin-1-like receptor 2 inhibitors include BI-655130.

IL-6 receptor modulators include olamkicept.

JAK tyrosine kinase inhibitors include tofacitinib (1/3), peficitinib (1/3), TD-3504, TD1473. Jak1 tyrosine kinase inhibitors include the compound described in WO2008/109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib ( SB1518) , peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tazocitinib), XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555, SHR0302 and brepocitinib (PF-06700841) (JAK1/Tyk2).

Jak3 tyrosine kinase inhibitors include PF-06651600.

Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

LanC-like protein 2 modulators include BT-11.

Leukocyte elastase inhibitors/leukocyte proteinase-3 inhibitors include tiprelestat.

MAdCAM inhibitors include SHP-647 (PF-547659).

Melanin-concentrating hormone (MCH-1) antagonists include CSTI-100.

Melanocortin MC1 receptor agonists include ASP-3291 and PL-8177. Metalloprotease-9 inhibitors include GS-5745.

Microbiome modulators include ABI-M201.

Natriuretic peptide receptor C agonists include plecanatide.

Neurogulin-4 ligands include NRG-4.

NK receptor antagonists that activate NKG2 D include JNJ-4500.

NLPR3 inhibitors include dapansutril, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

Farnesoid X receptor (FXR and NR1H4) agonists or modulators include AGN-242266, cilofexor tromethamine (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, nidufexor (LMB-763), obeticholic acid , TERN-101 and tropifexor.

Nuclear factor kappa B inhibitors include Tetanix.

Opioid receptor antagonists include naltrexone and IRT-103.

OX40 ligand inhibitors include KHK-4083.

Oxidoreductase inhibitors include olsalazine.

Pellino homologue 1 inhibitors include BBT-401.

Purinoceptor modulators of P2X7 include SGM-1019.

PDE 4 inhibitors include apremilast.

Alpha/delta PPAR agonists include elafbranor (GFT-1007).

PPAR gamma agonists include GED-0507-34-Levo.

Inhibitors of the fimH protein include sibofimlok (EB-8018).

P-selectin glycoprotein ligand-1 inhibitors include SEL-K2, AbGn-168H, and neyhulizumab.

Ret receptor tyrosine kinase inhibitors include GSK-3179106.

RIP-1 tyrosine kinase inhibitors include GSK-2982772.

RIP-2 tyrosine kinase inhibitors include GSK-2983559.

Sphingosine phosphatase 1 stimulants include etrasimod.

Sphingosine-1-phosphate receptor-1 agonists include ozanimod, mokravimod (KRP-203) and BMS-986166.

Sphingosine-1-phosphate receptor-1 agonists/sphingosine-1-phosphate receptor-5 agonists include ozanimod.

Sphingosine 1-phosphate receptor-1 antagonists include amiselimod (MT-1303).

Sphingosine 1-phosphate receptor-1 modulators include OPL-002.

Stem cell antigen-1 inhibitors include Ampion (DMI-9523).

Superoxide dismutase modulators include midismase.

Syk inhibitors include GS-9876.

Tissue transglutaminase inhibitors include zampilimab.

TLR-3 antagonists include PRV-300.

TLR-4 antagonists include JKB-122.

Toll-like receptor 8 (TLR8) inhibitors include E-6887, IMO-4200, IMO-8400, IMO9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463 and VTX-763.

TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod, lithenimod, MGN1601 and PUL-042.

TNF alpha ligand inhibitors include adalimumab, certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

- 45 045366

TNF antagonists include AVX-470, tulinercept, and etanercept.

TPL-2 inhibitors include GS-4875.

Tumor necrosis factor ligand 14 modulators include AEVI-002.

Tumor necrosis factor ligand 15 inhibitors include PF-06480605.

Tyk2 tyrosine kinase inhibitors include PF-06826647 and BMS-986165.

The TrkA receptor antagonist includes SNA-125.

IL-1 receptor type I antagonists include anakinra.

Zonulin inhibitors include larazotide acetate.

Provided herein are methods of treatment in which a compound described herein is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2-specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) receptor antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and hydroxychloroquine. Examples of NSAIDs also include specific COX-2 inhibitors (i.e., a compound that inhibits COX-2 with an IC ₅₀ that is at least 50 times lower than the IC ₅₀ of COX-1), such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate and prednisone.

In some embodiments, the anti-inflammatory therapeutic agent is a gold compound, such as sodium aurothiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, such as methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist such as entanercept, or infliximab, which is an anti-TNF-alpha monoclonal antibody.

Provided herein are methods of treatment in which a compound described herein is administered in combination with an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

Provided herein are methods of treatment in which a compound described herein is administered in combination with a class of agent for the treatment of IBD. Examples of classes of agents for the treatment of IBD that may be used in combination with a compound described herein include ASK1 inhibitors, beta-adrenergic receptor antagonists, BTK inhibitors, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, CXC chemokine ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythrocyte receptor agonists tropoetin, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA transcription factor 3 inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLA class II antigen modulators, IL-12 antagonists, IL-13 antagonists, IL antagonists -23, IL-6 antagonists, IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, alpha-4/beta-1 integrin antagonists, alpha-4/beta-7 integrin antagonists, alpha-E integrin antagonists, integrin antagonists, beta-7 integrin antagonists, interleukin ligand inhibitors, interleukin-2 ligand, interleukin-17A receptor antagonists, interleukin-1 beta ligands, interleukin-1 beta ligand modulators, IRAK4 inhibitors, tyrosine kinase inhibitors JAK, Jak1 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC-like protein 2 modulators, lipoxygenase modulators, MAdCAM inhibitors, matrix metalloprotease inhibitors, melanocortin agonists, metalloprotease-9 inhibitors, natriuretic peptide receptor C agonists, neuregulin-4 ligands, NK-activating receptor antagonists NKG2 D, opioid receptor antagonists, delta opioid receptor antagonists, oxidoreductase inhibitors, P2X7 purinoceptor agonists, PDE 4 inhibitors, peptide modulators stimulating phagocytosis, potassium inhibitors

- 46 045366 channels, alpha-PPAR agonists, delta-PPAR agonists, gamma-PPAR agonists, fimH protein inhibitors, P-selective glycoprotein ligand-1 inhibitors, RNA polymerase inhibitors, sphingosine-1-phosphate phosphatase 1 stimulators, sphingosine-1 modulators 1-phosphate phosphatase, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors, inhibitors stem cell antigen-1, superoxide dismutase modulators, superoxide dismutase stimulators, SYK inhibitors, TGF ligand beta-1 inhibitors, thymulin agonists, TLR antagonists, TLR agonists, TNF alpha ligand inhibitors, TNF antagonists, tumor necrosis factor ligand 14 modulators, TNF receptor modulators Type II, Tpl 2 inhibitors and zonulin inhibitors.

Provided herein are methods of treatment in which a compound described herein is administered in combination with an agent for the treatment of IBD. Examples of agents for the treatment of IBD that can be used in combination with a compound described herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or deuterated analogue include the agents provided herein for the treatment of an inflammatory disease or condition, and ABX -464, adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alekel; AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, VVT-401, balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; cibinetids; Clostridium butyricum; ETX-201, golimumab; GS-4997, GS-9876, GS-4875, GS-4059, infliximab; mesalazine, HLD-400, LYC30937; ECNIS-JIO1-2.5x, JRJR43-6500, JN447, naltrexone; natalizumab; neyhulizumab, olsalazine; PH46-A, propionyl-L-carnitine; PTG-100; remestemcell-L; tacrolimus; teduglutide; tofacitinib; ASP1002; ustekinumab; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605; PF-06651600; PF06687234; RBX-8225, SER-287; Tetanix; TOP-1288; VBY-129; 99tTc-annexin V-128; bertilimumab; DLX-105; dolcanatide; FFP-104; filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG-0974; Iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase; olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660, RG-7835; JKB122; SB-012; STNM-01; Debio-0512; TRK-170; zucapsaicin; AVT-494; Ampion; BI-655066; karotegastmethyl; cobitolimod; elafbranor; etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; pefikitinib; ketmolimab (E-6011); RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide; vidofludimus and AZD-058.

Provided herein are methods of treatment in which a compound described herein is administered in combination with an agent for treating graft-versus-host disease. Examples of agents for the treatment of graft-versus-host disease that can be used in combination with a compound described herein include agents provided herein for the treatment of an inflammatory disease or condition, and [18F]F-AraG, AM-01, a stimulant antitrypsin alpha 1: AAT-IV and CSL-964; Allocetra, efavaleukin alfa (AMG-592), arsenic trioxide, ATIR-101, belatacept, belimumab, beta-lactamase modulator: ribaxamase, bortezomib, brentuximab vedotin, brimonidine, brimonidine tartrate, canabidiol, cyclosporine, CYP-001, um, dilanubicel, dornase alfa, DSM-9843, eculizumab, EDP-1066, everolimus, furestem, GL-101, ibrutinib, IMSUT-CORD, IRX-4204, itolizumab, KD-025, MaaT-013, milatuzumab, mizoribine, mycophenolate mofetil, MSCTC- 0010, nalotimagen carmaleucel, MET-2, nilotinib, narsoplimab (OMS-721), pacritinib, PF-05285401, ProTmune, QPI-1002, remestemcel-L, RGI-2001, saratin, SCM-CGH, simrolus, T-allo10, telmisartan, TOP-1288, TZ-101, voclosporin; CCR5 chemokine antagonist: leronimab (PRO-140); CD40 ligand receptor antagonist: isqlimab; sub-component complement inhibitor C1s: CE-1145, sutimlimab, Cinryze, BIVV-009; CD20 B-lymphocyte antigen inhibitor: obinutuzumab, rituximab; CASP9 gene stimulator: rivogenlecleucel; CD3 antagonist or CD7 inhibitor: T-Guard; complement factor C5a inhibitor: olendalizumab; dipeptidyl peptidase IV inhibitor: begelomab; JAK1/2 tyrosine kinase inhibitor: ruxolitinib; Jak1 tyrosine kinase inhibitor: itacitinib; interleukin-2 ligand: aldesleukin; interleukin-22 ligand: F-652; IL-2 receptor alpha subunit inhibitor: basiliximab and inolimomab; IL-6 receptor agonist: PLX-1; IL-6 receptor antagonist: clazakizumab; OX40 ligand inhibitor: KY-1005; An example of such an OX40 inhibitor is the compound described in US Pat. No. 8,450,460, the entire contents of which are incorporated herein by reference; CD24 signal converter modulator: CD24-lgFc; somatostatin receptor agonist: Thymoglobulin and sphingosine-1-phosphate receptor-1 agonist: ponesimod.

Provided herein are methods of treatment in which a compound described herein is administered in combination with an agent for the treatment of primary sclerosing cholangitis. Examples of agents for the treatment of primary sclerosing cholangitis that can be used in combination with the compounds described herein include the agents provided herein for the treatment of an inflammatory disease or condition, and BTT-1023, CM101, Doconexent, GRI-0124, HTD -1801, HTD-2802, hymecromone, IDN-7314, NGM-282, norursodeoxycholic acid, ORBCEL-C, alpha-V/beta-1 integrin and beta-6 antagonist: PLN-74809; deltaPPAR agonist: seladelparlysine; SCT-5-27, PtGs2 gene and TGF beta-1 gene inhibitor: SCT-5-27 and STP-705; 47 045366 agonists or modulators of the farnesoid X receptor (FXR, NR1H4): AGN-242266, cilofexor tromethamine (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, nidufexor (LMB-763 ), obeticholic acid,

TERN-101, tropifexor; liver X receptor antagonist: DUR-928; and chemokine antagonist

CCR5/CCR2: cenicriviroc.

In some embodiments, one or more additional therapeutic agents is selected from the group consisting of: combination drugs for the treatment of HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors , HIV integrase inhibitors, HIV non-catalytic (or allosteric) site integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds that target the HIV capsid, immune therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans-isomerase A modulators, protein disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators , Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein-1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, dendritic ICAM-3 inhibitors, non-integrin capture 1, HIV GAG protein inhibitors, HIV POL protein inhibitors, modulators complement factor H, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, DDX3X ATP-dependent RNA helicase inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing or any combinations thereof.

In some embodiments, one or more additional therapeutic agents is selected from the group consisting of compounds that inhibit HIV protease, non-nucleoside HIV reverse transcriptase inhibitors, non-nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs for the treatment of HIV, or a pharmaceutically acceptable salt of any of the foregoing agents or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents is an immunomodulatory agent, such as an immunostimulant or an immunosuppressant. In certain other embodiments, the immunomodulatory agent is an agent capable of altering the function of immune checkpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and/or PD pathways. 1. In other embodiments, the immunomodulatory agent is immune checkpoint modulatory agents. Examples of immune checkpoint modulating agents include anti-CTLA-4 (eg, ipilimumab), anti-LAG-3, anti-B7-H3, anti-B7-H4, anti-Tim3, anti-BTLA, anti-KIR, A2aR, anti-CD200, anti-PD-1, anti-PD-L1, anti-CD28, anti-CD80 or -CD86, anti-B7RP1, anti-B7-H3, anti-HVEM, anti-CD137 or CD137L, anti anti-OX40 or -OX40L, anti-CD40 or -CD40L, anti-GAL9, anti-IL-10 and A2aR drug. For some of these immune pathway gene products, the use of antagonists or agonists of such gene products, as well as small molecule modulators of such gene products, is contemplated. In some embodiments, immunomodulatory agents include agents capable of altering the function of mediators in cytokine-mediated signaling pathways.

In some embodiments, a compound described herein (e.g., a compound described herein may be combined with one or more (e.g., one, two, three, four, one or two, one-three, or one-four) additional therapeutic agents at any dose level of a compound described herein (eg, from 10 mg to 1000 mg of a compound).

A compound described herein may be combined with the agents provided herein at any dosage level of the compound (eg, 50 to 500 mg of compound) in the same manner as if each dosage combination were specifically and separately stated.

In some embodiments, kits are provided containing a pharmaceutical composition comprising a compound described herein or a compound described herein and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable salt thereof. acceptable medium. Some embodiments provide kits containing a compound described herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analogue thereof in combination with one or more (e.g., one, two, three, four, one or two, or one - three or one to four) additional therapeutic agents. Any pharmaceutical composition provided herein may be used in kits in the same manner as if each composition were specifically and separately identified for use in the kit. In some embodiments, the kit contains instructions for use for treating an inflammatory disease or condition. In some embodiments, the instructions in the kit are directed to the use of a pharmaceutical composition for the treatment of IBD.

List of abbreviations and abbreviations % - Percent °C - Degree Celsius

Ac - Acetyl

AcOH - Acetic acid

ACN/CH ₃ CN/MeCN - Acetonitrile

ADME - Absorption, distribution, metabolism and excretion

AIBN - 2,2'-azobis(2-methylproprionitrile) aq. - Water

ASK - Apoptotic signal-regulating kinase

Bicarb. - Bicarbonate

W - Benzyl

BOC/Boc - Tert-butyloxycarbonyl

Bpin - Pinacolboran br - widened

CAS - Chemical Abstract Service cataCXium A - Di(1-adamantyl)-n-butylphosphine

CNS - Central nervous system

COPD - Chronic obstructive pulmonary disease

CREST - Calcinosis, Raynaud's syndrome, esophageal dyskinesia, sclerodactyly and telangiectasia CVP - Cyclophosphamide, vincristine, prednisone d - Doublet

D/d - Deuterium

DAST - Diethylaminosulfur trifluoride

DABCO® - 1,4-diazabicyclo[2.2.2]octane

DCC - N,N'-dicyclohexylcarbodiimide

DCE - Dichloroethane

DCM - Dichloromethane/methylene chloride dd - Doublet

DIEA - N-diisopropylethylamine

DIPEA - N-diisopropylethylamine

DMA - N,N-dimethylacetamide

DMAP - 4-dimethylaminopyridine

DME - Dimethoxyethane

DMF - Dimethylformamide

DMPK - Drug Metabolism and Pharmacokinetics

DMSO - Dimethyl sulfoxide

DPPA - Diphenylphosphoryl azide dppf - 1,1-bis(diphenylphosphino)ferrocene dppp - 1,3-bis(diphenylphosphino)propane

EC ₅₀ - Half-maximum effective concentration equiv./equiv. - Equivalents

EA - Ethyl acetate

Et - Ethyl

Et ₂ O - Diethyl ether

EtOAc/AcOEt - Ethyl acetate

EtOH - Ethanol

F - Fahrenheit

FBS - Fetal bovine serum g - grams

Gp - Glycoprotein h/h - clock

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HATU - (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate) hex - Hexanes

HPLC - High Pressure Liquid Chromatography

Hz - Hertz

IL - Interleukin

IUPAC - International Union of Pure and Applied Chemistry J - Interaction Constant (MHz) JAK - Janus Kinase Kg/kg - Kilogram KOAc - Potassium Acetate L - Liter LCMS/LC-MS - Liquid Chromatography-Mass Spectroscopy LHMDS - Lithium Hexamethyldisilazide

LiMg-TMP - Complex of lithium chloride and 2,2,6,6-tetramethylpiperidinylmagnesium chloride M - Molar m - Multiplet M+ - Mass peak

M+H - Mass peak plus hydrogen m-CPBA - Metachloroperbenzoic acid Me - Methyl

Me ₂ N - Dimethylamine Mel - Methyl iodide MeOH - Methanol

MeOTs - Methyl tosylate mg - Milligram MHz - Megahertz min/m - Minute ml - Milliliter mM - Millimolar mmol - Millimol mol - Mole

MS - Mass spectroscopy PC - Multiple sclerosis MsCl - Methanesulfonyl chloride MTBE - Methyl tert-butyl ether M/Z - Mass/charge H - Normal

NADH - Nicotinamide adenine dinucleotide phosphate, reduced NaOH - Sodium hydroxide NBS - N-bromosuccinimide ng - Nanogram NIS - N-iodosuccinimide nM - Nanomole

NMR - Nuclear magnetic resonance overnight Overnight PEG - Polyethylene glycol

PET - Positron emission tomography Ph - Phenyl PhMe - Toluene PhNO ₂ - Nitrobenzene

PhNTf ₂ - N-phenyltriflamide pH - Expression of the acidity or basicity of a solution of a prep - Preparative

RA - Rheumatoid arthritis Rf - Retention factor RPM - RPM CT/ct - Room temperature RuPhos - 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s Second(s) s - Singlet us. - Rich

SFC - Supercritical fluid chromatography SLE - Systemic lupus erythematosus

- 50 045366

SPECT - Single Photon Emission Computed Tomography

SPhos Pd G3 - methanesulfonate (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'biphenyl)]palladium(11)

SYK - Spleen tyrosine kinase t - Triplet

TBACI - Tetrabutylammonium chloride

TBS/TBDMS - Tert-butyldimethylsilyl

2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium

TBTU - tetrafluoroborate tBuOH - Tert-butanol tBuBrettPhos Pd G3 - methanesulfonate [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'triisopropyl-1,1'-biphenyl)-2-( 2'-amino-1,1'-biphenyl)]palladium(P)

TCA - Trichloroacetic acid

TEA/IB1 ₃ - Triethylamine temp. - Temperature

TES - Triethylsilane

TFA - Trifluoroacetic acid

TFAA - Trifluoroacetic anhydride

THF - Tetrahydrofuran

TLC - Thin Layer Chromatography

TMP - Tetramethylpiperidine

TMS - Trimethylsilyl

Tol - Toluene

TPL2 - Tumor progression locus kinase 2

Trityl - Triphenylmethyl

Vac. - Vacuum w/v - Weight/volume w/w - Weight/mass

XPhos Pd G3 - methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-[2-(2'amino-1,1-biphenyl)]palladium(P) ddd - Chemical shift (ppm) µg - Microgram µl - Microliter µM - Micromolar µm - Micrometer µmol - Micromolar

Synthesis

The compounds of the present invention can be prepared using the methods described herein and standard modifications thereof, which will be apparent from the present description and methods well known in the art. Traditional and known synthesis methods can be used in addition to those described herein. Synthesis of exemplary compounds of formula (I), for example, compounds having structures described by one or more formulas (I) or other formulas or compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or deuterated analogue can be carried out as described in the following examples.

Salts, such as TFA salts, can be converted to free base/acid salts or other pharmaceutically acceptable salts.

General schemes

Exemplary embodiments of the compounds of the present invention can be synthesized using the general reaction schemes and/or examples described below. From the above description it will be understood that the general schemes can be modified by replacing the starting materials with other substances having similar structures, obtaining products that will be correspondingly different. Descriptions of syntheses are provided to provide numerous examples of how the starting materials can be modified to provide the corresponding products. The starting materials are usually obtained from commercial sources or synthesized using published methods for the synthesis of compounds that are embodiments according to the present description, control of the structure of the synthesized compound will ensure the identity of each group of substituents. The identity of the final product will generally be determined to correspond to the identity of the required starting materials through a simple control process, taking into account the examples given herein.

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General scheme 1

Scheme 1 describes a general route that has been used to prepare certain compounds of formula (I). From intermediate AA1, having a hydroxyl or halogen group in the form Z and a halogen group in the form X, amino acid esters (AA2) can be prepared under a variety of conditions (for example, according to Scholkopf, Maruoka, etc.). After suitable protection of the free amine with protecting groups (PG), eg Trityl, Boc, etc., AA2 was converted to boric acid or boronic ester (AA3) under standard conditions (eg Miyaura). R ¹ was introduced under a variety of conditions to cross-couple to produce AA4. After removal of the amine protecting group (PG) under suitable conditions, the said amine was combined with acids to obtain heterocyclic compounds AA5.

General scheme 2

Scheme 2 describes a general route that has been used to prepare certain compounds of formula (I). From Intermediate BB1, which has a halogen group as Z, amino acid esters (BB2) can be prepared under a variety of conditions (mainly Negishi). After suitable deprotection (eg benzyloxycarbonyl, CBZ), BB2 was converted to the free amine (BB3) under standard conditions (eg Pd/ _H2 ). R ¹ was introduced under a variety of conditions to form urea with suitable carboxylic acid or amines to produce BB4. After removal of the amine protecting group (PG) under suitable conditions, the amine was combined with carboxylic acids or acid chlorides to produce heterocyclic compounds BB5.

Examples

Example 1.

Synthesis of 8-bromo-5-methylquinoline (1A):

Glycerol (1180 g, 6.45 mol) was added to a stirred solution of 2-bromo-5-methylaniline (1200 g, 6.45 mol) in nitrobenzene (660 ml) and 75% H ₂ SO ₄ (3.6 L) at RT and then slowly heated to 150°C for 3 hours. The mixture was cooled to RT and poured into ice water while maintaining the temperature below 10°C. The pH was adjusted to ~10 using aqueous 10 N. NaOH and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the material, which was dissolved in DCM/hexanes (5:1) and stirred for 30 minutes. The solid was filtered off and the filtrate was evaporated

- 52 045366 under reduced pressure to obtain 1A.

Synthesis of 8-bromo-5-(bromomethyl)quinoline (1B):

To a stirred solution of compound 1A (500 g, 2.25 mol) in benzene (7.5 L) was added NBS (481 g, 2.7 mol) at RT. The reaction mixture was heated to 80°C under incandescent lamp illumination for 12 hours. The reaction mixture was cooled to RT, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The specified substance was triturated with 20% ethyl acetate in hexane at RT. This material was filtered, washed with hexane and dried under reduced pressure to obtain 1B.

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (1C): To a stirred solution of 1B (392 g, 1.3 mol) in DCM (9 L ) (-)-cinchonidine (35 g, 0.12 mol) was added at RT. The reaction mixture was cooled to 10°C, KOH (2.4 L, 50% aq.) and then methyl 2((diphenylmethylene)amino)acetate (300 g, 1.2 mol) were added. The reaction mixture was left to stir at RT for 6 hours. The reaction mixture was diluted with water and stirred for 15 minutes. DCM was added and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The material was purified by 100-200 mesh silica gel column chromatography and eluted with 10-15% ethyl acetate in hexane to give compound 1C.

Synthesis of methyl (S)-2-amino-3-(8-bromoquinolin-5-yl)propanoate (1D): To a stirred solution of 1C (400 g, 845 mmol) in methanol (2 L) was added HCl at 1.4 -dioxane (2.8 L, 4 N) while maintaining the temperature below 5°C. The reaction mixture was left to stir at RT for 48 hours. The reaction mixture was concentrated under reduced pressure, dissolved in water and washed with ethyl acetate. The aqueous layer was brought to ~pH 8 using sat. NaHCO ₃ and extracted by adding DCM. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a 70:30 mixture of racemic 1D. A suspension of the material in MTBE was heated to boiling for 1 hour. The reaction mixture was cooled to RT, the solid was filtered, and the filtrate was evaporated under reduced pressure to obtain a solid, which was then stirred with MTBE at RT. The solid was filtered off and the filtrate was evaporated under reduced pressure to obtain 1D. The specified substance was dissolved in ethyl acetate, cooled to 0°C, and then 4 N was added. HCl and left to stir at RT for 1 hour. The reaction mixture was concentrated under reduced pressure and triturated with MTBE to give 1D.

Synthesis of methyl-(S)-2-amino-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoate (1E):

1D (50 mg, 0.145 mmol), (2-chloro-4cyanophenyl)boronic acid (45 mg, 0.246 mmol), Pd(PPh ₃ ) ₄ (8 mg, 0.007 mmol) and aq. were added to a microwave reactor vial. Na ₂ CO ₃ (0.217

- 53 045366 ml, 2M) in DME (2 ml). The reaction mixture was left to stir at 120°C for 20 minutes. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-30% MeOH in EA to give the title compound.

Synthesis of methyl (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methylbenzamido)propanoate (1F):

To a stirred solution of 1E (29 mg, 0.08 mmol) in THF (2 ml) was added 2-fluoro-6methylbenzoyl chloride (21 mg, 0.12 mmol) and DIEA (0.07 ml, 0.4 mmol). The reaction mixture was left to stir for 1 hour, then diluted with DCM and concentrated. The title compound was purified on silica gel eluting with MeOH in DCM (0-30%) to give the title compound.

Synthesis of (8)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methylbenzamido)propanoic acid (1):

To a stirred solution of 1F (35 mg, 0.07 mmol) in THF (3 mL) was added aqueous LiOH (0.35 mL, 0.035 mmol). The reaction mixture was left to stir for 1 hour, then concentrated under reduced pressure. The title compound was purified by reverse phase HPLC to give the title compound. MS (m/z) 488.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (d, J=8.4 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8 .64 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H) , 7.68 - 7.60 (m, 3H), 7.55 (d, J=7.9 Hz, 1H), 7.26 (d, J=6.1 Hz, 1H), 6.99 ( d, J=6.7 Hz, 2H), 4.82 (t, J=9.9 Hz, 1H), 3.39 (d, J=12.9 Hz, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 2.07 (s, 1H), 1.96 (s, 3H).

Example 2.

Synthesis of (8)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-chloro-6-fluorobenzamido)propanoic acid (2): The title compound was prepared according to the method presented to synthesize compounds 1F and 1, starting with 2-chloro-6-fluorobenzoyl chloride and 1E. MS (m/z) 508.1 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=8.3 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H), 8.65 (dd, J=8.6, 1.7 Hz, 1H), 8.16 (dd, J=1.7, 0.4 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.68-7.60 (m, 3H), 7.54 (d, J=7.9 Hz, 1H), 7.42 (td, J=8.3, 6.1 Hz, 1H ), 7.30-7.19 (m, 2H), 4.82 (s, 1H), 3.77 (d, J=14.7 Hz, 1H), 3.38 (dd, J=14, 6, 10.6 Hz, 1H).

Example 3.

Synthesis of methyl (8)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3A):

The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 2,6-difluorobenzoyl chloride and 1D.

Synthesis of methyl-(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3B):

The title compound was prepared according to the method presented for the synthesis of compound 1E, starting with 3A.

1D FOR

ZV 3

Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (3):

The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 3B. MS (m/z) 492.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 (d, J=8.1 Hz, 1H), 8.84 (dd,

- 54 045366

J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.8, 1.7 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.90 (dd, J=8.0, 1.7 Hz, 1H), 7.66-7.61 (m, 3H), 7.57 (d, J=7.9 Hz, 1H), 7 .53-7.41 (m, 1H), 7.10 (t, J=8.0 Hz, 2H), 4.77 (s, 1H), 3.76 (s, 1H), 3.41 ( s,

1H).

Example 4.

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (4A):

The title compound was prepared according to the method presented for the synthesis of compound 3A, starting with 2,6-dichlorobenzoyl chloride and 1D.

Synthesis of (S)-(5-(2-(2,6-dichlorobenzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acid (4B): To stirred solution 4A (0.61 g, 1 .4 mmol) in dioxane, bis(pinacolato)diboron (0.42 g, 1.6 mmol) was added and then KOAc (0.4 g, 4.1 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.03 mmol) and cataCXium A (0.04 g, 0.08 mmol). The reaction vessel was purged with nitrogen, then heated to 100°C for 4 hours. EA was added, then filtered through Celite and concentrated under reduced pressure to give the title compound, which was used without further purification.

Synthesis of methyl (8)-3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (4C):

To a stirred solution of 4B (0.08 g, 0.017 mmol) in DME was added 4-bromo-3,5dichlorobenzonitrile (0.08 g, 0.034 mmol), XPhos Pd G3 (0.014 g, 0.0017 mmol) and aq. K ₃ PO ₄ (0.6 ml, 1 M). The reaction mixture was degassed with nitrogen and heated at 90°C for 30 min. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used without further purification.

Synthesis of (S)-3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (4):

The title compound was prepared according to the method presented for the synthesis of compound 1 starting at 4C. MS (m/z) 558.0 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (d, J=8.4 Hz, 1H), 8.82 (dd, J=4.2, 1.6 Hz, 1H), 8 .65 (dd, J=8.7, 1.6 Hz, 1H), 8.25-8.15 (m, 2H), 7.74-7.62 (m, 2H), 7.60 (d , J=7.3 Hz, 1H), 7.457.32 (m, 3H), 4.83 (ddd, J=11.8, 8.6, 3.7 Hz, 1H), 3.78 (dd, J=14.5, 3.8 Hz, 1H), 3.38 (dd, J=14.5, 11.0 Hz, 1H).

Example 5.

Synthesis of (S)-(5-(2-(2,6-difluorobenzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acid (5A):

The title compound was prepared according to the method presented for the synthesis of compound 4B from Example 4, starting with 3A.

Synthesis of methyl (8)-3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (5B): Added to microwave reactor vial 5A (145 mg, 0.234 mmol), 1-bromo-4,5dichloro-2-methoxybenzene (50 mg, 0.195 mmol), Pd(PPh ₃ ) ₄ (11 mg, 0.01 mmol) and aq. Na ₂ CO ₃ ( 0.293 ml, 2M) in DME (2 ml). The reaction mixture was left to stir at 120°C for 30 min. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the title compound.

Synthesis of (S)-3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (5):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting at 5B. MS (m/z) 530.7 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.27 (d, J=8.1 Hz, 1H), 8.86 (dd, J=4.3, 1.6 Hz, 1H), 8.73-8 .61 (m, 1H), 7.66 (dd, J=8.6, 4.3 Hz, 1H), 7.60 (q, J=7.4 Hz, 2H), 7.52-7, 43 (m, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.16-7.05 (m, 2H), 4.78-4.70 (m, 1H), 3 .74 (dd, J=14.5, 4.4 Hz, 1H), 3.64 (s, 3H), 3.39 (dd, J=14.6, 10.1 Hz, 1H), 1, 05 (s, 1H).

- 55 045366

Example 6.

Synthesis of 2-bromo-5-fluoro-1-methoxy-3-(trifluoromethyl)benzene (6A): To a stirred solution of 2-bromo-5-fluoro-3-(trifluoromethyl)phenol (0.21 g, 0.64 mmol) in DMF was added with K ₂ CO ₃ (133 mg, 0.96 mmol) and iodomethane (0.105 g, 0.74 mmol). The reaction mixture was left to stir at RT. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure and purified by silica gel chromatography using hexanes/EA as a gradient.

Synthesis of methyl (28)-2-(2,6-difluorobenzamido)-3-(8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoate (6B): Title the compound was prepared according to the method presented for the synthesis of compound 5B, starting with 5A and 6A.

Synthesis of (28)-2-(2,6-difluorobenzamido)-3-(8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5yl)propanoic acid (6):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting with 6B. MC (m/z) 549.1 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (dd, J=12.4, 8.1 Hz, 1H), 8.81 (dd, J=4.2, 1.6 Hz, 1H ), 8.67 (d, J=8.7 Hz, 1H), 7.67-7.56 (m, 2H), 7.49 (dqd, J=8.2, 6.6, 1.6 Hz, 2H), 7.41-7.34 (m, 1H), 7.29 (dd, J=9.1, 2.5 Hz, 1H), 7.11 (ddd, J=8.3, 7.4, 3.8 Hz, 2H), 4.84-4.75 (m, 1H), 3.76 (dd, J=31.6, 4.3 Hz, 1H), 3.59 (d , J=5.7 Hz, 3H), 3.42 (ddd, J=21.3, 14.6, 10.4 Hz, 1H).

Examples 7 and 8.

Preparation of (S)-2-(2,6-difluorobenzαamido)-3-((R)-8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoic acid (7 ): 6 was separated into its 2 diastereomeric atropoisomers by supercritical liquid chromatography using 25% EtOH/TFA co-solvent, at a flow rate of 50 ml/min, using an AD-H 5 µm 21x250 mm column. The title compound was detected as the first eluting peak. MS (m/z) 549.1 [M+H]+.

1H NMR (400 MHz, methanol-d ₄ ) δ 9.36 (dd, J=8.7, 1.6 Hz, 1H), 8.95 (dd, J=5.0, 1.5 Hz, 1H ), 8.00 (dd, J=8.7, 5.0 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.78 (dd, J=7.4, 0.9 Hz, 1H), 7.45 (tt, J=8.4, 6.4 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.02- 6.95 (m,2H), 5.12 (dd, J=9.8, 5.2 Hz, 1H), 4.03 (dd, J=14.4, 5.2 Hz, 1H), 3 .71 -3.63 (m, 4H).

Preparation of (S)-2-(2,6-difluorobenzamido)-3-((S)-8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoic acid (8 ): 6 was separated into its 2 diastereomeric atropoisomers using

- 56 045366 supercritical liquid chromatography using 25% EtOH/TFA co-solvent, at a flow rate of 50 ml/min, using an AD-H 5 µm 21x250 mm column. The title compound was detected as the second eluting peak. MS (m/z) 549.1 [M+H] ⁺ .

1H NMR (400 MHz, methanol-d4) δ 9.35 (dd, J=8.7, 1.5 Hz, 1H), 8.95 (dd, J=5.0, 1.5 Hz, 1H) , 7.99 (dd, J=8.6, 5.0 Hz, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.45 (tt, J=8.6, 6.4 Hz, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 7.03-6.96 (m , 2H), 5.14 (dd, J=9.9, 5.0 Hz, 1H), 4.04 (dd, J=14.6, 5.1 Hz, 1H), 3.69-3, 61 (m, 4H).

Example 9.

Synthesis of methyl (S)-2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalene-2-yl)quinolin-5-yl)propanoate (9A):

The title compound was prepared according to the method presented for the synthesis of compound 5B, starting with 2-bromo-3-methoxynaphthalene and 5A.

Synthesis of (8)-2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalene-2-yl)quinolin-5-yl)propane acid (9):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting with 9A. MS (m/z) 513.0 [M+H] ⁺ . 1H NMR (400 MHz, DMSO^) δ 9.30 (d, J=8.2 Hz, 1H), 8.86 (d, J=4.8 Hz, 2H), 7.95-7.83 ( m, 2H), 7.81-7.64 (m, 3H), 7.55-7.43 (m, 3H), 7.38 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 7.17-7.08 (m, 2H), 4.80 (ddd, J=10.1, 8.1, 4.4 Hz, 1H), 3.80 (dd, J= 14.6, 4.5 Hz, 1H), 3.71 (s, 3H), 3.45 (dd, J=14.6, 10.1

Hz, 1H).

Example 10.

Synthesis of 1-bromo-2-(cyclopropylmethoxy)-4,5-difluorobenzene (10A):

To a stirred solution of 2-bromo-4,5-difluorophenol (1.2 g, 5.5 mmol) in MeCN was added K ₂ CO ₃ (2.3 g, 16.4 mmol) and (bromomethyl)cyclopropane (0.82 g, 6.0 mmol). The reaction mixture was left to stir for 2 hours at 70°C. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel chromatography using hexanes/EA as a gradient.

Synthesis of methyl (8)-3-(8-(2-(cyclopropylmethoxy)-4,5-difluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (10B):

The title compound was prepared according to the method presented for the synthesis of compound 5B, starting with 10A and 5A.

Synthesis of (8)-3-(8-(2-(cyclopropylmethoxy)-4,5-difluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (10):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting at 10B. MS (m/z) 538.6 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.81(s, 1H), 9.28 (d, J=8.1 Hz, 1H), 8.89 (d, J=4.1 Hz, 1H), 8.69 (s, 2H), 7.66 (d, J=7.3 Hz, 2H), 7.60 (d, J=7.4 Hz, 1H), 7.55-7, 45 (m, 1H), 7.37-7.21 (m, 2H), 7.16-7.08 (m, 2H), 4.76 (td, J=10.3, 9.2, 4 ,2 Hz, 1H), 3.78-3.74 (m, 2H), 3.41 (dd, J=14.6, 10.0 Hz,

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1H), 3.10 (p, J=4.8 Hz, 2H), 0.81 (d, J=4.8 Hz, 1H), 0.24 (dt, J=9.0, 2.9 Hz, 2H), -0.01 --0.05 (m, 2H).

Example 11.

Synthesis of methyl (S)-2-(2,6-difluorobenzamido)-3-(8-(3,5,6-trimethylpyridin-2-yl)quinolin-5-yl)propanoate (11A):

The title compound was prepared according to the method presented for the synthesis of compound 4C from Example 4, starting with 2-bromo-3,5,6-trimethylpyridine and 5A.

XPhos Pd G3

NON.THF

Synthesis of (8)-2-(2,6-difluorobenzamido)-3-(8-(3,5,6-trimethylpyridin-2-yl)quinolin-5-yl)propanoic acid (11):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting with 11A. MS (m/z) 476.2 [M+H]+. ¹ H NMR (400 MHz, DMSOC) δ 9.33 (d, J=8.3 Hz, 1H), 8.89 (dd, J=4.2, 1.6 Hz, 1H), 8.78- 8.72 (m, 1H), 8.36 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.78-7.69 (m, 2H), 7.49 (tt, J=8.5, 6.6 Hz, 1H), 7.11 (dd, J=8.4, 7.6 Hz, 2H), 4.84-4.74 (m, 1H), 3.85 (dd, J=14.3, 4.2 Hz, 1H), 3.43 (dd, J=14.4, 10.4 Hz, 1H), 2.64 (s, 3H), 2 .46 (s, 3H), 2.05 (s, 3H).

Example 12.

XPhos Pd G4

CF.

TsONDGF

Synthesis of methyl (8)-2-(2,6-difluorobenzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate (12A) :

The title compound was prepared according to the method presented for the synthesis of compound 4C from Example 4, starting with 2-bromo-5,6-dimethyl-3-(trifluoromethyl)pyridine and 5A with Pd XPhos G4.

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5yl)propanoic acid (12):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting with 12A. MS (m/z) 530.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (d, J=8.1 Hz, 1H), 8.77 (dd, J=4.1, 1.6 Hz, 1H), 8, 62 (dd, J=8.7, 1.6 Hz, 1H), 8.02 (s, 1H), 7.62-7.54 (m, 3H), 7.52-7.43 (m, 1H), 7.11 (dd, J=8.5, 7.5 Hz, 2H), 4.74 (td, J=9.0, 4.3 Hz, 1H), 3.75 (m, 1H ), 3.40 (m, 1H), 2.50 (s, 3H), 2.41 (s, 3H).

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Example 13.

Synthesis of methyl (S)-2-(2,6-difluorobenzamido)-3-(8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3yl)quinolin-5-yl)propanoate (13A):

The title compound was prepared according to the method presented for the synthesis of compound 4C from Example 4, starting with 3-bromo-4-methoxy-1-methylpyridin-2(1H)-one and 5A.

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propane acids (13):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting at 13A. MS (m/z) 464.1 [M+H]+. ¹ H NMR (400 MHz, DMSO-d^ δ 9.32 (d, J=7.9 Hz, 1H), 9.08-8.98 (m, 1H), 8.96 (d, J=4 .6 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.91-7.83 (m, 1H), 7.75-7.65 (m, 2H), 7 .50 (tt, J=8.4, 6.5 Hz, 1H), 7.16-7.08 (m, 2H), 6.49 (dd, J=7.7, 3.5 Hz, 1H ), 4.84-4.72 (m, 1H), 3.85-3.75 (m, 1H), 3.68 (d, J=7.5 Hz, 3H), 3.55-3, 40 (m, 4H).

Example 14.

XPhos Pd G3 water.KchROi

υΟΗ,ΤΓΦ

Synthesis of methyl (S)-2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinoline]-5 ^π yl)propanoate (14A ):

The title compound was prepared according to the method presented for the synthesis of compound 4C from Example 4, starting with 3-bromo-1-methylquinolin-2(1H)-one and 5A.

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8 ^π -biquinoline]-5 ^π -yl)propanoic acid (14 ):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting at 14A. MS (m/z) 514.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J=8.1 Hz, 1H), 8.88 (d, J=4.3 Hz, 1H), 8.77 (s, 1H), 7.98 (s, 1H), 7.78 (dd, J=7.8, 1.5 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 7, 70 - 7.56 (m, 3H), 7.49 (tt, J=8.4, 6.5 Hz, 1H), 7.35-7.27 (m, 1H), 7.18-7, 08 (m, 2H), 4.75 (td, J=9.5, 4.5 Hz, 1H), 3.77 (dd, J=14.5, 4.5 Hz, 1H), 3.68 (s, 3H), 3.44 (dd, J=14.5, 9.9 Hz, 1H).

Example 15.

Synthesis of methyl (S)-2-(2,6-difluorobenzamido)-3-(5'-fluoro-[8,8 ^π -biquinolin]-5-yl)propanoate (15A):

The title compound was prepared according to the method presented for the synthesis of compound 3B, starting with (5-fluoroquinolin-8-yl)boronic acid and 3A.

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-( ^5π- fluoro-[ ^8,8n -biquinolin]-5-yl)propanoic acid (15): The title compound was prepared according to the method presented for synthesis of compound 1, starting from 15A. MS (m/z) 502.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (d, J=8.1 Hz, 1H), 8.74 (dd, J=4.2, 1.8 Hz, 1H), 8 .70 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 7.77-7.43 (m, 8H), 7.19-7.05 (m, 2H), 4.79 (m, 1H), 3.77-3.65 (m, J=1H), 3.56-3.40 (m, 1H).

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Example 16.

Synthesis of methyl (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(3-(difluoromethoxy)-2,6-difluorobenzamido)propanoate (16A): To stirred to a solution of 1E (0.15 g, 0.41 mmol) in DCM was added 3(difluoromethoxy)-2,6-difluorobenzoic acid (0.11 g, 0.49 mmol), HATU (0.187 g, 0.49 mmol) and TEA (0.36 ml, 2.1 mmol). The reaction mixture was left to stir for 2 hours at RT. The reaction mixture was concentrated under reduced pressure and used without further purification.

Synthesis of (8)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(3-(difluoromethoxy)-2,6-difluorobenzamido)propanoic acid (16):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting with 16A. MS (m/z) 559.9 [M+H]+. 1H NMR (400 MHz, DMSO-d) δ 8.16 (m, J=8.4 Hz, 3H), 7.67 (d, J=8.5 Hz, 2H), 7.56-7.21 (m, 6H), 4.75 (ddd, J=11.7, 8.4, 3.7 Hz, 1H), 3.10 (m, 2H) 2.99 (dd, J=14.3, 11.3 Hz, 1H).

Example 17.

1E ₁₇

Synthesis of (8)-2-(6-chloro-2,3-difluorobenzamido)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoic acid (17):

The title compound was prepared according to the method presented for the synthesis of compounds 1F and 1, starting with 6-chloro-2,3-difluorobenzoyl chloride and 1E. MS (m/z) 559.9 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (d, J=8.4 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H), 8, 64 (dd, J=8.6, 1.6 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.91 (d, J=7.8 Hz , 1H), 7.67-7.64 (m, 1H), 7.63 (s, 2H), 7.55 (d, J=7.9 Hz, 1H), 7.33 (td, J= 8.7, 3.8 Hz, 1H), 4.83 (s, 1H), 3.84 - 3.74 (m, 1H), 3.38 (dd, J=14.6, 10.6 Hz , 1H).

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Example 18.

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (18):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid and 3A. MS (m/z) 551.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.09 (s, 1H), 9.30 (d,J=8.1 Hz, 1H), 9.10-8.69 (m, 2H), 7.96-7.30 (m, 4H), 7.11 (t, J=8.0 Hz, 2H), 6.75 (d, J=3.4 Hz, 2H), 4.85-4 .74 (m, 1H), 4.53 (s, 2H), 3.86-3.66 (m, 1H), 3.64-3.53 (m, 8H), 3.45 (dd, J =14.7, 10.1 Hz, 1H), 1.21 (t, J=7.0 Hz, 3H).

Example 19.

Synthesis of (8)-3-(8-(2,6-dichloro-4-fluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (19):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 2-bromo-1,3-dichloro-5-fluorobenzene and 5A. MS (m/z) 518.9 [M+H] ⁺ . 1H NMR (400 MHz, DMSOd6) δ 13.02 (s, 1H), 9.26 (d, J=8.1 Hz, 1H), 8.82 (dd, J=4.1, 1.6 Hz , 1H), 8.68-8.58 (m, 1H), 7.70-7.59 (m, 3H), 7.57 (d, J=7.3 Hz, 1H), 7.47 ( tt, J=8.5, 6.5 Hz, 1H), 7.15-7.03 (m, 2H), 4.78 (ddd, J=10.2, 8.1, 4.4 Hz, 1H), 3.76 (dd, J=14.5, 4.4 Hz, 1H), 3.41 (dd, J=14.6, 10.3 Hz, 1H).

Example 20.

Synthesis of (S)-3-(8-(3,5-dichloropyridin-4-yl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (20):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 4-bromo-3,5-dichloropyridine and 5A. MS (m/z) 501.9 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8, 75 (d, J=2.4 Hz, 2H), 8.66 (dd, J=8.7, 1.7 Hz, 1H), 7.697.60 (m, 3H), 7.47 (tt, J =8.5, 6.5 Hz, 1H), 7.09 (dd, J=8.4, 7.5 Hz, 2H), 4.80 (ddd, J=10.4, 8.2, 4 ,4 Hz, 1H), 3.78 (dd, J=14.5, 4.4 Hz, 1H), 3.43 (dd, J=14.6, 10.4 Hz, 1H).

Example 21.

Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-methoxybenzamido)propanoic acid (21):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 2,6-difluoro-4-methoxybenzoic acid and 1E. MS (m/z) 523.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 8.15-7.98 (m, 4H ), 7.11 (d, J=6.7 Hz, 3H), 6.82 (d, J=9.1 Hz, 2H), 6.67 (s, 2H), 4.47 (s, 2H ), 3.62 (s, 6H), 3.53 (q, J=7.0 Hz, 2H), 3.18 (dd, J=124.4, 13.3 Hz, 2H), 1.28 (s, 3H), 1.19 (t, J=7.0 Hz, 3H).

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Example 22.

Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-fluorobenzamido)propanoic acid (22):

The title compound was prepared according to the method presented for the synthesis of compounds 3A, 3B and 3, starting with 2,6-dichloro-4-fluorobenzoyl chloride and 1D. MS (m/z) 541.9 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.26 (d, J=8.5 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8.65 (dd , J=8.7, 1.7 Hz, 1H), 8.15 (dd, J=1.6, 0.4 Hz, 1H), 7.94-7.87 (m, 1H), 7, 69-7.58 (m, 3H), 7.50 (d, J=8.6 Hz, 3H), 4.84 (s, 1H), 3.76 (dd, J=14.5, 4, 1 Hz, 1H), 3.37 (s, 1H).

Example 23.

ci

OH

Β _χ ° ^H 1_UN,THF

Pd(PPh ₃ ) ₄ aq. Na ₂ CO ₃

Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methoxybenzamido)propanoic acid (23):

The title compound was prepared according to the method presented for the synthesis of compounds 1F and 1, starting with 2-fluoro-6-methoxybenzoyl chloride and 1E. MS (m/z) 504.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J=8.1 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H), 8, 64 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.68-7.64 (m, 2H), 7.58 (d, J=7.6 Hz, 1H), 7.35 (td, J=8.4, 6 .8 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.78 (t, J=8.6 Hz, 1H), 4.80-4.68 (m, 1H ), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 3.50-3.40 (m, 1H).

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Example 24.

24A 24V

24С 24

Synthesis of methyl 2,6-difluoro-4-(2-oxopropyl)benzoate (24A):

Acetone (1.8 ml), Pd(OAc) ₂ (18 mg, 0.081 mmol), Cs ₂ CO ₃ (1.05 g, 3.2 mmol) and 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (93.98 mg, 0.16 mmol). The mixture was purged with N ₂ for 5 minutes, then heated to 100°C for 2.5 hours. The reaction mixture was filtered through celite, washed with EA and purified by silica gel chromatography using EA in hexanes as eluent to give the title compound .

Synthesis of methyl 2,6-difluoro-4-(2-hydroxypropyl)benzoate (24B):

Ammonium acetate (1.04 g, 13.43 mmol) was added to a stirred solution of 24A (306.4 mg, 1.34 mmol) in MeOH. NaBH ₄ (83.81 mg, 2.22 mmol) was then added slowly to prevent excessive heat generation. The reaction mixture was stirred for 2 hours at RT and then NaOH (1M) and DCM were added. The organic layer was washed with brine, dried and concentrated under reduced pressure. The title compound was purified by silica gel chromatography using EA and hexanes as eluent to give the title compound.

Synthesis of 2,6-difluoro-4-(2-hydroxypropyl)benzoic acid (24C):

LiOH (79.56 mg, 1.9 mmol) was added to a stirred solution of 24B (87.3 mg, 0.38 mmol) in THF. The reaction mixture was stirred at RT for 3 hours, then HCl (1M) and EA were added. The organic layer was washed with brine, dried and concentrated under reduced pressure to give the title compound, which was used without further purification.

(2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(2-hydroxypropyl)benzamido)propanoic acid (24):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 1E and 24C. MS (m/z) 550.2 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (d, J=8.1 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8 .64 (dd, J=8.6, 1.6 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (d, J=7.9 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 4.80-4.69 (m, 1H), 3.80 (pd, J=8.9, 7.6, 3.0 Hz, 2H), 3.40 (s, 1H), 2.62 ( d, J=6.2 Hz, 2H), 1.02 (d, J=6.1 Hz, 3H).

Example 25.

Synthesis of tert-butyl-(S)-4-((3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-1-methoxy-1-oxopropan-2yl)carbamoyl)-3.5 -difluorobenzoate (25A):

The title compound was prepared according to the method presented for the synthesis of compound 16A, starting with 4-(tert-butoxycarbonyl)-2,6-difluorobenzoic acid and 1E.

Synthesis of (S)-4-((3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-1-methoxy-1-oxopropan-2-yl)carbamoyl)3,5-difluorobenzoic acid (25V):

TFA (1.5 mL) was added to a stirred solution of 25A (150 mg, 0.25 mmol) in DCM. The reaction mixture was stirred for 2 hours at RT, concentrated under reduced pressure and then purified by silica gel chromatography using DCM and MeOH as eluent to give the title compound.

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(S)-4-((1-carboxy-2-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)ethyl)carbamoyl)-3,5-difluorobenzoic acid (25): The title compound was prepared according to the method presented for the synthesis of compound 1, starting at 25B. MS (m/z) 535.8 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (d, J 8.2 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.95-7.86 (m, 1H), 7.64 ( t, J=4.3 Hz, 1H), 7.61 (d, J=5.1 Hz, 1H), 7.57 (dd, J=7.7, 6.0 Hz, 2H), 4, 80 (t, J=11.5 Hz, 1H), 3.79 (s, 1H), 3.41 (s, 1H).

Example 26.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylcarbamoyl)benzamido)propanoic acid (26):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 25B and aniline. MS (m/z) 611.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.41 (d, J=8.3 Hz, 1H), 8.88-8.80 (m, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7, 76-7.61 (m, 7H), 7.57 (d, J=7.9 Hz, 1H), 7.42-7.29 (m, 2H), 7.12 (t, J=7, 4 Hz, 1H), 4.81 (s, 1H), 3.76 (s, 1H), 3.25-3.17 (m, 1H).

Example 27.

Synthesis of methyl-(R)-2,6-difluoro-4-((1-phenylethyl)carbamoyl)benzoate (27A):

To a stirred solution of 3,5-difluoro-4-(methoxycarbonyl)benzoic acid (20 mg, 0.093 mmol) in DMF was added (R)-1-phenylethan-1-amine (13.46 mg, 0.11 mmol), HATU (42 mg, 0.11 mmol) and TEA (0.06 ml, 0.463 mmol). The reaction mixture was stirred for 1 hour at RT, concentrated under reduced pressure and then purified by silica gel chromatography using

- 64 045366 using DCM/MeOH as eluent.

Synthesis of (R)-2,6-difluoro-4-((1-phenylethyl)carbamoyl)benzoic acid (27B):

Aqueous LiOH (0.46 mL, 1 M) was added to a stirred solution of 27A (29.5 mg, 0.09 mmol) in THF. The mixture was left to stir at RT for 3 hours, concentrated under reduced pressure and then purified by silica gel chromatography using DCM/MeOH as eluent.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1-phenylethyl)carbamoyl)benzamido) propanoic acid (27):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 27B. MS (m/z) 639.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.35 (d, J=8.3 Hz, 1H), 8.98 (d, J=7.9 Hz, 1H), 8.84 (dd, J=4 ,1, 1.6 Hz, 1H), 8.64 (d, J=7.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (d, J =7.7 Hz, 1H), 7.66-7.53 (m, 6H), 7.32 (dt, J=15.1, 7.5 Hz, 4H), 7.21 (t, J= 7.1 Hz, 1H), 5.11 (t, J=7.3 Hz, 1H), 4.80 (s, 1H), 3.50-3.40 (m, 1H), 1.45 ( d, J=7.0 Hz, 3H).

Example 28.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((2,2,2-trifluoroethyl)carbamoyl)benzamido) propanoic acid (28):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 25B. MS (m/z) 616.9 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO) δ 9.38 (d, J=8.3 Hz, 1H), 9.29 (t, J=6.4 Hz, 1H), 8.84 (dd, J= 4.2, 1.6 Hz, 1H), 8.68-8.60 (m, 1H), 8.16 (d,J=1.6 Hz, 1H), 7.90 (d, J=8 ,1 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.62-7.58 (m, 3H), 7.57 (d, J=7.9 Hz, 1H ), 4.80 (s, 1H), 4.09 (dd, J=9.8, 6.4 Hz, 1H), 3.75-3.60 (m, 1H).

Example 29.

Synthesis of ethyl-(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-iodobenzamido)propanoate (29A):

The title compound was prepared according to the method presented for the synthesis of compound 16A, starting with 2,6-dichloro-4-iodobenzoic acid and 1E.

Synthesis of methyl-(8)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbut-1- in-1-yl)benzamido)propanoate (29B):

To a stirred solution of 29A (60 mg, 0.09 mmol) in THF was added 2-methylbut-3-yn-2-ol (0.02 mL, 0.27 mmol), CUI (3.44 mg, 0.02 mmol ), PdCl ₂ (PPh ₃ ) ₂ (12.71 mg, 0.02 mmol) and DIEA (0.08 ml, 0.45 mmol). The reaction mixture was left to stir for 1 hour at 60°C, then concentrated under reduced pressure and used without further purification.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbut-1-yn-1yl )benzamido)propanoic acid (29):

The title compound was prepared according to the method presented for the synthesis of compound 1, starting at 29B. MS (m/z) 606.0 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 9.30 (d, J=7.9 Hz, 1H), 8.83 (dd, J=4.1, 1 ,6 Hz, 1H), 8.64 (dd, J=8.6, 1.7 Hz, 1H), 8.18-8.13 (m, 1H), 7.91 (d, J=8, 2 Hz, 1H), 7.68-7.57 (m, 2H), 7.61-7.48 (m, 1H), 7.43 (s, 1H), 7.41-7.30 (m , 3H), 4.85 (s, 1H), 3.76 (dd, J=14.4, 4.2 Hz, 1H), 3.39 (t, J=12.4 Hz, 1H), 1 .43 (d, J=3.7 Hz, 6H).

- 65 045366

29A

29B 29

Example 30.

Synthesis of methylquinoline-5-carboxylate (30A):

To a stirred solution of 3-nitrobenzoic acid (244.0 g, 1.46 mol) in conc. H ₂ SO ₄ (750 ml) added glycerol (1.17 L, 15.33 mol) and 3-aminobenzoic acid (500.0 g, 3.65 mol). The resulting reaction mixture was heated to 150°C for 7 hours. The reaction mixture was then cooled to 0°C, exposed to methanol (5.0 L) and the resulting reaction mixture was heated to boiling for 12 hours. The reaction mixture was cooled to 0°C and quenched with ice water and neutralized with solid Na ₂ CO ₃ . The aqueous layer was extracted with EA (4 lx2), the organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The material was purified by column chromatography using EA/petroleum ether to give 30A.

Synthesis of 5-(methoxycarbonyl)quinoline-1-oxide (30C):

m-CPBA (604.8 g, 2.19 mol) was added to a solution of compound 30A (205.0 g, 1.095 mol) in chloroform (4.1 L) at 0°C. The resulting reaction mixture was left to warm to RT and stirred for 6 hours. The reaction mixture was cooled to 0°C and quenched with sat. NaHCO ₃ solution and extracted by adding DCM. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The compound was purified by column chromatography using 5% MeOH/DCM as eluent to give 30C.

He

ZOA CALL ZOS 30D

Br Br

ZOE 30F 30G ZON

F F

30L 30

- 66 045366

Synthesis of 5-(methoxycarbonyl)-3-nitroquinoline 1-oxide (30D):

t-BuONO (708.1 ml, 5.9 mol) was added to a solution of compound 30C (120.0 g, 0.59 mol) in acetonitrile (6.0 L) at RT and the resulting reaction mixture was heated to 100 °C at autoclave for 8 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The compound was washed with EA to obtain compound 30D.

Synthesis of methyl 3-aminoquinoline-5-carboxylate (30E):

Fe powder (39.38 g, 0.705 mol) and conc. HCl (50.0 ml) was added to a solution of compound 30D (25.0 g, 0.1 mol) in a mixture of ethanol (500 ml) and water (500 ml) at 70°C and the resulting reaction mixture was stirred for 18 hours. The reaction mixture was cooled to RT, filtered through celite, concentrated under reduced pressure and extracted by adding DCM. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The compound was purified by column chromatography using 50% EA in petroleum ether as eluent to give 30E.

Synthesis of methyl 3-fluoroquinoline-5-carboxylate (30F):

A solution of sodium nitrite (13.64 g, 0.197 mol) in water (60.0 ml) was added to a solution of compound 30E (20.0 g, 0.0989 mol) in 50% HBF4 (200 ml) at 0°C. The reaction mixture was left to warm to RT and stirred for 2 hours, then filtered under vacuum. The filtered compound was added to the chlorobenzene and the reaction mixture was refluxed at 125°C for 2 hours. The chlorobenzene was removed by distillation to give the material, which was dissolved in DCM and water. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The compound was purified by column chromatography using 4-5% EA in petroleum ether as eluent to give 30F.

Synthesis of methyl 8-bromo-3-fluoroquinoline-5-carboxylate (30G):

NBS (41.89 g, 0.243 mol) was added to a stirred solution of 30F (25.0 g, 0.121 mol) in H ₂ SO ₄ (500.0 ml) at 0°C and the resulting reaction mixture was allowed to warm to RT and left for stirring for 24 hours. The reaction mixture was poured onto crushed ice, and the resulting solid was filtered and dried under reduced pressure to obtain compound 30G.

Synthesis of (8-bromo-3-fluoroquinolin-5-yl)methanol (31H): To a stirred solution of 30G (26.0 g, 0.091 mol) in THF (260 ml) was added slowly 2M LiBH ₄ in THF (137 ml, 0.274 mol) at 0°C. The reaction mixture was heated to 40°C for 2 hours, then cooled to 0°C, quenched with ice water and stirred for 30 minutes. The reaction mixture was acidified with water. 2 n. HCl (pH 4-5) and heated to 40°C for 2 hours. The reaction mixture was cooled to RT and made alkaline sat. NaHCO ₃ solution (pH 8-9), extracted by adding DCM (250 mlx2). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The compound was washed with pentane to give 31H.

Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (30I): PBr ₃ (48.5 g, 0.179 mol) was added to a stirred solution of 31H (23.0 g, 0.0897 mol) in DCM (230 ml ) at 0°C, the mixture was left to warm to RT and left to stir for 18 hours. The reaction mixture was concentrated, cooled to 0°C and made alkaline with sat. Na ₂ CO ₃ solution (PH 8-9) to give a solid, which was collected by filtration and dried under vacuum to give 30I.

Synthesis of methyl (S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (30J):

To a stirred solution of methyl 2-((diphenylmethylene)amino)acetate (16.6 g, 0.0655 mol) in DCM (500 ml) was added (-)-cinchonidine (1.93 g, 0.0065 mol) at RT . The reaction mixture was cooled to 0°C. A solution of KOH (50%) (133 ml) and 30I (23.0 g, 0.0721) was added and the reaction mixture was left to stir at RT for 6 hours. The reaction mixture was diluted with water (200 ml) and stirred for 15 min . After washing with water and EA, the combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered through Celite, washed with EA and concentrated under reduced pressure to give 30J.

Synthesis of methyl (S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate free base (30K): 4M HCl in 1,4-dioxane (720 ml) was added to the stirred solution of 30J (60 g, 0.1221 mol) in methanol (420 ml) at 0°C. The reaction mixture was left to stir at RT for 36 hours. The reaction mixture was concentrated under reduced pressure, dissolved in water (100 ml) and washed with EA (100 ml x 2 L). The aqueous layer was separated and made alkaline (pH ~8) using sat. Na ₂ CO ₃ and extracted by adding DCM (500 mlx5). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 30K.

Chiral purification of methyl (S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride (30K): 30K was enriched with the desired enantiomer by supercritical liquid chromatography using 50% co-solvent (0. 5% TEA in IPA), at a flow rate of 100 ml/min, using a Chiralpak IC column (30x250 mm), 5 µm.

Synthesis of methyl (S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride (30K):

The free amine was dissolved in DCM (300 ml) and exposed to 4 M HCl in 1,4-dioxane (100 ml) at 0°C, and the reaction mixture was left to stir at RT for 30 min, then

- 67 045366 was concentrated under reduced pressure to obtain 30K as HCl salt.

Synthesis of methyl (S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (30L):

The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 30K and 2,6-dichlorobenzoyl chloride.

Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (30):

The title compound was prepared according to the method presented for the synthesis of compounds 3 B and 3, starting at 30L. MS (m/z) 542.0 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=8.4 Hz, 1H), 8.90 (d, J=2.7 Hz, 1H), 8.46 (d, J =10.3 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.73 (d , J=7.4 Hz, 1H), 7.62 (d, J=7.3 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.43-7.24 (m, 3H), 4.87 (s, 1H), 3.69 (dd, J=14.6, 4.2 Hz, 1H), 3.45-3.35 (m, 1H).

Example 31.

Synthesis of 5-bromo-8-iodo-2-methylquinoline (31A):

To a stirred solution of 2-iodo-5-bromoaniline (5 g, 17 mmol) in nitrobenzene (1.7 ml) and 75% H ₂ SO ₄ (15 ml) was added but-2-enal (2.35 g, 34 mmol ) at RT and then slowly heated to 150°C for 3 hours. Caution: highly exothermic reaction. The mixture was cooled to RT and poured into ice water while maintaining the temperature below 10°C. The pH was adjusted to ~12 using solids. KOH and the resulting substance was collected. This substance was washed three times with water, then diluted in ethyl acetate and filtered. The organic solution was concentrated, then purified by flash chromatography, eluting with a linear gradient of 5-100% DCM/hexanes to give 31A.

Synthesis of 5-bromo-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinoline (31B):

To a stirred solution of compound 31A (850 mg, 2.44 mmol) and (4-(ethoxymethyl)-2,6dimethoxyphenyl)boronic acid (586 mg, 2.44 mmol) in 1,2-dimethoxyethane (12 ml) was added 2M carbonate sodium in water (2.44 ml, 4.9 mmol) and the reaction mixture was degassed with dry nitrogen. Tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.12 mmol) was added, the reaction mixture was sealed and heated to 80°C for 16 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate and washed with water and brine .

It was then dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography, eluting with a linear gradient of 5-50% ethyl acetate/hexanes to give 31B.

Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2

- 68 045366 methylquinolin-5-yl)acrylate (31C):

Palladium(II) acetate was added to a stirred solution of 31B (190 mg, 0.46 mmol) in DMF (4.7 mL) and the reaction mixture was degassed with nitrogen for 30 min. To this was added methyl 2((tert-butoxycarbonyl)amino)acrylate (230 mg, 1.1 mmol), tetrabutylammonium chloride (152 mg, 0.55 mmol) and trimethylamine (0.074 ml, 0.53 mmol), and the reaction the mixture was sealed and heated to 90°C for 3 hours. It was cooled to RT, diluted with ethyl acetate and washed with 10% citric acid, saturated sodium bicarbonate and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered and concentrated. It was purified by flash chromatography, eluting with a linear gradient of 5-100% ethyl acetate/hexanes to give compound 31C.

Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate (31D):

To a stirred solution of 31C (150 mg, 0.28 mmol) and tosylhydrazide (781 mg, 4 mmol) in THF (3 ml) at 60°C, sodium acetate (609 mg, 4 mmol) in water (3 ml) was added dropwise. , then the reaction mixture was heated to boiling overnight. It was partitioned between ethyl acetate and water, and then the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The precipitate was subjected to these conditions twice more to obtain 31D.

Synthesis of methyl 2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate dihydrochloride (31E):

To a stirred solution of compound 31D (150 mg, 0.28 mmol) in ethyl acetate (2 ml) was added 4M hydrogen chloride in dioxane (0.7 ml, 1.8 mmol) and the reaction mixture was left to stir overnight at RT. It was diluted with EA and the resulting solids were collected by trituration to give 31E.

Synthesis of methyl 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate (31F):

The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 31E and 2,6-difluorobenzoyl chloride.

Synthesis of 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5yl)propanoic acid (31G):

Synthesized using the sodium hydroxide method to give 31G.

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5yl)propanoic acid (31):

2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31G) was separated into its two enantiomers using supercritical liquid chromatography using 20% MeOH/DEA co-solvent on an IC SFC column to obtain the desired enantiomer 31H as a second eluting peak. MS (m/z) 565.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J=8.7 Hz, 1H), 7.51-7.41 (m, 1H), 7.38 (d, J=7 .4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.15-7.05 (m, 2H ), 6.68 (s, 2H), 4.50 (s, 2H), 4.40 (s, 1H), 3.68-3.49 (m, 9H), 3.42-3.34 ( m, 1H), 2.45 (s, 3H), 1.20 (t, J=7.0 Hz, 3H).

- 69 045366

Example 32.

Synthesis of (8-bromo-3-fluoroquinolin-5-yl)methanol (32A):

The flask containing methyl 8-bromo-3-fluoroquinoline-5-carboxylate (1.06 g, 3.73 mmol) in THF (19 ml) was purged with N2 and then LiBH4 (813 mg, 37.3 mmol). After stirring at RT for 1 hour, the reaction mixture was cooled to 0°C and water (6 ml) was added, and then 1 M HCl (84 ml) was added dropwise. The reaction mixture was heated to 40°C for 2.5 h and then cooled to RT before dilution with water and EA. The aqueous layer was extracted, and the organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-100% EA in hexanes to give the title compound.

Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (32B):

Triphenylphosphine (1.12 g, 4.27 mmol) and CBr ₄ (1.42 g, 4.27 mmol) were added to a stirred solution of 32A (729 mg, 2.85 mmol) in DCM (5.7 ml) and stirred with CT scan for 20 minutes. The reaction mixture was then subjected to silica gel chromatography using 0-40% EA in hexanes to give the title compound.

Synthesis of tert-butyl-(S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (32C):

(-)-Cinchonidine (27 mg, 0.091 mmol) was added to a stirred solution of tert-butyl-2-((diphenylmethylene)amino)acetate (270 mg, 0.914 mmol) in DCM (7 mL). The mixture was cooled to 0°C with an ice bath, after which a 50% aqueous solution of KOH (1.8 ml) and then 32B (321 mg, 1.01 mmol) was added. The reaction mixture was stirred in an ice bath while slowly warming to RT. After 3.5 hours, the reaction mixture was diluted with water and DCM and the aqueous layer was extracted. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-30% EA in hexanes to give the title compound.

Synthesis of tert-butyl-(8)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (32D):

32C (65 mg, 0.122 mmol), (2,6-dichloro-4-fluorophenyl)boronic acid (51 mg, 0.244 mmol), K ₃ PO ₄ (91 mg, 0.426 mmol), SPhos Pd G3 (95 mg, 0.122 mmol) was dissolved in toluene (2.4 ml) and heated to 100°C for 3 hours. After cooling to RT, the reaction mixture was diluted with EA and filtered through celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography using 0-50% EA in hexanes to give the title compound.

Synthesis of tert-butyl-(S)-2-amino-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)propanoate (32E):

- 70 045366

2M HCl (0.43 mmol, 0.21 mL) was added to a stirred solution of 32D (88.2 mg, 0.14 mmol) in

THF (0.84 ml). After stirring at RT for 2 hours, sat. NaHCO ₃ and EA. The aqueous layer was extracted, and the organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The material was purified by silica gel chromatography using 090% EA in hexanes with 1% TEA to give the title compound.

Synthesis of tert-butyl-(S)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (32F):

TEA (23 μL, 0.161 mmol) was added to a stirred solution of 32E (36.6 mg, 0.081 mmol) in DCM (0.54 mL). The reaction mixture was cooled to 0°C, after which 2,6difluorobenzoyl chloride (15 μl, 0.121 mmol) was added dropwise. After stirring at RT for 1.25 hours, water and DCM were added. The aqueous layer was extracted, and the organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-40% EA in hexanes to give the title compound.

Synthesis of (S)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (32):

TFA (0.12 mL, 1.61 mmol) was added to a stirred solution of 32F (47.9 mg, 0.081 mmol) in DCM (0.40 mL). After stirring at RT for 3 hours, additional TFA (0.06 mL, 0.81 mmol) was added. The reaction mixture was stirred for another hour at RT and then concentrated under reduced pressure. The material was purified by prep HPLC using 0-100% MeCN in water with 1% TFA to give the title compound. MS (m/z) 537.0 [M+H]+. ^1H NMR (400 MHz, DMSO-th ₆ ) δ 13.04 (s, 1H), 9.27 (d, J=8.2 Hz, 1H), 8.90 (d, J=2.7 Hz , 1H), 8.45 (dd, J=10.5, 2.8 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.65 (d, J=8, 6 Hz, 2H), 7.59 (d, J=7.3 Hz, 1H), 7.48 (ddd, J=8.5, 6.5, 1.9 Hz, 1H), 7.15- 7.05 (m, 2H), 4.82 (ddd, J=10.2, 8.1, 4.5 Hz, 1H), 3.78-3.55 (m, 1H), 3.43 ( dd, J=14.7, 10.3 Hz, 1H).

