NZ715195B2 - Substituted benzofuranyl and benzoxazolyl compounds and uses thereof - Google Patents

Substituted benzofuranyl and benzoxazolyl compounds and uses thereof Download PDF

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NZ715195B2
NZ715195B2 NZ715195A NZ71519514A NZ715195B2 NZ 715195 B2 NZ715195 B2 NZ 715195B2 NZ 715195 A NZ715195 A NZ 715195A NZ 71519514 A NZ71519514 A NZ 71519514A NZ 715195 B2 NZ715195 B2 NZ 715195B2
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New Zealand
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cpd
compound
cancer
alkyl
substituted
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NZ715195A
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NZ715195A (en
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Erkan Baloglu
Gali Golan
Ori Kalid
Yosef Landesman
Dilara Mccauley
William Senapedis
Sharon Shacham
Sharon Shechter
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Karyopharm Therapeutics Inc
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Priority claimed from PCT/US2014/045479 external-priority patent/WO2015003166A1/en
Publication of NZ715195A publication Critical patent/NZ715195A/en
Publication of NZ715195B2 publication Critical patent/NZ715195B2/en

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Abstract

The invention generally relates to substituted benzofuranyl and substituted benzoxazolyl compounds, and more particularly to compounds represented by Structural Formula (VII) or (VIII) : or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of Structural Formula (VII) or (VIII), or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment of cancer (e.g., mantle cell lymphoma), and other diseases and disorders. ention also includes the synthesis and use of a compound of Structural Formula (VII) or (VIII), or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment of cancer (e.g., mantle cell lymphoma), and other diseases and disorders.

Description

SUBSTITUTED BENZOFURANYL AND BENZOXAZOLYL COMPOUNDS AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of US. Provisional Application No. ,856, filed on July 3, 2013, US. Provisional Application No. 61/879,070, filed on September 17, 2013, US. Provisional Application No. 61/904,843, filed on November 15, 2013, and US. Provisional Application No. 61/975,171, filed on April 4, 2014. The entire teachings of these applications are incorporated herein by reference.
BACKGROUND OF THE ION Cancer remains a disease for which existing treatments are insufficient. For e, of the approximately 66,360 new cases of non-Hodgkin lymphoma in the United States each year, about 6% of the cases involve mantle cell lymphoma (MCL). ents for MCL include combination therapies, chemotherapy and stem cell transplantation. Like many cancers, although treatments for MCL have improved, relapses remain common, and treatment resistance is observed.
There is a clear need for additional drug-like compounds that are ive for the treatment of cancer, such as non—Hodgkin ma.
Y OF THE INVENTION The present invention relates to substituted benzofuranyl and benzoxazolyl compounds, or pharmaceutically acceptable salts or compositions thereof, useful as anti- cancer agents. In one embodiment of the invention, the substituted uranyl compounds are represented by Structural Formula (A): (A), or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
Another embodiment ofthe invention is a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable r.
Yet another embodiment of the invention is a method for treating cancer in a subject in need thereof, the method comprising stering to a subject in need f a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a composition sing a compound of the invention, or a pharmaceutically acceptable salt thereof.
Without being bound by a ular theory, it is believed that the compounds described herein can modulate (e. g., inhibit) one or more p21-activated kinases (PAK), for example, one or more of PAKs 1-6. More specifically, and Without being bound by a particular theory, it is believed that the compounds bed herein can bind to one or more PAKs and function as allosteric modulators of one or more PAKs. For example, the compounds described herein may exert their modulatory effect(s) on one or more PAKs by binding to and ilizing one or more PAKs or buting to the degradation of one or more PAKs, thereby modulating (e. g, ting) the effect of one or more PAKs on one or more proteins ream of the one or more PAKs, for example, growth signaling proteins such as Akt, , p90RSK, B-catenin, cofilin, p21 and cyclin D1.
In a particular embodiment, one or more of the Group I PAKs (e. g. , PAKl, PAK2, PAK3) is inhibited. For example, PAKl is inhibited, PAK2 is inhibited, PAK3 is inhibited or a combination of PAKl, PAK2 and PAK3, such as PAKl and PAK2, PAKl and PAK3, PAKZ and PAK3, or PAKl, PAK2 and PAK3 is inhibited. In a particular embodiment, one or more of the group II PAKs (e. g., PAK4, PAKS, PAK6) is inhibited. For example, PAK4 is inhibited, PAKS is inhibited, PAK6 is inhibited or a combination of PAK4, PAKS and PAK6, such as PAK4 and PAKS, PAK4 and PAK6, PAKS and PAK6 or PAK4, PAKS and PAK6 is inhibited. Therefore, the nds described herein can be useful for treating PAK- mediated disorders.
As such, in another embodiment, the invention is a method of treating a PAK- mediated disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, or a ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.
Another embodiment of the invention is use ofa compound of the invention for treating cancer or a PAK—mediated disorder in a subject.
Another embodiment of the invention is use ofa compound of the invention for the manufacture of a ment for treating cancer or a diated disorder in a subject.
Compounds of the present invention, and pharmaceutically acceptable salts and/or compositions thereof, are useful for treating a variety of cancers, such as lymphoma and, more specifically, mantle cell lymphoma.
BRIEF DESCRIPTION OF THE DRAWINGS The foregoing will be nt from the following more particular description of example embodiments of the invention. is a schematic representation of a SILAC experiment and shows the experimental design. is images of Western blots, and shows the effect of 48-hour ent with increasing concentrations of nd 585 on the levels of markers of autophagy, such as pAMPK, AMPK and LC3, in U208 cells. is images of Western blots, and shows that 72-hour treatment with increasing concentrations of Compound 585 had little to no effect on PAK4 signalling in two normal cell lines, NHDF and IMR—90, as indicated by the levels of phospho-PAK4, PAK4, phospho—cofilin, cofilin, phospho-B-catenin, B-catenin, PARP and caspase 3. is a cal representation of cell cycle changes observed upon treatment ofU208 cells with 1 uM nd 585 for one, two or three days. is a graph of mean tumor volume as a function of time, and shows the effect of Compounds 504 and 510 on the volume of -468 xenografts in CB—17 SCID mice. is a graph of mean tumor volume as a function of time, and shows the effect of varying concentrations of Compound 585 on the volume of 2-138 xenografts in SCID mice. is a graph of mean tumor volume as a on of time, and shows the effect of g concentrations of Compound 585 on the volume of Hep 3B xenografts in SCID mice. is a graph of median tumor volume (as a percentage of pre-dose tumor volume) as a function of time, and shows the effect of Compound 667 and Compound 728 on the volume of Molt-4 xenografts in SCID mice.
DETAILED DESCRIPTION OF THE INVENTION A ption of example embodiments of the invention follows.
Definitions Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and Species disclosed herein. As used herein, the following definitions shall apply unless ise indicated. For purposes of this invention, the chemical elements are identified in ance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University e Books, ito: 1999, and "March’s Advanced Organic try", 5th Ed, Ed: Smith, MB. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
Unless specified otherwise within this specification, the nomenclature used in this cation generally follows the examples and rules stated in Nomenclature of c Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by reference herein for its exemplary» chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, ed Chemistry Development, Inc., Toronto, Canada.
Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e. g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, c mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
"Aliphatic" means an optionally substituted, saturated or unsaturated, branched or straight— chain monovalent hydrocarbon radical having the specified number of carbon atoms.
"Alkyl" means an optionally substituted saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms.
Thus, "(C1—C4) alkyl" means a radical having from 1-4 carbon atoms in a linear or branched arrangement. "(C1-C4)alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl.
"Alkylene" means an optionally substituted saturated aliphatic branched or straight-chain divalent hydrocarbon radical having the specified number of carbon atoms.
Thus, "(C1-C4)alkylene" means a divalent saturated aliphatic radical having from 1-4 carbon atoms in a linear arrangement, e. g., )n]-, where n is an r fiom l to 4. 4)alky1ene" includes methylene, ethylene, propylene, and ne. Alternatively, 4)alkylene" means a divalent saturated radical having from 1—4 carbon atoms in a branched arrangement, for example: -[(CH2CH(CH3)(CH2)]-, and the like.
"Amino" means -NH2.
As used herein, the term "dialkylamino" means (alkyl)2—N—, wherein the alkyl , which may be the same or different, are as herein defined. Particular dialkylamino groups are ((Cl—C4)alkyl)2—N—, wherein the alkyl groups may be the same or different.
Exemplary dialkylamino groups include dimethylamino, lamino and methylethylamino.
As used herein, the term "monoalkylamino" means a radical of the formula alkyl— NH, wherein the alkyl group is as herein defined. In one , a kylamino is a (C1- C6) alkyl-amino—. Exemplary monoalkylamino groups e methylamino and ethylamino.
"Aryl" or "aromatic" means an aromatic yclic ring system. An aryl moiety can be monocyclic, fused bicyclic, or polycyclic. In one embodiment, "aryl" is a 6-15 membered monocylic or polycyclic system. Aryl systems include, but are not limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.
Monocyclic aryls are aromatic rings having the specified number of carbon atoms.
A fused bicyclic aryl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic aryl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
Polycyclic aryls have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least two ring atoms in common. The first ring is a monocyclic aryl and the remaining ring structures are monocyclic carbocyclyls or clic heterocyclyls. Polycyclic ring systems include fused ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common.
"Carbocyclyl" means a cyclic group with only ring carbon atoms. "Carbocyclyl" includes 3-15 membered saturated, partially saturated or rated aliphatic cyclic hydrocarbon rings or 6-15 membered aryl rings. A carbocyclyl moiety can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic, or polycyclic.
Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclic hydrocarbon rings or aromatic hydrocarbon rings having the specified number of carbon atoms.
Monocyclic carbocyclyls include cycloalkyl, cycloalkenyl, cycloalkynyl and phenyl.
A fused bicyclic yclyl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
A bridged ic carbocyclyl has two rings which have three or more adjacent ring atoms in common. The first ring is a monocyclic yclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
A spiro bicyclic carbocyclyl has two rings which have only one ring atom in common. The first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
Polycyclic yclyls have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common. The first ring is a monocyclic carbocyclyl and the remaining ring structures are monocyclic carbocyclyls or monocyclic heterocyclyls. Polycyclic ring systems include fused, bridged and spiro ring s. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more nt ring atoms in . alkyl" means a saturated aliphatic cyclic hydrocarbon ring. Thus, "C3-C7 cycloalkyl" means a hydrocarbon radical of a (3—7 membered) ted aliphatic cyclic hydrocarbon ring. A C3—C7 cycloalkyl es, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
"Hetero" refers to the ement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O. "Hetero" also refers to the replacement of at least one carbon atom member in an acyclic system. In some ments, a hetero ring system may have 1, 2, 3 or 4 carbon atom members replaced by a heteroatom.
"Heteroatom" refers to an atom other than carbon. Examples of heteroatoms include nitrogen, oxygen and sulfur.
"Heterocyclyl" means a cyclic 4-15 membered saturated or rated tic or aromatic ring wherein one or more carbon atoms in the ring are independently replaced with a heteroatom. When a heteroatom is S, it can be optionally mono- or di-oxygenated (i.e., -S(O)- or -S(O)2—). The heterocyclyl can be monocyclic, fused bicyclic, bridged ic, spiro bicyclic or polycyclic.
"Saturated cyclyl" means an aliphatic heterocyclyl group without any degree of unsaturation (i.e., no double bond or triple bond). It can be monocyclic, fused bicyclic, d bicyclic, spiro bicyclic or polycyclic.
Examples of monocyclic saturated heterocyclyls include, but are not limited to, azetidine, pyrrolidine, dine, piperazine, azepane, hexahydropyrimidine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-ZH—l ,2—thiazine, tetrahydro-2H—l ,2-thiazine 1,1 -dioxide, isothiazolidine, isothiazolidine l, l —dioxide.
A fused bicyclic heterocyclyl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl. For example, the second ring is a (C3—C6)cycloalkyl, such as cyclopropyl, utyl, cyclopentyl and cyclohexyl. Alternatively, the second ring is . Examples of fused bicyclic heterocyclyls include, but are not limited to, octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline, 2,3-dihydro- l H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3 -dihydrobenzo [d]thiazole, octahydrobenzo [d]oxazole, octahydro— l H-benzo [d] imidazole, octahydrobenzo[d]thiazole, octahydrocyclopenta[c]pyrrole, 3 cyclo[3 . 1 .0]hexane, and 3 ~azabicyclo [3 .2.0]heptane.
A spiro bicyclic heterocyclyl has two rings which have only one ring atom in . The first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycle (such as a lkyl or saturated heterocyclyl) or a monocyclic heterocyclyl. For example, the second ring is a (C3-C6)cycloalkyl. Alternatively, the second ring is a (C3-C6) saturated heterocyclyl. es of spiro bicyclic heterocyclyls include, but are not limited to, ro[4.4]nonane, 7-azaspiro[4.4]nonane, azasprio[4.5]decane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane and azaspiro[5.5]undecane. Further examples of spiro bicyclic heterocyclyls include 2-oxaazaspiro[3.3]heptane, 1-oxa—6- azaspiro [3 .3]heptane and 2-azaspiro[3.3]heptane.
A d bicyclic heterocyclyl has two rings which have three or more nt ring atoms in common. The first ring is a monocyclic cyclyl and the other ring is a. monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
Examples of bridged bicyclic heterocyclyls include, but are not limited to, azabicyclo[3 .3 . 1 ]nonane, 3 -azabicyclo[3 .3 . l]nonane, azabicyclo [3 .2. 1 ]octane, 3-azabicyclo[3.2.1]octane, 6-azabicyclo[3.2.1]octane and azabicyclo[2.2.2] octane, 2-azabicyclo[2.2.2]octane. Further examples of bridged bicyclic cyclyls include 6-oxa— 3-azabicyclo[3.1.l]heptane, icyclo[3.l.0]hexane, 8-oxaazabicyclo[3.2.l]octane and 2-oxa—5-azabicyclo[2.2.1]heptane.
Polycyclic heterocyclyls have more than two rings, one of which is a heterocyclyl (e. g., three rings resulting in a tricyclic ring system) and adjacent rings having at least one ring atom in common. Polycyclic ring systems include fused, bridged and spiro ring systems.
A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common. oaryl" or "heteroaromatic ring" means a 5-15 membered monovalent heteroaromatic ring radical. A heteroaryl moiety can be monocyclic, fused bicyclic, or polycyclic. In one embodiment, a heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S. aryls include, but are not d to furan, oxazole, thiophene, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2,5-thiadiazole 1,1-dioxide, 1,2,5- thiadiazole l-oxide, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, ne-N—oxide, pyrazine, pyrimidine, pyrrole, tetrazole, and thiazole. Bicyclic aryl rings include, but are not limited to, bicyclo[4.4.0] and bicyclo[4.3.0] fused ring systems such as indolizine, indole, ole, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, oline, quinoxaline, l,8-naphthyridine, and pteridine.
Monocyclic heteroaryls are heteroaromatic rings having the specified number of carbon atoms.
A fused bicyclic heteroaryl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic heteroaryl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
Polycyclic heteroaryls have more than two rings (e. g., three rings resulting in a tricyclic ring system) and adjacent rings have at least two ring atoms in common. The first ring is a monocyclic heteroaryl and the remainding ring structures are monocyclic carbocyclyls or monocyclic cyclyls. Polycyclic ring systems include fused ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common.
"Halogen" and "halo" are used hangeably herein and each refers to fluorine, chlorine, bromine, or iodine.
"Chloro" means -C1.
"Fluoro" means -F.
"Cyano" means -CN.
"Sulfonate" means -S02H.
"Alkoxy" means an alkyl radical attached through an oxygen linking atom.
"(C1-C6)alkoxy" includes methoxy, ethoxy, propoxy, butoxy, y and hexoxy.
"Thioalkoxy" means an alkyl l attached through a sulfur linking atom.
"Haloalkyl" include mono, poly, and perhaloalkyl groups, where each halogen is ndently selected from fluorine, chlorine, and bromine.
It is understood that substituents and substitution patterns on the compounds of the ion can be selected by one of ordinary skill in the art to e nds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted group" can have a le substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an "optionally substituted group" can be unsubstitued.
Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or ally feasible compounds. If a tuent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results.
The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to ions to allow for their production, detection, and, in certain embodiments, their ry, purification, and use for one or more of the purposes disc105ed herein.
Suitable monovalent substituents on a tutable atom, for example, a substitutable carbon atom, of an "optionally substituted group" are independently halogen; haloalkyl; ~(CH2)04R°; —(CH2)040R°; -O(CH2)04R°; -O—(CH2)MC(O)OR°; —(CH2)0_ 4CH(OR°)2; ~(CH2)MSR°; —(CH2)MPh, which may be substituted with R0; ~(CH2)0_ )0_1Ph which may be tuted With R0 or halo (e.g, fluoro, chloro, bromo or iodo); Ph, which may be substituted with R°; —(CH2)MO(CH2)0_1-pyridyl which may be substituted with R0; -CH(OH)R° (e. g., 3,5-dimethylisoxazolyl, 4- fluorophenyl); -CH(CH3)R° (e, g. , 4,4-difluoropiperidin-1—y1); —N02; —CN; —N3; ~(CH2)0_ 4N(R°)2; MN(R°)C(O)R0; — N(R°)C(S)R°; o-4N(R°)C(O)NR°2; 0_4OC(O)NR°2; -N(R°)C(S)NR°2; -(CH2)o_ 4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; —N(R°)N(R°)C(O)OR°; — (CH2)MC(O)R°; —C(S)R°; ‘(CH2)0-4C(O)OR°; —(CH2)MC(O)SR°Q "(CH2)04C(O)OSiR°3; — (CH2)0—40C(O)R°; -OC(0)(CH2)MSR—, SC(S)SR°; —(CH2)MSC(0)R°; ~(CH2)04C(0)NR°2; —(CH2)MC(O)NR°2; —C(S)NR°2; —C(O)NR°NR°2; -C(S)SR°; — SC(S)SR°, -(CH2)0-4OC(O)NR°2; (OR°)R°; —C(O)C(O)R°; — C(0)C(O)NR°2; -C(0)CH2C(0)R°; -C(N0R°)R°; ‘(CH2)0—4$SR03 -(CH2)0.4$(0)2R°; — (CH2)0—4$(O)20R°; 040$(0)2R°; —S(O)2NR°2; "(CH2)0—4$(O)R°S -N(R°)S(0)2NR°2; — N(R°)S(0)2R°; -N(0R°)R°; -C(NH)NR°2; -P(0)2R°; -P(0)R°2; -OP(0)R°2; —OP(0)(0R°)2; SiR°3; —(CH straight or branched alkylene)O—N(R°)2; or —(C1.4 straight or branched alkylene)C(O)O—N(R°)2, wherein each R° may be substituted as defined below and is ndently hydrogen, CM aliphatic, —CH2Ph, —O(CH2)0_1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5—6—membered carbocyclyl or heterocyclyl, or, notwithstanding the definition above, two independent ences of R°, taken together with their intervening atom(s), form a 3—12—membered carbocyclyl or heterocyclyl, which may be substituted as defined below.