Example 33.

Synthesis of methyl (S)-2-(4-acetyl-2,6-difluorobenzamido)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoate (33A):

The title compound was prepared according to the method presented for the synthesis of compound 16A, starting with 1E and 4-acetyl-2,6-difluorobenzoic acid.

(2S)-3-(8-(2-Chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(1-hydroxyethyl)benzamido)propanoic acid (33):

The title compound was prepared according to the method presented for the synthesis of compounds 24B and 16, starting with 33A. MS (m/z) 563.2 [M+H]+. 1H NMR (400 MHz, DMSO-O δ 9.19 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.2, 1.6 Hz, 1H), 8.63 ( dd, J=8.7, 1.6 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H ), 7.73-7.50 (m, 4H), 7.03 (d, J=8.8 Hz, 2H), 4.71 (d, J=6.5 Hz, 1H), 1.27 (d, J=6.5 Hz, 3H).

Example 34.

Synthesis of 8-bromo-7-fluoro-5-methylquinoline (34A): The title compound was prepared according to the method presented for the synthesis of compound 1A in Example 1, starting with 2-bromo-3-fluoro-5-methylaniline. MS (m/z) 240.0 [M+H] ⁺ .

Synthesis of 8-bromo-5-(bromomethyl)-7-fluoroquinoline 34B: The title compound was prepared according to the method presented for the synthesis of compound 1B in Example 1, starting with 34A. MS (m/z) 317.9 [M+H] ⁺ .

Synthesis of 8-bromo-7-fluoro-5-(((2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinoline (34C):

A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.365 ml, 2.04 mmol) in THF (10 ml) was cooled to -78°C with stirring and positive nitrogen pressure. p-BuLi (0.98 mL, 1.6 M, 1.57 mmol) was added dropwise to the mixture. Then a solution of 34B (497 mg, 1.57 mmol) was added as

- 71 045366 THF solution (1.0 M). After 30 minutes, the reaction mixture was removed from the cooling bath, quenched with a saturated aqueous NH4Cl solution, and left to warm to RT with thorough stirring.

The resulting mixture was extracted twice with EA, and the combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EA in hexanes to give the title compound. MS (m/z) 422.1 [M+H]+.

Synthesis of methyl (S)-2-amino-3-(8-bromo-7-fluoroquinolin-5-yl)propanoate dihydrochloride (34D):

To a stirred solution of 34C (380 mg, 0.9 mmol) in THF (3.6 mL) was added 2M aqueous hydrochloric acid (2.7 mL, 5.4 mmol). After 3 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (as a mixture of valine methyl ester hydrochloride), which was used without further purification. MS (m/z) 327.0 [M+H]+.

F F

34A 34B

I

F

34C 34D

34E 34

Synthesis of methyl (8)-3-(8-bromo-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (34E): the title compound was prepared according to the method presented for the synthesis of compound 1F in Example 1, starting from 34. MS (m/z) 467.0 [M+H]+.

Synthesis of (28)-3-(8-(2-chloro-4-cyanophenyl)-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (34): the title compound was prepared according to the method presented for the synthesis of compounds ZV and 3, starting with 34E. MS (m/z) 510.1 [M+H]+. ^1H NMR (400 MHz, DMSO^) δ 9.27 (dd, J=8.3, 1.3 Hz, 1H), 8.87 (dt, J=3.9, 1.8 Hz, 1H) , 8.67 (dd, J=8.6, 1.6 Hz, 1H), 8.24 (t, J=1.9 Hz, 1H), 7.95 (ddd, J=7.9, 4 ,2, 1.7 Hz, 1H), 7.67-7.57 (m, 3H), 7.49 (ttd, J=8.7, 6.6, 2.3 Hz, 1H), 7, 16-7.08 (m, 2H), 4.82 (dddd, J=10.8, 8.4, 4.2, 2.2 Hz, 1H), 3.85 (ddd, J=18.1 , 14.5, 4.1 Hz, 1H), 3.42 (ddd, J=19.5, 14.6, 10.8 Hz, 1H).

Example 35.

F F

35A 35

Synthesis of (S)-(5-(2-(2,6-dichlorobenzamido)-3-methoxy-3-oxopropyl)-3-fluoroquinolin-8-yl)boronic acid (35A): the title compound was prepared according to the method presented for synthesis of compound 5A, starting from 30L.

Synthesis of (8)-2-(2,6-dichlorobenzamido)-3-(3-fluoro-8-(4-(trifluoromethyl)isoquinolin-3-yl)quinolin-5yl)propanoic acid (35): the title compound was prepared according to the method presented for the synthesis of compounds 4C and 4, starting with 35A and 3-bromo-4-(trifluoromethyl)isoquinoline (71B). MS (m/z) 601.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J=3.4 Hz, 1H), 9.29 (dd, J=14.2, 8.4 Hz, 1H), 8.81 (dd, J=3.4, 2.8 Hz, 1H), 8.46 (ddd, J=10.1, 6.9, 2.8 Hz, 1H), 8.38 (dd, J=8 ,2, 1.1 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 8.10-8.01 (m, 1H), 7.94-7.85 (m, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.69 (dd, J=7.3, 1.9 Hz, 1H), 7.45-7.35 (m, 3H ), 4.85 (dtd, J=23.5, 9.2, 4.5 Hz, 1H), 3.69 (dt, J=14.4, 4.4 Hz, 1H), 3.44 ( dd, J=14.6, 10.1 Hz, 1H).

Example 36.

Synthesis of methyl (8)-3-(8-bromo-3-iodoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (36A):

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A solution of 300 mg, 0.67 mmol in AcOH (2.5 ml) was exposed to N-iodosuccinimide (300 mg, 1.34 mmol) and stirred at 70°C for 24 hours. A second amount of N-iodosuccinimide (300 mg, 1.34 mmol) and continued stirring at 70°C for another 24 hours. The mixture was cooled to RT and concentrated under reduced pressure. The resulting precipitate was dissolved in DCM, and washed with saturated aqueous NaHCO ₃ , subjecting the aqueous layer to back-extraction with DCM twice. The combined organic layers were adsorbed onto silica gel for purification by silica gel chromatography using 0-100% EA in hexanes to give the title compound. MS (m/z) 575.0 [M+H]+.

Synthesis of methyl (S)-3-(8-bromo-3-cyanoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (36B):

A suspension of 36A (50 mg, 0.087 mmol) and copper cyanide (12 mg, 0.130 mmol) in DMF (1.5 ml) was stirred at 135 °C under microwave irradiation for 30 min. The reaction mixture was then cooled to RT, diluted with EA and saturated aqueous NaCl and filtered through celite. The phases were separated and the aqueous layer was additionally extracted twice with EA. The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography using 0-40% EA in hexanes to give the title compound. MS (m/z) 474.0 [M+H] ⁺ .

Synthesis of (S)-3-(3-cyano-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (36): titular the compound was prepared according to the method presented for the synthesis of compound 18, starting with 36B. MS (m/z) 576.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (d, J=8.1 Hz, 1H), 9.21 (d, J=2.1 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.49 (tt, J= 8.4, 6.6 Hz, 1H), 7.15-7.08 (m, 2H), 6.71 (q, J=1.3 Hz, 2H), 4.82 (ddd, J=10 ,0, 8.2, 4.5 Hz, 1H), 4.52 (s, 2H), 3.77-3.70 (m, 1H), 3.61-3.45 (m, 9H), 1.21 (t, J=7.0 Hz, 3H).

Example 37.

Synthesis of methyl (8)-3-(8-bromo-3-(trifluoromethyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (37A): The vial was filled with 36A (50 mg, 0.087 mmol ) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (98 mg, 0.313 mmol), sealed with a diaphragm cap, and purged with nitrogen for 15 min. DMF (1 ml, previously degassed by sparging with nitrogen for 15 min) was added and the mixture was thoroughly stirred at 50°C for 1 h. The reaction mixture was cooled to RT, diluted with EA and filtered through celite. The resulting filtrate was washed with saturated aqueous NaHCO ₃ and the aqueous layer was back-extracted with EA twice. The combined organic layers were adsorbed onto silica gel chromatography using 0-50% EA in hexanes to give the title compound. MS (m/z) 517.1 [M+H] ⁺ .

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-3-(trifluoromethyl)quinolin-5-yl)propanoic acid (37) : The title compound was prepared according to the method presented for the synthesis of compound 18, starting at 37A. MS (m/z) 619.2 [M+H]+. 1H NMR (400 MHz,

DMSO-d ₆ ) δ 9.31 (d, J=8.0 Hz, 1H), 9.08-9.06 (m, 1H), 8.97 (dd, J=2.3, 1.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H),

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7.63 (d, J=7.3 Hz, 1H), 7.50 (tt, J=8.5, 6.6 Hz, 1H), 7.15-7.08 (m, 2H), 6 .72 (q, J=1.3 Hz, 2H), 4.78 (ddd, J=9.7,

8.0, 4.6 Hz, 1H), 4.53 (s, 2H), 3.77 (dd, J=14.8, 4.6 Hz, 1H), 3.61-3.43 (m , 9H), 1.22 (t, J=7.0 Hz, 3H).

Example 38.

Synthesis of 4-((2-bromo-5-methylphenyl)amino)-1,1,1-trifluorobut-3-en-2-one (38A):

To a stirred solution of 2-bromo-5-methylaniline (2.149 g, 12 mmol) and 4-(tert-butylamino)1,1,1-trifluorobut-3-en-2-one (2.05 g, 10.5 mmol ) in glacial acetic acid (4 ml), TFA (4 ml) was added and the reaction mixture was heated to 75°C for 16 hours. It was cooled to rt, poured into water and the solids were collected by filtration to give 38A.

Synthesis of 8-bromo-5-methyl-2-(trifluoromethyl)quinoline (38B):

To a stirred suspension of compound 38A (2.81 g, 9.1 mmol) in heptane (9 ml) was added POCl ₃ (0.855 ml, 9.12 mmol) and the reaction mixture was heated to 100°C overnight. It was poured into a solution of 2M sodium carbonate in water. It was extracted twice with ethyl acetate and the combined organics were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. It was purified by flash chromatography, eluting with a linear gradient of 1-20% ethyl acetate/hexanes to give 38B.

Synthesis of 8-bromo-5-(bromomethyl)-2-(trifluoromethyl)quinoline (38C):

To a stirred solution of 38B (1.32 g, 4.6 mmol) in benzene (10 ml) was added Nbromosuccinimide (0.97 g, 5.5 mmol) and the reaction mixture was heated to boiling under a tungsten lamp for 16 hours. cooled to RT, filtered and concentrated. The precipitate was dissolved in ethyl acetate and washed twice with water and once with saturated sodium chloride solution. It was purified by flash chromatography, eluting with a linear gradient of 5-70% DCM/hexanes to give compound 38C.

Synthesis of tert-butyl-3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (38D):

A stirred solution of tert-butyl-2-((diphenylmethylene)amino)acetate (260 mg, 0.88 mmol) in tetrahydrofuran (3 ml) under dry nitrogen was cooled to -78°C. 1M lithium hexamethyldisilazide in THF (0.968 ml, 0.968 mmol) was added dropwise, then the reaction mixture was stirred at this temperature for 15 minutes. To the above solution of 38C (357 mg, 0.97 mmol) in THF (2 ml) was added and the reaction mixture was allowed to warm to RT and stir for 16 hours. It was quenched by adding saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. It was purified by flash chromatography, eluting with a linear gradient of 5-50% ethyl acetate/hexanes to give compound 38D.

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Synthesis of tert-butyl-2-amino-3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)propanoate (38E):

To a stirred solution of compound 38D (335 mg, 0.57 mmol) in tetrahydrofuran (6 ml) was added 0.5 M citric acid in water (5.7 ml, 2.87 mmol) and the reaction mixture was left to stir for 1 hour at CT. It was diluted with water and washed once with diethyl ether. The aqueous layer was exposed to 1M sodium hydroxide in water until pH ~8 was reached and it was extracted twice with diethyl ether. The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give 38E.

Synthesis of tert-butyl-3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (38F):

The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 38E and 2,6-difluorobenzoyl chloride.

Synthesis of tert-butyl 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-(trifluoromethyl)quinolin-5-yl)propanoate (38G):

To a solution of 38F (187 mg, 0.33 mmol) and (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid (104 mg, 0.44 mmol) in 1,2-dimethoxyethane (3 ml) was added 2M carbonate sodium in water (0.5 ml, 0.67 mmol), and the reaction mixture was degassed with nitrogen. To the above XPhos Pd G3 (14 mg, 0.017 mmol) was added, the reaction mixture was sealed and heated to 85°C for 1 hour. It was cooled to RT and purified by flash chromatography, eluting with a linear gradient of 1-10% MeOH/ DXM, producing 38G.

Synthesis of 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-(trifluoromethyl)quinolin-5-yl)propanoic acid (38):

To a solution of 38G (214 mg, 0.32 mmol) in DCM (1 mL) was added TFA (723 mg, 6 mmol) and the reaction mixture was left stirring at RT for 4 hours. It was concentrated and purified by preparative HPLC to give 38 MS (m/z) 619.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J=8.1 Hz, 1H), 8.85 (dd, J=8.9, 0.8 Hz, 1H), 7, 95 (d, J=8.8 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.3 Hz, 1H), 7.48 ( tt, J=8.4, 6.5 Hz, 1H), 7.11 (dd, J=8.5, 7.5 Hz, 2H), 6.72 (q, J=1.3 Hz, 2H ), 4.77 (ddd, J=10.1, 8.0, 4.5 Hz, 1H), 4.52 (d, J=0.7 Hz, 2H), 3.76 (dd, J= 14.7, 4.5 Hz, 1H), 3.64-3.50 (m, 8H), 3.44 (dd, J=14.8, 10.1 Hz, 1H), 1.20 (t , J=7.0 Hz, 3H).

Example 39.

Synthesis of 8-bromo-6-fluoro-5-methylquinoline (39A): The title compound was prepared according to the method presented for the synthesis of compound 1A in Example 1 using 2-bromo-4-fluoro-5methylaniline. MS (m/z) 240.0 [M+H] ⁺ .

Synthesis of 8-bromo-5-(bromomethyl)-6-fluoroquinoline (39B): The title compound was prepared according to the method presented for the synthesis of compound 1B in Example 1 using 39A. MS (m/z) 317.9 [M+H]+.

Synthesis of 8-bromo-6-fluoro-5-(((2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinoline (39C): the title compound was prepared according to the method presented for the synthesis of compound 34C4 using 39B. MS (m/z) 422.1 [M+H]+.

Synthesis of Methyl-(S)-2-amino-3-(8-bromo-6-fluoroquinolin-5-yl)propanoate (39D): The title compound was prepared according to the method presented for the synthesis of compound 34 using 39C. MS (m/z) 327.0 [M+H] ⁺ .

Synthesis of Methyl (8)-3-(8-bromo-6-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (39E): The title compound was prepared according to the method presented for the synthesis of compound 16A in Example 16, using 39D. MS (m/z) 467.0 [M+H] ⁺ .

Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-6-fluoroquinolin-5yl)propanoic acid (39): the title compound was obtained according to the method presented for the synthesis of compound 18 using 39E. MS (m/z) 569.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J=8.3 Hz, 1H), 8.83-8.70 (m, 2H), 7.68 (dd, J=8 ,8, 4.3 Hz, 1H), 7.55-7.44 (m, 2H), 7.11 (dd, J=8.5, 7.6 Hz, 2H), 6.75 (s, 2H), 4.77 (td, J=8.5, 6.2 Hz, 1H), 4.54 (s, 2H), 3.70-3.50 (m, 11H), 1.22 (t , J=7.0 Hz, 3H).

Example 40.

(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-7-fluoroquinolin-5yl)propanoic acid (40): the title compound was prepared according to the method presented for the synthesis of compound 18 using 34E. MS (m/z) 569.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (d, J=8.1 Hz, 1H), 8.83 (dd, J=4.3, 1.5 Hz, 1H), 8, 70 (d, J=5.0 Hz, 1H), 7.64 (dd, J=8.0, 3.9 Hz, 1H), 7.567.46 (m, 2H), 7.18-7.10 (m, 2H), 6.75 (d, J=1.7 Hz, 2H), 4.80 (ddd, J=10.6, 8.1, 4.1 Hz, 1H), 4.54 ( s, 2H), 3.80 (dd, J=14.6, 4.1 Hz, 1H), 3.62 - 3.55 (m, 8H), 3.43 (dd, J=14.8, 10.5 Hz, 1H), 1.22 (t, J=7.0 Hz, 3H).

Example 41.

Synthesis of 2,6-difluoro-4-((phenoxycarbonyl)amino)benzoic acid (41A):

Phenyl chloroformate (0.41 mL, 3.24 mmol) and pyridine (0.87 mL, 10.81 mmol) were added to a stirred solution of 4-amino-2,6-difluorobenzoic acid (504 mg, 2.16 mmol) in DCM. . The reaction mixture was left to stir for 3 hours at RT. The reaction mixture was concentrated under reduced pressure and purified by reverse phase preparative chromatography using aqueous 0.1% TFA/MeCN as eluent.

Synthesis of (8)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((phenoxycarbonyl)amino)benzamido)propanoic acid (41) : The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 41A and 1E. MS (m/z) 686.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 10.76 (s, 1H), 9.18 (d, J=8.0 Hz, 1H), 8.81 ( s, 1H), 7.85-7.37 (m, 6H), 7.327.13 (m, 5H), 6.72 (s, 2H), 4.74 (s, 1H), 4.52 (s , 2H), 3.85-3.75 (m, 1H), 3.60-3.51 (m, 8H), 1.20 (t, J=7.0 Hz, 3H).

1E, HATU^ υΟΗ,ΤΓΦ DIEA.flXM

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Examples 42 and 43.

42A

43

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(4-cyano-2,6-difluorobenzamido)propanoate (42A):

To a stirred solution of 4-cyano-2,6-difluorobenzoic acid (0.12 g, 0.65 mmol) in DCM was added 1D (0.2 g, 0.65 mmol), HATU (0.25 g, 0.65 mmol) and TEA (1 ml). The reaction mixture was left to stir overnight at RT. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography using EA in hexanes as eluent.

(S)-2-(4-cyano-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (42):

42A (0.24 g, 0.5 mmol), (4-(ethoxymethyl)-2,6dimethoxyphenyl)boronic acid (200 mg, 0.5 mmol), XPhos Pd G3 (0.043 g, 0 .05 mmol) and K ₃ PO ₄ (0.21 g, 0.15 mmol) in dioxane (2 ml). The reaction mixture was left to stir at 120°C for 30 min. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The mixture was purified by silica gel chromatography using MeOH and DCM as eluent to give both 42 and 43. MS (m/z) 576.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (dd, J=4.1, 1.6 Hz, 1H), 8.60 (s, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.53-7.46 (m, 2H), 7.36 (d, J=7.3 Hz , 1H), 6.68 (d, J=2.3 Hz, 2H), 4.61 (s, 1H), 4.50 (s, 2H), 3.68 (dd, J=14.0, 4.7 Hz, 1H), 3.56 (d, J=7.0 Hz, 1H), 3.52 (d, J=7.1 Hz, 6H), 3.44-3.33 (m, 1H), 1.20 (t, J=7.0 Hz, 3H).

(S)-2-(4-carbamoyl-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5yl)propanoic acid (43). MS (m/z) 595.5 [M+H]+. ^1H NMR (400 MHz, DMSO^) δ 13.15 (s, 1H), 9.48 (d, J=8.0 Hz, 1H), 8.74 (dd, J=4.1, 1, 7 Hz, 1H), 8.53 (dd, J=8.7, 1.7 Hz, 1H), 8.01-7.73 (m, 2H), 7.53 (dd, J=8.6 , 4.1 Hz, 1H), 7.48 (d, J=7.4 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 6.76-6.63 (m , 2H), 4.75 (td, J=8.8, 4.4 Hz, 1H), 4.50 (s, 2H), 3.91-3.61 (m, 1H), 3.55 ( t, J=7.0 Hz, 2H), 3.53 (s, 3H), 3.46-3.22 (m, 4H), 1.20 (t, J=7.0 Hz, 3H).

Example 44.

Synthesis of methyl-(S)-2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoate (44A):

The title compound was prepared according to the method presented for the synthesis of compound 1E, starting with (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid.

(S)-2-(4-Amino-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5yl)propanoic acid (44):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 44A and 4-amino-2,6-difluorobenzoic acid. MS (m/z) 567.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 8.67 (d, J=7.9 Hz, 1H), 7.64 (t, J=37.5 Hz, 3H ), 6.74 (d, J=2.2 Hz, 2H), 6.11 (d, J=10.7 Hz, 2H), 4.75-4.62 (m, 1H), 4.53 (s, 2H), 3.81-3.65(m, 1H), 3.58 (d, J=7.0 Hz, 2H), 3.55 (d, J=6.1 Hz, 7H) , 1.20 (t, J=7.0 Hz, 3H).

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Example 45.

Synthesis of methyl 2,6-difluoro-4-(methylsulfonamido)benzoate (45A):

To a stirred solution of methyl 4-amino-2,6-difluorobenzoate (500 mg, 0.3 mmol) in DCM was added methylsulfonyl chloride (0.31 mL, 0.4 mmol) and pyridine (1.08 mL, 1.3 mmol ). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EA, washed with 1M HCl, bicarbonate, brine and dried, filtered and concentrated. The specified substance was recrystallized from EA/hexanes to obtain the title compound.

Synthesis of 2,6-difluoro-4-(methylsulfonamido)benzoic acid (45B):

Aqueous LiOH (5 mL, 2 M) was added to a stirred solution of 45A (534 mg, 0.2 mmol) in THF. The mixture was left to stir at RT for 2 days, diluted with water and acidified with 1 M HCl. This material was extracted by adding DCM, dried, filtered and concentrated under reduced pressure. The title compound was purified by silica gel chromatography using EA/hexanes as eluent to give the title compound.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methylsulfonamido)benzamido)propanoic acid (45):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 45B. MS (m/z) 585.1 [M+H]+. 1H NMR (400 MHz, DMSO^) δ 10.46 (s, 1H), 9.15 (d, J=8.1 Hz, 1H), 8.85 (dd, J=4.1, 1.6 Hz, 1H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.17 (dd, J=1.6, 0.4 Hz, 1H), 7.92 (dd , J=7.9, 1.6 Hz, 1H), 7.70-7.55 (m, 4H), 6.83 (d, J=9.3 Hz, 2H), 4.83-4, 68 (m, 1H), 3.87-3.66 (m, 1H), 3.51-3.33 (m, 1H), 3.14 (s, 3H).

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Example 46.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylsulfonamido)benzamido)propanoic acid (46):

The title compound was prepared according to the method presented for the synthesis of compounds 45A, 45B and 45, starting with phenylsulfonyl chloride. MS (m/z) 647.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.12 (d, J=8.1 Hz, 1H), 8.84 (dd, J=4.2, 1 ,6 Hz, 1H), 8.63-8.60 (m, 1H), 8.17 (d,J=1.7 Hz, 1H), 7.92 (dd, J=7.9, 1, 7 Hz, 1H), 7.89-7.82 (m, 2H), 7.73-7.53 (m, 7H), 6.75 (d, J=9.2 Hz, 2H), 4, 75-4.65 (m, 1H), 3.82-3.65 (m, 1H), 3.47-3.27 (m, 1H).

Example 47.

47A 47

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoate (47A):

The title compound was prepared according to the method presented for the synthesis of compound 16 of Example 16, starting with 2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzoic acid.

Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl) Phenyl)sulfonamido)benzamido)propanoic acid (47):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting at 47A. MS (m/z) 742.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-06) δ 11.21 (s, 1H), 9.11 (d, J=8.1 Hz, 1H), 8.81 (dd, J=4.1, 1 .6 Hz, 1H), 8.59 (dd, J=8.6, 1.7 Hz, 1H), 8.33 (d, J=5.3 Hz, 1H), 8.14 (d,J =1.6 Hz, 1H), 8.09-8.03 (m, 2H), 8.01-7.94 (m, 2H), 7.89 (dd, J=7.9, 1.6 Hz, 1H), 7.72 (dt, J=5.4, 1.8 Hz, 1H), 7.64-7.51 (m, 5H), 6.78 (d, J=9.2 Hz , 2H), 4.83-4.59 (m, 1H), 3.71 (s, 1H), 3.34 (s, 1H).

Example 48.

Synthesis of 2,6-difluoro-4-((methylsulfonyl)methyl)benzoic acid (48A):

Methyl sodium sulfinate (96.28 mg, 0.94 mmol) was added to a stirred solution of methyl 4-(bromomethyl)-2,6-difluorobenzoate (125 mg, 0.47 mmol) in DMF. It was heated to 65°C and stirred for 1 hour. EA and water were added. The combined organics were washed with brine, dried and concentrated. The specified substance was then converted into the title compound according to the method presented for the synthesis of compound 1G.

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(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((methylsulfonyl)methyl)benzamido)propanoic acid (48):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 48A. MS (m/z) 584.2 [M+H]+. 1H NMR (400 MHz, DMSOC) δ 9.30 (d, J=8.2 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (dd , J=8.7, 1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H) , 7.68-7.53 (m, 4H), 7.16 (d, J=8.1 Hz, 2H), 4.84-4.73 (m, 1H), 4.55 (s, 2H ), 3.77 (s, 1H), 3.40 (s, 1H), 2.93 (s, 3H).

Example 49.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((phenylsulfonyl)methyl)benzamido)propanoic acid (49):

The title compound was prepared according to the method presented for the synthesis of compound 48A from Example 48, starting with sodium phenyl sulfinate, and then according to the method presented for 16 and 16C, starting with 49A. MS (m/z) 646.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8 .64 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.817.69 (m, 3H), 7.69-7.50 (m, 6H), 6.88 (d, J=8.1 Hz, 2H), 4.82-4.73 (m, 1H), 4.77 (s, 2H), 3.76 (s, 1H), 3.40 (s, 1H).

Example 50.

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(4-(ethoxymethyl)-2,6 -dimethoxyphenyl)quinolin-5-yl)propanoic acid (50):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid. MS (m/z) 802.4 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.24 (s, 1H), 9.16 (d, J=8.0 Hz, 1H), 8.83 (s, 2H), 8.35 ( d, J=5.3 Hz, 1H), 8.128.04 (m, 2H), 8.03-7.95 (m, 2H), 7.82-7.43 (m, 5H), 6.81 (d, J=9.0 Hz, 2H), 6.74 (s, 2H), 4.72 (q, J=8.3 Hz, 1H), 4.54 (s, 2H), 3.73 (dd, J=13.3, 3.5 Hz, 1H), 3.59 (d, J=7.0 Hz, 1H), 3.54 (d, J=2.0 Hz, 6H), 3 .43 (s, 1H), 1.22 (t, J=7.0 Hz, 3H).

- 80 045366

Example 51.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((methylsulfonyl)methyl)benzamido)propanoic acid (51):

The title compound was prepared according to the method presented for the synthesis of compounds 3 B and 3, starting with 47A and (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)boronic acid. MS (m/z) 741.4 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.12 (d, J=8.1 Hz, 1H), 8.87 (s, 1H), 8.71 ( s, 1H), 8.38-8.26 (m, 1H), 8.10-8.02 (m, 2H), 8.02-7.93 (m, 2H), 7.78-7, 47 (m, 5H), 6.90 (d, J=9.3 Hz, 2H), 6.79 (t, J=8.8 Hz, 2H),

4.67 (s, 1H), 4.20 (s, 2H), 4.05 (s, 2H), 3.71 (d, J=14.0 Hz, 1H), 3.42-3.27 (m, 1H).

Example 52.

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(thiophen-3yl)quinolin-5-yl )propanoic acid (52):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and thiophen-3-ylboronic acid. MS (m/z) 689.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSOd6) δ 11.23 (s, 1H), 9.11 (d, J=8.1 Hz, 1H), 8.97 (dd, J=4.1, 1.7 Hz , 1H), 8.60 (dd, J=8.6, 1.7 Hz, 1H), 8.37-8.32 (m, 1H), 8.09-8.04 (m, 3H), 8.01-7.96 (m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.74 (dt, J=5.4, 1.8 Hz, 1H), 7 ,69-7.59 (m, 4H), 7.51 (d, J=7.5 Hz, 1H), 6.81 (d, J=9.1 Hz, 2H), 4.66 (ddd, J=10.1, 8.1, 4.4 Hz, 1H), 3.69 (dd, J=14.3, 4.4 Hz, 1H), 3.31 (dd, J=14.5, 10.1 Hz, 1H).

Example 53.

Synthesis of (S)-3-(8-boronoquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid ( 53A):

The title compound was prepared according to the method presented for the synthesis of compound 4B, starting at 47A.

(S)-3-(8-(2-chloro-4-(cyanomethyl)phenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4yl) Phenyl)sulfonamido)benzamido)propanoic acid (53): The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 53A and 2-(4-bromo-3-81 045366 chlorophenyl)acetonitrile. MS (m/z) 756.1 [M+H]+. 1H NMR (400 MHz, DMSO-d^ δ 11.19 (s, 1H), 9.10 (d,

J=8.1 Hz, 1H), 8.81 (dd, J=4.1, 1.6 Hz, 1H), 8.58 (dd, J=8.7, 1.7 Hz, 1H), 8.33 (dt, J=5.3, 0.6 Hz, 1H), 8.09-8.02 (m, 2H), 8.01-7.94 (m, 2H), 7.72 ( dt, J=5.4, 1.8 Hz, 1H), 7.62-7.49 (m, 5H), 7.43-7.32 (m, 2H), 6.79 (d, J= 9.1

Hz, 2H), 4.67 (d, J=11.2 Hz, 1H), 4.14 (s, 2H), 3.36 (s, 2H).

Example 54.

1.Pd(PPh ₃ ) _{4 47A} aq. Na ₂ CO ₃

2. 1_UN,THF (S)-3-(8-(2-Chloro-4-cyclopropylphenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin- 4yl)phenyl)sulfonamido)benzamido)propanoic acid (54):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and (2-chloro-4-cyclopropylphenyl)boronic acid. MS (m/z) 757.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.12 (d, J=8.1 Hz, 1H), 8.82 (d, J=4.3 Hz, 1H ), 8.61 (d, J=8.7 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.13 - 8.05 (m, 2H), 8.03 -7.95 (m, 2H), 7.74 (dt, J=5.3, 1.8 Hz, 1H), 7.66-7.52 (m, 4H), 7.25 (d, J =1.8 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.11 (dd, J=8.1, 1.8 Hz, 1H), 6.80 (d , J=9.1 Hz, 2H), 4.76-4.64 (m, 1H), 3.82-3.62 (m, 1H), 3.45-3.25 (m, 1H), 2.02 (tt, J=8.4, 5.1 Hz, 1H), 1.07-0.99 (m, 2H), 0.84-0.73 (m, 2H).

Example 55.

1. Pd(PPh ₃ ) ₄ aq. Na ₂ CO ₃

2. LiOH THF

(S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3,5-dimethylisoxazol-4-yl )quinolin-5-yl)propanoic acid (55):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole . MS (m/z) 702.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 9.07 (d, J=8.2 Hz, 1H), 8.88 (dd, J=4.1, 1 ,6 Hz, 1H), 8.58 (dd, J=8.7, 1.6 Hz, 1H), 8.33 (d, J=5.3 Hz, 1H), 8.05 (s, 1H ), 8.01-7.93 (m, 2H), 7.72 (dt, J=5.4, 1.8 Hz, 1H), 7.65-7.57 (m, 3H), 7, 52 (d, J=7.4 Hz, 1H), 6.77 (d, J=9.1 Hz, 2H), 4.69 (s, 1H), 3.75-3.60 (m, 1H ), 3.30 (dd, J=14.4, 10.6 Hz, 1H), 2.22 (s, 3H), 2.01 (s, 3H).

Example 56.

(S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(pyrimidin-4yl)quinolin-5-yl )propanoic acid (56):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 53A and 4-bromopyrimidine. MS (m/z) 685.4 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.30 (d, J=1.4 Hz, 1H), 9.11 (d, J=8.2 Hz, 1H), 8.99 (dd, J=4.2, 1.6 Hz, 1H), 8.86 (d, J=5.4 Hz, 1H), 8.67 (dd, J=8.7 , 1.7 Hz, 1H), 8.42 -8.25 (m, 2H), 8.19 (d, J=7.5 Hz, 1H), 8.10-8.00 (m, 2H) , 8.01-7.92(m, 2H), 7.747.70 (m, 1H), 7.71-7.66 (m, 1H), 7.63 (d, J=7.6 Hz, 1H ), 7.59 (d, J=1.5 Hz, 1H), 6.78 (d, J=9.1 Hz, 2H), 4.68 (ddd, J=10.3, 8.2, 4.4 Hz, 1H), 3.81-3.65 (m, 1H), 3.34 (d, J=7.0 Hz, 1H).

- 82 045366

Example 57.

(S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(5-(trifluoromethyl)pyridin-2- yl)quinolin-5-yl)propanoic acid (57):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 53A and 2-bromo-5-(trifluoromethyl)pyridine. MS (m/z) 752.4 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.20-9.05 (m, 2H), 8.98 (dd, J=4.2, 1.6 Hz , 1H), 8.69 (dd, J=8.7, 1.7 Hz, 1H), 8.388.23 (m, 3H), 8.11 (d, J=7.5 Hz, 1H), 8 .09-8.02 (m, 2H), 8.00-7.90 (m, 2H), 7.76-7.65 (m, 2H), 7.63 (d, J=7.5 Hz , 1H), 7.58 (d, J=1.7 Hz, 1H), 6.78 (d, J=9.1 Hz, 2H), 4.78-4.62 (m, 1H), 3 .74 (dd, J=14.5, 4.4 Hz, 1H), 3.36 (dd, J=14.5, 10.2 Hz, 1H).

Example 58.

(S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(pyrimidin-2yl)quinolin-5-yl )propanoic acid (58):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 53A and 2-bromopyrimidine. MS (m/z) 685.4 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.22 (s, 1H), 9.29 (d, J=4.9 Hz, 1H), 9.23 (d, J=8.7 Hz, 1H), 9.15-9.02 (m, 3H), 8.76 (s, 1H), 8.33 (dd, J=5.3, 0.6 Hz, 1H), 8.10-8 .00 (m, 2H), 8.00 -7.92 (m, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.71 (dt, J=5.3, 1 .8 Hz, 1H), 7.67 (t, J=4.9 Hz, 1H), 7.58 (p, J=0.7 Hz, 1H), 6.76 (d, J=9.1 Hz, 2H), 4.77 (ddd, J=10.4, 8.3, 4.4 Hz, 1H), 3.92-3.79 (m, 1H), 3.47 (dd, J= 14.6, 10.4 Hz, 1H).

Example 59.

(S)-3-(8-(2-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido )propanoic acid (59):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 53A and 2-bromobenzonitrile. MS (m/z) 708.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.22 (d, J=15.6 Hz, 1H), 9.23-9.03 (m, 1H), 8.90-8.77 (m , 1H), 8.77-8.47 (m, 1H), 8.33 (dd, J=5.3, 2.2 Hz, 1H), 8.18-83 045366

7.82 (m, 5H), 7.82-7.15 (m, 7H), 6.89-6.72 (m, 2H), 4.78-4.36 (m, 1H), 3, 72 (d, J=10.6 Hz, 1H), 3.30 (m, 1H).

Example 60.

(S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3-fluoro-2 methoxyphenyl)quinoline- 5-yl)propanoic acid (60):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and (3-fluoro-2-methoxyphenyl)boronic acid. MS (m/z) 731.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 9.11 (d, J=8.1 Hz, 1H), 8.85 (dd, J=4.1, 1 ,6 Hz, 1H), 8.61 (d, J=8.6 Hz, 1H), 8.37-8.29 (m, 1H), 8.11-8.02 (m, 2H), 8 .02-7.93 (m, 2H), 7.72 (dt, J=5.3, 1.8 Hz, 1H), 7.65-7.50 (m, 4H), 7.31 (ddd , J=11.8, 8.2, 1.6 Hz, 1H), 7.15 (td, J=8.0, 5.1 Hz, 1H), 7.06-7.01 (m, 1H ), 6.79 (d,J=9.1 Hz, 2H), 4.74-4.62 (m, 1H), 3.71 (dd, J=14.4, 4.4 Hz, 1H) , 3.48 (d, J=1.4 Hz, 3H), 3.38-3.28 (m, 1H).

Example 61.

(S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(4-fluoro-2(methylsulfonyl)phenyl )quinolin-5-yl)propanoic acid (61):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and (4-fluoro-2-(methylsulfonyl)phenyl)boronic acid. MS (m/z) 779.3 [M+H]+. ^1H NMR (400 MHz, DMSO-d6) (50:50 diastereomer mixture) δ 11.21 (s, 1H), 9.12 (dd, J=8.1, 3.4 Hz, 1H), 8, 80 (td, J=3.8, 3.3, 1.5 Hz, 1H), 8.60 (t, J=7.4 Hz, 1H), 8.33 (d, J=5.3 Hz , 1H), 8.10-8.02 (m, 2H), 8.01-7.94 (m, 2H), 7.87 (ddd, J=8.9, 2.8, 1.2 Hz , 1H), 7.73 (dd, J=5.3, 1.7 Hz, 1H), 7.68-7.57 (m, 3H), 7.61-7.48 (m, 2H), 7.41-7.32 (m, 1H), 6.79 (dd, J=9.1, 1.9 Hz, 2H), 4.76-4.61 (m, 1H), 3.77 ( dd, J=14.3, 4.0 Hz, 0.5H), 3.62 (dd, J=14.7, 5.1 Hz, 0.5H), 3.44 (dd, J=14, 6, 9.6 Hz, 0.5H), 3.27 (dd, J=14.5, 10.5 Hz, 0.5H), 2.85 (s, 1.5H), 2.80 (s , 1.5H).

Example 62.

(S)-3-(8-(chroman-8-yl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido )benzamido)propanoic acid (62):

- 84 045366

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and chroman-8-ylboronic acid. MS (m/z) 739.2 [M+H]+. ¹ H NMR (400 MHz, DMSOd ₆ ) δ 11.22 (s, 1H), 9.12 (d, J=8.1 Hz, 1H), 8.88 (s, 1H), 8.33 (dt , J=5.4, 0.6 Hz, 1H), 8.10-8.01 (m, 2H), 8.017.90 (m, 2H), 7.72 (dt, J=5.4, 1 .8 Hz, 1H), 7.59 (q, J=1.1 Hz, 3H), 7.14 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.3 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.86-6.64 (m, 2H), 4.75-4.57 (m, 1H), 3.97 -3.85 (m,2H), 3.72 (d, J=14.3 Hz, 1H), 3.433.27 (m, 1H), 2.82 (t, J=6.5 Hz, 2H) , 1.87 (t, J=5.6 Hz, 3H).

OH

OH

1. Pd(PPh ₃ ) _{4 47A} aq. Na ₂ CO ₃

2. υΟΗ,ΤΓΦ

Example 63.

OH B

OH

1. Pd(PPh ₃ ) ₄ ,, _A aq. Na ₂ CO ₃

47A -----------

2. LiOH ,ΤΓΦ

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(o-tolyl)quinolin-5-yl )propanoic acid (63):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and o-tolylboronic acid. MS (m/z) 697.2 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 9.09 (d, J=8.2 Hz, 1H), 8.81 (dd, J=4.2, 1.6 Hz, 1H), 8.62 (d, J=8.7 Hz, 1H), 8.36-8.28 (m, 1H), 8.11-8.01 (m, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.72 (dt, J=5.4, 1.8 Hz, 1H), 7.65-7.55 (m, 2H), 7 .55-7.41 (m, 2H), 7.34-7.17 (m, 3H), 7.13 (d, J=7.0 Hz, 1H), 6.78 (d, J=9 .5 Hz, 2H), 4.70 (s, 1H), 3.72 (dd, J=14.4, 4.4 Hz, 1H), 3.32 (dd, J=14.4, 10, 3 Hz, 1H), 1.87 (s, 3H).

Example 64.

O

he is he

1. Pd(PPh ₃ ) ₄ water No. ₂ CO ₃ 47 A -----------

2. NON.THF

(2S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(2-methoxy-6methylphenyl)quinoline-5 -yl)propanoic acid (64):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and (2-methoxy-6-methylphenyl)boronic acid. MS (m/z) 727.5 [M+H]+. ¹ H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 11.20 (s, 1H), 9.08 (d, J=8.2 Hz, 1H), 8.73 (d, J=42.8 Hz, 2H), 8.33 (d, J=5.3 Hz, 1H), 8.13-7.89 (m, 4H), 7.72 (dt, J=5.3 , 1.7 Hz, 1H), 7.69-7.37 (m, 4H), 7.28 (t, J=7.9 Hz, 1H), 6.90 (t, J=8.9 Hz , 2H), 6.83-6.71 (m, 2H), 4.79-4.66 (m, 1H), 3.77 (d, J=14.2 Hz, 1H), 3.49 ( s, 3H), 3.28 (dd, J=14.4, 10.6 Hz, 1H), 1.74 (s, 3H).

- 85 045366

Example 65.

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(2-(trifluoromethyl)phenyl)quinoline- 5-yl)propanoic acid (65):

The title compound was prepared according to the method presented for the synthesis of compounds 3B and 3, starting with 47A and (2-(trifluoromethyl)phenyl)boronic acid. MS (m/z) 751.5 [M+H]+.

'H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (d, J=2.3 Hz, 1H), 9.10 (dd, J=8.2, 6.2 Hz, 1H), 8 .77 (dt, J=4.0, 1.9 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.33 (d, J=5.3 Hz, 1H) , 8.10-8.02 (m, 2H), 8.01-7.93 (m, 2H), 7.82 (dt, J=7.9, 1.9 Hz, 1H), 7.75 -7.54 (m, 6H), 7.51 (d, J=',9 Hz, 2H), 7.32 (dd, J=7.7, 4.4 Hz, 1H), 6.78 ( dd, J=9.0, 3.5 Hz, 2Н), 4.69 (ddd, J=10.2, 8.1, 4.6 Hz, 1Н), 3.71 (ddd, J=29, 9, 14.4, 4.4 Hz, 1H), 3.34 (ddd, J=25.9, 14.5, 10.2 Hz,

1H).

Example 66.

(S)-3-(8-(4-chloroisoquinolin-3-yl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (66):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 5A and 3-bromo-4-chloroisoquinoline. MS (m/z) 514.1 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J=8.1 Hz, 1H), 8.88 (d, J=4.3 Hz, 1H), 8.77 (s , 1H), 7.98 (s, 1H), 7.78 (dd, J=7.8, 1.5 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 7 ,70-7.56 (m, 3H), 7.49 (tt, J=8.4, 6.5 Hz, 1H), 7.35-7.27 (m, 1H), 7.18-7 .08 (m, 2H), 4.75 (td, J=9.5, 4.5 Hz, 1H), 3.77 (dd, J=14.5, 4.5 Hz, 1H), 3, 68 (s, 3H), 3.44 (dd, J=14.5, 9.9 Hz, 1H).

Example 67.

(S)-2-(2,6-difluorobenzamido)-3-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propane acid (67):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 5A and 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one. MS (m/z) 518.1 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J=0.8 Hz, 1H), 9.31 (d, J=8.1 Hz, 1H), 8.81 (dd, J=4.2, 1.6 Hz, 1H), 8.72 (dd, J=8.7, 1.7 Hz, 1H), 8.38-8.29 (m, 1H), 8.24 (dq, J=8.5, 0.9 Hz, 1H), 8.02 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.87 (ddd, J=8 ,1, 7.0, 1.1 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.72-7.64 (m, 2H), 7.48 (tt, J=8.5, 6.6 Hz, 1H), 7.16-7.07 (m, 2H), 4.80 (ddd, J=10.1, 8.1, 4.4 Hz, 1H) , 3.81 (dd, J=14.5, 4.4 Hz, 1H), 3.46 (dd, J=14.5, 10.1 Hz, 1H).

Example 68.

- 86 045366 (S)-2-(2,6-dichlorobenzamido)-3-(8-(6-methyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (68): The title compound was prepared according to the method presented for the synthesis of compounds 4C and 4, starting with 4B and 2-chloro-6-methyl-3-(trifluoromethyl)pyridine. MS (m/z) 549.5 [M+H]+. 1H NMR (400 MHz, DMSO-06) δ 9.31 (d, J=8.3 Hz, 1H), 8.81 (dd, J=4.2, 1.6 Hz, 1H), 8.69 (dd, J=8.7, 1.7 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.70-7.52 (m, 4H), 7.48- 7.35 (m, 3H), 4.84 (td, J=9.3, 4.3 Hz, 1H), 3.75 (dd, J=14.6, 4.4 Hz, 1H), 3 .44 (dd, J=14.6, 10.1 Hz, 1H), 2.58 (s, 3H).

Example 69.

(S)-2-(2,6-dichlorobenzamido)-3-(8-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (69): The title compound was obtained according to the method presented for the synthesis of compounds 4C and 4, starting with 4B and 2-chloro-6-methoxy-3-(trifluoromethyl)pyridine. MS (m/z) 565.9 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.83 (dd, J=4.2, 1.6 Hz, 1H), 8.68 (dd, J=8 ,7, 1.7 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H), 7.70-7.58 (m, 3H), 7.47-7.34 (m, 3H), 7.06 (dt, J=8.7, 0.8 Hz, 1H), 4.86 (m, 1H), 3.81 (s, 3H),

3.78 (m, 1H), 3.43 (m, 1H).

Example 70.

(S)-2-(2,6-difluorobenzamido)-3-(8-(5-methoxy-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)quinolin5-yl)propanoic acid (70 ): The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 5A and 4-chloro-5-methoxy-2-methylpyridazin-3(2H)-one. MS (m/z) 495.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J=7.6 Hz, 1H), 8.88 (d, J=4.4 Hz, 1H), 8.75 (d, J=8.6 Hz, 1H), 8.27 (s, 1H), 7.77-7.65 (m, 1H), 7.59 (d, J=7.8 Hz, 2H), 7, 48 (tt, J=8.5, 6.6 Hz, 1H), 7.12 (dd, J=8.4, 7.6 Hz, 2H), 4.74 (s, 1H), 3.86 -3.63 (m, 7H), 3.43 (q, J=13.6 Hz, 1H).

Example 71.

Synthesis of 4-(trifluoromethyl)isoquinoline-3-amine (71A):

To a stirred solution of 3-aminoisoquinoline (150 mg, 1.04 mmol) in MeCN was added 3,3dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (412.1 mg, 1.25 mmol) and tris(trimethylsilyl)silyl chloride (0.35 ml, 1.25 mmol). The mixture was heated to 80°C for 1 hour. The reaction mixture was filtered through celite, washed with EA and purified by silica gel chromatography using EA in hexanes as eluent to give the title compound.

Synthesis of 3-bromo-4-(trifluoromethyl)isoquinoline (71B): To a stirred solution of 71A (91 mg, 0.43 mmol) in HBr (6.9 mL) was added Br ₂ (0.13 mL, 2.57 mmol) . The reaction mixture was kept at 0°C for 10 minutes at which time NaNO ₂ (147.96 mg, 2.14 mmol) was added as a pre-prepared solution in water (5 ml). The reaction mixture was left to stir at 0°C for 30 min, then left to warm to RT for 60 min. The reaction mixture was quenched with sodium bicarbonate, extracted with DCM, concentrated and purified by silica gel chromatography eluting with Hex/EA to give the title compound.

- 87 045366 (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(trifluoromethyl)isoquinolin-3-yl)quinolin-5-yl)propanoic acid (71):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 4B and 71B. MS (m/z) 552.2 [M+H]+. ^1H NMR (400 MHz, DMSO^) δ 9.60 (d, J=3.3 Hz, 1H), 9.29 (t, J=7.6 Hz, 1H), 8.75 (dt, J =3.9, 1.8 Hz, 1H), 8.65 (ddd, J=8.7, 5.6, 1.7 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.05 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.90 (t, J =7.6 Hz, 1H), 7.70 (dd, J=7.3, 4.7 Hz, 1H), 7.66-7.58 (m, 2H), 7.55-7.41 ( m, 1H), 7.12 (q, J=8.2 Hz, 2H), 4.77 (dtd, J=18.5, 8.8, 4.4 Hz, 1H), 3.77 (ddd , J=25.7, 14.5, 4.5 Hz, 1H), 3.49-3.34 (m, 1H).

Example 72.

(S)-3-(8-(6-amino-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)-2-(2,6dichlorobenzamido)propanoic acid (72): The title compound was prepared according to the method , presented for the synthesis of compounds 4C and 4, starting with 4B and 6-chloro-5-(trifluoromethyl)pyridin-2-amine. MS (m/z) 550.4 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (d, J=8.3 Hz, 1H), 8.89 (dd, J=4.1, 1.6 Hz, 1H), 8, 70 (dd, J=8.7, 1.6 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.74-7.63 (m, 3H), 7.49 -7.36 (m, 3H), 6.81 (d, J=9.1 Hz, 1H), 4.80 (td, J=9.2, 4.4 Hz, 1H), 3.74 ( dd, J=14.5, 4.4 Hz, 1H), 3.43 (dd, J=14.6, 9.9 Hz, 1H).

Example 73.

(S)-2-(2,6-dichlorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3yl)quinolin-5-yl) propanoic acid (73):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 4B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one. MS (m/z) 578.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 9.27 (dd, J=27.2, 8.3 Hz, 1H), 8.83 (dt, J=4, 2, 2.0 Hz, 1H), 8.69 (d, J=8.6 Hz, 1H), 7.72-7.59 (m, 2H), 7.49-7.31 (m, 4H ), 6.55 (d, J=4.7 Hz, 1H), 4.90-4.71 (m, 1H), 3.73 (td, J=14.4, 4.0 Hz, 1H) , 3.47 (d, J=4.2 Hz, 3H), 3.38 (ddd, J=24.5, 14.7, 10.5 Hz, 1H), 2.52 (m, 3H).

Example 74.

Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (74A): To a stirred solution of 4-bromo-2,6difluorobenzoic acid (5 g, 21.1 mmol) in DCM (50 ml) and tert-butyl alcohol ( 50 ml) di-tert-butyl dicarbonate (9.2 g, 42.2 mol) and then 4-dimethylaminopyridine (0.8 g, 6.3 mmol) were added. The reaction mixture was left to stir at RT for 12 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (100 ml) and washed with 10% aqueous citric acid (100 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain the substance. The material was suspended in hexanes, the solid was filtered off, and the filtrate was evaporated under reduced pressure to give compound 74A. MS (m/z) 236.6 [M+H-C ₄ H ₈ ]+. 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.56 (m, 2H), 1.50 (s, 9H).

Synthesis of tert-butyl-(R)-2,6-difluoro-4-(( 1,1,1-trifluorobutan-2-yl)amino)benzoate (74B):

To a stirred suspension of tert-butyl-4-bromo-2,6-difluorobenzoate (74A) (250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutan-2-amine (85 mg, 0. 67 mmol) and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 ml) was added XPhos Pd G3 (42 mg, 0.06 mmol). The reaction mixture was bubbled with nitrogen and then heated to 90° C. for 12 hours. The mixture was cooled to RT and diluted with ethyl acetate (50 ml). The resulting suspension was filtered through a pad of celite and the filtrate was evaporated under reduced pressure to give compound 74B. MS (m/z) 284.1 [M+HC ₄ H ₈ ]+.

- 88 045366

Synthesis of (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (74C):

To a stirred solution of tert-butyl (R)-2,6-difluoro-4-(( 1,1,1-trifluorobutan-2-yl)amino)benzoate (74B) (188 mg, 0.55 mmol) in DCM (1 ml) TFA (1 ml) was added. The reaction mixture was left to stir at RT for 20 min. The reaction mixture was concentrated under reduced pressure to give the compound, which was purified by silica gel column chromatography and eluted with ethyl acetate in hexane to give compound 74C. MS (m/z) 338.1 [M+H]+.

(S)-3-(8-(2-Chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutane- 2-yl)amino)benzamido)propanoic acid (74):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 74C. MS (m/z) 617.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.87-8.77 (m, 2H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (dd , J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.73-7.44 (m, 4H), 6, 76 (d, J=9.4 Hz, 1H), 6.43 (d, J=11.6 Hz, 2H), 4.68 (s, 1H), 4.29 (d, J=10.2 Hz, 1H), 3.73 (s, 1H), 3.49-3.33 (m, 1H), 1.75 (ddt, J=10.1, 7.5, 3.8 Hz, 1H) , 1.51 (ddt, J=17.6, 14.4, 7.3 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).

Example 75.

75A 75

Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)piperidin-1-yl)benzoic acid (75A):

To a 150 mL pressure vessel equipped with a stirrer, add methyl 4-bromo-2,6 difluorobenzoate (700 mg, 1.8 mmol), RuPhos (169 mg, 0.36 mmol), tBuBrettPhos Pd G3 (155 mg, 0 .18 mmol), Cs ₂ CO ₃ (2.95 g, 9.1 mmol), (R)-2-(trifluoromethyl)piperidine (416 mg, 2.7 mmol) and toluene (18 ml). The reaction vessel was then sealed and heated at 90°C overnight. The reaction mixture was cooled to RT and filtered through a pad of celite, washed with EA and the filtrate evaporated to dryness under reduced pressure. This substance was purified by chromatography on silica gel using EA in hexane as eluent. THF (6 ml) and aqueous LiOH (6.2 ml, 1.0 M) were added to the above substance. The reaction mixture was stirred at 60°C for 20 hours. The reaction mixture was cooled to RT and acidified with 1.0 M HCl, after which it was extracted with EA. The organic layers were combined and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to obtain 75A.

(S)-3-(8-(2-Chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperidin-1yl) benzamido)propanoic acid (75):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 75A. MS (m/z) 645.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=8.1 Hz, 1H), 8.83 (dd, J=4.2, 1.6 Hz, 1H), 8, 64 (dd, J=8.6, 1.7 Hz, 1H), 8.15 (dd, J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.677.52 (m, 4H), 6.72 (d, J=12.0 Hz, 2H), 4.93 (d, J=9.0 Hz, 1H), 4 .70 (dt, J=9.7, 4.9 Hz, 1H), 3.74 (s, 1H), 3.59 (d, J=12.9 Hz, 1H), 3.41 (s, 1H), 2.99 (t,J=12.2 Hz, 1H), 1.94 (d,J=14.4 Hz, 1H), 1.85-1.67 (m, 2H), 1, 67-1.42 (m, 3H).

Example 76.

Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)benzoic acid (76A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (R)-2-(trifluoromethyl)pyrrolidine.

(S)-3-(8-(2-Chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)pyrrolidin1-yl) benzamido)propanoic acid (76):

- 89 045366

The title compound was prepared according to the method presented for the synthesis of compound 16A and

16, starting from 76A. MS (m/z) 629.5 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=8.2 Hz, 1H), 8.83 (dd,

J=4.1, 1.6 Hz, 1H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (dd, J=1.7, 0.4 Hz , 1H), 7.96-7.83 (m, 1H), 7.66-7.58 (m,

3H), 7.56 (dt, J=7.9, 0.6 Hz, 1H), 6.48 (d, J=11.5 Hz, 2H), 4.82 -4.63 (m, 2H ), 3.72 (d, J=13.0 Hz, 1H), 3.56 (t,

Example 77.

J=8.5 Hz, 1H), 3.41 (s, 1H), 3.15 (q, J=8.7 Hz, 1H), 2.16-1.91 (m, 4H).

Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)piperazin-1-yl)benzoic acid (77A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (R)-2-(trifluoromethyl)piperazine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperazin-1yl) Benzamido)propanoic acid (77): The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 77A. MC (m/z) 644.1 [M+H]+. ¹ H NMR (400 MHz,

DMSO-d6) δ 8.94 (d, J=8.1 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8.63 (dd, J=8 ,7, 1.7 Hz, 1H), 8.15 (dd, J=1.6, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H) , 7.67-7.57 (m, 3H), 7.58-7.53 (m, 1H), 6.79 (d, J=11.5 Hz, 2H), 4.71 (td, J =9.2, 8.2, 4.3 Hz, 1H), 4.26 (br, 1H), 4.05 (d, J=13.2 Hz, 1H), 3.84 (d, J= 10.9 Hz, 1H), 3.75 (s, 1H), 3.42 (s, 1H), 3.29 (d, J=10.7 Hz, 1H), 3.12-2.96 ( m, 3H).

Example 78.

78A ₇₈

Synthesis of 2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1-yl)benzoic acid (78A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 2-(trifluoromethyl)azetidine hydrochloride.

(28)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1yl)benzamido)propanoic acid (78): The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 78A. MS (m/z) 617.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J=8.1, 3.2 Hz, 1H), 8.87-8.77 (m, 1H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.67-.50 (m, 4H), 6.24 (d, J=9.9 Hz, 2H), 4.91 (q, J=6.3 Hz, 1H), 4.71 (d, J=9.6 Hz, 1H), 4.16-3.97 (m, 1H), 3.84-3.62 (m, 2H), 3.40 (s, 1H), 2.68-2 .53 (m, 1H), 2.37 (ddd, J=11.7, 5.6, 2.6 Hz, 1H).

- 90 045366

Example 79.

79A 79

Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (79A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with morpholine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-morpholinobenzamido)propanoic acid (79):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 79A. MS (m/z) 577.3 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (d, J=8.0 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8, 64 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.96-7.84 (m, 1H), 7.67 -7.58 (m, 3H), 7.56 (d, J=7.9 Hz, 1H), 6.61 (d, J=11.8 Hz, 2H), 4.69 (q, J= 5.9, 4.3 Hz, 1H), 3.74 (s, 1H), 3.70-3.61 (m, 4H), 3.42 (s, 1H), 3.22-3.12 (m, 4H).

Example 80.

80A 80

Synthesis of 4-(1,1-dioxidothiomorpholino)-2,6-difluorobenzoic acid (80A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with thiomorpholine 1,1-dioxide.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(4-(1,1-dioxidothiomorpholino)-2,6-difluorobenzamido)propanoic acid (80):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 80A. MS (m/z) 625.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=8.1 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H), 8, 64 (dd, J=8.6, 1.7 Hz, 1H), 8.15 (dd, J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.677.58 (m, 3H), 7.56 (dd, J=7.9, 0.4 Hz, 1H), 6.76 (d, J=11.7 Hz, 2H), 4.78-4.64 (m, 1H), 3.85 (s, 4H), 3.75 (s, 1H), 3.42 (s, 1H), 3.06 (s, 4H ).

Example 81.

Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (81A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 3-(trifluoromethyl)morpholine hydrochloride.

81A ₈₁

2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (81):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 81A. MS (m/z) 645.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (dd, J=8.0, 2.7 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H ), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.90 (dd, J= 7.9, 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (dt, J=7.9, 0.6 Hz, 1H), 6.74 (d , J=11.7 Hz, 2H), 4.89 (dd, J=8.7, 3.6 Hz, 1H), 4.71 (d, J=6.2 Hz, 1H), 4.14 (d, J=12.7 Hz, 1H), 3.93 (dd, J=11.5, 3.8 Hz, 1H), 3.72 (d, J=13.0 Hz, 2H), 3 .59-3.45 (m, 1H), 3.40 (d, J=12.7 Hz, 2H), 3.21 (t, J=12.2 Hz, 1H).

- 91 045366

Examples 82 and 83.

81B 82 83

Preparation of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido )propanoic acid (82): 81 was separated into its 2 stereoisomers by supercritical liquid chromatography using 25% MeOH/DEA co-solvent, at a flow rate of 50 ml/min, using a Chiralpak AD-H 5 µm 21x250 mm column. The title compound was detected as the first eluting peak. MS (m/z) 645.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (dd, J=4.2, 1.6 Hz, 1H), 8.74 (s, 1H), 8.14 (dd, J=1 ,6, 0.4 Hz, 1H), 8.0-8.4 (br, 1H), 7.88 (dd, J=7.9, 1.7 Hz, 1H), 7.61-7, 49 (m, 4H), 6.74 (d, J=11.9 Hz, 2H), 4.88 (d, J=9.0 Hz, 1H), 4.43 (s, 1H), 4, 14 (d, J=12.7 Hz, 1H), 3.93 (dd, J=11.5, 3.7 Hz, 1H), 3.72 (d, J=12.6 Hz, 2H), 3.60-3.48 (m, 1H), 3.41 (d, J=12.9 Hz, 1H), 3.21 (t, J=13.1 Hz, 2H).

Preparation of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-3-(trifluoromethyl)morpholino)benzamido )propanoic acid (83): 81 was separated into its 2 stereoisomers by supercritical liquid chromatography using 25% EtOH/TFA co-solvent, at a flow rate of 50 ml/min, using a Chiralpak AD-H 5 µm 21x250 mm column. The title compound was detected as the second eluting peak. MS (m/z) 645.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (dd, J=4.1, 1.5 Hz, 2H), 8.13 (dd, J=1.7, 0.4 Hz, 1H ), 8.08 (s, 1H), 7.88 (dd, J=7.9, 1.7 Hz, 1H), 7.65 7.42 (m, 4H), 6.74 (d, J =11.9 Hz, 2H), 4.88 (dt, J=9.4, 4.7 Hz, 1H), 4.40 (d, J=6.6 Hz, 1H), 4.14 (d , J=12.7 Hz, 1H), 3.93 (dd, J=11.5, 3.7 Hz, 1H), 3.71 (d, J=13.0 Hz, 2H), 3.60 -3.46 (m, 1H), 3.41 (d, J=13.0 Hz, 2H), 3.23 (d, J=11.8 Hz, 1H).

Example 84.

84A 84

Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (84A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (S)-2-methylmorpholine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-2-methylmorpholino)benzamido)propanoic acid ( 84):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 84A. MS (m/z) 591.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=8.1 Hz, 1H), 8.85 (dd, J=4.2, 1.5 Hz, 1H), 8, 65 (d, J=8.6 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 7.91 (dd, J=7.9, 1.6 Hz, 1H), 7.69-7.55 (m, 4H), 6.62 (d, J=11.9 Hz, 2H), 4.71 (t, J=11.2 Hz, 1H), 3.87 (dd , J=11.2, 3.4 Hz, 1H), 3.71 (d, J=12.4 Hz, 2H), 3.66-3.50 (m, 3H), 3.44 (s, 1H), 2.70 (td, J=11.8, 3.6 Hz, 1H), 2.38 (dd, J=12.3, 10.4 Hz, 1H), 1.13 (d, J =6.2 Hz, 3H).

Example 85.

Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (85A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (S)-2-(trifluoromethyl)morpholine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-2-(trifluoromethyl)morpholino)benzamido) propanoic acid (85):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 85A. MS (m/z) 645.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J=8.1 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8, 64 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz , 1H), 7.67-7.57 (m, 3H), 7.56 (d, J=7.9 Hz, 1H), 6.75 (d, J=11.6 Hz, 2H), 4 .77-4.66 (m, 1H), 4.29 (dq, J=6.7, 3.3 Hz, 1H), 4.03 (dd, J=10.9, 3.3 Hz, 1H ), 3.86 (d, J=12.2 Hz, 1H), 3.75 (m, 1H), 3.69 (t, J=10.4 Hz, 2H), 3.41 (s, 1H ), 2.92-2.72 (m, 2H).

- 92 045366

Example 86.

86A

Synthesis of (R)-2,6-difluoro-4-((2,2,2-trifluoro-1-phenylethyl)amino)benzoic acid (86A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (R)-2,2,2-trifluoro-1-phenylethan-1-amine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-2,2,2-trifluoro- 1-Phenylethyl)amino)benzamido)propanoic acid (86):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 86A. MS (m/z) 665.2 [M+H]+. 1H NMR (400 MHz, DMSO-d^δ 8.85-8.77 (m, 2H), 8.61 (dd, J=8.8, 1.7 Hz, 1H), 8.15 (dd, J=1.6, 0.4 Hz, 1H), 7.89 (dd, J=7.9, 1.6 Hz, 1H), 7.66-7.48 (m, 7H), 7.46 - 7.32 (m,

3H), 6.53 (d, J=11.6 Hz, 2H), 5.67 (q, J=8.7 Hz, 1H), 4.64 (d, J=11.6 Hz, 1H) , 3.71 (s, 1H), 3.37 (s, 1H). Example 87.

Synthesis of (R)-2,6-difluoro-4-(methyl(1,1,1-trifluoropropan-2-yl)amino)benzoic acid (87A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (R)-1,1,1-trifluoro-N-methylpropan-2-amine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methyl((R)-1,1,1-trifluoropropane -2yl)amino)benzamido)propanoic acid (87): The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 87A. MS (m/z) 617.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92-8.81 (m, 2H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (dd , J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.68-7.53 (m, 4H), 6, 63 (d, J=12.0 Hz, 2H), 4.93 (p, J=7.4 Hz, 1H), 4.70 (s, 1H), 3.74 (s, 1H), 3, 41 (s, 1H), 2.83-2.77 (m, 3H), 1.36 (d, J=6.8 Hz, 3H).

Example 88.

88A 88

Synthesis of 2,6-difluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)benzoic acid (88A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 1,1,1,3,3,3-hexafluoropropan-2-amine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((1,1,1,3,3,3- hexafluoropropane-2- 93 045366 yl)amino)benzamido)propanoic acid (88):

The title compound was prepared according to the method presented for the synthesis of compound 16A and

16, starting from 88A. MS (m/z) 657.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J=8.0 Hz, 1H), 8.83 (dd,

J=4.1, 1.6 Hz, 1H), 8.66-8.59 (m, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.90 (dd, J =7.8, 1.6 Hz, 1H), 7.67-7.53 (m, 5H),

6.69 (d, J=11.1 Hz, 2H), 5.93 (s, 1H), 4.70 (s, 1H), 3.62 (s, 1H), 3.40 (s, 1H ).

Example 89.

89A 89

Synthesis of 4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6-difluorobenzoic acid (89A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 1-cyclopropyl-2,2,2-trifluoroethane-1-amine.

(2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6difluorobenzamido )propanoic acid (89):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting at 89A. MS (m/z) 629.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO) δ 8.86-8.75 (m, 2H), 8.63 (dd, J=8.7, 1.6 Hz, 1H), 8.15 (dd, J =1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.67-7.53 (m, 4H), 6.93 ( d, J=9.5 Hz, 1H), 6.40 (d, J=11.8 Hz, 2H), 4.67 (s, 1H), 3.91 (q, J=8.1 Hz, 1H), 3.72 (s, 1H), 3.40 (s, 1H), 1.08-0.96 (m, 1H), 0.60 (dq, J=8.5, 4.1, 3.3 Hz, 1H), 0.49 (dd, J=11.1, 5.8 Hz, 2H), 0.34-0.23 (m, 1H).

Example 90.

90 148

Preparation of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido )propanoic acid (90): 89 was separated into its 2 stereoisomers by supercritical liquid chromatography using 30% EtOH/TFA co-solvent, at a flow rate of 45 ml/min, using an IE 5 μm 21x250 mm column. The title compound was detected as the first eluting peak. MS (m/z) 629.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.868.75 (m, 2H), 8.66-8.59 (m, 1H), 8.15 (dd, J=1.7, 0.4 Hz , 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.67-7.49 (m, 4H), 6.92 (d, J=9.5 Hz, 1H), 6.40 (d, J=11.8 Hz, 2H), 4.67 (s, 1H), 3.91 (d, J=7.8 Hz, 1H), 3.72 (s, 1H), 3.39 (s, 1H), 1.08-1.00 (m, 1H), 0.66-0.56 (m, 1H), 0.53-0.42 (m, 2H) , 0.33-0.26 (m, 1H).

- 94 045366

Example 91.

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(tritylamino)propanoate (91A):

To a stirred solution of 1D (15 g, 43.4 mmol) in DCM was added TEA (15.12 mL, 108.5 mmol) and trityl chloride (12.7 g, 45.57 mmol). The reaction mixture was stirred for 2 hours, then filtered through celite, and washed 3 times with EA. The filtrate was concentrated and purified by silica gel chromatography eluting with EA/hexanes to give the title compound.

Synthesis of (S)-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronic acid (91B): The title compound was prepared according to the method presented for the synthesis of compound 4B, starting with 91A.

Synthesis of methyl-(S)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5 yl)-2-(tritylamino )propanoate (91C):

The title compound was prepared according to the method presented for the synthesis of compound 11A, starting with 91B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

Synthesis of methyl (S)-2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate (91D): Triethylsilane (0.064 g, 0.49 mmol) and TFA (0.18 mL, 2.0 mmol) were added to a stirred solution of 91C (0.3 g, 0.46 mmol) in DCM. The reaction mixture was left to stir at RT for 1 hour and then concentrated under reduced pressure to give the material, which was used without further purification.

(S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl- 2-oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (91):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting with 91D. MS (m/z) 671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.84-8.70 (m, 2H), 8.62 (s, 1H), 7.55 (s, 2H), 7.42 (s, 1H ), 6.75 (dd, J=9.4, 5.5 Hz, 1H), 6.54 (s, 1H), 6.42 (dd, J=11.4, 4.2 Hz, 2H) , 4.66 (s, 1H), 4.29 (s, 1H), 3.66 (d, J=13.6 Hz, 1H), 3.59-3.21 (m, 5H), 2, 51 (s, 2H), 1.79-1.70 (m, 1H), 1.51 (ddd, J=13.7, 10.4, 7.1 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 92.

Synthesis of 2-chloro-4-methoxy-3-(trifluoromethyl)pyridine (92A):

Sodium methoxide powder (118.19 mg, 2.188 mmol) was added to a stirred solution of 2,4-dichloro-3-(trifluoromethyl)pyridine (157.5 mg, 0.729 mmol) in methanol at 0°C. The reaction mixture was allowed to warm to RT and stirred for 16 hours. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography using EA in hexanes as eluent to give the title compound.

Synthesis of methyl (8)-2-amino-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate (92B):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting with 92A.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(4-methoxy-3- (trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (92):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting with 92B. MS (m/z) 657.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J=8.9 Hz, 2H), 8.73 (d,

- 95 045366

J=5.9 Hz, 1H), 8.62 (t, J=7.9 Hz, 1H), 7.60 (t, J=6.8 Hz, 3H), 7.44 (d, J= 6.0 Hz, 1H), 6.76 (t, J=8.2 Hz, 1H), 6.45 (dd, J=11.7, 7.2 Hz, 2H), 4.68 (d, J=19.6 Hz, 1H), 4.30 (s, 1H), 4.07 (s, 3H), 3.74 (d, J=15.1 Hz, 1H), 3.69-3, 64 (m, 1H), 1.77 (s, 1H), 1.53 (s, 1H), 0.93 (t, J=7.4 Hz, 3H).

Example 93.

Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (93A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (R)-3-(trifluoromethyl)morpholine.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl )quinolin-5-yl)propanoic acid (93):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 92B and 93A. MS (m/z) 685.9 [M+H]+. 1H NMR (500 MHz, DMSO-06) δ 8.95 (dd, J=11.7, 8.0 Hz, 1H), 8.80 (d, J=3.7 Hz, 1H), 8.74 (d, J=6.0 Hz, 1H), 8.63 (t, J=8.7 Hz, 1H), 7.61 (dd, J=13.0, 5.4 Hz, 3H), 7 .46 (d, J=6.1 Hz, 1H), 6.76 (t, J=11.2 Hz, 2H), 4.91 (d, J=9.3 Hz, 1H), 4.77 -4.64 (m, 1H), 4.19-4.13 (m, 1H), 4.08 (s, 3H), 3.95 (d, J=11.7 Hz, 1H), 3, 80-3.66 (m, 2H), 3.55 (t, J=11.8 Hz, 1H), 3.51-3.36 (m, 2H), 3.23 (t, J=12, 5 Hz, 1H).