In some embodiments, suitable monovalent tuents on a substitutable atom, for example, a substitutable carbon atom, of an "optionally substituted group" are independently halogen; haloalkyl; —(CH2)0_4R°; —(CH2)MOR°; -O(CH2)0_4R°, -O~(CH2)0_ 4C(O)OR°; —(CH2)0_4CH(OR°)2; —(CH2)0_48R°; —(CH2)0_4Ph, which may be substituted with R"; 0_40(CH2)0_1Ph which may be substituted with R°; —CH=CHPh, which may be substituted with R°; —(CH2)040(CH2)0_1-pyridyl which may be substituted with R°; —CH(OH)(3,5-dimethylisoxazol—4-yl); —N02; —CN; —N3; 04N(R°)2; 0_ 4N(R°)C(O)R°; — (S)R°; "(CH2)0-4N(R°)C(O)NR°2; "(CH2)040C(O)NR°2; 'N(R°)C(S)NR°2; '(CH2)0— 4N(R°)C(0)0R°; -N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR°2; -N(R°)N(R°)C(0)0R°; — (CH2)0_4C(O)R°; —C(S)R°; -(CH2)0-4C(O)OR°; —(CH2)04C(O)SR°; -(CH2)0_4C(O)OSiR°3; — 40C(0)R°; -OC(O)(CH2)O4SR—, SC(S)SR°; *(CH2)0—48C(O)ROQ —(CH2)04C(O)NR°2; —(CH2)0_4C(O)NR°2; ~C(S)NR°2; —C(O)NR°NR°2; —C(S)SR°; — SC(S)SR°, —(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; —C(O)C(O)R°; — C(0)C(0)NR°2; -C(O)CH2C(O)R°; —C(NOR°)R°; 0—4$SROQ ‘(CH2)0—48(O)2ROS — (CH2)0_4S(O)20R°; -(CH2)MOS(O)2R°; —S(O)2NR°2; -(CH2)0_48(O)R°; —N(R°)S(O)2NR°2; — N(R°)S(0)2R°; -N(OR°)R°; *C(NH)NR°2; —P(0)2R°; -P(0)R°2; -OP(0)R°2; —OP(0)(OR°)2; SiR°3; —(C14 straight or branched alkylene)O—N(R°)2; or —(C14 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is ndently hydrogen, C1_6 aliphatic, —CH2Ph, —O(CH2)0_M1Ph, —CH2-(5-6 membered heteroaryl ring), or a 5—6—membered yclyl or heterocyclyl, or, notwithstanding the definition above, two independent occurrences of R0, taken together with their intervening atom(s), form a 3—12—membered carbocyclyl 0r heterocyclyl, which may be substituted as defined below.
In some embodiments, suitable monovalent substituents on a substitutable atom, for example, a substitutable carbon atom, of an "optionally substituted group" are independently n; haloalkyl; —(CH2)0_4R°; —(CH2)MOR°; -O(CH2)0-4R°, —O—(CH2)0- R°; —(CH2)MCH(OR°)2; —(CH2)MSR°; 0_4Ph, which may be substituted with RO; —(CH2)MO(CH2)(HPh which may be substituted with R°; —CH=CHPh, which may be substituted with R0; —(CH2)04O(CH2)0_1-pyridyl which may be tuted with RO; —N02; — CN; —N3; '(CH2)0—4N(RO)2§ -(CH2)04N(R°)C(0)R°; — N(R°)C(S)R°; -(CH2)0_4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)o— 4N(R°)C(O)OR°; —N(R°)N(R°)C(O)R°; —N(R°)N(R°)C(O)NR°2; N(R°)C(O)OR°; — (CH2)04C(0)R°; —C(S)R°; o—4C(0)0R°; 04C(O)SR°; -(CH2)04C(O)OSiR°3; — (CH2)04OC(0)R°; -0C(0)(CH2)04SR—, SC(S)SR°; 0—48C(O)R°; —(CH2)04C(O)NR°2; -(CH2)04C(0)NR°2; -C(S)NR°2; -C(0)NR°NR°2; -C(S)SR°; — SC(S)SR°, —(CH2)0_4OC(O)NR°2; -C(O)N(OR°)R°; —C(O)C(O)R°; — C(O)C(O)NR°2; -C(O)CH2C(O)R°; —C(N0R°)R°; ‘(CH2)0—4$SR°; —(CH2)MS(0)2R°; — (CH2)04$(0)20R°; '(CH2)0—408(O)2R°; ~S(O)2NR°2; -(CH2)0~4$(0)R°; -N(R°)S(0)2NR°2; — N(R°)S(O)2R°; -N(0R°)R°; -C(NH)NR°2; —P(0)2R5; °2; -0P(0)R°2; —OP(0)(0R°)2; SiR°3; —(C14 straight or ed alkylene)O—N(R°)2; or —(C1_4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1_6 aliphatic, ~CH2Ph, —O(CH2)0~1Ph, —CH2—(5—6 membered heteroaryl ring), or a 5—6—membered carbocyclyl or cyclyl, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3—] 2—membered carbocyclyl or heterocyclyl, which may be substituted as defined below.
Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, kyl, —(CH2)0.2R°, -(haloR°), ~(CH2)0_2OH, 0_20R°, —(CH2)0_ 2CH(OR°)2; -O(haloR°), ~CN, —N3, ~(CH2)0_2C(O)R°, —(CH2)0_2C(O)OH, —(CH2)0_ 2C(O)OR.= "(CHM—2311.: —(CH2)0*23H, *(CH2)HNH2, "(CH2)0—2NHR', —(CH2)0~2NR°2, ‘ N02, —SiR°3, —OSiR°3, -C(O)SR', —(C1_4 straight or branched alkylene)C(O)OR°, or —SSR° wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from (31.4 aliphatic, —CH2Ph, —O(CH2)0_1Ph, or a 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms ndently selected from en, , and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
"Heteroaryl substituent," as used herein, refers to a substituent on a heteroaryl group. Such substituents include the suitable monovalent substituents for a substitutable atom, as bed above. Preferred heteroaryl substituents include halogen; MR°; — (CH2)040R°; -O(CH2)0_4R°,—(CH2)04SR°; ~(CH2)04Ph, which may be substituted with R0; (CH2)040(CH2)0r1Ph which may be substituted with R0; —N02; ~CN; ~N3; or —(CH2)0_ 4N(R°)2, wherein each R° is defined above and may be substituted as defined above.
Particularly preferred heteroaryl substituents include hydrogen, halogen; (C1-C4)alky1; (C1- oalky1; (C1-C4)alkoxy; (C1-C4)thioalkoxy; -N02; -CN; -N3; or -N(R°)2, wherein each R° is defined above and may be substituted as defined above.
Suitable divalent substituents on a saturated carbon atom of an "optionally substituted group" include the following: :0, =3, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, —O(C(R*2))2_30—, and —S(C(R*2))2_3S—, wherein each independent occurrence of R* is selected from hydrogen, CH, aliphatic which may be tuted as defined below, or an unsubstituted 5—6-membered ted, lly unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. le nt substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: —O(CR*2)2H30—, wherein each independent occurrence of R* is selected from hydrogen, C1_6 aliphatic which may be substituted as defined below, or an unsubstituted 5—6~membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
Suitable substituents on the aliphatic group of R* include n, — R', -(haloR'), —OH, —OR°, —O(haloR'), —CN, —C(O)OH, —C(O)OR°, —NH2, —NHR’, —NR‘2, and —N02, wherein each R' is unsubstituted or where preceded by "halo" is tuted only with one or more halogens, and is independently C14 aliphatic, —CH2Ph, )0_1Ph, or a —6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
Suitable substituents on a substitutable nitrogen of an "optionally substituted group" include —RT, —NRT2, —C(0)RT, —C(O)ORT, —C(O)C(O)RT, —C(O)CH2C(O)RT, ~ S(O)2Rl, NRT2, —C(S)NRT2, —C(NH)NRT2, and —N(RT)S(O)2RT; wherein each RT is ndently hydrogen, CH5 tic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5—6—membered saturated, lly unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of RT, taken together with their intervening atom(s) form an unsubstituted 3—12—membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. le substituents on the aliphatic group of RT are independently halogen, — R', -(haloR°), —OH, —OR‘, —O(haloR°), —CN, —C(O)OH, —C(O)O_R°, —NH2, —NHR', —NR°2, or -NOZ, wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more ns, and is independently C1_4 aliphatic, —CH2Ph, )0_1Ph, or a mbered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and .
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, tion, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1—19, the relevant teachings of which are incorporated herein by reference in their entirety.
Pharmaceutically acceptable salts of the compounds of this ion include salts derived from le inorganic and organic acids and bases that are compatible with the treatment of patients.
Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, ic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate,ybenzoate, bisulfate, , butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, sulfonate, e, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, oate, hexanoate, hydroiodide, 2~hydroxy~ ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, e, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3—phenylpropionate, ate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p—toluenesulfonate, undecanoate, valerate salts, and the like.
In some embodiments, exemplary nic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfiiric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and boxylic acids. Illustrative of such acids are, for example, acetic, glycolic, , pyruvic, malonic, succinic, glutaric, fumaric, malic, ic, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p—toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono— or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and s hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
In some embodiments, acid on salts of the compounds of formula I are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with nic acids, e. g., hydrochloric, sulfuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
Other non-pharmaceutically acceptable salts, e. g., oxalates can be used, for example, in the isolation of compounds of formula I for laboratory use, or for uent conversion to a pharmaceutically acceptable acid on salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and um , solvates and hydrates of compounds of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying rd techniques, well known to one d in the art.
A "pharmaceutically acceptable basic addition salt" is any non-toxic organic or inorganic base addition salt of the acid compounds represented by formula I, or any of its intermediates. Illustrative nic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
Illustrative organic bases Which form suitable salts include aliphatic, alicyclic or aromatic —16— organic amines such as methylamine, hyl amine and picoline or a. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
Salts derived from appropriate bases e alkali metal, alkaline earth metal, ammonium and 4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, m, potassium, calcium, magnesium, and the like. Further pharrnaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine s formed using rions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
Pharmaceutically acceptable salts e (C1—C6)alkylhalide salts. A (C1— C6)alkylhalide salt of a nd described herein can be formed, for example, by treating a compound of Formula II (e. g., wherein q is 0) with a (C1-C6)a1kylhalide salt, thereby alkylating a nitrogen atom (e. g. , the nitrogen atom beta to the group -[C(R4a)(R4b)]n- in Formula II) and forming_a (C1—C6)alkylhalide salt of a compound of Formula II. es of (C1-C6)alkylhalide salts include methyl iodide and ethyl iodide.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e. g, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E mational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the ion. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the ement of a hydrogen with deuterium 13 C- or tritium, or of a carbon with a or l4C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present ion. For example, in the case of variable R1, the (C1-C4)alky1 or the -O-(C]-C4)alky1 can be suitably deuterated (e. g., —CD3, -OCD3). -17_ The term "stereoisomers" is a general term for all isomers of an dual molecule that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one r ereomers).
The term "pharmaceutically acceptable carrier" means a non—toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, 126., a dosage form capable of being administered to a patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral stration. Pharmaceutically acceptable carriers are well known in the art.
When introducing elements disclosed herein, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "having" and "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements.
Compounds ofthe Invention A first ment of the invention is a compound represented by Structural Formula A: R4a R3a O \ ,\/>R9 R2 Y \X R4b 3b n R m (A), or a pharmaceutically acceptable salt thereof, wherein: X is )— or —N-; R30 is hydrogen, deuterium, (C1~C4)alkyl or halo; Y is selected from -C(R8)=C(R6)-R5-N(R7)-* and -N(R7)-R5-C(R6)=C(R8)-*, n "*" represents a portion of Y directly adjacent to -[C(R3a)(R3b)]m-; R5 is selected from —C(O)-, —C(S)- and -S(O)2-; R6 is ed from hydrogen, CN, and (C1-C4)alkyl; R7 is selected from hydrogen, (C1-C4)alkyl and (C3—C6)cycloalkyl; and R8 is selected from hydrogen and (C1—C4)alkyl; —18— Z is —C(H)— or -N—; each R1 is independently selected from carbocyclyl, heterocyclyl, halo, halo(C1- C4)alky1, (C1-C4)alkyl, —O-(C1—C4)all In a first aspect of the first embodiment, R2 is optionally substituted and is selected from pyridinyl, isoxazolyl, thiazolyl, pyridazinyl, and phenyl. The values for the remaining les are as described in the first embodiment.
In a second aspect of the first embodiment, R2 is selected from 6-aminopyridin—3- yl, 6-trifluoromethylpyridin—3-yl, 6—chloropyridinyl, pyridin—3-y1, pyridin-Z-yl, pyridin yl, 3,5-dimethy1isoxazolyl, thiazol—4—yl, zinyl, 4-aminophenyl and 6- hylamino)pyridinyl. The values for the remaining variables are as described in the first embodiment, or first aspect thereof.
In a third aspect of the first embodiment, each of R4a and R4b, if present, is hydrogen. The values for the remaining variables are as described in the first embodiment, or the first or second aspect thereof.
. In a fourth aspect of the first ment, n is O. The values for the remaining variables are as described in the first embodiment, or first through third aspects thereof.
In a fifth aspect ofthe first embodiment, Y is -C(R8)=C(R6)-R5-N(R7)—*. The values for the remaining variables are as described in the first embodiment, or first through fourth aspects thereof.
In a sixth aspect of the first embodiment, Y is —C(O)-NH—*. The values for the remaining variables are as bed in the first embodiment, or first h fifth aspects thereof.
In a seventh aspect of the first embodiment, m is l or 2. The values for the remaining variables are as described in the first embodiment, or first through sixth aspects thereof.
In an eighth aspect of the first embodiment, m is l. The values for the remaining variables are as described in the first embodiment, or first h ninth aspects thereof.
In a ninth aspect of the first embodiment, each of R3a and R3b, if present, is independently selected from hydrogen and methyl. The values for the remaining variables are as described in the first embodiment, or first through eighth aspects thereof.
In a tenth aspect of the first embodiment, each of R3a and R3b, if present, is hydrogen. The values for the remaining variables are as described in the first embodiment, or first through ninth aspects thereof.
In an eleventh aspect of the first embodiment, X is —C(H)—. The values for the remaining les are as described in the first embodiment, or first through tenth aspects In a twelfth aspect of the first embodiment, X is -N-. The values for the remaining les are as described in the first embodiment, or first through elventh aspects thereof.
In a thirteenth aspect of the first embodiment, p is 0 or 1. The values for the remaining variables are as described in the first embodiment, or first through twelfth aspects thereof.
In a fourteenth aspect of the first embodiment, p is l. The values for the ing variables are as bed in the first embodiment, or first through thirteenth aspects thereof.
In a fifteenth aspect of the first embodiment, each R1 is independently selected from halo, halo(C1-C4)alkyl, optionally substituted (C1-C4)alky1 and optionally substituted -O-(C1-C4)alkyl. The values for the remaining variables are as bed in the first embodiment, or first through fourteenth aspects f.
In a sixteenth aspect of the first embodiment, R9 is optionally and independently substituted with 1, 2 or 3 substituents and is phenyl or a mbered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as described in the first embodiment, or first through fifteenth aspects thereof.
In a seventeenth aspect of the first embodiment, Y is -NH—C(O)—CH=CH—* or —CH=CH—C(O)—NH—*. The values for the remaining variables are as described in the first embodiment, or first through sixteenth aspects thereof.
In an eighteenth aspect of the first ment, R9 is: phenyl or a 6-membered aryl having 1, 2 or 3 heteroatoms independently ed from nitrogen, oxygen and sulfur; substituted at the meta or para position relative to its attachment point with one substituent selected from -C(O)(C1—C4)alkyl; -C(O)(C0-C1 alkylene)NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3—C7)heterocyclyl; -S(O)2NR"R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3-C7)heterocyclyl; and —C(O)NHNHR12, wherein R12 is an optionally substituted (C5—C6)heteroaryl; and further optionally substituted with 1 or 2 substituents independently selected from halogen, )alkyl and (C1—C4)haloalky1.
The values for the remaining variables are as defined in the first ment, or first through seventeenth s thereof.
In a nineteenth aspect of the first embodiment, the compound is represented by Structural a I: R4b n (I), or a pharmaceutically acceptable salt thereof, wherein: X is -C(H)- or -N-; Y is selected from -C(R8)=C(R6)-R5-N(R7)-* and -N(R7)-R5-C(R6)=C(R8)—*, wherein "*" represents a portion of Y ly adjacent to -[C(R3a)(R3b)]m—; R5 is selected from -C(O)- and -; R6 is selected from hydrogen, CN, and (C1-C4)alkyl; R7 and R8 are each independently selected from hydrogen and (C1-C4)alkyl; - each R1 is independently selected from carbocyclyl, heterocyclyl, halo (e. g., fluoro, , bromo, iodo), 1-C4)a1kyl, (C1-C4)a1kyl, -O—(C1—C4)alkyl, cyano, sulfonate, and -S(O)0.2(C1—C4)alkyl; R2 is aryl or aryl; each of R321 and R", if present, is independently selected from hydrogen and (C1-C4)alkyl; each of R421 and R413, if present, is independently selected from hydrogen, (C1-C4)alkyl, and (C3-C6)cycloa1ky1; R9 is carbocyclyl or heterocyclyl; m is O, l or 2; n is O or 1; and p is O, 1, 2 or 3, wherein: each aryl, heteroaryl, yclyl, heterocyclyl, alkyl or cycloalkyl is Optionally and ndently substituted. Alternative values for the variables are as defined in the first embodiment, or first through enth aspects thereof.