Example 94.

94A

94B 94

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoate (94A):

The title compound was prepared according to the method presented for the synthesis of compound 16A in Example 16, starting at 93A.

Synthesis of (5-((S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-methoxy-3-oxo-96 045366 propyl)quinoline-8 -yl)boronic acid (94B): The title compound was prepared according to the method presented for the synthesis of compound 4B, starting at 94A.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridine-2 -yl)quinolin-5-yl)propanoic acid (94):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 94B and 2-chloro-5,6-dimethyl-3-(trifluoromethyl)pyridine. MS (m/z) 683.2 [M+H]+. 1H NMR (400 MHz, DMSOC) δ 8.96 (d, J=8.0 Hz, 1H), 8.77 (dd, J=4.0, 1.5 Hz, 1H), 8.67-8 .59 (m, 1H), 8.03 (s, 1H), 7.68-7.47 (m, 3H), 6.74 (d, J=11.7 Hz, 2H), 4.95- 4.84 (m, 1H), 4.72-4.61 (m, 1H), 4.14 (d, J=12.8 Hz, 1H), 3.983.86 (m, 1H), 3.72 (d,J=13.1 Hz, 2H), 3.58-3.30 (m, 3H), 3.21 (s, 1H), 2.50 (s, 3H), 2.41 (s, 3H).

Example 95.

(S)-2-(2,6-difluoro-4-((R)-3 -(trifluoromethyl)morpholino)benzamido)-3 -(8-(1,4,6-trimethyl-2-oxo-1, 2dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (95):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 94B and 3-chloro-1,4,6-trimethylpyridin-2(1H)-one. MS (m/z) 645.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 8.99-8.81 (m, 3H), 7.76 (s, 1H), 7.65 (dd, J=13.5, 7.3 Hz, 1H), 7.53 (t, J=8.1 Hz, 1H), 6.72 (dd, J=11.5, 2.7 Hz, 2H), 6.20 (s, 1H), 4, 88 (d, J=9.4 Hz, 1H), 4.74-4.69 (m, 1H), 4.14 (d, J=12.7 Hz, 1H), 3.93 (dd, J =11.5, 3.8 Hz, 1H), 3.79 (s, 1H), 3.70 (t, J=9.9 Hz, 1H), 3.51 (d, J=10.7 Hz , 2H), 3.46-3.34 (m, 4H), 3.21 (t, J=12.3 Hz, 1H), 2.40 (s, 3H), 1.73 (d, J= 10.6 Hz, 3H).

Example 96.

(S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4(trifluoromethyl) -1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (96):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 94B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one. MS (m/z) 699.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=7.9, 4.2 Hz, 1H), 8.86-8.79 (m, 1H), 8.67 (s, 1H), 7.60 (dt, J=25.1, 8.5 Hz, 2H), 7.48-7.39 (m, 1H), 6.74 (dd, J=11.6, 4, 3 Hz, 2H), 6.54 (s, 1H), 4.90 (dd, J=8.7, 3.6 Hz, 1H), 4.72-4.63 (m, 1H), 4, 14 (d, J=12.7 Hz, 1H), 3.93 (dd, J=11.5, 3.8 Hz, 1H), 3.75-3.62 (m, 2H), 3.60 -3.32 (m, 6H), 3.23 (d, J=12.4 Hz, 1H), 2.52 (s, 3H).

Example 97.

(S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4,5-dimethylpyrimidin-2yl)quinolin-5-yl) propanoic acid (97):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 94B and 2-chloro-4,5-dimethylpyrimidine. MS (m/z) 617.0 [M+H] ⁺ . 1H NMR (400 MHz, DMSOd6) δ 9.37 (s, 1H), 9.31 (s, 1H), 8.94 (d, J=8.3 Hz, 1H), 8.78 (s, 2H ), 8.11 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 6.77

- 97 045366 (dd, J=37.8, 12.3 Hz, 2H), 4.97-4.75 (m, 2H), 4.16 (dd, J=12.9, 8.0 Hz, 1H), 3.91 (ddd, J=25.2, 12.9, 4.2 Hz,

2H), 3.72 (d, J=13.1 Hz, 1H), 3.59-3.53 (m, 2H), 3.41-3.36 (m, 1H), 3.22 (dd , J=14.4, 11.1 Hz, 1H), 2.66 (s, 3H),

2.39(s, 3H).

Example 98.

(S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (98):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 94B and 3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. MS (m/z) 685.2 [M+H]+. 1H

NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.96 (d, J=8.0 Hz, 1H), 8.89 (d, J=4.2 Hz, 1H ), 8.71 (d, J=8.6 Hz,

1H), 8.50 (s, 1H), 7.73-7.64 (m, 3H), 7.61 (d, J=7.3 Hz, 1H), 6.76 (d, J=11 ,8 Hz, 2H), 4.91 (d, J=9.7 Hz, 1H), 4.68 (s, 1H), 4.16 (d, J=12.7 Hz, 1H), 3, 95 (d, J=11.4 Hz, 1H), 3.73 (d, J=13.4 Hz, 2H), 3.57 (s, 4H), 3.44 (dd,

J=14.0, 9.3 Hz, 2H), 3.24 (t, J=12.5 Hz, 1H).

Example 99.

1.94B,

XPhos Pd G3 aq. K3PO4

Br--------2. LiOH THF

ABOUT

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-6-methylpyrimidin-2-yl)quinolin- 5-yl)propanoic acid (99):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 94B and 2-chloro-4-methoxy-6-methylpyrimidine. MS (m/z) 632.2 [M+H]+. ¹ H NMR (400 MHz,

DMSO-d ₆ ) δ 9.49 (d, J=4.9 Hz, 1H), 9.39 (d, J=8.7 Hz, 1H), 9.04 (d, J=7.5 Hz , 1H), 8.95 (d, J=8.4 Hz, 1H), 8.18 (dd, J=8.7, 5.0 Hz, 1H), 8.00 (d, J=7, 8 Hz, 1H), 7.10 (s, 1H), 6.72 (d, J=12.2 Hz, 2H), 4.94-4.78 (m, 2H), 4.15 (s, 4H), 4.00-3.84 (m, 2H), 3.74 (t, J=16.0 Hz, 1H), 3.65-3.46 (m, 2H), 3.39 (d , J=12.8 Hz, 1H), 3.21 (t, J=12.5 Hz, 1H), 2.70 (s, 3H).

Example 100.

100

Synthesis of methyl-(S)-2-amino-3-(8-(4-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5yl)propanoate (100A):

The title compound was prepared according to the method presented for the synthesis of compound 91C and

- 98 045366

91D, starting with 4-chloro-3-iodo-1,6-dimethylpyridin-2(1H)-one.

(S)-3-(8-(4-Chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2,6-difluoro- 4-((R)3-(trifluoromethyl)morpholino)benzamido)propanoic acid (100):

The title compound was prepared according to the method presented for the synthesis of compound 93, starting at 100A. MS (m/z) 665.7 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (d, J=7.9 Hz, 1H), 8.87 (d, J=4.3 Hz, 1H), 8.73 (s , 1H), 7.67 (d, J=9.1 Hz, 1H), 7.63 (dd, J=7.6, 4.2 Hz, 1H), 7.54 (d, J=7, 3 Hz, 1H), 6.76 (dd, J=11.7, 3.9 Hz, 2H), 6.49 (d, J=2.8 Hz, 1H), 4.91 (dd, J= 8.9, 3.6 Hz, 1H), 4.70 (dd, J=12.5, 7.4 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3, 97-3.93 (m, 2H), 3.73 (dd, J=12.0, 8.5 Hz, 2H), 3.52 (d, J=22.8 Hz, 1H), 3.45 (d, J=1.9 Hz, 3H), 3.41 (d, J=3.5 Hz, 1H), 3.24 (t, J=12.4 Hz, 1H), 2.46 (s , 3H).

Example 101.

Synthesis of methyl-(S)-2-amino-3-(8-(3-(dimethylamino)pyridin-2-yl)quinolin-5-yl)propanoate (101A):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting with 2-bromo-N,N-dimethylpyridin-3-amine.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(3-(dimethylamino)pyridin2-yl)quinolin-5-yl )propanoic acid (101):

The title compound was prepared according to the method presented for the synthesis of compound 93, starting with 101A. MS (m/z) 630.3 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04-8.92 (m, 2H), 8.77 (dd, J=8.8, 1.6 Hz, 1H), 8.32 (d , J=5.3 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.91 (t, J=7.9 Hz, 2H), 7.81-7.71 (m, 2H), 6.74 (d, J=11.8 Hz, 2H), 4.90 (dd, J=8.8, 3.5 Hz, 1H), 4.81-4.72 ( m, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.96 (dd, J=11.4, 3.7 Hz, 1H), 3.82 (dd, J=14 ,2, 4.4 Hz, 1H), 3.73 (d,J=12.8 Hz, 1H), 3.62-3.36 (m, 3H), 3.23 (t, J=12, 1 Hz, 1H), 2.50 (m, 6H).

N—

1.91 V, XPhos Pd G3 aq. K3PO4

2.TFU, TES

102A

1. 93A, HATU TEA, DXM

2. ΗΟΗ,ΤΓΦ

1.93A, HATU TEA, DXM

2. 1_UN, TGF

Example 102.

1. 91 V, XPhos Pd G3 aq. K3PO4

2. TFU, TES

102

Synthesis of methyl (S)-2-amino-3-(8-(4-methoxy-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin5-yl)propanoate (102A):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting with 3-bromo-4-methoxy-1,6-dimethylpyridin-2(1H)-one.

(S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-1,6-dimethyl-2oxo-1, 2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (102):

The title compound was prepared according to the method presented for the synthesis of compound 93, starting with 102A. MS (m/z) 661.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 9.09 (s, 1H), 9.048.93 (m, 2H), 7.91 (s, 1H), 7, 71 (d, J=14.6 Hz, 2H), 6.76 (d, J=11.8 Hz, 2H), 6.46 (s, 1H), 4.92 (s, 1H), 4, 72 (s, 1H), 4.16 (d, J=12.7 Hz, 1H), 4.00-3.91 (m, 1H), 3.70 (m, 5H), 3.61-3 .37 (m, 6H), 3.23 (t, J=12.3 Hz, 1H).

- 99 045366

Example 103.

Synthesis of 1,6-dimethyl-2-oxo-1,2-dihydropyridin-4-yl 4-methylbenzenesulfonate (103A):

To a stirred suspension of 4-hydroxy-1,6-dimethylpyridin-2(1H)-one (1.5 g, 10.8 mmol) in TEA (1.8 mL, 12.9 mmol) in DMF (27 mL) N-Ph triflimide (3.85 g, 10.8 mmol). The reaction mixture was stirred for 15 minutes, during which time the suspended solids went into solution. This solution was concentrated under reduced pressure and purified by silica gel chromatography using EA in hexanes to give the title compound.

Synthesis of 4-(azetidin-1-yl)-1,6-dimethylpyridin-2(1H)-one (103B): 103A (450 mg, 1.66 mmol), azetidine (0.11 ml, 1.66 mmol), XPhos Pd G3 (140 mg, 0.17 mmol) and Cs ₂ CO ₃ (1.08 g, 3.3 mmol) in toluene (5.5 ml). After bubbling N ₂ , the mixture was heated to 90°C and left to mix thoroughly for 90 minutes. The reaction mixture was cooled and filtered through a pad of celite, washing with EA. This solution was concentrated under reduced pressure and purified by silica gel chromatography using MeOH in DCM to give the title compound.

Synthesis of 4-(azetidin-1-yl)-3-iodo-1,6-dimethylpyridin-2(1H)-one (103C):

Niodosuccinimide (125 mg, 0.56 mmol) was added to a stirred solution of 103B (90 mg, 0.5 mmol) in acetic acid (0.5 mL). After 10 minutes, the mixture was concentrated and a 1:1 mixture of saturated water with NaHCO ₃ and saturated water with Na ₂ S ₂ O ₃ was added. The aqueous layer was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The material was purified by silica gel chromatography using EA in hexanes to give the title compound.

Synthesis of methyl-(S)-2-amino-3-(8-(4-(azetidin-1 -yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3 -yl)quinolin-5 -yl)propanoate (103D):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting at 103C.

(S)-3-(8-(4-(azetidin-1 -yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3 -yl)quinolin-5-yl)-2-( 2,6difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (103E):

The title compound was prepared according to the method presented for the synthesis of compound 93, starting with 103D. MS (m/z) 686.4 [M+H]+. 1H NMR (400 MHz, DMSOM) δ 9.20 (s, 1H), 9.05 (d, J=4.9 Hz, 1H), 8.91 (dd, J=8.3, 3.5 Hz , 1H), 7.98 (d, J=27.1 Hz, 1H), 7.84-7.55 (m, 2H), 6.73 (dd, J=17.5, 11.8 Hz, 2H), 5.74 (d, J=2.8 Hz, 1H), 4.90 (s, 1H), 4.82-4.70 (m, 1H), 4.16 (dd, J=12 ,6, 4.0 Hz, 1H), 4.01-3.88 (m, 1H), 3.73 (d, J=13.2 Hz, 1H), 3.68-3.48 (m, 2H), 3.35 (d, J=5.2 Hz, 4H), 3.21 (s, 3H), 2.42-2.36 (m, 3H), 1.83 (dt, J=27 ,5, 7.6 Hz, 1H).

- 100 045366

Example 104.

Synthesis of methyl-(S)-2-amino-3-(1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinoline]-5 ^π -yl)propanoate (104A):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting with 3-bromo-1-methylquinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(1-methyl-2-oxo-1,2-dihydro[3,8 '-biquinolin]-5'-yl)propanoic acid (104): The title compound was prepared according to the method presented for the synthesis of compound 93, starting with 104A. MS (m/z) 667.2 [M+H]+. 1H NMR (400 MHz,

DMSOC) δ 8.99 (1H, d, J=8.0 Hz), 8.90 (1H, d, J=4.2 Hz), 8.79 (1H, m), 7.99 (1H, s), 7.82-7.58 (6H, m), 7.32 (1H, t, J=7.4 Hz), 6.78 (2H, d, J=11.8 Hz), 4, 95-4.88 (1H, m), 4.76-4.66 (1H, m), 4.16 (1H, d, J=12.7 Hz), 3.96 (2H, dd, J= 11.4, 3.9 Hz), 3.70 (4H, m), 3.50 (3H, ddd, J=44.1, 17.5, 11.8 Hz), 3.24 (1H,t , J=12.6 Hz).

Example 105.

105

Synthesis of 2-chloro-N,N-dimethyl-3-(trifluoromethyl)pyridin-4-amine (105A):

The title compound was prepared according to the method presented for the synthesis of compound 92A in Example 92, starting with dimethylamine.

Synthesis of methyl-(S)-2-amino-3-(8-(4-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)quinolin-5yl)propanoate (105B):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting at 105 A.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-(dimethylamino)-3(trifluoromethyl)pyridine-2- yl)quinolin-5-yl)propanoic acid (105):

The title compound was prepared according to the method presented for the synthesis of compound 93, starting at 105B. MS (m/z) 698.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 9.00 (dd, J=30.1, 6.7 Hz, 2H), 8.74 (s, 1H), 8.38 (d, J=7.5 Hz, 1H), 7.96 (s, 1H), 7.72 (d, J=21.3 Hz, 2H), 7.43 (d, J=7 .4 Hz, 1H), 6.75 (d, J=11.7 Hz, 2H), 4.91 (s, 1H), 4.74 (s, 1H), 4.16 (d, J=12 .7 Hz, 1H), 3.96 (dd, J=11.4, 3.8 Hz, 1H), 3.85 (d, J=14.5 Hz, 1H), 3.74 (d, J =13.0 Hz, 2H), 3.55 (t, J=12.1 Hz, 1H), 3.41 (d, J=12.5 Hz, 1H), 3.31 (s, 6H), 3.23(s, 1H).

- 101 045366

Example 106.

Synthesis of 1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (106A):

NaH (25 mg, 0.62 mmol) was added to a stirred solution of 4-methyl-5-(trifluoromethyl)pyridin-2(1H)-one (100 mg, 0.056 mmol) in DMF and the reaction mixture was left to stir for 30 min. , during this time the bubbling stopped. The reaction mixture was cooled to 0°C and methyl p-toluenesulfonate (116 mg, 0.062 mmol) was added dropwise. After 4 hours, the reaction mixture was allowed to warm to RT, concentrated under reduced pressure, and purified by silica gel chromatography, eluting with Hex/EA 0-100% to give the title compound.

Synthesis of 3-iodo-1,4-dimethyl-5-(trifluoromethyl)pyridin-2 (III)-one (106B):

TFUA (1.6 g, 8 mmol) was added to a stirred solution of 106A (0.72 g, 4 mmol) in pure TFA. The reaction mixture was heated to 100°C for 5 minutes in a sealed vial, followed by the addition of NIS (1.08 g, 5 mmol) and further heating at 60°C for 3 hours. The reaction mixture was cooled and TFA was removed under reduced pressure. The precipitate was dissolved in EA and washed with sat. sodium bicarbonate, then saline. The organic layer was filtered then concentrated to give the title compound without further purification.

Synthesis of (S)-2-amino-3-(8-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin5-yl)propanoic acid (106C) :

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting at 106B.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,4-dimethyl-2-oxo-5(trifluoromethyl) -1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (106):

The title compound was prepared according to the method presented for the synthesis of compound 93, starting at 106C. MS (m/z) 699.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 8.94 (t, J=7.2 Hz, 1H), 8.86 (t, J=3.0 Hz , 1H), 8.73 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 7.74-7.58 (m, 2H), 7.53 (dd, J= 11.4, 7.3 Hz, 1H), 6.74 (d, J=12.3 Hz, 2H), 4.90 (d, J=9.0 Hz, 1H), 4.74 (dd, J=9.1, 5.0 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 4.003.90 (m, 1H), 3.86-3.64 (m, 2H ), 3.56 (d, J=13.1 Hz, 1H), 3.51 (d, J=1.7 Hz, 3H), 3.46-3.31 (m, 2H), 3.23 (t, J=12.4 Hz, 1H), 1.83 (d, J=10.2 Hz, 3H).

Example 107.

107 147

Preparation of (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl2 -oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (107): 91 was separated into its 2 atropisomeric enantiomers by supercritical liquid chromatography using 30% MeOH co-solvent, at a flow rate of 60 ml/min, using an IC 5 µm 21x250 mm column. The title compound was detected as the first eluting peak. MS (m/z) 671.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO^) δ 8.85-8.72 (m, 2H), 8.63 (d, J=8.1 Hz, 1H), 7.67-7.60 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.74 (d, J=9.2 Hz, 1H) , 6.54 (s, 1H), 6.42 (d, J=11.8 Hz, 2H), 4.66 (s, 1H), 4.29 (s, 1H), 3.75-3, 66 (m, 1H), 3.41 (m, 7H), 1.75 (s, 1H), 1.58-1.46 (m, 1H), 0.91 (t, J=7.3 Hz , 3H).

- 102 045366

Example 108. Synthesis of methyl (S)-3-(8-aminoquinolin-5-yl)-2-(tritylamino)propanoate (108A).

To a stirred solution of (91A) (1.148 g, 2.08 mmol) in dioxane (5 mL) was added cesium carbonate (2.04 g, 6 mmol), benzophenone imine, (755 mg, 4.16 mmol), rac-Binap -Pd-G3 (103 mg, 0.1 mmol). The mixture was heated at 90°C overnight, cooled to RT, diluted with THF and hydroxylamine hydrochloride (289 mg, 4.1 mmol) and sodium acetate (850 mg, 6 mmol) and methanol (1 ml) were added and left to stir for 4 hours. The mixture was diluted with ethyl acetate and washed with water. The organic extracts were dried over magnesium sulfate and chromatographed on silica gel, eluting with hexanes and ethyl acetate, to give the title compound.

Synthesis of methyl (S)-3-(8-(5-(dimethylamino)-2-((ethoxycarbonyl)amino)benzamido)quinolin-5-yl)-2(tritylamino)propanoate (108B).

A stirred solution of 2-amino-5-(dimethylamino)benzoic acid (299 mg, 1.6 mmol) and acetonitrile (3 ml) was cooled to 0°C and pyridine (672 μl, 8.3 mmol) and ethyl chloroformate (0.635 ml) were added , 6.645 mmol). The mixture was removed from the ice bath and allowed to warm to RT for 30 min. Ethanol was then added and the mixture was stirred for a further 1 hour. The entire mixture was then added to 108A (675 mg, 1.38 mmol) dissolved in DMF (4 ml) and left to stir for 4 hours. The solvents were removed by rotary evaporation and the product mixture was suspended with DCM and added to silica gel, which was eluted with hexanes and ethyl acetate to give the title compound.

108E 108

Synthesis of methyl-(S)-3-(8-(6-(dimethylamino)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)quinolin-5yl)-2-(tritylamino)propanoate ( 108C).

To a stirred solution of 108B (100 mg, 0.14 mmol) in DMF (2 ml) was added potassium carbonate (96 mg, 0.695 mmol) and methanol (1 ml). The mixture was stirred overnight and then adsorbed directly onto silica gel and subjected to chromatography, eluting with hexanes and ethyl acetate, to give the title compound.

Synthesis of methyl-(S)-3-(8-(6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)yl)quinolin-5-yl)-2- (tritylamino)propanoate (108D):

To a stirred solution of 108C (250 mg, 0.37 mol) in DMF (1 ml) was added potassium carbonate (51 mg, 0.37 mmol) and methyl tosylate (103 mg, 0.55 mmol). The reaction mixture was stirred overnight and concentrated under reduced pressure to give the compound, which was subjected to silica gel column chromatography eluting with EA in hexane to give the title compound.

Synthesis of methyl-(8)-2-amino-3-(8-(6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin3(2H)-yl)quinolin-5-yl) propanoate (108E).

108D was dissolved in DCM (1 ml) and TFA (1 ml) was added and left to stir for 4 hours. The mixture was concentrated and used without further purification.

- 103 045366 (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(6-( dimethylamino)-1methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)quinolin-5-yl)propanoic acid (108):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting with 108E. MS (m/z) 699.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-4 ₆ ) δ 9.00-8.79 (m, 2H), 8.64 (d, J=8.4 Hz, 1H), 7.78-7.55 (m , 3H), 7.44 (d, J=9.1 Hz, 1H), 7.37 (dd, J=9.5, 2.9 Hz, 1H), 7.25 (s, 1H), 6 .78 (d, J=9.4 Hz, 1H), 6.45 (d, J=11.7 Hz, 3H), 5.74 (s, 1H), 4.66 (s, 1H), 3 .51 (d, J=1.7 Hz, 3H), 3.49-3.30 (m, 1H), 2.94 (s, 6H).

Example 109.

Synthesis of N-(4-fluorophenyl)-N-methyl-3-oxobutanamide (109A):

2,2,6-Trimethyl- 4I-1,3-dioxin-4one (0.568 g, 4.00 mmol) and the mixture was heated at 110°C for 3 hours. Once complete, the solvent was evaporated under reduced pressure. The material was purified by flash chromatography using EA in hexanes to give the title product (a mixture of keto and enol forms).

Synthesis of 6-fluoro-1,4-dimethylquinolin-2(1H)-one (109B):

A mixture of 109A (0.250 g, 1.20 mmol) and concentrated H ₂ SO ₄ (5.53 g, 56.4 mmol) was heated at 95°C for 2 hours. Once complete, the reaction mixture was poured onto ice. The precipitate was filtered to obtain the title product, which was used without further purification.

Synthesis of 6-fluoro-1,4-dimethylquinolin-2(1H)-one (109C):

109B (0.210 g, 1.10 mmol), NBS (0.489 g, 2.75 mmol) and CH3CN (11 ml) were added to a microwave reactor vial and the mixture was heated at 100°C for 1 hour. The precipitate was filtered to give of the title compound and used without further purification.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-fluoro-1,4-dimethyl -2-oxo1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (109):

The title compound was prepared according to the method presented for the synthesis of compound 113, starting at 109C. MS (m/z) 671.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.82 (dd, J=9.8, 6.2 Hz, 3H), 7.807.49 (m, 6H), 6.76 (d, J= 9.4 Hz, 1H), 6.49-6.38 (m, 2H), 4.72 (ddd, J=10.6, 8.3, 4.2 Hz, 1H), 4.29 (d , J=8.5 Hz, 2H), 3.81 (d, J=4.1 Hz, 3H), 3.65 (d, J=2.6 Hz, 1H), 3.35 (dd, J =14.3, 10.5 Hz, 1H), 2.06 (d, J=9.3 Hz, 3H), 1.75 (ddd, J=13.8, 7.4, 3.3 Hz, 1H), 1.51 (ddd, J=13.7, 10.4, 7.0 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 110.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (110A):

LiOH (64.0 mg, 2.67 mmol) and the mixture was heated at 65°C for 3 hours.

- 104 045366

The precipitate was filtered off to obtain the title compound and used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (110B):

110A (0.200 g, 1.05 mmol), NIS (0.828 g, 3.68 mmol), LiOAc (0.104 g, 1.58 mmol) and DMF/water (9:1, 12 mL) were added to the microwave reactor vial ). The reaction mixture was then stirred under microwave heating at 120° C. for 1 hour. The solvent was removed under reduced pressure and the material was used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (110C):

NaH (32.0 mg, 1.00 mmol) was added to a solution of 110B (0.275 g, 1.01 mmol) in DMF (5 mL) at 0°C. The mixture was stirred for 5 min at 0°C followed by the addition of iodomethane (0.187 g, 1.31 mmol). The cold bath was removed and the mixture was stirred for 45 min at RT. Once complete, the solvent was removed under reduced pressure and the material was purified by flash chromatography using MeOH in DCM (0-25%) to give the title compound.

(S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(8-( 1 -methyl-2- Oxo-1,2-dihydro-1,7-naphthyridin-3-yl)quinolin-5-yl)propanoic acid (110):

The title compound was prepared according to the method presented for the synthesis of compound 113, starting at 110C. MS (m/z) 640.2 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.01 (s, 1H), 8.87-8.79 (m, 2H), 8.65 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.01 (s, 1H), 7.77-7.68 (m, 2H), 7.65-7.57 (m, 2H), 6.78 (d , J=9.4 Hz, 1H), 6.50-6.42 (m, 2H), 4.72-4.64 (m, 1H), 4.36-4.25 (m, 1H), 3.77 (s, 5H), 3.75-3.69 (m, 8H), 3.43 (dd, J=13.8, 9.4 Hz, 3H), 1.83-1.73 ( m, 1H), 1.60-1.47 (m, 1H), 0.93 (t, J=7.4 Hz, 3H).

Example 111 Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (111A)

To a suspension of methyl 2-oxo-4-(trifluoromethyl)-1,2-dihydro-1,7-naphthyridine-3-carboxylate (0.109 g, 0.534 mmol) in THF/H2O (1:1/0.76 ml) LiOH (64.0 mg, 2.67 mmol) was added and the mixture was heated at 65°C for 3 hours. The precipitate was filtered to give the title compound and used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (111B):

111A (0.200 g, 1.05 mmol), NIS (0.828 g, 3.68 mmol), LiOAc (0.104 g, 1.58 mmol) and DMF/water (9:1, 12 ml) were added to the microwave reactor vial ). The reaction mixture was then stirred under microwave heating at 120°C for 1 hour. The solvent was removed under reduced pressure and the material was used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (111C):

NaH (32.0 mg, 1.00 mmol) was added to a solution of 111B (0.275 g, 1.01 mmol) in DMF (5 ml) at 0°C. The mixture was stirred for 5 min at 0°C followed by the addition of iodomethane (0.187 g, 1.31 mmol). The cold bath was removed and the mixture was stirred for 45 min at RT. Once complete, the solvent was removed under reduced pressure and the material was purified by flash chromatography using MeOH in DCM (0-25%) to give the title compound.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)αmino)benzamido)-3-(8-(1-methyl-2- Oxo-4-(trifluoromethyl)-1,2-dihydro-1,7-naphthyridin-3-yl)quinolin-5-yl)propanoic acid (111):

The title compound was prepared according to the method presented for the synthesis of compound 113, starting at 111C. MS (m/z) 708.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=2.2 Hz, 1H), 8.86-8.75 (m, 2H), 8.61 (t, J=8, 8 Hz, 2H), 7.76 (d, J=5.2 Hz, 1H), 7.60 (ddd, J=18.7, 8.8, 5.3 Hz, 3H), 7.24 ( dd, J=36.0, 7.8 Hz, 1H), 6.76 (t, J=7.4 Hz, 1H), 6.57-6.36 (m, 2H), 4.70 (s , 1H), 4.32 (s, 1H), 3.79 (s, 3H), 3.77-3.61 (m, 1H), 2.89 (d, J=2.2 Hz, 1H) , 2.81 -2.65(m, 1H), 1.77 (dd, J=14.3, 7.2 Hz, 1H), 1.61-1.44 (m, 1H), 1.24 (s, 1H), 0.93 (t, J=7.4 Hz, 3H).

Example 112 Synthesis of 2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid (112A)

To a stirred solution of 4-aminonicotinaldehyde (0.15 g, 1.2 mmol) in EtOH (2 ml) was added Meldrum's acid (0.17 g, 1.2 mmol), piperidine (10 μl, 0.13 mmol) and acetic acid (20 µl, 0.36 mmol). The reaction mixture was stirred at RT for 20 minutes and then heated at 100°C for 2 hours. After cooling to RT, the product was filtered, washed with EtOH and dried under vacuum to give the title compound.

112С 112

Synthesis of 3-iodo-1,6-naphthyridin-2(1H)-one (112B):

NIS (331 mg, 1.47 mmol) and LiOAc were added to a microwave reactor vial (10 mL) containing a solution of compound 112A (80 mg, 0.42 mmol) in DMF/water (9:1, 5 mL). (42 mg, 0.63 mmol). The vial was sealed and then heated using microwave radiation at 120°C for 30 minutes. After cooling, water was added and the mixture was extracted by adding DCM. The organic layer was washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used without further purification.

Synthesis of 3-iodo-1-methyl-1,6-naphthyridin-2-one (112C):

To a stirred solution of compound 112B (114 mg, 0.42 mmol) in DMF (4 ml) at 0°C was added sodium hydride (60%, 20 mg, 0.5 mmol) and the mixture was stirred for 10 min at 0°C followed by the addition of MeI (31 μl, 0.5 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 30 min. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The title compound was purified by silica gel chromatography using MeOH in DCM as eluent to give the title compound.

(S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1-methyl-2- Oxo-1,2dihydro-1,6-naphthyridin-3-yl)quinolin-5-yl)propanoic acid (112):

The title compound was prepared according to the method presented for the synthesis of compound 113, starting at 112C. MS (m/z) 640.3 [M+H]+. ^1H NMR (400 MHz, DMSO^) δ 9.16 (s, 1H), 8.87-8.81 (m, 2H), 8.79 (d, J=6.6 Hz, 1H), 8 .67 (d, J=8.6 Hz, 1H), 8.19 (s, 1H), 7.87 (d, J=6.6 Hz, 1H), 7.72 (d, J=7, 3 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.63 (d, J=7.4 Hz, 1H), 6.78 (d, J= 9.4 Hz, 1H), 6.46 (d, J=11.6 Hz, 2H), 4.76 - 4.61 (m, 1H), 4.31 (d, J=8.8 Hz, 1H), 3.76 (d, J=4.6 Hz, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.5, 9.9 Hz, 1H), 1, 78 (ddd, J=13.7, 7.2, 3.2 Hz, 1H), 1.61-1.50 (m, 1H), 0.93 (t, J=7.3 Hz, 3H) .

Example 113.

Synthesis of methyl-(S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)ben- 106 045366 zamido)propanoate ( 113A):

The title compound was prepared according to the method presented for the synthesis of compound 16A in Example 16, starting at 74C.

Synthesis of (5-((S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acids (113V):

The title compound was prepared according to the method presented for the synthesis of compound 4B, starting with 113A.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,3-dimethyl- 2,4-dioxo1,2,3,4-tetrahydropyrimidin-5-yl)quinolin-5-yl)propanoic acid (113):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 5-bromo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione. MS (m/z) 620.2 [M+H]+. ¹ H NMR (400 MHz, DMSO-06) δ 8.98-8.83 (m, 1H), 8.78 (dd, J=15.0, 8.3 Hz, 2H), 7.92 (s , 1H), 7.79-7.64 (m, 2H), 7.60 (d, J=7.4 Hz, 1H), 6.84-6.69 (m, 1H), 6.43 ( d, J=11.6 Hz, 2H), 4.63 (td, J=9.3, 4.5 Hz, 1H), 4.30 (d, J=10.0 Hz, 1H), 3, 70 (dd, J=14.4, 4.5 Hz, 1H), 3.39 (s, 4H), 3.24 (s, 3H), 1.75 (ddt, J=15.0, 7, 7, 3.9 Hz, 1H), 1.51 (ddt, J=17.8, 14.5, 7.3 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 114.

1. 113V,\/XPhos Pd G3

N^< aq. K3PO4 O=\ 9—Br -------

2. LiOH ΤΓΦ ' O (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(8-( 1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)quinolin-5-yl)propanoic acid (114):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 5-bromo-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione. MS (m/z) 634.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=4.3 Hz, 1H), 8.78 (dd, J=8.0, 2.3 Hz, 1H), 7, 76-7.44 (m, 3H), 6.78-6.67 (m, 1H), 6.41 (dd, J=11.3, 3.5 Hz, 2H), 4.73-4, 57 (m, 1H), 4.29 (s, 1H), 3.72 (ddd, J=56.2, 14.3, 4.5 Hz, 1H), 3.45 (d, J=1, 6 Hz, 4H), 3.21 (d, J=2.4 Hz, 3H), 1.92 (d, J=10.1 Hz, 3H), 1.75 (ddd, J=13.6, 7.3, 3.2 Hz, 1H), 1.50 (ddd, J=13.7, 10.3, 7.0 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H ).

Example 115.

1.113B, F /=0

XPhos Pd G3 \ / HN 0 aq. K3PO4 l—l }—\

2. ίίΟΗ,ΤΓΦ N115 (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-( 1,4,5,6-tetramethyl-2oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (115):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 3-bromo-1,4,5,6-tetramethylpyridin-2(1H)-one. MS (m/z) 631.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.91-8.86 (m, 1H), 8.79 (dd, J=7.8, 3.0 Hz, 1H), 7.80-7 .71 (m, 1H), 7.66 (dd, J=11.8, 7.3 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.76 (dd, J=9.2, 4.4 Hz, 1H), 6.47-6.39 (m, 2H), 4.77-4.66 (m, 1H), 4.36-4.25 (m, 1H), 3.71-3.64 (m, 2H), 3.53 (s, 1H), 3.49 (s, 3H), 3.37 (dd, J=13.8, 10.2 Hz , 1H), 2.43 (s, 3H), 2.32 (s, 1H), 2.09 (d, J=6.8 Hz, 3H), 1.75 (d, J=10.8 Hz , 3H), 1.58-1.47 (m, 1H), 0.92 (t, J=7.3 Hz, 3H).

- 107 045366

Example 116.

1.113V, F >0

116 (S)-3-(8-(5-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2,6-difluoro) -4-(((R)1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoic acid (116):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 3-bromo-5-chloro-1,6-dimethylpyridin-2(1H)-one.

MC (m/z) 637.3 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (dd, J=4.5, 1.5 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 8, 81 (d, J=8.0 Hz, 1H), 7.82-7.72 (m, 2H), 7.65 (d, J=7.5 Hz, 1H), 7.58 (s, 1H ), 6.78 (d, J=9.4 Hz, 1H), 6.45 (d, J=11.7 Hz, 2H), 4.72 - 4.62 (m, 1H), 4.37 -4.23 (m, 1H), 3.74 (dd, J=14.5, 4.6 Hz, 1H), 3.56 (s, 3H), 3.44 (dd, J=14.5 , 9.8 Hz, 1H), 2.58 (s, 3H), 1.84-1.70 (m, 1H), 1.60-1.45 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 117 ,6trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)quinolin-5-yl)propanoic acid (117)

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 3-chloro-1,5,6-trimethylpyrazin-2(1H)-one. MS (m/z) 618.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSOL) δ 8.91 (d, J=4.4 Hz, 1H), 8.80 (d, J=7.9 Hz, 2H), 7.84-7.69 (m , 2H), 7.64 (d, J=7.4 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.45 (d, J=11.6 Hz, 2H ), 4.68 (dt, J=8.6, 4.1 Hz, 1H), 4.36-4.29 (m, 1H), 3.73 (dd, J=14.4, 4.6 Hz, 1H), 3.53 (s, 3H), 3.45 (dd, J=14.4, 9.7 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H ), 1.77 (ddd, J=13.8, 7.2, 3.3 Hz, 1H), 1.57-1.47 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

113B,\XPhos Pd G3

VN water K3PO4\^-Cl-------

2. LiOH THF/O

Example 118.

1.113B,

XPhos Pd G3

N-x WATER.KZRO4 —Br ------

2. LiOH THF ^z O (S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(8-( 1,2-dimethyl-6-oxo-1,6dihydropyrimidin-5-yl)quinolin-5-yl)propanoic acid (118).

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 5-bromo-2,3-dimethylpyrimidin-4(3H)-one. MS (m/z) 604.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J=4.3, 1.5 Hz, 1H), 8.80 (d, J=7.9 Hz, 1H), 8.70 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 7.68 (dd, J=7.9, 3.9 Hz, 2H), 7.59 (d, J= 7.4 Hz, 1H), 6.77 (d, J=9.4 Hz, 1H), 6.44 (d, J=11.5 Hz, 2H), 4.70 - 4.55 (m, 1H), 4.30 (s, 1H), 3.70 (dd, J=14.4, 4.6 Hz, 1H), 3.53 (s, 3H), 3.41 (dd, J=14 ,5, 9.8 Hz, 1H), 2.62 (s, 3H), 1.77 (ddd, J=13.7, 7.3, 3.2 Hz, 1H), 1.52 (ddd, J=13.7, 10.4, 7.2 Hz, 1H), 0.92 (t, J=7.3 Hz, 3H).

- 108 045366

Example 119.

119 (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,4-dimethyl -6-oxo-1,6dihydropyridazin-3-yl)quinolin-5-yl)propanoic acid (119):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 6-chloro-2,5-dimethylpyridazin-3(2H)-one. MS (m/z) 604.2 [M+H]+. 1H NMR (400

MHz, DMSO-06) δ 8.87 (dd, J=4.2, 1.5 Hz, 1H), 8.76 (d, J=8.1 Hz, 1H), 8.64 (dd, J =8.7, 1.6 Hz, 1H), 7.70-7.56 (m, 3H), 6.86 (d, J=1.4 Hz, 1H), 6.75 (d, J= 9.4 Hz, 1H), 6.42 (d, J=11.6 Hz, 2H), 4.67 (t, J=11.3 Hz, 1H), 4.29 (d,

J=9.4 Hz, 1H), 3.72 (dd, J=14.3, 4.5 Hz, 1H), 3.64 (s, 3H), 3.39 (dd, J=14.3 , 10.1 Hz, 1H), 1.74 (d, J=1.2 Hz,

4H), 1.50 (ddd, J=13.7, 10.4, 7.1 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).

Example 120.

120 (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(3-methoxy-6 -methylpyridin-2-yl)quinolin-5-yl)propanoic acid (120):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 2-bromo-3-methoxy-6-methylpyridine. MS (m/z) 603.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 8.88 (dd, J=11.7, 5.9 Hz, 2H), 8.74 (d, J=8.6 Hz, 1H), 8.16 (s, 1H), 7.85 (d, J=24.9 Hz, 2H), 7.71 (d, J=7.1 Hz, 2H), 6.79 (d, J=9.4 Hz , 1H), 6.46 (d, J=12.0 Hz, 2H), 4.70 (s, 1H), 4.31 (d, J=10.1 Hz, 1H), 3.79 (s , 4H), 3.50 - 3.41 (m, 1H), 2.62 (s, 3H), 1.77 (s, 1H), 1.54 (dd, J=15.7, 7.7 Hz, 1H), 0.93 (t, J=7.0 Hz, 3H).

Example 121.

Synthesis of 4-(4-bromo-3,5-dimethoxybenzyl)morpholine (121A):

To a stirred solution of (4-bromo-3,5-dimethoxyphenyl)methanol (300 mg, 1.214 mmol) in DCM (3 mL) was added N,N-diisopropylethylamine (0.306 mL, 2.428 mmol). Methanesulfonyl chloride (0.094 mL, 1.214 mmol) was added dropwise and the reaction mixture was allowed to stir at RT for 5 min. Morpholine (0.134 mL, 3.642 mmol) was added dropwise and the reaction mixture was left stirring at RT for 14 hours. The reaction mixture was concentrated under reduced pressure, dissolved in toluene (2 mL) and concentrated again under reduced pressure to give the title compound without additional cleaning.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(2,6-dimethoxy- 4-(morpholinomethyl)phenyl)quinolin-5-yl)propanoic acid (121):

The title compound was prepared according to the method presented for the synthesis of compounds 5B and 5, starting with 113B and 121A. MS (m/z) 717.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 10.01 (s, 1H), 8.84 (d, J=7.9 Hz, 1H), 8.75 ( dd, J=4.2, 1.6 Hz, 1H), 8.60 (d, J=8.5 Hz, 1H), 7.57 (dd, J=16.9, 8.0 Hz, 2H ), 7.40 (d, J=7.3 Hz, 1H), 6.91 (q, J=1.3 Hz, 2H), 6.78 (d, J=9.4 Hz, 1H), 6.44 (d, J=11.5 Hz, 2H), 4.66 (td, J=8.8, 8.1, 4.3 Hz, 1H), 4.39 (s, 2H), 4 .30 (d, J=9.5 Hz, 1H), 4.02 (d, J=12.6 Hz, 2H), 3.70 (t, J=12.1 Hz, 5H), 3.58 (d, J=5.6 Hz, 6H), 3.38 (dd, J=14.2, 10.2 Hz, 3H), 3.19 (d, J=10.8 Hz, 3H), 1 .76 (ddt, J=10.7, 7.3, 3.1 Hz, 1H), 1.51

- 109 045366 (ddt, J=17.5, 14.2, 7.3 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 122. Synthesis of methyl (S)-2-amino-3-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinolin]5-yl)propanoate (122A )

The title compound was prepared according to the method presented for the synthesis of compound 91C and

91D, starting with 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one.

2.TFU, TES

1. 91V, XPhos Pd G3 aq. KZRO4

2. Ι,ίΟΗ,ΤΓΦ

122

1.74C. HATU TEA, DCM (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(4-methoxy-1 -methyl-2-oxo1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (122):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting with 122A. MS (m/z) 669.3 [M+H]+. 1H NMR (400 MHz, DMSO-d^) δ 8.95 (d, J=5.1 Hz, 2H), 8.81 (dd, J=8.2, 2.6 Hz, 1H), 7, 97 (dt, J=8.0, 1.9 Hz, 1H), 7.89-7.66 (m, 4H), 7.68-7.59 (m, 1H), 7.42-7, 32 (m, 1H), 6.77 (d, J=9.4 Hz, 1H), 6.44 (dd, J=11.5, 8.0 Hz, 2H), 4.80-4.69 (m, 1H), 4.37-4.22 (m, 1H), 3.76-3.52 (m, 4H), 3.30 (d, J=2.1 Hz, 3H), 1, 84-1.70 (m, 1H), 1.61-1.44 (m, 1H), 0.92 (td, J=7.4, 2.4 Hz, 3H).

Example 123.

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one (123A):

To a stirred solution of 1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one (243 mg, 1.07 mmol) in THF, LiMg-TMP (1.74 ml, 1 M) was added dropwise at -78°C . The reaction mixture was left to stir for 30 minutes, then a solution of iodine (488 mg, 2 mmol) in THF was added at -78°C. The reaction mixture was allowed to warm to RT, then concentrated under reduced pressure, and purified by silica gel chromatography using EA/hexanes as eluent to give the title compound.

(S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(1-methyl-2-oxo-4 -(trifluoromethyl)-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (123):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 123A. MS (m/z) 707.2 [M+H]+. 1H NMR (400 MHz, DMSO-d^) δ 8.85-8.77 (m, 2H), 8.65 (d, J=8.6 Hz, 1H), 7.91 (d, J=8 ,1 Hz, 1H), 7.85-7.72 (m, 2H), 7.67-7.57 (m, 2H), 7.54 (t, J=7.3 Hz, 1H), 7 .46 (t, J=7.7 Hz, 1H), 6.76 (dd, J=9.4, 5.6 Hz, 1H), 6.45 (dd, J=11.4, 3.7 Hz, 2H), 4.70 (tt, J=8.8, 4.7 Hz, 1H), 4.39-4.24 (m, 1H), 3.80-3.63 (m, 4H) , 3.44 (ddd, J=35.4, 14.5, 9.8 Hz, 1H), 1.85-1.69 (m, 1H), 1.60-1.43 (m,

1H), 0.93 (t, J=7.3 Hz, 3H).

Example 124.

- 110 045366

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one (124A):

The title compound was prepared according to the method presented for the synthesis of compound 123A, starting with 6-fluoro-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(1 -methyl-2-oxo-4 -(trifluoromethyl)-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (124):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 124A. MS (m/z) 724.9 [M+H]+. ^1H NMR (400 MHz, DMSOL) δ 8.95-8.70 (m, 2H), 8.62 (d, J=8.6 Hz, 1H), 6.75 (dd, J=9.4 , 5.6 Hz, 1H), 6.43 (dd, J=11.3, 3.7 Hz, 2H), 4.76-4.62 (m, 1H), 4.28 (s, 2H) , 3.69 (d, J=2.0 Hz, 3H), 3.43 (d, J=47.0 Hz, 1H), 1.89-1.69 (m, 1H), 1.51 ( dt, J=17.5, 7.4 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 125.

125A 125

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one (125A):

The title compound was prepared according to the method presented for the synthesis of compound 123A, starting with 6-(dimethylamino)-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1 -trifluorobutan-2-yl)amino)benzamido)-3 -(6-(dimethylamino)-1 -methyl2 -oxo-4-(trifluoromethyl)-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (125):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 125A. MS (m/z) 724.9 [M+H]+. ^1H NMR (400 MHz, DMSO) δ 8.95-8.70 (m, 2H), 8.62 (d, J=8.6 Hz, 1H), 6.75 (dd, J=9.4 , 5.6 Hz, 1H), 6.43 (dd, J=11.3, 3.7 Hz, 2H), 4.76-4.62 (m, 1H), 4.28 (s, 2H) , 3.69 (d, J=2.0 Hz, 3H), 3.43 (d, J=47.0 Hz, 1H), 1.89-1.69 (m, 1H), 1.51 ( dt, J=17.5,7.4 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 126.

N.H.

126A 126

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (126A):

The title compound was prepared according to the method presented for the synthesis of compound 123A, starting with 1 -methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(8-( 1 -methyl-2- Oxo-4-(trifluoromethyl)-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)quinolin-5-yl)propanoic acid (126): The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 126A. MS (m/z) 697.3 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.89-8.75 (m, 2H), 8.68 (d, J=8.1 Hz, 1H), 7.65 (dt, J=8 ,9, 4.9 Hz, 1H), 7.58 (dd, J=7.4, 5.8 Hz, 1H), 7.43 (dd, J=7.3, 5.4 Hz, 1H) , 6.76 (dd, J=9.4, 6.4 Hz, 1H), 6.56 (q, J=1.1 Hz, 1H), 6.44 (dd, J=11.4, 4 ,9 Hz, 2H), 4.77-4.53 (m, 1H), 4.30 (s, 1H), 3.863.56 (m, 1H), 3.10 (q, J=7.2, 6.8 Hz, 2H), 2.98 (dt, J=17.6, 7.4 Hz, 3H), 2.85-2.72 (m, 2H), 2.24-1.98 (m , 3H), 1.89-1.67 (m, 1H), 1.53 (ddd, J=13.7, 10.3, 7.0 Hz, 1H), 0.93 (t, J=7 ,3 Hz, 3H).

- 111 045366

Example 127.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-fluoro-1,2-dimethyl -4-oxo1,4-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (127):

The title compound was prepared according to the method presented for the synthesis of compounds 11A and 11, starting with 113B and 3-bromo-6-fluoro-1,2-dimethylquinolin-4(1H)-one. MS (m/z) 671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (d, J=3.9 Hz, 2H), 8.84-8.78 (m, 1H), 8.01 (dd, J=9 ,6, 4.4 Hz, 1H), 7.84-7.79 (m, 1H), 7.78-7.65 (m, 3H), 7.60 (dd, J=12.7, 8 ,4 Hz, 1H), 6.76 (dd, J=10.0, 2.5 Hz, 1H), 6.44 (d, J=13.0 Hz, 2H), 4.78-4.68 (m, 1H), 4.35-4.25 (m,2H), 3.90-3.88 (m, 3H), 3.84 (dd, J=14.8, 3.8 Hz, 1H ), 3.71-3.66 (m, 1H), 3.583.51 (m, 1H), 3.38 (dd, J=14.6, 10.5 Hz, 1H), 2.16 (d, J=8.7 Hz, 3H), 1.83-1.71 (m, 1H), 1.59-1.47 (m, 1H), 0.93 (t, J=7.4 Hz, 3H ).

Example 128. Synthesis of (R)-2,6-difluoro-4-((1,1,1-trifluoropropan-2-yl)amino)benzoic acid (128A)

The title compound was prepared according to the method presented for the synthesis of compound 75A from Example 75, starting with (R)-1,1,1-trifluoropropan-2-amine.

(S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluoropropan-2-yl)amino)benzamido)-3 -(8-(1,6-dimethyl- 2-oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (128):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 128A. MS (m/z) 657.2 [M+H]+. ^1H NMR (400 MHz, DMSO^) δ 8.80 (t, J=6.0 Hz, 2H), 8.60 (d, J=8.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.46-7.33 (m, 1H), 6.88-6.76 (m, 1H), 6.53 (s, 1H), 6.40 (dd, J=11 ,2, 4.3 Hz, 2H), 4.65 (dt,J=13.4, 4.7 Hz, 1H), 4.50 (dd, J=15.4, 7.7 Hz, 1H) , 3.73-3.56 (m, 2H), 3.47 (d, J=2.2 Hz, 4H), 3.16-3.03 (m, 1H), 2.51 (s, 2H ), 1.27-1.23 (m, 4H).

Example 129.

75A 129 (S)-2-(2,6-Difluoro-4-((R)-2-(trifluoromethyl)piperidin-1-yl)benzamido)-3-(8-(1,6-dimethyl-2- Oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (129):

The title compound was prepared according to the method presented for the synthesis of compound 75, starting with 91D. MS (m/z) 697.8 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (dd, J=7.8, 4.2 Hz, 1H), 8.86 (d, J=4.0 Hz, 1H), 8, 73 (d, J=7.7 Hz, 1H), 7.74-7.64 (m, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.48 (dd, J =7.1, 3.7 Hz, 1H), 6.73 (dd, J=11.9, 4.0 Hz, 2H), 6.57 (s, 1H), 5.00-4.87 ( m, 1H), 4.77-4.71 (m, 1H), 3.73 (td, J=19.1, 14.5, 4.2 Hz, 1H), 3.66-3.56 ( m, 1H), 3.53-3.37 (m, 4H), 3.02 (t, J=12.4 Hz, 1H), 2.54 (s, 3H), 1.97 (d, J =14.5 Hz, 1H), 1.871.67 (m, 2H), 1.67-1.43 (m, 3H).

- 112 045366

Example 130.

130A 130

Synthesis of (S)-4-(3-(2,2-difluoroethyl)morpholino)-2,6-difluorobenzoic acid (130A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (S)-3-(2,2-difluoroethyl)morpholine.

(S)-2-(4-((S)-3-(2,2-Difluoroethyl)morpholino)-2,6-difluorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4 (trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (130):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 130A. MS (m/z) 695.2 [M+H]+. ^1H NMR (400 MHz, DMSO-06) δ 8.85 (d, J=10.4 Hz, 2H), 8.72 (s, 1H), 7.65 (s, 1H), 7.52 ( d, J=10.0 Hz, 1H), 6.78 (d, J=9.3 Hz, 1H), 6.46 (d, J=12.0 Hz, 2H), 6.40 (d, J=3.6 Hz, 1H), 4.67 (s, 1H), 4.32 (s, 1H), 3.66 (d, J=3.2 Hz, 7H), 3.44 (s, 5H), 1.77 (s, 1H), 1.55 (d, J=15.1 Hz, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 131.

131A 131

Synthesis of (S)-2,6-difluoro-4-(3-(2,2,2-trifluoroethyl)morpholino)benzoic acid (131A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (S)-3-(2,2,2-trifluoroethyl)morpholine.

(S)-2-(2,6-Difluoro-4-((S)-3-(2,2,2-trifluoroethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2- Oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (131):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 131A. MS (m/z) 713.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (dd, J=7.9, 4.2 Hz, 1H), 8.86-8.77 (m, 1H), 8.65 (s , 1H), 7.63 (dd, J=8.7, 4.4 Hz, 1H), 7.57 (t, J=7.1 Hz, 1H), 7.44 (dd, J=7, 3, 4.5 Hz, 1H), 6.66-6.50 (m, 3H), 4.78-4.66 (m, 1H), 4.28 (s, 1H), 3.89 (dd , J=11.4, 3.6 Hz, 1H), 3.78 (d,J=11.9 Hz, 1H), 3.67 (dd, J=22.0, 13.3 Hz, 2H) , 3.57-3.36 (m, 6H), 3.07 (td, J=12.6, 3.8 Hz, 1H), 2.77 (ddd, J=15.4, 11.8, 8.1 Hz, 1H), 2.53 (s, 3H), 2.39-2.20 (m, 1H).

Example 132.

76A 132 (S)-2-(2,6-Difluoro-4-((R)-2-(trifluoromethyl)pyrrolidin-1 -yl)benzamido)-3 -(8-( 1,6-dimethyl-2- Oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (132):

The title compound was prepared according to the method presented for the synthesis of compound 76, starting with 91D. MS (m/z) 683.7 [M+H]+. 1H NMR (400 MHz, DMSOL) δ 8.89 (dd, J=8.0, 3.8 Hz, 1H), 8.84 (dd, J=4.3, 1.5 Hz, 1H), 8 .70 (t, J=7.6 Hz, 1H), 7.71-7.63 (m, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.47 (dd, J=7.3, 4.1 Hz, 1H), 6.56 (t,J=1.1 Hz, 1H), 6.49 (dd, J=11.3,4.1 Hz, 2H), 4.83-4.66 (m, 2H), 3.72 (td, J=15.5, 4.6 Hz, 1H), 3.58 (t, J=8.5 Hz, 1H), 3 .53-3.36 (m, 4H), 3.18 (q, J=8.8 Hz, 1H), 2.54 (s, 3H), 2.19-1.93 (m, 4H).

Example 133. Synthesis of 2,6-difluoro-4-(propylamino)benzoic acid (133A)

The title compound was prepared according to the method presented for the synthesis of compound 75A,

- 113 045366 starting with propan-1-amine.

(S)-2-(2,6-difluoro-4-(propylamino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2dihydropyridin-3-yl )quinolin-5-yl)propanoic acid (133):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 133A. MS (m/z) 603.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.82 (d, J=4.1 Hz, 1H), 8.65 (dd, J=7.8, 5.4 Hz, 2H), 7, 63 (dd, J=8.4, 4.1 Hz, 1H), 7.60-7.53 (m, 1H), 7.44 (dd, J=7.3, 3.0 Hz, 1H) , 6.55 (s, 1H), 6.15 (dd, J=11.6, 4.4 Hz, 2H), 4.74-4.61 (m, 1H), 3.78-3.61 (m, 1H), 3.49 (d, J=1.9 Hz, 3H), 3.47-3.36 (m, 1H), 2.97 (t, J=7.0 Hz, 2H) , 2.53 (s, 3H), 1.51 (h, J=7.3 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).

133A 133

Example 134.

134A 134

Synthesis of (S)-4-(sec-butylamino)-2,6-difluorobenzoic acid (134A):

The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (8)-butan-2-amine.

(S)-2-(4-(((S)-sec-butyl)amino)-2,6-difluorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl) 1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (134):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 134A. MS (m/z) 617.2 [M+H]+. ^1H NMR (400 MHz, DMSOM) δ 8.86-8.77 (m, 1H), 8.738.57 (m, 2H), 7.63 (dd, J=8.4, 4.1 Hz, 1H ), 7.58 (t, J=6.4 Hz, 1H), 7.48-7.40 (m, 1H), 6.55 (s, 1H), 6.33 (s, 1H), 6 .15 (dd, J=11.7, 4.4 Hz, 2H), 4.67 (dt, J=14.5, 5.6 Hz, 1H), 3.77-3.62 (m, 1H ), 3.49 (d, J=2.0 Hz, 3H), 3.47-3.24 (m, 2H), 2.53 (s, 3H), 1.57-1.31 (m, 2H), 1.06 (d, J=6.3 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H).

Example 135.

87A 135 (S)-2-(2,6-Difluoro-4-(methyl((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-( 1,6 -dimethyl-2oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (135):

The title compound was prepared according to the method presented for the synthesis of compound 87, starting with 91D. MS (m/z) 671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (dd, J=7.9, 2.5 Hz, 1H), 8.84 (dd, J=4.3, 1.5 Hz, 1H ), 8.69 (s, 1H), 7.72-7.54 (m, 2H), 7.46 (dd, J=7.4, 3.3 Hz, 1H), 6.64 (dd, J=12.0, 4.4 Hz, 2H), 6.56 (d, J=1.5 Hz, 1H), 5.02-4.90 (m, 1H), 4.70 (dt, J =4.7, 2.4 Hz, 1H), 3.72 (td, J=15.0, 4.5 Hz, 1H), 3.543.35 (m, 4H), 2.82 (s, 3H) , 2.54 (s, 3H), 1.38 (d, J=6.7 Hz, 3H).

- 114 045366

Example 136.

136A 136

Synthesis of 2,6-difluoro-4-((2R,5R)-2-methyl-5-(trifluoromethyl)morpholino)benzoic acid (136A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 2-methyl -5-(trifluoromethyl)morpholine. The mixture of stereoisomers was separated into four peaks by supercritical liquid chromatography by chiral SFC (OJ-H column), eluting with 5% TFA in EtOH to give intermediate 136A. The title compound was detected as the first eluting peak.

(S)-2-(2,6-difluoro-4-((2R,5R)-2-methyl-5-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2oxo- 4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (136):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 136A. MS (m/z) 713.2 [M+H]+. 1H NMR (400 MHz, DMSO-06) δ 8.95 (d, J=7.7 Hz, 1H), 8.80 (d,J=4.1 Hz, 1H), 8.61 (d, J =8.4 Hz, 1H), 7.66-7.51 (m, 2H), 7.47-7.35 (m, 1H), 6.75 (dd, J=11.5, 4.4 Hz, 2H), 6.54 (s, 1H), 4.85 (s, 1H), 4.70 (s, 1H), 4.10 (s, 13H), 3.87 (d, J=12 .9 Hz, 1H), 3.69 (d, J=16.9 Hz, 1H), 3.49 (d, J=2.1 Hz, 3H), 3.42 (d, J=20.5 Hz, 4H), 2.53 (s, 4H), 1.20 (d, J=6.6 Hz, 3H).

Example 137.

137A 137

Synthesis of 2,6-difluoro-4-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)benzoic acid (137A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (cis) -2-methyl-3-(trifluoromethyl)morpholine. The mixture of stereoisomers was separated into two peaks by supercritical liquid chromatography by chiral SPC (IG-H column), eluting with 10% TFA in EtOH, to give intermediate 137A. The title compound was detected as the first eluting peak.

(S)-2-(2,6-Difluoro-4-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2oxo- 4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (137):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 91D and 137A. MS (m/z) 712.7 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (dd, J=7.9, 3.4 Hz, 1H), 8.80 (dd, J=4.2, 1.5 Hz, 1H ), 8.61 (d, J=8.7 Hz, 1H), 7.65-7.52 (m, 2H), 7.48-7.38 (m, 1H), 6.74 (dd, J=11.7, 4.5 Hz, 2H), 6.53 (s, 1H), 4.86 (d, J=6.9 Hz, 1H), 4.69 (td, J=9.1 , 8.7, 4.3 Hz, 1H), 3.94 (dd, J=11.4, 3.7 Hz, 1H), 3.85 (s, 1H), 3.48 (d, J= 2.0 Hz, 3H), 3.46 (s, 2H), 3.39 (dd, J=13.9, 9.6 Hz, 1H), 3.08 (dd, J=14.3, 10 .6 Hz, 1H), 2.52 (s, 4H), 1.34-1.24 (m, 3H).

Example 138. Synthesis of 7-fluoro-5-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2yl)methyl)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (138A)

To 34C (676 mg, 1.601 mmol), bis(pinacolato)diboron (813 mg, 3.202 mmol), potassium acetate (471 mg, 4.802 mmol), CataCXium A (86 mg, 0.192 mmol) and tris(dibenzylideneacetone)dipalladium (0 ) (46 mg, 0.080 mmol), dioxane (13.5 ml) was added and the reaction mixture was purged with N ₂ for 10 min. The reaction mixture was sealed, a bottle of N ₂ was attached, and left to stir at 105°C for 14 hours. The reaction mixture was cooled to RT, diluted with EA and filtered. The filtrate was collected and concentrated under reduced pressure to give the title compound without further purification.

- 115 045366

138

Synthesis of 3-(7-fluoro-5-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinolin8-yl)-4-methoxy-1 ,6-dimethylpyridin-2(1H)-one (13 8B):

To a stirred solution of 138A (325 mg, 0.277 mmol), 3-bromo-4-methoxy-1,6-dimethylpyridin2(1H)-one (128 mg, 0.554 mmol) and XPhos Pd G3 (70 mg, 0.083 mmol) in dioxane (5 ml) 1M potassium phosphate (0.96 ml, 0.989 mmol) was added. The reaction mixture was purged with N ₂ for 5 minutes, sealed and left to stir at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with Hex/EA 0-100%, then DCM/ MeOH 0-30% to obtain the title compound.

Synthesis of methyl-(8)-2-amino-3-(7-fluoro-8-(4-methoxy-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl )propanoate (138C): To a stirred solution of 138B (80 mg, 0.162 mmol) in acetonitrile (3.8 ml) was added 2M HCl (0.404 ml, 0.809 mmol). The reaction mixture was left stirring at RT for 2 hours, then concentrated under reduced pressure to give the title compound without further purification.

(S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(7-fluoro-8-(4- methoxy-1,6dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (138):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting at 137C. MS (m/z) 650.6 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (d, J=10.4 Hz, 2H), 8.72 (s, 1H), 7.65 (s, 1H), 7.52 ( d, J=10.0 Hz, 1H), 6.78 (d, J=9.3 Hz, 1H), 6.46 (d, J=12.0 Hz, 2H), 6.40 (d, J=3.6 Hz, 1H), 4.67 (s, 1H), 4.32 (s, 1H), 3.66 (d, J=3.2 Hz, 7H), 3.44 (s, 5H), 1.77 (s, 1H), 1.55 (d, J=15.1 Hz, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 139. Synthesis of methyl (8)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-(tritylamino)propanoate (139A)

The title compound was prepared according to the method presented for the synthesis of compound 91A, starting at 30K.

Synthesis of methyl (8)-3-(8-bromo-3-(dimethylamino)quinolin-5-yl)-2-(tritylamino)propanoate (139B): 139A (445 mg, 0.781 mmol) dissolved in DMF (2, 4 ml) and K ₂ CO ₃ (113 mg, 0.82 mmol) and dimethylamine (4.69 mmol, 2.3 ml, 2.0 M in THF) were added thereto. The reaction mixture was heated to 100°C and stirred for 21.5 hours. After cooling to RT, EA and water were added to the reaction mixture. The aqueous layer was extracted, and the organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-50% EA in hexanes to give the title compound.

Synthesis of (8)-(3-(dimethylamino)-5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronic acid (139C)

The title compound was prepared according to the method presented for the synthesis of compound 4B, starting with 91A.

Synthesis of methyl-(S)-2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3 (dimethylamino)quinoline- 5-yl)propanoate (13 9D)

The title compound was prepared according to the method presented for the synthesis of compound 91C and

- 116 045366

91D, starting at 139C and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3 -(8-(1,6-dimethyl- 2-oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-(dimethylamino)quinolin-5-yl)propanoic acid (139):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting with 139D. MS (m/z) 714.5 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J=7.8 Hz, 1H), 8.62 (t, J=3.0 Hz, 1H), 7.58 (s , 1H), 7.44 (t, J=5.8 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.84-6.73 (m, 1H), 6 .55 (d, J=2.7 Hz, 1H), 6.45 (dd, J=11.3, 3.9 Hz, 2H), 4.67 (dt, J=13.4, 9.0 Hz, 1H), 4.31 (d, J=8.8 Hz, 1H), 3.65-3.54 (m, 1H), 3.48 (d, J=1.7

Hz, 3H), 3.39-3.26 (m, 1H), 3.10 (d, J=3.9 Hz, 6H), 2.53 (s, 3H), 1.77 (ddd, J =10.7, 7.5, 3.7 Hz, 1H), 1.61-1.46 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 140. Synthesis of (8)-(3-fluoro-5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8yl)boronic acid (140A)

The title compound was prepared according to the method presented for the synthesis of compound 4B, starting at 139A.

Synthesis of methyl-(8)-2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3 fluoroquinolin-5-yl )propanoate (140V):

The title compound was prepared according to the method presented for the synthesis of compounds 91C and 91D, starting with 140A and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

- 117 045366 (S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6 -dimethyl-2-oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluoroquinolin-5-yl)propanoic acid (140):

The title compound was prepared according to the method presented for the synthesis of compound 74, starting at 140B. MS (m/z) 689.0 [M+H]+. 1H NMR (400 MHz, DMSO^) δ 8.85 (d, J=2.6 Hz, 1H), 8.81 (d, J=7.9 Hz, 1H), 8.37 (dt, J= 10.6, 3.3 Hz, 1H), 7.60 (t, J=7.4 Hz, 1H), 7.41 (dd, J=7.3, 5.2 Hz, 1H), 6, 77 (d, J=9.3 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J=11.8 Hz, 2H), 4.68 (td, J=8.8 , 4.5 Hz, 1H), 4.31 (d, J=9.1 Hz, 1H), 3.62 (td, J=14.1, 4.4 Hz, 1H), 3.48 (d , J=1.7 Hz, 3H), 3.41 (td, J=15.3, 9.9 Hz, 1H), 2.52 (s, 3H), 1.77 (ddd, J=13, 9, 7.1, 3.3 Hz, 1H), 1.52 (ddd, J=13.6, 10.2, 6.9 Hz, 1H), 0.92 (t, J=7.3 Hz , 3H).

Example 141.

141A 141

Synthesis of (R)-2-fluoro-6-methyl-4-(3-(trifluoromethyl)morpholino)benzoic acid (141A):

The title compound was prepared according to the method presented for the synthesis of compound 93A, starting with methyl 4-bromo-2-fluoro-6-methylbenzoate.

(S)-3-(8-(1,6-Dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2-fluoro6- Methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (141):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 141A and 91D. MS (m/z) 695.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.89-8.77 (m, 2H), 8.63 (d, J=8.6 Hz, 1H), 7.68-7.53 (m , 2H), 7.43 (t, J=7.2 Hz, 1H), 6.71-6.61 (m, 2H), 6.55 (d, J=3.2 Hz, 1H), 4.894 .69 (m, 2H), 4.14 (d,J=12.6 Hz, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.80 -3.64 (m, 2H), 3.59-3.19 (m, 7H), 2.53 (s, 3H), 1.99-1.97 (m, 3H).

Example 142.

Synthesis of (R)-2-fluoro-6-methyl-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (142A):

The title compound was prepared according to the method presented for the synthesis of compounds 74B and 74C, starting with methyl 4-bromo-2-fluoro-6-methylbenzoate.

(S)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2-fluoro6- Methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoic acid (142):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 142A and 91D. MS (m/z) 667.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (dt, J=3.9, 1.8 Hz, 1H), 8.71 (dd, J=9.9, 8.1 Hz, 1H ), 8.63 (d, J=8.5 Hz, 1H), 7.61 (ddd, J=20.7, 9.0, 4.6 Hz, 2H), 7.43 (t, J= 6.8 Hz, 1H), 6.55 (d, J=3.5 Hz, 1H), 6.41-6.34 (m, 2H), 6.28 (d, J=9.2 Hz, 1H), 4.80-4.67 (m, 1H), 4.18 (brs, 1H), 3.71 (ddd, J=28.0, 14.6, 4.0 Hz, 1H), 3 .53-3.29 (m, 4H), 2.53 (s, 3H), 1.95-1.91 (m, 3H), 1.80-1.70 (m, 1H), 1.59 -1.47 (m, 1H), 0.96-0.87 (m, 3H).

Example 143 Synthesis of (R)-2,6-dichloro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (143A) The title compound was prepared according to the method presented for the synthesis of compounds 74B and 74C , starting with tert-butyl-4-bromo-2,6-dichlorobenzoate.

143A 143

- 118 045366 (S)-2-(2,6-Dichloro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6 -dimethyl-2-oxo-4(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (143):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 143A and 91D. MS (m/z) 703.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (dd, J=26.1, 8.3 Hz, 1H), 8.82 (d, J=3.5 Hz, 1H), 8, 66 (d, J=8.6 Hz, 1H), 7.65 (dd, J=18.5, 9.6 Hz, 2H), 7.43 (dd, J=7.4, 3.8 Hz , 1H), 6.77 (s, 1H), 6.55 (q, J=5.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.33 (s, 1H) , 3.69 (ddd, J=19.3, 14.5, 4.0 Hz, 1H), 3.49 (d, J=4.0 Hz, 3H), 3.42-3.31 (m , 1H), 2.53 (s, 3H), 1.85-1.60 (m, 1H), 1.51 (dt, J=11.8, 7.9 Hz, 1H), 0.93 ( td, J=7.3, 3.0 Hz, 3H).

Example 144. Synthesis of (R)-2-chloro-6-fluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (144A)

The title compound was prepared according to the method presented for the synthesis of compounds 74B and 74C, starting with tert-butyl 4-bromo-2-chloro-6-fluorobenzoate.

(S)-2-(2-Chloro-6-fluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6- dimethyl-2-oxo4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (144)

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 144A and 91D. MC (m/z) 687.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (dd, J=12.0, 8.1 Hz, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 7.69-7.54 (m, 2H), 7.43 (d, J=6.2 Hz, 1H), 6.67-6.61 (m, 2H), 6.61-6.51 ( m, 2H), 4.71 (dd, J=23.5, 11.8 Hz, 1H), 4.31 (s, 1H), 3.76-3.63 (m, 1H), 3.49 (d, J=3.4 Hz, 3H), 3.48-3.28 (m, 1H), 2.53 (s, 3H), 1.75 (d, J=8.3 Hz, 1H) , 1.66-1.46 (m, 1H), 1.01-0.88 (m, 3H).