] In a twentieth aspect of the first embodiment, R2 is ally substituted phenyl or optionally substituted C5—C6 heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as described in the first embodiment, or first through nineteenth aspects thereof.
In a twenty-first aspect of the first embodiment, R2 is optionally substituted with 1, 2 or 3 substituents independently selected from amino, halogen, C1—C4 alkyl and C1-C4 haloalkyl. The values for the variables are as bed in the first embodiment, or first through twentieth aspects thereof.
In a twenty-second aspect of the first embodiment, R9 is substituted with one or more substituents independently selected from halogen, (C1-C4)alkyl, (C1- C4)haloalkyl, -C(O)(C1-C4)alkyl, -C(O)(C0-C4 alkylene)NR"R12,-S(O)2NR"R12 and R13NR1 1R", wherein: R11 and R12 are each independently hydrogen, optionally substituted C1—C4 alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; or R11 and R12 are taken er with the nitrogen atom to which they are commonly attached to form an optionally substituted heterocyclyl; and R13 is hydrogen or optionally tuted )alkyl.
TmvfimfiflflwmmmmgvmhflwfleumfihwomdflmflflhRumdwfimm (mmmdmmmmmmfin&emm®figvmflflwUflqwmwbmflmHMmR5mew described in the first embodiment, or first through twenty-first aspects thereof.
In a twenty-third aspect of the first embodiment, R9 is substituted with l, 2 or 3 substituents independently selected from halogen; (C1-C4)alky1; (C1-C4)haloalkyl; -C(O)(C1- C4)a1kyl; -C(O)(Co—C1 alkylene)NR"R12, wherein R" and R12 are taken er with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3- C7)heterocyclyl; —S(O)2NR11R12, wherein R11 and R'2 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3- C7)heterocyclyl; and ~C(O)NHNHR12, wherein R12 is an optionally substituted (C5- C6)heteroaryl. The values for the remaining variables (112., variables other than R11 and R12) and al tuents for the remaining variables (1'. e. , variables other than R9) are as described in the first embodiment, or first through twenty—second aspects thereof.
In a twenty—fourth aspect of the first embodiment, R9 is substituted with one tuent selected from -C(O)(C1-C4)alkyl; -C(O)(C0-C1 alkylene)NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3-C7)heterocyclyl; -S(O)2NRHR12, wherein R11 and R12 are taken together with the en atom to which they are commonly attached to form an ally substituted (C3-C7)heterocyclyl; and HNHR12, wherein R12 is an optionally substituted (C5-C6)heteroaryl; and is r optionally substituted with l or 2 substituents independently selected from halogen, optionally substituted (C1-C4)alkyl and (C1- C4)haloalkyl. The values for the remaining variables (223., variables other than R11 and R12) and optional substituents for the remaining variables (16., variables other than R9) are as bed in the first embodiment, or first through twenty-third aspects thereof.
In a twenty-fifth aspect of the first embodiment, the heterocyclyl formed by R11 and R12 taken together with the nitrogen atom to which they are commonly attached is optionally substituted with l, 2, 3 or 4 substituents independently selected from halo, hydroxyl, halo(C1-C3)alkyl, (C1—C3)alkyl and )alkoxy. Values for the variables and optional substituents for the remaining variables (i.e., variables other than R11 and R12) are as defined in the first embodiment, or first h twenty-fourth aspects thereof.
A second embodiment of the invention is a compound represented by Structural Formula B: Zl>IR11p % \ Z4 Rsa O \ /\/R9 N \ Y Z1 x n R3b m (B), or a pharmaceutically acceptable salt f, wherein: Z is —N— or -C(H)-; and each of 21, 22, Z3 and Z4 is ndently selected from N and C(Rlo), n: no more than one of Z, ZZ, Z3 and Z4 is nitrogen, and each R10 is independently hydrogen or a suitable heteroaryl substituent.
Values and alternative values and optional substituents for the remaining les in Structural Formula B are as defined in the first embodiment, or any aspect thereof.
In a first aspect of the second embodiment, the portion of the compound in 23 N \ 4 / / Structural Formula II represented by u; is selected from: @ 53,, "1‘ / / / 1 | (\N Q" N \ N é \ \ N NJV and My and is optionally further substituted. The D 5 , , values and optional substituents for the remaining variables are as described in the first embodiment, or any aspect thereof, or the second embodiment.
In a second aspect of the second embodiment, the portion of the compound in N\ JV N / Structural a II represented by is NJ: . The values and optional substituents for the remaining variables are as described in the first embodiment, or any aspect thereof, or the second ment, or first aspect thereof.
In a third aspect of the second embodiment, the compound is represented by Structural Formula II: (II), or a pharmaceutically acceptable salt f. Values and alternative values and optional substituents for the les in Structural Formula II are as described in the first embodiment, or any aspect thereof, or the second embodiment, or first or second aspect thereof.
In a fourth aspect of the second embodiment, each R10 is independently hydrogen, amino, halogen, C1-C4 alkyl or C1-C4 haloalkyl, The values and optional substituents for the remaining variables are as described in the first embodiment, or any aspect thereof, or the second embodiment, or first through third aspects f.
A third embodiment of the invention is a compound represented by ural Formula 111 or IV: R4a R3a OER 2 \ R4b RSD n m (111) or R4a R33 0/Q 4b Y%X R R3b n m (IV), or a pharmaceutically acceptable salt thereof, wherein: R121 is selected from hydrogen, halogen, halo(C1-C4)alkyl, (C1- yl, -O-(C;-C4)alky1, -O-halo(C1—C4)alkyl, (C3—C12)carbocyclyl and (C3- C12)heterocyclyl, wherein each alkyl, carbocyclyl and cyclyl is optionally and independently substituted; and R931 is optionally substituted aryl or optionally substituted heteroaryl.
Values and ative values for the ing variables in Structural Formulas III and IV and optional substituents for all the variables in Structural Formulas III and IV are as defined in the first or second embodiment, or any aspect of the foregoing.
In a first aspect of the third embodiment, Rla is selected from hydrogen, fluoro, chloro, -CF3, -CHF2, —OCH3 and )3. The values and al substituents for the remaining variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment.
] In a second aspect of the third embodiment, R13 is selected from fluoro, chloro, -CF3 and —CHF2. The values and optional substituents for the remaining variables are as defined in the first or second embodiment, or any aspect of the ing, or the third embodiment, or first aspect thereof.
In a third aspect of the third embodiment, R1a is chloro or -CF3. The values and optional substituents for the remaining variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first or second aspect thereof.
In a fourth aspect of the third embodiment, R9a is optionally and independently substituted with l, 2 or 3 substituents and is phenyl or a 5—6-membered heteroaryl having I, 2 or 3 heteroatoms independently selected from en, oxygen and sulfur. The values and optional substituents for the remaining variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through third s thereof.
In a fifth aspect of the third embodiment, R9a is substituted with one or more substituents independently selected from halogen, (C1-C4)alkyl, (C1—C4)haloalkyl, —C(O)(C1— C4)alkyl, -C(O)(C0-C4 alkylene)NR1 IR12, —S(0)2NR"R12 and —C(0)NR13NR"R12, wherein: R11 and R12 are each ndently en, optionally tuted C1—C4 alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; or R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted heterocyclyl; and R13 is hydrogen or optionally substituted (C1—C4)alkyl.
The values for the remaining variables (£16., variables other than R1 1, R12 and R13) and optional substituents for the remaining variables (i.e., variables other than Rga) are as defined —26- in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through fourth aspects thereof.
In a sixth aspect of the third embodiment, R921 is substituted with l, 2 or 3 substituents independently selected from halogen; (C1-C4)alkyl; (C1-C4)haloalky1; -C(O)(C1— C4)alkyl; -C(O)(C0-C1 all In a seventh aspect of the third embodiment, R9a is substituted with one substituent selected from -C(O)(C1—C4)alkyl', —C(O)(C0-C1 alkylene)NR"R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally tuted (C3—C7)heterocycly1; —S(O)2NR"R12, wherein R11 and Rlz‘are taken together with the en atom to which they are commonly attached to form an optionally substituted (C3—C7)heterocyclyl; and —C(O)NHNHR12, wherein R12 is an optionally substituted (C5—C6)heteroaryl; and is further ally substituted with 1 or 2 substituents independently selected fromhalogen, (C1-C4)alkyl and (C1-C4)haloalkyl. The values for the remaining variables (126., les other than R11 and R12) and al substituents for the remaining variables (i.e., variables other than R9a) are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or the first through sixth aspects thereof.
In an eighth aspect of the third embodiment, R93 is: phenyl or a 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently ed from nitrogen, oxygen and sulfur; substituted at the meta or para position relative to its attachment point with one tuent selected from -C(O)(C1-C4)alkyl; —(:(0)(c0.c1 a1kylene)NR1 1R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are ly attached to form an optionally substituted (C3—C7)heterocyclyl; —S(O)2NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an ally substituted (C3-C7)heterocyclyl; and —C(O)NHNHR12, wherein R12 is an optionally substituted (C5-C6)heteroaryl; and further optionally substituted with l or 2 substituents independently selected from n, (C1-C4)alkyl and )haloalky1.
The values and optional tuents for the remaining variables (i.e., variables other than R9a, R11 and R12) and optional substituents for the remaining variables (i.e., variables other than R93) are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through seventh aspects thereof.
In a ninth aspect of the third embodiment, R9a is selected from 4-(morpholinosulfonyl)phenyl, morpholine—4—carbonyl)pyridin—2-yl, 4—(morpholine—4— carbonyl)phenyl, 3~(morpholine—4—carbonyl)phenyl, 5-acety1thiophen—2—yl, 4—(2—(pyrazin—2- yl)hydrazine—l—carbonyl)phenyl, 4-(2—morpholinoacetyl)phenyl, 4-(3,3-difluoroazetidine-l- carbonyl)phenyl), 4-(3-methylmorpholinecarbonyl)pheny1, 4-(3,3-dimethylmorpholine—4— carbonyl)phenyl, 4—(2,2—dimethylmorpholine-4—carbonyl)phenyl, 4-(2~(pyridin—2— yl)hydrazine-l—carbonyl)phenyl, 4-(3—fluoropyrrolidine-l-carbonyl)phenyl, 4-(3- fluoroazetidine— l -carbony1)pheny1, 4—(3,3 -dimethylazetidine- l -carbony1)pheny1, 4-((3 - yrrolidin—l—yl)sulfonyl)phenyl, 4—((3-fluoroazetidin—l-yl)sulfonyl)phenyl, 5- (morpholine—4—carbonyl)pyridin—3-yl, 5-fluoro—6-(morpholine—4-carbonyl)pyridin—3—y1, 4-(2- morpholino—Z-oxoacetyl)phenyl, 2-(morpholinecarbonyl)pyrimidin—5~y1, 2,5—difluoro (morpholine—4-carbonyl)phenyl, 2,3-difluoro-4—(morpholine-4—carbonyl)phenyl, 3—fluoro—4— (morpholine—4—carbonyl)phenyl, 6—(morpholine—4-carbony1)pyridazin—3-yl, 4—(2—morpholino- 2—oxoethyl)phenyl, 4-aminocarbonylphenyl, 2-methyl- l -oxoisoindolin—5—yl)benzofuran—2—yl, and 2-methyl—1,3-dioxoisoindolinyl. The values and optional substituents for the remaining variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through eighth aspects thereof.
] In a tenth aspect of thethird ment: Rla is selected from hydrogen, halogen, halo(C1-C4)a1kyl, optionally substituted (C1— C4)alkyl, and optionally substituted —O—(C 1-C4)a1ky1; and R9a is optionally substituted aryl or optionally tuted heteroaryl. The values for the remaining les and al substituents for all the variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through ninth aspects thereof.
In an th aspect of the third- embodiment: R1a is selected from ally tuted (Cg-Ciz)carbocyclyl and ally substituted (C3-C12)heterocyclyl; and R9a is optionally tuted aryl or optionally substituted heteroaryl. The values for the remaining variables and optional substituents for all the variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first throughtenfliaspectsthereof In a twelfth aspect of the third embodiment, Rla is selected from optionally substituted (C6-C12)aryl and optionally substituted (C5-C12)heteroaryl. The values for the remaining variables and optional substituents for all the variables are as defined in the first or second embodiment, or any aspect of the ing, or the third embodiment, or first h eleventh aspects thereof.
In a thirteenth aspect of the third embodiment, R1a is selected from ally substitued phenyl and optionally substituted (C6)heteroaryl. The values for the remaining variables and optional substituents for all the variables are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through twelfth aspectsthereof In a fourteenth aspect of the third embodiment, the compound is represented by Structural Formula III, or a pharmaceutically acceptable salt thereof. Values and alternative values and optional substituents for the variables in Structural Formula 111 are as defined in the first or second embodiment, or any aspect of the ing, or the third embodiment, or first through enth aspects thereof.
In a fifteenth aspect of the third embodiment, the compound is represented by Structural Formula IV, or a pharmaceutically able salt thereof. Values and alternative values and optional substituents for the variables in ural Formula IV are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through thirteenth aspects thereof.
In a sixteenth aspect of the third embodiment: R1a is selected from hydrogen, halogen, halo(C1—C4)alkyl, (C1-C4)alkyl, -O—(C1- C4)alkyl, (C3-C12)carbocyclyl and (C3-C12)heterocyclyl, n each alkyl, carbocyclyl and heterocyclyl is optionally and ndently substituted; and R9a is optionally substituted aryl or optionally substituted heteroaryl. The values for the remaining variables and optional substituents for all the variables are as defined in the first or second embodiment, or any aspect ofthe foregoing, or the third embodiment, or first through th aspects thereof.
In a seventeenth aspect of the third embodiment, R9:1 is: phenyl or a 6—membered heteroaryl having 1, 2 or 3 heteroatoms independently ed from nitrogen, oxygen and sulfur; substituted at the meta or para position relative to its ment point with one substituent ed from —C(O)(C1—C4)a1kyl; —C(O)(C0-C1 alkylene)NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally tuted (C3—C7)heterocyclyl; —S(O)2NR11R12, ' wherein R11 and R12 are taken together with the nitrogen atom to which they are ly attached to form an optionally substituted (C3—C7)heterocyclyl; and —C(O)NHNHR12, wherein R12 is an optionally substituted (C5-C6)heteroaryl; and further optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C4)alkyl and (C1—C4)haloalkyl.
The values for the remaining variables (2‘. e. , variables other than Rga, R11 and R12) and optional substituents for the ing variables (1'. e. , variables other than Rga) are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through sixteenth s thereof.
In an enth aspect of the third embodiment, the heterocyclyl formed by R11 and R12 taken together with the nitrogen atom to which they are commonly attached is optionally substituted with l, 2, 3 or 4 (preferably, 1 or 2) substituents independently selected from halo, hydroxyl, halo(C1-C3)alkyl, (C1—C3)alkyl and (C1—C3)alkoxy. Values for all the variables and optional substituents for the remaining variables (i.e., variables other than R11 and R12) are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through seventeenth aspects thereof.
In a nineteenth aspect of the third ment, the heterocyclyl formed by R11 and R12 taken together with the nitrogen atom to which they are commonly attached is optionally substituted with l or 2 substituents independently selected from halo (6. g., , (C1—C3)alkyl, 1-C3)alkyl (e. g. , trifluoromethyl), hydroxy, (C1-C3)alkoxy (e. g., methoxy) and halo(C1-C3)alkoxy (e. g., romethoxy). Values for all the variables and optional substituents for the ing variables (31a, variables other than R11 and R12) are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through eighteenth aspects thereof.
] In a twentieth aspect of the third embodiment, the carbocyclyl or heterocyclyl of Rla is optionally substituted with l, 2 or 3 substituents independently selected from halo (e.g., fluoro, chloro), cyano, (C1-C3)alky1, halo(C1-C3)alky1 (e.g., trifluoromethyl), hydroxy, (C1- C3)alkoxy (e. g. , methoxy) and 1-C3)alkoxy (e. g. , trifluoromethoxy). Values for all the variables and optional substituents for the remaining variables (1'. e, , variables other than R") are as defined in the first or second embodiment, or any aspect of the foregoing, or the third embodiment, or first through nineteenth aspects thereof.
A fourth embodiment of the invention is a compound represented by ural a V or VI: O (V) or (V1), or a pharmaceutically able salt thereof, wherein m’ is l or 2. Values and alternative values and optional substituents for the remaining variables are as described in the first through third embodiments, or any aspect of the foregoing.
In a first aspect of the fourth embodiment, R1a is selected from fluoro, chloro, -CF3, -CHF2, -C(CH3)3 and -OCH3; and R921 is optionally and independently substituted with l, 2 or 3 substituents and is phenyl or a 5membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the remaining variables (z'.e., variables other than R12‘ and Rga) and optional substituents for all the les are as defined in the first through third embodiments, or any aspect of the ing, or the fourth embodiment.
In a second aspect of the fourth embodiment, R9a is: phenyl or a 6—membered aryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; substituted at the meta or para position relative to its attachment point with one ""bstituent selected from —C(O)(C1-C4)alkyl; -C(O)(C0-C1 alkylene)NR"R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3-C7)heterocyclyl; -S(O)2NRHR12, wherein R11 and R12 are taken together with the nitrogen atom to which they are ly attached to form an optionally substituted (C3-C7)heterocyclyl; and -C(O)NHNHR12, wherein R12 is an optionally substituted (C5-C6)heteroaryl; and further optionally substituted with 1 or 2 tuents independently selected from . halogen, (C1-C4)alkyl and (C1-C4)haloalky1.
The values for the remaining variables (22a, variables other than R9a, R11 and R12) and optional substituents for the remaining variables (1'. e. , variables other than Rga) are as defined in the first through third embodiments, or any aspect of the ing, or the fourth embodiment, or first aspect thereof.
In a third aspect of the fourth embodiment, R2 is optionally substituted pyridinyl.
The values for the remaining variables and optional substituents for all the variables are as defined in the first through third embodiments, or any aspect of the ing, or the fourth embodiment, or first or second aspect thereof.
In a fourth aspect of the fourth embodiment, R9a is selected from 4-(morpholinosulfonyl)phenyl, 5-(5—(morpholine-4—carbonyl)pyridin—2—yl, 4-(morpholine carbonyl)phenyl, 3-(morpholine—4-carbonyl)phenyl, 5-acetylthiophenyl, 4-(2—(pyrazin—2— razine—1—carbonyl)phenyl, orpholinoacetyl)phenyl, -difluoroazetidine—1- carbonyl)phenyl), 4-(3 -methylmorpholinecarbonyl)phenyl, 4-(3 ,3 -dimethylmorpholine—4- carbonyl)phenyl, 4-(2,2-dimethylmorpholinecarbonyl)phenyl, 4-(2-(pyridin—2- razine-1 -carbonyl)phenyl, 4-(3-fluoropyrrolidinecarbonyl)phenyl, 4-(3 - fluoroazetidinecarbonyl)pheny1, 4-(3,3-dimethy1azetidinecarbonyl)phenyl, 4-((3- fluoropyrrolidinyl)sulfony1)phenyl, 4-((3 -fluoroazetidinyl)sulfonyl)phenyl, 5 - (morpholinecarbonyl)pyridiny1, 5-fluoro(morpholinecarbonyl)pyridin-3~y1, 4-(2- morpholinooxoacetyl)phenyl, 2-(morpholinecarbony1)pyrimidinyl, 2,5-difluoro (morpholinecarbonyl)phenyl, 2,3-difluoro(morpholinecarbonyl)phenyl, 3-fluoro (morpholinecarbony1)phenyl, 6-(morpholinecarbonyl)pyridazinyl, and 4-(2- morpholinooxoethy1)phenyl. The values and optional substituents for the remaining variables are as defined in the first through third ments, or any aspect of the foregoing, or the fourth embodiment, or first through third aspects thereof.
In a fifth aspect of the fourth embodiment, m’ is 1. The values and optional tuents for the remaining les are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through fourth aspects thereof.
In a sixth aspect of the fourth embodiment, R2 is selected from 6-aminopyridin yl, pyridinyl, pyridin-2—yl, 3,5-dimethylisoxazolyl, and thiazolyl. The values and optional substituents for the remaining variables are as defined in the first through third ments, or any aspect of the ing, or the fourth embodiment, or first through fifth aspects thereof.
In a seventh aspect of the fourth embodiment, the compound is represented by Structural Formula V, or a ceutically acceptable salt thereof. Values and alternative values and optional substituents for the variables in ural Formula V are as defined in the first through third ments, or any aspect of the foregoing, or the fourth embodiment, or first through sixth aspects thereof.
In an eighth aspect of the fourth embodiment, the compound is ented by Structural Formula VI, or a pharmaceutically acceptable salt thereof. Values and alternative values and optional substituents for the variables in Structural Formula VI are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through seventh aspects thereof.
In a ninth aspect of the fourth ment, R121 is selected from fiuoro, chloro, -CF3, —CHF2, )3, -OCH3 and -OCF3; and R921 is optionally and independently substituted with 1, 2 or 3 substituents and is phenyl or a 5membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the remaining variables (i.e., variables other than R1a and Rga) and optional substituents for all the variables are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through eighth aspects thereof.
In a tenth aspect of the fourth embodiment: m’ is 1 or 2‘, Rlais halogen, halo(C1—C4)alkyl (e. g., trifluoromethyl), (C1-C4)alkyl, -O-(C1-C4)alkyl (e. g, methoxy), -O—halo(C1-C4)alkyl (e. g. , trifluoromethoxy), optionally substituted (C5— ' C12)aryl or ally substituted (Cs-Clz)heteroaryl; and R921 is optionally and independently substituted with 1, 2 or 3 substituents and is phenyl or a 5membered heteroaryl having 1, 2 or 3 heteroatoms ndently selected from nitrogen, oxygen and sulfur. The values for the ing variables (i. 9., variables other than m’, R", and Rga) and optional substituents for all the variables are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through ninth aspects thereof.
In an eleventh aspect of the fourth embodiment, R9a is substituted with one or more substituents independently selected from halogen, (C1-C4)alky1, (C1- C4)haloa1ky1, -C(O)(C1-C4)a1ky1, -C(O)(Co-C4 alkylene)NR"R12,-S(O)2NR"R12 and —C(0)NR‘3NR"R12, wherein: R11 and R12 are each independently hydrogen, optionally tuted C1-C4 alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; or R11 and R12 are taken together with the nitrogen atom to which they are ly attached to form an optionally substituted heterocyclyl; and R13 is hydrogen or optionally substituted (C1-C4)a1kyl.
Values for the remaining variables (1'. e. , variables other than R", R12 and R13) and optional substituents for the remaining variables (1'. e. , variables other than Rga) are as defined in the first h third embodiments, or any aspect of the ing, or the fourth embodiment, or first h tenth aspects thereof.
In a twelfth aspect of the fourth embodiment, R9a is tuted with 1, 2 or 3 substituents independently selected from n; (C1-C4)a1ky1; (C1—C4)haloalkyl; -C(O)(C1- C4)alkyl; -C(O)(C1-C1 alkylene)NR11R]2, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3- C7)heterocyc1y1; -S(O)2NR1 1R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3- C7)heterocyclyl; and -C(O)NHNHR12, wherein R12 is an optionally substituted (C5- C6)heteroaryl. Values for the remaining variables (116., variables other than R11 and R12) and optional substituents for the remaining variables (1'. e. , variables other than Rga) are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through eleventh s thereof. -34_ In a thirteenth aspect of the fourth embodiment, R9a is substituted with one substituent selected from -C(O)(C1-C4)alkyl; -C(O)(Co-C1 alkylene)NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3-C7)heterocyclyl; —S(O)2NR"R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted )heterocyclyl; and HNHR12, wherein R12 is an optionally substituted (C5-C6)heteroaryl; and is further optionally substituted with 1 or 2 substituents independently selected from halogen, optionally substituted (C1-C4)alkyl and (C1-— C4)haloa1kyl. Values for the remaining variables (226., variables other than R11 and R12) and optional substituents for the remaining variables (i.e., variables other than Rga) are as defined in the first through third ments, or any aspect of the foregoing, or the fourth embodiment, or first through twelfth aspects thereof.
In a fourteenth aspect of the fourth embodiment, the heterocyclyl formed by R11 and R12 taken together with the en atom to which they are commonly attached is optionally tuted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxyl, halo(C1—C3)alkyl, )alkyl and (C 1—C3)alkoxy. Values for all the les and optional substituents for the remaining variables (i. e., variables other than R11 and R12) are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through thirteenth aspects thereof.
In a fifteenth aspect of the fourth ment, the heterocyclyl formed by R11 and R12 taken together with the nitrogen atom to which they are commonly attached is ally substituted with 1 or 2 tuents independently selected from halo (e. g., , (C1- C3)alkyl, halo(C1-C3)alky1 (e.g., trifluoromethyl), hydroxy, (C1-C3)alkoxy (e. g., methoxy) and halo(C1—C3)alkoxy (e. g., romethoxy). Values for all the variables and optional substituents for the remaining variables (3'. 6., variables other than R11 and R12)are as defined in the first through third embodiments, or any aspect of the foregoing, or the fourth embodiment, or first through thirteenth aspects thereof.
A fifth embodiment of the invention is a compound represented by Structural Formula VII or VIII: H2N / R93 (VII) or H2N / (VIII), or a pharmaceutically acceptable salt thereof. Values and ative values and optional substituents for the variables in Structural Formulas VII and VIII are as described in the first through fourth embodiments, or any aspect of the foregoing.
In a first aspect of the fifth embodiment, R1a is selected from chloro, -CF3, and —OCH3. The values and optional substituents for the ing variables are as defined in the first through fourth embodiments, or any aspect of the foregoing, or the fifth embodiment.
] In a second aspect of the fifth embodiment, R9a is selected from 4-(morpholinosulfonyl)phenyl, 5-(5-(morpholine—4-carbonyl)pyridin-2—yl, 4-(morpholine carbonyl)phenyl, and 3-(morpholinecarbonyl)phenyl. The values and optional substituents for the ing variables are as defined in the first through fourth embodiments, or any aspect of the foregoing, or the fifth embodiment, or first aspect thereof.
] In a third aspect of the fifth embodiment, the compound is represented by Structural Formula VII, or a pharmaceutically acceptable salt thereof. Values and alternative values and optional substituents for the variables in Structural Formula VII are as defined in the first through fourth embodiments, or any aspect of the foregoing, or the fifth ment, or first or second aspect thereof.
In a fourth aspect of the fifth embodiment, the compound is represented by Structural Formula VIII, or a pharmaceutically acceptable salt thereof. Values and alternative values and al substituents for the variables in Structural Formula VIII are as defined in the first through fourth embodiments, or any aspect of the ing, or the fifth embodiment, or first or second aspect thereof.
A sixth embodiment of the invention is a compound represented by Structural Formula VII: or a pharmaceutically acceptable salt thereof, wherein: m' is l or 2; R121 is halogen, halo(C1-C4)alkyl (e. g., trifluoromethyl), )alkyl, -O-(C1-C4)alkyl (e. g., methoxy), -O-halo(C1-C4)alky1 (e.g., romethoxy), ally substituted (C5- C12)aryl or optionally substituted (Cs-Clz)heteroaryl; and R9a is optionally and independently substituted with 1, 2 or 3 substituents and is phenyl or a 5membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Optional substituents for les R1a and R9a are as defined in the first through fifth embodiments, or any aspect of the foregoing.
In a first aspect of the sixth embodiment, Rla is an optionally substituted C6 aryl or an optionally substituted )heteroaryl. The values for the remaining variables (i.e., variables other than R") and optional substituents for all the variables are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment.
In a second aspect of the sixth embodiment, R121 is an optionally substituted phenyl. The values for the ing variables (1‘. e. , variables other than R") and optional substituents for all the variables are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first aspect thereof.
In a third aspect of the sixth embodiment, R1a is an optionally substituted C5-6 heteroaryl. The values for the remaining variables (i.e., variables other than R") and al substituents for all the variables are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first or second aspect f.
In a fourth aspect of the sixth embodiment, R1a is optionally substituted pyridine.
The values for the remaining variables (£26., variables other than R1 a) and optional substituents for all the variables are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first through third s thereof.
In a fifth aspect of the sixth embodiment, m’ is 1. The values and optional substituents for the remaining variables are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first through fourth aspects thereof.
In a sixth aspect of the sixth embodiment, Rla is halogen, halo(C1-C4)alkyl (e. g, trifluoromethyl), (C1-C4)alkyl, -O-(C1-C4)alkyl (e.g, methoxy) or o(C1-C4)alky1 (e. g, trifluoromethoxy). The values and optional substituents for the remaining variables are as defined in the first through fifth ments, or any aspect of the foregoing, or the sixth embodiment, or first through fifth aspects thereof.
In a seventh aspect of the sixth embodiment, Rla is optionally substituted (C5- C12)aryl or optionally substituted (C5—C12)heter0ary1. The values for the remaining variables (1'. e., variables other than R") and optional substituents for all the les are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first through sixth aspects thereof.
In an eighth aspect of the sixth embodiment, the aryl or heteroaryl (e. g, (C5- C12)aryl, (Cs-Clg)heteroaryl, (C5-C6)heteroaryl, phenyl, pyridinyl) of R1a is ally substituted With l, 2 or 3 substituents ndently selected from halo (e. g, fluoro, ), cyano, (C1—C3)alkyl, halo(C1-C3)alkyl (e. g, trifluoromethyl), hydroxy, )alkoxy (e.g, methoxy) and halo(C1—C3)alkoxy (e. g. , trifluoromethoxy). Values for all the variables and optional substituents for the remaining variables (1'. e. , les other than R") are as defined in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first through seventh s thereof.
] A seventh embodiment ofthe invention is a compound represented by Structural Formula IX: or a pharmaceutically acceptable salt thereof, wherein: m’ is l or 2; -38— Rlais halogen, halo(C1-C4)alkyl (e. g., trifluoromethyl), (C1-C4)alkyl, -O-(C1-C4)alkyl (e. g., y), -O-halo(C1-C4)alkyl (e.g, trifluoromethoxy), optionally substituted (C5- C15)aryl or Optionally substituted (C5—C15)heteroaryl; is -N- or -C(H)-; R20 is (C1-C4)alkyl, (C1-C4)haloalkyl, -O-(C0-C4 alkylene)carbocyclyl, -C4 alkylene)heterocyclyl, -C(H)(OH)-carbocyclyl, -C(H)(OH)-heterocyclyl, —C(H)(CH3)-car bocyclyl, -C(H)(CH3)-heterocycly1, -C(O)(C1-C4)alkyl, -C(S)(C1-C4)alkyl, -C(O)(C0—C4 alkylene)NR"R12, -C(S)(C0-C4 alkylene)NR"R12,-S(O)2(C1-C4)alkyl, -S(O)2NR"R12 or —C(0)NR13NR"R12, wherein: R11 and R12 are each independently hydrogen, ally substituted C1-C4 alkyl, Optionally substituted carbocyclyl, or optionally substituted heterocyclyl; or R11 and R12 are taken together with the en atom to which they are commonly attached to form an optionally substituted heterocyclyl; and R13 is hydrogen or ally substituted (C1-C4)alkyl; each R21, if present, is independently halo; and q is 0, l, 2, 3 or 4 if 25 is -C(H)— and 0, 1, 2 or 3 if 25 is -N-. Alternative values and optional substituents for the variables in Structural Formula IX are as described in the first through sixth ments, or any aspect of the foregoing.
In a first aspect of the seventh ment, q is 0, l or 2, preferably, 0 or 1. The values and optional substituents for the remaining variables are as defined in the first through sixth embodiments, or any aspect ofthe foregoing, or the seventh embodiment.
In a second aspect of the seventh embodiment, R21, for each occurrence and if present, is fluoro. The values and optional substituents for the remaining variables are as defined in the first through sixth embodiments, or any aspect of the foregoing, or the seventh embodiment, or first aspect thereof.
In a third aspect of the seventh embodiment, R20 is Co-C4 ne)NR"R12 or -C(_S)(C0-C4 alkylene)NR"R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted (C3— C7)heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the ing les (i.e., les other than R20, R11 and R12) and optional substituents for all the variables are as defined in the first through sixth embodiments, or any aspect of the foregoing, or the seventh embodiment, or first or second aspect thereof.
In a fourth aspect of the seventh embodiment, 25 is -C(H)-. The values and optional substitutents for the remaining variables are as defined in the first through sixth embodiments, or any aspect of the foregoing, or the h embodiment, or first through third aspects thereof.
In a fifth aspect of the seventh embodiment, 25 is —N—. The values and optional substituents for the ing variables are as defined in the first h sixth embodiments, or any aspect of the foregoing, or the seventh embodiment, or first through fourth aspects thereof.
In a sixth aspect of the seventh embodiment, the compound is represented by Structural a X: or a pharmaceutically acceptable salt thereof. Values and alternative values and al substituents for the variables in Structural Formula X are as described in the first through sixth ments, or any aspect of the foregoing, or the seventh embodiment, or first through fifth aspects thereof. [001 77] An eighth embodiment is a compound represented by Structural a XI: or a pharrnaceutically acceptable salt thereof, wherein: m’ is l or 2, preferably 1; is -N- or -C(H)-; each of Z6 and Z7 is independently -N— or -C(H)-, preferably -C(H)-, wherein no more than one of Z6 and Z7 is nitrogen; each R21, if present, is independently halo (6. g. each R22, if present, is independently halo (e. g., fluoro, ), cyano, (C1-C3)alkyl, halo(C1- C3)alkyl (e. g. ,‘trifluoromethyD, hydroxy, (C1-C3)alkoxy (e. g., methoxy) or halo(C1- C3)alkoxy (e. g., trifluoromethoxy), preferably halo; q is 0, 1, 2, 3 or 4 MS is -C(H)- and 0,1,2 or 3 if25 is -N-; and q’ is O, 1, 2 or 3, preferably 0, l or 2, more preferably 0 or 1. Values and alternative values for the remaining les in ural Formula XI are as bed in the first through seventh embodiments, or any aspect ofthe foregoing.
In a first aspect of the eighth embodiment, Z6 and Z7 are each -C(H)-. The values for the remaining variables are as bed in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment.
In a second aspect of the eighth embodiment, Z6 is -N- and Z7 is —C(H)—. The values for the remaining variables are as described in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment, of first aspect thereof.
In a third aspect of the eighth embodiment, 26 is -C(H)— and Z7 is -N—. The values for the remaining variables are as described in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment, of first or second aspect thereof.
A ninth ment is a compound represented by Structural a XII: or a pharmaceutically acceptable salt thereof, wherein: m' is l or 2, preferably 1; is -N- or —C(H)-; each of 26 and Z7 is independently -N~ or -C(H)-, preferably -C(H)-, wherein no more than one of 26 and Z7 is nitrogen; R20 is )alkyl, (C1—C4)haloalkyl, -O-(C0-C4 alkylene)carbocyclyl, —O—(C0—C4 alkylene)heterocyclyl, -C(H)(OH)-carbocyclyl, -C(H)(OH)—heterocyclyl, -C(H)(CH3)—car bocyclyl, —C(H)(CH3)-heterocyclyl, C1-C4)alkyl, C1-C4)alkyl, -C(O)(C0—C4 alkylene)NR"R12, -C(S)(C0-C4 alkylene)NR"R12,-S(O)2(C1-C4)alkyl, -S(O)2NR"R12 or —C(0)NR13NR"R12, wherein: R11 and R12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted yclyl, or optionally substituted heterocyclyl; or R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted heterocyclyl; and R13 is hydrogen or optionally tuted (C1—C4)alkyl; each R", if present, is independently halo (e.g., fluoro); each R22, if present, is independently halo (e.g., fluoro, chloro), cyano, (C1—C3)alkyl, halo(C1- C3)alkyl (e.g, trifluoromethyl), hydroxy, (C1—C3)alkoxy (e. g., methoxy) or halo(C1— C3)alkoxy (e. g, trifluoromethoxy), preferably halo; q is 0, 1, 2, 3 or 4 iff is —C(H)- and o, 1, 2 or 3 ifz5 is —N—; and q' is 0, 1, 2 or 3, preferably 0, l or 2, more preferably 0 or 1. Alternative values and optional substituents for the variables in Structural Formula XII are as described in the first through eighth ments, or any aspect of the foregoing.