Example 145.

145

Synthesis of tert-butyl-(K)-2-fluoro-5-methyl-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (145B)

The title compound was prepared according to the method presented for the synthesis of compounds 74B and 74C, starting with tert-butyl 4-bromo-2-fluoro-5-methylbenzoate.

(S)-3-(8-(1,6-Dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2-fluoro5- Methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoic acid (145):

The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16, starting with 145B and 91D. MS (m/z) 667.2 [M+H]+. 1H NMR (400 MHz, DMSOL) δ 8.83 (d, J=4.0 Hz, 1H), 8.75 (t, J=11.1 Hz, 1H), 7.94 (d, J=7 ,2 Hz, 1H), 7.60 (dd, J=24.9, 7.1 Hz, 2H), 7.53-7.41 (m, 1H), 7.36-7.18 (m, 1H), 6.76-6.61 (m, 1H), 6.55 (s, 1H), 5.52 (d, J=8.6 Hz, 1H), 4.78 (s, 1H), 4.38 (s, 1H), 3.73 (t, J=13.5 Hz, 1H), 3.59 (dd, J=15.9, 9.6 Hz, 1H), 3.53-3 .41 (m, 3H), 2.53 (d, J=2.3 Hz, 3H), 2.10 (t, J=2.9 Hz, 3H), 1.96- 1.62 (m, 2H), 0.98-0.82 (m, 3H).

Example 146. Synthesis of (R)-3-bromo-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (146A).

To a stirred solution of 74C (216 mg, 0.76 mmol) in dichloroethane (4 ml) was added TFA (0.292

- 119 045366 ml, 3.8 mmol) and N-bromosuccinimide (143 mg, 0.80 mmol) and the mixture was heated to 50°C. After 1 hour, the mixture was added to silica gel and chromatographed, eluting with ethyl acetate in hexanes to give the title compound.

Synthesis of (trimethylsilyl)methyl-2,6-difluoro-3-((E)-3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1yl)-4-(((R )-1,1,1-trifluorobutan-2-yl)amino)benzoate (146B).

Added 146A (230 mg, 0.635 mmol), dioxane (4 mL), (trimethylsilyl)diazomethane solution (1 N ether) (0.635 mL, 0.635 mmol), potassium carbonate (176 mg, 1.3 mmol) to the microwave reactor vial ) tetrakistriphenylphosphine palladium (73.4 mg, 0.06 mmol) and (E)-(3-((tetrahydro-2H-pyran-2yl)oxy)prop-1-en-1-yl)boronic acid (236.31 mg , 1.27 mmol). The vessel was sealed and heated to 110°C for 35 minutes. The mixture was then added to silica gel and chromatographed, eluting with ethyl acetate in hexanes, to give the title compound.

Synthesis of (trimethylsilyl)methyl-(R)-2,6-difluoro-3-(3-hydroxypropyl)-4-((1,1,1-trifluorobutan-2yl)amino)benzoate (146C). 146B (160 mg, 0.314 mmol) was added to a Parr mixing flask with 5% palladium black (25 mg) and the mixture was shaken overnight at 50 PSI (3.06 atm) H2 pressure. The mixture was filtered and HCl in methanol (9 ml, 3N) was added and the mixture was stirred for 4 hours. The volatile components of the mixture were removed by rotary evaporation, dissolved in DCM, washed with sodium bicarbonate (aq) and the residue was subjected to chromatography on silica gel, eluting with methanol in DXM to obtain the title compound.

146C 146D 146E

Synthesis of (trimethylsilyl)methyl-(R)-5,7-difluoro-1-(1,1,1-trifluorobutan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (146D). To a stirred solution of 146C (107 mg, 0.215 mmol) and TEA (0.1 mL, 0.9 mmol) in DCM (1 mL) was added methanesulfonyl chloride (39 μL, 0.5 mmol) and left to stir for 10 min. The mixture was washed with sodium bicarbonate (aq), the volatile components of the organic layer were removed by rotary evaporation and diluted with THF (2 ml), potassium carbonate (173 mg, 1.25 mmol) was added and the mixture was heated to 70°C overnight. The mixture was subjected to chromatography on silica gel, eluting with ethyl acetate in hexanes, to give the title compound.

Synthesis of (R)-5,7-difluoro-1-(1,1,1-trifluorobutan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (146E).

To 146D (95 mg, 0.2 mmol) methanol (10 ml) and lithium hydroxide (4 mg) and water (2 ml) were added and the mixture was stirred over the weekend at 85°C. The mixture was neutralized with HCl in dioxane and the solvents were removed by rotary evaporation. The title compound thus obtained was used without further purification.

(S)-2-(5,7-difluoro-1-((R)-1,1,1-trifluorobutan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamido)-3- (8(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (146): The title compound was prepared according to the method presented for the synthesis connections 16A and 16, starting with 91D and 146E. MS (m/z) 711.3 [M+H]+. ^1H NMR (400 MHz, chloroform-d) δ 9.30 (dd, J=86.9, 8.7 Hz, 1H), 7.87 -7.50 (m, 3H), 7.00 (d, J=35.4 Hz, 1H), 6.53 (d, J=12.4 Hz, 1H), 6.24 (dd, J=14.4, 6.2 Hz, 1H),

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5.00 (dd, J=29.5, 6.2 Hz, 1H), 4.22-3.85 (m, 1H), 3.89-3.64 (m, 1H), 3.56 ( d, J=7.5 Hz, 3H), 3.25 (s, 2H), 2.742.61 (m, 2H), 2.10-1.66 (m, 4H), 0.95 (t, J =7.4 Hz, 3H).

Example 147.

Preparation of (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl2 -oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (147): 91 was separated into its 2 atropisomeric enantiomers by supercritical liquid chromatography using 30% MeOH co-solvent flow rate of 60 ml/min, using an IC 5 µm 21x250 mm column. The title compound was detected as the second eluting peak. MS (m/z) 671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.82 (t, J=6.4 Hz, 2H), 8.67 (d, J=8.7 Hz, 1H), 7.70-7, 50 (m, 2H), 7.45 (d, J=7.3 Hz, 1H), 6.76 (d, J=9.3 Hz, 1H), 6.55 (s, 1H), 6, 43 (d, J=11.9 Hz, 2H), 4.68 (m, 1H), 4.374.24 (m, 1H), 3.67-3.63 (m, 1H), 3.48 (m , 4H), 2.52 (s, 3H), 1.74 (m, 1H), 1.53 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).

Example 148.

Preparation of (8)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((K)-3-(trifluoromethyl)morpholino)benzamido )propanoic acid (148): 89 was separated into its 2 enantiomers by supercritical liquid chromatography using 30% EtOH/TFA co-solvent at a flow rate of 45 ml/min, using an IE 5 µm 21x250 mm column. The title compound was detected as the second eluting peak. MS (m/z) 629.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.86-8.75 (m, 2H), 8.63 (dd, J=8.6, 1.6 Hz, 1H), 8.15 (dd , J=1.6, 0.4 Hz, 1H), 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.66-7.51 (m, 4H), 6, 92 (d, J=9.4 Hz, 1H), 6.40 (d, J=11.8 Hz, 2H), 4.67 (s, 1H), 3.97-3.89 (m, 1H ), 3.72 (s, 1H), 3.40 (s, 1H), 1.03 (ddt, J=13.0, 8.1, 4.2 Hz, 1H), 0.66-0, 55 (m, 1H), 0.55-0.43 (m, 2H), 0.30 (dd, J=9.7, 4.9 Hz, 1H).

Example 355. Synthesis of methyl (8)-3-(8-((diphenylmethylene)amino)quinolin-5-yl)-2-(tritylamino)propanoate (355A)

2,2'bis(diphenylphosphino)-1,1'-binaphthalene (Binap ligand) (1.26 g, 2.029 mmol, 0.10 eq) in dioxane was added to a flame-dried 200 mL flask equipped with a stirrer. (101 ml, 0.2 M) and the flask was evacuated and then purged with N ₂ three times. Bis(dibenzylideneacetone)palladium (Palladium dba) (0.93 g, 1.015 mmol, 0.05 eq) was added and the reaction mixture was allowed to stir at room temperature for 10 minutes. Cesium carbonate (19.83 g, 60.87 mmol, 3 eq), benzophenone imine (6.81 mL, 40.58 mmol, 2 eq) and methyl (8)-3-(8bromoquinoline-5- yl)-2-(tritylamino)propanoate (91A) (11.19 g, 20.29 mmol, 1 eq.), the reaction mixture was heated to 100°C under N ₂ pressure and stirred overnight. The reaction mixture was cooled to room temperature and quenched by adding water (100 ml). The reaction mixture was then extracted with ethyl acetate (100 ml, 3x), the combined organic phases were washed with brine (100 ml) and dry placed on silica gel. Purification was accomplished by chromatography on silica gel, eluting with 20% EtOAc in hexanes until excess iminebenzophenone eluted (−20 min), then the percentage of EtOAc was increased to 25% in hexanes to elute the product. Fractions containing the product were concentrated under vacuum.

Synthesis of methyl (S)-3-(8-aminoquinolin-5-yl)-2-(tritylamino)propanoate (355B): 355A (11.19 g, 17.17 mmol, 1 eq.) dissolved in THF (100 ml), hydroxylamine HCl (4.77 g, 68.67 mmol, 4 eq.) and sodium acetate trihydrate (14.02 g, 103.01 mmol, 6 eq.) were added. MeOH (50 ml) was added and the reaction mixture was left to stir at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and absorbed into prepacked silica gel. Purification was carried out by chromatography on silica gel using 20% EtOAc in hexanes to elute the excess hydroxylimine (-20 min), then the percentage of EtOAc was increased to 25% in hexanes to elute the product. Fractions containing the product were concentrated in vacuo.

Ph Ph nm^ ^P p ^Pd 2dba ₃ , Binap, η N O _ , \_Benzophenonymine,

Br ' 0—

Cs ₂ CO ₃ , Dioxane

Hydroxylamine HCl, sodium acetate trihydrate,

THF, MeOH

Synthesis of methyl-(S)-3-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)isonicotinate (355C):

To a flame-dried flask equipped with a stirrer, add 4-methoxycarbonylpyridine3-carboxylic acid (0.22 g, 1.23 mmol, 1.2 eq), tritylamine (0.43 mL, 3.08 mmol, 3 eq), DPPA (0.24 ml, 1.13 mmol, 1.1 eq.), 355B and toluene (5.12 ml, 0.2 M). The reaction mixture was capped (open to atmosphere) and heated to 50°C for 2 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (50 ml, 3x). The combined organic phases were washed with sat. sodium bicarbonate (25 ml), saline and dried over anhydrous Na ₂ SO ₄ . The organic phases were concentrated and used without further purification.

Synthesis of methyl-(S)-3-(8-(2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2(tritylamino )propanoate (355D): 355C (0.68 g, 1.03 mmol, 1.0 eq.) was dissolved in THF (4 ml) and MeOH (4 ml) and solid potassium carbonate (0.71 g, 5.13 mmol, 5 eq.). The reaction mixture was left to stir for 1 hour at room temperature. The reaction mixture was diluted with water and sat. NH ₄ Cl (4 ml), extracted with EtOAc (20 ml, 3x), washed with brine and dried over Na ₂ SO ₄ . The combined organic phases were concentrated, EtOAc (-10 ml) was added, then hexanes were added dropwise with stirring to form a precipitate. The filtrate was collected and dried under high vacuum.

Synthesis of methyl-(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin5-yl)-2 -(tritylamino)propanoate (355E):

Intermediate 355D (4.05 g, 6.396 mmol, 1.0 eq), potassium carbonate (0.88 g, 6.4 mmol, 1.0 eq) and DMF (32 mL, 0 eq) were added to the flame dried flask. ,2 M). The reaction mixture was stirred for 10 min at room temperature, then methyl tosylate (0.97 mL, 6.4 mmol, 1.0 eq.) was added and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated and purified by chromatography on silica gel, eluting with DCM/MeOH 0-5%.

Synthesis of methyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl2,4-dioxo-1 ,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (355): 355E (1.49 g, 2.29 mmol, 1 eq.) dissolved in DCM (51 mL) and triethylsilane (0.44 mL, 2.75 mmol, 1.2 eq.), and TFA (0.53 mL, 6.88 mmol, 3 eq.) was added. The reaction mixture was left to stir at room temperature for 2 hours and then concentrated. The resulting material was resuspended in DCM and again concentrated in vacuo to remove residual TFA. This substance was used without further purification. The resulting substance (1.47 g, 2.31 mmol, 1.0 eq.), 141A (0.85 g,

- 122 045366

2.78 mmol, 1.2 eq.) and HATU (1.06 g, 2.78 mmol, 1.2 eq.) were added to the vial and dissolved in DMF (10 ml). DIEA (2.42 mL, 13.89 mmol, 6.0 eq.) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc, the organic phases were washed with brine and dried over Na _{2SO4 .} The organic phases were concentrated and purified by silica gel chromatography using DCM/MeOH 0-5%. ER/MS m/z [M+H]: 695.198; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.95-8.80 (m, 2H), 8.71 (dd, J=8.7, 1.6 Hz, 1H), 8.60 (dd, J=4.9, 1.4 Hz, 1H), 7.92 (ddd, J=4.8, 3.8, 0.7 Hz, 1H), 7 .77 (d, J=7.6 Hz, 1H), 7.75-7.63 (m, 2H), 6.73-6.63 (m, 2H), 4.90-4.72 (m , 2H), 4.14 (d, J=12.6 Hz, 1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.83-3.69 (m, 3H), 3.66 (d, J=2.5 Hz, 3H), 3.51 (ddd, J=25.5, 13.6, 9.8 Hz, 2H), 3.35 (d, J =12.2 Hz, 1H), 3.26 (d, J=12.3 Hz, 1H), 2.09-1.95 (m, 3H).

Example 356.

355 356 (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo- 1,4dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoic acid (356): 355 (0.49 g, 0.70 mmol, 1.0 eq.) dissolved in THF (10 ml) and added 1M LiOH (3.5 ml, 5 eq.). The reaction mixture was left to stir at room temperature for 2 hours. 4 M HCl in dioxane (1.75 mL, 10 eq.) was then added to re-cyclize, and the reaction mixture was left to stir for 1 hour. The reaction mixture was concentrated and purified by reverse phase HPLC, lyophilized to give the title compound as the mono-TFA salt. ER/MS (m/z) [M+H]: 681.151 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.92-8.77 (m, 2H), 8.68 (d, J=8.6 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 7.91 (t, J=4.3 Hz, 1H), 7, 76 (d, J=7.6 Hz, 1H), 7.67 (dd, J=8.3, 4.5 Hz, 2H), 6.74-6.58 (m, 2H), 5.004.59 (m, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.99-3.91 (m, 1H), 3.66 (d, J=2.4 Hz, 4H) , 3.59-3.40 (m, 1H), 3.31 (dd, J=35.1, 12.3 Hz, 3H), 2.03 (s, 3H).

Example 357.

356 357 (((S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4- dioxo1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoyl)oxy)methyl pivalate (357): 356 (611 mg, 0.898 mmol) dissolved in acetonitrile (44 ml ) and iodomethyl 2,2-dimethylpropanoate (434.6 mg, 1.8 mmol) and N,N-diisopropylethylamine (0.31 ml, 2 mmol) were added and stirred for 1 hour. The solvents were removed by rotary evaporation and the mixture subjected to reverse phase chromatography to obtain the title compound as the TFA salt. ER/MS (m/z) 735.063 [M+H]; 1H NMR (400 MHz,

DMSO-d ₆ ) δ 9.15-9.00 (m, 2H), 8.85 (d, J=3.9 Hz, 1H), 8.67-8.57 (m, 2H), 7, 91 (ddd, J=5.0, 3.1, 0.8 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.73-7.61 (m, 2H) , 5.83 (s, 2H), 4.85 (d, J=9.2 Hz, 2H), 4.14 (d, J=12.6 Hz, 1H), 4.063.88 (m, 1H) , 3.84-3.68 (m, 2H), 3.65 (d, J=2.2 Hz, 3H), 3.53 (dt, J=14.8, 9.7 Hz, 2H), 3.36 (d, J=12.3 Hz, 1H), 3.26 (d, J=12.1 Hz, 1H), 2.03 (s, 3H), 1.18 (s, 9H).

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Example 358.

356 358

2-(diethylamino)ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1methyl-2,4- dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoate (358):

To 356 (45 mg, 0.066 mmol) was added THF (3 ml), 2-(diethylamino) ethanol (23.24 mg, 0.2 mmol), triphenylphosphine (0.05 g, 0.2 mmol), diethylazodicarboxylate, 95 % (0.1 ml, 0.2 mmol) and DIEA (0.41 ml, 2.28 mmol). The mixture was stirred for 1 hour, then the solvents were removed by rotary evaporation and the mixture was subjected to reverse phase chromatography to obtain the title compound as the TFA salt after lyophilization. ER/MS (m/z) 780.300 [M+H]; 1H NMR (400 MHz, chloroform-d) δ 9.28 (dt, J=4.8, 1.6 Hz, 1H), 9.20 (ddd, J=8.7, 4.6, 1.5 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.62 (dd, J=5.0, 1.6 Hz, 1H), 8.04 (dd, J=24 ,7, 5.0 Hz, 1H), 7.83 (dd, J=8.6, 4.7 Hz, 1H), 7.75 (d, J=1.2 Hz, 2H), 7.46 (d, J=7.0 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.43-6.27 (m, 1H), 5.18 (q, J= 7.6 Hz, 1H), 4.97 (dd, J=12.8, 6.4 Hz, 1H), 4.53 (td, J=9.2, 7.8, 4.6 Hz, 1H ), 4.31 (d, J=12.4 Hz, 1H), 4.16 (ddt, J=19.3, 8.0, 3.3 Hz, 1H), 4.10-3.90 ( m, 2H), 3.82 (dd, J=12.5, 2.2 Hz, 1H), 3.72 (d, J=9.4 Hz, 3H), 3.60 (ddt, J=32 ,1, 17.2, 8.3 Hz, 3H), 3.28 (d, J=12.0 Hz, 1H), 3.223.09 (m, 1H), 3.03 (s, 4H), 2 .32 (s, 3H), 1.49 -1.10 (m, 9H), 1.02 (d, J=7.6 Hz, 2H).

Example 359.

Phenyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (359): 356 (567 mg, 0.833 mmol) was dissolved in THF (5 ml), phenol (0) was added .12 g, 1.25 mmol), TBTU (0.4 g, 1.25 mmol), DIEA (0.44 ml, 2.5 mmol) and DMAP (0.1 g, 0.83 mmol) and stirred reaction mixture for 1 hour. The reaction mixture was then loaded directly onto silica and chromatographed, eluting with ethyl acetate in methanol (0-10%), to give the title compound. ER/MS (m/z) 757.213 [M+H]; ^1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=7.1 Hz, 1H), 9.05 (s, 1H), 8.89-8.83 (m, 1H), 8.76 (d, J=8.6 Hz, 1H), 8.61 (d, J=5.0 Hz, 1H), 7.93 (d, J=5.0 Hz, 1H), 7. 85-7.77 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.64 (m, 1H), 7.487.38 (m, 2H), 7.31- 7.23 (m, 1H), 7.10-7.01 (m, 2H), 6.77-6.69 (m, 1H), 6.68 (s, 1H), 5.09-4, 99 (m, 1H), 4.914.79 (m, 1H), 4.15 (d, J=12.7 Hz, 1H), 4.00-3.89 (m, 1H), 3.89-3 .82 (m, 2H), 3.67 (s, 3H), 3.61-3.49 (m, 2H), 3.43-3.32 (m, 1H), 3.32-3.19 (m, 1H), 2.15-2.05 (m, 3H).

356 359

Example 360.

356 360

Ethyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropyrido[3,4-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoate (3 60):

To a solution of 356 (150 mg, 0.22 mmol) in DMF (1.0 mL) was added triphenylphosphine (173 mg, 0.66 mmol) followed by DIEA (117 μL, 0.66 mmol) and ethanol (129 μL, 2 .2 mmol). DIAD (217 µL, 1.1 mmol) was then added and the reaction mixture was allowed to stir for 2 hours. The reaction mixture was then diluted with EtOAc and washed with water, 10% citric acid, saturated bicarbonate,

- 124 045366 sodium and saturated saline solution, followed by drying the combined organic compounds over sodium sulfate. After filtration, the solvent was removed under reduced pressure and the product was purified by normal phase using a 0-30%, 30-60% and 60-100% 9:1 DCM:MeOH in DCM elution gradient. ER/MS (m/z) [M+H]: 709.2. 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.99 (d, J=7.7 Hz, 1H), 8.84 (dd, J=4.2, 1.4 Hz , 1H), 8.64 (dd, J=8.7, 1.6 Hz, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.91 (dd, J=5, 0, 2.2 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.66 (dt, J=8.6, 2.5 Hz, 2H), 6.76- 6.63 (m, 2H), 4.82 (td, J=14.4, 12.1, 5.3 Hz, 2H), 4.20-4.04 (m, 3H), 3.95 ( dd, J=11.5, 3.6 Hz, 1H), 3.80-3.66 (m, 2H), 3.65 (d, J=1.6 Hz, 3H), 3.60-3 .46 (m, 2H), 3.36 (d, J=13.7 Hz, 1H), 3.31-3.18 (m, 1H), 2.07 (s, 3H), 1.16 ( td, J=7.1, 1.1 Hz, 3H).

Example 361.

356 361

1-((Ethoxycarbonyl)oxy)ethyl-(2S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3 -(8-(1 - Methyl 2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoate (361):

To a solution of 356 (30 mg, 0.044 mmol) in DMF (1 ml) was added potassium carbonate (8.2 mg, 0.132 mmol), followed by sodium iodide (26 mg, 0.176 mmol) and 1-chloroethylethyl carbonate (20 mg, 0.132 mmol) . The reaction mixture was heated to 65°C for 2 hours. The reaction mixture was then cooled to RT and filtered. The resulting filtrate was purified by reverse phase HPLC to give the title compound as the TFA salt. ER/MS (m/z) [M+H]: 797.2 ^1H NMR (400 MHz, DMSOC) δ 9.05 (d, J=5.5 Hz, 2H), 8.90-8.81 (m, 1H), 8.70-8.57 (m, 2H), 7.91 (d, J=5.1 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H) , 7.67 (d, J=7.9 Hz, 2H), 6.74-6.64 (m, 2H), 4.86 (s, 2H), 4.35-4.06 (m, 3H ), 3.95 (d, J=11.0 Hz, 1H), 3.74 (d, J=13.2 Hz, 6H), 3.53 (q, J=14.3, 13.3 Hz , 2H), 3.42-3.13 (m, 2H), 2.03 (d, J=20.9 Hz, 3H), 1.53 (d, J=5.4 Hz, 1H), 1 .38 (d, J=5.4 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H).

Example 362 8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5yl)propanoate (362)

356 (0.52 g, 0.76 mmol) was dissolved in DMF (3 ml) and triphenylphosphine (0.6 g, 2.28 mmol), diisopropyl azodicarboxylate (0.46 ml, 2.28 mmol) was added, (2R) -tetrahydrofuran-2-yl]methanol (0.23 g, 2.28 mmol) and diisopropylethylamine (0.41 ml, 2.28 mmol). The mixture was stirred for 1 hour and subjected to chromatography on silica gel, eluting with ethyl acetate and methanol (0-10%) to obtain the title compound. ER/MS (m/z) 735.063 [M+H]; 1H NMR (400 MHz, DMSO) δ 9.02 (d, J=7.5 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.80 (d, J=11 ,8 Hz, 3H), 5.05-4.84 (m, 1H), 4.58 (q, J=7.5, 6.9 Hz, 1H), 4.17 (d, J=12, 7 Hz, 1H), 4.09-3.92 (m, 7H), 3.74 (q, J=6.0 Hz, 2H), 3.70-3.54 (m, 2H), 3, 24 (t, J=12.5 Hz, 1H), 3.10 (dd, J=14.5, 5.1 Hz, 1H), 2.96 (dd, J=14.4, 9.3 Hz , 1H), 2.76 (d, J=5.3 Hz, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 1.86 (ddq, J=40.9, 13.8, 6.4 Hz, 6H), 1.57 (q, J=8.7, 8.1 Hz, 1H), 1.26 (d, J=12.8 Hz, 2H), 0, 97-0.74 (m, 2H).

356 362

Example 363.

356 363

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Cyclopropyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl2,4-dioxo-1, 4-dihydropyrido[3,4-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoate (363)

To a solution of 356 (0.650 g, 0.955 mmol) in THF (4.80 mL) was added cyclopropyl alcohol (0.166 g, 2.87 mmol), DMAP (0.117 g, 0.955 mmol), DIEA (0.370 g, 2.87 mmol) and TBTU (0.920 g, 2.87 mmol), and the mixture was stirred at 50°C for 25 minutes. Once complete, the reaction mixture was diluted with EtOAc and washed with water (x2). The organic layer was then concentrated under reduced pressure and the residue was purified using flash chromatography, eluting with EtOAc in hexanes 0-100%, then MeOH in EtOAc 0-50%. Suitable fractions were combined and concentrated to obtain the product. The product was then dissolved in DMSO (12 ml) and purified using reverse phase HPLC to give the title compound. ER/MS (m/z) 721.3 [M+H]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.98 (d, J=7.6 Hz, 1H), 8.83 (d, J=4.2 Hz , 1H), 8.61 (dd, J=11.5, 6.8 Hz, 2H), 7.91 (d, J=4.9 Hz, 1H), 7.75 (d, J=7, 6 Hz, 1H), 7.72-7.59 (w,2H), 6.79-6.61 (m, 2H), 4.79 (dd, J=21.2, 12.1 Hz, 2H ), 4.22-4.05 (m, 2H), 4.053.87 (m, 1H), 3.80-3.43 (m, 7H), 3.42-3.21 (m, 4H), 3.21-3.10 (m, 1H), 2.69 (d, J=1.3 Hz, 1H), 2.05 (d, J=7.2 Hz, 3H), 0.80-0 .48 (m, 3H).

Example 364.

356 364

2-(2-Methyl-1 H-imidazol-1 -yl)ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3 -(trifluoromethyl)morpholino)benzamido)-3 -(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (364)

To a stirred solution of 356 (438.6 mg, 0.64 mmol) and 1-(2-chloroethyl)-2-methyl-1H-imidazole (279.6 mg, 1.93 mmol) in DMF (4.3 ml) sodium iodide (289.8 mg, 1.93 mmol) was added, followed by triethylamine (0.27 mL, 1.93 mmol). The reaction mixture was heated using microwave irradiation at 120°C for 45 minutes. After cooling to RT, the reaction mixture was concentrated under reduced pressure and the material was purified using reverse phase preparative HPLC to give the title compound. MS (m/z) 789.3 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (d, J=8.2 Hz, 2H), 8.87 (d, J=4.1 Hz, 1H), 8.64-8, 57 (m, 2H), 7.91 (t, J=4.8 Hz, 1H), 7.77 (d, 1H), 7.71-7.59 (m, 3H), 7.56 (s , 1H), 6.74-6.65 (m, 2H), 4.90-4.76 (m, 2H), 4.52-4.42 (m, 1H), 4.41-4.28 (m, 3H), 4.15 (d, J=12.6 Hz, 1H), 3.94 (d, J=3.5 Hz, 1H), 3.73 (d, J=12.7 Hz , 1H), 3.69-3.60 (m, 4H), 3.59-3.47 (m, 2H), 3.34 (d, 1H), 3.25 (t, 1H), 2, 53 (s, 3H), 2.03 (s, 3H).

Example 365 -1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (365)

Cesium carbonate (72 mg, 0.22 mmol) and n-propyl iodide (15 mg, 0.088 mmol) were added to a stirred solution of 356 (30 mg, 0.044 mmol) in acetonitrile (1 mL). The mixture was heated to 50°C for 16 hours. The mixture was cooled to air temperature, diluted with dimethyl sulfoxide and trifluoroacetic acid, then the mixture was purified using preparative HPLC to obtain the title compound. ER/MS (m/z) 723.3 (M+H)+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.99 (d, J=7.8 Hz, 1H), 8.84 (d, J=4.2 Hz, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.60 (d, J=5.1 Hz, 1H), 7.91 (dd, J=4.9, 2.4 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.67 (dd, J=8.0, 2.7 Hz, 2H), 6.71 (dd, J=13 ,7, 5.1 Hz, 1H), 6.66 (s, 1H), 4.85 (s, 2H), 4.15 (d, J=12.6 Hz, 1H), 4.05 (q , J=6.3 Hz, 2H), 4.00-3.89 (m, 1H), 3.73 (d, J=13.5 Hz, 2H), 3.66 (s, 3H), 3 .54 (t, J=7.7 Hz, 2H), 3.36 (d, J=12.4 Hz, 1H), 3.25 (t, J=12.1 Hz, 1H), 2.05 (d, J=6.8 Hz, 3H), 1.58 (h, J=7.2 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H).

356 365

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Example 366.

Isopropyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl2,4-dioxo-1, 4-dihydropyrido[3,4-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoate (366):

Cesium carbonate (72 mg, 0.22 mmol) and isopropyl iodide (15 mg, 0.088 mmol) were added to a stirred solution of 356 (30 mg, 0.044 mmol) in acetonitrile (1 mL). The mixture was heated to 50°C for 16 hours. The mixture was cooled to air temperature, diluted with dimethyl sulfoxide and trifluoroacetic acid, then the mixture was purified using preparative HPLC to give 366. ES/MS (m/z) 723.3 (M+H) +. 1H NMR (400 MHz, DMSO-06) δ 9.05 (s, 1H), 8.97 (d, J=7.7 Hz, 1H), 8.84 (d, J=4.1 Hz, 1H ), 8.65 (d, J=8.7 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 7.91 (d, J=5.0 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.71-7.62 (m, 2H), 6.71 (d, J=13.1 Hz, 1H), 6.68 - 6 .63 (m, 1H), 4.97-4.90 (m, 1H), 4.84 (dd, J=29.2, 20.4 Hz, 2H), 4.15 (d, J=12 ,7 Hz, 1H), 3.95 (d, J=11.3 Hz, 1H), 3.73 (d, J=13.7 Hz, 2H), 3.66 (s, 3H), 3, 53 (q, J=13.5, 11.7 Hz, 2H), 3.36 (d, J=12.3 Hz, 1H), 3.27 (d, J=12.5 Hz, 1H), 2.08 (d, J=6.7 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 1.13 (d, J=6.3 Hz, 3H).

Example 398.

355V 398A

398

Synthesis of methyl (8)-3-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)picolinate (398A)

355B (50 mg, 0.1 mmol), 2-methoxycarbonylpyridine-3-carboxylic acid (27.86 mg, 0.15 mmol), triethylamine (0.04 ml, 0.31 mmol) was added to the vial and dissolved in 0. .2 M toluene (0.51 ml). DPPA (0.03 mL, 0.12 mmol) was added and the reaction mixture was sealed and heated to 90°C for 20 min. The reaction was quenched with water (20 ml), extracted with EtOAc (3x40 ml), the organic phases were washed with brine (20 ml) and concentrated to give the title compound.

Synthesis of methyl-(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin5-yl)-2 -(tritylamino)propanoate (398B):

The title compound was prepared according to the method presented for the synthesis of compound 355E, starting at 398A.

Methyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (398): The title compound was prepared according to the method presented for the synthesis of compound 355, starting at 398B. ER/MS (m/z) 695.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSOL) δ 13.11-12.65 (s, 1H), 8.87 (d, J=8.1 Hz, 1H), 8.85-8.83 (m, 1H) , 8.73-8.65 (m, 1H), 8.61 (ddd, J=4.4, 2.3, 1.2 Hz, 1H), 8.08 (dd, J=8.8, 1.3 Hz, 1H), 7.87 (dd, J=8.6, 4.4 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.71-7, 63 (m, 2H), 6.69 (d, J=13.4 Hz, 1H), 6.65 (s, 1H), 4.88-4.80 (m, 1H), 4.77 (d , J=11.5 Hz, 1H), 4.14 (d, J=12.6 Hz, 1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.81 -3.68 (m, 2H), 3.57 (d, J=2.5 Hz, 3H), 3.55-3.42 (m, 2H), 3.35 (d, J=12.4 Hz, 1H), 3.25 (t, J=12.1 Hz, 1H), 2.03 (d, J=2.5 Hz, 3H).

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Example 399.

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1, 4dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoic acid (399):

The title compound was prepared according to the method presented for the synthesis of compound 356, starting at 398. ER/MS (m/z) 681.2 (M+H)+. 1H NMR (400 MHz, DMSO^) δ 9.00 (d, J=7.8 Hz, 1H), 8.88-8.81 (m, 1H), 8.67 (d, J=8.6 Hz, 1H), 8.61 (ddd, J=4.4, 2.1, 1.3 Hz, 1H), 8.08 (dd, J=8.8, 1.3 Hz, 1H), 7 .87 (dd, J=8.6, 4.4 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.67 (dt, J=7.8, 3.3 Hz, 2H), 6.70 (dd, J=13.0, 2.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 4.86 (d, J=4 ,3 Hz, 1H), 4.83 (m, 1H), 4.14 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.3, 3.7 Hz, 1H ), 3.78 - 3.70 (m, 2H), 3.69 (d, J=3.6 Hz, 3H), 3.57 (d, J=2.4 Hz, 3H), 3.53 (d, J=3.7 Hz, 1H), 3.51 (d, J=9.9 Hz, 1H), 3.36 (d, J=12.3 Hz, 1H), 3.25 (t , J=12.2 Hz, 1H), 2.05 (s, 3H).

Example 400. Synthesis of methyl-(S)-4-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8yl)ureido)nicotinate (400A)

Phosgene (15% solution in toluene, 2.18 ml, 3.06 mmol, 2 eq.) was added to a flame-dried vial containing a solution of methyl 4-aminonicotinate (0.466 g, 3.06 mmol, 2 eq.), DIEA ( 0.8 ml, 4.59 mmol, 3 equiv.) and DCM (2 ml). The combined reagents were stirred at room temperature for 1 hour, then 355B (0.746 g, 1.53 mmol, 1 eq.) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then adsorbed onto silica gel and purified by column chromatography using methanol in DCM as eluent (0-5%). Suitable fractions were then combined and concentrated in vacuo to give the title compound.

Synthesis of methyl-(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)quinolin5-yl)-2 -(tritylamino)propanoate (400V):

The title compound was prepared according to the method presented for the synthesis of compound 355E, starting at 400A.

400

Methyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (400):

The title compound was prepared according to the method presented for the synthesis of compound 355, starting at 400B. ER/MS (m/z) 695.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (d, J=3.0 Hz, 1H), 9.00 (d, J=7.7 Hz, 1H), 8.88-8, 80 (m, 2H), 8.66 (dd, J=8.7, 1.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.67 (td, J =5.8, 5.3, 2.6 Hz, 2H), 7.61 (d, J=6.1 Hz, 1H), 6.74-6.59 (m, 2H), 4.88- 4.78 (m, 2H), 4.15 (d,J=12.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.77-3.64 (m, 5H) , 3.57 (d, J=2.2 Hz, 5H), 3.36 (d, J=12.3 Hz, 1H), 3.25 (t, J=12.1 Hz, 1H), 2 .05 (s, 3H).

Example 401 ,4-dihydropyrido[3,2-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoic acid (401)

The title compound was prepared according to the method presented for the synthesis of compound 356, starting at 400. ER/MS (m/z) 681.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSO^) δ 9.10 (d, J=3.6 Hz, 1H), 8.95-8.76 (m, 3H), 8.68 (d, J=8.7 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.74-7.56 (m, 3H), 6.74-6.56 (m, 2H), 4.90 -4.72 (m, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.75 ( t, J=13.4 Hz, 2H), 3.57 (d, J=2.4 Hz, 3H), 3.55-3.48 (m, 1H), 3.47 (s, 1H), 3.35 (d, J=12.6 Hz, 1H), 3.25 (t, J=12.4 Hz, 1H), 2.03 (s, 3H).

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400

Example 402.

402C

Synthesis of methyl-(S)-2-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)nicotinate (402A): To a solution of 355B (60, 0 mg, 0.123 mmol) in DCM (0.62 mL, 0.2 mmol) in a flame-dried vial were added methyl 2-aminonicotinate (37.0 mg, 0.246 mmol) and DIEA (48.0 mg, 0.369 mmol), and the mixture was stirred for 2 min at room temperature. A solution of phosgene in toluene (162 mg, 0.246 mmol) was added dropwise and the reaction mixture was stirred for an additional hour at room temperature. Upon completion, the solvent was removed under reduced pressure and the product was purified by flash chromatography, eluting with MeOH in 0-20% dichloromethane to give the title compound.

Synthesis of methyl-(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)quinolin5-yl)-2 -(tritylamino)propanoate (400V):

The title compound was prepared according to the method presented for the synthesis of compound 355E, starting with 402A.

Methyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (402C):

The title compound was prepared according to the method presented for the synthesis of compound 355, starting with 402B.

402С 402 (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo- 1,4dihydropyrido[3,2-d]pyrimidin-3 (2H)-yl)quinolin-5-yl)propanoic acid (402):

The title compound was prepared according to the method presented for the synthesis of compound 356, starting at 402C. ER/MS (m/z) 681.2 (M+H)+. ¹ H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=8.0 Hz, 3H), 8.68 (d, J=8.4 Hz, 1H), 8.42 (d, J=9.3 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.70-7.63 (m, 2H), 7.45-7.39 (m, 1H ), 6.73-6.63 (m, 2H), 4.87-4.72 (m, 3H), 4.14 (d, J=12.6 Hz, 1H), 3.99-3, 91 (m, 2H), 3.74 (s, 2H), 3.63 (s, 3H), 3.58-3.51 (m, 1H), 3.50-3.42 (m, 1H) , 3.38-3.31 (m, 1H), 3.28-3.21 (m, 1H), 2.03 (s, 3H).

Example 403 Synthesis of methyl (S)-3-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8yl)ureido)pyrazine-2-carboxylate (403A)

3-(methoxycarbonyl)pyrazine-2-carboxylic acid was added to a vial equipped with a stirrer.

- 129 045366 slot (0.18 g, 1.01 mmol, 1.5 eq.), triethylamine (0.28 ml, 2.02 mmol, 3.0 eq.), DPPA (0.17 ml, 0. 81 mmol, 1.2 eq.), 355B (0.33 g, 0.67 mmol, 1.0 eq.) and toluene (3.36 ml, 0.2 M). The reaction mixture was then heated to 100°C for 30 minutes. The reaction mixture was quenched with water (10 ml) and extracted with EtOAc (25 ml, 3x). The combined organic phases were washed with saturated sodium bicarbonate, brine and dried over anhydrous Na ₂ SO ₄ . The organic phases were concentrated and the product was purified by column chromatography using a step gradient elution with 0100% EtOAc in hexanes.

Synthesis of methyl-(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropteridin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate ( 403B):

The title compound was prepared according to the method presented for the synthesis of compound 355E, starting with 403A.

Methyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropteridin-3(2H)-yl)quinolin-5-yl)propanoate (403):

The title compound was prepared according to the method presented for the synthesis of compound 355, starting with 403B. ER/MS (m/z) 696.1 (M+H)+. ^1H NMR (400 MHz, DMSOL) δ 9.00 (d, J=7.8 Hz, 1H), 8.928.86 (m, 2H), 8.73-8.68 (m, 2H), 7, 78 (d, J=7.5 Hz, 1H), 7.73-7.67 (m, 2H), 6.74-6.64 (m, 2H), 4.90-4.79 (m, 2H), 4.15 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.5, 3.5 Hz, 1H), 3.80-3.65 (m, 5H ), 3.61 (s, 3H), 3.55 (t, J=13.9, 7.6, 2.5 Hz, 2H), 3.36 (d, J=11.8 Hz, 1H) , 3.25 (t, 1H), 2.05 (s, 3H).

Example 404 ,4-dihydropteridin-3(2H)-yl)quinolin-5-yl)propanoic acid (404)

The title compound was prepared according to the method presented for the synthesis of compound 356, starting at 403. ER/MS (m/z) 682.7 (M+H) ⁺ . 1H NMR (400 MHz, DMSO^) δ 8.93-8.83 (m, 3H), 8.75-8.67 (m, 2H), 7.77 (d, J=7.5 Hz, 1H ), 7.74-7.66 (m, 2H), 6.73-6.62 (m, 2H), 4.89-4.75 (m, 2H), 4.14 (d, J=12 ,6 Hz, 1H), 3.94 (dd, J=11.7, 3.5 Hz, 1H), 3.81-3.69 (m, 2H), 3.61 (s, 3H), 3 .59-3.43 (m, 2H), 3.35 (d, J=12.2 Hz, 1H), 3.25 (t, 1H), 2.03 (d, J=2.4 Hz, 3H).

403 404

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Example 405.

Synthesis of methyl-(S)-4-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)pyrimidine-5-carboxylate (405A): DIEA ( 0.5 ml, 3.1 mmol, 3 eq.) and triphosgene (212 mg, 0.72 mmol, 0.7 eq.) were added to a solution of methyl 4-aminopyrimidine-5-carboxylate (314 mg, 2.0 mmol, 2 eq.) in DCM (0.2 M). The solution was stirred at air temperature for 1 hour. 355B (500 mg, 1 mmol, 1 eq.) was then added to the solution and stirred for an hour at air temperature. The reaction mixture was concentrated directly on silica gel and chromatographed, eluting with 0-100% ethyl acetate in hexanes; the product was eluted at 75%.

Synthesis of methyl-(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)quinolin-5-yl) -2-(tritylamino)propanoate (405B):

The title compound was prepared according to the method presented for the synthesis of compound 355E, starting with 405A.

Methyl-(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1, 4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (405):

The title compound was prepared according to the method presented for the synthesis of compound 355, starting at 405B. ER/MS (m/z) 696.8 (M+H)+. 1H NMR (400 MHz, DMSO^) δ 9.32 (s, 1H), 9.26-9.18 (m, 1H), 8.99 (d, J=7.8 Hz, 1H), 8, 91-8.84 (m, 1H), 8.67 (d, J=8.7 Hz, 1H), 7.82-7.73 (m, 1H), 7.72-7.63 (m, 2H), 6.76-6.64 (m, 2H), 4.88-4.80 (m, 2H), 4.15 (d, J=12.6 Hz, 1H), 3.98-3 .91 (m, 1H), 3.78-3.70 (m, 2H), 3.68 (s, 3H), 3.61 (s, 3H), 3.58-3.51 (m, 2H ), 3.42-3.32 (m, 1H), 3.30-3.18 (m, 1H), 2.04 (s, 3H).

Example 406.

405 406 (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo- 1,4dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoic acid (406):

The title compound was prepared according to the method presented for the synthesis of compound 356, starting at 405. ER/MS (m/z) 682.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSO^) δ 9.32 (s, 1H), 9.25-9.18 (m, 1H), 8.91-8.82 (m, 2H), 8.69 (d , J=8.6 Hz, 1H), 7.80-7.73 (m, 1H), 7.73-7.64 (m, 2H), 6.75-6.60 (m, 2H), 4.90-4.74 (m, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.95 (d, J=10.8 Hz, 1H), 3.81-3 .68 (m, 2H), 3.60 (s, 3H), 3.58-3.40 (m, 2H), 3.39-3.31 (m, 1H), 3.31-3.18 (m, 1H), 2.02 (s, 3H).

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Examples 407 and 408.

356

407 408

Preparation of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1,4 -dihydropyrido[3,4^]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoic acid (407): 356 was separated into its 2 atropisomeric enantiomers by supercritical liquid chromatography using 30% EtOH co-solvent, at flow 3 ml/min, using an AD-H 5 µm 4.6x100 mm column. The title compound was detected as the second eluting peak. ER/MS (m/z) 681.2 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.84-8.72 (m, 2H), 8.66 (d, J=8.6 Hz, 1H), 8.55 (s, 1H), 8 .00 (s, 1H), 7.58 (s, 2H), 7.44 (dd, J=8.6, 4.2 Hz, 1H), 6.66 (d, J=6.5 Hz, 1H), 6.46 (s, 1H), 6.37 (d, J=13.6 Hz, 1H), 5.08 (d, J=7.0 Hz, 1H), 4.29 (d, J=12.4 Hz, 1H), 4.11 (dd, J=8.2, 3.8 Hz, 1H), 4.04 (dd, J=11.3, 3.5 Hz, 1H), 3.84-3.70 (m, 3H), 3.68 (s, 3H), 3.65-3.56 (m, 1H), 3.50 (t, J=12.0 Hz, 1H) , 3.26 (d, J=12.2 Hz, 1H), 2.38 (s, 3H).

Preparation of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4dioxo-1,4 -dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoic acid (408): 356 was separated into its 2 atropisomeric enantiomers by supercritical liquid chromatography using 30% EtOH co-solvent, flow rate 3 ml/min, using an AD-H 5 µm 4.6x100 mm column. The title compound was detected as the first eluting peak. ER/MS (m/z) 681.2 (M+H) ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.83-8.72 (m, 2H), 8.64 (d, J=8.6 Hz, 1H), 8.56 (d, J=5, 0 Hz, 1H), 8.03 (d, J=5.0 Hz, 1H), 7.59 (q, J=7.6 Hz, 2H), 7.46 (dd, J=8.6, 4.2 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H), 6.47 (s, 1H), 6.38 (dd, J=13.4, 2.4 Hz, 1H), 5.13-5.02 (m, 1H), 4.30 (d, J=12.4 Hz, 1H), 4.12 (dd, J=8.0, 3.8 Hz, 1H ), 4.04 (dd, J=11.2, 3.5 Hz, 1H), 3.86-3.78 (m, 1H), 3.72 (t, J=5.6 Hz, 2H) , 3.69 (s, 3H), 3.653.59 (m, 1H), 3.51 (t, J=11.7 Hz, 1H), 3.27 (d, J=12.3 Hz, 1H) , 2.39 (s, 3H).

Examples 487 and 488.

Preparation of ethyl-(8)-2-(2-fluoro-6-methyl-4-((K)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1 methyl-2,4-dioxo- 1,4-Dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (487): 360 was separated into its 2 atropisomeric enantiomers by supercritical liquid chromatography using 30% EtOH co-solvent , at a flow rate of 3 ml/min, using an AD-H 5 µm 4.6x100 mm column. The title compound was detected as the first eluting peak. ER/MS (m/z) 709.2 (M+H)+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.99 (d, J=7.7 Hz, 1H), 8.84 (dd, J=4.1, 1 .5 Hz, 1H), 8.64 (dd, J=8.6, 1.6 Hz, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.91 (dd, J =4.9, 0.7 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.69-7.63 (m, 2H), 6.76-6.63 ( m, 2H), 4.90-4.74 (m, 2H), 4.19-4.06 (m, 3H), 3.95 (dd, J=11.4, 3.6 Hz, 1H) , 3.78-3.67 (m, 2H), 3.65 (s, 3H), 3.61-3.46 (m, 2H), 3.37 (s, 1H), 3.31-3 .18 (m, 1H), 2.07 (s, 3H),

1.16 (t,J=7.1 Hz, 3H).

Preparation of ethyl-(8)-2-(2-fluoro-6-methyl-4-((K)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo) -1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate (488): 360 was separated into its 2 atropisomeric enantiomers using simulated moving bed (SMB) chromatography using EA/heptanes (80/20) using a ChiralPak IC column. The title compound was detected as the second eluting peak. ER/MS (m/z) 709.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.99 (d, J=7.7 Hz, 1H), 8.84 (dd, J=4.2, 1 .5 Hz, 1H), 8.64 (dd, J=8.7, 1.6 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 7.91 (d, J =4.9 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.69-7.63 (m, 2H), 6.75-6.62 (m, 2H) , 4.91-4.75 (m, 2H), 4.20-4.07 (m, 3H), 3.95 (dd, J=11.4, 3.6 Hz, 1H), 3.78 -3.67 (m, 2H), 3.66 (s, 3H), 3.60-3.47 (m, 2H), 3.36 (d, J=12.3 Hz, 1H), 3, 25 (t, J=12.3 Hz, 1H), 2.07 (s, 3H), 1.16 (t, J=7.1 Hz, 3H).

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α4β7 Integrin Cell Uptake Assay

The effectiveness of the inhibitors to prevent the interaction of α4β7 integrin with MadCAM-1 was measured by monitoring the uptake of cells expressing α4β7 integrin onto a plate coated with the recombinant extracellular domain of MadCAM-1. 384-well plates (Corning 3702) were coated with MadCAM-1 extracellular domain by dispensing 20 μl of MAdCAM-1 at 1.0 μg/ml per well and incubating overnight at 4°C. The plates were then washed with PBS and blocked with 3% BSA for 2 h before washing again.

RPMI8866 cells were centrifuged and resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl ₂ ) at a density of 0.5 x 106 cells/ml. The cells were then distributed (60 μl/well) into a 384-well plate (Greiner 781280) which had previously been coated with 60 nl of test compound per well. The plates were incubated at 37°C for 1 hour. 50 μl of cells were transferred to blocked MadCAM-1 coated plates and incubated for 30 minutes at 37°C. 10 μl of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg/ml) was added to the cells (2% glutaraldehyde and 0.01 mg/ml final concentrations). The plates were incubated for 90 min at room temperature. The plates were then washed 3 times with 70 μl PBS per well and imaged on a Cellomics ArrayScan instrument. Cells that were bound to the plate were counted and plotted against compound concentration to determine the EC50 of test compounds. The results are presented in table. 1 and 2.

Table 1

Example No. EC ₅₀ α4β7 (nM) Example No. EC ₅₀ α4β7 (nM) Example No. EC ₅ o α4β7 (nM) Example No. EC ₅ o α4β7 (nM) 1 21.2 38 29.7 75 80.4 112 0.4 2 31.1 39 81.6 76 78.4 113 1.2 3 63.8 40 8.6 77 90.7 114 0.6 4 6.7 41 7.7 78 134.3 115 0.6 5 17.4 42 13.4 79 26.1 116 1.2 6 4.5 43 4.6 80 18.1 117 0.7 7 1.9 44 10.9 81 6.0 118 1.5 8 41.4 45 3.4 82 4.7 119 20.5 9 25.1 46 20.0 83 32.9 120 1.3 10 21.2 47 2.4 84 11.7 121 1.7 eleven 22.9 48 52.1 85 25.4 122 0.2 12 7.0 49 33.7 86 8.3 123 0.9 13 8.5 50 0.4 87 15.0 124 0.6 14 3.7 51 2.9 88 8.2 125 1.0 15 9.3 52 91.5 89 14.4 126 0.6 16 67.4 53 3.0 90 11.3 127 9.3 17 36.7 54 37.4 91 0.3 128 0.3 18 9.0 55 27.4 92 2.0 129 0.7 19 50.0 56 9.1 93 0.4 130 0.5 20 185.8 57 30.0 94 0.5 131 0.8 21 96.6 58 2.0 95 0.3 132 1.3 22 48.5 59 3.2 96 0.2 133 3.2 23 46.7 60 3.0 97 3.2 134 4.2 24 56.7 61 4.2 98 1.4 135 0.4 25 3.3 62 1.8 99 11.2 136 0.2 26 32.8 63 30.5 100 0.7 137 0.4

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27 12.8 64 0.8 101 4.1 138 0.8 28 33.5 65 8.4 102 0.3 139 11.7 29 68.7 66 18.9 103 0.7 140 0.5 thirty 16.9 67 1.6 104 0.5 141 0.1 31 19.3 68 14.0 105 4.1 142 0.2 32 75.9 69 28.9 106 0.3 143 0.3 33 60.5 70 10.7 107 0.2 144 0.2 34 39.5 71 9.5 108 1.0 145 3.1 35 6.2 72 5.5 109 0.3 146 0.6 36 21.0 73 2.5 110 0.3 147 1.9 37 69.6 74 13.6 111 0.1 148 60.6

Examples 149-354 from table. 2 were obtained according to the methods described herein.

table 2

Example Structure 1H-NMR M/Z [M+H] + EC50 α4β7 (nM) 149 _F R ^F Н ^F >° Ο Η—N 0 ^F—oH Cl Ν _χ \ 1H NMR (400 MHz, DMS0-C16) δ 9.26 (dd, J = 8.0, 3.2 Hz, 1H), 8.81 (dd, J = 4.2, 1.5 Hz, 1H) , 8.62 (d, J = 8.9 Hz, 1H), 7.66-7.54 (m, 3H), 7.54-7.41 (m, 2H), 7.32-7.23 (m, 1H), 7.14-7.04 (m, 3H), 6.89 (d, J = 1.6 Hz, 1H), 4.78 (d, J = 2.4 Hz, 1H) , 3.85-3.67 (m, 1H), 3.41 (ddd, J = 21.8, 14.7, 10.2 Hz, 1H), 1.21 (s, 1H). 550.9 50.3 150 ABOUT F F )=0 Cl n-N 0 NEC——'' O-H ABOUT 1H NMR (400 MHz, flMC0-d6) δ 9.24 (d, J = 8.2 Hz, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.70-7.61 (m, 3H), 7.58 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 9.3 Hz, 2H), 6, 49 (tt, J = 3.1, 1.5 Hz, 1H), 4.78 (ddd, J = 10.2, 8.1, 4.4 Hz, 1H), 4.22 (p, J = 3.4, 2.9 Hz, 2H), 3.79 (t, J = 5.4 Hz, 2H), 3.42 (s, 1H), 2.46-2.34 (m, 2H). 573.8 43.6

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151 ^FF L=o \ HN 0 CHNYa-n ^N w / \ ' °w 1H NMR (400 MHz, DMSO-06) δ 8.96 (d, J = 8.0 Hz, 1H), 8.88 (s, 1 Η), 8.74 (s, 1H), 7.66 ( d, J = 29.5 Hz, ZN), 6.77 (d, J = 11.8 Hz, 2H), 4.98-4.84 (m, 1H), 4.68 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.993.90 (m, 1 Η), 3.72 (s, ZN), 3.52 (d, J = 1.6 Hz, ZN) , 3.49-3.37 (m, 2H), 3.23 (t, J = 12.5 Hz, 1H), 2.41 (s, ZN), 2.33 (d, J = 2.0 Hz, ZN). 646.2 0.2 152 /N f Cl n-N 0 w 1H NMR (400 MHz, flMCO-d6) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (d, J = 8.0 Hz, 1 Η), 8, 64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz , 1H), 7.70-7.58 (m, ZN), 7.57 (d, J = 7.9 Hz, 1 Η), 7.01 (s, 1 Η), 5.94 (d, J = 11.0 Hz, 2H), 4.67 (s, 1H), 4.54 (d, J = 6.1 Hz, 2H), 4.47 (dd, J = 6.0, 1.2 Hz, 2H), 3.72 (s, 1 Η), 3.41 (s, 1H), 1.51 (s, ZN). 578.1 51.7 153 ^F %° HN ⁰ F )=0 \ O HN p fMH ^- ' ^{OH 4=7} w 1H NMR (400 MHz, flMCO-d6) δ 9.25 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 4.4 Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.82-7.57 (m, 5H), 7.46-7.11 (m, ZN), 6.93 (dd, J = 17.5, 9.3 Hz, ZN), 4.78-4.70 (m, 1H), 3.77 (dd, J = 14.5, 4.5 Hz, 1 Η), 3, 68 (s, ZN), 3.43 (dd, J = 14.5, 9.9 Hz, 1H). 643.1 0.2 154 F. > R: ^Cl H-N\ N=C—γ 2—C 'v—'' O-H ABOUT 1H NMR (400 MHz, flMCO-d6) δ 9.38 (d, J = 8.2 Hz, 1H), 9.01 (d, J = 8.5 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 -7.53 (m, 7H), 1.34 (d, J = 7.1 Hz, 4H). 630.8 44.6

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155 U I' E FF )=O U-F Η—N O -AAu-M-i ⁿ A / \ ^{z 0 N} \ /7 1H NMR (400 MHz, DMSO-06) δ 8.86-8.74 (m, 2H), 8.64 (s, 1H), 7.62 (dd, J = 8.7, 4.4 Hz, 1H), 7.55 (dd, J = 7.4, 5.1 Hz, 1H), 7.42 (dd, J = 7.3, 4.2 Hz, 1 Η), 6.92 (dd, J = 9.5, 5.5 Hz, 1H), 6.54 (s, 1H), 6.40 (dd, J = 11.4, 4.1 Hz, 2H), 4.71 4.60 ( m, 1 Η), 3.91 (q, J = 8.0 Hz, 1H), 3.75-3.60 (m, 1H), 3.47 (d, J = 2.4 Hz, ZN) , 3.44-3.30 (m, 1 Η), 2.51 (s, ZN), 1.03 (ddd, J = 13.0, 8.8, 4.9 Hz, 1H), 0, 68-0.56 (m, 1H), 0.54-0.41 (m, 2H), 0.30 (dd, J = 9.6, 4.8 Hz, 1H). 682.6 0.3 156 \ ⁿ N ^fff 0 \ F >0 /=\ 0 n—N ,0 CH/uN-n ^N A / \ / 0 Ν _χ /) 1H NMR (400 MHz, flMCO-d6) δ 8.98-8.88 (m, 2H), 8.81 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8, 0 Hz, 1 Η), 7.88-7.66 (m, 4Η), 7.64 (d, J = 8.7 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H ), 6.84 (d, J = 9.1 Hz, 1H), 6.48 -6.36 (m, 2H), 4.80-4.69 (m, 1 Η), 4.58 - 4 .43 (m, 1 Η), 3.87 (dd, J = 14.1, 4.0 Hz, 1H), 3.76-3.52 (m, 4H), 3.29 (d, J = 2.5 Hz, ZN), 1.28 (d, J = 6.6 Hz, ZN). 655.3 0.3 157 SU ^s| Cl· )=0 HN 0 ^рА- ^Н о- _Н Ме o 1H NMR (400 MHz, flMCO-d6) b 9.29 (d, J = 8.4 Hz, 1H), 8.85 (dd, J = 4.1, 1.5 Hz, 1H), 8.70 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.83 - 7.72 (t, ZN), 7.69 (dd, J = 8.6, 4.2 Hz, 1H), 7.54 (ddd, J = 8.3, 6.5, 1.9 Hz, 1H), 7.46-7.35 (t, ZN), 7 .27 (dd, J = 15.0, 7.3 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 4.85 (s, 1H), 3.42 (dd, J = 14.5, 10.3 Hz, 1H). 532.0 44.0 158 ω ^f TK _f FF ^F /=0 У-F Η-Ν ,0 κΗΖλ i 0Я ⁷ LL U ^0-n A / \ ⁷ 0 Ν _χ /) 1H NMR (400 MHz, flMCO-d6) δ 12.85 (s, 1H), 8.97 (dd, J = 8.0, 4.9 Hz, 1H), 8.86 (d, J = 4, 3 Hz, 1H), 8.79-8.70 (t, 1H), 7.69 (td, J = 7.8, 4.4 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.49 (dd, J = 7.4, 3.8 Hz, 1H), 6.75 (dd, J = 11.7, 3.7 Hz, 2H), 6.34 (s , 1H), 4.90 (dt, J = 11.7, 5.8 Hz, 1H), 4.77-4.67 (t, 1H), 4.16 (d, J = 12.7 Hz, 2H), 3.95 (dd, J = 11.5, 3.7 Hz, 1H), 3.81 -3.67 (t, 1H), 3.66 (s, ZH), 3.61 -3 .37 (t, ZN), 3.24 (t, J = 12.2 Hz, 1H), 2.17 (td, J = 8.4, 4.2 Hz, 1H), 1.10 (d, J = 8.6 Hz, 2H), 0.94 (dq, J = 17.4, 7.0, 4.0 Hz, 2H). 725.2 0.3

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159 О ^Fp z ^F FFF )=O Af hn p -Уу+У-А-н N—к )=<' ^{0 N} Y F 1H NMR (400 MHz, DMSO-C16) δ 8.97 (d, J = 7.9 Hz, 1H), 8.86 (d, J = 2.7 Hz, 1H), 8.38 (dt, J = 10.6, 2.6 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 7.3, 5.2 Hz, 1H), 6 .75 (d, J = 11.7 Hz, 2H), 6.54 (s, 1H), 4.91 (dd, J = 9.0, 3.5 Hz, 1H), 4.70 (tt, J = 7.9, 3.6 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.4, 3.8 Hz, 1H), 3.73 (d, J = 12.9 Hz, 1H), 3.65 (dd, J = 14.1, 4.4 Hz, 1H), 3.62-3.51 (m, 1H), 3 .48 (d, J = 1.5 Hz, ZN), 3.47-3.38 (m, 2H), 3.23 (t, J = 12.4 Hz, 1H), 2.52 (s, 3H). 717.0 0.3 160 ^F LL FF 0/)=0 Af HN o ^N Y )=< / on) 1H NMR (400 MHz, flMCO-d6) δ 8.96-8.80 (m, 2H), 8.75-8.64 (m, 1H), 7.73-7.61 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 9.3 Hz, 1H), 6, 56 (d, J = 4.5 Hz, 1H), 4.914.69 (m, 2H), 4.13 (d, J = 12.7 Hz, 1H), 3.93 (d, J = 11.3 Hz, 1H), 3.82-3.64 (m, 2H), 3.58-3.41 (m, 4H), 3.36 - 3.20(m, 3H), 2.54 (s, 3H), 2.02 (s, 3H). 711.2 0.3 161 ^FF pr ^F F /=° Cl HN p -н/ууу-Н-н ' ⁰ w 1H NMR (400 MHz, flMCO-d6) δ 8.99-8.93 (m, 2H), 8.85 (d, J = 8.7 Hz, 1H), 7.80-7.71 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.57 (s, 1H), 6.76 (d, J = 11.7 Hz, 2H), 4.96-4, 85 (m, 1H), 4.74-4.66 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3, 7 Hz, 1H), 3.79 - 3.69 (m, 2H), 3.60 - 3.51 (m, 4H), 3.50 - 3.37 (m, 2H), 3.23 (t , 1H), 2.57 (s, 3H). 665.2 0.3 162 fyp p - 'fc Cl H-N 0 NEC——'' O-H ABOUT 1H NMR (400 MHz, flMCO-d6) δ 9.35 (d, J = 8.2 Hz, 1H), 8.97 (d, J = 7.9 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.68-8.60 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.60 (td, J = 15.7, 15.0, 8.2 Hz, 6H), 7.38-7.28 (m, 4H), 7.21 (t , J = 7.1 Hz, 1H), 5.11 (t, J = 7.3 Hz, 1H), 4.79 (d, J = 12.5 Hz, 1H), 3.41 (s, 1H ), 2.65 (s, 1H), 2.31 (s, 1H), 1.45 (d, J = 7.0 Hz, en). 639.2 53.5

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163 S ⁿ / ^N 'A F. F ^F )=0 U-F Η—N 0 Lol- N % \ ' ^{0 N} \ # 1H NMR (400 MHz, DMSO-06) δ 13.00 (s, 1H), 8.86 (d, J = 3.8 Hz, 1H), 8.81 (dd, J = 7.9, 5, 5 Hz, 1H), 8.73 (t, J = 7.5 Hz, 1H), 7.69 (dt, J = 8.8, 5.1 Hz, 1H), 7.60 (t, J = 6.6 Hz, 1H), 7.48 (dd, J = 7.4, 3.2 Hz, 1H), 6.76 (dd, J = 9.5, 4.7 Hz, 1H), 6, 44 (dd, J = 11.4, 3.6 Hz, 2H), 6.34 (s, 1H), 4.70 (tt, J = 8.2, 4.1 Hz, 1H), 4.35 -4.26 (m, 1H), 3.79 -3.63 (m, 4H), 3.52-3.35 (m, 1H), 2.17 (ddd, J = 13.8, 8, 4, 5.5 Hz, 1H), 1.85-1.70 (m, 1H), 1.61 -1.45 (m, 1H), 1.16-1.04 (m, 2H), 1 .02 - 0.87 (m, 2H), 0.93 (t, J = 7.3 Hz, ZN). 697.2 0.4 164 Cl n-N ,0 NEC—e )—a /—' oh ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 8.86 - 8.79 (m, 2H), 8.63 (dd, J = 8.6, 1.7 Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.68-7.51 (m, 4H), 7.16 (s, 1H), 6.09 (d, J = 11.1 Hz, 2H), 4.68 (s, 1H), 3.72 (s, 1H), 3.41 (s, 1H), 2 .53 (dd, J = 13.0, 6.5 Hz, 2H), 2.36 - 2.26 (m, 2H), 1.95 (dd, J = 15.1, 6.8 Hz, 2H ). 629.2 88.6 165 ^р Рм ^FF AA ^F F )=0 Cl / HN 0 K/uI-n ^N A /\ / 0 N _χ β 1H NMR (400 MHz, flMCO-d6) δ 8.98-8.88 (m, 2H), 8.84 (t, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7 ,81 7.71 (m, 1 Η), 7.67 (dd, J = 15.1, 7.4 Hz, 1 Η), 7.57 (dd, J = 10.9, 7.3 Hz, 1 Η), 6.74 (dd, J = 11.7, 2.5 Hz, 2H), 4.95-4.84 (m, 1H), 4.804.68 (m, 1H), 4.16 ( d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.77-3.65 (m, 1H), 3.603.49 (m , 2H), 3.48 - 3.33 (m, 5H), 3.29-3.17 (m, 1H), 1.82 (d, J = 10.8 Hz, ZN). 665.2 0.4 166 ^f K ^FF \ ^F /=0 0 Η—N 0 nunuA-n Ν-ά /\ ^{7 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 9.16-9.01 (m, 1H), 8.97 (d, J = 4.7 Hz, 1H), 8.84 (d, J = 7, 9 Hz, 1H), 7.98-7.82 (m, 1H), 7.767.63 (m, 2H), 6.96 (d, J = 9.5 Hz, 1H), 6.50-6, 38 (m, ZN), 4.744.64 (m, 1 Η), 3.93 (q, J = 8.0 Hz, 1H), 3.84-3.69 (m, 1H), 3.67 ( d, J = 4.4 Hz, ZN), 3.55-3.41 (m, 4H), 2.51 (s, ZN), 1.11 -1.00 (m, 1H), 0.67 -0.59 (m, 1H), 0.560.44 (m, 2H), 0.35 - 0.27 (m, 1H). 645.2 0.4

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167 О ✓ ^N А FF >0 >—F Η—N О ^{Z 0 N} _x / 1H NMR (400 MHz, DMS0-C16) δ 12.93 (s, 1H), 8.92-8.85 (m, 1H), 8.82 - 8.73 (m, 2H), 7.78 - 7.68 (m, 1H), 7.64 (dd, J = 16.6, 7.4 Hz, 1H), 7.52 (dd, J = 9.7, 7.3 Hz, 1H), 6 .77 (d, J = 9.3 Hz, 1H), 6.49 (d, J = 3.0 Hz, 1H), 6.43 (dd, J = 11.4, 4.7 Hz, 2H) , 6.12 (td, J = 54.6, 12.8 Hz, 1H), 4.78-4.65 (m, 1H), 4.35-4.25 (m, 1H), 3.85 -3.63 (m, 1H), 3.51-3.48 (m, 3H), 3.54 -3.32 (m, 1H), 2.53 (s, 3H), 1.84 -1 .70 (m, 1H), 1.61 -1.44 (m, 1H), 0.92 (t, J = 7.3 Hz, ZN). 653.2 0.4 168 ( F /A ^F Η—NF / И7 —N F. FF )=0 )=\ FF Η—N O —AL—<' _O _ _H /A / \ ' ° ^N \ # 1H NMR (400 MHz, flMC0-d6) δ 8.75 (s, 1H), 8.61 (s, 1H), 7.58 (dd, J = 22.2, 8.5 Hz, 2H), 7 .45 (d, J = 7.0 Hz, 1H), 7.36 (dd, J = 9.4, 2.7 Hz, 1H), 7.03 (s, 1H), 6.75 (d, J = 9.4 Hz, 1 Η), 6.53 (s, 1 Η), 6.45 (d, J = 11.6 Hz, 2H), 4.31 (s, 1H), 3.73 ( d, J = 13.2 Hz, 1H), 3.66 (s, ZN), 2.97 (s, 5H), 2.74 - 2.59 (m, 1H), 2.39-2.21 (m, 1H), 1.77 (s, 1H), 1.53 (s, 1H), 0.93 (t, J = 7.3 Hz, ZN). 750.9 0.5 169 0 /=\ ,¾ Cl Η—N p NEC—7 7—\ 7—' ° ^-H w 1H NMR (400 MHz, DMSODb) δ 10.62 (s, 1H), 9.16 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz , 1H), 8.65 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.97-7.86 (t, ZN), 7.67 - 7.58 (t, 5H), 7.58 7.50 (t, 4H), 4.76 (q, J = 5.3, 4.7 Hz, 1H), 3, 43 (s, 2H). 612.2 88.6 170 .—. H\FF F )=0 Cl n-N p NEC—7 2—£ ft—' 0—H ⁿ O 1H NMR (400 MHz, flMC0-d6) δ 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.71 (d, J = 8.0 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.52 (t, 4H), 6.58 (d, J = 9.0 Hz, 1H), 6.34 (d, J = 12.1 Hz, 2H), 4, 69 (d, J = 12.1 Hz, 1H), 3.89 (d, J = 21.4 Hz, 1H), 3.72 (s, 1H), 3.42 (s, 1H), 1, 81 (s, 4H), 1.66 (s, 2H), 1.40 (s, 3H). 625.2 93.7

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171 0—\ F —( )—C ^F YF b ^F F. FF /=0 У-F Η—N 0 YwV-XH nA /=< / 0 Ν _χ / 1H NMR (400 MHz, DMSO-C16) δ 8.96 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 4.2 Hz, 1H), 8.67 (s, 1H ), 7.64 (s, 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 6.76 (dd, J = 11.6, 4.1 Hz, 2H), 6.55 (s, 1H), 4.87 (d, J = 9.2 Hz, 1H), 4.71 (td, J = 8.9, 4.5 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.74-3.57 (m, 1H), 3.573.34 (m, 5H), 2.82 (t, J = 11.7 Hz, 1H), 2.53 (s, 3H), 1.20 (d, J = 6.6 Hz, 1H), 1.15 (d, J = 6.1 Hz, ZN). 713.0 0.5 172 —\ F / '/ ^F tb F EFF /=0 FF hn p YwV-Xh nA /=<' ^{0 N} \ ? 1H NMR (400 MHz, flMCO-d6) δ 8.93 (dd, J = 7.9, 3.4 Hz, 1H), 8.82 (d, J = 4.2 Hz, 1H), 8.65 (s, 1H), 7.69-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.1 Hz, 1H) , 6.64 (dd, J = 12.0, 4.1 Hz, 2H), 6.55 (d, J = 1.3 Hz, 1H), 5.67 (ddd, J = 21.8, 10 ,0, 4.8 Hz, 1H), 5.25 - 5.10 (m, 2H), 4.80 (s, 1H), 4.68 (td, J = 8.6, 7.7, 4 ,1 Hz, 1H), 4.00 (s, 2H), 3.71 (td, J = 14.7, 4.5 Hz, 1H), 3.54-3.31 (m, 4H), 2 .53 (s, ZN), 1.91 (ddd, J = 14.2, 10.2, 7.1 Hz, 1H), 1.78 (ddd, J = 14.1, 7.2, 4, 1 Hz, 1H), 0.86 (t, J = 7.3 Hz, ZN). 711.0 0.5 173 F Ef h Λ-Ν F )=0 Cl H-N 0 ABOUT 1H NMR (400 MHz, flMCO-d6) δ 8.80 (dd, J = 4.1, 1.6 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.55 (s, 1H), 8.14 (dd, J = 1.6, 0.4 Hz, 1H), 7.88 (dd, J = 7.9, 1.7 Hz, 1H), 7.687.49 ( m, 4H), 7.01 (d, J = 7.5 Hz, 1H), 6.23 (d, J = 11.2 Hz, 2H), 4.58 (s, 1H), 4.46- 4.30 (m, 1H), 3.70 (s, 1H), 3.45 (s, 1H), 2.422.28 (m, 2H), 2.21 (dt, J = 15.3, 8, 8 Hz, 1H), 1.68-1.49 (m, 1H). 598.0 81.5