Exemplary compounds are set forth in Table 1.
Formulation and Administration Another embodiment ofthe invention is a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adj uvant, or vehicle. In certain embodiments, a composition of the invention is ated for stration to a patient in need of the composition, In some embodiments, a composition of the invention is formulated for oral, enous, subcutaneous, intraperitoneal or ological administration to a patient in need thereof.
The term "patient," as used , means an animal. In some embodiments, the animal is a mammal. In certain embodiments, the patient is a veterinary patient (Le, a non— human mammal t). In some embodiments, the patient is a dog. In other embodiments, the patient is a human.
"Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, ations should meet sterility, pyrogenicity, and general safety and purity standards, as ed by FDA Office of Biologics standards.
The phrase "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adj uvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adj uvants or vehicles that may be used in the compositions of this invention include, but are not d to, ion exchangers, a, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, e, sorbic acid, potassium e, partial glyceride mixtures of ted vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium en phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based nces, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene—polyoxypropylene—block polymers, polyethylene glycol and wool fat.
Compositions of the present invention may be administered orally, parenterally (including subcutaneous, uscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and/or intraperitoneally.
The term "parenteral," as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra—articular, intra—arterial, intra- synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal intralesional and ranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. ceutically acceptable compositions of this invention can be orally stered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and ons. In the case of tablets for oral use, rs commonly used include e and corn starch. Lubricating agents, such as magnesium te, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and/or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and/or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
In some embodiments, an oral formulation is formulated for immediate release or sustained/delayed e.
] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or ium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) s, such as ymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, (1) disintegrating agents such as aga --agar, m carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium salts, g) g agents, such as acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Compositions suitable for buccal or sublingual administration include s, lozenges and les, wherein the active ingredient is formulated with a carrier such as sugar and acacia, anth, or n and glycerin.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be ed with gs and shells such as enteric coatings and other coatings well known in the pharmaceutical ating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed . Examples of embedding compositions that can be used include polymeric substances and waxes.
A compound of the invention can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound of the invention can be admixed with at least one inert diluent such as sucrose, e or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e. g., tableting ants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.
] In another embodiment, a compound of the invention can be provided in an extended (or "delayed" or "sustained") release composition. This d-release composition comprises a compound of the invention in combination with a delayed-release component. Such a composition allows targeted release of a provided compound into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and/or the rectum. In certain embodiments, the delayed-release composition comprising a compound of the invention r comprises an c or endent coating, such as cellulose acetate phthalates and other phthalates (e. g., polyvinyl acetate phthalate, rylates (Eudragits)). Alternatively, the delayed-release ition provides controlled release to the small intestine and/or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release ition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be ed by coatings which are digested by bacterial s such as amylose or pectin, by pH dependent rs, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and/or by acrylic acid linked to azoaromatic bonds coatings.
In certain ments, the delayed-release composition of the present invention comprises hypromellose, rystalline cellulose, and a lubricant. The e of a compound of the invention, hypromellose and microcrystalline cellulose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.
Alternatively, pharmaceutically acceptable compositions" of this invention can be administered in the form of itories for rectal administration. These can be prepared by mixing the compound of the ion with a suitable ritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
Pharmaceutically acceptable itions of this invention can also be administered topically, especially when the target of treatment es areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be ed in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches can also be used.
For other topical applications, the pharmaceutically acceptable compositions of the ion can be formulated in a suitable ointment containing the active ent suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, pharmaceutically able compositions of the invention can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the ceutical ition can be formulated with a suitable lotion or cream containing the active compound suspended or ved in a carrier with suitable emulsifying agents. In some embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. In other embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyld0decanol, benzyl l and water and penetration enhancers.
] For ophthalmic use, pharmaceutically able compositions of the invention can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile , either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be ated in an ointment such as petrolatum.
] Pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well—known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
In some embodiments, pharmaceutically acceptable compositions of this ion are formulated for oral administration.
In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for intra-peritoneal administration.
In some embodiments, ceutically acceptable compositions of this invention are formulated for l stration.
The amount of compounds ofthe present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host d, the particular mode of administration and the activity of the compound employed. Preferably, compositions should be formulated so that a dosage of n 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving the composition.
It should also be understood that a specific dosage and treatment n for any particular patient will depend upon a variety of factors, including the activity of the c compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular e being treated. The amount of a compound of the t invention in the composition will also depend upon the particular compound in the composition.
Other phamiaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, a, aluminum stearate, in, self-emulsifying drug delivery systems (SEDDS) such as d-oc-tocopherol polyethylene glycol 1000 succinate, surfactants used in ceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of ted vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium icate, polyvinyl pyrrolidone, cellulose—based nces, polyethylene glycol, sodium carboxymethylcellulose, rylates, waxes, polyethylene-p0lyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as 0t-, [3-, and y-cyclodextrin, or chemically modified tives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- B-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described .
The pharmaceutical compositions of this invention are ably administered by oral administration or by injection. The pharmaceutical itions of this invention can contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
The pharmaceutical compositions can be in the form of a sterile injectable ation, for example, as a sterile inj ectable aqueous or oleaginous suspension. This suspension can be formulated according to ques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and ding agents. The sterile inj ectable preparation can also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or erides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of ables, as are natural ceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil ons or suspensions can also contain a long—chain alcohol diluent or dispersant, or carboxymethyl ose or similar dispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other r emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional eutic or prophylactic agents, both the nd and the additional agent should be present at dosage levels of between about 1 to 100%, and more ably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agent(s) can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. atively, the additional agent(s) can be part of a single dosage form, mixed together with the compound of this invention in a single composition.
The compounds described herein can, for e, be administered by injection, intravenously, intraarterially, intraocularly, intravitreally, subdermallym, orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight or, alternatively, in a dosage ranging from about 1 mg to about 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate stration of an effective amount of a compound ofthe invention, or a composition thereof, to achieve the desired or stated effect. lly, the ceutical compositions of this invention will be administered from about 1 to about 6 times per day or, alternatively, as a continuous infusion.
Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical ation will contain from about 5% to about 95% active compound (w/w). Alternatively, a preparation can contain from about 20% to about 80% active compound.
Doses lower or higher than those recited above may be ed. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body , general health , sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the e, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this invention can be administered, if necessary.
Subsequently, the dosage or frequency of stration, or both, can be reduced, as a function of the ms, to a level at which the improved condition is retained when the symptoms have been alleviated to the d level. Patients may, however, require intermittent treatment on a erm basis upon recurrence of disease symptoms.
Uses ofCompounds and Pharmaceutically Acceptable Compositions As used herein, "PAK—mediated" disorder or condition means any disease or other rious condition in which one or more p21-activated kinases (PAK) plays a role. ingly, another embodiment of the present invention relates to treating, for example, ing the severity of, a PAR-mediated er or condition. PAK-mediated disorders e cancer, neurodegenerative diseases and immune system diseases. Specific examples of PAK-mediated ers are set forth in detail below.
P21-activated kinases (PAKs) can be classified into two groups: group I and group II. Group I comprises PAKl, PAK2 and PAK3, and group 11 ses PAK4, PAKS and PAK6. Some embodiments of the invention relate to treating a group I diated disorder or condition, for example, a PAKI —mediated disorder or condition, a PAK2- mediated disorder or condition, a PAK3—mediated disorder or condition or a disorder or condition mediated by a combination ofPAKI and PAK3, for example, a disorder or , PAK2, condition mediated by PAKl and PAK2, PAKl and PAK3, PAK2 and PAK3 or PAKl , PAK2 and PAK3. Other embodiments of the ion relate to treating a group II PAK- mediated disorder or condition, for example, a PAK4—mediated disorder or Condition, a PAKS-mediated disorder or condition, a PAK6—mediated er or condition or a disorder or condition mediated by a COmbination of PAK4, PAKS and PAK6, for example, a disorder or condition mediated by PAK4 and PAKS, PAK4 and PAK6, PAKS and PAK6 or PAK4, PAKS and PAK6.
When "PAK" is followed by a numeral, as in "PAK4", the particular PAK isoform corresponding to that numeral is being designated. Thus, as used herein, "PAK4— mediated" disorder or condition means any disease or other deleterious ion in which PAK4 is known to play a role. Accordingly, another embodiment of the present invention relates to treating, for example, lessening the severity of, a PAK4-mediated disorder or condition. PAK4-mediated disorders include cancer, egenerative diseases and immune system diseases. Specific examples of PAK4-mediated disorders are set forth in detail below.
Compounds provided by this invention are also useful as tools, for example, to study PAK modulation in biological and pathological phenomena, to study cancer or for the identification and/or comparative evaluation of PAK modulators. Accordingly, in particular embodiments, the present invention es a method for studying an effect of a compound described herein, or a salt or ition thereof, on a sample, the method comprising contacting a sample comprising cells in culture or one or more PAKs with the compound, or the salt or composition f; and measuring the effect of the compound, or salt or composition thereof, on the cells or the one or more PAKs. For example, the compounds described herein can be used as a standard or control substance in binding assays (e,g., competitive binding assays) to identify or evaluate potential PAK modulators or as a discovery tool to probe the role of PAK modulation in certain disorders or ions, such as those described herein, including cancer and PAK-mediated disorders or conditions. tion, for example, modulation of one or more PAKs, can be accomplished by ligands, particularly PAK ligands, that act as, for example, ts, l agonists, inverse agonists, antagonists or allosteric modulators (e. g., allosteric agonists, positive allosteric modulators, negative allosteric modulators). Agonists act directly to activate a receptor, whereas antagonists act indirectly to block receptor signaling by preventing agonist activity through their association with the receptor. Allosteric modulation occurs when a ligand binds at an allosteric site of a or, rather than at an orthosteric binding site.
Allosteric modulators can include both positive and negative modulators of orthosteric -mediated activity. t being bound by a particular theory, it is believed that the compounds described herein can bind to one or more PAKs and function as allosteric modulators.
] Compounds and compositions bed herein are useful for treating cancer in a subject in need thereof. Thus, in certain embodiments, the present invention provides a method for treating cancer, comprising the step of administering to a patient in need thereof a nd of the present ion, or pharmaceutically acceptable salt or composition thereof. The compounds and itions described herein can also be administered to cells in culture, 6. g., in vitro or ex vivo, or to a subject, e. g, in vivo, to treat, prevent, and/or diagnose a variety of disorders, ing those described herein below.
The activity of a nd ed in this ion as an anti-cancer agent may be assayed in vitro, in vivo or in a cell line. Detailed conditions for assaying a compound utilized in this invention as an anti-cancer agent are set forth in the Exemplification.
As used herein, the term "treat" or "treatment" is defined as the application or administration of a compound, alone or in combination with a second compound, to a subject, e.g., a patient, or application or administration of the compound to an ed tissue or cell, 6. g., cell line, from a subject, 6. g., a patient, who has a disorder (6. g, a disorder as described herein), a symptom of a disorder, or a position toward a disorder, in order to cure, heal, alleviate, relieve, alter, remedy, rate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e. g, to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the er). In the case of wound healing, a therapeutically effective amount is an amount that promotes healing of a wound.
As used herein, "promoting wound healing" means treating a subject with a wound and achieving healing, either partially or fully, of the wound. Promoting wound healing can mean, e. g., one or more of the following: promoting epidermal closure; ing migration of the dermis; promoting dermal e in the dermis; reducing wound healing complications, e.g., hyperplasia of the epidermis and adhesions; reducing wound dehiscence; and promoting proper scab formation.
As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, ing or improving one or more symptoms of a disorder. In the case of wound healing, a therapeutically effective amount is an amount that es healing of a wound.
As used herein, an amount of a compound effective to t a disorder, or a "prophylactically ive amoun " of the compound refers to an amount ive, upon single- or multiple-dose administration to the subject, in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of the disorder.
As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e. g, a disorder described herein or a normal subject. The term "non-human animals" of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e. g, sheep, cow, pig, etc., and companion animals (dog, cat, horse, eta).
For example, provided herein are methods of treating various cancers in mammals (including humans and non-humans), comprising administering to a patient in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof. Such cancers include hematologic malignancies (leukemias, lymphomas, myelomas, ysplastic and myeloproliferative syndromes) and solid tumors (carcinomas such as oral, gall bladder, prostate, breast, lung, colon, pancreatic, renal, ovarian as well as soft tissue and osteo- sarcomas, and stromal tumors). Breast cancer (BC) can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC. In addition, breast cancer can include invasive or non-invasive ductal or lobular carcinoma, tubular, medullary, mucinous, papillary, cribriform oma of the breast, male breast cancer, recurrent or atic breast cancer, des tumor of the breast and Paget’s disease of the nipple. In some embodiments, the present invention provides a method of treating lymphoma, specifically, mantle cell lymphoma.
In some ments, the present invention provides a method of treating atory disorders in a patient, comprising administering to the patient a nd of the invention, or a pharmaceutically acceptable salt f. Inflammatory disorders treatable by the compounds of this invention include, but are not limited to, multiple sclerosis, rheumatoid arthritis, degenerative joint disease, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium and large vessel), atherosclerosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, tis, sepsis, psoriasis and other dermatological inflammatory disorders (such as eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, and dermatosis with acute inflammatory components, pemphigus, pemphigoid, allergic dermatitis), and urticarial mes.
Viral diseases treatable by the nds of this ion e, but are not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, cellular carcinoma, primary HSV-l infection (e.g., ostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-l infection (e. g., herpes labialis and cold sores), primary HSV—2 infection, latent HSV—2 ion, aseptic meningitis, infectious cleosis, Cytomegalic inclusion e, Kaposi’s sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious alomyelitis, Mumps, hyperplastic epithelial lesions (e. g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical oma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, influenza-like syndrome, severe bronchiolitis with pneumonia, German s, congenital rubella, Varicella, and herpes zoster. Viral diseases ble by the nds of this invention also include chronic viral infections, including hepatitis B and hepatitis C.
Exemplary ophthalmology disorders include, but are not limited to, macular edema (diabetic and nondiabetic macular edema), aged related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic is, retrobulbar optic neuritis, keratitis, blepharitis, ive retinal detachment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, ophthalmic e associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic retinopathy, idal choroidal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein occlusion, Coats' disease, familial ive vitreoretinopathy, pulseless disease (Takayasu‘s disease), Eales e, antiphospholipid antibody syndrome, leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon- associated retinopathy, hypertensive retinopathy, radiation retinopathy, l epithelial stem cell deficiency or cataract.
Neurodegenerative diseases treatable by a compound of Formula I include, but are not d to, Parkinson’s, Alzheimer’s, and Huntington’s, and Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease). nds and compositions described herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative myopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephn'tis, polycystic kidney disorder (PKD) and other renal disorders. nds and compositions described herein may also be used to treat disorders related to food intake such as obesity and hyperphagia.
In another embodiment, a compound or composition described herein may be used to treat or prevent allergies and respiratory disorders, including asthma, bronchitis, ary fibrosis, ic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic ctive pulmonary disease (COPD).
Other disorders treatable by the compounds and compositions described herein include muscular dystrophy, arthritis, for example, osteoarthritis and rheumatoid arthritis, sing spondilitis, tic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart e, chronic heart failure, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, ary disease, cystic fibrosis, acid—induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary e, n’s syndrome, e membrane disease, kidney disease, glomerular disease, lic liver disease, gut diseases, peritoneal endometriosis, skin diseases, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia-ID, behcet’s disease, incontinentia pigmenti, tuberculosis, asthma, crohn’s disease, colitis, ocular y, appendicitis, paget’s e, pancreatitis, onitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica- induced diseases, sleep apnea, AIDS, HIV-l, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial mediterranean fever, hereditary periodic fever me, psychosocial stress diseases, neuropathological diseases, familial dotic polyneuropathy, inflammatory neuropathy, parkinson’s disease, multiple sclerosis, alzheimer’s disease, amyotropic lateral sclerosis, huntington’s disease, cataracts, or hearing loss.
Yet other disorders treatable by the compounds and compositions described herein e head injury, uveitis, inflammatory pain, allergen induced asthma, non-allergen d asthma, glomerular nephritis, ulcerative colitis, necrotizing colitis, hyperimmunoglobulinemia D with recurrent fever (HIDS), TNF receptor associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndromes, Muckle-Wells syndrome (urticaria deafness amyloidosis),familial cold urticaria, neonatal onset multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), Blau syndrome, pyogenic e arthritis, pyoderrna gangrenosum,acne (PAPA), deficiency of the interleukin-l—receptor antagonist (DIRA), subarachnoid hemorrhage, polycystic kidney disease, transplant, organ transplant, tissue lant, myelodysplastic syndrome, irritant-induced inflammation, plant irritant-induced inflammation, poison ivy/ urushiol oil-induced inflammation, chemical irritant—induced inflammation, bee sting-induced inflammation, insect bite-induced inflammation, sunburn, burns, dermatitis, endotoxemia, lung injury, acute respiratory distress syndrome, alcoholic hepatitis, or kidney injury caused by tic ions.
Yet another disorder treatable by the compounds and compositions described herein is schizophrenia.
In further s, the present ion provides a use of a compound of the ion, of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In some ments, the present invention provides a use of a compound of the invention in the manufacture of a medicament for the treatment of any of cancer and/or neoplastic disorders, angiogenesis, mune disorders, inflammatory disorders and/or es, epigenetics, hormonal disorders and/or diseases, viral diseases, neurodegenerative disorders and/or diseases, wounds, and ophthamalogic disorders.
Neoplastic Disorders A compound or composition described herein can be used to treat a neoplastic disorder. A "neoplastic er" is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e. g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders, e.g., tumors g from prostate, brain, bone, colon, lung, breast, ovarian, and liver origin, hematopoietic neoplastic disorders, e.g., ias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors. ent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers.
Treatment with the nd can be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell eration, reduced tumor mass, etc.
] The disclosed methods are useful in the prevention and treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast—Ovarian Cancer (BRCAl or BRAC2 mutations) Syndromes, and others. The disclosed methods are also useful in treating non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the s organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e. g., renal, lial, or testicular tumors) tracts, pharynx, te, and ovary. Exemplary adenocarcinomas include colorectal cancers, cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.
Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; cortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related ma; AIDS—Related Malignancies; Anal ; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, ood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, ood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual y and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood ); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; ood Cancers; Chronic cytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CeIl ma; Endometrial Cancer; Ependymoma, Childhood; lial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye , Retinoblastoma; adder ; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; , Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine as); Kaposi's Sarcoma; Kidney Cancer; Laryngeal ; Laryngeal Cancer, Childhood; Leukemia, Acute blastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non—Small Cell; Lung , Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS- Related; Lymphoma, l Nervous System (Primary); Lymphoma, Cutaneous T—Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, ood; Lymphoma, Hodgkin’s During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant elioma, Adult; ant Mesothelioma, Childhood; Malignant Thymoma; Mantle Cell Lymphoma; Medulloblastoma, Childhood; ma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; atic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell sm; Mycosis Fungoides; Myelodysplastic mes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's ma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; all Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low ant ial Tumor; Pancreatic Cancer; Pancreatic , Childhood; Pancreatic Cancer, Islet Cell; —58— Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial ive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non—Hodgkin’s Lymphoma; y Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell , Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; ry Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi’s; Sarcoma (Osteosarcoma)/Malignant Fibrous cytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin ; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; h (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- CeIl Lymphoma, Cutaneous; Testicular Cancer; Thymoma, ood; Thymoma, ant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; blastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual y and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms‘ Tumor. Further exemplary cancers include diffuse large B— cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and serous and endometrioid cancer.
Yet a further exemplary cancer is alveolar soft part sarcoma. r exemplary cancers include diffuse large B-cell lymphoma (DLBCL) and mantle cell ma (MCL). Yet further exemplary cancers include endocervical , B- cell ALL, T-cell ALL, B- or T-cell lymphoma, mast cell cancer, glioblastoma, neuroblastoma, follicular ma and Richter’s syndrome. Yet further exemplary cancers include glioma.
Metastases of the aforementioned cancers can also be treated or ted in accordance with the methods described herein.
Combination therapies ] In some embodiments, a compound described herein is stered together with an additional "second" therapeutic agent or treatment. The choice of second therapeutic agent may be made from any agent that is lly used in a monotherapy to treat the indicated disease or condition. As used herein, the term "administered together" and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with r eutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of any of the formulas bed herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In anOther embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this be minimized. way, undesired side effects ated with high doses of either agent may Other potential advantages (including without limitation improved dosing ns and/or reduced drug cost) will be apparent to those of skill in the art. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. atively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
Cancer Combination ies In some embodiments, a compound described herein is administered together with an additional cancer treatment. Exemplary cancer treatments include, for example, chemotherapy, targeted therapies such as antibody therapies, kinase tors, therapy, and hormonal therapy, and anti-angiogenic therapies. Examples of each of these treatments are provided below.
As used herein, the term "combination,73 ‘6combined," and related terms refer to the aneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the t invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adj uvant, or vehicle.
] The amount of both a compound of the invention and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound ofthe invention can be stered.
Chemotherapy In some embodiments, a compound described herein is administered with a chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in l, in st with ed therapy. Chemotherapy drugs interfere with cell division in various le ways, e. g., with the duplication ofDNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
Examples of chemotherapeutic agents used in cancer therapy e, for e, antimetabolites (e. g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase tors and others).
Exemplary agents include Aclarubicin, Actinomycin, Alitretinon, amine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, lide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Cannofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, xel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, abine, icin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (SFU), Fotemustine, abine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, ven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal ubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, rexate, Methyl evulinate, Mitobronitol, Mitoguazone, Mitotane,‘Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, TegafiJr-uracil, Temoporfin, lomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, stinev, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.
Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more herapy agents are used as combination chemotherapy. In some embodiments, the chemotherapy agents (including ation chemotherapy) can be used in combination with a compound described herein.
Targeted therapy Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule ed therapy drugs are generally inhibitors of tic domains on mutated, pressed, or otherwise critical proteins within a cancer cell.
Prominent examples are the tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and also cyclin-dependent kinase inhibitors such as dib and seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HERZ/neu antibody trastuzumab (Herceptin®) typically used in breast cancer, and the anti-CD20 antibody rituximab and momab typically used in a variety of B-cell malignancies. Other exemplary antibodies e cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. ary fusion proteins include aflibercept and ukin diftitox. In some embodiments, targeted therapy can be used in ation with a compound described herein, e. g., GleeVec (Vignari and Wang 2001).
Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface ors or affected extracellular matrix surrounding a tumor.
Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.
Angiogenesis Compounds and methods described herein may be used to treat or prevent a disease or disorder associated with angiogenesis. Diseases associated with angio genesis include cancer, cardiovascular disease and macular degeneration.
Angiogenesis is the physiological process involving the growth of new blood vessels from isting vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. However, it is also a fundamental step in the transition rs from a dormant state to a malignant one.
Angiogenesis may be a target for combating diseases characterized by either poor vascularisation or abnormal vasculature.
Application of c compounds that may inhibit or induce the creation of new blood s in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a ing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several es, such as ic chronic wounds, are the result of e or insufficient blood vessel formation and the site, may be treated by a local expansion of blood vessels, thus bringing new nutrients to facilitating repair. Other diseases, such as age-related r degeneration, may be created by a local expansion of blood s, interfering with normal physiological processes.
Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given k.
Upregulation of VEGF is a major component of the physiological se to exercise and its role in enesis is suspected to be a possible treatment in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, ally forming tube structures resembling capillaries. ~63- Tumors induce blood vessel growth (angio genesis) by secreting s growth factors (e.g., VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion.
Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new eral vessels to overcome the ischemic .
Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angio genesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, g loss of vision.
Anti-angiogenic therapy can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sunitinib, nib, or monoclonal antibodies or receptor "decoys" to VEGF or VEGF receptor ing bevacizumab or VEGF~Trap, or thalidomide or its analogs (lenalidomide, pomalidomide), or agents targeting non-VEGF angiogenic targets such as fibroblast growth factor (FGF), oietins, or angiostatin or endostatin.
Epigenetics Compounds and methods described herein may be used to treat or prevent a disease or disorder associated with epigenetics. Epigenetics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA ce. One e of etic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, stem cells become the various cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while‘inhibiting others.
Epigenetic changes are ved when cells . Most epigenetic changes only occur Within the course of one individual organism's me, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many s of teratogens, tion of histone modifications and heterochromatin, and technical limitations affecting nogenesis and cloning.
Exemplary diseases associated with epigenetics include ATR-syndrome, fragile X-syndrome, ICF syndrome, Angelman’s syndrome, Prader-Wills syndrome, BWS, Rett syndrome, oc-thalassaemia, cancer, leukemia, Rubinstein-Taybi syndrome and Coffin-Lowry syndrome.
The first human disease to be linked to etics was cancer. Researchers found that diseased tissue from patients with colorectal cancer had less DNA methylation than normal tissue from the same patients. Because methylated genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chromatin. On the other hand, too much methylation can undo the work of tive tumor suppressor genes. , DNA methylation occurs at CpG sites, and a ty of CpG cytosines are methylated in mammals. However, there are hes ofDNA near er regions that have higher concentrations of CpG sites (known as CpG islands) that are free of methylation in normal cells. These CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off. This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer.
Hypermethylation of CpG islands can cause tumors by shutting off tumor—suppressor genes.
In fact, these types of changes may be more common in human cancer than DNA sequence mutations.
] Furthermore, gh epigenetic changes do not alter the sequence of DNA, they can cause ons. About half of the genes that cause familial or inherited forms of cancer are turned off by methylation. Most of these genes normally suppress tumor formation and help repair DNA, including O6-methylguanine-DNA methyltransferase (MGMT), MLHl cyclin—dependent kinase tor 2B (CDKNZB), and A. For example, hyperrnethylation of the promoter ofMGMT causes the number of G-to-A mutations to increase.
Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA. Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH] can make a microsatellite unstable and lengthen or n it.
Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers.
Fragile X syndrOme is the most frequently inherited mental disability, particularly in males. Both sexes can be. affected by this condition, but because males only have one X chromosome, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. People with this syndrome have'severe intellectual disabilities, delayed verbal development, and "autistic-like" behavior.
Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a cope; it usually appears as if it is hanging by a thread and easily breakable. The syndrome is caused by an abnormality in the FMR] (fragile X mental retardation 1) gene. People who do not have fragile X syndrome have 6 to 50 s of the trinucleotide CGG in their FMRI gene. However, individuals with over 200 repeats have a full mutation, and they usually show symptoms of the syndrome. Too many CGGs cause the CpG‘ islands at the promoter region of the FMR] gene to become methylated; normally, they are not. This ation turns the gene off, stopping the FMR] gene from producing an important protein called fragile X mental retardation protein. Loss of this c protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion on as the cause of fragile X, the epigenetic change associated with FMR] ation is the real syndrome culprit.
Fragile X me is not the only disorder associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein-Taybi, Coffin- Lowry, Prader—Willi, Angelman, Beckwith—Wiedemann, ATR-X, and Rett syndromes. etic therapies e tors of enzymes controlling epigenetic modifications, cally DNA methyltransferases and histone deacetylases, which have shown promising anti-tumorigenic effects for some malignancies, as well as antisense oligonucloetides and siRNA.
Immunoz‘herapy In some embodiments, a compound described herein is administered with an immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the t’s own immune system to fight the tumor. Contemporary ~66- methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, te cancer vaccine Provenge, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and ma patients.
Allogeneic hematopoietic stem cell transplantation can be ered a form of immunotherapy, since the donor’s immune cells will often attack the tumor in a graft-versus— tumor effect. In some embodiments, the immunotherapy agents can be used in combination with a compound described herein.
Hormonal therapy In some embodiments, a compound described herein is administered with a hormonal therapy. The growth of some cancers can be ted by providing or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostate cancers, as well as certain types of leukemia which d to certain retinoids/retinoic acids. Removing or blocking estrogen or testosterone is often an important additional ent. In certain cancers, administration ofhormone agonists, such as progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in ation with a compound described herein.
Hormonal y agents include the administration of hormone agonists or hormone antagonists and e ids/retinoic acid, compounds that inhibit estrogen or testosterone, as well as administration of togens.
Inflammation andAutoimmune Disease The compounds and methods described herein may be used to treat or prevent a disease or disorder associated with inflammation, particularly in humans and other mammals.
A compound described herein may be administered prior to the onset of, at, or after the initiation of inflammation. When used prophylactically, the compounds are preferably provided in advance of any atory response or symptom. Administration of the compOunds can prevent or attenuate inflammatory responses or symptoms. Exemplary inflammatory conditions include, for e, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, rative joint disease, spondouloarthropathies, other seronegative inflammatory arthridities, polymyalgia rheumatica, various vasculidities (e. g., giant cell arteritis, ANCA+ vasculitis), gouty arthritis, systemic lupus matosus, le arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e. g., insulin dependent diabetes mellitus or juvenile onset diabetes), menstrual , cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis (acute or chronic), le organ injury syndrome (e.g., secondary to septicemia or trauma), myocardial infarction, atherosclerosis, stroke, reperfusion injury (e.g., due to cardiopulmonary bypass or kidney dialysis), acute ulonephritis, thermal injury (i.e., sunburn), necrotizing enterocolitis, granulocyte transfusion associated syndrome, and/or Sj ogren's syndrome. Exemplary inflammatory conditions of the skin include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory components.
In another embodiment, a compound or method described herein may be used to treat or t allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute atory distress syndrome, and any c obstructive pulmonary disease (COPD). The compounds may be used to treat c hepatitis infection, including hepatitis B and hepatitis C.
Additionally, a compound or method described herein may be used to treat autoimmune diseases and/or ation associated with mune diseases, such as organ-tissue autoimmune diseases (e. g., Raynaud's syndrome), scleroderma, enia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiple sis, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), and Grave's disease.
] In a particular embodiment, the nds described herein can be used to treat multiple sis.
Combination therapy In certain embodiments, a nd described herein may be administered alone or in combination with other compounds useful for treating or preventing inflammation.
Exemplary anti-inflammatory agents include, for example, steroids (e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6[alpha]-methylprednisone, triamcinolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e.g., n, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide). In r embodiment, the other therapeutic agent is an otic (e. g. , vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, inmetronidazole, doxycycline or streptomycin). In another embodiment, the other therapeutic agent is a PDE4 inhibitor (e. g. roflumilast or rolipram). In another embodiment, the other therapeutic agent is an antihistamine (e.g, cyclizine, hydroxyzine, promethazine or diphenhydramine). In another embodiment, the other therapeutic agent is an anti-malarial (e. g, artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline e, proguanil hydrochloride, uone or halofantrine). In one embodiment, the other compound is drotrecogin alfa. r examples of anti-inflammatory agents include, for example, aceclofenac, acemetacin, amidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclometasone, alfentanil, one, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3—amino—4- ybutyric acid, o—4- picoline, aminopropylon, yrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, rine, antrafenine, apazone, beclomethasone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, betamethasone, betamethasone- 17-Valerate, bezitramide, [alpha]—bisabolol, bromfenac, p- bromoacetanilide, 5-bromosa1icylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, budesonide, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butorphanol, carbamazepine, carbiphene, caiprofen, carsalam, chlorobutanol, chloroprednisone, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, ac, clobetasol, clocortolone, clometacin, clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine ate, codeine sulfate, cortisone, cortivazol, cropropamide, crotethamide, cyclazocine, deflazacort, dehydrotestosterone, desomorphine, desonide, desoximetasone, dexamethasone, dexamethasone-2l- isonicotinate, drol, dextromoramide, dextropropoxyphene, deoxycorticosterone, dezocine, diampromide, diamorphone, diclofenac, difenamizole, iramide, sone, rtolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, etyl, dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, enoxolone, epirizole, eptazocine, late, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, -69— etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, inol, feprazone, floctafenine, ort, flucloronide, flufenamic acid, flumethasone, flum'solide, flunixin, flunoxaprofen, fluocinolone ide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocoitolone, fluoresone, fluorometholone, fluperolone, flupirtine, fluprednidene, fluprednisolone, fluproquazone, renolide, flurbiprofen, fluticasone, formocortal, fosfosal, gentisic acid, glafenine, etacin, glycol salicylate, guaiazulene, halcinonide, halobetasol, halometasone, haloprednone, heroin, hydrocodone, hydro cortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, ortisone hemisuccinate, hydrocortisone 21 -lysinate, hydrocortisone cypionate, orphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole late, indomethacin, indoprofen, isofezolac, isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p- lactophenetide, lefetamine, levallorphan, levorphanol, levophenacyl-morphan, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, medrysone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mine, metazocine, methadone, methotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone nate, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, mometasone, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine, tone, nalbuphine, nalorphine, l-naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5’-nitro-2'— propoxyacetanilide,norlevorphanol, hadone,-normorphine, norpipanone, olsalazine, opium, rol, oxametacine, oxaprozin, oxycodone, oxymorphone, nbutazone, papaveretum, paramethasone, paranyline, parsalmide, pentazocine, perisoxal, etin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, zone, piperylone, pirazolac, piritramide, cam, pirprofen, pranoprofen, prednicarbate, prednisolone, sone, prednival, prednylidene, proglumetacin, proheptazine, promedol, propacetamol, idine, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o- acetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverine, simetride, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, fenic acid, tiaramide, tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, l, xenbucin, ximoprofen, zaltoprofen and zomepirac.
In one embodiment, a compound described herein may be administered with a selective COX-2 inhibitor for treating or preventing inflammation. Exemplary selective COX-2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib', etoricoxib, and lumiracoxib.
In some embodiments, a provided compound is administered in combination with an anthracycline or a Topo II inhibitor. In certain embodiments, a provided compound is stered in ation with Doxorubicin (Dox). In certain embodiments, a provided compound is administered in combination with bortezomib (and more y including carfilzomib). It was singly found that a provided compound in combination with Dox or bortezomib resulted in a synergystic effect (i.e., more than additive).
Viral ions ] Compounds and methods described herein may be used to treat or prevent a disease or disorder associated with a viral infection, particularly in humans and other s. A compound described herein may be administered prior to the onset of, at, or after the initiation of viral ion. When used prophylactically, the compounds are preferably provided in advance of any viral infection or symptom thereof.
Exemplary viral diseases include acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, c cirrhosis, hepatocellular oma, primary HSV-l infection (e.g, gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-l infection (e.g., herpes is and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi’s sarcoma, multicentric Castleman disease, y effusion ma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic lial lesions (6. g., common, flat, plantar and anogenital warts, laryngeal omas, epiderrnodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, influenza-like me, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes zoster.
Exemplary viral pathogens include Adenovirus, Coxsackievirus, Dengue virus, Encephalitis Virus, Epstein-Barr virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Herpes simplex virus type 1, Herpes simplex virus type 2, cytomegalovirus, Human herpesvirus type 8, Human immunodeficiency virus, Influenza virus, measles virus, Mumps virus, Human papillomavirus, Parainfluenza virus, Poliovirus, Rabies virus, Respiratory ial virus, Rubella virus, Varicella-zoster virus, West Nile virus, Dungee, and Yellow fever virus. Viral pathogens may also include viruses that cause ant viral infections.