- 140 045366

174 Η / Χ-Ν Τ >=\ ^1г ^С1 ci ^/ >=o Η-Ν ο ci Ν _χ β 1H NMR (400 MHz, DMSO-06) δ 11.19 (s, 1H), 8.99 (s, 1H), 8.83 (d, J = 3.6 Hz, 1H), 8.66 (d , J = 8.4 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.727.57 (m, 2H ), 7.54 (d, J = 7.9 Hz, 1H), 7.18 (s, 1 Η), 4.86 (s, 1H), 3.78 - 3.68 (m, 1 Η) , 3.42 (s, 1 Η), 2.27 (d, J = 11.2 Hz, 6H). 591.0 97.8 175 ' - CI Η—Ν ,0 νξο—с 2—\ /—' Ο-Η Ο 1H NMR (400 MHz, flMCO-d6) δ 9.12 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.62 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (dd, J = 1.6, 0.4 Hz, 1H), 7.91 (dd, J = 7.9, 1 .7 Hz, 1 Η), 7.65 - 7.54 (m, 6Η), 7.50 - 7.42 (m, ZN), 6.93 (d, J = 9.4 Hz, 2H), 6.45 (q, J = 6.6 Hz, 1H), 4.75 -4.67 (m, 1H), 3.81 -3.67 (m, 1H), 3.44-3.29 (m, 1H). 666.1 97.1 176 “D / ^Η ✓ ^{Ν 4} α —\ Η-Ν ρ Μ ^ζ λΛ r~ ^Ο-Η ν% Αχ ^{7 0 Ν} \ / 1H NMR (400 MHz, flMCO-d6) δ 8.91 (d, J = 4.3 Hz, 1H), 8.79 (t, J = 10.4 Hz, 2H), 7.78-7.69 (m, 2H), 7.64 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1 Η), 6.45 (d, J = 11.9 Hz, 2H), 4.78-4.58 (m, 1 Η), 4.30 (m, 1H), 3.72 (dd, J = 14.5, 4.6 Hz, 1H), 3, 55 (d, J = 1.3 Hz, ZN), 3.45 (dd, J = 14.5, 9.7 Hz, 1H), 2.81 (q, J = 7.4 Hz, 2H), 2.66 (d, J = 7.3 Hz, 1H), 1.76 (d, J = 11.7 Hz, 1H), 1.62-1.43 (m, 1H), 1.25 (t , J = 7.4 Hz, ZN), 1.22 1.08 (m, ZN), 0.93 (t, J = 7.3 Hz, ZN). 646.3 0.9 177 q I 0 Η—Ν O ° ^-H F ^N \ # 1H NMR (400 MHz, flMCO-d6) δ 9.26 (d, J = 8.2 Hz, 1H), 8.86 (d, J = 4.1 Hz, 1H), 8.63 (d, J = 8.6 Hz, 1 Η), 7.67 - 7.59 (m, 1 Η), 7.57 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 8, 4 Hz, 1H), 7.36-7.24 (m, 1H), 7.10 (t, J = 8.0 Hz, 2H), 7.03 (dd, J = 12.9, 7.1 Hz, 1 Η), 4.74 (s, 1 Η), 4.61 (t, J = 7.0 Hz, 1H), 3.79- 3.70 (m, 1H), 3.42- 3 .33 (m, 2H), 2.22 (s, ZN), 1.74- 1.62 (m, 2H), 1.57 (d, J = 9.7 Hz, 1H), 1.51 - 1.42 (m, 1H). 539.0 28.0

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178 R: Cl n-N,0 NEC—/ X—ά ft—' O-H ABOUT 1H NMR (400 MHz, DMSO-06) δ 9.35 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.74 (d, J = 5.4 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7 .90 (d, J = 8.2 Hz, 1H), 7.67 7.60 (m, ZN), 7.56 (dd, J = 8,1,6,2 Hz, ZN), 4.79 (d, J = 7.6 Hz, 1H), 3.78 (s, 1H), 3.50-3.32 (t, ZN), 3.24 (s, ZN), 2.65 (s, 1H), 2.31 (s, 1H). 593.6 37.1 179 I n^n^ ^h I/ Cl >0 Cl n-N 0 ⁿ O 1H NMR (400 MHz, flMC0-d6) δ 9.13 (d, J = 8.3 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1 Η), 8.17 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.74-7.58 (t, ZN), 7.54 (d, J = 7.9 Hz, 1H), 7.46 (s, 1H), 4.86 (s, 1H), 3.76 (dd, J = 14.3, 4.1 Hz, 1H), 3.39 (t, J = 12.7 Hz, 1H), 2.14 (ddd, J = 12.9, 8.3, 5 ,0 Hz, 1H), 1.19-0.98 (t, ZN). 604.1 37.7 180 p Pn P- ^f EFF )=0 pF HN ,0 ^N A /\ / 0 Ν _χ λ 1H NMR (400 MHz, flMC0-d6) δ 8.90-8.81 (t, 2H), 8.74 (t, J = 7.8 Hz, 1H), 7.74-7.64 (t, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.49 (dd, J = 7.4, 2.5 Hz, 1H), 6.60-6.48 (t, ZN ), 4.78-4.65 (t, 1H), 4.01 3.84 (t, 2H), 3.79 - 3.57 (t, 4H), 3.54 - 3.38 (t, 5H), 3.38 - 3.30 (t, 1H), 2.98 (td, J = 12.4, 3.9 Hz, 1H), 1.04 (d, J = 6.6 Hz, ZN ). 645.7 0.9 181 d N Cb F. FF )=0 pF Η—N O Χν/ν+ο-Η ⁿ P )=< ⁷ 0 Ν _χ ft 1H NMR (400 MHz, flMC0-d6) δ 12.93 (s, 1H), 8.94-8.85 (t, 1H), 8.81 (dd, J = 4.2, 1.5 Hz, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.5, 4.2 Hz, 1H), 7.57 (t, J = 6.9 Hz, 1H), 7.43 (dd, J = 7.4, 3.8 Hz, 1H), 6.63 (dd, J = 11.8, 4.5 Hz, 2H), 6.55 (s , 1H), 4.69 (ddd, J = 12.8, 7.9, 4.0 Hz, 1H), 3.90-3.83 (t, 1H), 3.72 (d, J = 11 .8 Hz, ZN), 3.58 (s, 2H), 3.49 (d, J = 2.0 Hz, ZN), 3.47-3.36 (t, 1H), 2.762.64 (t , 1H), 2.53 (d, J = 4.1 Hz, ZN), 2.44-2.29 (t, 1H), 1.13 (d, J = 6.2 Hz, ZN). 645.1 0.7

- 142 045366

182 Ο / ^N /=\ Η—N 0 muo“ ⁴ °- ^{n N} A ⁷ O Ν _χ b 1H NMR (400 MHz, DMSO-C16) δ 8.93-8.86 (m, 1H), 8.83 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.837 .55 (m, 6H), 7.31 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1H), 6, 44 (d, J = 11.6 Hz, 2H), 4.72-4.57 (m, 1H), 4.30 (d, J = 8.3 Hz, 1H), 3.68 (s, 4H ), 3.44 (dd, J = 14.5, 9.9 Hz, 1H), 1.75 (ddd, J = 10.6, 7.4, 3.6 Hz, 1H), 1.51 ( ddd, J = 13.7, 10.4, 7.1 Hz, 1H), 0.91 (t, J = 7.3 Hz, ZN). 639.2 0.9 183 --- _H F Χ>··(-Ρ HN F % F. FF /=О У-F Η—Ν 0 ^Ν % /\ ^{7 0 Ν} \ # 1H NMR (400 MHz, flMCO-d6) δ 8.78 (t, J = 7.7 Hz, 1H), 8.57 (s, 1H), 7.51 (s, 2H), 7.40 (s , 1H), 6.81 -6.67 (m, 1H), 6.56 (s, 1 Η), 6.44 (dd, J = 11.4, 5.9 Hz, 2H), 4.66 (s, 1H), 4.29 (s, 1H), 3.67 (t, J = 16.9 Hz, 1H), 3.50 (d, J = 2.6 Hz, ZN), 3.47 - 3.28 (m, 1H), 2.58 (s, 3H), 2.54 (s, 3H), 1.87-1.65 (m, 1H), 1.53 (dt, J = 17 ,9, 7.3 Hz, 1H), 0.93 (t, J = 7.3 Hz, ZN). 685.2 0.9 184 Jy ^FF th P CH ^N A /X ⁷ Ο Ν _χ } 1H NMR (400 MHz, flMCO-d6) δ 9.24 (d, J = 8.5 Hz, 1 Η), 9.06 (d, J = 5.0 Hz, 1H), 8.74 (t, J = 7.8 Hz, 1H), 8.10-7.93 (m, 1H), 7.847.59 (m, 2H), 6.77 (t, J = 9.0 Hz, 1H), 6, 42 (dd, J = 16.1, 11.9 Hz, 2H), 5.75 (d, J = 3.5 Hz, 1H), 4.81 -4.68 (m, 1 Η), 4, 29 (s, 2H), 3.46 - 3.30 (m, 5H), 3.22 (s, ZN), 2.39 (d, J = 2.3 Hz, ZN), 1.81 (ddt , J = 28.3, 13.5, 6.1 Hz, ZN), 1.601.43 (m, 1 Η), 0.92 (td, J = 7.4, 2.8 Hz, ZN). 658.3 0.9 185 Ή FF^h ⁰ >=\ / Η—Ν O OGlM-i nk ⁷ o ^N _v ) 1H NMR (400 MHz, flMCO-d6) δ 8.86-8.65 (m, ZH), 7.75-7.49 (m, 6H), 6.76 (d, J = 9.5 Hz, 1H), 6.43 (d, J = 11.4 Hz, 2H), 4.70 (dd, J = 9.2, 5.0 Hz, 1 Η), 4.30 (d, J = 10, 0 Hz, 1H), 3.65 (d, J = 2.4 Hz, 4H), 3.50 (dd, J = 14.5, 9.6 Hz, 1H), 2.04 (d, J = 8.8 Hz, ZN), 1.75 (ddd, J = 13.8, 7.3, 3.3 Hz, 1H), 1.57-1.47 (m, 1H), 0.91 (t , J = 7.3 Hz, ZN). 671.2 1.0

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1H NMR (400 MHz, DMSO-06) δ 8.98 (m, J = 25.3 Hz, 2H), 8.85 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.91 -7.81 (m, 1H), 7.747.62 (m, 2H), 6.79 (d, J = 9.4 Hz, 1H), 6.51 -6.39 (m, ZN), 4.724.64 (m, 1H), 4.37-4.25 (m, 1H), 3.81-3.70 (m, 1 H), 3.67 ( d, J = 5.6 Hz, ZN), 3.53 - 3.40 (m, 4H), 1.83-1.71 (m, 1H), 1.59-1.46 (m, 1H) , 0.92 (t, J = 7.3 Hz, ZN).

1H NMR (400 MHz, flMCO-d6) δ 8.81 (d, J = 7.0 Hz, 2H), 8.73 (s, 1 Η), 7.79-7.45 (m, 6Η), 6.84 (d, J = 9.1 Hz, 1H), 6.40 (d, J = 11.4 Hz, 2H), 4.70 (dt, J = 8.8, 4.3 Hz, 1 Η), 4.54-4.48 (m, 1H), 3.68 (d, J = 4.9 Hz, 1H), 3.64 (d, J = 2.3 Hz, ZN), 3, 50 (dd, J = 14.5, 9.7 Hz, 1H), 2.04 (d, J = 8.2 Hz, ZN), 1.26 (d, J = 6.7 Hz, ZN).

1H NMR (400 MHz, flMCO-d6) δ 12.92 (s, 1H), 8.87 (d, J = 4.3 Hz, 1 Η), 8.77 (q, J = 10.9, 9 .3 Hz, 2H), 8.39 (s, 1H), 7.76-7.58 (m, 2H), 7.54 (t, J = 7.7 Hz, 1 Η), 6.75 ( dd, J = 9.3, 6.7 Hz, 1 Η), 6.43 (dd, J = 11.4, 3.9 Hz, 2H), 4.71 (dt, J = 13.6, 9 .5 Hz, 1H), 4.30 (d, J = 9.4 Hz, 1H), 3.74 (ddd, J = 51.1, 14.5, 4.5 Hz, 1H), 3.51 (d, J = 2.2 Hz, ZN), 3.36 (dd, J = 14.4, 10.5 Hz, 1H), 1.83 (d, J = 9.6 Hz, ZN), 1 .77 (td, J = 7.4, 4.2 Hz, 1H), 1.53 (h, J = 7.4 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN) .

1H NMR (400 MHz, flMCO-d6) δ 9.37 (d, J = 5.1 Hz, 1 Η), 9.05 (s, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.92 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 5.1 Hz, 1 Η), 7.83 (s, 1H), 7.78 (d, J = 7.6 Hz, 1 Η), 6.75 (d, J = 11.8 Hz, 2H), 4.97-4.83 (m, 1H), 4.81 -4.70 (m, 1H), 4.16 (d, J = 12.8 Hz, 1H), 3.95 (dd, J = 11.5, 3.7 Hz, 1H), 3.82 (dd, J = 14.4, 4.5 Hz, 1H), 3.73 (d, J = 12.9 Hz, 1 Η), 3.57 (d, J = 3.3 Hz, 1H), 3.54 (s , 1H), 3.53-3.47 (m, 1H), 3.41 (d, J = 12.5 Hz, 1H), 3.29-3.16 (m, 1H), 2.54 ( s, 1H).

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190 0 n-N 0 n%tu-N>-n ^N V /\ ⁷ on) 1H NMR (400 MHz, DMSO-siO) δ 9.20 (s, 1H), 9.01 (d, J = 4.9 Hz, 1H), 8.94 (d, J = 8.0 Hz, 1H ), 7.98 (s, 1H), 7.83-7.70 (m, 2H), 6.74 (d, J = 12.0 Hz, 2H), 6.48 (s, 1H), 5 .00-4.88 (t, 1H), 4.78-4.69 (t, 1H), 3.79 (t, J = 12.8 Hz, 1H), 3.69 (s, ZN), 3.61 (d, J = 12.8 Hz, 1H), 3.52 (d, J = 10.8 Hz, 1H), 3.45 (s, ZN), 3.02 (t, J = 12 ,2 Hz, 1H), 2.52 (s, ZN), 2.02-1.89 (t, 1H), 1.86-1.68 (t, 2H), 1,671.42 (t, ZN) . 659.7 1.2 191 Yn E FF )=0 U-F HN ,0 -L-lu-M-n ⁿ A / \ ⁷ 0 Ν _χ L 1H NMR (400 MHz, flMCO-d6) δ 13.18-12.57 (s, 1 Η), 8.91 (dd, J = 7.9, 3.0 Hz, 1H), 8.81 (s , 1H), 8.63 (s, 1H), 7.58 (t, J = 18.1, 10.7 Hz, 2H), 7.43 (s, 1H), 6.62 (dd, J = 11.2, 3.9 Hz, 2H), 6.54 (s, 1H), 4.75-4.65 (t, 1H), 3.93 (t, 2H), 3.71 (t, J = 12.9 Hz, 1H), 3.633.54 (t, 1H), 3.49 (d, J = 2.0 Hz, ZN), 3.47 - 3.37 (t, 1H), 3.34 (dd, J = 11.6, 5.0 Hz, 1H), 3.27 (dd, J = 12.6, 3.6 Hz, 1H), 2.96 (dd, J = 12.5, 5 .4 Hz, 1H), 2.53 (s, ZN), 1.15 (d, J = 6.4 Hz, ZN), 1.01 (d, J = 6.3 Hz, ZN). 659.4 1.3 192 O 'U: Ν=\ Η—Ν O m% yy ⁷ 0 Ν ) 1H NMR (400 MHz, flMCO-d6) δ 9.16 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 4.1 Hz, 1H ), 8.79 (d, J = 6.6 Hz, 1 Η), 8.68 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.87 (d, J = 6.5 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.69-7.61 (t, 2H), 6.77 (d, J = 11.7 Hz, 2H), 4.96-4.84 (t, 1H), 4.70 (dt, J = 8.4, 5.3 Hz, 1H), 4.17 (d, J = 12.7 Hz , 1H), 3.96 (dd, J = 11.4, 3.7 Hz, 1H), 3.79-3.75 (t, 1H), 3.73 (t, 4H), 3.6- 3.55 (t, 1H), 3.45 (dd, J = 15.3, 10.7 Hz, 2H), 3.24 (t, J = 12.2 Hz, 1H). 668.2 1.4

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193 0 ) y' .¾ Ko-N-i \=N )=< w 1H NMR (400 MHz, DMSO-06) δ 9.01 -8.91 (m, 1H), 8.80 (s, 1H), 8.73 (d, J = 5.5 Hz, 1H), 8 .64 (t, J = 7.6 Hz, 1H), 7.62 (s, ZN), 7.46 (s, 1H), 6.82-6.70 (m, 2H), 4.91 ( d, J = 9.4 Hz, 1H), 4.72 (dd, J = 22.6, 8.8 Hz, 1H), 4.40 (d, J = 8.1 Hz, 2H), 4, 16 (d, J = 12.8 Hz, 1H), 3.95 (d, J = 11.1 Hz, 1H), 3.73 (q, J = 14.1, 12.5 Hz, 2H), 3.61-3.35 (m, ZN), 3.24 (t, J = 12.3 Hz, 1H), 1.42 (t, J = 7.0 Hz, ZN). 699.3 1.4 194 p p- FFF )=° Af η—np dA-Hr ^N A\ Η—Ν _χ 'н ⁴ — 1H NMR (400 MHz, flMCO-d6) δ 8.98 (d, J = 8.0 Hz, 1H), 8.86 (dd, J = 4.3, 1.5 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1 Η), 7.73-7.54 (m, ZN), 6.74 (d, J = 11.7 Hz, ZN), 4.90 (dt, J = 8.8, 5.3 Hz, 1H), 4.75-4.56 (m, 1H), 4.15 (d, J = 12.7 Hz, 1 Η), 3.94 (dd, J = 11.5, 3.8 Hz, 1H), 3.80-3.63 (m, 2H), 3.62-3.46 ( m, 1H), 3.41 (dd, J = 12.9, 7.8 Hz, 2H), 3.21 (t, J = 12.3 Hz, 1H). 670.2 1.4 195 E ^? FJ--\ /° FN—( H )=\ AA ^FF /=° Cl HN 0 NEC—° ^-H O 1H NMR (400 MHz, flMCO-d6) δ 9.38 (d, J = 8.2 Hz, 1H), 9.01 (d, J = 8.5 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7 .91 (d, J = 7.9 Hz, 1H), 7.687.59 (m, 5H), 7.56 (d, J = 7.9 Hz, 1H), 4.81 (d, J = 7, 9 Hz, 2H), 3.79 (s, 1H), 3.41 (s, 1H), 2.65 (s, 1H), 2.31 (d, J = 1.9 Hz, 1H), 2 .06 (s, 1H), 1.34 (d, J = 7.1 Hz, ZN). 631.2 62.3 196 C^ ⁰¹ SG /=0 /Г-л HN 0-H Оуо-П оГ )=( on) 1H NMR (400 MHz, flMCO-d6) δ 9.33 (dd, J = 15.0, 8.3 Hz, 1H), 8.93 (d, J = 4.2 Hz, 1H), 8.73 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.867.79 (m, 2H), 7.77 - 7.65 (m, ZN), 7.53 (d, J = 8.3 Hz, 1H), 7.51 7.37 (m, 4H), 4.87 (td, J = 9.2, 4.7 Hz, 1H), 3.77 (dd, J = 14.4, 4.7 Hz, 1H), 3.46 (dd, J = 14.5, 10.0 Hz, 1H). 533.1 63.1

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197 Cl HN 0 NEC—° ^-H w 1H NMR (400 MHz, DMSO-C16) δ 9.35 (d, J = 8.3 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.91 (d , J = 7.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.61 (d, J = 2.8 Hz, 2H), 7.56 (d, J = 7, 9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 4.79 (s, 1H), 2.83 (d, J = 4.0 Hz, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 0.68 (dd, J = 7.0, 4.7 Hz, 2H), 0.61 - 0.48 (m, 2H). 575.0 63.4 198 F ..... F ^y _F F. FF )=0 У-F Η—N 0 —<Γ/~' ^0-H nY /\ ' ⁰ 1H NMR (400 MHz, flMCO-d6) δ 8.96 (d, J = 8.3 Hz, 1H), 8.81 (d, J = 4.1 Hz, 1H), 8.63 (d, J = 8.7 Hz, 1H), 7.59 (ddd, J = 15.7, 8.0, 4.0 Hz, 2H), 7.44 (dd, J = 7.4, 3.9 Hz, 1H), 6.76 (dd, J = 11.6, 4.3 Hz, ZN), 6.54 (s, 1H), 4.87 (d, J = 8.8 Hz, 1H), 4, 74-4.64 (m, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.82-3.57 (m, 4H), 3.53 (d, J = 12, 4 Hz, 1H), 3.49 (d, J = 2.1 Hz, 4H), 3.473.36 (m, 1H), 3.15-3.04 (m, 1H), 2.82 (t, J = 11.6 Hz, 1H), 2.54 (d, J = 3.7 Hz, 4H), 1.18 (d, J = 7.3 Hz, 1H), 1.15 (d, J = 6.1 Hz, 4H). 713.3 1.4 199 ^FF LL F )=0 E / Η—N ,0 rCfy-YH NY / \ ' °w 1H NMR (400 MHz, flMCO-d6) δ 13.16-12.62 (s, 1H), 8.87 (s, 1H), 8.79 (t, J = 7.3 Hz, 1H), 7 .99 (s, 1 Η), 7.76-7.45 (m, 4H), 6.76 (dd, J = 9.4, 5.7 Hz, 1 Η), 6.43 (dd, J = 11.4, 4.5 Hz, 2H), 4.71 (m, 1H), 4.30 (m, 1 Η), 3.73 (dd, J = 51.5, 14.6 Hz, 1H ), 3.42 (m, J = 2.2 Hz, 4H), 1.75 (d, J = 9.1 Hz, 4H), 1.60 -1.43 (m, 1H), 0.92 (t, J = 7.3 Hz, ZN). 621.3 1.5 200 ( H γ- к ,¾ Cl / Η—N p HOYh NA )=( ¹ °w 1H NMR (400 MHz, flMCO-d6) δ 8.96-8.84 (m, 2H), 8.79 (t, J = 8.1, 6.7 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.85-7.73 (m, 1H), 7.68 (dd, J = 12.8, 7.4 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1 Η), 6.76 (dd, J = 9.5, 5.0 Hz, 1H), 6.43 (dd, J = 11.4, 2.8 Hz, 2H), 4.72 (ddt, J = 15.3, 10.4, 4.6 Hz, 1H), 4.30 (q, J = 8.8 Hz, 1H), 3.83 (dd, J = 14, 3, 4.3 Hz, 1 Η), 3.56-3.33 (m, 4Η), 1.83 (d, J = 10.6 Hz, ZN), 1.80-1.70 (m, 1H), 1.60-1.45 (m, 1H), 0.92 (t, J = 7.3 Hz, ZN). 637.2 1.5

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201 — ₄ F Υύ HN F R \ ^F >0 0 HN 0 /° ⁿ D 1H NMR (400 MHz, DMSO-06) δ 8.83 (d, J = 8.1 Hz, 1H), 7.66 (s, 3N), 6.77 (d, J = 10.2 Hz, 3N ), 6.44 (d, J = 11.6 Hz, 2H), 4.70 (s, 1 Η), 4.54 (s, 2H), 4.41 -4.24 (m, 1H), 3.73 (d, J = 13.5 Hz, 1 Η), 3.67 - 3.52 (m, 6H), 3.52 - 3.25 (m, 1H), 1.76 (dd, J = 7.3, 3.9 Hz, 1H), 1.62-1.40 (m, 1 Η), 1.21 (t, J = 7.0 Hz, ZN), 0.92 (t, J = 7.3 Hz, ZN). 676.2 1.5 202 .a. ”R: / Η—N p Yrr” ^N A /\ / 0 Ν _χ b 1H NMR (400 MHz, flMCO-d6) δ 9.03 (t, J = 9.0 Hz, 1H), 8.998.92 (m, 1H), 8.90 (d, J = 8.1 Hz, 1H ), 7.86 (ddd, J = 17.7, 8.7, 5.0 Hz, 1H), 7.72 (dd, J = 15.8, 7.4 Hz, 1H), 7.62 ( t, J = 9.0, 7.4 Hz, 1H), 6.71 (d, J = 12.0 Hz, 2H), 6.24 (d, J = 2.4 Hz, 1 Η), 4 .99-4.86 (m, 1 Η), 4.81 -4.68 (m, 1 Η), 3.85 (dd, j = 14.3, 4.3 Hz, 1H), 3.73 (dd, J = 14.6, 4.7 Hz, 1H), 3.65-3.49 (m, 2H), 3.48 - 3.36 (m, 4H), 3.01 (t, J = 12.3 Hz, 1H), 2.43 (s, ZN), 2.02 -1.90 (m, 1H), 1.86-1.67 (m, ZN), 1.67-1, 42 (m, ZN). 643.7 1.5 203 Q .¾ \ / Η—N 0 N> zr^x Y> 0=( %—A %—' 0—H ^N A / \ / 0 Ν _χ 1H NMR (400 MHz, flMCO-d6) δ 13.08 (s, 1H), 9.28 (dd, J = 8.2, 2.8 Hz, 1H), 8.93 (dd, J = 4, 5, 2.4 Hz, 1H), 8.83 (s, 1H), 7.75 (ddt, J = 6.9, 4.7, 1.5 Hz, 4H), 7.70 - 7.50 (m, 4H), 6.91 -6.82 (m, 2H), 4.85 - 4.72 (m, ZN), 3.46 (d, J = 3.5 Hz, ZN), 3, 22 (d, J = 2.7 Hz, ZN), 1.92 (d, J = 9.6 Hz, ZN). 662.8 1.6 204 .....π..... Y EFF )=0 >F HN p rY-Hh N> )=( ⁷ 0 Ν _χ > 1H NMR (400 MHz, flMCO-d6) δ 13.19-12.63 (s, 1H), 8.89-8.76 (m, 2H), 8.63 (s, 1H), 7.66- 7.54 (m, 2H), 7.48-7.39 (m, 1H), 6.57 (d, J = 4.6 Hz, 1 Η), 6.54 (s, 2H), 4, 71 (d, J = 9.5 Hz, 1H), 3.93 (d, J = 7.1 Hz, 1H), 3.68 (m, J = 4.4 Hz, ZN), 3.57- 3.50 (m, 1H), 3.49 (d, J = 1.8 Hz, ZN), 3.47-3.37 (m, 2H), 2.58 (d, J = 11.7 Hz , 1 Η), 2.53 (s, ZN), 1.16 (d, J = 6.1 Hz, ZN), 1.02 (d, J = 6.5 Hz, ZN). 658.9 1.7

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205 0 \ ^F z=\ 0 Η—N 0 Qin M ₀ _ _H nA / \ ^{z 0 N} \ # 1H NMR (400 MHz, DMS0-C16) δ 9.01-8.88 (m, ZN), 7.96 (d, J = 8.0 Hz, 1H), 7.88-7.69 (m, 4H), 7.64 (d, J = 8.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.75 (dd, J = 11.6, 8.0 Hz, 2H), 4.97-4.70 (m, 2H), 4.16 (d, J = 12.7 Hz, 1H), 4.003.85 (m, 2H), 3.73 (d, J = 13.9 Hz, 2H), 3.64 (d, ZN), 3.56 (t, J = 13.5, 7.5 Hz, 1H), 3.42 (d, J = 12.1 Hz , 1H), 3.30 (s, 3H), 3.25 (t, J = 13.4 Hz, 1H). 697.3 1.7 206 0 ”R: ξ Η—N 0 kA 1H NMR (400 MHz, flMC0-d6) δ 9.41 (s, 1H), 9.34 (s, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.56 (dd , J = 9.1, 6.1 Hz, 1 Η), 8.27-8.07 (m, 2H), 7.98 (d, J = 3.5 Hz, 1H), 7.80 (td , J = 8.9,2.6 Hz, 1 Η), 6.73 (d, J = 11.7 Hz, 2H), 4.94 - 4.78 (m, 2H), 4.15 (d , J = 12.7 Hz, 1H), 3.93 (dt, J = 13.7, 7.1 Hz, 2H), 3.72 (d, J = 14.8 Hz, 2H), 3.61 - 3.50 (m, 2H), 3.39 (d, J = 13.1 Hz, 1 Η), 3.21 (t, J = 15.5 Hz, 1H), 3.11 (s, ZN ). 670.2 1.7 207 F, F F> Η—N \ ^F >0 Ο Η—Ν O ^OH nA )=< / 0 Ν _χ 1H NMR (400 MHz, DMSO) δ 8.88-8.80 (m, 2H), 8.71-8.62 (m, 1H), 8.27 (s, 1H), 7.69-7, 49 (t, ZN), 6.86 (d, J = 9.2 Hz, 1H), 6.43 (d, J = 11.5 Hz, 2H), 4.704.61 (t, 1H), 4, 58-4.45 (t, 1H), 3.78 (S, ZN), 3.68 (S, ZN), 3.493.38 (t, 2H), 1.28 (d, J = 6.7 Hz , ZN). 606.2 1.7 208 4k- FF ^F /=° У-F Η—N 0 CAZA ^oh )= ⁿ ы— ^N \ Ν _χ A to ^x ' 1H NMR (400 MHz, DMSO) δ 8.82 (dd, J = 12.6, 6.1 Hz, 2H), 8.63 (d, J = 8.7 Hz, 1H), 7.90 (d , J = 9.2 Hz, 1 Η), 7.68 - 7.50 (t, ZN), 6.77 (d, J = 9.4 Hz, 1 Η), 6.43 (d, J = 11.5 Hz, 2H), 4.65 (td, J = 9.1, 4.5 Hz, 1H), 4.30 (s, 1H), 3.71 (d, j = 14.4 Hz, 1H), 3.45-3.32 (m, 1H), 1.89-1.61 (m, 1H), 1.661.34 (m, 1H), 0.91 (t, J = 7.3 Hz , ZN). 642.1 1.8

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209 ^F \ ^F fA / Η—N ,2 \ Η—N p AA ^N A / \ ' ° w 1H NMR (400 MHz, DMSO-C16) δ 8.89 (d, J = 4.3 Hz, 1H), 8.78 (dd, J = 20.1, 8.3 Hz, 2H), 7.79 -7.67 (m, 2H), 7.62 (t, J = 3.7 Hz, 2H), 6.77 (d, J = 9.4 Hz, 1H), 6.43 (d, J = 11.5 Hz, 2H), 4.69-4.59 (m, 1H), 4.29 (d, J = 10.4 Hz, 1H), 3.71 (dd, J = 14.4, 4 ,6 Hz, 1H), 3.45 (s, 4H), 2.23 (d, J = 0.9 Hz, ZN), 1.75 (ddd, J = 13.9, 7.3, 3, 2 Hz, 1H), 1.51 (ddd, J = 13.7, 10.4, 7.2 Hz, 1H), 0.91 (t, J = 7.3 Hz, ZN). 604.2 1.9 210 < , ^H ✓ ^N F. FF )=° fA η—np SuuuA- _n )=< / on) 1H NMR (400 MHz, flMCO-d6) δ 8.92 (dd, J = 4.4, 1.5 Hz, 1H), 8.80 (t, J = 9.0 Hz, 2H), 8.51 (dt, J = 2.8, 1.4 Hz, 1H), 7.77-7.67 (m, ZN), 7.62 (d, J = 7.5 Hz, 1H), 6.78 ( d, J = 9.4 Hz, 1 Η), 6.43 (d, J = 11.5 Hz, 2H), 4.65 (ddd, J = 9.9, 8.0, 4.5 Hz, 1H), 4.28 (t, J = 8.9 Hz, 1H), 3.72 (dd, J = 14.4, 4.5 Hz, 1H), 3.55 (s, ZN), 3, 41 (dd, J = 14.5, 9.9 Hz, 1H), 1.75 (dtt, J = 14.8, 7.4, 3.7 Hz, 1H), 1.51 (ddt, J = 17.7, 14.5, 7.3 Hz, 1H), 0.90 (t, J = 7.3 Hz, ZN). 656.7 1.9 211 F. F ^F \ Η—N ,2 \ Η—Ν p _o yyyy_M _o _ _H Ny /\ ' ^{0 N} _x y 1H NMR (400 MHz, flMCO-d6) δ 8.98 (dd, J = 4.4, 1.5 Hz, 1H), 8.85 -8.79 (m, 2H), 7.94 (s, 1H), 7.77 (dd, J = 8.5, 4.4 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.43 (d, J = 11.5 Hz, 2H), 4.66 (ddd, J = 9.6, 8 ,1, 4.4 Hz, 1H), 4.51 (dq, J = 14.7, 7.1 Hz, 1H), 3.73 (dd, J = 14.4, 4.5 Hz, 1H) , 3.47-3.38 (m, 4H), 3.26 (s, ZN), 1.28 (d, J = 6.7 Hz, zn). 606.2 1.9 212 ^FF \ \ N— HN P Nul-An w 1H NMR (400 MHz, flMCO-d6) δ 8.99 (d, J = 8.3 Hz, 1H), 8.93 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (dd, J = 8.7, 1.7 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7 .84 (d, J = 7.4 Hz, 1H), 7.76 (dd, J = 7.9, 3.2 Hz, 2H), 6.74 (d, J = 11.8 Hz, 2H) , 4.91 (dd, J = 8.8, 3.6 Hz, 1H), 4.77 (ddd, J = 10.4, 8.3, 4.3 Hz, 1H), 4.17 (d , J = 12.7 Hz, 1H), 3.96 (dd, J = 11.4, 3.8 Hz, 1 Η), 3.84 (dd, J = 14.1, 4.2 Hz, 1H ), 3.73 (d, J = 12.8 Hz, 1H), 3.59-3.35 (m, ZN), 3.23 (t, J = 12.2 Hz, 1H), 2.60 (s, ZN), 2.29 (s, 6H). 644.4 1.9 213 dΛ Cl H-N^__ NEC A 2—C \O-H w 1H NMR (400 MHz, flMCO-d6) δ 8.89-8.78 (m, 2H), 8.66 (dd, J = 8.6, 1.6 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.60 (m, ZN), 7.58 (d, J = 7.9 Hz, 1 Η), 6.60 (d, J = 12.0 Hz, 2H), 4.77 - 4.66 (m, 1 Η), 3.75 (s, 1 Η), 3 .68 (dd, J = 6.0, 4.1 Hz, 2H), 3.43 (s, 1 Η), 3.19 (t, J = 5.1 Hz, 2H), 3.11 (s , 2H), 1.16 (s, 6H). 605.9 28.6 214 HN ,¾ Cl n-N p NEC—7 2—\ /—' ° ^-H O 1H NMR (400 MHz, flMCO-d6) δ 12.98 (s, 1H), 8.84 (dd, J =4.1, 1.6 Hz, 1H), 8.76 (d, J = 7, 9 Hz, 1 Η), 8.64 (dd, J = 8.6, 1.7 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1 Η), 7.67-7.55 (m, 4Η), 7.25 (d, J = 6.4 Hz, 1H), 6.12 (d, J = 11.3 Hz, 2H), 4.83 (t, J = 6.5 Hz, 2H), 4.68 (d, J = 7.3 Hz, 1H), 4.55 (h, J = 6 .5 Hz, 1H), 4.36 (t, J = 6.0 Hz, 2H), 3.74 (s, 1H), 3.44 (qd, J = 7.0, 4.9 Hz, 1H ). 563.8 28.6

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215 Y\ ^F Ο Η—Ν 0 fY^>——'' Ο-Η Υ ο 1H NMR (400 MHz, DMS0-C16) δ 9.27 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.64 (s, 1H ), 7.677.53 (m, ZN), 7.53 - 7.44 (m, 2H), 7.33 (d, J = 13.3 Hz, 1 Η), 7.11 (t, J = 8 ,0 Hz, 2H), 4.74 (t, J = 9.1 Hz, 1H), 3.78-3.71 (m, ZZN), 3.70 (s, ZN), 3.38 (dd , J = 14.6, 10.0 Hz, 1H). 548.6 29.0 216 Ο ^Η ,¾ CI Η-Ν 0 ^Ν Υ 1H NMR (400 MHz, DMS0-06) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.80 (d, J = 8.0 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1 Η), 8.15 (dd, J = 1.6, 0.4 Hz, 1 Η), 7.90 (dd, J = 7.9 , 1.7 Hz, 1 Η), 7.67 - 7.59 (m, ZN), 7.57 (dd, J = 7.9, 0.4 Hz, 1 Η), 6.56 (d, J = 12.3 Hz, 2H), 4.71 (m, 1H), 3.73 (s, 1H), 3.44 (d, J = 13.2 Hz, ZN), 3.26-3, 05 (m, 2H), 1.43 (d, J = 11.2 Hz, 4H), 1.10 (s, ZN). 605.6 31.0 217 0 γ Ε FF )=Ο Af η-ν ,0 ηΥΥ-Α-η ^Ν ν /\ ⁷ 0 Ν ) 1H NMR (400 MHz, DMS0-06) δ 8.88 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 4.2 Hz, 1H), 8.66 (d, J = 7.9 Hz, 1 Η), 7.64 (dd, J = 8.6, 4.3 Hz, 1H), 7.58 (t, J = 7.0 Hz, 1H), 7.45 ( dd, J = 7.5, 3.2 Hz, 1H), 6.62 (dd, J = 11.6, 4.3 Hz, 2H), 6.55 (s, 1H), 4.71 (d , J = 10.4 Hz, 1H), 3.783.63 (m, 5H), 3.55 - 3.34 (m, 4H), 3.20 (t, J = 4.9 Hz, 4H), 2 .53 (s, ZN). 631.2 2.0 218 Υ FFF )=0 U-F Η-Ν Ο h^uO-A-n ^ν ν /Υ ⁷ 0 ^Ν _χ / 1H NMR (400 MHz, Chloroformd) δ 9.48 -8.74 (m, 1H), 7.827.65 (m, 2H), 7.56 (d, J = 7.4 Hz, 1 Η), 7, 35 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 0.8 Hz, ZN), 6.91 (dt, J = 19.9, 8.1 Hz, 2H), 6.56 (d, J = 11.9 Hz, 1H), 5.04 (t, J = 9.9 Hz, 1H), 3.94 (dd, J = 14.3, 6.2 Hz, 1H ), 3.59 (d, J = 14.2 Hz, 2H), 2.55 (d, J = 7.6 Hz, ZN). 546.0 2.1

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219 I' ⁿ AL ^Cl \ ^{C |/} )=o 0 Η—N 0 ^l ° /° o 1H NMR (400 MHz, DMSO-06) δ 11.65 (s, 1H), 9.12 (d, J = 8.6 Hz, 1H), 8.88 (s, 1H), 7.72 (d , J = 23.5 Hz, ZN), 7.67 - 7.43 (m, 2H), 6.77 (d, J = 6.7 Hz, 2H), 6.50 (dd, J = 3, 1, 1.9 Hz, 1H), 4.88 (d, J = 9.5 Hz, 1H), 4.54 (s, 2H), 3.79 (d, J = 14.4 Hz, 1H) , 3.67-3.51 (t, 8H), 3.43 (t, J = 12.8 Hz, 1H), 1.21 (t, J = 7.0 Hz, ZN). 621.9 2.1 220 'B .¾ Cl Η-N o ABOUT 1H NMR (400 MHz, flMCO-d6) δ 8.88 (d, J = 8.1 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.58 (t, ZH), 7.56 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 11.9 Hz, 2H), 4, 71 (d, J = 7.7 Hz, 1H), 3.74 (s, 1H), 3.45 (t, J = 5.8 Hz, 5H), 1.95 (tt, J = 13.7 , 5.7 Hz, 5H). 611.5 45.2 221 CI n-N 0 NEC——'' 0—N ABOUT 1H NMR (400 MHz, flMCO-d6) δ 13.04 (s, 1H), 9.24 (d, J = 8.2 Hz, 1H), 8.83 (dd, J = 4.1, 1, 6 Hz, 1H), 8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.63 (d, J = 13.6 Hz, ZN), 7.56 (d, J = 7.9 Hz, 1 Η), 6.93 (d , J = 8.5 Hz, 2H), 4.81 4.70 (t, 1H), 3.84 (s, 2H), 3.76 (s, 1H), 2.14 (s, ZH). 548.1 48.2 222 L: Cl F H-N 0 NEC——'' O-N ABOUT 1H NMR (400 MHz, flMCO-d6) δ 9.21 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.91 (dd, J = 7.9, 1 .6 Hz, 1H), 7.68-7.58 (t, ZN), 7.56 (dd, J = 7.9, 0.4 Hz, 1H), 7.48 (td, J = 8, 4, 6.5 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7.11 -7.01 (t, 1H), 6.90 (s, 1H), 4, 77 (s, 1H), 3.73 (s, 1H), 3.41 (s, 1H). 540.1 48.3

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223 ^FF H ^F F ^FF /=° \ U-F n-N p Nuu-N>-n w 1H NMR (400 MHz, DMSO-06) δ 8.97 (t, J = 7.8 Hz, 1H), 8.838.76 (m, 1H), 8.71 (d, J = 5.0 Hz, 1H ), 8.65 (t, J = 7.7 Hz, 1H), 7.67 -7.54 (m, 4H), 6.76 (dd, J = 11.6, 7.8 Hz, 2H) , 4.91 (d, J = 9.3 Hz, 1H), 4.70 (d, J = 14.6 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3 .95 (dd, J = 11.6, 3.7 Hz, 1H), 3.75 (t, J = 14.8 Hz, 2H), 3.62 - 3.35 (m, 3H), 3, 23 (t, J= 12.3 Hz, 1H), 2.59 (q, J = 2.3 Hz, ZN). 669.6 2.2 224 A\ ^F >0 0 HN p GBChU-An ^l ° 1H NMR (400 MHz, flMCO-d6) δ 13.08 (s, 1H), 9.31 (d, J = 8.1 Hz, 1 Η), 8.86 (d, J = 4.3 Hz, 2H), 7.93 -7.70 (m, 5H), 7.62 (dd, J = 8.7, 6.9 Hz, ZN), 6.89 (d, J = 8.1 Hz, 2H ), 6.76 (d, J = 4.0 Hz, 2H), 4.85 -4.70 (m, 1 Η), 4.78 (s, 2H), 4.54 (s, 2H), 3.84-3.67 (m, 1H), 3.58 (q, J = 7.0 Hz, 2H), 3.56 (s, ZN), 3.55 (s, ZN), 3.43 (dd, J = 14.7, 10.1 Hz, 1H), 1.21 (t, J = 7.0 Hz, ZN). 705.4 2.2 225 T ο ο ^ο< γ° о III z 1H NMR (400 MHz, flMCO-d6) δ 11.41 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 8.3 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.74-8.61 (m, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.92 (s, 1 Η ), 7.76-7.45 (m, 4Η), 7.20 (d, J = 0.9 Hz, 1H), 6.10 (s, 1H), 3.74 (dd, J = 14, 3, 4.1 Hz, 1H), 3.493.31 (m, 1H), 2.01 (td, J = 8.4, 4.2 Hz, 1H), 1.05-0.91 (m, 2H ), 0.79 (ddd, J = 6.4, 5.3, 3.9 Hz, 2H). 605.2 53.7 226 “8 .2 \ 0 Η—N 0 ^N \ 0=( /)—/ ' oH nA. >=< Ό 1H NMR (400 MHz, flMCO-d6) δ 8.93 (s, 1H), 8.87 (d, J = 8.1 Hz, 1H), 8.81 (s, 1H), 7.74 (s , 1H), 7.70 - 7.51 (m, 2H), 6.75 (dd, J = 11.6, 4.2 Hz, 2H), 4.70 (q, J = 12.2.9 .9 Hz, 1H), 4.19 (d, J = 15.1 Hz, 1 Η), 4.08 (d, J = 14.7 Hz, 1H), 3.87-3.62 (m, 1H), 3.57-3.30 (m, 5H), 3.30-3.14 (m, 5H), 3.14 -2.94 (m, 2H), 1.92 (d, J = 9.6 Hz, ZN), 1.18 (d, J = 6.7 Hz, ZN). 656.2 1.1

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227 bx X ^f EFF /=0 Yf h—np -Х/у-Н-и n4 /\ ^λ ° ^N \ # 1H NMR (400 MHz, DMSO-06) δ 8.96 (d, J = 7.9 Hz, 1H), 8.868.77 (m, 1 Η), 8.62 (d, J = 8.7 Hz, 1 Η), 7.67-7.53 (m, 2H), 7.43 (d, J = 7.2 Hz, 1H), 6.83-6.70 (m, 2H), 6.54 ( s, 1 Η), 4.86 (d, J = 9.3 Hz, 1H), 4.70 (d, J = 10.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H), 3.87 (s, 1H), 3.68 (dd, J = 14.7, 4.3 Hz, 1H), 3.61 (t, J = 11.0 Hz, 1 Η), 3.48 (d, J = 2.2 Hz, ZN), 3.43 (d, J = 14.6 Hz, 1 Η), 3.08 (t, J = 12.2 Hz, 1 Η), 2.52 (s, 5H), 2.46 (s, 1H), 1.36-1.17 (m, ZN). 712.7 1.1 228 X X ^ci ci >0 Cl Η—N 0 ^с^b/^bЧ'Че-н ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 11.47 (s, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.85 (dd, J = 4.1, 1, 6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1 Η), 7.79 - 7.50 (m, 4Η), 7.36 (d, J = 0.6 Hz, 1 Η), 6.05 (d, J = 1.9 Hz, 1 Η), 4.86 (s, 1H), 3.75 (dd, J = 14.4, 4.1 Hz, 1H), 3.52-3.31 (m, 1H), 2, 12-1.98 (m, 1H), 1.070.89 (m, 2H), 0.89 - 0.70 (m, 2H). 604.9 57.8 229 An X Cl n-N p νξο—ev—a i—' oh ^N O 1H NMR (400 MHz, flMCO-d6) δ 8.91 -8.77 (m, 2H), 8.63 (dd, J = 8.7, 1.7 Hz, 1 Η), 8.15 (dd , J = 1.6, 0.4 Hz, 1 Η), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (s, 2H), 7.57 (dd , J = 7.9, 0.4 Hz, 1H), 7.50 (s, 1H), 6.29 (d, J = 11.2 Hz, 2H), 4.68 (s, 1H), 3 .73 (s, 1H), 3.40 (s, 1H), 1.461.30 (m, 2H), 1.03 (s, 2H). 615.2 60.5 230 ff F /=0 Af hn p XXh-h N-<)=< / 0 Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 8.72 (d, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.09 (s, 1H), 7.54-7 .43 (m, 2H), 7.33 (d, J = 7.3 Hz, 1 Η), 6.72 (d, J = 12.1 Hz, 2H), 6.51 (s, 1H), 4.99-4.83 (m, 1H), 4.46-4.31 (m, 1H), 3.72 - 3.56 (m, 2H), 3.52 - 3.39 (m, 4H), 3.32 (s, ZN), 3.02 (t, J = 12.2 Hz, 1 Η), 1.95 (d, J = 14.5 Hz, 1H), 1.87-1 .67 (m, 2H), 1.66-1.44 (m, ZN). 697.3 2.2

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231 F O-ur F Q ^f F. FF )=0 U-F Η—Ν O -b/—bb—° ^-H ΝΛ /\ ^{Z 0 N} \ # F-/ FF 1H NMR (400 MHz, DMSO-C16) δ 8.97 (t, J = 7.2 Hz, 1H), 8.90 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.8, 6.1 Hz, 1H), 7.72 (dd, J = 10.6, 7.3 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 6 .75 (dd, J = 11.5, 3.9 Hz, 2H), 6.57 (s, 1H), 4.91 (d, J = 9.1 Hz, 1H), 4.74 (s, 1H), 4.16 (d, J= 12.7 Hz, 1H), 4.01 -3.90 (m, 1H), 3.85 -3.64 (m, 2H), 3.63-3 .37 (m, 6H), 3.23 (t, J = 12.3 Hz, 1H), 2.54 (s, 3H). 767.2 0.9 232 F. ^F UChSU ^s| Η—N R:\ Η—N 0 n^. z^x UL 0=( p—Г У—' 0-H nA /\ ^{z 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 8.91 (d, J = 3.9 Hz, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.68 (s, 1H ), 7.89 (s, 1H), 7.66 (dd, J = 12.4, 5.9 Hz, 2H), 7.62 - 7.47 (m, 7H), 6.52 (d, J = 11.2 Hz, 2H), 5.79-5.70 (m, 1H), 4.60 (td, J = 9.2, 4.4 Hz, 1H), 3.67 (dd, J = 14.5, 4.4 Hz, 1H), 3.38 (s, 3H), 3.24 (s, 3H). 702.1 0.9 233 p F. F F )=0 b^O У-F H-N 0 GNU-Lb-H \=N )=( w 1H NMR (400 MHz, flMCO-d6) δ 12.92 (brs, 1H), 8.95 (t, J = 9.3 Hz, 1H), 8.78 (d, J = 15.1 Hz, 2H ), 8.63 (s, 1H), 7.70 (s, 1H), 7.60 (s, 3H), 6.76 (t, J = 10.6 Hz, 2H), 4.91 (d , J = 9.4 Hz, 1H), 4.69 (d, J = 7.4 Hz, 1H), 4.27 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H ), 3.99-3.91 (m, 1H), 3.73 (d, J = 13.0 Hz, 2H), 3.61 3.35 (m, 3H), 3.23 (t, J = 12.2 Hz, 1H), 0.96 (d, J = 6.1 Hz, 2H), 0.81 (q, J = 10.9, 9.6 Hz, 2H). 711.2 2.2 234 F^F Η—N ,¾ \ / Η—N 0 nZ z»x Ul 0=( У—P У—' о-н N—< )=( ^{Z 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 8.92 (d, J = 4.4 Hz, 1H), 8.78 (d, J = 7.9 Hz, 1H), 7.73 (s, 1H ), 7.697.52 (m, 2H), 6.76 (d, J = 9.4 Hz, 1H), 6.41 (d, J = 11.5 Hz, 2H), 4.68 (td, J = 9.0, 8.5, 4.6 Hz, 1H), 4.29 (s, 1H), 3.66 (dd, J = 14.3, 4.8 Hz, 1H), 3.54- 3.39 (m, 4H), 3.22 (d, J = 2.4 Hz, ZN), 1.92 (d, J = 10.3 Hz, ZN), 1.75 (ddd, J = 13 .8, 7.2, 3.2 Hz, 1H), 1.50 (ddd, J = 13.8, 10.4, 7.2 Hz, 1H), 0.90 (t, J = 7.3 Hz, ZN). 634.2 2.3

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235 Η / ί >=\ ^Cl \ CI %Ο 0 n-N ρ αΧγύ-Άη ^Λ ° 1H NMR (400 MHz, DMSO-bb) δ 11.54 (s, 1H), 9.06 (d, J = 8.5 Hz, 1H), 8.84 (s, 1H), 7.71 (s , 2H), 7.50 (dd, J = 3.2, 2.4 Hz, 1H), 7.40 (d, J = 0.9 Hz, 1H), 6.75 (d, J = 6, 2 Hz, 2H), 6.44 (d, u = 2.9 Hz, 1H), 4.88 (s, 1H), 4.54 (s, 2H), 3.76 (d, J = 14.1 Hz, 1H), 3.67-3.49 (t, 8H), 3.41 (t, J = 12.7 Hz, 1H), 1.21 (t, J = 7.0 Hz, ZN). 622.4 2.3 236 —< F ^C ^F Η—Ν F Λ Ε FF )=Ο \ FF Η-Ν ρ -К/уН-н / ^Ν Λ\ W 1H NMR (400 MHz, flMCO-d6) δ 8.93-8.73 (t, 2H), 8.62 (t, J = 8.7 Hz, 1H), 7.59 (dd, J = 11, 1, 5.2 Hz, ZN), 6.76 (t, J = 8.9 Hz, 1H), 6.45 (dd, J = 11.6, 7.8 Hz, 2H), 4.68 ( t, 1H), 4.31 (s, ZN), 3.803.59 (t, 1H), 3.54-3.32 (t, 1H), 2.54 (s, ZN), 2.46 (s , ZN), 2.35 (s, ZN), 1.76 (s, 1H), 1.52 (s, 1H), 0.92 (t, J = 7.3 Hz, ZN). 669.2 2.6 237 ο4 / ο .¾ \ 0 Η—Ν 0 ^Ν \ ΛΑ )—\ ο=( еρ—' ο-η ^Ν \ Λ\ / ' ^Ν _χ / 1H NMR (400 MHz, flMCO-d6) δ 8.94 (s, 1H), 8.88 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.71 -7 .52 (t, 2H), 6.75 (dd, J = 11.7, 4.2 Hz, 2H), 4.72 (td, J = 14.3, 12.8, 6.6 Hz, 1H ), 4.19 (d, J = 15.3 Hz, 1H), 4.08 (d, J = 14.9 Hz, 1H), 3.76 (ddd, J = 51.1, 14.4, 4.4 Hz, 1H), 3.55-3.29 (t, 6H), 3.27-3.14 (t, 5H), 3.14-2.97 (t, 2H), 1.93 (d, J = 10.5 Hz, ZN), 1.18 (d, J = 6.7 Hz, ZN). 656.2 2.6 238 \ / ^Η / ^Ν Λ FFF >0 YF Η—Ν Ρ αγ r ^N ΛΑ Η—Ν _χ λ ^ch n ⁴ —' 1H NMR (400 MHz, flMCO-d6) δ 8.91 -8.73 (t, 2H), 8.64 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.667 .54 (t, 2H), 6.84 (d, J = 9.2 Hz, 1H), 6.75 (s, 1H), 6.41 (d, J = 11.4 Hz, 2H), 4 .65 (td, J = 9.0, 8.2, 4.5 Hz, 1H), 4.49 (dt, J = 14.8, 7.4 Hz, 1H), 3.76-3.66 (t, 1H), 3.453.33 (t, 1H), 1.26 (d, J = 6.7 Hz, ZH). 628.1 2.8

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239 ft: z—z 1H NMR (400 MHz, DMSO-06) δ 10.72 (s, 1H), 9.23 (d, J = 8.1 Hz, 1H), 8.91 (dd, J = 4.2, 1, 5 Hz, 1H), 8.71 -8.55 (m, 2H), 7.71 (dd, J = 8.6, 4.2 Hz, 1H), 7.60-7.41 (m, 5H ), 7.12 (dd, J = 8.4, 7.6 Hz, 2H), 4.68 (ddd, J = 9.6, 8.1,4.6 Hz, 1H), 3.71 - 3.60 (m, 1H), 3.34 (dd, j = 14.4, 9.7 Hz, 1H). 544.1 77.9 240 o Y h 1 <^N L>\ ^Cl Cl · /=0 Cl Η—N 0 NEC——XY—'' 0-H O 1H NMR (400 MHz, flMCO-d6) δ 11.51 (d, J = 2.2 Hz, 1 Η), 9.03 (d, J = 8.3 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.727.48 (m, 4H), 7.37 - 7.15 (m, 6H), 6.17 (s, 1H), 4.85 (s, 1H), 4.07 (s, 2H), 3.75 (dd, J = 14.5, 4.2 Hz, 1 Η), 3.40 (dd, J = 14.4, 10, 6 Hz, 1H). 655.2 79.2 241 % Cl HN 0 NEC——'' OH ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 9.41 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7 ,68-7.42 (m, 5H), 4.98 - 4.59 (m, 1H), 2.58 (s, ZN), 534.2 80.1 242 p ^F _FF A / F >0 —N / Η—N ,0 K/uN-n ^N Y /\ ⁷ 0 Ν _χ λ 1H NMR (400 MHz, flMCO-d6) δ 8.95 (dd, J = 8.1,4.0 Hz, 1H), 8.92 -8.83 (m, 2H), 7.77 (ddd, J = 16.0, 8.5, 4.6 Hz, 1H), 7.67 (dd, J = 13.4, 7.4 Hz, 1H), 7.63-7.52 (m, 2H) , 6.74 (d, J = 11.8 Hz, 2H), 4.95 - 4.85 (m, 1 Η), 4.74 (ddq, J = 13.1, 8.7, 4.5 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.4, 3.8 Hz, 1H), 3.83 (dd, J = 14 ,6, 4.3 Hz, 1H), 3.73 (m, 1H), 3.45 (d, J = 2.2 Hz, ZN), 3.41 -3.32 (m, 2H), 3 .23 (t, J = 12.4 Hz, 1H), 3.17 (s, 1H), 2.68 (d, J = 11.0 Hz, 6H), 1.80 (d, J = 10, 7 Hz, ZN). 674.3 2.8

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243 °A A F. FF )=0 У-F Η—N ,0 уу/уМ-н N—у )=< ^{1 0 N} \ # 1H NMR (400 MHz, DMSO-C16) δ 13.29-12.42 (s, 1H), 8.92 (dd, J = 7.9, 2.7 Hz, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 7.63 (s, 1H), 7.58 (t, J = 7.0 Hz, 1H), 7.45 (s, 1H), 6.62 ( dd, J = 11.3, 4.3 Hz, 2H), 6.55 (s, 1H), 4.70 (q, J = 7.8, 6.1 Hz, 1H), 3.99 -3 .88 (m, 2H), 3.78-3.64 (m, 1H), 3.64-3.55 (m, 1H), 3.49 (d, J = 2.1 Hz, ZN), 3.47-3.37 (m, 1H), 3.34 (dd, J = 11.6, 5.0 Hz, 1H), 3.27 (dd, J = 12.5, 3.6 Hz, 1H), 3.00-2.91 (m, 1H), 2.53 (s, 3H), 1.15 (d, J = 6.4 Hz, ZN), 1.01 (d, J = 6 ,3 Hz, ZN). 659.4 2.9 244 ^Fp У-F Η—Ν p 4у/уМ-н Ν—ζ /=<' ^{0 N} \ / 1H NMR (400 MHz, flMCO-d6) δ 8.93 (dd, J = 8.0, 4.1 Hz, 1H), 8.83 (d, J = 4.2 Hz, 1H), 8.71 -8.63 (m, 1H), 7.64 (dt, J = 9.1, 5.1 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.45 ( dd, J = 7.3, 5.0 Hz, 1 Η), 6.55 (s, 1 Η), 6.25 (dd, J = 9.8, 4.1 Hz, 2H), 4.92 (p, J = 6.6 Hz, 1H), 4.71 (td, J = 8.6, 8.1,4.1 Hz, 1H), 4.08 (td, J = 8.3, 5 ,1 Hz, 1H), 3.81-3.64 (m, 2H), 3.49 (d, J = 2.2 Hz, ZN), 2.69 -2.57 (m, 1H), 2 .53 (s, 3H), 2.39 (ddd, J = 14.6, 11.9, 6.6 Hz, 1H). 669.3 2.9 245 pH? F .2 Cl Η—N 0 ⁿ Q 1H NMR (400 MHz, flMCO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.59 (m, ZN), 7.57 (d, J = 7.9 Hz, 1 Η), 6.75 (d, J = 11.6 Hz, 2H), 4 .78 - 4.64 (m, 1 Η), 4.29 (ddd, J = 10.1,6.8, 3.1 Hz, 1H), 4.03 (dd, J = 10.7, 3 ,3 Hz, 1H), 3.92-3.82 (m, 1H), 3.79-3.62 (m, ZN), 3.42 (s, 1 Η), 2.92-2.73 (m, 2H). 645.8 33.6 246 Δ01^/=0 Cl H-N 0 NEC—0-H ABOUT 1H NMR (400 MHz, flMCO-d6) δ 11.55 (s, 1H), 9.06 (d, J = 8.3 Hz, 1H), 8.84 (dd, J = 4.1, 1, 6 Hz, 1H), 8.67 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.74-7.45 (m, 4H), 7.41 (d, J = 0.9 Hz, 1H), 6.45 (s, 1H), 4.87 (s, 1H), 3.75 (dd, J = 14.4, 4.3 Hz, 1H), 3.41 (dd, J = 14.5, 10.4 Hz, 1H). 563.2 34.3

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247 F F—(-F /--\ )—( ⁰ Η—N ' ⁷ F )=0 Cl Η—N 0 o 1H NMR (400 MHz, DMS0-C16) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.80 (d, J = 8.1 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.66-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 10.2 Hz, 1H), 6, 50 (d, J = 11.9 Hz, 2H), 4.69 (d, J = 7.8 Hz, 1H), 4.37 (q, J = 8.2 Hz, 1H), 3.84 ( td, J = 12.2, 4.0 Hz, 2H), 3.73 (s, 1H), 3.40 (s, 1H), 3.26 (qd, J = 9.3, 8.0, 4.2 Hz, 2H), 2.05-1.89 (m, 1H), 1.55 (d, J = 13.0 Hz, 2H), 1.49-1.33 (m, 2H). 674.4 35.2 248 ^FF M ^F )— HN 0 \=N )=< w 1H NMR (500 MHz, flMC0-d6) δ 8.98 (d, J = 8.2 Hz, 1H), 8.88 (dd, J = 4.1, 1.6 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.75 (dd, J = 8.7, 1.6 Hz, 1H), 8.63 (s, 1H), 8.02 (s, 1H) , 7.91 (d, J = 7.3 Hz, 1H), 7.77 7.69 (m, 2H), 6.73 (d, J = 11.7 Hz, 2H), 4.91 (dd , J = 8.7, 3.6 Hz, 1H), 4.78 (ddd, J = 10.4, 8.3, 4.4 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.6, 3.8 Hz, 1H), 3.82 (dd, J = 14.3, 4.4 Hz, 1H), 3.78-3 .70 (m, 1H), 3.60-3.51 (m, 1H), 3.51-3.38 (m, 2H), 3.23 (t, J = 12.5 Hz, 1H), 2.59 (p, J = 6.9 Hz, 1H), 1.08 (dd, J = 6.9, 4.2 Hz, 6H). 629.5 3.0 249 EFF )=0 )Y HN p 4muN- _n N% )=< ⁷ 0 Ν _χ E 1H NMR (400 MHz, flMC0-d6) δ 13.12-12.65 (s, 1H), 8.89-8.76 (m, 2H), 8.63 (d, J = 8.4 Hz, 1H), 7.66-7.53 (m, 2H), 7.44 (d, J = 7.3 Hz, 1 Η), 6.57 (d, J = 4.6 Hz, 1H), 6 .54 (d, J = 5.1 Hz, 2H), 4.76 -4.63 (m, 1H), 3.93 (d, J = 7.3 Hz, 1H), 3.75-3, 63 (m, ZN), 3.55 (d, J = 6.8 Hz, 1H), 3.49 (d, J = 1.9 Hz, ZN), 3.47 - 3.37 (m, 2H ), 2.58 (d, J = 11.7 Hz, 1 Η), 2.53 (s, ZN), 1.16 (d, J = 6.1 Hz, ZN), 1.02 (d, J = 6.6 Hz, ZN). 659.4 3.0 250 E 0 ^- \ )—F Yn EFF )=0 У-F Η—Ν p 4у/уН-н NA /\ ⁷ 0 N _v ) 1H NMR (400 MHz, flMC0-d6) δ 8.89 (dd, J = 8.0, 3.1 Hz, 1H), 8.82 (dd, J = 4.5, 1.5 Hz, 1H) , 8.65 (d, J = 8.4 Hz, 1H), 7.63 (dt, J = 8.4, 4.2 Hz, 1H), 7.61 -7.53 (m, 1H), 7.49 -7.39 (m, 1 Η), 6.62-6.52 (m, ZN), 6.17 (tt, J = 56.2, 4.6 Hz, 1H), 4.69 (td, J = 8.6, 7.8, 4.0 Hz, 1H), 4.08 (s, 1H), 3.89 (dd, J = 11.4, 3.6 Hz, 1H), 3.83 (d, J = 11.7 Hz, 1H), 3.71 (td, J = 14.1,4.4 Hz, 1H), 3.61 (d, J = 11.5 Hz, 1H ), 695.2 3.1

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3.55-3.35 (m, 5H), 3.05 (td, J = 12.5, 3.8 Hz, 1H), 2.53 (s, ZN), 2.45-2.26 ( m, 1H), 1.84 (td, J = 18.7, 14.2 Hz, 1H). 251 O Mind ”,¾ \ / HN 0 -NuuU-n mU )=< ^{7 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 8.96 (d, J = 2.2 Hz, 1H), 8.86 (s, 1H), 8.82 (d, J = 9.4 Hz, 1H ), 7.78 -7.70 (m, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.49 (t, J = 8.3 Hz, 1H), 6.77 -6.72 (m, 2H), 4.90 (q, J = 10.1 Hz, 1H), 4.77-4.67 (m, 2H), 4.16 (d, J = 12.9 Hz, 1 Η), 3.95 (d, J = 8.3 Hz, 1H), 3.88-3.81 (m, 1H), 3.77-3.70 (m, 1H), 3, 66 (s, 1H), 3.58-3.51 (m, 1H), 3.49 (d, J = 2.1 Hz, ZN), 3.45-3.36 (m, 2H), 3 .30-3.17 (m, 1H), 2.43 (s, ZN), 2.09 (s, ZN), 1.74 (d, J = 11.0 Hz, ZN). 658.2 3.1 252 WITH Mind at F F F )=O \U-F Η—N ,0 Nuu-U-n \=m )=( 1H NMR (400 MHz, flMCO-d6) δ 8.85-8.77 (m, 2H), 8.71 (d, J = 5.1 Hz, 1H), 8.65 (t, J = 7, 6 Hz, 1 Η), 7.68 - 7.54 (m, 4Η), 6.77 (t, J = 7.6 Hz, 1 Η), 6.45 (dd, J = 11.7, 5 .7 Hz, 2H), 4.78-4.61 (m, 1H), 4.40-4.22 (m, 1H), 3.83-3.64 (m, 1H), 3.53- 3.33 (m, 1H), 2.59 (q, J = 2.3 Hz, ZN), 1.86-1.69 (m, 1H), 1.62-1.43 (m, 1H) , 0.92 (t, J = 7.3 Hz, ZN). 641.8 3.1 253 —k F ^C ^F HN F y F. FF )=0 U-F Η—N 0 —(y— ^E-n mU )=( ^{7 0 N} \ U 1H NMR (400 MHz, flMCO-d6) δ 8.80 (dd, J = 12.3, 5.4 Hz, 2H), 8.64 (s, 1H), 7.74-7.51 (m, 2H), 7.44 (dd, J = 7.4, 3.7 Hz, 1 Η), 6.75 (dd, J = 9.5, 5.2 Hz, 1 Η), 6.54 (s , 1Η), 6.44 (dd, J = 11.4, 3.8 Hz, 2H), 4.68 (s, 1Η), 4.30 (s, 1Η), 3.75-3.62 (m, 1H), 3.48 (d, J = 2.3 Hz, ZN), 3.46 - 3.31 (m, 1 Η), 2.53 (s, ZN), 1.75 (s , 1H), 1.52 (ddd, J = 13.8, 10.4, 7.0 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 671.2 3.2 254 Г ^F с%' y FFF Uo U-F Η—N ,0 -IuluU-n mU y=< ^{7 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 8.89 (dd, J = 7.8, 4.3 Hz, 1H), 8.85 -8.78 (m, 1H), 8.64 (s, 1H), 7.60 (ddd, J = 17.6, 8.0, 4.3 Hz, 2H), 7.44 (dd, J = 7.3, 3.7 Hz, 1 Η), 6, 66 -6.49 (m, ZN), 4.69 (d, J = 11.1 Hz, 1 Η), 4.29 (s, 2Η), 3.89 (dd, J = 11.4, 3 ,6 Hz, 1H), 3.85-3.59 (m, ZN), 3.57 - 3.38 (m, 5H), 3.08 (td, J = 12.6, 3.8 Hz, 1H), 2.77 (ddd, J = 15.4, 11.7, 8.2 Hz, 1H), 2.53 (s, ZN), 2.42-2.20 (m, 1H). 713.2 3.2

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255 O U-n L=0 \ HN o Yaya-Ya nA z\ ^{1 0 N} \ # 1H NMR (400 MHz, DMSO-C16) δ 9.03-8.89 (m, 2H), 8.81 (s, 1H), 7.78 (d, J = 25.5 Hz, 2H), 7 .70 7.61 (m, 1H), 6.77 (d, J = 11.7 Hz, 2H), 4.90 (d, J = 8.8 Hz, 1H), 4.69 (td, J = 9.0, 4.4 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H), 3 ,82-3.68 (m, 2H), 3.63 - 3.35 (m, 6H), 3.24 (m, 1 Η), 2.42 (s, ZN), 2.34 (s, ZN). 646.2 3.4 256 ^FF lА ^F F. FF )=° У-F Η—N 0 F—ЯА—ЯА—'' 0-H Ά / ^NN \ # 1H NMR (400 MHz, flMCO-d6) δ 13.17-12.71 (s, 1H), 8.82 (dd, J = 15.0, 6.1 Hz, 2H), 8.63 (dd, J = 10.8, 6.2 Hz, ZN), 7.92 (d, J = 10.4 Hz, 1H), 7.73 (dd, J = 8.5, 4.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 7.3 Hz, 2H), 6.76 (d, J = 9.4 Hz, 1 Η), 6 .45 (d, J = 11.7 Hz, 2H), 4.82-4.69 (m, 1H), 4.31 (m, 1H), 3.85-3.76 (m, 1H), 3.43 (dd, J = 14.6, 10.1 Hz, 1H), 1.88-1.68 (m, 1H), 1.63-1.45 (m, 1H), 0.93 ( t, J = 7.3 Hz, ZN). 695.3 3.5 257 /'Yal An Ch F. FF )=0 Af hn p -А/У-Я ^N 4 /А ^, ° ^N \ # 1H NMR (400 MHz, flMCO-d6) δ 8.83 (d, J = 4.3 Hz, 1H), 8.778.62 (m, 2H), 7.62 (dt, J = 24.9, 5, 7 Hz, 2H), 7.45 (d, J = 7.3 Hz, 1 Η), 6.55 (s, 1 Η), 6.33 (dd, J = 12.2, 4.5 Hz, 2H), 4.69 (tt, J = 9.1, 5.0 Hz, 1H), 4.01 (d, J = 17.4 Hz, 2H), 3.96-3.86 (m, 2H ), 3.783.65 (m, 1H), 3.60 (d, J = 10.9 Hz, 1 Η), 3.52-3.37 (m, 4Η), 3.30 (d, J = 10 .8 Hz, 1H), 2.53 (s, ZN), 2.09-1.94 (m, 1H), 1.87 (d, J = 8.6 Hz, 2H), 1.74-1 .59 (m, 1H). 657.3 3.5 258 C An '' ,¾ \H-N 0 AiT 1H NMR (400 MHz, flMCO-d6) δ 9.34-9.18 (m, 1H), 8.81 (d, J = 8.1 Hz, 1H), 8.55 (dd, J = 9, 0, 6.1 Hz, 1H), 8.21 -8.10 (m, 2H), 7.98 -7.87 (m, 1H), 7.82-7.73 (m, 1 Η), 6.79-6.75 (m, 1 Η), 6.43 (d, J = 11.5 Hz, 2H), 4.83-4.73 (m, 1H), 4.36-4.22 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.93 (dt, J = 13.7, 7.1 Hz, 2H), 3.72 (d, J = 14.8 Hz, 2H), 3.61 - 3.50 (m, 2H), 3.39 (d, J = 13.1 Hz, 1H), 3.21 (t, J = 15.5 Hz, 1H), 3.09 (s, ZN), 1.75 (d, J = 24.4 Hz, 1H), 1.56-1.44 (m, 1H), 0.91 (t, J = 7 ,3 Hz, ZN). 642.2 3.6