] Antiviral drugs are a class of medications used specifically for treating viral infections. Antiviral action generally falls into one of three mechanisms: interference with the ability of a virus to infiltrate a target cell (e.g, amantadine, rimantadine and pleconaril), inhibition of the synthesis of virus (e,g., nucleoside analogues, e.g., acyclovir and zidovudine (AZT), and tion of the release of virus (e.g, zanamivir and oseltamivir).
In some embodiments, the viral pathogen is selected from the group consisting of viridae, flaviviridae, iridae, arenaviridae, picornaviridae, togaviridae, papovaviridae, poxviridae, respiratory viruses, hepatic viruses, and other viruses.
Exemplary herpesviridae include herpes simplex virus-l; herpes x virus-2; cytomegalovirus, for example, human cytomegalovirus; Varicella-Zoster virus; Epstein-Barr virus; herpes virus-6, for example, human herpes virus-6', and herpes virus-8, for example, human herpes virus-8.
Exemplary flaviviridae include Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and en virus.
Exemplary bunyaviridae include Rift Valley fever virus, Punta Toro virus, LaCrosse virus, and Marporal virus.
Exemplary arenaviridae include Tacaribe virus, Pinchinde virus, Junin virus, and Lassa fever virus, Exemplary picomaviridae e polio virus; enterovirus, for example, enterovirus-7 l; and Coxsackie virus, for example, Coxsackie virus B3.
Exemplary togaviridae include encephalitis virus, for example, Venezuelan equine encephalitis virus, n equine alitis virus, and n equine encephalitis virus; and Chikungunya virus.
Exemplary papovaviridae include BK virus, JC virus, and papillomavirus. ary idae e vaccinia virus, cowpox virus, and monkeypox virus.
Exemplary respiratory viruses include SARS coronavirus; influenza A virus, for example, H1N1 virus; and respiratory syncytial virus.
Exemplary hepatic viruses include hepatitis B and hepatitis C s.
Exemplary other viruses include adenovirus, for e, adenovirus-S; rabies virus; measles virus; ebola virus; nipah virus; and norovirus.
OphthalmOlogy [003 02] Compounds and methods described herein may be used to treat or prevent an ophthalmology disorder. Exemplary ophthalmology disorders include macular edema (diabetic and nondiabetic macular edema), age related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, l vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, l pigment epithelitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, ctival ulcer, chronic nummular keratitis, ophthalmic disease associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic pathy, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein occlusion, Coats' disease, familial exudative vitreoretinopathy, ess disease asu's disease), Eales disease, antiphospholipid antibody syndrome, ic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon- associated retinopathy, hypertensive retinopathy, radiation retinopathy, corneal epithelial stem cell deficiency and cataract.
Other ophthalmology disorders treatable using the nds and methods bed herein include proliferative vitreoretinopathy and chronic retinal detachment.
Inflammatory eye es are also treatable using the nds and methods described .
Neurodegenerative disease Neurodegeneration is the umbrella term for the progressive loss of structure or function ofneurons, including death of neurons. Many neurodegenerative diseases including _73_ Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of egenerative processes.
As ch progresses, many rities appear which relate these es to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic es that could ameliorate many diseases simultaneously. There are many els between different neurodegenerative disorders ing atypical n assemblies as well as induced cell death.
Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
Huntington’s disease causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, ng in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum’s subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the teristic movements of the disorder. Exemplary treatments for Huntington’s disease include tetrabenazine, neuroleptics, benzodiazepines, amantadine, remacemide, valproic acid, selective serotonin reuptake inhibitors (SSRIs), mirtazapine and antipsychotics.
The mechanism by which the brain cells in son's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein—ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms naceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of e has shown that the death of nergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles — the endoplasmic reticulum (ER) and the Golgi apparatus. Certain ns like Rabl may reverse this defect caused by alpha-synuclein in animal models. ary Parkinson’s disease therapies include levodopa, dopamine agonists such as include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride, dopa decarboxylate inhibitors, MAO-B inhibitors such as selegilene and rasagilene, anticholinergics and amantadine.
Amyotrophic lateral sclerosis (ALS/Lou ’s Disease) is a disease in which motor neurons are selectively targeted for degeneration. Exemplary ALS therapies include riluzole, baclofen, diazepam, trihexyphenidyl and amitriptyline.
Other exemplary neurodegenerative therapeutics include antisense oligonucleotides and stem cells.
Wound Healing Wounds are a type of condition characterized by cell or tissue damage. Wound healing is a dynamic pathway that optimally leads to restoration of tissue integrity and function. The wound g process consists of three overlapping phases. The first phase is an inflammatory phase, which is characterized by homeostasis, platelet aggregation and degranulation. Platelets as the first response, release le growth factors to recruit immune cells, epithelial cells, and elial cells. The atory phase typically occurs over days 0-5. The second stage ofwound healing is the proliferative phase during which macrophages and granulocytes invade the wound. Infiltrating asts begin to produce collagen. The ple characteristics of this phase are epithelialization, angiogenesis, granulation tissue formation and collagen production. The proliferative phase typically occurs over days 3-14. The third phase is the remodeling phase where matrix formation occurs. The fibroblasts, lial cells, and endothelial cells continue to produce collagen and collagenase as well as matrix oproteases (MMPs) for remodeling. Collagen crosslinking takes place and the wound undergoes contraction. The remodeling phase typically occurs from day 7 to one year.
Compounds and compositions described herein can be used for promoting wound healing (e. g., promoting or accelerating wound closure and/or wound healing, mitigating scar s of the tissue of and/or around the wound, inhibiting apoptosis of cells surrounding or proximate to the wound). Thus, in certain embodiments, the t invention provides a method for promoting wound healing in a subject, comprising administering to the subject a therapeutically effective amount of a compound (e. g., a CRMI inhibitor), or pharrnaceutically acceptable salt or composition thereof. The method need not achieve complete g or closure of the wound; it is sufficient for the method to promote any degree ofwound closure. In this t, the method can be employed alone or as an adjunct to other methods for healing wounded tissue.
The compounds and itions described herein can be used to treat wounds during the inflammatory (or early) phase, during the proliferative (or middle) wound healing phase, and/or during the remodeling (or late) wound healing phase.
In some ments, the subject in need d healing is a human or an animal, for example, a dog, a cat, a horse, a pig, or a rodent, such as a mouse.
In some embodiments, the compounds and compositions described herein useful for wound g are administered lly, for e, proximate to the wound site, or systemically.
More cally, a therapeutically effective amount of a compound or composition described herein can be administered (optionally in combination with other agents) to the wound site by coating the wound or applying a bandage, packing material, stitches, etc., that are coated or treated with the compound or composition described herein.
As such, the compounds and compositions described herein can be formulated for topical administration to treat surface wounds. Topical formulations include those for delivery via the mouth (buccal) and to the skin such that a layer of skin (i. e., the epidermis, dermis, and/or subcutaneous layer) is contacted with the compound or composition described herein.
Topical delivery systems may be used to administer topical formulations of the compounds and compositions described herein.
Alternatively, the compounds and itions described herein can be administered at or near the wound site by, for e, injection of a s01ution, injection of an extended release formulation, or uction of a biodegradable implant comprising the compound or composition described herein.
The compounds and compositions described herein can be used to treat acute wounds or chronic wounds. A c wound s when the normal reparative process is interrupted. c wounds can develop from acute injuries as a result of unrecognized persistent infections or inadequate y treatment. In most cases however, chronic lesions are the end stage of progressive tissue breakdown owing to venous, arterial, or metabolic vascular disease, pressure sores, radiation damage, or tumors.
In chronic wounds, healing does not occur for a variety of reasons, including improper circulation in diabetic ulcers, significant necrosis, such as in burns, and infections.
In these chronic wounds, viability or the recovery phase is often the rate-limiting step. The —76- cells are no longer viable and, thus, initial recovery phase is prolonged by unfavorable wound bed environment.
Chronic wounds include, but are not limited to the following: chronic ischemic skin lesions; derma ulcers; al ulcers; diabetic foot ulcers; pressure ulcers; venous ; non-healing lower extremity ; ulcers due to inflammatory conditions; and/or long-standing wounds. Other examples of chronic wounds include chronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, and al insufficiencies, and pressure wounds and cold and warm burns. Yet other examples of chronic wounds include chronic ulcers, ic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, arterial insufficiencies, and pressure wounds.
Acute wounds include, but are not limited to, post-surgical wounds, lacerations, hemorrhoids and fissures.
In a particular embodiment, the compounds and compositions described herein can be used for diabetic wound healing or accelerating healing of leg and foot ulcers secondary to diabetes or ischemia' in a subject.
In one embodiment, the wound is a surface wound. In another embodiment, the wound is a surgical wound (e.g., abdominal or gastrointestinal surgical wound). In a r embodiment, the wound is a burn. In yet another embodiment, the wound is the result of radiation exposure.
The nds and compositions bed herein can also be used for ic wound healing, gastrointestinal wound healing, or healing of an adhesion due, for e, to an operation.
The compounds and compositions described herein can also be used to heal wounds that are secondary to r disease. For example, in inflammatory skin diseases, such as psoriasis and dermatitis, there are numerous incidents of skin lesions that are secondary to the disease, and are caused by deep ng of the skin, or scratching of the skin. The compounds and compositions described herein can be used to heal wounds that are secondary to these diseases, for example, inflammatory skin es, such as psoriasis and dermatitis.
In a further embodiment, the wound is an internal wound. In a specific aspect, the internal wound is a chronic wound. In another specific aspect, the wound is a vascular wound. In yet another specific aspect, the internal wound is an ulcer. Examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, internal indications, Crohn’s disease, tive colitis, internal al sutures and skeletal fixation. Other examples of al wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, al indications, internal surgical sutures and skeletal n.
Examples of wounds include, but are not limited to, abrasions, avulsions, blowing wounds (i.e., open pneumothorax), burn wounds, ions, gunshot wounds, incised , open wounds, penetrating wounds, perforating wounds, re wounds, séton wounds, stab wounds, surgical , subcutaneous wounds, diabetic lesions, or tangential wounds. Additional examples of wounds that can be treated by the compounds and compositions described herein include acute conditions or wounds, such as thermal burns, chemical burns, radiation burns, burns caused by excess exposure to ultraviolet radiation (e.g., sunburn); damage to bodily tissues, such as the perineum as a result of labor and childbirth; injuries sustained during medical procedures, such as episiotomies; trauma— induced es including cuts, incisions, excoriations; es sustained from accidents; po st-surgical injuries, as well as chronic ions, such as pressure sores, bedsores, ions related to diabetes and poor circulation, and all types of acne. In addition, the wound can include dermatitis, such as impetigo, intertrigo, folliculitis and eczema, wounds following dental surgery; ontal disease; wounds following ; and tumor— associated wounds. Yet other examples of wounds include animal bites, arterial disease, insect stings and bites, bone infections, compromised skin/muscle grafts, gangrene, skin tears or lacerations, skin aging, surgical incisions, including slow or non-healing surgical wounds, intracerebral hemorrhage, aneurysm, dermal asthenia, and post-operation infections.
In preferred embodiments, the wound is selected from the group consisting of a burn wound, an incised wound, an open wound, a surgical or post surgical wound, a diabetic lesion, a thermal burn, a chemical burn, a radiation burn, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation. In more preferred embodiments, the wound is selected from the group consisting of an incised wound, an open wound, a surgical or post al wound, a diabetic lesion, a re sore, a bedsore, and a condition or wound related to diabetes or poor circulation.
In some embodiments, the wound is selected from the group consisting of a non- radiation burn wound, an incised wound, an open wound, a surgical or post surgical wound, a diabetic lesion, a l burn, a chemical burn, a pressure sore, a bedsore, and a condition related to es or poor circulation. In some embodiments, the wound is selected from the group consisting of an d wound, an open wound, a surgical or post surgical wound, a diabetic lesion, a pressure sore, a bedsore, and a condition d to diabetes or poor ation.
The present disclosure also relates to methods and compositions of reducing scar ion during wound healing in a subject. The compounds and compositions described herein can be administered directly to the wound or to cells proximate the wound at an amount effective to reduce scar formation in and/or around the wound. Thus, in some embodiments, a method of reducing scar formation during wound healing in a subject is provided, the method comprising administering to the subject a therapeutically ive amount of a compound described herein (e.g., a CRMl inhibitor), or a pharmaceutically acceptable salt thereof.
] The wound can include any injury to any portion of the body of a t.
According to embodiments, methods are provided to ameliorate, reduce, or decrease the formation of scars in a subject that has suffered a burn injury. According to preferred embodiments, methods are provided to treat, reduce the occurrence of, or reduce the probability of developing hypertrophic scars in a subject that has suffered an acute or c wound or .
Other disorders Compounds and compositions bed herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and other renal disorders.
Combination Radiation Therapy Compounds and compositions described herein are useful as radiosensitizers.
Therefore, compounds and compositions described herein can be administered in combination with radiation therapy. Radiation therapy is the medical use of high-energy radiation (e,g, X-rays, gamma rays, charged particles) to shrink tumors and kill malignant cells, and is generally used as part of cancer treatment. Radiation therapy kills ant cells by damaging their DNA.
Radiation therapy can be delivered to a patient in several ways. For example, radiation can be delivered from an external source, such as a machine outside the patient’s body, as in external beam radiation therapy. External beam radiation therapy for the treatment of cancer uses a radiation source that is external to the patient, typically either a radioisotope, such as "CO, 137Cs, or a high energy x-ray source, such as a linear accelerator.
The external source produces a collimated beam directed into the patient to the tumor site.
External-source radiation therapy avoids some of the problems of internal-source radiation therapy, but it undesirably and necessarily ates a significant volume of non-tumorous or healthy tissue in the path of the radiation beam along with the tumorous .
The e effect of irradiating of healthy tissue can be reduced, while maintaining a given dose of ion in the tumorous tissue, by projecting the external radiation beam into the patient at a variety of "gantry" angles with the beams ging on the tumor site. The particular volume elements of healthy tissue, along the path of the radiation beam, change, reducing the total dose to each such element of healthy tissue during the entire treatment.
The irradiation of y tissue also can be reduced by tightly collimating the radiation beam to the general cross section of the tumor taken perpendicular to the axis of the radiation beam. Numerous systems exist for producing such a circumferential collimation, some of which use multiple sliding shutters which, ise, can generate a radio-opaque mask of ary outline.
For administration of external beam radiation, the amount can be at least about 1 Gray (Gy) fractions at least once every other day to a treatment volume. In a particular embodiment, the radiation is administered in at least about 2 Gray (Gy) ons at least once per day to a ent volume. In another particular embodiment, the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume for five consecutive days per week. In another ular embodiment, radiation is administered in 10 Gy fractions every other day, three times per week to a treatment volume.
In another ular embodiment, a total of at least about 20 Gy is stered to a patient in need thereof. In another particular embodiment, at least about 30 Gy is administered to a patient in need thereof. In another particular embodiment, at least about 40 Gy is administered to a patient in need thereof. —80— Typically, the patient receives al beam therapy four or five times a week.
An entire course of treatment y lasts from one to seven weeks depending on the type of cancer and the goal of ent. For example, a patient can receive a dose of 2 Gy/day over days.
Internal radiation therapy is localized radiation therapy, meaning the radiation source is placed at the site of the tumor or affected area. Internal radiation therapy can be delivered by placing a radiation source inside or next to the area ing treatment. Internal mfifibnmamyfidmcdhdemmmmmnBmdwmawymdmhMmamew treatment and interstitial treatment. In intracavitary treatment, containers that hold radioactive sources are put in or near the tumor. The sources are put into the body es.
In interstitial treatment, the radioactive sources alone are put into the tumor. These radio active sources can stay in the patient permanently. Typically, the radioactive sources are removed from the patient after several days. The radioactive sources are in containers.
There are a number of methods for administration of a radiopharmaceutical agent.
For example, the radiopharmaceutical agent can be administered by targeted delivery or by systemic ry of targeted radioactive ates, such as a abeled antibody, a radiolabeled peptide and a liposome delivery . In one particular embodiment of targeted delivery, the radiolabelled pharmaceutical agent can be a radiolabelled dy.
See, for example, Ballangrud A. M., et al. Cancer Res., 2001; 61 :2008-2014 and Goldenber, D.M. J Nucl. Med, 2002; 43(5):693—713, the contents ofwhich are incorporated by reference herein.
In another particular embodiment of targeted delivery, the radiopharmaceutical agent can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. mes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. See, for example, Emfletzoglou D, Kostarelos K, Sgouros G. An analytical dosimetry study for the use of radionuclide-liposome conjugates in internal herapy. J Nucl Med 2001', 42:499-504, the contents of which are incorporated by reference herein.
In yet another particular embodiment of targeted delivery, the radiolabeled pharmaceutical agent can be a radiolabeled e. See, for example, Weiner RE, Thakur ML. Radiolabeled es in the diagnosis and therapy of oncological diseases. Appl Radiat Isot 2002 Nov;57(5):749-63, the ts of which are orated by reference herein.
In addition to targeted delivery, brachytherapy can be used to deliver the harmaceutical agent to the target site. Brachytherapy is a technique that puts the radiation sources as close as possible to the tumor site. Often the source is inserted directly into the tumor. The radioactive sources can be in the form of wires, seeds or rods. Generally, cesium, m or iodine are used. ] ic radiation therapy is another type of radiation therapy and involves the use of radioactive substances in the blood. Systemic radiation y is a form of targeted therapy. In systemic radiation therapy, a patient lly s or receives an injection of a radioactive substance, such as radioactive iodine or a radioactive substance bound to a monoclonal antibody.
A "radiopharmaceutical agent," as defined herein, refers to a pharmaceutical agent Which contains at least one radiation-emitting radioisotope. Radiopharrnaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term "radioisotope" includes ic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical . When the radioisotope is a metallic radioisotope, a chelator is lly employed to bind the metallic radioisotope to the rest of the molecule. When the sotope is a non-metallic radioisotope, the tallic radioisotope is typically linked directly, or Via a , to the rest of the molecule.