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259 kk ^FF m ^F / F>0 —Ν HN 0 ' ⁰ w 1H NMR (400 MHz, DMSO-C16) δ 8.97 (d, J = 8.0 Hz, 1H), 8.94 (dd, J = 4.6, 1.5 Hz, 1H), 8.86 (d, J = 8.3 Hz, 1H), 7.76 (dd, J = 14.9, 6.0 Hz, 2H), 7.71 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 11.8 Hz, 2H), 4.91 (s, 1H), 4.69 (td, J = 8.8, 4.6 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.76 (s, 1H), 3, 72 (m, 1H), 3.55 (d, J = 3.6 Hz, 1H), 3.53 (s, 3H), 3.49 - 3.40 (m, 2H), 3.24 (t , J = 12.4 Hz, 1H), 2.65 (s, 6H), 2.52 (s, 3H). 674.3 3.7 260 p ^FpF X ^F F. FF /=0 У-F Η—Ν p ^pr-N-n \=N )=( w 1H NMR (400 MHz, flMCO-d6) δ 12.93 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H), 8.77 (dd, J = 4.1, 1, 5 Hz, 1H), 8.73 (s, 1H), 8.64 (dt, J = 8.7, 1.7 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H) , 7.66-7.54 (m, 3H), 6.76 (d, J = 11.7 Hz, 2H), 4.96-4.85 (m, 1H), 4.71 (ddd, J = 9.8, 8.1, 4.5 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.79 - 3.70 (m, 2H), 3.62 - 3.49 (m, 1H), 3.44 (dd, J = 14.2, 10.4 Hz, 2H), 3 .23 (t, J = 12.4 Hz, 1H), 2.50 (s, 3H). 669.3 3.8 261 O >~N X: \ Η—Ν η 1H NMR (400 MHz, flMCO-d6) δ 9.40 (s, 1H), 9.30 (s, 1H), 8.94 (d, J = 8.3 Hz, 1H), 8.79 (s , 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 6.73 (d , J = 11.8 Hz, 2H), 4.93-4.83 (m, 1H), 4.83-4.74 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.92 (ddd, J = 25.6, 12.9, 4.1 Hz, 2H), 3.75-3.69 (m, 1H), 3.58 (s, 1H), 3 .55 (d, J = 5.6 Hz, 1H), 3.38 (s, 1H), 3.22 (t, J = 12.5 Hz, 1H), 2.65 (s, 6H). 617.3 4.0 262 0 Η—N ,¾ Cl n-N p nec—e )( 2—' o-h w 1H NMR (400 MHz, flMCO-d6) δ 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.71 -8.61 (m, 2H), 8.15 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz, 1H), 6.21 (d, J = 12.0 Hz, 2H), 4.73-4.62 (m, 1H), 3.82 (dt, J = 11.5, 3.5 Hz, 2H), 3.72 (s, 2H), 3.51 -3.33 (m, 4H), 1.81 (ddt, J = 12.5, 4.4, 2.1 Hz , 2H), 1.38-1.23 (m, 2H). 591.8 30.6

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263 0/ ^N \HN0w 1H NMR (400 MHz, DMS0-06) δ 9.35 (d, J = 22.1 Hz, 2H), 8.98 8.91 (m, 2H), 8.87 (s, 1H), 8, 13 (d, J = 9.6 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 5.3 Hz, 1H), 6.73 ( d, J = 11.8 Hz, 2H), 4.954.76 (m, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.99-3.84 (m, 2H), 3.773.64 (m, 2H), 3.56 (dd, J = 14.2, 10.5 Hz, 1H), 3.34 (s, 1H), 3.23 (d, J = 12.9 Hz , 1H), 2.70 (s, 3H). 602.3 4.0 264 O / ^N HN 0 F—ΑΛ—ΑΛ—OH Ά / ^NN \ # 1H NMR (400 MHz, flMCO-d6) δ 8.85 (t, J = 10.3 Hz, 2H), 8.798.71 (m, 2H), 8.59 (dd, J = 8.4, 1, 8 Hz, 1H), 7.80 - 7.67 (m, 4H), 7.67 - 7.55 (m, 2H), 6.78 (d, J = 9.4 Hz, 1H), 6, 46 (d, J = 11.8 Hz, 2H), 4.74 (t, J = 11.0 Hz, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.85- 3.74 (m, 1H), 3.48 (dd, J = 14.5, 9.8 Hz, 1H), 1.76 (d, J = 8.2 Hz, 1H), 1.62 -1 .46 (m, 1H), 0.93 (t, J = 7.3 Hz, ZN). 626.7 4.1 265 4-0 F ^N .¾ ^ ^Cl Α ^-Ν Λ O 1H NMR (400 MHz, flMCO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.57 (m, ZN), 7.56 (d, J = 7.9 Hz, 1 Η), 6.75 (d, J = 11.6 Hz, 2H), 4 .77 - 4.66 (m, 1 Η), 4.29 (dq, J = 6.7, 3.3 Hz, 1 Η), 4.03 (dd, J = 10.9, 3.3 Hz , 1H), 3.86 (d, J = 12.2 Hz, 1H), 3.75 (m, 1H), 3.69 (t, J = 10.4 Hz, 2H), 3.41 (s , 1H), 2.92-2.72 (m, 2H). 760.0 68.8 266 H 1 O=\ Cl )=0 Cl Η—N O NEC——'' O-H ABOUT 1H NMR (400 MHz, flMCO-d6) δ 11.53 (s, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.68 (dd, J = 8, 4, 2.4 Hz, 2H), 8.16 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.74 - 7.53 (m, 4H), 7.48 (t, J = 2.8 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.98 (s, 1 Η) , 6.47 (d, J = 3.0 Hz, 1H), 4.80 (ddd, J = 10.5, 8.2,4.2 Hz, 1H), 3.79 (dd, J = 14 ,4, 4.1 Hz, 1H), 3.48 (dd, J = 14.4, 10.6 Hz, 1H). 530.6 72.2

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267 ⁿ -0 P: Cl n-N 0 NEC——'' O-N O 1H NMR (400 MHz, DMS0-06) δ 9.35 (d, J = 8.2 Hz, 1H), 8.878.80 (m, 1H), 8.74 (d, J = 7.5 Hz, 1H ), 8.64 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.58 7.53 (m, 2H), 4.79 (s, 1H), 3.953.78 (m, 1H), 2.65 (s, 1H ), 2.31 (s, 1H), 1.88 (d, J = 10.1 Hz, 2H). 605.2 77.0 268 C / ^N / ^F >0 —N n—N O Du/uM-n ^N 4 / \ ^{7 0 N} \ / 1H NMR (400 MHz, flMCO-d6) δ 8.93 (d, J = 4.5 Hz, 1H), 8.898.76 (m, 2H), 7.82 - 7.59 (m, 4H), 6 .79 (d, J = 9.4 Hz, 1 Η), 6.45 (d, J = 11.9 Hz, 2H), 4.67 (dt, J = 13.3, 6.3 Hz, 1H ), 4.30 (s, 1H), 3.53 (s, ZN), 3.49 - 3.38 (m, 2H), 2.64 (s, 6H), 2.52 (s, ZN) , 1.84-1.68 (m, 1H), 1.61-1.45 (m, 1H), 0.93 (t, J = 7.3 Hz, ZN). 646.3 4.3 269 ---VF ^P ^F Η—NF FFF )=0 pF HN O XWV+oH NP )=< ^{7 0 N} _x / ^f P FF 1H NMR (400 MHz, DMSO-bb) δ 8.93-8.86 (m, 1H), 8.80 (t, J = 7.2 Hz, 1H), 8.00 (dd, J = 8, 8, 3.9 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1 Η), 6.75 (dd, J = 9.5, 4.7 Hz, 1 Η), 6.56 (s, 1 Η), 6.43 (dd, J = 11.3, 3.4 Hz, 2H), 4.71 (s, 1H), 4.31 (s, 1H), 3.843.66 (m, 1H), 3.58 - 3.33 (m, 4H), 2.54 (s, 3H), 1.87-1.70 (m, 1H), 1.52 (ddd, J = 13.8, 10.1, 6.9 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 739.2 4.4 270 p E F F )=0 pF Η—N p X/pL pN )=< 1H NMR (400 MHz, flMCO-d6) δ 8.98 (d, J = 8.0 Hz, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1 Η), 8.20 (d, J = 8.2 Hz, 1 Η), 7.67 - 7.53 (m, 4H), 6, 76 (d, J = 11.7 Hz, 2H), 4.91 (dd, J = 8.8, 3.7 Hz, 1H), 4.71 (ddd, J = 9.9, 8.0, 4.5 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.81 -3, 69 (m, 2H), 3.55 (td, J = 11.9, 3.3 Hz, 1H), 3.45 (dd, J = 18.1, 11.9 Hz, 2H), 3.23 (t, J = 12.1 Hz, 1H), 2.58 (s, 3H). 669.4 4.4

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271 ^FF M ^F FA ⁰ \ / Η—N ,0 \=N )=< w 1H NMR (400 MHz, DMSO-06) δ 13.10 (s, 1H), 9.02 (d, J = 8.3 Hz, 1H), 8.90 (dd, J = 4.2, 1, 6 Hz, 1H), 8.77 (dd, J = 8.7, 1.6 Hz, 1H), 8.73 (d, J = 5.9 Hz, 1H), 8.00-7.88 ( m, 2H), 7.79 - 7.70 (m, 2H), 6.75 (d, J = 11.8 Hz, 2H), 4.90 (td, J = 8.7, 3.6 Hz , 1H), 4.77 (ddd, J = 10.4, 8.3, 4.3 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.84 (dd, J = 14.2, 4.3 Hz, 1H), 3.78-3.69 (m, 1H), 3.603.37 (m, 3H), 3.23 (t, J = 12.3 Hz, 1H), 2.63 (s, 3H), 2.06-2.01 (m, 3H). 615.2 4.5 272 H— A ^F F. FF )=0 U-F Η—N O ΑΧ-Η-η ⁿ A / \ ⁷ 0 Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 8.87-8.76 (m, 1H), 8.63 (q, J = 7.1 Hz, 2H), 7.70-7.52 (m, 2H), 7.52-7.34 (m, 1H), 6.55 (s, 1H), 6.29 (s, 1H), 6.17 (dd, J = 11.9, 4.5 Hz , 2H), 4.74-4.63 (m, 1H), 3.80-3.59 (m, 1H), 3.49 (d, J = 2.1 Hz, ZN), 3.47- 3.35 (m, 1H), 3.20 (s, 1H), 2.53 (s, 3H), 1.50 (ddd, J = 13,1,7,3, 5.3 Hz, 2H) , 1.37 (dp, J = 14.4, 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 6H). 631.2 4.5 273 0 / ^N / ^H F /=° Η—N Η—N 0 ^ууу-И-н ^N V /\ ⁷ on) 1H NMR (400 MHz, flMCO-d6) b 8.97 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 4.0 Hz, 1H), 8.67 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.1, 4.0 Hz, 2H), 7.58 (d, J = 7.4 Hz, 1 Η), 7.50 ( s, 1H), 6.76 (d, J = 11.7 Hz, 2H), 4.90 (dt, J = 12.0, 6.0 Hz, 1H), 4.69 (td, J = 8 ,8, 8.3, 4.5 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1 Η), 3.96 (dd, J = 11.6, 3.8 Hz, 1H ), 3.80-3.66 (m, 2H), 3.56 (s, 4H), 3.43 (m, 1H), 3.32-3.16 (m, 2H), 2.43 ( s, ZN). 646.2 4.7 274 o U N < /H-Np y-Qy-H-H w 1H NMR (400 MHz, flMCO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.84 (d, J = 4.2 Hz, 1H), 8.68 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 3.5 Hz, ZN), 6.75 (d, J = 11.7 Hz, 2H), 4.90 (d, J = 9 .4 Hz, 1H), 4.73 (td, J = 9.0, 4.3 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.84 - 3.63 (m, 2H), 3.49 (ddd, J = 45.5, 14.7, 10.8 Hz, ZN), 3.23 (s, 1H), 2.54 (s, ZN), 2.48 (s, ZN), 2.07 (s, ZN). 630.6 4.8

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275 (у n—NF U F. FF /=0 —o Af η—np μm. / ^N / \ w 1H NMR (400 MHz, DMSO-C16) δ 8.88-8.73 (m, 2H), 8.65 (t, J = 8.9 Hz, 1H), 7.63 (dd, J = 12, 3, 5.2 Hz, ZN), 7.49 (s, 1H), 6.77 (t, J = 8.9 Hz, 1H), 6.45 (dd, J = 11.7, 7.9 Hz, 2H), 4.76-4.58 (m, 1H), 4.31 (s, 1H), 4.10 (s, 3H), 3.72 (ddd, J = 34.5, 14, 4, 4.5 Hz, 1H), 3.44 (ddd, J = 29.6, 14.4, 9.7 Hz, 1H), 2.58 (s, 3H), 1.76 (d, J = 10.8 Hz, 1H), 1.53 (t, J = 15.8 Hz, 1H), 0.93 (t, J = 7.3 Hz, ZN). 671.2 4.8 276 F^F Η—N F. F F )=0 /=\ U-F Η—N p CH-Uu-A-n w 1H NMR (400 MHz, flMCO-d6) δ 9.66-9.50 (m, 1H), 8.91-8.72 (m, 2H), 8.65 (td, J = 8.4, 1 .7 Hz, 1 Η), 8.39 (dd, J = 8.3, 1.3 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.05 (ddd, J = 8.6, 6.9, 1.4 Hz, 1H), 7.957.80 (m, 1 Η), 7.79 - 7.47 (m, ZN), 6.76 (t, J = 8 .3 Hz, 1 Η), 6.44 (dd, J = 11.5, 7.1 Hz, 2H), 4.75-4.59 (m, 1H), 4.30 (s, 1H), 3.83-3.60 (m, 1H), 3.44 (ddd, J = 25.0, 14.3, 9.9 Hz, 1H), 1.90-1.66 (m, 1H), 1.61 -1.21 (m, 1H), 0.97-0.79 (m, ZN). 677.2 4.9 277 0 / ^N :' A Ν— Η—Ν P u%уу-А>-н 1H NMR (400 MHz, flMCO-d6) δ 9.03 - 8.92 (m, 2H), 8.76 (dd, J = 8.6, 1.6 Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.80-7.69 (m, 2H), 6.74 (d, J = 11 .8 Hz, 2H), 4.97-4.84 (m, 1 Η), 4.80-4.70 (m, 1 Η), 4.17 (d, J = 12.7 Hz, 1H) , 3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.81 (dd, J = 14.3, 4.4 Hz, 1H), 3.73 (d, J = 12 .8 Hz, 1H), 3.61 -3.35 (m, ZN), 3.23 (t, J = 12.5 Hz, 1H). 644.3 5.2 278 Q ,¾ Cl HN p NEC—( 2—\ /—' ^0-H w 1H NMR (400 MHz, flMCO-d6) δ 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.69-7.60 (m, ZN), 7.59 (d, J = 7.9 Hz, 1 Η), 6.56 (d, J = 12.3 Hz, 2H), 4 .71 (td, J = 8.8, 8.1, 4.3 Hz, 1H), 3.77 (d, J = 18.6 Hz, 1H), 3.44 (s, 1H), 3, 26 (t, J = 5.0 Hz, 4H), 1.52 (dd, J = 9.7, 5.6 Hz, 6H). 574.8 82.2

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279 R Cl Η—Ν 0 f—^ ^0-H A=< OH Cl ^N \ / 1H NMR (400 MHz, DMSO-06) δ 10.35 (d, J = 1.2 Hz, 1 Η), 8.84 (tt, J = 3.2, 1.6 Hz, 2H), 8, 50 (dd, J = 8.6, 1.7 Hz, 1H), 7.99 (s, 1H), 7.73 -7.55 (m, 5H), 7.12 (t, J = 8, 1 Hz, 2H), 3.30 (s, 1H).;1H NMR (400 MHz, flMCO-d6) δ 9.03 (d, J = 8.9 Hz, 1H), 8.85 (dd, J = 4.1, 1.5 Hz, 1H), 8.61 (dd, J = 8.7, 1.7 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.747 .57 (m, 4H), 7.43 (tt, J = 8.4, 6.4 Hz, 1H), 7.14-6.95 (m, 2H), 6.07 (d, J = 2 .8 Hz, 1H), 4.91 (dd, J = 8.9, 2.7 Hz, 1H). 535.0 82.4 280 A Cl Η—Ν p nec—e 2—\ /—' o-h w 1H NMR (400 MHz, flMCO-d6) δ 9.31 (d, J = 8.2 Hz, 1 Η), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8, 64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.69- 7.54 (m, 4H), 7.30 (d, J = 8.9 Hz, 2H), 6.96 (s, 1H), 4.85- 4.71 (m, 1H), 3.77 (s, 1H), 3.39 (s, 1H). 604.2 86.1 281 p ^FfF A ^f F. FF )=° Kf η—np >ру-Н>-н nA /А ^z ο Ν _ξ ) Ν— / 1H NMR (400 MHz, flMCO-d6) δ 8.99 (d, J = 7.9 Hz, 1 Η), 8.62 (t, J = 2.7 Hz, 1H), 7.58 (s, 1H), 7.45 (t, J = 6.6 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1 Η), 6.77 (dd, J = 11.6, 4, 2 Hz, 2H), 6.55 (d, J = 2.2 Hz, 1 Η), 4.98 -4.87 (m, 1H), 4.75-4.65 (m, 1H), 4 .16 (d, J = 12.7 Hz, 1H), 3.99-3.93 (m, 1H), 3.74 (d, J = 13.1 Hz, 2H), 3.67-3, 50 (m, 1H), 3.48 (d, J = 1.5 Hz, ZN), 3.463.18 (m, ZN), 3.10 (d, J = 4.4 Hz, 6H), 2, 53 (s, ZN). 742.6 5.5 282 F. ^F HN~ R: Cl Η—Ν O F—-AA-'' OH Cl Ν _χ 4 1H NMR (400 MHz, flMCO-d6) δ 8.84 - 8.80 (m, 2H), 8.62 (dd, J = 8.7, 1.6 Hz, 1H), 7.66-7, 49 (m, 8H), 7.45 - 7.35 (m, ZH), 6.54 (d, J = 11.3 Hz, 2H), 5.70 (p, J = 8.3 Hz, 1H ), 4.70 (ddd, J = 10.1, 8.0, 4.4 Hz, 1H), 3.72 (dd, J = 14.4, 4.4 Hz, 1H), 3.39 ( dd, J = 14.5, 10.3 Hz, 1H). 692.0 26.8

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283 F^F Η—N Y E F F /=0 U-F Η—N ,0 GSH-N-n \=N /=< w 1H NMR (400 MHz, DMS0-C16) δ 8.90 (ddd, J = 4.8, 1.6, 0.7 Hz, 1H), 8.81 (d, J = 8.0 Hz, 1H) , 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.33-8.29 (m , 1H), 7.70 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.64-7.59 (m, 3H), 6.84 (d, J = 9 ,2 Hz, 1H), 6.42 (d, J = 11.4 Hz, 2H), 4.73-4.66 (m, 1H), 4.51 (td, J = 14.3, 6, 9 Hz, 1H), 3.74 (dd, J = 14.3, 4.4 Hz, 1H), 3.44 (dd, J = 14.4, 10.1 Hz, 1H), 1.27 ( d, J = 6.7 Hz, ZN). 613.1 5.7 284 •Y F )=0 Cl Η—N p NEC—e )—4 λ—' 0—H ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 8.86 - 8.75 (m, 2H), 8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1 Η), 7.67 - 7.53 (m, 4H), 7, 25 (s, 1H), 6.27 (d, J = 11.5 Hz, 2H), 5.81 (t, J = 55.6 Hz, 1H), 4.67 (s, 1H), 3, 72 (s, 1H), 3.41 (s, 1H), 1.18 - 1.10 (m, 2H), 0.85 (s, 2H). 597.2 45.9 285 ci >o Cl Η—N 0 ^NEC Yj^pY^oH ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 9.08 (d, J = 8.4 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 -8.61 (m, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H), 7.72-7.58 (m, 3H), 7. 55 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 6.44 (d, J = 3.1 Hz, 1H), 4.87 ( s, 1H), 3.77 (s, 3H), 3.74 (d, J = 4.2 Hz, 1H), 3.483.34 (m, 1H). 577.0 46.2 286 g ^H I: Cl HN p _/Ύλ nec—c )—e )' ο-н O 1H NMR (400 MHz, flMCO-d6) δ 9.18 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 4, 80 - 4.69 (m, 1H), 3.80 (pd, J = 8.9, 7.6, 3.0 Hz, 2H), 3.40 (s, 1H), 2.62 (d, J = 6.2 Hz, 2H), 1.02 (d, J = 6.1 Hz, ZN). 550.2 47.3

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287 O / ^{N Fff} Y / F >0 —N / Η—N ,0 K/uM-n nA /\ / 0 ^N _x / 1H NMR (400 MHz, DMSO-C16) δ 8.93 (dd, J = 11.1, 6.5 Hz, 2H), 8.80 (dd, J = 8.1,4.4 Hz, 1H) , 7.81 (ddd, J = 15.3, 8.5, 4.8 Hz, 1H), 7.72-7.63 (m, 2H), 7.59 (t, J = 6.5 Hz , 1H), 6.76 (dd, J = 9.4, 4.1 Hz, 1H), 6.48 - 6.33 (m, 2H), 4.72 (qd, J = 10.7, 4 .5 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 3.70 (dd, J = 14.6, 4.8 Hz, 1H), 3.57 - 3.32 (m, 4H), 2.75-2.62 (m, 6H), 1.82 (d, J = 11.0 Hz, ZN), 1.75 (dd, J = 7.1, 3.5 Hz, 1H), 1.53 (ddd, J = 13.7, 10.4, 7.1 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 646.3 5.7 288 EF ^F \ Η—N ,¾ Cl Η—N p jYrY^ N=C—/ 2—\ /—' ° ^-H Cl Ν _χ U 1H NMR (400 MHz, DMSODb) δ 8.83 - 8.79 (m, 2H), 8.65 (dd, J = 8.7, 1.7 Hz, 1 Η), 8.23-8.22 (m, 2H), 7.68 - 7.59 (m, ZH), 6.84 (d, J = 9.2 Hz, 1 Η), 6.41 (d, J = 11.4 Hz, 2H ), 4.73 (ddd, J = 10.1, 8.0, 4.5 Hz, 1H), 4.51 (dq, J = 14.2, 6.9 Hz, 1H), 3.75 ( dd, J = 14.6, 4.5 Hz, 1H), 3.44 (dd, J = 14.5, 10.2 Hz, 1H), 1.27 (d, J = 6.7 Hz, ZN ). 637.1 5.8 289 < , ⁿ ✓ ^N - γ EFF /=0 У-F HN p / ^N /\ ^N Y 1H NMR (400 MHz, flMCO-d6) δ 12.86 (s, 1H), 8.86 - 8.78 (m, 2H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.66-7.59 (t, ZH), 7.56 (d, J = 8.2 Hz, 1H), 6, 78 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.5 Hz, 2H), 4.69 (ddd, J = 9.8, 7.9, 4.5 Hz , 1H), 4.38-4.25 (t, 1H), 3.74 (dd, J = 14.3, 4.5 Hz, 1H), 3.44 (dd, J = 14.4, 9 ,9 Hz, 1H), 2.58 (s, ZN), 1.76 (ddt, J = 13.1, 10.5, 5.3 Hz, 1H), 1.52 (ddq, j = 14, 4, ω,4, 7.3 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 641.8 6.5 290 Y ^Fff Y EFF /=0 У-F Η—N p QO-0-н ( _Z N ^N Y 1H NMR (400 MHz, DMSO-06) δ 8.87 (dd, J = 14.3, 7.8 Hz, 1H), 8.72 (ddd, J = 8.7, 4.1, 1.8 Hz, 1 Η), 8.68 - 8.58 (t, 2H), 8.55 (dt, J = 8.4, 1.8 Hz, 1 Η), 8.29 (d, J = 8, 8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1 Η), 7.67 - 7.51 (m, ZN), 6.76 (dd, J = 9.5, 5, 2 Hz, 1H), 6.53-6.38 (m, 2H), 4.75 (t, J = 11.1 Hz, 1H), 4.31 (s, 1H), 3.70 (d, J = 5.3 Hz, 1H), 1.77 (s, 1H), 1.53 (q, J = 13.4, 10.2 Hz, 1H), 1.02-0.83 (m, ZN ). 677.2 6.5

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291 O y ^N Y b-F \ ^F /=o 0 Η—Ν O gk>ch- _n / ^Ν / \ w 1H NMR (400 MHz, DMSO-06) δ 9.03 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.1 Hz, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 7.85 (d, J = 27.1 Hz, 2H), 7.74 - 7.67 (m, 2H), 6.77 (d, J = 12.0 Hz, 2H), 4.91 (d, J = 9.4 Hz, 1H), 4.72 (m, 1H), 4.17 (d, J = 12.7 Hz , 1H), 3.95 (m, 1H), 3.76 (m, 4H), 3.60 - 3.38 (m, 4H), 3.24 (t, J = 12.6 Hz, 1H) , 2.62 (s, 3H). 631.2 6.9 292 ex ,¾ X ⁱ “W НШ-х-н О 1H NMR (400 MHz, flMCO-d6) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.65 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.69-7.58 (m, 3H), 7.57 (d, J = 7.9 Hz, 1H), 6.50 (d, J = 12.8 Hz, 2H), 4, 69 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 11.7 Hz, 1H), 3.843.64 (m, 2H), 3.48 (t, J = 11.7 Hz, 2H), 3.38 (dtd, J = 11.4, 5.8, 3.0 Hz, 2H), 3.13 (td, J = 12.7, 3.7 Hz, 1H), 2 .39-2.23 (m, 1H), 0.94 (d, J = 6.6 Hz, ZN), 0.68 (d, J = 6.8 Hz, ZN). 620.4 26.9 293 Q ,¾ Cl n-N p nec—e 2—c 2—' ο-n Cl Ν _χ J) 1H NMR (400 MHz, flMCO-d6) δ 9.29 (d, J = 8.2 Hz, 1 Η), 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8, 64 (dd, J = 8.7, 1.7 Hz, 1H), 8.22 (q, J = 1.6 Hz, 2H), 7.75 (dtd, J = 9.1, 3.1, 1.6 Hz, ZN), 7.68 - 7.56 (m, 5H), 6.91 -6.81 (m, 2H), 4.84-4.73 (m, ZN), 3.77 (dd, J = 14.5, 4.4 Hz, 1H), 3.41 (dd, J = 14.6, 10.5 Hz, 1H). 680.2 6.9 294 < , ^H / ^N -¾ \ HN 0 A 1H NMR (400 MHz, flMCO-d6) δ 9.39 (d, J = 4.9 Hz, 1H), 9.35 (d, J = 8.8 Hz, 1H), 8.95 (d, J = 5.2 Hz, 1H), 8.90 (s, 1H), 8.79 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 8.6, 5.0 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1 Η), 6.77 (d, J = 9.4 Hz , 1H), 6.41 (d, J = 11.6 Hz, 2H), 4.78 (ddd, J = 10.3, 8.3, 4.5 Hz, 1H), 4.29 (d, J = 8.9 Hz, 1H), 3.89 (dd, J = 14.4, 4.5 Hz, 1H), 3.55 (dd, J = 14.4, 10.4 Hz, 1H), 2.71 (s, ZN), 1.77 (ddd, J = 13.7, 7.3, 3.3 Hz, 1H), 1.52 (ddd, J = 13.8, 10.4, 7 ,1 Hz, 1H), 0.91 (t, J = 7.3 Hz, ZN). 575.3 7.4

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295 ^F yZ ^{F F} )=0 / HN o 1H NMR (400 MHz, DMSO-06) δ 8.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.78 (d, J = 8.1 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 7.65 (d, J = 9.3 Hz, ZN), 6.76 (d, J = 9.4 Hz, 1H), 6 .44 (d, J = 11.6 Hz, 2H), 4.70 (td, J = 9.2, 8.1,4.5 Hz, 1H), 4.31 (d, J = 3.2 Hz, 1H), 3.74 (dd, J = 14.3, 4.6 Hz, 1H), 3.43 (dd, J = 14.4, 10.0 Hz, 1H), 2.54 (s , ZN), 2.48 (s, ZN), 2.07 (s, ZN), 1.77 (ddd, J = 14.0, 7.4, 3.4 Hz, 1H), 1.52 ( ddt, J = 17.6, 14.2, 7.3 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 602.2 7.4 296 ^FF >y ^F RFF ^/ )=o Yf hn o _o p5yy_n_ _H / ^N \ # 1H NMR (400 MHz, flMCO-d6) δ 8.89 (d, J = 4.1 Hz, 1H), 8.79 (t, J = 10.0 Hz, 1H), 8.64 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 10.9 Hz, 1H), 7.66-7.57 (m, 2H), 6.89 (d, J = 10.7 Hz , 1H), 6.76 (d, J = 9.2 Hz, 1H), 6.44 (d, J = 11.9 Hz, 2H), 4.66 (s, 1H), 4.30 (d , J = 8.8 Hz, 1H), 3.75 (d, J = 14.2 Hz, 1H), 3.51 (s, ZN), 3.45-3.30 (m, 1H), 1 .76 (ddd, J = 13.8, 7.3, 3.3 Hz, 1H), 1.58-1.45 (m, 1H), 0.92 (t, J = 7.3 Hz, ZN ). 657.2 7.7 297 o H %-N _ Cl \ Cl )=0 0 Η—N ,0 ^l ° /° o 1H NMR (400 MHz, flMCO-d6) δ 11.52 (d, J = 2.2 Hz, 1 Η), 9.03 (d, J = 8.6 Hz, 1H), 8.90 (d, J = 4.3 Hz, 1H), 7.95-7.71 (m, 2H), 7.64 (s, 1H), 7.36-7.17 (m, 6H), 6.78 (d , J = 6.0 Hz, 2 Η), 6.17 (dd, J = 2.2, 1.0 Hz, 1H), 4.89 (ddd, J = 10.7, 8.5, 4, 0 Hz, 1H), 4.55 (s, 2H), 4.07 (s, 2H), 3.79 (dd, J = 14.5, 4.0 Hz, 1H), 3.61 (s, ZN), 3.59 (q, J = 7.0 Hz, 2H), 3.57 (s, ZN), 3.51 -3.37 (m, 1H), 1.22 (t, J = 7 ,0 Hz, ZN). 712.5 7.9 298 ^Fp У-F HN p уАуу-А-н N—ά )=< ⁷ 0 Ν _χ b 1H NMR (400 MHz, flMCO-d6) δ 8.93 (dd, J = 7.9, 4.5 Hz, 1H), 8.83 (d, J = 4.2 Hz, 1H), 8.71 -8.64 (m, 1H), 7.68-7.61 (m, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.46 (dd, J = 7.4 , 3.7 Hz, 1H), 6.55 (s, 1H), 6.26 (dd, J = 9.9, 5.2 Hz, 2H), 4.99-4.87 (m, 1H) , 4.75-4.65 (m, 1H), 4.12 -4.03 (m, 1H), 3.80-3.65 (m, 2H), 3.49 (d, J = 2, 3 Hz, ZN), 2.69 -2.56 (m, 1 Η), 2.53 (s, ZN), 2.44 -2.34 (m, 1H). 669.3 7.9

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299 Chk ^FF Μ ^F F /=° HN 0 w 1H NMR (400 MHz, DMSO-06) δ 13.11 (s, 1H), 9.40 (t, J = 8.4 Hz, 2H), 9.03-8.92 (m, 2H), 8 .90 (s, 1H), 8.17 (dd, J = 8.7, 5.1 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1 Η), 6.72 (d , J = 11.8 Hz, 2H), 4.93-4.77 (m, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.93 (td, J = 15, 3, 13.6, 4.2 Hz, 2H), 3.74-3.68 (m, 1H), 3.61 3.48 (m, 2H), 3.40 (d, J = 12.7 Hz, 1H), 3.28-3.05 (m, 5H), 2.20 (p, J = 7.7 Hz, 2H). 628.3 8.2 300 O / ^N \ ^F >0 \ N— Η—N p Х/У-Нь-н w 1H NMR (400 MHz, flMCO-d6) δ 8.93 (dd, J = 4.2, 1.6 Hz, 1H), 8.83 (d, J = 8.3 Hz, 1H), 8.76 (dd, J = 8.7, 1.7 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1 Η), 7.84 (d, J = 7.3 Hz, 1H), 7.76 (dd, J = 8.3, 4.3 Hz, 2H), 6.78 (d, J = 9.4 Hz, 1H ), 6.44 (d, J = 11.5 Hz, 2H), 4.73 (td, J = 9.2, 8.3, 4.2 Hz, 1H), 4.31 (d, J = 9.7 Hz, 1H), 3.83 (dd, J = 14.2, 4.3 Hz, 1H), 3.45 (dd, J = 14.2, 10.4 Hz, 1H), 2, 60 (s, ZN), 2.29 (s, 6H), 1.78 (ddd, J = 13.7, 7.3, 3.3 Hz, 1H), 1.53 (ddd, J = 13, 8, 10.4, 7.2 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 616.1 8.4 301 n y—N 'Ύ Η—N 0 X- 1H NMR (400 MHz, flMCO-d6) δ 9.24-9.17 (m, 1H), 9.18-9.09 (m, 1H), 8.95 (s, 1H), 8.94 ( s, 1H), 8.51 -8.40 (m, 1H), 8.02-7.92 (m, 1H), 7.87-7.80 (m, 1H), 6.74 (d, J = 11.7 Hz, 2H), 4.95-4.85 (m, 1H), 4.82-4.72 (m, 1H), 4.15 (d, J = 12.6 Hz, 1 Η), 3.95 (dd, J = 11.6, 3.6 Hz, 1H), 3.85 (dd, J = 14.4, 4.2 Hz, 1H), 3.72 (d, J = 12.6 Hz, 1 Η), 3.59 - 3.46 (m, 2H), 3.44 -3.38 (m, 1H), 3.27-3.15 (m, 1H), 2 .65 (s, ZN). 620.2 9.4 302 < F /Ύ Η—NF / X ^F —N F. FF )=0 X\ / ^FH—N /° X;— ^{0H N} A /\ ⁷ Ο N y 1H NMR (400 MHz, flMCO-d6) δ 8.82 (d, J = 7.7 Hz, 1 Η), 8.808.75 (m, 1 Η), 8.61 (d, J = 8.6 Hz , 1H), 7.60 (td, J = 8.7, 7.7, 4.9 Hz, ZN), 7.49 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 10.1 Hz, 1H), 7.03 (s, 1H), 6.77 (d, J = 9.3 Hz, 1 Η), 6.46 (d, J = 11.6 Hz, 2H ), 4.67 (d, J = 11.0 Hz, 1H), 4.31 (s, 1H), 3.67 (s, 4H), 2.97 (s, 6H), 1.53 (s , 1H), 0.93 (t, J = 7.3 Hz, ZN). 750.9 9.4

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303 C^ ^ci CI^>0 /=\ Br Η—Ν o-n QVy-H \=Ν )=< w 1H NMR (400 MHz, DMSO-06) δ 9.41 (d, J = 0.8 Hz, 1H), 9.339.23 (m, 1 Η), 8.83 - 8.68 (m, 2H), 8.34 - 8.18 (m, 2H), 8.02 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.86 (ddd, J = 8.1, 6 ,9, 1.1 Hz, 1H), 7.81 -7.58 (m, ZN), 7.47 - 7.33 (m, ZN), 4.92 -4.81 (m, 1H), 3.79 (dd, J = 14.5, 4.3 Hz, 1H), 3.45 (dd, J = 14.5, 10.4 Hz, 1H). 594.1 9.4 304 A ^CI CI^>0 Cl Η—Ν 0 NEC—C 2—d У—' ° ^-H Cl Ν _χ E F 1H NMR (400 MHz, flMCO-d6) δ 9.27 (d, J = 8.6 Hz, 1H), 8.89 (d, J = 2.8 Hz, 1H), 8.46 (dd, J = 10.5, 2.8 Hz, 1H), 8.25-8.18 (m, 1H), 7.78 (d, J = 7.4 Hz, 1 Η), 7.62 (d, J = 7.3 Hz, 1 Η), 7.47 - 7.28 (m, 2Η), 4.85 (s, 1 Η), 3.73 - 3.65 (m, 1 Η), 3.41 (d, J = 11.0 Hz, 1H). 576.0 9.6 305 C A )—H-N p fyvyA-H w 1H NMR (400 MHz, flMCO-d6) δ 13.01 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz, 1H), 8.85-8.70 (m, ZN), 8.61 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.3 Hz, 1 Η), 7.72 (dd, J = 8.3, 4.1 Hz, 2H), 6.77 (d, J = 9.4 Hz, 1 Η), 6.43 (d, J = 11.7 Hz, 2H), 4.76 (td, J = 9 ,4, 8.4, 4.2 Hz, 1 Η), 4.30 (s, 2Η), 3.82 (dd, J = 14.3, 4.3 Hz, 1H), 3.45 (dd , J = 14.4, 10.3 Hz, 1H), 2.62-2.56 (m, 1H), 1.77 (ddd, J = 14.0, 7.4, 3.2 Hz, 1H ), 1.52 (ddd, J = 13.6, 10.3, 7.0 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.3 Hz, ZN). 601.1 10.2 306 R ^{f F} >° /—V Ν Η—Ν p ou 4-L V-' o-n O 1H NMR (400 MHz, flMCO-d6) δ 9.35 (d, J = 8.1 Hz, 1H), 8.88 (s, 1H), 8.77 (dd, J = 4.4, 1, 5 Hz, 1H), 8.68 (d, J = 4.9 Hz, 1H), 7.897.68 (m, ZN), 7.51 (tt, J = 8.4, 6.5 Hz, 1H) , 7.29 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 8.4, 7.6 Hz, 2H), 4.83 (td, J = 9.3, 4 .3 Hz, 1H), 4.58 (t, J = 5.9 Hz, 2H), 3.85 (dd, J = 14.5, 4.4 Hz, 1H), 3.57-3.36 (m, ZN). 525.9 11.2 307 C ^H / ^N l \ / HN p K/uL-n w 1H NMR (400 MHz, flMCO-d6) δ 13.05 (s, 1H), 8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.86 (d, J = 8, 2 Hz, 1 Η), 8.80-8.70 (m, 2H), 7.98 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H ), 7.79-7.71 (m, 2H), 6.80 (d, J = 9.4 Hz, 1H), 6.44 (d, J = 11.5 Hz, 2H), 4.79 -4.69 (m, 1H), 4.39 - 4.23 (m, 1 Η), 3.83 (dd, J = 14,2,4,3 Hz, 1H), 3.45 (dd, J = 14.3, 10.3 Hz, 1H), 2.63 (s, ZN), 2.04 (s, ZN), 1.85-1.70 (m, 1H), 1.61-1 .44 (m, 1H), 0.92 (t, J = 7.3 Hz, ZN). 587.5 11.4 308 CX ^ci EF Cl )=0 Af HN OH [ Ν Λ )=( ^ ⁷ on) 1H NMR (400 MHz, flMCO-d6) δ 9.29 (dd, J = 25.4, 8.3 Hz, 1H), 8.87 (p, J = 4.1, 1.9 Hz, 1H) , 8.72 (d, J = 8.6 Hz, 1H), 7.74-7.61 (t, 2H), 7.52 - 7.33 (t, 4H), 6.59 (dt, J =4.7, 1.2 Hz, 1H), 4.83 (dddd, J = 36.2, 10.6, 8.3, 3.9 Hz, 1H), 4.10 - 3.98 (t , 2H), 3.81 - 3.68 (t, 1H), 3.50-3.33 (t, 1H), 3.333.15 (t, 2H), 2.27 - 2.13 (t, 2H ). 589.8 11.9

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309 O ✓ ^N '-.A n—N 0 1H NMR (400 MHz, DMSO-C16) δ 9.51-9.46 (m, 1H), 9.44 (d, J = 8.8 Hz, 1H), 9.05 (d, J = 7, 7 Hz, 1H), 8.82 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.21 (dd, J = 8.7, 5.2 Hz, 1H) , 8.00 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1H), 6.41 (d, J = 11.6 Hz, 2H), 4 .80 (ddd, J = 10.3, 8.3, 4.5 Hz, 1H), 4.28 (d, J = 8.8 Hz, 1H), 3.90 (dd, J = 14.3 , 4.6 Hz, 1H), 3.56 (dd, J = 14.4, 10.3 Hz, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 1.76 (dtd, J = 14.7, 7.4, 3.2 Hz, 1H), 1.52 (dtd, J = 13.8, 7.2, 3.1 Hz, 1H), 0.91 (t , J = 7.3 Hz, ZN). 589.6 11.9 310 О / ^{Ν FFF} ^ ^F F. FF )=° У-F Η—N ,0 XVO-HH w 1H NMR (400 MHz, flMCO-d6) δ 12.86 (s, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.78 (dd, J = 4.2, 1, 5 Hz, 1 Η), 8.73 (d, J = 1.9 Hz, 1H), 8.64 (dt, J = 8.7, 1.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1 Η), 7.67 - 7.55 (m, ZN), 6.77 (d, J = 9.4 Hz, 1 Η), 6.44 (d, J = 11, 6 Hz, 2H), 4.74-4.65 (m, 1H), 4.31 (d, J = 9.7 Hz, 1H), 3.73 (dd, J = 14.5, 4.5 Hz, 1 Η), 3.43 (dd, J = 14.5, 10.0 Hz, 1 Η), 2.50 (s, ZN), 1.77 (ddd, J = 13.9, 7, 2,3,3 Hz, 1H), 1.52 (ddd, J = 13.7, 10.4, 7.1 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 641.8 12.3 311 < , ^H / ^N /X Η—N 0 /—\ /—' °“ ^Η \=N )=( w 1H NMR (400 MHz, flMCO-d6) δ 13.03 (s, 1H), 9.26 (d, J = 28.9 Hz, 2H), 8.86 (s, 1H), 8.79 (d , J = 8.2 Hz, 1H), 8.73 (s, 1H), 8.05 (s, 1 Η), 7.89 (d, J = 7.6 Hz, 1 Η), 6.77 (d, J = 9.4 Hz, 1H), 6.42 (d, J = 11.7 Hz, 2H), 4.75 (d, J = 12.0 Hz, 1H), 4.29 (d , J = 9.4 Hz, 1 Η), 3.86 (d, J = 14.2 Hz, 1H), 3.57-3.48 (m, 1H), 3.09 (q, J = 7 .6 Hz, 4H), 2.19 (p, J = 7.6 Hz, 2H), 1.76 (ddd, J = 10.6, 7.4, 3.6 Hz, 1H), 1.52 (ddd, J = 13.7, 10.3, 7.1 Hz, 1H), 0.91 (t, J = 7.3 Hz, ZN). 600.2 12.3

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312 0 / ^N ”R: HN 0 /—( )—cp—' he —N )=N )=( w 1H NMR (400 MHz, DMSO-06) δ 9.19 (d, 1H), 9.12 (d, J = 7.7 Hz, 1H), 8.96 (d, J = 8.3 Hz, 1H ), 8.92 (s, 1H), 8.47 (s, 1H), 7.97 (dd, J = 8.5, 4.7 Hz, 1H), 7.85 (d, J = 7, 6 Hz, 1 Η), 6.74 (d, J = 11.9 Hz, 2H), 4.95-4.84 (m, 1H), 4.83-4.73 (m, 1H), 4 .54 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 4.00-3.67 (m, 4H), 3.60-3.46 (m, 4H), 3.40 (d, J = 12.4 Hz, 1H), 3.33 (t, 2H), 3.283.18 (m, 1H), 3.05 (s, ZN). 657.2 12.5 313 C ^ppr y \ ^F >0 N— HN ,0 \=N )=( w 1H NMR (400 MHz, flMCO-d6) δ 8.95 (dd, J = 4.2, 1.4 Hz, 1H), 8.82 (d, J = 8.3 Hz, 1H), 8.75 (dd, J = 8.8, 1.6 Hz, 1 Η), 8.22 (s, 1 Η), 7.98 (s, 1Η), 7.90 (d, J = 7.4 Hz, 1H), 7.81 -7.68 (m, 2H), 6.78 (d, J = 9.4 Hz, 1H), 6.43 (d, J = 11.6 Hz, 2H), 4, 72 (ddd, J = 10.1, 8.1, 4.4 Hz, 1 Η), 4.30 (d, J = 8.4 Hz, 2H), 3.80 (dd, J = 14.2 , 4.4 Hz, 1H), 3.44 (dd, J = 14.2, 10.3 Hz, 1H), 1.85-1.69 (m, 1H), 1.62-1.43 ( m, 1H), 0.92 (t, J = 7.3 Hz, ZN). 616.3 13.3 314 Ch F. F Ct pO F-Y Cl H-N O X<u-I-n w 1H NMR (400 MHz, flMCO-d6) δ 9.29 (d, J = 8.4 Hz, 1 Η), 8.90 (d, J = 5.0, 0.7 Hz, 1H), 8, 86 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = 8.7, 1.7 Hz, 1H), 7.97 (d, J = 5.1 Hz , 1H), 7.76-7.64 (m, ZN), 7.467.35 (m, ZN), 4.92-4.83 (m, 1H), 3.79 (dd, J = 14.5 , 4.2 Hz, 1H), 3.44 (dd, J = 14.6, 10.6 Hz, 1H). 569.4 13.4 315 О / ^N У У \ ^F >0 Ν— Η—Ν p Ηλύ-Ή-η ^N )=( w 1H NMR (400 MHz, flMCO-d6) δ 8.96 (d, J = 4.2 Hz, 1H), 8.82 (d, J = 8.2 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 5.3 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.81 -7.67 (m, 2H), 6.78 (d, J = 9.4 Hz, 1 Η), 6.44 (d, J = 11.6 Hz, 2H), 4.80- 4.67 (m, 1H), 4.30 (s, 1H), 3.81 (dd, J = 14.1, 4.4 Hz, 1H), 3.45 (dd, J = 14.2, 10.3 Hz, 1H), 1.78 (ddd, J = 13.7, 7.3, 3.3 Hz, 1H), 1.54 (dt, J = 10.2, 6.8 Hz, 1 Η), 0.92 (t, J = 7.3 Hz, ZN). 602.3 13.6

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316 I I—z n 1H NMR (400 MHz, DMSO-06) δ 11.26 (s, 1H), 9.23 (d, J = 8.1 Hz, 1H), 8.93 (dd, J = 4.2, 1, 5 Hz, 1H), 8.73 (s, 1H), 8.67-8.54 (m, 2H), 7.71 (dd, J = 8.6, 4.2 Hz, 1H), 7, 57 -7.38 (m, 2H), 7.12 (dd, J = 8.5, 7.6 Hz, 2H), 4.68 (td, J = 9.0, 4.6 Hz, 1H) , 3.66 (dd, J = 14.3, 4.6 Hz, 1H), 3.34 (dd, J = 14.4, 9.8 Hz, 1H). 545.1 13.7 317 Cf ^cl c|/>o Cl n-N 0 ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 11.67 (s, 1H), 9.11 (d, J = 8.4 Hz, 1H), 8.84 (dd, J = 4.2, 1, 6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1 Η), 7.80 - 7.39 (m, 5H), 6.50 (dd, J = 3.1, 1.9 Hz, 1 Η), 4.87 (s, 1H ), 3.76 (dd, J = 14.4, 4.1 Hz, 1 Η), 3.41 (dd, J = 14.5, 10.7 Hz, 1H). 565.0 13.8 318 E F F )=0 /=\ U-f H-N P OruD-n w 1H NMR (400 MHz, flMCO-d6) δ 9.42-9.22 (m, 1H), 8.78 (dt, J = 3.8, 1.8 Hz, 1H), 8.68 (t, J = 8.2 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1 Η), 8.05 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1 Η), 7.79 - 7.58 (m, ZN), 7.56 -7.45 (m, 1H), 7.14 (q, J = 7.9 Hz, 2H), 4.91 -4.66 (m, 1H), 3.78 (ddd, J = 28.6 , 14.5, 4.7 Hz, 1 Η), 3.47 (ddd, J = 24.2, 14.5, 9.8 Hz, 1 Η), 2.99 (d, J = 2.0 Hz, ZN). 566.2 14.3 319 Q ^CI D EF Cl po )=\ U-F Η—N O RRA-An \=N )=( w 1H NMR (400 MHz, flMCO-d6) δ 13.02 (s, 1H), 9.46 (d, J = 4.4 Hz, 1H), 9.16 (br, 1H), 8.78-8 .62 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 7.68-7.56 (m, ZN), 7.50 ( dd, J = 8.5, 1.5 Hz, 1H), 7.467.35 (m, ZN), 4.75 (m, 1 Η), 3.85 3.58 (m, 1H), 3.43 (t, J = 11.9 Hz, 1H), 2.37-2.19 (m, 1H), 1.241.10 (m, 2H), 0.99-0.79 (m, 2H). 626.0 14.4

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320 O y~NX w ~m· ⁰ °-» 1H NMR (400 MHz, DMSO-06) δ 8.85 (d, J = 4.2 Hz, 1H), 8.78 (d, J = 8.1 Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H), 7.71-7.45 (m, 3H), 6.76 (d, J = 9.3 Hz, 1H), 6.44 (d, J = 11.6 Hz , 2H), 4.71 (td, J = 9.0, 4.4 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 3.76 (dd, J = 14, 3, 4.5 Hz, 1H), 3.43 (dd, J = 14.3, 10.1 Hz, 1H), 2.61 (s, 3H), 2.54 (s, 3H), 1, 85 (s, 3H), 1.77 (ddd, J = 13.8, 7.2,3.2 Hz, 1H), 1.53 (ddt, J = 17.6, 14.4, 7.3 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 602.2 15.3 321 О Ή Cl HN 0 ГНрЧ-н / ^N / \ w 1H NMR (400 MHz, flMCO-d6) δ 8.85-8.79 (m, 2H), 8.66-8.61 (m, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1H), 6, 45 (d, J = 11.5 Hz, 2H), 4.73-4.61 (m, 1H), 4.38-4.23 (m, 1H), 3.78-3.69 (m, 1H), 3.48 -3.38 (m, 1 Η), 2.50 (s, ZN), 1.84 -1.69 (m, 1H), 1.61 -1.45 (m, 1H ), 0.92 (t, J = 7.3 Hz, ZN). 607.2 15.8 322 Н-О/ )—\ P F NH''R: Cl HN 0 NEC^k)——'' OH ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 9.36 (d, J = 8.2 Hz, 1H), 8.91 8.79 (m, 2H), 8.64 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.69-7.59 (m, 2H), 7.57 (d, J = 8.3 Hz, ZN), 4.80 (s, 1 Η), 4.30 (d, J = 39.4 Hz, 1H), 3.38 (s, 2H) , 2.65 (s, 1H), 2.31 (s, 1H). 639.3 16.2 323 N^N^ Cl >0 Cl Η—N 0 ^NECH O~'^oh w 1H NMR (400 MHz, flMCO-d6) δ 9.17 (d, J = 8.5 Hz, 1H), 8.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.41 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1 Η), 7.72 - 7.58 (m, 4Η), 7.55 (d, J = 7.9 Hz, 1 Η), 4.87 (s, 1 Η), 3 .77 (dd, J = 14.4, 4.2 Hz, 1H), 3.49-3.33 (m, 1H). 564.0 17.1

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324 Ch/ -2 Cl Η—Ν Ο ^ΝΞ0 \ ' ^ο—Η w 1H NMR (400 MHz, DMSO-06) δ 8.85 - 8.72 (m, 2H), 8.60 (dd, J = 8.7, 1.6 Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1 Η), 7.66 - 7.50 (m, 4H), 7, 49 -7.41 (m, 2H), 7.41 -7.24 (m, 4H), 6.43-6.11 (m, ZN), 5.165.04 (m, 1 H), 4.64 (s, 1H), 3.70 (s, 1H), 3.37 (s, 1H). 647.1 18.7 325 ( Ζ ^Η )-Ν X \ CI Η—Ν 0 Κο-Χη )=< 1H NMR (400 MHz, flMCO-d6) δ 8.86 - 8.80 (m, 2H), 8.67 - 8.62 (m, 1H), 8.47 (d, J = 4.9 Hz, 1H), 7.63-7.60 (m, 2H), 7.49 (d, J = 5.0 Hz, 1 Η), 6.78 (d, J = 9.4 Hz, 1H), 6 .45 (d, J = 11.6 Hz, 2H), 4.74-4.60 (m, 1H), 4.39-4.25 (m, 1H), 3.74 (dd, J = 14 ,5, 4.5 Hz, 1 Η), 3.47-3.37 (m, 1 Η), 2.45 (s, ZN), 1.85-1.70 (m, 1H), 1, 52 (dt, J = 17.7, 7.2 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN). 607.1 18.8 326 4/ -2 CI Η—Ν ρ ^ΝΞ ° \ ' ^ο—Η w 1H NMR (400 MHz, flMCO-d6) δ 8.85-8.73 (m, 2H), 8.61 (d, J = 8.7 Hz, 1H), 8.15 (dd, J = 1, 7, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.66-7.52 (m, 4H), 7.497.42 (m, 2H ), 7.41 - 7.26 (m, 4H), 6.44-6.10 (m, ZN), 5.10 (q, J = 12.3 Hz, 1H), 4.64 (s, 1H), 3.70 (s, 1H), 3.37 (s, 1H). 647.2 19.1 327 Ο Fn X Cl n-N 0 )=< w 1H NMR (400 MHz, flMCO-d6) δ 8.84 - 8.79 (m, 2H), 8.62 (dd, J = 8.7, 1.7 Hz, 1H), 8.47-8, 43 (m, 1H), 7.88-7.85 (m, 1H), 7.647.59 (m, 2H), 6.78 (d, J = 9.4 Hz, 1H), 6.45 (d , J = 11.5 Hz, 2H), 4.73-4.63 (m, 1H), 4.37-4.24 (m, 1H), 3.77-3.67 (m, 1H), 3.48 -3.36 (m, 1H), 2.41 (s, ZN), 1.83 -1.69 (m, 1H), 1.59-1.45 (m, 1H), 0, 92 (t, J = 7.3 Hz, ZN), . 607.2 19.3

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328 O ,¾ Cl Η—N 0 NEC——'' 0—Η W 1H NMR (400 MHz, DMSO-C16) δ 8.88 (d, J = 8.1 Hz, 1H), 8.85 (dd, J = 4.1, 1.6 Hz, 1H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.60 (m, 3H), 7.58 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 11.9 Hz, 2H), 4, 72 (td, J = 9.1, 8.7, 4.3 Hz, 1H), 3.91 -3.83 (m, 1H), 3.71 (d, J = 12.3 Hz, 1H) , 3.65-3.49 (m, 3H), 3.43 (s, 2H), 2.70 (td, J = 12.1,3.7 Hz, 1H), 2.38 (dd, J = 12.4, 10.4 Hz, 1H), 1.13 (d, J = 6.2 Hz, ZN). 591.8 19.4 329 _ο Α % \ F >0 ρ Η-Ν Ο Υ2ηΥ-·Υ> ^{η Γ} ° Ρ 1H NMR (400 MHz, flMCO-d6) δ 10.38 (s, 1H), 9.13 (d, J = 8.1 Hz, 1 Η), 8.86 (d, J = 4.6 Hz, 1H), 7.91 -7.45 (m, ZH), 7.37-7.16 (m, 2H), 6.75 (d, J = 3.0 Hz, 2H), 4.76 (td , J = 8.8, 8.1,4.5 Hz, 1H), 4.53 (s, 2H), 3.79-3.73 (m, 1H), 3.57 (dd, J = 8 ,2, 7.4 Hz, 8H), 3.493.38 (m, 1 Η), 2.05 (s, ZN), 1.21 (t, J = 7.0 Hz, ZN). 608.4 20.1 330 i R ^CI C U-F HN ρ HOY-n w 1H NMR (400 MHz, flMCO-d6) δ 9.29 (t, J = 9.2 Hz, 1H), 8.83-8.74 (m,2H), 8.65 (dd, J = 8, 7, 1.6 Hz, 1H), 7.68-7.58 (m, 4H), 7.487.34 (m, ZN), 4.90-4.74 (m, 1H), 3.74 (dt , J = 14.8 Hz, 1 Η), 3.42 (dd, J = 14.5, 10.2 Hz, 1H), 1.68 (ddd, J = 13.2, 8.4, 4, 9 Hz, 1H), 1.07-0.95 (m, 2H), 0.87-0.78 (m, 2H). 599.7 21.0 331 ъ. pi Η—Ν p lgH/=\ NEC—C 2—/' OH ⁿ O 1H NMR (400 MHz, flMCO-d6) δ 8.90-8.74 (m, 2H), 8.61 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.69-7.43 (m, 6H), 7.31 -7.21 (m, 2H), 6.52 (d, J = 11.4 Hz, 2H), 5.73 (p, J = 8.3 Hz, 1H), 4.66 (s, 1H) , 3.71 (s, 1H), 3.37 (s, 1H). 683.1 22.9

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332 Η / Χ ^{Ν F} FF F pO Cl n-N 0 _λ4/=\ /4 NEC—/ y—ά ft—' Ο-Η Ό 1H NMR (400 MHz, DMSO-06) δ 8.86 - 8.76 (m, 2H), 8.63 (dd, J = 8.8, 1.6 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (s, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 6.9 Hz, 1H), 6.42 (d, J = 11.4 Hz, 2H), 4.784.59 (m, 1H), 4.08 - 3.95 (m, 2H), 3.72 (s, 1H), 3.41 (s, 1H). 589.1 23.7 333 Ρ Ν CI Η—Ν ρ /^4/=4/4 NEC—/ 2—K /—' °“ ^{Η N} O 1H NMR (400 MHz, flMCO-d6) δ 8.86-8.76 (m, 2H), 8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 - 7.49 (m, 4H), 6.70 (d, J = 9.7 Hz, 1H), 6.47 (d, J = 11.7 Hz, 2H), 4.68 (s, 1H), 4.42 (d, J = 8.1 Hz , 2H), 3.73 (s, 1H), 3.41 (s, 1H), 2.61 (q, J = 8.2 Hz, 1H), 1.98-1.71 (m, 6H) . 643.2 24.1 334 Ch/ ^F f4 F pO Cl Η—Ν p /+4/=4/4 NEC—/ 2—G ft—' OH w 1H NMR (400 MHz, flMCO-d6) δ 8.86 - 8.79 (m, 2H), 8.62 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 - 7.37 (m, 8H), 7.28 -7.18(m, 1H), 6.53 (d, J = 11.4 Hz, 2H), 5.76 (p, J = 8.1 Hz, 1H), 4.65 (d, J = 10.7 Hz, 1H), 3.773.65 (m, 1H), 3.36 (s, 1H). 683.2 24.2 335 O Ax H / <^N L>\ LL ^F \ F>0 0 HN p p/pl ^r ° ? \j 1H NMR (400 MHz, flMCO-d6) δ 12.96 (s, 1H), 11.47 (s, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.85 (s , 1H), 7.63 (d, J = 40.1 Hz, 2H), 7.40 7.12 (m, 5H), 6.94 (d, J = 9.8 Hz, 1H), 6, 85-6.69 (m, 2H), 6.22 (d, J = 2.0 Hz, 1H), 4.76 (d, J = 11.0 Hz, 1H), 4.53 (s, 2H ), 4.04 (s, 2H), 3.75 (d, J = 13.8 Hz, 1H), 3.57 (dd, J = 9.5, 6.9 Hz, 1H), 1.21 (t, J = 7.0 Hz, ZN). 680.3 25.1

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336 SU ^s| Cl ⁷ /=0 HN About MN=\ N—C 2—' OH Λ-Λ^ν Ν)Λ 1H NMR (400 MHz, DMSO-06) δ 9.92 (s, 1H), 9.27 (d, J = 8.3 Hz, 1H), 9.01 (dd, J = 4.2, 1, 5 Hz, 1H), 8.81 (d, J = 5.8 Hz, 1H), 8.758.68 (m, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7 .97 (d, J = 5.9 Hz, 1H), 7.78 (dd, J = 8.6, 4.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H) , 7.47-7.30 (t, 4H), 4.81 (td, J = 8.9, 4.9 Hz, 1H), 3.39 (dd, J = 14.5, 9.7 Hz , 2H). 532.0 26.1 337 H F-/\-N Cl Η—N 0 NEC——LL—O-H ABOUT 1H NMR (400 MHz, flMCO-d6) δ 11.02 (s, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.2, 1, 6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.927.85 ( t, 2H), 7.81 (t, J = 7.6 Hz, 1H), 7.77-7.70 (t, 2H), 7.677.59 (t, ZH), 7.57 (dd, J = 7.9, 0.4 Hz, 1H), 7.38 (d, J = 9.7 Hz, 2H), 4.76 (s, 1H), 3.8 (br, 1H). 679.1 26.2 338 F F—G ^F /—\ /—\ ⁰ Η—N ' / ,2 Cl Η—N 0 w 1H NMR (400 MHz, flMCO-d6) δ 8.86 - 8.74 (t, 2H), 8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.67 - 7.59 (t, ZN), 7.57 (dd, J = 7.9, 0.4 Hz, 1H), 6.73 (d, J = 10.2 Hz, 1H), 6.50 (d, J = 11.8 Hz, 2H), 4 .65-4.72 (t, 1H), 4.444.32 (t, 1H), 3.84 (td, J = 12.2, 4.2 Hz, 2H), 3.72 (s, 1H), 3.40 (s, 1H), 3.33-3.21 (t, 2H), 1.97 (d, J = 10.8 Hz, 1H), 1.55 (d, J = 13.2 Hz , 2H), 1.48-1.32 (t, 2H). 788.1 26.5 339 NF \/ ^FF 4° yF Η—N p du/uD-n ^ν Λ /K ⁷ on) 1H NMR (400 MHz, flMCO-d6) δ 8.92 (dd, J = 7.9, 4.3 Hz, 1H), 8.84 (dd, J = 4.3, 1.4 Hz, 1H) , 8.68 (d, J = 8.0 Hz, 1H), 7.66 (dt, J = 8.7, 4.4 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.46 (dd, J = 7.3, 2.1 Hz, 1 Η), 6.63 (dd, J = 12.0, 4.7 Hz, 2H), 6.56 (d, J = 1.8 Hz, 1 Η), 4.69 (ddd, J = 13.2, 8.8, 4.9 Hz, 2H), 3.80 - 3.63 (t, 1H), 3, 49 (d, J = 2.2 Hz, ZH), 3.48-3.34 (t, 1H), 3.34-3.21 (t, 1H), 3.21-3.07 (t, 1Н), 2.54 (s, ЗН), 1.90 (ddd, J = 14.2, 10.5, 7.1 Hz, 1Н), 1.76 (ddt, J = 11.2, 7, 3, 4.0 Hz, 1H), 1.61 -1.34 (t, 2H), 0.86 (dt, J = 10.9, 7.3 Hz, 6H). 713.2 0.6

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1H NMR (400 MHz, flMCO-d6) δ 8.93 (d, J = 4.4 Hz, 1H), 8.898.71 (m, 2H), 7.75 (s, 1H), 7.62 (td , J = 18.5, 17.8, 7.5 Hz, 2H), 6.93-6.77 (m, 1H), 6.38 (dd, J = 11.3, 2.7 Hz, 2H ), 4.76-4.61 (m, 1H), 4.49 (q, J = 7.5 Hz, 1H), 3.87 -3.74 (m, 1H), 3.66 (dd, J = 14.5, 4.8 Hz, 1H), 3.54-3.48 (m, 1H), 3.45 (d, J = 1.7 Hz, ZH), 3.34 (dd, j = 14.4, 10.6 Hz, 1H), 3.22 (d, J = 2.5 Hz, ZN), 1.93 (d, J = 9.9 Hz, ZN), 1.25 (d , J = 6.7 Hz, ZN).

1H NMR (400 MHz, flMCO-d6) δ 12.97 (s, 1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.84 (d, J = 8.0 Hz , 1H), 7.89 (s, 1H), 7.78-7.60 (m, 2H), 6.79 (d, J = 9.4 Hz, 1 Η), 6.51 6.38 ( m, ZN), 4.69 (s, 1 Η), 4.31 (d, J = 9.6 Hz, 1H), 3.74 (d, J = 11.7 Hz, 1H), 3.67 (d, J = 4.4 Hz, ZN), 3.45 (s, 4H), 1.78 (dt, J = 10.8, 3.7 Hz, 1H), 1.53 (ddd, J = 13.8, 10.5, 7.1 Hz, 1H), 0.92 (t, J = 7.3 Hz, ZN).

1H NMR (400 MHz, DMSO-06) δ 8.95-8.83 (m, 2H), 8.80 (d, J = 8.0 Hz, 1H), 7.84-7.70 (m, 1H), 7.70-7.61 (m, 1H), 7.61-7.50 (m, 1 Η), 6.94 (dd, J = 9.5, 4.6 Hz, 1H), 6.40 (dd, J = 11.4, 3.6 Hz, 2H), 6.21 (d, J = 2.7 Hz, 1 Η), 4.77 -4.65 (m, 1Η), 3.99-3.87 (m, 1H), 3.84-3.64 (m, 1H), 3.533.32 (m, 4H), 2.42 (s, ZN), 1.801.70 (m, ZN), 1.11 -0.98 (m, 1H), 0.68 - 0.58 (m, 1H), 0.55 - 0.44 (m, 2H), 0.35-0.27 (m, 1H).

1H NMR (400 MHz, flMCO-d6) δ 8.87 (d, J = 4.3 Hz, 1H), 8.858.79 (m, 1H), 8.75 (d, J = 8.7 Hz, 1 Η), 7.74 - 7.65 (m, 1 Η), 7.63 (dd, J = 7.4, 3.1 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1 Η), 6.77 (dd, J = 9.3, 3.8 Hz, 1 Η), 6.52 - 6.42 (m, ZN), 4.68 (qd, J = 8.4, 4.5 Hz, 1H), 4.384.19 (m, 1H), 3.74-3.66 (m, 1H), 3.53 - 3.37 (m, 4H), 2.46 (s, ZN ), 1.77 (ddd, J = 13.6, 7.2,3.2 Hz, 1H), 1.61 -1.45 (m, 1H), 0.93 (t, J = 7.3 Hz, 4H).

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344 F. FF /=0 U-F Η—N ,0 hh-£U-N- _n , ^N 4 / \ ^{0 N} \ ? 1H NMR (400 MHz, DMSO-06) δ 8.76 - 8.64 (m, 2H), 7.54 - 7.42 (m, 2H), 7.32 (d, J = 7.3 Hz, 1H), 6.72 (d, J = 12.1 Hz, 2H), 6.51 (s, 1H), 5.00-4.85 (m, 1H), 4.36 (s, 1H), 3.73-3.55 (m, 2H), 3.48 (s, 3H), 3.29 (s, 3H), 3.02 (t, J = 12.1 Hz, 1H), 1.95 (d, J = 14.7 Hz, 1H), 1.87-1.67 (m, 2H), 1.67-1.43 (m, 3H), 0.91-0.77 (m, 2H ). 697.2 0.8 345 E^F Η—N ,2 / Η—N p hAtu-^o- ^N V /\ ⁷ 0 Ν _χ 1H NMR (400 MHz, flMCO-d6) δ 8.89 (s, 2H), 8.79 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 11.8 Hz, 1H ), 7.65 (dd, J = 11.1, 7.4 Hz, 1H), 7.54 (t, J = 6.8 Hz, 1H), 6.75 (dd, J = 9.5, 4.3 Hz, 1H), 6.41 (dd, J = 11.3, 3.2 Hz, 2H), 6.20 (d, J = 2.9 Hz, 1H), 4.69 (dt, J = 13.3, 9.3 Hz, 1H), 4.29 (d, J = 9.7 Hz, 1H), 3.74 (ddd, J = 46.6, 14.4, 4.6 Hz , 1H), 3.55-3.30 (m, 4H), 2.41 (s, 3H), 1.74 (d, J = 11.1 Hz, ZN), 1.50 (ddd, J = 13.9, 10.5, 7.1 Hz, 1H), 0.90 (t, J = 7.3 Hz, ZN). 617.2 0.8 346 At ^FF ΛΑ ^F EFF /=° У-F Η—N 0 -GnU-Pp Ho A 1H NMR (400 MHz, flMCO-d6) δ 9.00 (dd, J = 12.1, 7.5 Hz, 1H), 8.82 (d, J = 4.2 Hz, 1 Η), 8, 57 (d, J = 8.7 Hz, 1 Η), 7.68 - 7.56 (m, 2H), 7.44 (dd, J = 7.2, 2.9 Hz, 1H), 6, 81 -6.73 (m, 1 Η), 6.55 (s, 1 Η), 6.45 (dd, J = 11.5, 5.6 Hz, 2H), 5.76 (dd, J = 11.1, 6.1 Hz, 2H), 4.74 (dd, J = 13.7, 7.1 Hz, 1H), 4.34 (d, J = 2.1 Hz, 1H), 3, 70-3.61 (m, 1 Η), 3.51 (s, ZN), 3.43 (d, J= 10.0 Hz, 1H), 2.53 (s, ZN), 1.76 ( d, J = 8.0 Hz, 1H), 1.53 (dq, J = 13.7, 7.1 Hz, 1H), 1.16 (d, J = 1.9 Hz, 9H), 0, 92 (t, J = 7.3 Hz, ZN). 785.2 N/A 347 “L z ^H ✓ ^N EFF /=0 U-F Η—N p chuAu-Oul ⁿ A tt '— ^{/ 7} on) 1H NMR (400 MHz, flMCO-d6) δ 8.98 (t, J = 6.8 Hz, 1H), 8.82 (d, J = 4.2 Hz, 1H), 8.62 (d, J = 8.6 Hz, 1 Η), 7.63 (dd, J = 8.5, 4.3 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.45 ( d, J = 7.3 Hz, 1H), 6.79 (dd, J = 9.5, 4.4 Hz, 1 Η), 6.55 (s, 1 Η), 6.47 (dd, J = 11.4, 3.9 Hz, 2H), 4.86 (d, J = 9.4 Hz, 1H), 4.69 (d, J = 13.6 Hz, 1H), 4.35-4 .28 (m, 1H), 3.823.60 (m, ZN), 3.57 - 3.36 (m, 6H), 2.53 (s, ZN), 1.85-1.65 (m, ZN ), 1.53 (ddd, J = 17,2,8,9, 5.3 Hz, 2H), 1.39 (t, J = 9.7 Hz, 1H), 0.93 (t, J = 7.3 Hz, ZN). 755.2 N/A

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348 EFF )=0 Af HN 0 -/w-A ⁿ A pA lA / 0 N^J> 0 1H NMR (400 MHz, DMS0-06) δ 9.00 (t, J = 7.1 Hz, 1H), 8.83 (d, J = 4.2 Hz, 1H), 8.63 (s, 1H ), 7.62 (dd, J = 8.9, 4.6 Hz, 1H), 7.55 (t, J = 7.0 Hz, 1H), 7.44 (t, J = 6.6 Hz , 1H), 6.78 (d, J = 9.8 Hz, 1H), 6.55 (s, 1H), 6.45 (d, J = 11.9 Hz, 2H), 5.06-4 .96 (m, 2H), 4.74 (d, J = 7.9 Hz, 1H), 4.32 (d, J = 9.2 Hz, 1H), 3.67 (dt, J = 12, 6, 5.8 Hz, 1H), 3.49 (s, 4H), 2.53 (s, 3H), 2.14 (d, J = 3.7 Hz, ZN), 1.76 (d, J = 10.4 Hz, 1H), 1.53 (d, J = 9.1 Hz, 1H), 0.93 (t, J = 7.3 Hz, ZN). 783.2 N/A 349 —\ ^H Ar/ ^Fff A ^f EFFA ⁰ Af h—N 0 nA АЧ oA ^z ο ν ' 1H NMR (400 MHz, flMC0-d6) δ 9.06-8.93 (m, 1H), 8.81 (d, J = 4.0 Hz, 1H), 8.56 (t, J = 10, 6 Hz, 1H), 7.65-7.51 (m, 2H), 7.44 (d, J = 6.4 Hz, 1 Η), 6.85-6.69 (m, 2H), 6 .54 (s, 1 Η), 6.50-6.35 (m, 2H), 4.79-4.65 (m, 1H), 4.32 (s, 1H), 3.63 (d, J = 13.8 Hz, 1H), 3.49 (s, 4H), 2.53 (s, ZN), 2.081.97 (m, 2H), 1.77 (s, 1H), 1.55 ( d, J = 15.3 Hz, 1H), 1.44 (t, J = 5.0 Hz, 1H), 1.29 (d, J = 5.4 Hz, 1H), 0.93 (q, J = 6.5, 5.8 Hz, 2H), -0.00 (d, J = 1.6 Hz, ZN). 757.2 N/A 350 AA nk FFF AO AF Η—N p An ⁿ AA\ \ / 0 ^N E ) o cA 1H NMR (400 MHz, flMC0-d6) δ 9.81 (d, J = 41.6 Hz, 1H), 9.08 (t, J = 8.0 Hz, 1H), 8.83 (t, J = 5.3 Hz, 1 Η), 8.58 (dd, J = 37.4, 9.3 Hz, 1H), 7.66-7.56 (m, 1H), 7.46 (dd, J = 9.5, 6.6 Hz, 1 Η), 6.85 (d, J = 9.6 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.49 ( dd, J = 11.5, 2.6 Hz, 2H), 4.86-4.76 (m, 1H), 4.474.37 (m, 1H), 4.38-4.29 (m, 1H) , 4.24-4.14 (m, 1H), 3.99-3.90 (m, 1H), 3.73 (dd, J = 15.6, 4.8 Hz, 1H), 3.70 -3.60 (m, 2H), 3.593.52 (m, 1 Η), 3.50 (s, 2H), 3.433.34 (m, 1 Η), 3.34-3.26 (m, 2H ), 3.22-3.08 (m, 2H), 2.54 (d, J = 2.3 Hz, ZN), 1.83-1.72 (m, 1H), 1.57-1, 46 (m, 1H), 0.96-0.90 (m, ZN). 784.2 N/A

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351 F F—4-F Η—N ' H FFF )=O U-F Η—N O ' ⁰ W 1H NMR (400 MHz, DMSO-C16) δ 9.01-8.91 (m, 1H), 8.79 (d, J = 4.3 Hz, 1H), 8.57 (d, J = 8, 5 Hz, 1H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.78 (dd, J = 9.4, 6.0 Hz, 1H), 6.53 (d, J = 0.9 Hz, 1H), 6.44 (dd, J = 11.5, 5.7 Hz, 2H), 4.72 (dd, J = 10.4, 7.2 Hz, 1H), 4.30 (s, 1H), 3.72-3.29 (m, 6H), 2.51 (s, 3H), 1.80-1.71 (m, 1H), 1.58-1.45 (m, 1H), 0.91 (t, J = 7 ,3 Hz, ZN). 685.2 N/A 352 o ✓ ^N CH M y ^FF yH ^D F. FF )=° AF HN O chEAU-kn N k )=( / 0 N b 1H NMR (400 MHz, flMCO-d6) δ 8.88-8.77 (m, 2H), 8.66 (d, J = 8.7 Hz, 1H), 7.70-7.56 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 6.71 6.60 (m, 2H), 6.55 (d, J = 3.3 Hz, 1 Η), 4, 89-4.69 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.89 (m, 1H), 3.81 -3.73 (m, 2H), 3.553.42 (m, 4H), 3.41 -3.30 (m, 1H), 3.30-3.17 (m, 1H), 2.53 (s, 3H). 698.13 N/A 353 / bg ₃ y Ά (Af no ^N A / \ ' ⁰ w 1H NMR (400 MHz, flMCO-d6) δ 8.78 (s, 1H), 8.64 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.52-7 .35 (m, 2H), 7.00 (t, J = 10.6 Hz, 1H), 6.50 (d, J = 30.6 Hz, ZN), 5.31 (d, J = 6, 2 Hz, 1H), 5.08 (s, 1H), 4.67 (s, 1H), 4.57 (s, 1H), 4.35 (s, 1H), 3.49 (s, ZN ), 2.53 (s, ZN), 1.78 (s, 1H), 1.53 (d, J = 15.1 Hz, 1H), 1.25 (d, J = 6.4 Hz, 1H ), 0.93 (d, J = 6.2 Hz, ZN). 683.2 n/a 354 A A \ NO Vn Vk --\ --\ /--'° ⁿ 4 /H ' ⁰ w 1H NMR (400 MHz, flMCO-d6) δ 8.86 (m, 2H), 7.75 (s, 1H), 7.67 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 9.4 Hz, 1 Η), 6.54 (d, J = 12.4 Hz, 2H), 5.36 (d, J = 4.4 Hz , 1 Η), 5.03 (m,2H), 3.79 (d, J = 6.2 Hz, 1H), 3.53 (s, ZN), 2.42 (s, ZN), 2, 34 (s, ZN), 1.79 (m, 1H), 1.55 (s, 1H), 0.94 (t, J = 7.4 Hz, ZN) 630.2 N/A

Examples 355-406 from table. 3 was prepared according to the methods described herein.

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Table 3

Example Structure 1H-NMR M/Z [M+N] + α4β7 ECso (nM) 355 O-y F .4 /=\ O n-N r ./a n ^A ⁿ A /—' °— /I /I ^{0 N} \ # 1H NMR (400 MHz, DMSO-C16) δ 9.05 (s, 1H), 9.00 (d, J = 7.7 Hz, 1H), 8.85 (d, J = 4.1 Hz, 1H ), 8.66 (dd, J = 8.7, 1.5 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.91 (dd, J = 4.9, 3.2 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.72-7.58 (m, 2H), 6.79-6.61 (m, 2H), 4.83 (td, J = 9.2, 8.4, 4.4 Hz, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.93 (d, J = 3, 7 Hz, 1H), 3.68 (s, 3H), 3.66 (d, J = 2.3 Hz, 4H), 3.53 (dp, J = 14.9, 5.8, 5.2 Hz, 2H), 3.403.18 (m, 2H), 2.05 (s, 3H). 695.2 n/a 356 F F ,4 /=\P n-N p vYh aa_44 ^A N—C V-' O-H 4) 1H NMR (400 MHz, flMCO-d6) 6 9.05 (s, 1H), 8.92-8.77 (m, 2H), 8.68 (d, J = 8.6 Hz, 1H), 8 .60 (d, J = 5.0 Hz, 1H), 7.91 (t, J = 4.3 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.67 (dd, J = 8.3, 4.5 Hz, 2H), 6.74-6.58 (m, 2H), 5.00-4.59 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.91 (m, 1H), 3.66 (d, J = 2.4 Hz, 4H), 3.59-3.40 (m, 1H) , 3.31 (dd, J = 35.1, 12.3 Hz, ZN), 2.03 (s, ZN). 681.2 0.05 357 OAf F 4 /=\ p Η—N p YYh chapter 44 ^AN—\ V—' p MA ⁰ WA 1H NMR (400 MHz, flMCO-d6) δ 9.15-9.00 (m, 2H), 8.85 (d, J = 3.9 Hz, 1H), 8.67-8.57 (m, 2H), 7.91 (ddd, J = 5.0, 3.1,0.8 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.73-7.61 (m, 2H), 5.83 (s, 2H), 4.85 (d, J = 9.2 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1 Η), 4, 06-3.88 (m, 1H), 3.84-3.68 (m, 2H), 3.65 (d, J = 2.2 Hz, ZN), 3.53 (dt, J = 14, 8, 9.7 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.26 (d, J = 12.1 Hz, 1H), 2.03 (s, ZN) , 1.18 (s, 9H). 795.3 N/A

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358 0—\F F I /=\ 0 H-N p Qt/yM 5 mU )=< ^N /Λ) 1H NMR (400 MHz, Chloroformcl) δ 9.28 (dt, J = 4.8, 1.6 Hz, 1H), 9.20 (ddd, J = 8.7, 4.6, 1.5 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.62 (dd, J = 5.0, 1.6 Hz, 1H), 8.04 (dd, J = 24.7 , 5.0 Hz, 1H), 7.83 (dd, J = 8.6, 4.7 Hz, 1H), 7.75 (d, J = 1.2 Hz, 2H), 7.46 (d , J = 7.0 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.43-6.27 (m, 1H), 5.18 (q, J = 7, 6 Hz, 1H), 4.97 (dd, J = 12.8, 6.4 Hz, 1H), 4.53 (td, J = 9.2, 7.8, 4.6 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 4.16 (ddt, J = 19.3, 8.0, 3.3 Hz, 1H), 4.103.90 (m, 2H), 3 .82 (dd, J = 12.5, 2.2 Hz, 1H), 3.72 (d, J = 9.4 Hz, ZN), 3.60 (ddt, J = 32.1, 17.2 , 8.3 Hz, ZN), 3.28 (d, J = 12.0 Hz, 1H), 3.22-3.09 (m, 1H), 3.03 (s, 4H), 2.32 (s, 3H), 1.49-1.10 (m, 9H), 1.02 (d, J = 7.6 Hz, 2H). 780.3 N/A 359 OU ^NF ,4 /=\ p n-N p ^N O^· ΛΑ_ .W _/=\ N—/ y-' 0—p yy ^{7 0 N} \ ? 1H NMR (400 MHz, flMCO-d6) δ 9.22 (d, J = 7.1 Hz, 1 Η), 9.05 (s, 1H), 8.86 (dd, J = 4.1, 1 .5 Hz, 1H), 8.76 (dd, J = 8.7, 1.5 Hz, 1H), 8.61 (d, J = 4.9 Hz, 1H), 7.93 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1 Η), 7.68 (dd, J = 8.6, 4.2 Hz, 1H), 7.44 (td, J = 8.4, 7.9, 1.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H ), 7.06 (ddd, J = 8.5, 2.3, 1.1 Hz, 2H), 6.73 (d, J = 13.4 Hz, 1H), 6.706.64 (m, 1H) , 5.05 (q, J = 7.3 Hz, 1H), 4.93-4.78 (m, 1H), 4.15 (d, J = 12.5 Hz, 1H), 3.95 ( dd, J = 11.4, 3.6 Hz, 1H), 3.86 (dd, J = 14.6, 5.6 Hz, 1H), 3.72 (dd, J = 14.3, 9, 9 Hz, 2H), 3.67 (s, 3H), 3.60-3.49 (m, 1H), 3.37 (d, J = 12.4 Hz, 1H), 3.26 (t, J = 12.1 Hz, 1H), 2.10 (d, J = 1.7 Hz, ZN). 757.2 N/A 360 0^. ^F ^NF 4 /=\ 0 Η—N 0 VJH λα M / /H H ^{7 0 N} \ / 1H NMR (400 MHz, flMCO-d6) δ 9.04 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.84 (dd, J = 4.2, 1, 4 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.91 (dd, J = 5.0, 2.2 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.66 (dt, J = 8.6, 2.5 Hz, 2H), 6, 76-6.63 (m, 2H), 4.82 (td, J = 14.4, 12.1, 5.3 Hz, 2H), 4.20-4.04 (m, ZN), 3, 95 (dd, J = 11.5,3.6 Hz, 1H), 3.80-3.66 (m, 2H), 3.65 (d, J = 1.6 Hz, ZN), 3.60 -3.46 (m, 2H), 709.2 N/A

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3.36 (d, J = 13.7 Hz, 1H), 3.31 3.18 (m, 1H), 2.07 (s, 3H), 1.16 (td, J = 7.1, 1 ,1 Hz, ZN). 361 F He F 0. /=\ p Η—N p ΛΑ-Y/ N—/ /' OH p /4 /x Y ' ABOUT 1H NMR (400 MHz, DMSO-06) δ 9.05 (d, J = 5.5 Hz, 2H), 8.908.81 (m, 1H), 8.70-8.57 (m, 2H), 7 .91 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1 Η), 7.67 (d, J = 7.9 Hz, 2H), 6, 74-6.64 (m, 2H), 4.86 (s, 2H), 4.35 - 4.06 (m, ZN), 3.95 (d, J = 11.0 Hz, 1H), 3 .74 (d, J= 13.2 Hz, 6H), 3.53 (q, J = 14.3, 13.3 Hz, 2H), 3.423.13 (m, 2H), 2.03 (d, J = 20.9 Hz, ZN), 1.53 (d, J = 5.4 Hz, 1H), 1.38 (d, J = 5.4 Hz, 2H), 1.23 (t, J = 7.1 Hz, ZN). 797.2 N/A 362 F F ,4 /=\ p n-N p Yx 1H NMR (400 MHz, DMSO-06) δ 9.03 (d, J = 13.5 Hz, 2H), 8.85 (d, J = 4.3 Hz, 1 Η), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.96-7.88 (m, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.72-7.61 (m, 2H), 6.81 -6.59 (m, 2H), 4.86 (d, J = 11.5 Hz, 2H), 4.21 4.05 (m, 2H), 3.95 (dd, J = 11.7, 3.9 Hz, 1H), 3.75 (dd, J = 15.2, 9.4 Hz, ZN), 3 .66 (s, 4H), 3.36 (d, J = 13.6 Hz, 1H), 3.27 (d, J = 11.9 Hz, 1H), 2.41 -2.22 (m, 1H), 2.07 (d, J = 6.2 Hz, 2H), 1.87 (ddt, J = 33.9, 14.4, 7.2 Hz, 2H), 1.76-1.36 (m, 1H). 765.3 N/A 363 00 F .4 /=\ 0 n-N 0 ^/N 1 1H NMR (400 MHz, DMSO-06) δ 9.04 (s, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.83 (dd, J = 4.1, 1, 5 Hz, 1H), 8.68-8.56 (m, 2H), 7.91 (dt, J = 4.9, 1.0 Hz, 1 Η), 7.75 (d, J = 7, 6 Hz, 1H), 7.71 -7.60 (m, 2H), 6.76-6.59 (m, 2H), 4.894.72 (m, 2H), 4.14 (dt, J = 9 ,3, 3.7 Hz, 2H), 3.95 (dd, J = 11.1, 3.6 Hz, 1H), 3.80-3.62 (m, 5H), 3.52 (q, J = 14.4, 13.6 Hz, 2H), 3.36 (d, J = 12.2 Hz, 1H), 3.22 (s, 1 Η), 2.04 (s, ZN), 0 .75-0.52 (m, 4H). 721.3 N/A

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1H NMR (400 MHz, DMSO-06) δ 9.04 (d, J = 8.2 Hz, 2H), 8.87 (d, J = 4.1 Hz, 1H), 8.64-8.57 (m, 2H), 7.91 (t, J = 4.8 Hz, 1 Η), 7.77 (d, 1H), 7.71 -7.59 (m, ZN), 7.56 (s , 1H), 6.74-6.65 (m, 2H), 4.90 - 4.76 (m, 2H), 4.52 - 4.42 (m, 1 Η), 4.41 -4, 28 (m, ZN), 4.15 (d, J = 12.6 Hz, 1 Η), 3.94 (d, J = 3.5 Hz, 1 Η), 3.73 (d, J = 12 .7 Hz, 1H), 3.69-3.60 (m, 4H), 3.59-3.47 (m, 2H), 3.34 (d, 1H), 3.25 (t, 1H) , 2.53 (s, 3N), 2.03 (s, 3N).______________________ 1H NMR (400 MHz, flMCO-d6) δ 9.04 (d, J = 2.1 Hz, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.89-8.79 (m, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1 Η), 7.91 (dt, j = 4.9, 2.4 Hz, 1 Η), 7.77 (dd, J = 7.5, 2.1 Hz, 1H), 7.71 -7.63 (m, 2H), 6.76-6.61 (m, 2H), 4.84 (d, J = 9.4 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1 Η), 4.05 (q, J = 6.7 Hz, 2H), 3.95 (d, J = 11.3 Hz, 1H), 3.73 (dd, J = 14 ,0, 4.4 Hz, 2H), 3.65 (d, J = 2.3 Hz, ZN), 3.54 (t, J = 8.7 Hz, 2H), 3.36 (d, J = 12.4 Hz, 1H), 3.25 (t, J = 12.6 Hz, 1H), 2.05 (s, ZN), 1.58 (h, J = 7.0 Hz, 2H), 0.88 (td, J = 7.4, 2.1 Hz, ZH).______________________________ 1H NMR (400 MHz, flMCO-d6) δ 9.05 (s, 1H), 8.97 (d, J = 7 .7 Hz, 1H), 8.84 (d, J = 4.1 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1 Η), 8.60 (d, J = 5, 0 Hz, 1H), 7.91 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.71 -7.62 (m, 2H) , 6.71 (d, J = 13.1 Hz, 1H), 6.68-6.63 (m, 1 Η), 4.97-4.90 (m, 1 Η), 4.84 (dd , J = 29.2, 20.4 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.73 (d, J = 13.7 Hz, 2H), 3.66 (s, ZN), 3.53 (q, J = 13.5, 11.7 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.27 (d, J = 12.5 Hz, 1 Η), 2.08 (d, J = 6.7 Hz, ZN), 1.22 (d, J = 6 ,2 Hz, ZN), 1.13 (d, J = 6.3 Hz, ZN).

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367 F F .¾ /=\ Ο Η—Ν O /Well ' O D 1H NMR (400 MHz, DMSO-C16) δ 9.15-9.00 (m, 2H), 8.85 (d, J = 3.9 Hz, 1H), 8.67-8.57 (m, 2H), 7.91 (ddd, J = 5.0, 3.1,0.8 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.73-7.61 (m, 2H), 5.83 (s, 2H), 4.85 (d, J = 9.2 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1H), 4.06 -3.88 (m, 1H), 3.84-3.68 (m, 2H), 3.65 (d, J = 2.2 Hz, ZN), 3.53 (dt, J = 14.8 , 9.7 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.26 (d, J = 12.1 Hz, 1H), 2.03 (s, 3H), 1.18(s,9H). 795.3 N/A 368 F (^'Ή F ,4 /=\ ,0 n-N 0 Ή n—y V-' o—( p /4 /=\ ° d ^z o d ? ^x 1H NMR (400 MHz, flMCO-d6) δ 9.02 (d, J = 18.4 Hz, 2H), 8.85 (d, J = 4.1 Hz, 1H), 8.63 (dd, J = 22.3, 7.3 Hz, 2H), 7.92 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (t , J = 6.5 Hz, 2H), 6.82 (dq, J = 27.7, 5.5 Hz, 1H), 6.75-6.63 (m, 2H), 4.84 (d, J = 10.7 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.813.61 (m, 5H) , 3.53 (q, J = 13.5, 12.8 Hz, 2H), 3.36 (d, J = 12.5 Hz, 1H), 3.26 (d, J = 12.5 Hz, 1H), 2.15-1.96 (m, 6H), 1.42 (dd, J = 53.9, 5.5 Hz, ZN). 767.2 N/A 369 Οχ F Οχρ F ,4 1H NMR (400 MHz, flMCO-d6) δ 9.19 (d, J = 7.3 Hz, 1H), 9.05 (s, 1H), 8.86 (d, J = 4.1 Hz, 1H ), 8.75 (d, J = 8.6 Hz, 1 Η), 8.61 (d, J = 5.0 Hz, 1H), 7.92 (d, J = 5.0 Hz, 1H) , 7.80 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1 Η), 7.68 (dd, J = 8.7, 4.2 Hz , 1 Η), 7.24 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 13.7 Hz, 1H), 6.67 (s, 1H), 6.56- 6.47 (m, 2H), 5.00 (s, 1H), 4.90-4.79 (m, 1 Η), 4.59 (t, J = 8.7 Hz, 2H), 4, 15 (d, J = 12.7 Hz, 1 Η), 3.993.91 (m, 1H), 3.85 (dd, J = 14.8, 5.2 Hz, 1H), 3.72 (t, J = 11.9 Hz, 2H), 3.66 (s, ZN), 3.54 (dd, J = 13.2, 9.8 Hz, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.27 (d, J = 12.0 Hz, 1H), 3.17 (t, J = 8.7 Hz, 2H), 2.08 (d, J = 7.3 Hz, ZN). 799.2 N/A

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370 ^F F .4 1H NMR (400 MHz, DMSO-06) δ 9.20 (d, J = 7.0 Hz, 1H), 9.05 (s, 1H), 8.86 (d, J = 4.1 Hz, 1H ), 8.74 (d, J = 8.5 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 7.93 (d, J = 5.0 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.74-7.64 (m, 2H), 6.85 (s, 1H), 6.79-6.64 (m, 4H) , 4.99 (s, 1H), 4.85 (d, J = 9.7 Hz, 1H), 4.54 (t, J = 8.7 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.96 (d, J = 11.5 Hz, 2H), 3.81 (dd, J = 14.7, 6.2 Hz, 1H), 3.77-3, 69 (m, 1H), 3.67 (s, 3H), 3.55 (t, J = 11.3 Hz, 1H), 3.40-3.33 (m, 1H), 3.27 (d , J = 12.5 Hz, 1H), 3.19 (t, J = 8.8 Hz, 2H), 2.12 (d, J = 6.0 Hz, ZN). 799.2 N/A 371 F O-y F 4 /=\ p n-N p QlyyM_ Ά γ MJ 1H NMR (400 MHz, flMCO-d6) δ 9.05 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.85 (d, J = 4.2 Hz, 1H ), 8.60 (d, J = 5.0 Hz, 1 Η), 8.52 (d, J = 8.6 Hz, 1H), 7.91 (t, J = 4.4 Hz, 1H) , 7.75 (d, J = 7.5 Hz, 1H), 7.64 (dt, J = 16.5, 5.8 Hz, 2H), 7.30 (d, J = 4.5 Hz, 5H), 7.23 (dt, J = 8.8, 4.9 Hz, 1H), 6.76-6.60 (m, 2H), 4.84 (d, J = 8.8 Hz, 1H ), 4.75 (d, J= 11.5 Hz, 1H), 4.31 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 9.8 Hz, 1H), 3.79-3.69 (m, 2H), 3.56 (dt, J = 20.4, 9.0 Hz, 2H), 3.48-3.31 ( m, 2H), 3.31 -3.18 (m, 1H), 2.90 (t, J = 6.9 Hz, 2H), 2.05 (s, 3H). 785.2 N/A 372 P^ ^F ^NF 4 /=\ p Η—N p У-УУ ^/N 1 θ ^ν ^° 1H NMR (400 MHz, flMCO-d6) δ 9.82 (s, 1H), 9.10-9.04 (m, 2H), 8.86 (d, J = 4.2 Hz, 1H), 8 .66 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.67 (dt, J = 7.9, 3.9 Hz, 2H), 6.78-6.64 (m, 2H), 4.96- 4.81 (m, 2H), 4.43 (s, 1H), 4.38-4.26 (m, 1H), 4.16 (d, J = 12.6 Hz, 1H), 3.96 (d, J = 11.8 Hz, ZN), 3.74 (d, J = 12.6 Hz, 2H), 3.65-3.51 (m, 4H), 3.37 (d, J = 12.0 Hz, 4H), 3.27 (d, J = 13.6 Hz, 2H), 3.10 (d, J = 43.0 Hz, 2H), 2.10 (d, J = 2, 4 Hz, ZN). 794.3 N/A

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373 F ρΛΆ F 4 z=\ ,0 n-N p CH /% \ ^N \ /—' ⁰ \ J /A Ax ^{7 0 N} \ ? 1H NMR (400 MHz, DMS0-06) δ 9.04 (s, 1H), 8.95 (d, J = 7.7 Hz, 1H), 8.84 (d, J = 4.1 Hz, 1H ), 8.65 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 6.7 Hz, 2H), 6.71 (d, J = 13.1 Hz, 1H), 6, 66 (s, 1H), 5.16-5.10 (m, 1H), 4.88-4.75 (m, 2H), 4.15 (d, J = 12.8 Hz, 1H), 3 .95 (d, J = 12.5 Hz, 1H), 3.76 - 3.67 (m, 2H), 3.65 (s, 3H), 3.58-3.46 (m, 2H), 3.36 (d, J = 12.1 Hz, 1H), 3.27 (d, J = 11.5 Hz, 1H), 2.04 (s, 2H), 1.90-1.75 (m , 2H), 1.72-1.50 (m, 6H). 749.3 N/A 374 F ρΡ·Ά ^N F 4 1H NMR (400 MHz, flMC0-d6) δ 9.23 (d, J = 7.0 Hz, 1H), 9.05 (s, 1H), 8.85 (d, J = 4.1 Hz, 1H ), 8.75 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 7.93 (t, J = 4.4 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.68 (dd, J = 8.9, 4.2 Hz, 1H ), 7.26 (t, J = 8.6 Hz, 2H), 7.14-7.02 (m, 2H), 6.74 (d, J = 13.3 Hz, 1H), 6.68 (s, 1H), 5.03 (s, 1H), 4.85 (d, J = 9.4 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 3.84 (d, J = 10.6 Hz, 1H), 3.74 (d, J = 13.2 Hz, 2H), 3.67 (s , 3H), 3.55 (t, J = 11.7 Hz, 1H), 3.37 (d, J = 12.2 Hz, 1H), 3.27 (d, J = 12.8 Hz, 1H ), 2.11 (d, J = 6.3 Hz, ZN). 775.2 N/A 375 Ο·Α ^N F /=\ p n-N p 1H NMR (400 MHz, flMC0-d6) δ 9.05 (s, 1H), 9.00 (d, J = 7.6 Hz, 1H), 8.86 (d, J = 4.2 Hz, 1 Η), 8.75 (s, 1H), 8.68 (d, J = 5.3 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1 Η), 8.25 (s, 1H), 7.91 (t, J = 3.7 Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H ), 7.65 (td, J = 9.1, 3.2 Hz, 2H), 6.76-6.62 (m, 2H), 4.92-4.70 (m, 2H), 4.454, 28 (m, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 10.9 Hz, 1H), 3.73 (d, J = 12.6 Hz, 1H), 3.65 (s, ZN), 3.63 - 3.44 (m, 2H), 3.36 (d, J= 12.3 Hz, 1H), 3.25 (t, J = 12.3 Hz, 1H), 3.03 (d, J = 6.2 Hz, 2H), 2.04 (d, J = 5.4 Hz, ZN). 786.2 N/A

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376

377

378

1H NMR (400 MHz, DMSO-C16) δ 9.05 (d, J = 4.4 Hz, 1H), 9.01 (d, J = 7.4 Hz, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.59 (dd, J = 14.4, 6.8 Hz, 2H), 8.30 (d, J = 8.3 Hz , 1H), 7.90 (dd, J = 4.8, 2.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.66 (td, J = 9, 4, 8.6, 5.8 Hz, 2H), 6.79 - 6.60 (t, ZN), 4.94 - 4.69 (t, 2H), 4.38 (s, 1H), 4 .31 (dt, J = 11.4, 6.2 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 10.9 Hz, 1H) , 3.73 (d, J = 12.4 Hz, 1H), 3.65 (s, ZN), 3.63-3.45 (t, ZN), 3.36 (d, J = 12.4 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 3.122.92 (t, 2H), 2.63 (s, ZN), 2.04 (d, J = 4.7 Hz, ZH).________________ 1H NMR (400 MHz, flMCO-d6) δ 9.05 (d, J = 2.6 Hz, 1 Η), 9.01 8.94 (t, 1H), 8.84 ( d, J = 3.4 Hz, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.60 (t, J = 3.7 Hz, 1H), 7.91 (q, J = 3.7 Hz, 1H), 7.81 -7.73 (t, 1H), 7.68 (dd, J = 8.0, 2.9 Hz, 2H), 6.80 - 6.62 (t, 2H), 4.83 (s, 2H), 4.20-4.05 (t, ZN), 3.95 (d, J = 11.4 Hz, 1H), 3.79-3, 60 (t, 5H), 3.54 (s, 2H), 3.36 (d, J = 12.5 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 2, 05 (s, ZN), 1.66 (q, J = 6.8 Hz, 1H), 1.51 -1.35 (t, 2H), 0.89 (dd, J = 6.8, 2, 3 Hz, 6H).

1H NMR (400 MHz, flMCO-d6) δ 9.23 (d, J = 7.7 Hz, 1 Η), 9.06 (s, 1Η), 8.87 (d, J = 4.1 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 7.93 (d, J = 5.0 Hz, 1H) , 7.82 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1 Η), 7.71 (dd, J = 8.6, 4.2 Hz , 1 Η), 7.57 (d, J = 8.0 Hz, 1H), 7.54-7.41 (t, 2H), 7.29 (d, J = 8.1, 2.7 Hz , 1H), 6.72 (dd, J = 13.2, 6.7 Hz, 1H), 6.66 (s, 1H), 5.24-5.12 (t, 1H), 4.91 - 4.76 (t, 1H), 4.14 (d, J = 12.6 Hz, 1H), 4.00-3.87 (t, 2H), 3.72 (d, 2H), 3.67 (s, ZN), 3.54 (t, J = 3.0 Hz, 1H), 3.34 (d, 1H), 3.25 (t, 1H), 2.05 (d, J = 7, 6 Hz, ZN).

800.2

751.3

841.1

N/A

N/A

N/A

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379 F F w/ 1H NMR (400 MHz, DMSO-06) δ 9.04 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.84 (d, J = 4.2 Hz, 1H ), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 4.3 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 13.4 Hz, 1H), 6, 65 (s, 1H), 4.86 (s, 2H), 4.14 (d, J = 12.7 Hz, 1H), 3.98-3.82 (m, 3H), 3.73 (d , J = 13.3 Hz, 2H), 3.66 (s, 3H), 3.53 (d, J = 9.2 Hz, 2H), 3.36 (d, J = 12.5 Hz, 1H ), 3.27 (d, J = 12.7 Hz, 1H), 2.03 (d, J = 6.9 Hz, ZN), 1.89 (p, J = 6.6 Hz, 1H), 0.90 (d, J = 6.7 Hz, 6H). 737.3 n/a 380 F O+ ^f F ,4 1H NMR (400 MHz, flMCO-d6) δ 9.20 (d, J = 7.1 Hz, 1H), 9.05 (s, 1H), 8.90-8.82 (m, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.64-8.57 (m, 1 Η), 7.92 (d, J = 5.0 Hz, 1H), 7.81 ( d, J = 7.6 Hz, 1 Η), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 8.7, 4.2 Hz, 1H), 7 .24 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.81 -6.69 (m, 2H), 6.68 (s, 1H), 5.00 ( d, J = 8.7 Hz, 2H), 4.85 (d, J = 9.7 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.84 (dd, J = 14.6, 5.7 Hz, 1H), 3.73 (d, J = 10.6 Hz, 2H), 3.67 ( s, ZN), 3.55 (t, J = 11.4 Hz, 1H), 3.42-3.32 (m, 1 Η), 3.26 (t, J = 12.1 Hz, 1H) , 2.85 (q, J = 8.1 Hz, 4H), 2.11 (d, J = 6.3 Hz, ZN), 2.04 (p, J = 7.5 Hz, 2H). 797.3 N/A 381 OR. F.4 1H NMR (400 MHz, flMCO-d6) δ 9.12-8.95 (m, 2H), 8.84 (d, J = 4.2 Hz, 1H), 8.65 (d, J = 8, 7 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.97-7.86 (m, 1 Η), 7.76 (d, J = 7.5 Hz, 1H ), 7.67 (d, J = 7.8 Hz, 2H), 6.71 (dd, J = 20.6, 7.9 Hz, 2H), 4.82 (d, J = 8.7 Hz , 2H), 4.21 (t, J = 5.0 Hz, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H ), 3.73 (d, J = 14.0 Hz, 2H), 3.52 (d, J = 7.9 Hz, 4H), 3.36 (d, J = 12.6 Hz, 1H), 3.27 (d, J = 1.5 Hz, 4H), 2.09 (d, J = 6.3 Hz, ZN). 739.2 N/A

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382 F O< ^f =NF ,R /=\ 0 Η—N 0 Ol “I 1H NMR (400 MHz, DMSO-06) δ 9.05 (s, 1H), 8.98 (d, J = 7.7 Hz, 1H), 8.86 (d, J = 4.1 Hz, 1H ), 8.67 (d, J = 8.6 Hz, 1 Η), 8.60 (d, J = 5.0 Hz, 1H), 7.91 (t, J = 4.2 Hz, 1H) , 7.77 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.7 Hz, 2H), 6.81 6.57 (m, 2H), 4.84 (dt , J = 10.6, 6.3 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1 Η), 4.07 (q, J = 6.4 Hz, 2H), 3, 95 (dd, J = 11.5, 3.5 Hz, 1H), 3.72 (dd, J = 14.4, 5.6 Hz, 2H), 3.53 (tt, J = 9.3, 5.5 Hz, 2H), 3.36 (d, J = 12.4 Hz, 1H), 3.30-3.18 (m, 1H), 2.06 (s, 3H), 1.55 ( p, J = 6.8 Hz, 2H), 1.25 (d, J = 13.8 Hz, 14H), 0.83 (t, J = 6.5 Hz, ZN). 821.4 N/A 383 F O<F =NF b /=\ 0 HN 0 y /H oH Ν—/ 0, ^ν 4. Λ. Α, ⁰ w Q °Y ^F T ^F 1H NMR (400 MHz, flMCO-d6) δ 9.26 (d, J = 6.9 Hz, 1 Η), 9.06 (s, 1H), 8.86 (d, J = 4.1 Hz, 1H), 8.77 (d, J = 8.7 Hz, 1 Η), 8.61 (d, J = 5.0 Hz, 1H), 7.93 (d, J = 4.9 Hz, 1H ), 7.81 (d, J = 7.6 Hz, 1H), 7.77-7.65 (m, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 9.0, 3.5 Hz, 2H), 6.78-6.71 (m, 1H), 6.68 (s, 1H), 5.04 (d, J = 7.2 Hz, 1H), 4.91 -4.79 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.85 (d, J = 9.5 Hz, 1H), 3.74 (d, J = 13.1 Hz, 2H), 3.67 (s, ZN), 3.55 (t, J = 11 .5 Hz, 1H), 3.37 (d, J = 12.4 Hz, 1H), 3.26 (t, J = 12.4 Hz, 1H), 2.12 (d, J = 6.2 Hz, ZN). 841.1 N/A 384 F PP(-F ^NFA /=4 0 Η—N 0 vJm st ^/N 10 o =0 1H NMR (400 MHz, flMCO-d6) δ 9.66 (s, 1H), 9.07 (d, J = 7.2 Hz, 2H), 8.86 (s, 1H), 8.63 (dd , J = 16.9, 6.9 Hz, 2H), 7.91 (s, 1H), 7.78 (d, J = 7.6 Hz, 1 Η), 7.67 (d, J = 7 ,1 Hz, 2H), 6.79-6.65 (m, 2H), 4.84 (s, 2H), 4.16 (d, J = 12.5 Hz, 2H), 4.08-3 .90 (m, 4H), 3.79-3.48 (m, 8H), 3.37 (d, J = 11.6 Hz, ZN), 3.27 (d, J = 13.1 Hz, 1H), 3.13-2.92 (m, 5H), 2.11 (d, J = 5.1 Hz, ZH), 1.94 (s, 2H). 808.0 N/A

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385 0¾ F O< ^f NF γ /=\ Ο Η—N p N4 ^Z +—' 0 /X x / 0 N E 0 b 1H NMR (400 MHz, DMSO-06) δ 9.03 (d, J= 16.1 Hz, 2H), 8.86 (d, J = 4.2 Hz, 1H), 8.69-8.56 (m, 2H), 7.92 (d, J = 4.7 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.69 (dd, J = 7.9, 4.8 Hz, 2H), 6.71 (dt, J = 24.9, 7.3 Hz, ZN), 4.84 (d, J = 9.1 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.78-3.62 (m, 5H), 3.61 -3.43 (m, 2H ), 3.36 (d, J = 12.5 Hz, 1H), 3.27 (d, J = 12.6 Hz, 1H), 2.34 (ddd, J = 20.9, 13.2, 7.6 Hz, 1H), 2.08 (s, 1H), 2.02 (s, 1H), 1.81 (s, 4H), 1.74 (d, J = 5.7 Hz, 1H) , 1.65 (s, 2H), 1.57 (dd, J = 10.5, 4.6 Hz, 1H), 1.50 (d, J = 5.4 Hz, 1H), 1.30 ( tq, J = 20.3, 9.9, 9.4 Hz, 6H). 835.0 N/A 386 0¾ F O<FF X z=\ p Η—N p Y l mn—</ e—' o /X /=+ ( / ON/ )=0 _ _n \ 1H NMR (400 MHz, flMCO-d6) δ 9.06 (d, J = 7.0 Hz, 2H), 8.86 (d, J = 4.2 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.92 (t, J = 4.6 Hz, 1H), 7.807.66 (m, ZN), 6.73-6.62 (m, 2H), 5.06 (d, J = 14.8 Hz, 1H), 4.95-4.77 (m, ZN), 4.15 (d, J = 12.6 Hz, 1H), 4.01 -3.90 (m, 2H), 3.73 (d, J = 12.7 Hz, 1H), 3.66 (t, J = 2.0 Hz, ZN), 3.53 (qd, J = 14.9, 13.4, 6.7 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.5 Hz, 1H), 2.98 (s, ZN), 2.88 (s, ZN), 2.02 (s, ZN). 766.6 N/A 387 OYp F X z=\ P Η—N p 'X nX X' och /X / + ^{0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 9.05 (s, 1H), 8.98 (d, J = 7.9 Hz, 1H), 8.85 (d, J = 4.2 Hz, 1H ), 8.65 (d, J = 8.7 Hz, 1 Η), 8.60 (d, J = 5.0 Hz, 1H), 7.91 (dd, J = 5.1, 2.5 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 6.74-6.61 (m, 2H), 4.86 (s, 2H), 4.75 (q, J = 6.7, 6.2 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d , J = 10.2 Hz, 1H), 3.73 (d, J = 13.3 Hz, 2H), 3.53 (q, J = 11.6 Hz, 2H), 3.36 (d, J = 12.7 Hz, 1H), 3.25 (t, J = 12.7 Hz, 1 Η), 2.03 (s, ZN), 1.54 (dtt, J = 29.8, 14.0 , 7.1 Hz, 4H), 0.89 (t, J = 7.4 Hz, ZN), 0.82 (t, J = 7.5 Hz, ZN). 751.3 N/A

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388 F F .4 /=\ 0 n-N p ^N O^ _y N—/ V-' 0-( /4 / \ ^{7 0 N} \ ? 1H NMR (400 MHz, DMSO-C16) δ 9.05 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H), 8.86-8.83 (m, 1H), 8 .65 (d, J = 9.0 Hz, 1 Η), 8.60 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 4.9 Hz, 1H), 7. 76 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 6.71 (d, J = 13.3 Hz, 1H), 6.67 ( s, 1H), 4.82 (d, J = 22.8 Hz, ZN), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 13.7 Hz, 1H), 3.76-3.68 (m, 2H), 3.65 (s, ZN), 3.53 (q, J = 11.1, 10.3 Hz, 2H), 3.36 (d , J = 13.6 Hz, 1H), 3.30-3.20 (m, 1H), 2.07 (s, ZN), 1.58-1.50 (m, 2H), 1.07 ( d, J = 6.2 Hz, ZN), 0.87 (t, J = 7.3 Hz, ZN). 737.2 n/a 389 O-A ^N F 4. z=\ p H-N p W.Y. ) 1H NMR (400 MHz, flMCO-d6) δ 9.33 (s, 1H), 9.26 (d, J = 6.8 Hz, 1H), 9.06 (s, 1H), 8.86 (d , J =4.1 Hz, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 4.9 Hz, 1 Η), 7.92 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.68 (dd, J = 8.9, 4.1 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.13 (d, J = 8.3 Hz, 1 Η), 6.74 (d, J = 13.4 Hz, 1H), 6.69 (s, 1H), 5.04 (d , J = 8.3 Hz, 1 Η), 4.85 (d, J = 9.1 Hz, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (d, J = 11.1 Hz, 1H), 3.903.80 (m, 1H), 3.76 (t, J = 12.0 Hz, 2H) , 3.67 (s, ZN), 3.55 (t, J = 11.5 Hz, 1H), 3.37 (d, J = 12.2 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 3.08 (s, 4H), 2.13 (d, J = 5.0 Hz, ZH), 1.22 (t, J = 7.2 Hz, 6H). 842.3 N/A 390 ^F 4JV4 ^f ^NF 4 z=\ ρ Η—Ν p 44 N—/ ) /N 4l k ⁷ 0 Ν _χ Λ Λ 1H NMR (400 MHz, flMCO-d6) δ 9.02 (d, J = 19.3 Hz, 2H), 8.86 (d, J = 4.1 Hz, 1 Η), 8.69 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.92 (dt, J = 4.8, 2.1 Hz, 1H), 7.78 ( d, J = 7.4 Hz, 1 Η), 7.72 - 7.60 (m, 2Η), 6.75 - 6.57 (m, 2H), 4.84 (d, J = 7.6 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1 Η), 3.94 (t, J = 7.0 Hz, ZN), 3.76-3.59 (m, 5H) , 3.54 (dd, J = 13.9, 10.1 Hz, 2H), 3.31 (dd, J = 36.7, 12.3 Hz, 2H), 2.09 (s, ZN), 1.10-0.98 (m, 1H), 0.51 (d, J = 7.9 Hz, 2H), 0.27 (d, J = 4.5 Hz, 2H). 735.3 N/A

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391 F ρΧ'Ή F .4 /=\ O HN p CH « n ' ^{0 N} \ # 1H NMR (400 MHz, DMSO-06) δ 9.04 (s, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.84 (d, J = 4.1 Hz, 1H ), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.91 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 6.72 (s, 1H), 6.65 (s, 1H), 4.88-4.79 (t, ZN), 4.15 (d, J = 12.5 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.75 (s , 2H), 3.65 (s, ZN), 3.56 - 3.48 (t, 2H), 3.36 (d, J = 10.2 Hz, 1H), 3.25 (t, J = 11.4 Hz, 1H), 2.04 (s, ZN), 1.58-1.47 (t, 2H), 1.22 (d, J = 6.1 Hz, ZN), 0.87- 0.81 (t, ZN). 737.2 N/A 392 OR 4 /=\ p Η—Ν p OL^уМ /Ή ( ' Ο Ν Λ /= O o o— ⁷ 1H NMR (400 MHz, flMCO-d6) δ 9.06 (d, J = 7.8 Hz, 2H), 8.86 (d, J = 4.1 Hz, 1H), 8.64 (d, J = 8.7 Hz, 1 Η), 8.60 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 4.9 Hz, 1H), 7.76 (dd, J = 9.5, 7.6 Hz, 2H), 7.71 7.67 (t, 1H), 6.69 (d, J = 13.7 Hz, 1H), 6.66 (s, 1H), 5 .08 (d, J = 14.9 Hz, 1H), 4.92 (d, J = 14.9 Hz, 2H), 4.85 (d, J = 16.2 Hz, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.97 (s, 1H), 3.93 (s, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.66 (d, J = 2.3 Hz, ZN), 3.64 - 3.55 (t, 4H), 3.48 (dd, J = 23.3, 15.5 Hz, 5H), 3.36 ( d, J= 12.4 Hz, 1H), 3.26 (d, J = 12.6 Hz, 1H), 2.02 (s, ZN). 808.3 N/A 393 ^F ρΧ'Ή ^NF 4 ' ^0N 3 _o ts° _ъ 1H NMR (400 MHz, flMCO-d6) δ 9.02 (d, J = 16.9 Hz, 2H), 8.85 (d, J = 3.9 Hz, 1H), 8.66-8.57 (t, 2H), 7.92 (d, J = 4.9 Hz, 1H), 7.81 -7.73 (t, 1H), 7.68 (d, J = 8.8 Hz, 2H) , 6.71 -6.62 (t, 2H), 4.93-4.75 (t, ZN), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.1 Hz, 1H), 3.73 (d, J = 13.5 Hz, 6H), 3.53 (q, J = 14.6, 13.8 Hz, 2H), 3.36 (d , J = 12.8 Hz, 1H), 3.26 (d, J = 12.5 Hz, 1H), 2.03 (d, J = 23.8 Hz, ZN), 1.57-1.31 (t, ZN), 1.25 (dd, J = 6.3, 2.9 Hz, 6H). 811.3 N/A

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394 0—\F F ,¾ f °Ό ots° 1H NMR (400 MHz, DMS0-06) δ 9.10-8.99 (m, 2H), 8.85 (t, J = 3.0 Hz, 1H), 8.62 (dd, J = 16, 4, 6.9 Hz, 2H), 7.92 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.67 (dd, J = 8.9, 4.9 Hz, 2H), 6.66 (d, J = 8.2 Hz, 2H), 4.86 (s, 1H), 4.62-4.57 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.73 (d, J = 13.3 Hz, 5H), 3, 54 (t, J = 12.6 Hz, 2H), 3.36 (d, J = 12.6 Hz, 1H), 3.26 (d, J = 12.5 Hz, 1H), 2.03 ( d, J = 22.0 Hz, ZN), 1.84 (d, J = 7.9 Hz, 2H), 1.76 (dd, J = 5.8, 2.0 Hz, 2H), 1, 64 (s, 2H), 1.53 (d, J = 5.5 Hz, 2H), 1.48-1.41 (m, 3H), 1.36 (t, J = 8.1 Hz, ZN ), 1.261.20 (m, 1H). 851.3 N/A 395 CY F NF .2 /=\ ρ Η—Ν p Υ, Ν—{ ' 0 /¼ /=4 ( ⁰ \ ? > o 1H NMR (400 MHz, flMC0-d6) δ 9.17 (s, 1H), 9.14-9.00 (m, 2H), 8.86 (t, J = 2.7 Hz, 1H), 8 .66 (d, J = 8.8 Hz, 1H), 8.63-8.54 (m, 1H), 7.91 (d, J = 5.0 Hz, 1H), 7.78 (dd, J = 7.6, 1.9 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 6.776.66 (m, 2H), 4.88 (dd, J = 20.8 , 9.6 Hz, 2H), 4.40 (s, 1 Η), 4.32 (s, 1H), 4.16 (d, J = 12.6 Hz, 1H), 3.96 (d, J= 11.8 Hz, 1H), 3.74 (d, J = 11.3 Hz, 2H), 3.56 (dd, J = 23.8, 12.5 Hz, 2H), 3.47- 3.34 (m, ZN), 3.32-3.17 (m, ZN), 2.94 (d, J= 11.3 Hz, 1H), 2.84 (s, 1H), 2.11 (s, 3H), 1.77 (t, J = 16.7 Hz, 2H), 1.67-1.52 (m, 3H), 1.33 (d, J = 12.7 Hz, 1H) . 792.3 N/A 396 o< _f A z=\ ρ Η—Ν p Ayi °w Qi 1H NMR (400 MHz, flMC0-d6) δ 9.24 (d, J = 6.8 Hz, 1H), 9.06 (s, 1H), 8.86 (t, J = 3.0 Hz, 1 Η), 8.76 (d, J = 8.7 Hz, 1 Η), 8.65-8.57 (m, 1 Η), 7.93 (d, J = 5.0 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.71 (dd, J = 17.1, 7.8 Hz, 2H), 7.33 (d, J = 8.1 Hz, 1 Η), 6.90 (dd, J = 15.0, 5.8 Hz, 2H), 6.75 (d, J = 13.1 Hz, 1H), 6.69 (s, 1H), 5, 03 (m, 1 Η), 4.99 (s, 4H), 4.88 - 4.86 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.96 ( d, J = 11.4 Hz, 1H), 3.84 - 3.69 (m, ZN), 3.67 (s, ZN), 3.55 (t, J = 11.7 Hz, 1 Η) , 3.37 (d, J = 12.4 Hz, 1H), 3.26 (t, J = 12.9 Hz, 1H), 2.14 (d, J = 5.4 Hz, ZN). 799.2 N/A

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397 ^F NF A ED 1H NMR (400 MHz, DMSO-06) δ 9.17 (d, J = 7.4 Hz, 1H), 9.06 (s, 1H), 8.87 (s, 1H), 8.77 (d , J = 8.5 Hz, 1H), 8.61 (s, 1H), 7.92 (s, 1H), 7.76 (dt, J = 25.0, 12.6 Hz, ZN), 7 .02 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 10.1 Hz, 2H), 6.73 (d, J = 13.9 Hz, 1 Η), 6, 67 (s, 1H), 5.03 (s, 1 Η), 4.85 (s, 1 Η), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.0 Hz, 1H), 3.86 (s, 2H), 3.83 (s, ZN), 3.73 (d, J = 12.4 Hz, 1H), 3.66 (s, ZN ), 3.54 (s, 1H), 3.36 (d, J = 10.4 Hz, 1H), 3.32-3.12 (m, 1 Η), 2.08 (d, J = 7 ,2 Hz, ZN), 1.32 (s, 9H). 843.1 N/A 398 0^. F O< ^F ^NF ,4 /=N O HN p €H<yM /¼ ^{7 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 9.00 (d, J = 7.8 Hz, 1H), 8.888.81 (m, 1H), 8.67 (d, J = 8.6 Hz, 1H ), 8.61 (ddd, J = 4.4, 2.1, 1.3 Hz, 1H), 8.08 (dd, J = 8.8, 1.3 Hz, 1H), 7.87 ( dd, J = 8.6, 4.4 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (dt, J = 7.8, 3.3 Hz, 2H ), 6.70 (dd, J = 13.0, 2.3 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1 Η), 4.86 (d, J = 4.3 Hz, 1H), 4.83 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.3, 3.7 Hz, 1H), 3.783.70 (m, 2H), 3.69 (d, J = 3.6 Hz, ZN), 3.57 (d, J = 2.4 Hz, ZN), 3.53 (d, J = 3 .7 Hz, 1 Η), 3.51 (d, J = 9.9 Hz, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12, 2 Hz, 1H), 2.05 (s, ZN). 695.2 N/A 399 F F .4 QApy-H /H o 1H NMR (400 MHz, flMCO-d6) δ 13.11-12.65 (s, 1H), 8.87 (d, J = 8.1 Hz, 1H), 8.85-8.83 (m, 1H), 8.73-8.65 (m, 1 Η), 8.61 (ddd, J = 4,4,2,3, 1.2 Hz, 1H), 8.08 (dd, J = 8 ,8, 1.3 Hz, 1 Η), 7.87 (dd, J = 8.6, 4.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7, 71 -7.63 (m, 2H), 6.69 (d, J= 13.4 Hz, 1 Η), 6.65 (s, 1 Η), 4.88-4.80 (m, 1 Η ), 4.77 (d, J = 11.5 Hz, 1 Η), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.81 -3.68 (m, 2H), 3.57 (d, J = 2.5 Hz, ZH), 3.553.42 (m, 2H), 3.35 (d, J = 12.4 Hz, 1H), 3.25 (t, J = 12.1 Hz, 1H), 2.03 (d, J = 2.5 Hz, ZN). 681.2 0.1

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400 F AF Λ N=\ 0 Η—N 0 Μ-ΧΛ—'' 0 /¼ /x ' ^{0 N} \ y 1H NMR (400 MHz, DMSO-06) δ 9.10 (d, J = 3.0 Hz, 1H), 9.00 (d, J = 7.7 Hz, 1H), 8.88-8.80 (m, 2H), 8.66 (dd, J = 8.7, 1.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.67 (td, J = 5.8, 5.3, 2.6 Hz, 2H), 7.61 (d, J = 6.1 Hz, 1H), 6.746.59 (m, 2H), 4.88-4.78 (m , 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.77-3.64 (m, 5H), 3.57 ( d, J = 2.2 Hz, 5H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.1 Hz, 1H), 2.05 (s, 3H). 695.2 N/A 401 <AF Ο'Ά AF ,4 N=\ O HN p QXyy-A A O ^H 1H NMR (400 MHz, flMCO-d6) δ 9.10 (d, J = 3.6 Hz, 1H), 8.958.76 (m, 3H), 8.68 (d, J = 8.7 Hz, 1H ), 7.76 (d, J = 7.5 Hz, 1H), 7.74 - 7.56 (m, 3H), 6.74 - 6.56 (m, 2H), 4.90-4, 72 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.75 (t, J = 13.4 Hz, 2H), 3.57 (d, J = 2.4 Hz, ZN), 3.55-3.48 (m, 1H), 3.47 (s, 1H), 3.35 (d, J = 12.6 Hz, 1H), 3.25 (t, J = 12.4 Hz, 1H), 2.03 (s, 3H). 681.2 0.1 402 Oy _F 4 /=\ p Η—Ν p 44 ΝΛ NV \' 0 /M M ^{H 0 N} \ y 1H NMR (400 MHz, flMCO-d6) δ 8.86 (d, J = 8.0 Hz, ZH), 8.68 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.45 - 7.39 (m, 1H) , 6.73-6.63 (m, 2H), 4.87-4.72 (m, 3H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.91 (m, 2H), 3.74 (s, 2H), 3.63 (s, 3H), 3.58-3.51 (m, 1H), 3.50-3.42 (m, 1H), 3.38-3.31 (m, 1H), 3.28-3.21 (m, 1H), 2.03 (s, 3H). 681.2 0.1 403 0—\ F O'<F ^NF 4 /=NP HN p XXX o. H n+ νΛ ^x )—' o /% /=4 ^{z 0 N} \ y 1H NMR (400 MHz, flMCO-d6) δ 9.00 (d, J = 7.8 Hz, 1H), 8.928.86 (m, 2H), 8.73-8.68 (m, 2H), 7 .78 (d, J = 7.5 Hz, 1H), 7.73 - 7.67 (m, 2H), 6.74 - 6.64 (m, 2H), 4.90-4.79 (m , 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.5, 3.5 Hz, 1H), 3.803.65 (m, 5H), 3 .61 (s, 3H), 3.55 (t, J = 13.9, 7.6, 2.5 Hz, 2H), 3.36 (d, J = 11.8 Hz, 1H), 3, 25 (t, 1H), 2.05 (s, 3H). 696.8 N/A

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404 0—\ F F ,4 /=N O HN p nA nA ⁷ y—' o /Y GD ⁿ ' ⁰ A # 1H NMR (400 MHz, DMSO-C16) δ 8.93 - 8.83 (m, ZN), 8.75 - 8.67 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.74 - 7.66 (m, 2H), 6.73 - 6.62 (m, 2H), 4.89-4.75 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.7, 3.5 Hz, 1H), 3.81 3.69 (m, 2H), 3.61 (s, ZN), 3.593 .43 (m, 2H), 3.35 (d, J = 12.2 Hz, 1H), 3.25 (t, 1 Η), 2.03 (d, J = 2.4 Hz, ZN). 682.7 0.1 405 0—\ F θΆ ^Ν F ,4 Ν=\ ρ Η-Ν ρ nA νΑ ^Ζ У—' 0 Η 1H NMR (400 MHz, flMCO-d6) δ 9.32 (s, 1H), 9.26-9.18 (m, 1H), 8.99 (d, J = 7.8 Hz, 1 Η), 8.91 8.84 (m, 1H), 8.67 (d, J = 8.7 Hz, 1H), 7.82-7.73 (m, 1H), 7.727.63 (m, 2H), 6.76-6.64 (m, 2H), 4.88-4.80 (m, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.98-3.91 ( m, 1H), 3.78-3.70 (m, 2H), 3.68 (s, ZN), 3.61 (s, ZN), 3.583.51 (m, 2H), 3.42-3 .32 (m, 1H), 3.30-3.18 (m, 1H), 2.04 (s, ZN). 696.8 N/A 406 OAf 4 Ν=\ Ρ Η—Ν Ρ <\ /l I nA ^ν Α 7—' ⁰ / ^Ν 1 ο 1H NMR (400 MHz, flMCO-d6) δ 9.32 (s, 1H), 9.25-9.18 (m, 1H), 8.91 -8.82 (m, 2H), 8.69 ( d, J = 8.6 Hz, 1H), 7.80-7.73 (m, 1H), 7.73 - 7.64 (m, 2H), 6.75 - 6.60 (m, 2H) , 4.90-4.74 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.81- 3.68 (m, 2H), 3.60 (s, ZN), 3.58 - 3.40 (m, 2H), 3.39-3.31 (m, 1H), 3.31 -3, 18(m, 1Н), 2.02 (s, ЗН). 682.2 0.08 407 OAf 4 ζ=\ ρ Η—Ν ρ O ^{1 7} / L Μ Μ ' θ-n /I /I ⁰ A ? 1H NMR (400 MHz, Chloroformd) δ 8.84 -8.72 (m, 2H), 8.66 (d, J = 8.6 Hz, 1H), 8.55 (s, 1H), 8.00 (s, 1H), 7.58 (s, 2H), 7.44 (dd, J = 8.6, 4.2 Hz, 1 Η), 6.66 (d, J = 6.5 Hz, 1H ), 6.46 (s, 1H), 6.37 (d, J = 13.6 Hz, 1H), 5.08 (d, J = 7.0 Hz, 1 Η), 4.29 (d, J = 12.4 Hz, 1H), 4.11 (dd, J = 8.2, 3.8 Hz, 1H), 4.04 (dd, J = 11.3, 3.5 Hz, 1H), 3.84-3.70 (m, ZN), 3.68 (s, ZN), 3.65-3.56 (m, 1H), 3.50 (t, J = 12.0 Hz, 1H) , 3.26 (d, J = 12.2 Hz, 1H), 2.38 (s, ZN). 681.2 0.162

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408 ίΑ F F .2 /=\ Ο Η—Ν ρ ^N kH ΛΑ .Η >. Ν—/ E' Ο-Η /4 GD ^{0 Ν} \ # 1H NMR (400 MHz, Chloroformcl) δ 8.83-8.72 (m, 2H), 8.64 (d, J = 8.6 Hz, 1H), 8.56 (d, J = 5.0 Hz , 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.59 (q, J = 7.6 Hz, 2H), 7.46 (dd, J = 8.6, 4, 2 Hz, 1 Η), 6.63 (d, J = 6.1 Hz, 1H), 6.47 (s, 1H), 6.38 (dd, J = 13.4, 2.4 Hz, 1 Η), 5.13-5.02 (m, 1H), 4.30 (d, J = 12.4 Hz, 1H), 4.12 (dd, J = 8.0, 3.8 Hz, 1H ), 4.04 (dd, J = 11.2, 3.5 Hz, 1H), 3.86-3.78 (m, 1H), 3.72 (t, J = 5.6 Hz, 2H) , 3.69 (s, ZN), 3.65-3.59 (m, 1H), 3.51 (t, J = 11.7 Hz, 1H), 3.27 (d, J = 12.3 Hz, 1H), 2.39 (s, ZN). 681.2 0.049 409 F to ζ=\ ρ Η—Ν ρ sn Ά; nA ρ—' o—n /4 gd ^{0 Ν} \ / 1H NMR (400 MHz, flMCO-d6) δ 13.21-12.53 (s, 1H), 9.05 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8 .84 (dd, J = 4.2, 1.4 Hz, 1H), 8.718.65 (m, 1H), 8.60 (dd, J = 4.9, 1.8 Hz, 1H), 7, 91 (ddd, J = 5.0, 3.4, 0.7 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.71 -7.65 (t, 2H) , 6.70 (d, J = 13.1 Hz, 1H), 6.64 (s, 1H), 4.83 (d, J = 6.1 Hz, 1H), 4.81 -4.73 ( t, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.2, 3.6 Hz, 1H), 3.81 -3.69 (t , 2H), 3.66 (d, J = 2.6 Hz, ZN), 3.60 3.51 (t, 1H), 3.46 (dd, J = 14.7, 10.6 Hz, 1H ), 3.35 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.2 Hz, 1H), 2.08-2.01 (t, ZN). 681.2 0.401 410 0 \^S ,0 Η—Ν ρ /4 /D ^{0 Ν} \ # 1H NMR (400 MHz, DMSO) δ 8.91-8.82 (t, 2H), 8.68 (d, J = 8.6 Hz, 1H), 7.73 (d, 1H), 7.71 7.63 (t, 2H), 6.72 -6.61 (t, 2H), 4.92-4.71 (t, 2H), 4.14 (d, J = 12.6 Hz, 1H) , 3.94 (d, J = 11.4 Hz, 1H), 3.80-3.68 (t, 2H), 3.61 (s, ZN), 3.59-3.40 (t, 2H ), 3.35 (d, J = 12.7 Hz, 1H), 3.26 (t, 1H), 2.86 (d, J = 1.9 Hz, ZN), 2.01 (d, ZN ). 701.7 0.054

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411 0 )- Ν H /— _H p HN p '—{ N—/ )' OH ^/N A o 1H NMR (400 MHz, DMSO-C16) δ 8.89-8.82 (m, 2H), 8.65 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 3, 8 Hz, 1H), 7.62 (s, 2H), 6.68 (d, J = 13.1 Hz, 1H), 6.64 (s, 1H), 4.84 (d, J = 2, 8 Hz, 1H), 4.78-4.72 (m, 1H), 4.71 -4.61 (m, 2H), 4.16 (s, 1H), 3.93 (s, 1H), 3.82 (s, 2H), 3.73 (d, J = 14.0 Hz, 2H), 3.55 (d, J = 11.7 Hz, 1H), 3.503.38 (m, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.25 (s, 4H), 2.34 (d, J = 8.3 Hz, 2H), 2.03 (s, 3H). 686.2 0.06 412 0 4 O~\ 0 Η—N 0 —У'\i—00—f 0-H Ά O 1H NMR (400 MHz, flMCO-d6) δ 8.88-8.82 (m, 2H), 8.64 (d, J = 9.0 Hz, 1H), 7.68-7.64 (m, 1H), 7.62 (s, 2H), 6.68 (d, J = 13.3 Hz, 1H), 6.64 (s, 1H), 4.88-4.79 (m, 1H), 4.79-4.70 (m, 1H), 4.30 (m, 2H), 4.14 (d, J = 12.9 Hz, 1H), 3.93 (m, 3H), 3.73 (d, J = 14.6 Hz, 2H), 3.55 (d, J = 8.1 Hz, 1H), 3.49-3.38 (m, 2H), 3.34 (s, 3H) , 3.24 (t, J = 13.0 Hz, 1H), 2.87-2.68 (m, 1H), 2.02 (s, 3H). 686.2 0.091 413 0 / F >O _N ,NP HN O 'x' ^N— ° ^-H /Ή w. '° ^N \/ 1H NMR (400 MHz, flMCO-d6) δ 8.86 (t, J = 5.9 Hz, 2H), 8.68 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.67 (td, J = 8.1, 4.9 Hz, ZN), 6.73-6.60 (m, 2H), 4.904.71 (m, 2H) , 4.14 (d, J = 12.6 Hz, 1H), 4.05 (s, 3H), 3.99-3.91 (m, 1H), 3.74 (d, J = 12.8 Hz, 2H), 3.50 (ddd, J = 35.8, 13.4, 9.9 Hz, 2H), 3.37 (d, J = 2.3 Hz, 4H), 3.25 (t , J = 12.5 Hz, 1H), 2.03 (s, 3H). 684.3 0.529 414 F ^NF ,2 /=\ p Η—Ν p N—/ V- OH /4 / \ ⁰ w 1H NMR (400 MHz, flMCO-d6) δ 9.12 (d, J = 8.2 Hz, 1H), 9.05 (d, J = 1.6 Hz, 1H), 8.88 (d, J = 4.0 Hz, 1H), 8.76 (t, J = 7.7 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 7.92 (p, J = 2 .0 Hz, 1H), 7.79 (dd, J = 7.7, 2.5 Hz, 1H), 7.72 (t, J = 5.9 Hz, 2H), 6.91 (t, J = 6.2 Hz, 2H), 4.92 (h, J = 7.9 Hz, 1H), 4.87-4.75 (m, 1H), 4.15 (d, J = 12.7 Hz , 1H), 3.95 (dd, J = 11.7, 3.6 Hz, 1H), 3.86-3.69 (m, 2H), 3.603.34 (m, 3H), 3.25 ( t, J = 12.2 Hz, 1H). 701.1 0.048

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415 o )—N Ά 0 Η—N O /°<N AA m /A sK ' ^{0 Ν} \ # 1H NMR (400 MHz, DMSO-06) δ 8.86 (d, J = 8.0 Hz, 2H), 8.70 (d, J = 8.6 Hz, 1H), 8.34-8.30 (m, 1H), 7.75 (d, 1H), 7.72-7.65 (m, 2H), 7.46-7.42 (m, 1H), 6.73 - 6.62 (m , 2H), 4.90 - 4.73 (m, 2H), 4.14 (d, J = 12.7 Hz, 1H), 4.06 (s, 3H), 3.94 (d, J = 11.2 Hz, 1H), 3.75 (t, 2H), 3.623.41 (m, 5H), 3.35 (d, J = 12.3 Hz, 1H), 3.26 (t, 1H) , 2.03 (s, 3H). 711.3 0.091 416 U. Tu —NF )=0 )=\ 0 Η-Ν ,0 ^N \ / ' ^{0-N /Ν} Λ y 1H NMR (400 MHz, flMCO-d6) δ 8.90-8.82 (m, 2H), 8.68 (d, J = 8.6 Hz, 1H), 8.57 (s, 1H), 7 .73 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.04 (t, J = 2.5 Hz, 1H), 6.72 -6.62 (m, 2H), 4.82 (s, 1H), 4.79 (d, J = 8.9 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H) , 3.94 (d, J = 11.3 Hz, 1H), 3.80-3.67 (m, 2H), 3.60-3.53 (m, 4H), 3.47 (dd, J = 23.9, 11.6 Hz, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.26 (d, J = 12.0 Hz, 1H), 3.09 (s , 6H), 2.02 (s, 3H). 724.2 0.126 417 уу F ,2 /=\ О n—N р \ ^N \ ' ° ^-Н /Ά / \ — ^{0 N} \ / 1H NMR (400 MHz, flMCO-d6) δ 13.12-12.64 (s, 1H), 9.10 (s, 1H), 8.85 (t, J = 6.8 Hz, 2H), 8 .68 (d, J = 8.6 Hz, 1H), 8.58 (d, J = 5.1 Hz, 1H), 7.92 (d, J = 4.6 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.727.63 (m, 2H), 6.69 (d, J = 13.3 Hz, 1H), 6.65 (s, 1H), 4.84 (d, J = 8.6 Hz, 1H), 4.79 (d, J = 11.1 Hz, 2H), 4.27 (d, J = 7.5 Hz, 2H), 4.14 (d , J = 12.7 Hz, 1H), 3.95 (d, J = 11.1 Hz, 1H), 3.79-3.69 (m, 2H), 3.54 (t, J = 12, 5 Hz, 1H), 3.50-3.41 (m, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.25 (t, J = 12.3 Hz, 1H) , 2.03 (s, 3H), 1.30 (t, J = 7.2 Hz, ZN). 695.3 0.117 418 F F . У r\t ^N 4° yt / \ ⁰ w 1H NMR (400 MHz, flMCO-d6) δ 12.94 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.84 (d, J = 4.2 Hz, 1H ), 8.67 (d, J = 8.8 Hz, 1H), 8.07 (s, 2H), 7.93 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H ), 7.68 (d, J = 7.1 Hz, 2H), 7.66 (s, 1H), 6.73-6.63 (m, 2H), 4.90-4.72 (m, 3H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.82-3.70 (m, 2H), 3, 64 (s, 3H), 3.50 (dt, J = 33.6, 12.1 Hz, ZN), 3.35 (d, J = 13.4 764.4 0.104

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Hz, 1H), 3.27 (d, J = 12.8 Hz, 1H), 2.04 (s, ZN). 419 Μ ⁴ Ν'' ъ /=\ O HN р N—/ E—' O-N ⁷ 0 Ν λ 1H NMR (400 MHz, flMC0-d6) δ 9.27 (d, J = 8.1 Hz, 1H), 9.05 (s, 1H), 8.85 (d, J = 3.8 Hz, 1H ), 8.70 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.72-7.63 (m, ZH), 7.53-7.41 (m, 2H), 7.39 (s, 1H) , 5.21 (dd, J = 13.7, 5.4 Hz, 2H), 4.88 (s, 1H), 3.82 (d, J = 15.3 Hz, 1H), 3.66 ( d, J = 2.9 Hz, ZN), 3.48 (dd, J = 14.7, 10.9 Hz, 1H), 2.14 (S, ZN). 676.2 0.369 420 Ok F ^NF . Μ >K\ р n-N р (V kN gК ⁷ 0 Ν _χ b 1H NMR (400 MHz, flMC0-d6) δ 8.85 (t, J = 6.2 Hz, 2H), 8.68 (d, J = 5.8 Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.68 (dd, J = 8.2, 4.8 Hz, ZN), 6.71 -6.61 (m, 2H), 4.884.73 (m, 2H) , 4.14 (d, J = 12.7 Hz, 1 Η), 3.97 - 3.92 (m, 2Η), 3.75 (m, 1H), 3.63 (d, J = 2, 5 Hz, ZN), 3.56 (dd, J = 13.0, 2.7 Hz, 1H), 3.46 (dd, J = 14.6, 10.8 Hz, 1H), 3.35 ( d, J = 12.6 Hz, 1 Η), 3.26 (d, J = 12.4 Hz, 1H), 2.02 (s, ZN). 699.1 0.116 421 Ok FO^ ^f ^NF Μ /=\ ρ Η—Ν ρ ΑΛ_ \ ^Ν \ /—' ° ^-Η ζ ^Ν % γΚ Η 0 N^J> 1H NMR (400 MHz, flMC0-d6) δ 13.31-12.61 (s, 1H), 11.90 (d, J = 3.2 Hz, 1H), 8.87 (d, J = 8, 2 Hz, 2H), 8.72 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 6.69 (d, J = 13.3 Hz , 1H), 6.65 (s, 1H), 4.84 (d, J = 9.4 Hz, 1H), 4.77 (s, 1H), 4.14 (d, J = 12.7 Hz , 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.76 (d, J = 10.6 Hz, 2H), 3.54 (t, J = 12.0 Hz, 1H ), 3.46 (t, J = 12.8 Hz, 1H), 3.35 (d, J = 12.5 Hz, 1H), 3.25 (t, J = 12.2 Hz, 1H), 2.04 (s, ZN). 667.2 0.191 422 OJ ^Ν F y Ε ^F /=° )=ξ 0 Η—Ν 0 ^F A/A Μ_Μ ₀ _ _Η , ^Ν + κ. 1H NMR (400 MHz, flMC0-d6) δ 13.10-12.83, (s, 1H), 9.01 (d, J = 7.8 Hz, 1H), 8.84 (d, J = 4 .2 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.00 (t, J = 9.1 Hz, 1H), 7.80 (dd, J = 12.1 , 6.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 11 ,8 Hz, 2H), 4.92 (d, J = 9.8 Hz, 1 Η), 4.70 (s, 1H), 4.16 (d, J = 12.8 Hz, 1H), 3 .99-3.91 (m, 1H), 3.74 (d, J = 13.7 Hz, 2H), 3.57 (s, 1 Η), 3.55 720.1 0.231

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(s, 3H), 3.44 (d, J = 12.1 Hz, 2H), 3.26 (d, J = 12.7 Hz, 1H). 423 o ✓ ^N ''' ,¾ O n-N O r--// \\-------- \---1/ ^ν— °-н _Ζ Υ Υχ ° ^Ν \ 4 1H NMR (400 MHz, DMSO-06) δ 9.01 (d, J = 7.8 Hz, 1H), 8.878.82 (m, 1H), 8.67 (d, J = 8.6 Hz, 1H ), 8.14-8.06 (m, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.70-7.62 (m, 2H), 7.53-7, 46 (m, 1H), 7.21 (t, J = 8.4 Hz, 1 Η), 6.78 (d, J = 11.8 Hz, 2H), 4.96-4.86 (m, 1H), 4.76-4.65 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 4.00-3.90 (m, 1H), 3.78-3 .70 (m, 2H), 3.62-3.39 (m, 6H), 3.24 (t, J = 12.3 Hz, 1H). 702.2 0.08 424 ρ ''' .¾ >=\ Ο Η—Ν ρ ^ν Ω% Ύ \ ^Ν \ ' ° ^-Η /Н /Υ ° ^Ν \ # 1H NMR (400 MHz, DMSO-06) δ 9.02 (d, J = 7.8 Hz, 1H), 8.90 (s, 1 Η), 8.84 (d, J = 4.2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.807.72 (m, 2H), 7.67 (t, J = 6.7 Hz, 2H), 6.78 (d, J = 11.8 Hz, 2H), 4.92 (dd, J = 10.0, 3.4 Hz, 1H), 4.71 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 4.01 -3.90 (m, 1H), 3.74 (d, J = 13.3 Hz, 2H), 3.63 (s, ZN), 3.50 (dt, J = 42.0, 12.4 Hz, ZN), 3.24 (t, J = 12.3 Hz, 1 Η), 2.60 (s, ZN). 700.1 0.15 425 .Hu. . I >=\ ρ Η—Ν ρ VjY ΑΛ_ /Ή /Υ ° ^Ν \ # 1H NMR (400 MHz, DMSO-06) δ 8.93-8.81 (m, ZN), 8.68 (d, J = 8.6 Hz, 1H), 7.81 -7.71 (m, 2H), 7.67 (dd, J = 8.4, 4.2 Hz, 2H), 6.73-6.61 (m, 2H), 4.91-4.71 (m, 2H), 4 .14 (d, J = 12.6 Hz, 1H), 3.99-3.89 (m, 1H), 3.803.68 (m, 2H), 3.63 (t, J = 1.8 Hz, ZN), 3.50 (ddd, J = 33.4, 13.8, 10.0 Hz, 2H), 3.35 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.5 Hz, 1 Η), 2.60 (s, ZN), 2.02 (s, ZN). 695.2 0.185 426 F Ρ^Ύ F ζ=\ ρ Η—Ν ρ ^ν Ο^ _αα_ ύ Ν—/ X—' Ο-Η _Ζ ^Ν Υ /χ^ ^{0 Ν} \ # F 1H NMR (400 MHz, DMSO-06) δ 9.04 (s, 1H), 8.90 (t, J = 1.8 Hz, 1H), 8.85 (d, J = 8.1 Hz, 1H ), 8.60 (d, J = 5.0 Hz, 1H), 8.51 - 8.44 (m, 1H), 7.91 (t, J = 3.9 Hz, 1H), 7.75 (d, J = 2.5 Hz, 2H), 6.82-6.68 (t, ZH), 6.65 (d, J = 7.6 Hz, 2H), 4.97-4.73 ( t, 4H), 4.15 (dd, J = 12.7, 7.7 Hz, 2H), 4.03 - 3.87 (t, ZN), 3.84 - 3.68 (t, 1H) , 3.65 (s, ZN), 3.59-3.40 (t, 2N), 3.40-3.16 (t, ZN), 2.01 (s, ZN). 699.2 0.096

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427 0 / ^N ''A ^H V UD'Ν——·ί ₀ _ _n ζ ^Ν % / \ ⁰ F 1H NMR (400 MHz, DMSO-C16) δ 9.10 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.88-8.83 (m, 2H), 8 .49 (d, J = 10.3 Hz, 1H), 7.75 (d, J = 1.7 Hz, 2H), 7.60 (d, J = 6.0 Hz, 1H), 6.73 -6.60 (m, 2H), 4.81 (d, J = 11.0 Hz, 2H), 4.14 (d, J = 12.5 Hz, 1H), 3.94 (d, J = 11.8 Hz, 1H), 3.72 (s, 1H), 3.68 (d, J = 4.5 Hz, 1H), 3.60-3.42 (m, 5H), 3.35 ( d, J = 12.4 Hz, 1H), 3.25 (t, J = 12.1 Hz, 1H), 2.02 (d, J = 7.4 Hz, ZN). 699.2 0.355 428 0 F )=0 Hx Ρ Η-Ν 0 Ή Ν—у у—' O-n /Ή /\ / 0 Ν J 1H NMR (400 MHz, flMCO-d6) δ 9.01 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 4.2, 1.4 Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.61 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.71 -7.64 (m, 2H) , 7.29 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 11.7 Hz, 2H), 4.974.86 (m, 1 Η), 4.76-4.67 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.99-3.91 (m, 4H), 3.75 (dd, J = 14.4, 4.4 Hz, 2H), 3.60 (s, ZN), 3.58-3.39 (m, ZN), 3.25 (t, J = 11.2 Hz, 1H). 715.3 0.18 429 0 , ^Fpp ^ Ηχ Ρ Η-Ν ρ Ή ID y—' Ο-Η /1 & 1H NMR (400 MHz, flMCO-d6) δ 8.88-8.84 (m, 2H), 8.70 (d, J = 8.6 Hz, 1H), 8.62 (s, 1H), 7 .76 (d, J = 7.5 Hz, 1H), 7.71 -7.66 (m, 2H), 7.29 (d, J = 3.4 Hz, 1H), 6.72 - 6, 63 (m, 2H), 4.89 - 4.73 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.90 (m, 4H), 3 .81 3.69 (m, 2H), 3.60 (d, J = 2.5 Hz, ZN), 3.58-3.41 (m, 2H), 3.35 (d, J = 10, 6 Hz, 1 Η), 3.26 (d, J = 12.3 Hz, 1H), 2.03 (s, ZN). 711.4 0.162 430 0 / ^Ν % \=( Ν—/ у—'' Ο-Η ζ ^Ν Η /=( ^{0 Ν} \ / F 1H NMR (400 MHz, flMCO-d6) δ 9.09 (s, 1H), 9.01 (d, J = 7.9 Hz, 1H), 8.91 (d, J = 2.5 Hz, 1H ), 8.85 (d, J = 6.0 Hz, 1H), 8.548.41 (m, 1H), 7.74 (q, J = 7.8 Hz, 2H), 7.59 (d, J = 6.1 Hz, 1H), 6.77 (d, J = 11.8 Hz, 2H), 4.984.85 (m, 1H), 4.73 (tt, J = 9.3, 4.3 Hz , 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.7, 3.7 Hz, 1H), 3.76 (s, 2H), 3 .66 (m, 1H), 3.57 (s, ZN), 3.43 (d, J = 14.8 Hz, 2H), 3.30-3.17 (m, 1H). 703.8 0.469

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431 PT I P Η—N O ^x =\ N—C U—' 0-N /A /=( ⁷ 0 Ν _χ ft 1H NMR (400 MHz, DMSORB) δ 8.87 (d, J = 8.1 Hz, 1H), 8.868.83 (m, 1H), 8.70-8.65 (m, 1H), 8.14 -8.07 (m, 1H), 7.757.72 (m, 1H), 7.70-7.64 (m, 2H), 7.53-7.46 (m, 1H), 7.257.17 ( m, 1H), 6.72 - 6.63 (m, 2H), 4.89-4.80 (m, 1H), 4.804.72 (m, 1H), 4.14 (d, J = 12, 6 Hz, 1H), 3.97-3.91 (m, 1H), 3.80-3.69 (m, 2H), 3.61-3.53 (m, ZN), 3.53-3 .42 (m, 1H), 3.35 (d, J = 12.6 Hz, 1 Η), 3.26 (d, J = 15.6 Hz, 2H), 2.03 (s, ZN). 698.2 0.094 432 o y—N /G^X P n-N p ^N \ ^N \ ' O—N /L /=( ⁷ O Ν _χ L 1H NMR (400 MHz, DMSORB) δ 8.86 (d, J = 8.0 Hz, ZH), 8.68 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 9 .3 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.45 - 7.39 (m, 1H), 6 .73-6.63 (m, 2H), 4.87-4.72 (m, ZN), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.91 (m , 2Н), 3.74 (s, 2Н), 3.63 (s, ЗН), 3.58-3.51 (m, 1Н), 3.50-3.42 (t, 1Н), 3, 38-3.31 (t, 1H), 3.28-3.21 (t, 1H), 2.03 (s, ZN). 681.2 0.11 433 0^. F F γ /Г^Х ρ F. n-N O -Сн >a_m ^x =\ n—e У—' ο-н /¼ /=( ⁷ 0 Ν _χ ft 1H NMR (400 MHz, DMSO-bb) δ 9.07 (s, 1H), 8.88 (dd, J = 8.2, 3.2 Hz, 2H), 8.69 (dd, J = 8, 7, 1.5 Hz, 1H), 8.63 (dd, J = 5.0, 1.4 Hz, 1H), 7.94 (t, J = 4.4 Hz, 1H), 7.69 ( td, J = 9.8, 9.3, 3.4 Hz, 2H), 6.79 -6.60 (t, 2H), 4.81 (dtd, J = 12.0, 7.6, 3 .7 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H), 3.83 (dd, J = 14.7, 3.9 Hz, 1H), 3.77-3.64 (t, 4H), 3.64-3.41 (t, 2H), 3.35 (d, J = 12.3 Hz, 1H), 3.31 3.18 (t, 1H), 2.04 (d, J = 7.5 Hz, ZN). 699.2 0.076 434 0 F. y—N p N=\ Ο Η—N 0 0ChlL.„ Η ⁷ 0 Ν _χ ft 1H NMR (400 MHz, DMSO-bb) δ 9.10 (d, J = 3.6 Hz, 1H), 8.958.76 (t, 3H), 8.68 (d, J = 8.7 Hz, 1H ), 7.76 (d, J = 7.5 Hz, 1H), 7.74 - 7.56 (t, ZN), 6.74 - 6.56 (t, 2H), 4.90-4, 72 (t, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.75 (t, J = 13.4 Hz, 2H), 3.57 (d, J = 2.4 Hz, ZH), 3.55-3.48 (t, 1H), 3.47 (s, 1H), 3.35 (d, J = 12.6 Hz, 1H), 3.25 (t, J = 12.4 Hz, 1H), 2.03 (s, ZN). 681.2 0.103

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435 f ^F У-F N=/ „I У-F Η—Ν O УуСУУ mУ /У ⁷ ° ^N \ У 1H NMR (400 MHz, DMSO-06) δ 9.23 (t, J = 9.0 Hz, 1H), 8.82 (dt, J = 4.0, 1.9 Hz, 1H), 8.64 (d, J = 8.7 Hz, 1H), 7.69-7.55 (m, ZN), 7.42 (ddd, J = 24.4, 15.8, 6.8 Hz, 4H), 6.55 (d, J = 2.9 Hz, 1H), 5.24 -5.16 (m, 2H), 4.90-4.80 (m, 1H), 3.86-3.70 ( m, 1H), 3.49 (s, 2H), 3.51 -3.32 (m, 2H), 2.53 (s, 4H), 2.18 (t, J = 7.3 Hz, 2H ), 2.10 (d, J = 3.5 Hz, ZN), 1.52-1.43 (t, ZN), 0.85 (t, J = 6.6 Hz, 4H). 690.2 0.524 436 n—NF ^F F )=0 /=\ O Η—N O /y. УС /у ⁰ \у 1H NMR (400 MHz, DMSORB) δ 9.05 (d, J = 2.1 Hz, 1H), 8.938.80 (t, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.92 (dt, J = 5.3, 3.3 Hz, 1H ), 7.76 (dd, J = 7.7, 2.2 Hz, 1H), 7.73-7.61 (t, 2H), 6.39 (d, J = 7.7 Hz, 2H) , 6.30 (d, J = 9.2 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.18 (s, 2H), 3.75 (d, J = 16.7 Hz, 1H), 3.66 (d, J = 2.6 Hz, ZN), 3.44 (dd, J = 14.6, 10.8 Hz, 1H), 1.98 (s, ZN), 1.85-1.68 (t, 1H), 1.53 (dt, J = 15.8, 8.1 Hz, 1H), 1.01 -0.87 (t, ZN). 653.3 0.076 437 r y \ ^F /=O Ν—\ Η-N o Olu-Un ν y )U ^{7 0 N} \ y 1H NMR (400 MHz, flMCO-d6) δ 10.19 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H), 8.86 (dd, J = 4.2, 1, 5 Hz, 1H), 8.68 (dd, J = 8.8, 1.7 Hz, 1H), 7.69-7.56 (t, ZH), 7.35 (s, 1H), 6, 76 (d, J = 11.7 Hz, 2H), 4.98-4.85 (t, 1H), 4.73-4.63 (t, 1H), 4.31 (d, J = 14, 7 Hz, 1H), 4.21 -4.06 (t, 2H), 3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.81 3.66 (t, ZN) , 3.61 -3.47 (t, 4H), 3.47-3.36 (t, ZN), 3.31 3.06 (t, ZN), 2.97 (s, ZN). 686.3 0.261 438 r u ^N \ ^F )=O /U Η—Ν o 0>0-U-k mu /U ⁷ ° ^Ν \ y 1H NMR (400 MHz, flMCO-d6) δ 9.11 (s, 2H), 8.97 (d, J = 8.0 Hz, 1H), 8.88-8.82 (t, 1H), 8 .67 (d, J = 8.7 Hz, 1H), 7.69-7.55 (t, ZN), 7.37 (s, 1H), 6.76 (d, J = 12.0 Hz, 2H), 4.96-4.86 (t, 1H), 4.73-4.63 (t, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.09 (s , 2H), 3.96 (d, J = 11.6 Hz, 1H), 3.73 (t, J = 12.0 Hz, 2H), 3.61 -3.52 (t, 1H), 3 .51 -3.46 (t, 4H), 3.463.37 (t, 2H), 3.25 (t, J = 12.6 Hz, 1H), 3.10-3.02 (t, 2H). 672.3 0.291

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439 ( F >Ά Η—NF Y. ,0 Η—N O (V l I ^χ =( ν—е ρ—' ο-н , ^Ν Υ / \ 1H NMR (400 MHz, DMSO-06) δ 9.05 (d, J = 2.1 Hz, 1H), 8.938.80 (m, 1H), 8.75 (d, J = 8.1 Hz, 1H ), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.92 (dt, J = 5.3, 3.3 Hz , 1H), 7.76 (dd, J = 7.7, 2.2 Hz, 1H), 7.73-7.61 (m, 2H), 6.39 (d, J = 7.7 Hz, 2H), 6.30 (d, J = 9.2 Hz, 1 Η), 4.74 (d, J = 10.0 Hz, 1H), 4.18 (s, 2H), 3.75 (d , J = 16.7 Hz, 1 Η), 3.66 (d, J = 2.6 Hz, ZN), 3.44 (dd, J = 14.6, 10.8 Hz, 1H), 1, 98 (s, ZN), 1.85-1.68 (m, 1H), 1.53 (dt, J = 15.8, 8.1 Hz, 1H), 1.01 -0.87 (m, ZN). 653.3 0.049 440 F ΟΑ F ή / Η-Ν ,0 ^АуНо-н ΝΥ /\ ⁷ Ο Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 13.18-12.55 (s, 1H), 8.94 (s, 1H), 8.87 (s, 1H), 8.72 (s, 1H) , 7.64 (dd, J = 18.1, 9.8 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1 Η), 6.74 (d, J = 12.2 Hz , 2H), 4.90 (d, J = 9.7 Hz, 1H), 4.72 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (d , J = 11.5 Hz, 1H), 3.81 (s, 1H), 3.71 (t, J = 14.1 Hz, 2H), 3.55 (t, J = 11.9 Hz, 1H ), 3.48 (s, ZN), 3.45-3.33 (m, 1H), 3.25 (d, J = 12.7 Hz, 1H), 2.62 (d, J = 2, 6 Hz, ZN), 1.86 (d, J = 10.0 Hz, ZN). 646.3 0.25 441 G y FFF )=Ο У-F Η—Ν ρ -ΑΡνΉ>-Η ^Ν γ /\ ⁷ Ο Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 8.84 (d, J = 4.2 Hz, 1H), 8.76 (dd, J = 7.8, 2.7 Hz, 1H), 8.69 (d, J = 7.9 Hz, 1H), 7.66 (dd, J = 8.6, 4.3 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7 .46 (d, J = 7.3 Hz, 1H), 6.56 (s, 1H), 6.42 (dd, J = 11.9, 4.3 Hz, 2H), 4.69 (tt, J = 9.9, 5.6 Hz, 1H), 3.77-3.62 (m, ZN), 3.56 (dt, J = 11.9, 5.6 Hz, 6H), 3.49 (s, 4H), 2.54 (s, ZH), 1.84 (p, J = 5.9 Hz, 2H). 645.2 0.412 442 ο /—Ν A / Η—Ν 0 Α%>-Α _Η ΝΥ /\ ⁷ Ο Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 8.90-8.82 (m, 1H), 8.73-8.63 (m, 2H), 7.73-7.58 (m, 2H), 7.58-7.50 (m, 1H), 6.41-6.32 (m, 2H), 6.28 (d, J = 9.2 Hz, 1H), 4.80-4.68 ( m, 1H), 4.25-4.11 (m, 1H), 3.87-3.72 (m, 1H), 3.51 -3.44 (m, ZN), 3.38-3, 27 (m, 1H), 2.60 (s, ZN), 1.92 (s, ZN), 1.89-1.79 (m, ZN), 1.81 1.67 (m, 1H), 1.60-1.46 (m, 1H), 0.92 (t, J = 7.3 Hz, ZN). 614.3 0.227

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443 I 1H NMR (400 MHz, DMSO-06) δ 9.44 (t, J = 8.3 Hz, 1H), 9.369.27 (m, 1 Η), 8.81 (d, J = 8.4 Hz, 1H), 8.18-8.11 (m, 1H), 7.96 (d, J = 7.3 Hz, 1 Η), 6.63 (t, J = 5.8 Hz, 2H), 4 .86-4.76 (m, ZN), 4.14 (d, J = 12.7 Hz, 1H), 3.953.86 (m, ZN), 3.72 (m, 1H), 3.53 ( d, J = 11.5 Hz, 2H), 3.32 (d, J = 12.1 Hz, 1H), 3.24 (d, J = 9.8 Hz, 1 Η), 2.69 (s , 6H), 2.36 (s, 3N), 2.01 (s, 3N). 626.2 0.714 444 o Pn 'X Η—Ν O gr p< ⁷ 0 Ν _χ ft 1H NMR (400 MHz, flMCO-d6) δ 8.93 (s, 1H), 8.91 -8.78 (m, 2H), 7.77 (s, 1H), 7.72-7.62 ( m, 2H), 7.40 (d, J = 7.0 Hz, 1H), 6.726.61 (m, 2H), 6.31 (d, J = 7.1 Hz, 1H), 4.89- 4.70 (m, 1H), 4.14 (d, J = 12.6 Hz, 1 Η), 3.94 (dd, J = 11.2, 3.6 Hz, 1H), 3.81 - 3.69 (m, 2H), 3.50 (s, 4H), 3.47-3.18 (m, ZN), 2.46 (s, ZN), 2.00 (s, ZN). 627.1 0.161 445 Ε FF pO p ^f P' ⁿ m° °-н ⁿ a / \ ⁷ o nV 1H NMR (400 MHz, flMCO-d6) δ 8.93-8.77 (m, 2H), 8.65 (s, 1H), 7.74-7.52 (m, 2H), 7.43 ( dd, J = 7.4, 3.3 Hz, 1H), 6.69-6.48 (m, ZN), 4.75-4.59 (m, 1H), 3.77-3.56 ( m, ZN), 3.55-3.33 (m, 4H), 3.19 (d, J = 7.1 Hz, 2H), 3.17-3.03 (m, 2H), 2.53 (s, ZN), 1.66 (dq, J = 14.8, 7.4 Hz, 1H), 1.40 (dq, J = 14.6, 7.4 Hz, 1H), 1.09 ( s, ZN), 0.83 (t, J = 7.5 Hz, ZN). 673.2 0.984 446 FF ,, / US n-N r urrU ^N y /=( ⁷ 0 1H NMR (400 MHz, flMCO-d6) δ 12.92 (s, 1H), 8.80 (t, J = 5.3 Hz, 1H), 8.68 (d, J = 8.3 Hz, 1H ), 8.61 (d, J = 8.4 Hz, 1H), 7.677.54 (m, 2H), 7.42 (dd, J = 11.0, 7.2 Hz, 1H), 6.59 (d, J = 11.2 Hz, 2H), 6.54 (d, J = 5.6 Hz, 1H), 4.90 (s, 1H), 4.84-4.63 (m, 2H) , 4.12 (d, J = 13.4 Hz, 1H), 3.92 (d, J = 11.3 Hz, 2H), 3.80 (d, J = 15.7 Hz, 1H), 3 .71 (d, J = 15.7 Hz, 1H), 3.70 (m, 1H), 3.49 (d, J = 3.6 Hz, ZN), 3.31 (d, J = 11, 7 Hz, 1H), 3.26 (s, ZH), 1.93 (d, J = 6.7 Hz, 6H). 691.2 0.318

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447 A' tb F> ^F >° ><,_ Η—N 0 nA )=< ⁷ 0 Ν _χ λ 1H NMR (400 MHz, DMSO-C16) δ 8.94 (d, J = 7.8 Hz, 1H), 8.848.77 (m, 1H), 8.68-8.59 (m, 1H), 7 .66-7.53 (m, 2H), 7.43 (dd, J = 7.4, 4.0 Hz, 1H), 6.76 (dd, J = 11.5, 4.1 Hz, 2H ), 6.54 (s, 1H), 4.75-4.65 (m, 1H), 4.38 -4.24 (m, 1H), 4.09-4.01 (m, 1H), 3.92-3.85 (m, 1H), 3.783.62 (m, 3H), 3.53-3.37 (m, 4H), 2.92 - 2.77 (m, 2H), 2. 53 (s, 3H). 699.2 0.271 448 FO^ ^f =NF VA F> HN p Ywy» Ύ /Y ⁷ on) 1H NMR (400 MHz, flMCO-d6) δ 13.07-12.69 (s, 1H), 8.87 (d, J = 4.1 Hz, 1H), 8.81 (d, J = 8, 2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.677.63 (m, 1H), 7.60 (m, 2H), 6.66 (d, J = 16.6 Hz, 2H), 4.83 (d, J = 9.5 Hz, 1H), 4.76 (d, J = 11.4 Hz , 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 11.5 Hz, 1H), 3.73 (d, J = 13.3 Hz, 2H ), 3.60 (s, 3H), 3.54 (dd, J = 13.7, 10.4 Hz, 1H), 3.44-3.38 (m, 1H), 3.35 (d, J = 16.3 Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 2.60 (s, 3H), 2.00 (s, 3H). 695.1 0.307 449 0 Ύ Cl Η—N p l5lu-> ₀ -n N>)=< ⁷ on) 1H NMR (400 MHz, flMCO-d6) δ 8.88 (d, J = 3.5 Hz, 1H), 8.83 (t, J = 7.6 Hz, 1H), 8.75 (d, J = 8.6 Hz, 1H), 7.74-7.68 (m, 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.55 (dd, J = 7.3, 4.5 Hz, 1H), 6.70-6.61 (m, 2H), 6.49 (d, J = 4.1 Hz, 1H), 4.79 (dtd, J = 19.1, 11 ,2, 9.8, 5.4 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H) , 3.81 -3.69 (m, 4H), 3.45 (d, J = 3.3 Hz, ZN), 3.40-3.32 (m, 1H), 3.24 (t, J = 12.5 Hz, 1H), 2.46 (s, 3H), 1.98 (d, J = 6.2 Hz, ZN). 661.1 0.092 450 0 )—N / F >0 —N Η—N p Duuu> ^o - ⁿ N>)=< ⁷ on) 1H NMR (400 MHz, flMCO-d6) δ 8.95 (d, J = 4.5 Hz, 1 Η), 8.89 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 8.1 Hz, 1H), 7.82-7.72 (m, 2H), 7.68 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 13.0 Hz, 2H), 4.82 (dt, J = 10.8, 5.4 Hz, 1H), 4.79-4.70 (m, 1H), 4.15 (d, J = 12.6 Hz , 1H), 3.98-3.92 (m, 2H), 3.75 (s, 1H), 3.53 (s, 4H), 3.44 (dd, J = 14.6, 10.2 Hz, 1H), 3.34 (d, J = 12.1 Hz, 1H), 3.29-3.20 (m, 670.3 1.02

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1Η), 2.66 (s, 6Η), 2.53 (s, 4Η), 2.03 (s, 3Η). 451 o X Cl / Η—N 0 Huu-Ύ-η ^N X / \ ^Z 0 Ν _χ / 1H NMR (400 MHz, DMSO-06) δ 8.90 (t, J = 4.3 Hz, 1H), 8.878.78 (m, 2H), 8.12 (d, J = 1.9 Hz, 1H ), 7.81-7.65 (m, 2H), 7.57 (t, J = 7.8 Hz, 1 Η), 6.70-6.60 (m, 2H), 4.88-4 .73 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.6, 3.7 Hz, 1H), 3.84 (dd, J = 14.4, 3.9 Hz, 1H), 3.76-3.66 (m, 2H), 3.58-3.48 (m, 1H), 3.45 (d, J = 2, 8 Hz, ZN), 3.41 3.29 (m, 1H), 3.29-3.18 (m, 1H), 1.98 (d, J = 3.5 Hz, ZN), 1.82 (d, J = 12.7 Hz, ZN). 661.1 0.208 452 X Ύ \ Η-Ν Ο —( ^ζ ρ—e 2—' o—n ^Ν y / \ ^f ° ^Ν \ / F 1H NMR (400 MHz, flMCO-d6) δ 8.86 (d, J = 2.7 Hz, 1H), 8.81 (d, J = 8.1 Hz, 1 Η), 8.40 (dd, J = 10.7, 2.8 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 6.67 ( d, J = 14.5 Hz, 2H), 4.874.79 (m, 1H), 4.73 (ddd, J = 10.1.8,1.4.4 Hz, 1H), 4.14 (d , J = 12.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H), 3.73 (dt, J = 12.0, 2.9 Hz, 1H) , 3.65 (dd, J = 14.6, 4.4 Hz, 1H), 3.55 (dd, J = 12.0, 3.5 Hz, 1H), 3.51 (s, ZN), 3.42 (dd, J = 14.6, 10.0 Hz, 1H), 3.35 (d, J = 12.2 Hz, 1 Η), 3.25 (t, J = 12.2 Hz, 1H), 2.40 (s, ZN), 2.31 (s, ZN), 2.06 (d, J = 8.9 Hz, ZN). 660.2 0.232 453 Ύ \ Η—Ν ρ —( ^ζ 2—\ τ—' ^0-Η νΥ ζχ ⁷ ΟΝ/ 1H NMR (400 MHz, flMCO-d6) δ 8.88 (d, J = 4.2 Hz, 1 Η), 8.828.70 (m, 2H), 7.77-7.66 (m, 2H), 7.64 (d, J = 7.3 Hz, 1H), 6.69 - 6.60 (m, 2H), 4.90 - 4.77 (m, 1H), 4.77-4.66 ( m, 1H), 3.74 (dd, J = 14.3, 4.3 Hz, 1H), 3.59-3.48 (m, 4H), 3.44 (dd, J = 14.5, 10.2 Hz, 1H), 3.03 (t, J = 12.0 Hz, 1H), 2.42 (s, ZN), 2.33 (s, ZN), 2.05 (s, ZN) , 1.99-1.89 (m, 1H), 1.86-1.67 (m, 2H), 1.67-1.41 (m, ZN). 640.2 0.677

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454 0 ^F F f ^ci \ HN О —{ )—ep—' ο-н nA )=< / ο Ν _χ ) 1H NMR (400 MHz, DMSO-06) δ 9.09 (d, J = 8.1 Hz, 1H), 8.928.83 (m, 1H), 8.78-8.67 (m, 1H), 7 .77-7.58 (m, 3H), 6.956.85 (m, 2H), 4.98-4.86 (m, 1H), 4.80-4.69 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.99-3.91 (m, 1H), 3.77-3.69 (m, 2H), 3.52 (s, 3H), 3, 42-3.35 (m, 2H), 3.30-3.15 (m, 2H), 2.41 (s, 3H), 2.33 (s, 3H). 663.2 0.14 455 0 A \ Η—Ν p -ЪхА'А- ^н NA /А / 0 Ν _χ λ 1H NMR (400 MHz, flMCO-d6) δ 8.93 (dd, J = 17.1,6.7 Hz, 2H), 8.81 (d, J = 8.2 Hz, 1H), 7.957.54 (m, 3H), 7.38 (s, 1H), 6.66 (d, J = 13.4 Hz, 2H), 4.86-4.73 (m, 2H), 4.14 (d, J = 12.7 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.78-3.67 (m, 2H), 3.57 (d, J = 3.2 Hz, ZN), 3.51-3.16 (m, 4H), 2.40 (s, ZN), 2.15 (s, ZN), 2.01 (s, ZN). 641.2 0.211 456 O F ^X^F F / ⁰ y Η—N 0 y ν /=4 m: ^0-H n A AA / 0 Ν _χ 1H NMR (400 MHz, flMCO-d6) δ 8.98 (d, J = 8.0 Hz, 1H), 8.91 (s, 1H), 8.78 (s, 1H), 7.75 (d , J = 18.6 Hz, 2H), 7.63 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 12.3, 6.4 Hz, 1H), 6.71 (d, J = 9.3 Hz, 1H), 4.68 (dd, J = 9.0, 4.8 Hz, 1H), 4.38-4.36 (m, 1H), 3.75 ( dd, J = 14.5, 4.5 Hz, 1H), 3.53 (s, ZN), 3.44 (dd, J = 14.5, 9.9 Hz, 1H), 2.42 (s , ZN), 2.34 (s, ZN), 1.831.70 (m, 2H), 0.92 (t, J = 7.3 Hz, ZN). 636.2 0.248 457 Pa ^f NF F. FF )=0 fA / Η—N 0 —'' o—n nA )=A ⁷ 0 N 1H NMR (400 MHz, flMCO-d6) δ 13.07-12.67 (s, 1H), 8.85 (s, 1H), 8.81 (dd, J = 8.3, 5.2 Hz, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 7.757.59 (s, 2H), 7.56-7.47 (s, 1H), 6.71 -6.57 (m, 2H), 4.83 (s, 1H), 4.80 (s, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 10, 2 Hz, 1H), 3.82 (d, J = 14.7 Hz, 1 Η), 3.70 (t, J = 14.2 Hz, 1H), 3.56 (s, 1H), 3, 51 (d, J = 2.7 Hz, ZN), 3.33 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 13.0 Hz, 1H), 1.97 ( s, ZN), 1.83 (d, J = 12.7 Hz, ZN). 695.2 0.238

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458 Ν F ν R 0<>U- ^I o-n ^Ν f /\ / 0 Ν0 1H NMR (400 MHz, DMSO-06) δ 13.24-12.52 (s, 1H), 8.88-8.77 (m, 2H), 8.67-8.59 (m, 1H), 7.62 (ddd, J = 17.7, 8.6, 5.0 Hz, 2H), 7.49 (t, J = 6.9 Hz, 1H), 6.72 -6.59 (m, 2H), 4.83 (d, J = 12.2 Hz, 1H), 4.80-4.70 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3, 94 (dd, J = 11.9, 3.6 Hz, 1H), 3.73 (q, J = 12.6, 11.1 Hz, 2H), 3.53 (d, J = 4.4 Hz , 1H), 3.51 (d, J = 3.3 Hz, ZN), 3.49-3.38 (m, 1H), 3.34 (d, J = 12.1 Hz, 1H), 3 .26 (d, J = 12.5 Hz, 1H), 2.66 (s, 3H), 1.96 (s, 3H). 696.2 0.09 459 У >- Ν FFF )=O %F HN p hЧ-О-А-н Ν Λ )=< ^Z ° ^N \ # 1H NMR (400 MHz, flMCO-d6) δ 8.90 (d, J = 7.9 Hz, 1H), 8.84 (s, 1H), 8.69 (s, 1H), 7.73-7 .55 (m, 2H), 7.46 (s, 1H), 6.73 (dd, J = 11.5, 4.1 Hz, 2H), 6.56 (s, 1H), 4.70 ( d, J = 11.3 Hz, 1H), 4.45 (d, J = 6.8 Hz, 2H), 4.41 (d, J = 6.3 Hz, 2H), 3.82-3, 61 (m, 3H), 3.57-3.34 (m, 6H), 3.15 (t, J = 5.0 Hz, 2H), 2.54 (s, 3H). 673.2 2,066 460 0^. F уУУ ^р =NF b / Η—Ν p 0<py_H _o _ _H ^N Ж /\ ^{z 0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 13.31-12.56 (s, 1H), 8.88 (s, 1H), 8.81 (dd, J = 8.3, 6.2 Hz, 1H), 8.75 (s, 1H), 7.67 (dd, J = 17.8, 10.3 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 6, 67 (s, 1H), 6.66-6.59 (m, 2H), 4.88-4.73 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3 .98-3.90 (m, 1H), 3.81 (d, J = 12.8 Hz, 1H), 3.72 (d, J = 13.4 Hz, 2H), 3.53 (dd, J = 12,1,8,6 Hz, 1H), 3.49 (d, J = 3.3 Hz, ZN), 3.34 (d, J = 14.5 Hz, 1H), 3.24 ( t, J = 12.4 Hz, 1H), 2.63 (s, 3H), 1.96 (d, J = 8.2 Hz, ZN), 1.92 (s, ZN). 642.2 0.15 461 P 'R FF ^F 00 0F Η—N p , ^N < M °w 1H NMR (400 MHz, flMCO-d6) δ 8.93-8.75 (m, 2H), 8.61 (d, J = 8.7 Hz, 1H), 7.68-7.56 (m, 2H), 7.42 (t, J = 7.2 Hz, 1H), 6.726.61 (m, 2H), 6.54 (d, J = 3.1 Hz, 1H), 4.86-4, 68 (m, 2H), 4.14 (d, J = 12.5 Hz, 1 Η), 3.94 (d, J = 11.1 Hz, 1H), 3.65 (m, ZN), 3 .49 (d, J = 3.3 Hz, 4H), 3.30 (dd, J = 33.7, 11.9 Hz, ZN), 2.53 (s, ZN), 1.98 (d, J = 3.0 Hz, ZN). 695.2 0.093

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462 0 FFF )=0 У-F Η—Ν О nA )=< ^z о ) 1H NMR (400 MHz, DMSO-06) δ 8.88-8.77 (m, 2H), 8.66 (d, J = 8.7 Hz, 1H), 7.70-7.56 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 6.71 6.60 (m, 2H), 6.55 (d, J = 3.3 Hz, 1H), 4.89 -4.69 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.89 (m, 1H), 3.81-3.73 (m, 2H ), 3.55-3.42 (m, 4H), 3.41-3.30 (m, 1H), 3.30-3.17 (m, 1H), 2.53 (s, 3H). 698.1 0.102 463 ^FF F. ^FF /=° У-F Η—Ν p ху-SU-А-н ⁿ v /\ ⁷ 0 Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 8.95 (dd, J = 8.0, 2.7 Hz, 1H), 8.84 (dd, J = 4.3, 1.5 Hz, 1H) , 8.74-8.65 (m, 1H), 7.70-7.64 (m, 1H), 7.62 (dd, J = 7.5, 1.7 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 6.62 (ddd, J = 12.8, 4.2, 2.2 Hz, 1H), 6.57-6.53 (m, 1H), 6.18 (dd, J = 13.7, 2.2 Hz, 1H), 4.934.71 (m, 2H), 4.13 (d, J = 12.6 Hz, 1H), 3.93 (dd , J = 11.5, 3.6 Hz, 1H), 3.77-3.66 (m, 2H), 3.58-3.39 (m, 5H), 3.35-3.17 (m , 3H), 2.54 (s, 3H), 1.87-1.68 (m, 1H), 0.71 (dd, J = 8.2, 3.5 Hz, 2H), 0.65- 0.51 (m, 1H). 721.2 0.205 464 0 ⁴ a N=\ F. Η—Ν P Olb-N-. nA /\ ^{z 0 N} \ / 1H NMR (400 MHz, flMCO-d6) 6 9.16 (d, J = 8.4 Hz, 1H), 8.888.82 (m, 2H), 8.80 (d, J = 6.5 Hz, 1H ), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.22 (s, 1H), 7.90-7.81 (m, 1H), 7.70-7, 52 (m, 2H), 6.736.62 (m, 2H), 4.90-4.72 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.98-3 .92 (m, 1H), 3.85 (d, J = 14.3 Hz, 1H), 3.80 (d, J = 4.2 Hz, 1H), 3.74 (s, 3H), 3 .54 (dd, J = 13.7, 10.4 Hz, 1H), 3.48-3.40 (m, 1H), 3.40-3.31 (m, 1H), 3.26 (d , J = 12.5 Hz, 1H), 2.04 (d, J = 6.4 Hz, ZN). 682.1 0.13 465 0 ⁴ y 1H NMR (400 MHz, flMCO-d6) δ 8.86 - 8.77 (m, 2H), 8.69 - 8.56 (m, 2H), 7.62 (dd, J = 8.6, 4 ,2 Hz, 1H), 7.56 (d, J = 10.2 Hz, 1H), 6.75-6.62 (m, 2H), 4.83 (dd, J = 8.9, 3, 4 Hz, 1 Η), 4.75 (ddd, J = 11.7, 8.1, 3.9 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (s, 1H), 3.75 (s, 1H), 3.71 (s, 1H), 3.54 (td, J = 11.6, 3.3 Hz, 1H), 3.43 (dd, J = 14.5, 10.8 Hz, 1H), 3.35 (d, J = 11.8 Hz, 1 Η), 3.24 (t, 630.1 1.527

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J = 12.4 Hz, 1Η), 2.49 (s, ZN), 2.34 (s, ZN), 2.07 (s, ZN). 466 ν Λ У-F Η—Ν Ο ^Ν А ' ° ^Ν \ у 1H NMR (400 MHz, DMSO-06) δ 8.87-8.72 (m, 2H), 8.64 (d, J = 8.6 Hz, 1H), 7.69-7.54 (m, 2Н), 7.44 (t, J = 6.9 Hz, 1Н), 6.586.44 (m, ЗН), 4.75 (dd, J = 19.5, 9.1 Hz, 1Н), 3, 81 -3.56 (m, ZN), 3.56-3.25 (m, 4H), 3.19 (s, 2H), 3.12 (s, 1H), 2.53 (s, ZN) , 1.97 (s, ZN), 0.66 (d, J = 38.0 Hz, 4H). 653.2 0.581 467 0—\ F O-<FF ΖΧ- F )=° Η—Ν 0 Ν^. Αχ —/—\/—'' ° ^-Η nA /A / 0 Ν J 1H NMR (400 MHz, flMCO-d6) δ 13.14-12.59 (s, 1H), 8.89 (dd, J = 4.4, 1.4 Hz, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.70 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 7.4 Hz, 2H) , 7.61 (d, J = 7.4 Hz, 1H), 6.74-6.55 (m, 2H), 4.83 (d, J = 7.2 Hz, 1 Η), 4.78 -4.70 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.7 Hz, 1H), 3.783.68 ( m, 2H), 3.54 (s, 4H), 3.41 (dd, J = 14.5, 10.5 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.24 (t, J = 12.1 Hz, 1 Η), 2.63 (s, ZN), 1.99 (s, ZN). 628.2 0.238 468 Ν F tV ^F F. FF )=Ο Af η—ν ρ уугА-н nA / \ ⁷ 0 Ν _χ b 1H NMR (400 MHz, flMCO-d6) δ 12.90 (s, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.80 (d, J = 5.1 Hz, 1H ), 8.62 (s, 1H), 7.65-7.52 (m, 2H), 7.43 (d, J = 5.8 Hz, 1 Η), 6.79 (dd, J = 11 ,5, 4.4 Hz, 2H), 6.54 (s, 1 Η), 4.69 (t, J = 8.4 Hz, 2H), 4.29 (q, J = 6.7 Hz, 1H), 3.91 3.81 (m, 1H), 3.73 (d, J = 14.7 Hz, 1H), 3.65 (dd, J = 11.9, 4.3 Hz, 1H) , 3.49 (d, J = 2.2 Hz, ZN), 3.46 (s, 1H), 3.38 (d, J = 14.3 Hz, 1H), 3.23 (t, J = 12.5 Hz, 1H), 2.53 (s, ZN), 1.37 (d, J = 6.6 Hz, ZN). 713.3 0.189 469 η Α Ν A ^Η ~ ^Ν 0 4χν ^Μ ο-Η ^Ν V / \ ' ^{0 Ν} \ y 1H NMR (400 MHz, flMCO-d6) δ 9.20 (s, 1H), 8.88-8.84 (m, 1H), 8.83-8.78 (m, 1H), 8.69 ( dd, J = 8.7, 1.7 Hz, 1H), 8.19 (s, 1 Η), 7.90 (d, J = 6.7 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.70-7.62 (m, 2H), 6.71 -6.61 (m, 2H), 4.924.70 (m, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.2, 3.6 Hz, 1H), 3.78 (d, J = 4.2 Hz, 1H), 3.74 (s , 4H), 3.60-3.50 (m, 1H), 664.4 0.103

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3.43 (dd, J = 14.5, 10.5 Hz, 1Η), 3.34 (d, J = 12.3 Hz, 1 Η), 3.25 (t, J = 12.4 Hz, 1H), 2.02 (s, ZH). 470 O'Y F Ο\ F. FF )=Ο У-F Η—Ν ,0 Ν—X /\ ⁷ 0 Ν _χ β 1H NMR (400 MHz, flMCO-d6) δ 8.92 (dd, J = 8.0, 4.6 Hz, 1H), 8.84 (d, J = 4.2 Hz, 1 Η), 8, 68 (d, J = 8.6 Hz, 1H), 7.73-7.55 (m, 2H), 7.46 (d, J = 7.3 Hz, 1H), 6.71 (d, J = 6.4 Hz, 1 Η), 6.64 (d, J = 13.0 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 4.91 (d, J = 9.3 Hz, 1H), 4.74 (q, J = 12.2, 10.6 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.72 (t, J = 14.4 Hz, 2H), 3.55 (t, J = 11.2 Hz, 1H), 3.49 (d, J = 3.1 Hz, ZN), 3.46 - 3.17 (m, 2H), 2.84 (dq, J = 13.7, 6.7 Hz, 1H), 2.54 (s, ZN), 1.05 (dt, J = 11.2, 5.8 Hz, 6H). 723.2 0.181 471 Ο-Α F „ A У-F Η—Ν Ο -Λ+ΖΎ-Υ-η ΝΛ /\ ⁷ 0 Ν _χ ) 1H NMR (400 MHz, flMCO-d6) δ 8.85 (dd, J = 12.2, 6.2 Hz, 2H), 8.68 (d, J = 8.7 Hz, 1H), 7.737.55 (m, 2H), 7.46 (d, J = 7.0 Hz, 1H), 6.66 (d, J = 11.4 Hz, 2H), 6.56 (s, 1H), 4.94 -4.66 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.72 (t, J = 14.9 Hz, 2H), 3.63-3.31 (m, 5H), 3.27 (d, J = 12.4 Hz, 1H), 2.54 (s, ZH), 2.39 ( q, J = 7.5 Hz, 2H), 1.06-0.90 (m, ZN). 709.2 0.179 472 Υ 'Λ Ε FF /=0 Yf η—ν ρ уу/уН-н Ν% )=< ⁷ 0 Ν _χ Λ 1H NMR (400 MHz, flMCO-d6) δ 8.94 (d, J = 7.8 Hz, 1H), 8.83 (s, 1H), 8.68 (s, 1H), 7.78- 7.54 (m, ZN), 7.48 (t, J = 9.3 Hz, 2H), 7.34 (dq, J = 16.4, 7.8 Hz, ZN), 6.82 (dd , J = 12.1, 3.7 Hz, 2H), 6.56 (d, J = 5.4 Hz, 1 Η), 6.00 (q, J = 7.9 Hz, 1H), 4, 71 (s, 1H), 3.71 (dt, J = 12.2, 5.8 Hz, 2H), 3.49 (s, 4H), 3.01 (t, J = 6.4 Hz, 2H ), 2.54 (s, ZN). 745.2 0.331 473 О-е Ν F ,¾ Ν^χ ρ Η-Ν ρ SM « i ^χ =< Ν—χ ^χ >—' Ο-Η ' ^{0 Ν} \ Φ 1H NMR (400 MHz, flMCO-d6) δ 9.12 (t, J = 1.7 Hz, 1H), 9.02 (d, J = 7.8 Hz, 1H), 8.86 (t, J = 4.7 Hz, 2H), 8.69 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.717.47 (m, ZN), 6.78 (d, J = 11.7 Hz, 2H), 4.91 (dd, J = 8.8, 3.6 Hz, 1H), 4.71 (dt, J = 8.6, 4, 6 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.6, 3.7 Hz, 1H), 3.86-3.70 ( m, ZN), 3.62-3.38 (m, 7H), 3.35-3.14 (m, 1H). 685.4 0.196

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474 Ο4 ^ρ '4 /^. 0 Η—Ν 0 Ν υ—ν /—< \—ν Ν——'' Ο-Η /Ή /=( ^{0 Ν} \ / 1H NMR (400 MHz, DMSO-06) δ 13.24-12.63 (bs, 1H), 9.05 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8 .84 (d, J = 4.1 Hz, 1H), 8.68 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.91 (dd, J = 5.0, 2.3 Hz, 1H), 7.76 (dd, J = 7.6, 1.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 6.78 (d, J = 11.9 Hz, 2H), 4.91 (d, J = 9.9 Hz, 1H), 4.71 (s, 1 Η), 4.16 (d , J = 12.7 Hz, 1H), 4.003.92 (m, 1 Η), 3.74 (d, J = 13.0 Hz, 2H), 3.65 (s, ZN), 3.61- 3.40 (m, ZN), 3.26 (d, J = 12.4 Hz, 1H). 685.3 0.112 475 ( F >0 Η—Ν F ,2 Ρ Η—Ν ρ <]Η ΛΑ Μ ^χ =\ Ν—C 2—' Ο-Η /Η / \ ' ° ^Ν \ / 1H NMR (400 MHz, flMCO-d6) δ 9.05 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.85 (d, J = 4.2 Hz, 1H ), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.95-7.86 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.68 (t, J = 6.5 Hz, 2H), 6.80 (dd, J = 17.6, 12.4 Hz, 5H), 4 .93 (ddt, J = 17.8, 8.9, 4.6 Hz, 2H), 4.784.55 (m, 1H), 4.17 (dd, J = 12.8, 4.3 Hz, ZN ), 4.00-3.91 (m, ZN), 3.75 (dd, J = 14.4, 4.2 Hz, 4H), 3.65 (s, ZN), 3.54 (td, J = 14.7, 13.3, 9.5 Hz, 4H), 3.44 (d, J = 15.1 Hz, 1H), 3.31 -3.14(m, 2H). 657.2 0.157 476 ο ic Η-Ν ο αΑπΑΤ. ^Ν Η / \ ⁷ 0 Ν _ξ ) 1H NMR (400 MHz, flMCO-d6) δ 9.12 (dd, J = 18.2, 8.5 Hz, 1H), 9.02 (d, J = 4.8 Hz, 1H), 8.92 (dd, J = 10.8, 8.3 Hz, 1H), 7.93 (dt, J = 32.7, 6.7 Hz, 1H), 7.827.55 (m, 2H), 6.70 ( dd, J = 14.9, 11.7 Hz, 2H), 5.84 (d, J = 6.9 Hz, 1H), 4.97-4.84 (m, 1H), 4.834.69 (m , 1H), 4.15 (dd, J = 12.8, 3.1 Hz, 1H), 3.94 (dd, J = 9.7, 5.7 Hz, 2H), 3.66 (ddt, J = 51.3, 42.1, 11.8 Hz, 7H), 3.37 (d, J = 6.2 Hz, 4H), 3.26 (d, J = 26.6 Hz, 2H), 2.41 (d, J = 2.9 Hz, ZN). 722.3 0.337

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477 0 Ν '4 \ ^N ~H /0 ^N V /\ / O Ν _χ /) 1H NMR (400 MHz, DMS0-C16) δ 8.88 (d, J = 4.2 Hz, 1H), 8.82 (d, J = 8.1 Hz, 1H), 8.74 (d, J = 8.6 Hz, 1H), 7.71 (s, 2H), 7.64 (d, J = 7.4 Hz, 1 Η), 6.67 (d, J = 14.4 Hz, 2H) , 4.83 (d, J = 9.6 Hz, 1H), 4.78-4.70 (m, 1H), 4.14 (s, 1H), 3.93 (s, 1H), 3, 73 (s, 1H), 3.55 (d, J = 9.6 Hz, 4H), 3.44 (dd, J = 14.5, 10.2 Hz, 2H), 3.33 (s, 1H ), 3.26 (d, J = 12.4 Hz, 1 Η), 2.41 (s, ZN), 2.33 (s, ZN), 2.05 (s, ZN). 642.2 0.115 478 О—\ F F / У —NF )=0 )=\ О HN p SUCH /=\ h w ^0-н ν Ά rА ' ^{0 Ν} \ # 1H NMR (400 MHz, flMC0-d6) δ 9.02 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 4.2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.78-7.61 (m, ZN), 7.46 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 3.0 Hz, 1H), 7.28 (t, J = 2.9 Hz, 1H), 6.78 (d, J = 11.7 Hz, 2H), 4.91 (dd, J = 9, 0, 3.7 Hz, 1H), 4.71 (td, J = 8.7, 4.3 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 ( dd, J = 11.5, 3.8 Hz, 1H), 3.76 (d, J = 3.2 Hz, 2H), 3.53 (s, 4H), 3.46 (dd, J = 19 ,1, 8.8 Hz, 2H), 3.24 (d, J = 3.4 Hz, 1H), 2.96 (s, 6H). 727.3 0.394 479 4 Ά ^ρ Η—Ν F y Ε FF )=0 \ У-F Η—Ν ρ Κ/Λ Η < ν—с )—' ^0-Η ° ^Ν \ # 1H NMR (400 MHz, flMC0-d6) δ 8.85-8.74 (m, 2H), 8.62 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7 .61 (dt, J = 8.8, 4.5 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.36 (dd, J = 10.4, 7.3 Hz, 1H), 6.76 (t, J = 8.6 Hz, 1H), 6.44 (dd, J = 11.4, 6.3 Hz, 2H), 4.75-4.56 (m , 1H), 4.31 (s, 1H), 3.88-3.79 (m, 4H), 3.68 (ddd, J = 44.6, 14.4, 4.7 Hz, 1H), 3.35 (m, 1H), 1.90 (t, J = 1.3 Hz, ZN), 1.77 (t, J = 10.1 Hz, 1H), 1.64-1.41 (m , 1H), 0.93 (t, J = 7.3 Hz, ZN). 671.2 1,188 480 ^-Ν 4 Ε FF )=0 U-F Η—Ν ρ chUk-A-n ^N k /CH ^ζ ° ^Ν \ # 1H NMR (400 MHz, flMC0-d6) δ 8.89 - 8.60 (m, ZH), 7.73 - 7.55 (m, 2H), 7.46 (d, J = 7.0 Hz, 1H), 6.56 (s, 1H), 6.32 (d, J = 12.2 Hz, 2H), 4.77-4.61 (m, ZH), 3.783.64 (m, 2H), 3.59 (d, J = 7.5 Hz, 1H), 3.49 (d, J = 1.8 Hz, ZN), 3.48-3.38 (m, 1H), 3.00 (d , J = 9.7 Hz, 1H), 2.54 (s, ZN), 1.941.87 (m, 1H), 1.84 (d, J = 9.9 Hz, 1H). 643.2 0.297

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481 Ο Αν ^FfF ^ ^F / F >O Ο Η—N p nA )=< ^Z ° ^N \ # 1H NMR (400 MHz, DMSO-C16) δ 12.93 (s, 1H), 8.93 (dd, J = 4.4, 1.5 Hz, 1H), 8.81 (dd, J = 8, 3, 3.0 Hz, 2H), 7.77-7.69 (m, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 3.3 Hz, 1H), 7.38 (d, J = 3.3 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.5 Hz, 2H), 4.67 (ddd, J = 9.8, 7.9, 4.6 Hz, 1H), 4.31 (d, J = 9.2 Hz, 1H), 3.74 (d, J = 4.7 Hz, 1H), 3.71 (s, 3H), 3.49 (s, 3H), 3.43 (dd, J = 14.5, 9.8 Hz, 1H), 1.77 (ddq, J = 11.6, 7.5, 4.3, 3.8 Hz, 1H), 1.53 (ddt, J = 17.5, 14.3, 7.2 Hz, 1H), 0 .93 (t, J = 7.3 Hz, ZN). 619.3 1.483 482 o An kA 1H NMR (400 MHz, flMCO-d6) δ 9.39 (s, 1H), 9.34 (d, J = 9.2 Hz, 1H), 8.88 (s, 1H), 8.83-8 .76 (m, 2H), 8.13 (d, J = 6.7 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 6.696.57 (m, 2H), 4 .83 (ddt, J = 16.3, 8.2, 3.9 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.97-3.82 (m, 2H ), 3.71 (d, J = 12.9 Hz, 1H), 3.593.54 (m, 1H), 3.31 (s, 1H), 3.24 (d, J = 13.4 Hz, 2H ), 2.67 (s, ZN), 2.40 (s, ZN), 2.01 (s, ZN). 612.3 1,496 483 c F. FF >0 Af η—ν p 4pyM-„ nA /\ ^{z 0 N} \ L 1H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 8.96 (dd, J = 8.0, 5.0 Hz, 1H), 8.85 (dd, J = 4.3, 1.5 Hz, 1H), 8.70 (d, J = 7.8 Hz, 1H), 7.72-7.63 (m, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.47 (dd, J = 7.3, 4.9 Hz, 1H), 6.59-6.49 (t, ZN), 5.02 (p, J = 5.7 Hz, 1H ), 4.72 (dddd, J = 10.0, 7.4, 4.5, 2.2 Hz, 1H), 3.80-3.74 (t, 1H), 3.743.65 (t, 1H ), 3.49 (d, J = 2.5 Hz, ZN), 3.48 - 3.36 (t, 2H), 2.54 (s, ZN), 2.07-1.98 (t, 1H), 1.90 (dq, J = 13.1, 7.8, 6.1 Hz, 1H), 0.88 (td, J = 8.1, 5.1 Hz, 1H), 0.79 (s, 1H). 695.3 0.544 484 n Ά: /=\ hn P Ασ--— N% ^{z 0 N} \ / 1H NMR (400 MHz, DMSO) δ 8.99 (d, J = 7.9 Hz, 1H), 8.85 (d, J = 4.2 Hz, 1H), 8.73 (d, J = 8 .6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.757.62 (t, 4H), 7. 44 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 11.8 Hz, 2H), 4.97-4.86 (t, 1H), 4.75-4.67 (t, 1H), 4.16 (d, J = 12.7 Hz, 1H), 4.00-3.90 (t, 1H), 3.803.71 (t, 2H), 3.69 (s, ZN), 3.61 - 668.2 0.143

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3.40(m, 3H), 3.31 -3.18(m, 1H). 485 Ά F. FF )=0 U-F Η—N ,0 -UULu-I-n / ^N A / ^- ( ' ^{0 N} _x / 1H NMR (400 MHz, DMSO-06) δ 9.03 (d, J = 7.7 Hz, 1H), 8.79 (d, J = 4.1 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 8.7, 4.2 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.40 (d , J = 7.2 Hz, 1H), 6.606.45 (m, 3H), 4.86-4.69 (m, 2H), 3.67 (dd, J = 14.5, 5.5 Hz, 1H), 3.63-3.55 (m, 1H), 3.523.40 (m, 4H), 3.19 (q, J = 8.7 Hz, 1H), 2.52 (s, 3H), 2.17-1.96 (m, 4H). 683.3 0.233 486 \ N—\ F O-+ NF % _F f ^F Г ⁰ 7+ ^H -w /У VA ^{0 N} \ / 1H NMR (400 MHz, flMCO-d6) δ 9.01 (d, J = 8.0 Hz, 1H), 8.80 (d, J = 4.2 Hz, 1H), 8.60 (d, J = 8.5 Hz, 1H), 7.60 (m, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 11.5 Hz, 2H), 6.53 (s, 1H), 5.37 (s, 1H), 4.70 (m, 1H), 3.83-3.91 (m, 4H), 3.73 (dd, J = 14.5, 4.1 Hz, 1H), 3.48 (s, 3H), 3.44-3.35 (m, 1H), 3, 32 (s, 1H), 2.83 (bs, 3H), 2.53 (s, 3). 712.2 1,307 487 0 У N 'У /=\ Ο Η—N p ^-У N—7 p—' 0 WW ( ' 0 ^N \ b ⁴ 1H NMR (400 MHz, flMCO-d6) δ 9.04 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.84 (dd, J = 4.1, 1, 5 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.91 (dd, J = 4.9, 0.7 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.697.63 (m, 2H), 6.76 -6.63 (m, 2H), 4.90-4.74 (m, 2H), 4.194.06 (m, 3H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.78-3.67 ( m, 2H), 3.65 (s, 3H), 3.61 -3.46 (m, 2H), 3.37 (s, 1H), 3.31 -3.18(m, 1H), 2 .07 (s, 3H), 1.16 (t, J = 7.1 Hz, ZN). 709.2 N/A

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488 0 Ύ /=\ O Η—N p /H gr < 1H NMR (400 MHz, DMS0-C16) δ 9.04 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.84 (dd, J = 4.2, 1, 5 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.69-7.63 (m, 2H), 6.75-6.62 (m, 2H), 4.91 4.75 (m, 2H), 4.20-4.07 (m, 3H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.78-3 .67 (m, 2H), 3.66 (s, 3H), 3.60-3.47 (m, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 ( t, J = 12.3 Hz, 1H), 2.07 (s, 3H), 1.16 (t, J = 7.1 Hz, ZN). 709.2 N/A 489 p Ύ /--< p n—N p '—// _N —(/ \\—- o /H ^{λ 7} on) 1H NMR (400 MHz, flMC0-d6) δ 8.99 (d, J = 7.6 Hz, 1H), 8.87 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H ), 7.67 (s, 1H), 7.61 (s, 2H), 6.70 (d, J = 13.0 Hz, 1H), 6.66 (s, 1H), 4.89-4 .77 (m, 2H), 4.76-4.61 (m, 2H), 4.18-4.12 (m, 1H), 3.93 (s, 1H), 3.87-3.79 (m, 2H), 3.73 (d, J = 12.9 Hz, 2H), 3.67 (s, 4H), 3.60-3.46 (m, 2H), 3.35 (d, J = 9.6 Hz, 1H), 3.37 (m, 1H), 3.25 (s, 4H), 2.37 (d, J = 10.2 Hz, ZN), 2.05 (s, ZN). 700.2 N/A 490 О—\ F Ν F у FF )=0 P=\ p Η—N p ^F Ap _N Y-po /4 ^{0 N} \ A 1H NMR (400 MHz, flMCO-d6) δ 9.15 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 4.2 Hz, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.00 (t, J = 9.2 Hz, 1H), 7.80 (dd, J = 12.3, 6.4 Hz, 1H), 7.74 (d , J = 7.5 Hz, 1 Η), 7.697.60 (m, 2Η), 6.79 (d, J = 11.8 Hz, 2H), 5.01 -4.86 (m, 1H), 4.76 (q, J = 7.9 Hz, 1 Η), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.9, 3.6 Hz, 1H), 3.80-3.67 (m, 2H), 3.64 (s, 3H), 3.58 (s, 1H), 3.55 (s, 3H), 3.44 (d, J = 12.9 Hz, 1H), 3.24 (t, J = 12.4 Hz, 1H), 2.53 (s, 1H). 733.7 N/A 491 o Ύ /=N 0 Η—N 0 /°<Hyy_p /4 ^{0 N} \ # 1H NMR (400 MHz, flMCO-d6) δ 9.00 (d, J = 7.7 Hz, 1H), 8.85 (d, J = 4.1 Hz, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.34-8.30 (m, 1H), 7.75 (d, J = 7.5 Hz, 1 Η), 7.717.63 (m, 2H), 7, 46-7.42 (m, 1 Η), 6.74-6.64 (m, 2Η), 4.904.78 (m, ZN), 4.14 (d, J = 12.6 Hz, 1 Η) , 4.06 (s, ZN), 3.95 (d, J = 11.7 Hz, 1H), 3.79-3.65 (m, 5H), 3.62-3.47 (m, 6H ), 3.34 725.8 N/A

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(d, 1Η), 3.25 (t, J = 12.6 Hz, 1 Η), 2.05 (s, ZN). 492 O X +% N—/ ' O / ^N 4 /=\ ° ^N \ / 1H NMR (400 MHz, DMSO-bb) δ 9.00 (d, J = 7.7 Hz, 1 Η), 8.90 (s, 1H), 8.84 (d, J = 4.2 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1 Η), 7.807.73 (m, 2H), 7.67 (t, J = 6.7 Hz, 2H), 6.75-6 .61 (m, 2H), 4.84 (d, J = 10.4 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.99-3.89 (m, 1H), 3.77-3.70 (m, 2H), 3.68 (s, 2H), 3.63 (t, J = 1.7 Hz, ZN), 3.53 (dt, J = 14 ,6, 9.9 Hz, 2H), 3.34 (s, 1H), 2.59 (s, ZN), 2.05 (s, ZN). 709.6 N/A 493 F O<F F /: N—a ρ Η—Ν Ρ SM ΛΑ +=( νΜ ⁷ ')—' ο ^{0 Ν} \ ? 1H NMR (400 MHz, flMCO-d6) δ 9.26 - 9.06 (m, 2H), 8.88 (d, J = 6.8 Hz, 2H), 8.68 (d, J = 8, 7 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 8.3 Hz, ZN), 6.79 (d, J = 12.1 Hz , 2H), 4.92 (d, J = 9.3 Hz, 1H), 4.78 (q, J = 7.7 Hz, 1 Η), 4.17 (d, J = 12.7 Hz, 1H), 3.94 (s, 2H), 3.65 (s, 3H), 3.58 (m, 4H), 3.44 (d, J = 12.9 Hz, 1H), 3.26 ( d, J = 12.7 Hz, 1H). 699.8 N/A 494 F O/ ^f F ,Μ Ο Η—Ν ρ ⁿ CM^m^ +=<Ν—</' Ο /=4 ⁷ ° ^Ν \ # 1H NMR (400 MHz, DMSO-bb) δ 9.15 (d, J = 7.5 Hz, 1 Η), 9.05 (s, 1H), 8.86 (d, J = 4.2 Hz, 1H), 8.64 (dd, J = 28.6, 6.8 Hz, 2H), 7.91 (dd, J = 4.9, 1.9 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1 Η), 7.727.55 (m, 2H), 6.79 (d, J = 11.8 Hz, 2H), 4.96-4.82 (m, 1H), 4, 77 (q, J = 8.0 Hz, 1 Η), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.6,3.6 Hz, 1 Η ), 3.82-3.68 (m, 2H), 3.56 (dd, J = 14.0, 9.9 Hz, 2H), 3.44 (d, J = 13.3 Hz, 1H) , 3.24 (t, J = 12.0 Hz, 1H) 699.2 N/A 495 η ΜΝ 'Ρ- \ F ρ _ο ,Ν~\ Η—Ν ο Ό+μλ-Ά ν Μ p( / ⁷ Ο Ν _χ ft 1H NMR (400 MHz, flMCO-d6) δ 10.19 (s, 1H), 9.11 (d, J = 7.7 Hz, 1H), 8.86 (dd, J = 4.2, 1, 6 Hz, 1H), 8.65 (dd, J = 8.7, 1.6 Hz, 1H), 7.69-7.54 (m, ZN), 7.34 (s, 1H), 6, 78 (d, J= 11.8 Hz, 2H), 4.97-4.86 (m, 1H), 4.80-4.69 (m, 1H), 4.31 (d, J = 14, 6 Hz, 1H), 4.21 -4.06 (m, 2H), 3.96 (dd, J = 11.6, 3.8 Hz, 1H), 3.81 3.70 (m, 2H) , 3.70-3.64 (m, ZN), 3.61 -3.35 (m, 9H), 3.303.08 (m, 2H), 2.97 (s, ZN). 700.3 N/A 496 ρ / fPo Η-Ν ο Όμ+μΆ ν Μ pp / ⁷ ον) 1H NMR (400 MHz, flMCO-d6) δ 9.11 (d, J = 7.4 Hz, ZH), 8.85 (t, J = 3.1 Hz, 1H), 8.63 (d, J = 8.6 Hz, 1H), 7.60 (dtd, J = 23.9, 7.6, 2.8 Hz, ZN), 7.36 (d, J = 2.4 Hz, 1H), 6 .78 (d, J = 12.3 Hz, 2H), 4.91 (d, J = 9.3 Hz, 1 Η), 4.74 (q, J = 7.8 Hz, 1H), 4. 17 (d, J = 12.7 Hz, 2H), 3.96 (d, J = 11.7 Hz, 1H), 3.79-3.62 (m, 5H), 3.61 3.38 ( m, 8H), 3.24 (t, J = 12.6 Hz, 1H), 3.07 (d, J = 6.3 Hz, 2H). 686.4 n/a

α4β1 Cell Capture Assay

The effectiveness of inhibitors to prevent interaction of α4β1 integrin with VCAM-1 was measured by monitoring the uptake of cells expressing α4β1 integrin onto a plate coated with recombinant VCAM-1 extracellular domain.

384-well plates (Corning 3702) were coated with VCAM-1 extracellular domain by dispensing 20 μl of VCAM-1 at 0.5 μg/ml per well and incubating overnight at 4°C. The plates were then washed with PBS and blocked with 3% BSA for 2 hours before washing again.

Jurkat cells were centrifuged and resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl ₂ ) at a density of 0.5 x 10 ⁶ cells/ml. The cells were then distributed (60 μl/well) into a 384-well plate (Greiner 781280) which had previously been coated with 60 nl of test compound per well. The plates were incubated at 37°C for 1 h. 50 μl of cells were transferred to blocked VCAM-1-coated plates and incubated for 30 min at 37°C. 10 μl of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg/ml) was added to the cells (2% glutaraldehyde and 0.01 mg/ml final concentrations of Hoechst 33342). The plates were incubated for 90 minutes at room temperature. The plates were then washed 3 times with 70 µl PBS per well and imaged on a Cellomics instrument

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ArrayScan. Cells that were bound to the plate were counted and plotted against compound concentration to determine the EC ₅₀ of the test compounds.

The starting carboxylic acids in the table. 3 demonstrate selectivity at least 70-fold higher compared to α4β 1, calculated from the ratio of EC ₅₀ values in cell capture assays for α4β 1 and α4β7. These assays measure the capture of cells expressing α4β1 or α4β7 by a recombinant plate coated with the extracellular domain of VCAM-1 or MadCAM-1, respectively.

Bioavailability experiments in dogs

Pharmacokinetic studies were conducted in exposed male Beagle dogs (three animals per route of administration) in accordance with Federal and Institutional Animal Care and Use Committee (IACUC) guidelines. Intravenous (IV) administration was carried out by infusion over 30 minutes. The intravenous dosage for dogs was formulated in a sterile solution. One solution composition was 20% polyethylene glycol 300 and 80% water, pH 8-9. The oral dose was administered to dogs via gastric tube as a solution. One formulation for dogs was 72% 10 mM HCl, 5% N-methylpyrrolidone, 20% polyethylene glycol 200, and 3% vitamin E TPGS, pH 2-3. Blood samples were collected within 24 hours of dosing, plasma was isolated, and plasma concentrations of the test compound were determined by LC/MS/MS after protein precipitation with acetonitrile. Non-compartmental pharmacokinetic analysis was performed based on plasma drug concentration-time data.

Bioavailability (%F) is defined as the area under the concentration/time curve (AUC) of the parent carboxylic acid in the systemic circulation after oral administration of the ester prodrug divided by the AUC of the amount of parent carboxylic acid in the systemic circulation after intravenous administration of the parent carboxylic acid normalized to the same dose . The results of assessing oral bioavailability in dogs are presented in table. 4.

Table 4

Example of a prodrug %F Parent carboxylic acid 346 5 Example 91 347 eleven Example 91 348 3 Example 91 349 9 Example 91 351 35 Example 91 355 18 Example 356 357 9 Example 356 358 2 Example 356 359 12 Example 356 360 37 Example 356 361 5 Example 356 363 37 Example 356 364 3 Example 356 365 16 Example 356 368 8 Example 356 487 20 Example 408 494 8 Example 474

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3. Connection fight

4. Connection fight

5. Connection fight

Claims (9)

1. A compound or a pharmaceutically acceptable salt thereof, which is 2. Connection a pharmaceutically acceptable salt, wherein the compound is clause 1 clause 1 p.1 or or or his his his co- a pharmaceutically acceptable salt, wherein the compound is a pharmaceutically acceptable salt, wherein the compound is pharmaceutically acceptable salt, where the compound is a coco- 227 045366 the battle 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where the compound is co- /=\about mA A )-N fight 7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound 8. A pharmaceutical composition for treating a disease or condition associated with α4β7 integrin, comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to claim 8, further containing at least one or more additional therapeutic agents. 10. The pharmaceutical composition according to claim 9, wherein the additional therapeutic agent is a JAK tyrosine kinase inhibitor, wherein the JAK tyrosine kinase inhibitor is filgotinib. 11. Application of connection according to any of ππ. 1-7 or a pharmaceutically acceptable salt thereof for the treatment of an inflammatory disease or condition. 12. Application according to and. 10, wherein said inflammatory disease or condition is selected from inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, graft-versus-host disease (GvHD), and primary sclerosing cholangitis (PSC).