As used herein, a "metallic radioisotope" is any suitable metallic radioisotope useful in a therapeutic or diagnostic procedure in vivo or in vitro. Suitable metallic radioisotopes include, but are not limited to: Actinium-225, Antimony-124, Antimony-125, Arsenic-74, Barium-103, Barium-140, Beryllium-7, Bismuth-206, Bismuth-207, Bismuth212, Bismuth213, Cadmium-109, Cadmium-115m, Calcium-45, Cerium-139, Cerium-141, Cerium-144, Cesium-137, Chromium-51, Cobalt-55, Cobalt—56, Cobalt—57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-60, Copper-62, Copper-64, Copper-67, Erbium—169, Europium-152, Gallium-64, Gallium—67, Gallium-68, Gadolinium153, Gadolinium—157 Gold-195, Gold-199, Hafnium-175, Hafnium181, Holmium—166, Indium-110, Indium— 111, Iridium—192, Iron 55, Iron-59, Krypton85, 03, Lead-210, Lutetium-177, Manganese-54, Mercury- 197, Mercury203 , Molybdenum-99, Neodymium- 147, Neptunium— 237, Nickel-63, Niobium95, Osmium-l 85+l 91, Palladium-103, Palladium-109, Platinum— 1 95m, Praseodymium- 143, Promethium- 147, hium— 149, Protactinium-233, Radium— 226, Rhenium—186, Rhenium—188, Rubidium—86, Ruthenium-97, Ruthenium—103, Ruthenium-105, Ruthenium-106, Samarium-153, Scandium—44, Scandium-46, Scandiurn-47, Selenium-75, -1 10m, Silver-1 1 1, Sodium-22, Strontium-85, Strontium-89, Strontium- 90, Sulfur-35, Tantalum-182, Technetium-99m, Tellurium-125, Tellurium-132, Thallium- 204, m-228, Thorium-232, Thallium-170, Tin-113, 4, Tin-117m, Titanium-44, en—185, Vanadium—48, Vanadium—49, Ytterbium-169, Yttrium—86, Yttrium-88, Yttrium—90, Yttrium-91, Zinc-65, Zirconium-89, and Zirconium-95.
As used herein, a "non-metallic radioisotope" is any suitable allic radioisotope (non—metallic radioisotope) useful in a therapeutic or stic procedure in vivo or in vitro. le non—metallic radioisotopes include, but are not limited to: Iodine— 131, Iodine—125, Iodine-123, orus—32, Astatine—21 1, Fluorine—18, Carbon-11, Oxygen— , e—76, and Nitrogen—13.
Identifying the most appropriate isotope for radiotherapy requires weighing a variety of factors. These include tumor uptake and retention, blood clearance, rate of radiation delivery, half—life and specific activity of the radioisotope, and the feasibility of large—scale production of the radioisotope in an economical fashion. The key point for a therapeutic harmaceutical is to deliver the requisite amount of radiation dose to the tumor cells and to achieve a xic or tumoricidal effect while not causing unmanageable side-effects.
It is preferred that the al half-life of the therapeutic radioisotope be similar to the biological half-life of the harmaceutical at the tumor site. For example, if the half-life of the radioisotope is too short, much of the decay will have occurred before the radiopharmaceutical has reached m target/background ratio. On the other hand, too long a half-life could cause unnecessary radiation dose to normal tissues. Ideally, the radioisotope should have a long enough half-life to attain a minimum dose rate and to irradiate all the cells during the most radiation sensitive phases of the cell cycle. In addition, the half-life of a radioisotope has to be long enough to allow adequate time for manufacturing, release, and transportation.
Other practical considerations in selecting a radioisotope for a given application in tumor therapy are availability and quality. The purity has to be sufficient and reproducible, as trace amounts of impurities can affect the radiolabeling and radiochemical purity of the radiopharmaceutical.
The target receptor sites in tumors are typically limited in number. As such, it is preferred that the radioisotope have high specific activity. The c ty depends primarily on the production method. Trace metal inants must be minimized as they often compete with the radioisotope for the chelator and their metal complexes compete for receptor binding with the radiolabeled chelated agent.
] The type of radiation that is suitable for use in the methods of the present invention can vary. For e, radiation can be electromagnetic or particulate in .
Electromagnetic radiation useful in the practice of this invention includes, but is not limited to, x-rays and gamma rays. Particulate radiation useful in the practice of this invention includes, but is not limited to, electron beams (beta particles), protons beams, neutron beams, alpha particles, and ve pi mesons. The radiation can be delivered using tional radiological treatment apparatus and methods, and by intraoperative and stereotactic methods.
Additional discussion regarding radiation treatments suitable for use in the ce of this invention can be found throughout Steven A. Leibel et al., Textbook of Radiation Oncology (1998) (publ. W. B. Saunders y), and particularly in Chapters 13 and 14. Radiation can also be delivered by other methods such as targeted delivery, for example by radioactive "seeds," or by systemic delivery of targeted ctive ates. J. Padawer er al., Combined Treatment with Radioestradiol hone in Mouse C3HBA Mammary Adenocarcinoma and with Estradiol lucanthone in an Estrogen Bioassay, Int. J. Radiat.
Oncol. Biol. Phys. 7:347-357 . Other radiation delivery methods can be used in the practice of this invention.
For tumor therapy, both or and B-particle emitters have been investigated. Alpha particles are particularly good cytotoxic agents because they dissipate a large amount of energy within one or two cell diameters. The B-particle rs have relatively long penetration range (2-12 mm in the tissue) depending on the energy level. The long-range penetration is ularly important for solid tumors that have heterogeneous blood flow and/or receptor expression. The B—particle emitters yield a more homogeneous dose distribution even when they are heterogeneously distributed within the target tissue.
In a particular embodiment, therapeutically ive amounts of the compounds and compositions bed herein are administered in combination with a eutically effective amount of radiation therapy to treat cancer (6.g. , lung , such as non-small cell lung cancer). The amount of radiation necessary can be determined by one of skill in the art based on known doses for a particular type of cancer. See, for example, Cancer Medicine 5th ed., Edited by RC. Bast et al., July 2000, BC Decker.
The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following ic Examples. These Examples are described solely for purposes of illustration and are not intended to’limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.
EXEMPLIFICATION Abbreviations Ac acetyl ACN , acetonitrile Boc utoxy carbonyl CI Chemical ionization DIPEA N,N-Diisopropyl ethylamine DMF Dimethylformamide DMSO dimethylsulfoxide dppf (diphenylphosphino)ferrocene EDCI yliminomethyleneamino)-N,N—dimethylpropan—1 -amine EDTA ethylenediamine tetraacetic acid E1 electron impact ionization equiv(s). lent(s) EtOAc ethyl acetate EtOH Ethanol Et Ethyl g grarn(S) h hour(s) HATU (Dimethylamino)-N,N—dimethyl(3H-[l ,2,3]triazolo[4,5-b]pyridin-3 - yloxy)methaniminium hexafluorophosphate HOBt l -Hydroxybenzotriazole LAH lithium um hydride LCMS liquid chromatography mass spectrometry LRMS low tion mass spectrometry Me methyl mg milligram(s) min Minute(s) mL milliliter(s) Ms l or mesyl NMR Nuclear ic resonance PBS phosphate-buffered saline PEG polyethylene glycol Ph phenyl RT, rt, r.t. Room temperature SDS—PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis T3P Propylphosphonic anhydride (available from ica) TFA trifluoroacetic acid THF tetrahydrofuran IR ion time Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently d from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any ediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities d by the molecule at that stage to the conditions or reagents employed in the ormation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be tood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions on other suitable transformations are given in "Comprehensive Organic Transformations — A Guide to Functional Group Preparations" R.
C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other le reactions are described in textbooks of organic chemistry, for example, "Advanced c Chemistry", March, 4th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill, (1994).
Techniques for purification of intermediates and final products e for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily tood by the one skilled in the art. The definitions of substituents and groups are as in formula 1 except where defined differently. The term "room temperature" and "ambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 °C.
The term " shall mean, unless otherwise stated, in nce to an employed solvent a temperature at or above the boiling point of named t.
A typical LCMS method used to characterize synthesized compounds is described below: Mobile phase: A: water (0.01% TFA); B: CAN (0.01% TFA) Gradient: 5% B increase to 100% B within 1.2 min, 100% B for 1.3 min Flow Rate: 2.0 mL/min Column: SunFire C18, 4.6*50mm, 3.5 pm Column ature: 50 °C Detection: UV (214, 254 nm) and MS (ESI, Pos mode, 110-1000 amu).
Unless otherwise indicated, retention times reported for synthesized compounds were obtained using this LCMS method.
It is understood that compounds for which a specific synthesis is not shown can be made in accordance with the general procedures disclosed herein. —87- Example 1. tic s Synthesis of (E)-N-((5—(5-acetylthiophen-Z-yl)—7—chlorobenzofuran-Z-yl)methyl)—3-(6- aminopyridinyl) acrylamide (500) and (E)-N-((5-(5-acetylthiophenyl)benzofuran- 2-yl)methyl)(6-amin0pyridinyl)acrylamide (503).
(:QW——»0 OH HAM: /° PEG- 400 /° Br La;chogoMF "Le/:33 MsCI, Et3N, CHZCIZ CI 1 C1 % Pd/C H2N o NaN3, 15--crown——5 M30 0 H2 EtOH N\3——<€/\§B\Br \ DMSO CH30N \ Br Br 7 5 EDCI,HOBt, \ \ OH DIPEA, CH2C|2 | H2N N ‘O:\_ Synthesis of ethyl 5-br0m0-7—chlorobenzofuran-Z-carboxylate (3): S—Bromo— 3—chloro—2—hydroxybenzaldehyde (2) (13.90 g, 59.03 mmol) was dissolved in DMF at room —88— temperature. Ethyl 2-bromoacetate (10.19 mL, 88.55 mmol) and potassium carbonate (20.40 g, 147.58 mmol) were added and the reaction mixture was heated at 120 °C for 2 h. The reaction mixture was allowed to cool to room ature, transferred into iced water and extracted with ethyl acetate (3 x 500 mL). .The combined organic layers were washed with brine and dried over anhydrous Na2S04. The organic layer was concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (0-4% ethyl acetate / n-hexane) to obtain ethyl 5-bromochlorobenzofuran—Z-carboxylate (3). : 4.40 g, 25%). 1H NMR (400 MHZ, DMSO-dg) 6 7.71-7.66 (m, 1H), 7.51 (s, 1H), 6.80 (s, 1H), 4.10-4.08 (m, 2H), 1.50-1.49 (m, 3H). sis of (5-br0m0—7—chlorobenzofuran-Z-yl) methanol (4): Ethyl 5-bromo- 7—chlorobenzofurancarboxylate (3) (4.80 g, 15.82 mmol) was dissolved in THF (150 mL) at room temperature. The reaction e was cooled to -20 °C and 1M lithium aluminum hydride in THF (11 mL, 11 mmol) was added dropwise. The reaction mixture was stirred for min, transferred into iced water and extracted with ethyl acetate (3 x 250 mL). The ed c layers were washed with brine and dried over anhydrous Na2804. The organic layer was concentrated under reduced pressure to give crude product which was purified by silica gel chromatography (0-15% ethyl acetate / n—hexane) to obtain (5-bromo— 7-chlorobenzofuranyl) methanol (4). (Yield: 3 g, 73 %). 1H NMR (400 MHZ, DMSO-dg) 7.84 (s, 1H), 7.63 (s, 1H), 6.86 (s, 1H), 5.66—5.63 (m, 1H), 4.62 (d, J: 4 HZ, 2H).
LCMS: m/z 262.5 [M+H]+, IR = 2.30 min.
Synthesis of (5-br0m0chlorobenzofuranyl) methyl methanesulfonate (5): (5-Bromo—7-chlorobenzofuran—2—y1) methanol (4) (4 g, 15.29 mmol) was dissolved in dichloromethane (40 mL). The reaction e was cooled to 0 °C and triethylamine (3.19 mL, 22.94 mmol) was added dropwise followed by methanesulphonyl chloride (1.44 mL, 18.35 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was transferred into iced water and extracted with dichloromethane (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give 48 g of crude (5~bromo~7—chlorobenzofi1ran—2—yl) methyl methanesulfonate (5), which was used in the next step t r purification. 1H NMR (400 MHZ, DMSO-ds) 5 7.96 (s, 1H), 7.76 (s, 1H), 7.25 (s, 1H), 5.50 (s, 2H), 3.33 (s, 3H). LCMS: m/z 339.56 [M+H]+, IR: 2.78 min.
Synthesis of 2-(azid0methyl)br0m0chlor0benz0furan (6): (5-Bromo chlorobenzofuranyl)methy1methanesulfonate (5) (4.8 g, 14.13 mmol) was dissolved in acetonitrile (48 mL) at room ature. Sodium azide (1.83 g, 28.26 mmol), dimethyl sulfoxide (1.50 mL, 21.20 mmol) and wn-5 (0.48 g, 2.12 mmol) were added to the reaction mixture at room temperature and then the reaction mixture was heated at 90 °C for min. The reaction mixture was then cooled to room temperature, transferred into iced water and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine and dried over anhydrous Na2804. The organic layer was concentrated under reduced pressure to give 4 g of crude 2-(azidomethyl)-5 -bromochlorobenzofuran (6), which was used in the next step without further purification. 1H NMR (400 MHZ, DMSO—dg) 6 7.91 (s, 1H), 7.70 (s, 1H), 7.07 (s, 1H), 4.75 (s, 2H).
Synthesis of m0-7—chlor0benz0furan-Z-yl) amine (7): 2- (Azidomethyl)bromo—7-chlorobenzofuran (6) (4 g, 13.96 mmol) was dissolved in ethanol (40 mL) at room temperature. The reaction mixture was degassed with N2 gas and 10% palladium on carbon (0.8 g) was added. The reaction mixture was purged with H2 gas and stirred for 2 h. The reaction mixture was filtered and washed with dichloromethane (3 x 100 mL). The combined organic layers were concentrated under reduced pressure to give 3.45 g of crude (5~bromochlorobenzofuran—2-yl) methanamine (7), which was used in the next step without further purification. 1H'NMR (400 MHz, DMSO-d6) 6 7.81 (s, 1H), 7.58 (s, 1H), 6.79 (s, 1H), 3.86 (s, 2H), 2.02-1.94 (m, 2H). LCMS: m/z 262.0 [M+H]+, tR= 1.80 min.
Synthesis of (E)(6~amin0pyridinyl)-N—((5-brom0chlor0benzofuran-Z-yl) methyl) acrylamide (8): l Procedure 1: Amide ng \\ Cl EDCI, HOBt DIPEA CHZCIZ __ Br (5-Bromochlorobenzofuran-2—yl) methanamine (7) (3.45 g, 13.24 mmol) was dissolved in dichloromethane (35 mL). The on e was cooled to 0 °C and (E)—3—(6- aminopyridin—3-yl) acrylic acid (3.25 g, 19.86 mmol), EDCI (3.04 g, 15.89 mmol) and HOBt (2.14 g, 15.89 mmol) were added followed by DIPEA (6.80 mL, 39.72 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction mixture was transferred into iced water and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced re to give crude product, which was purified by silica gel chromatography (0—5% MeOH in CH2Cl2) to obtain (E)—3—(6—aminopyridin—3—yl)—N-((5- bromochlorobenzofuranyl) methyl) acrylamide (8). (Yield: 5.14 g, 95%). 1H NMR (400 MHZ, DMSO-ds) 5 8.91 (s, 1H), 8.69—8.67 (m, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.68- 7.63 (m, 2H), 7.35 (d, J: 16 Hz, 1H), 6.83 (s, 1H), 6.64 (s, 2H), 6.54—6.52 (m, 1H), 6.43 (d, J: 15.6 Hz, 1H), 4.59—4.57 (m, 1H). LCMS: m/z 406.6 [M+H]+, tR=2.04 min.
Synthesis of (E)-N-((5-(5-acetylthi0phenyl)chlorobenzofuran-Z-yl) methyl)(6- aminopyridinyl) acrylamide (500) and ((5-(5-acetylthiophenyl)benz0furan- ethyl)(6-amin0pyridinyl)acrylamide (503): General Procedure 2: Cross—coupling HHO.MB chog, H20 H2’" 8 (E)(6-Aminopyridin—3-yl)-N—((5 —bromochlorobenzofuran—2-yl) methyl) acrylamide (8) (0.23 g, 0.56 mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature and degassed with N2 gas for 5 min. is(triphenylphosphine)palladium (0) (0.032 g, 0.02 mmol) and 5-acetyl thiopheneboronic acid (0.14 g, 0.84 mmol) were added at room temperature and stirred for 5 min. A degassed solution ofK2C03 (0.12 g, 0.84 mmol) in 0.5 mL of water was added and the reaction mixture was irradiated under microwave for 15 min at 80 °C. The reaction mixture was allowed to cool to room temperature, transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over ous NaZSO4 and concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (0-6% MeOH in CHzClz) to obtain (E)-N—((5—(5—acetylthiophen-2—yl)—7—chlorobenzofuran—2—yl) methyl)—3-(6- aminopyridin—3—yl) mide (500) and ((5—(5-acetylthiophen—2—yl)benzofuran—2— yl)methyl)—3-(6-aminopyridin-3 —yl)acrylamide (503).
Data for 500: (Yield: 0.017 g, 6.65%). 1H NMR (400 MHZ, DMSO-d6) 5 8.66- 8.63 (m, 1H), 8.09 (s, 1H), 7.99-7.97 (m, 2H), 7.85 (s, 1H), 7.73 (d, J: 4 HZ, 1H), 7.64- 7.62 (m, 1H), 7.36 (d, J: 15.6 Hz, 1H), 6.90 (s, 1H), 6.49-6.40 (m, 4H), 4.60 (d, J: 5.6 HZ, 2H), 2.55-2.50 (m, 3H). LCMS: m/z 452.93 [M+H]+, IR = 2.06 min.
] Data for 503: (Yield: 0.02 g, 8%). 1H NMR (400 MHZ, DMSO—ds) 6 8.61-8.58 (m, 1H), 8.08 (d, J: 2 HZ, 1H), 8.02 (d, J= 1.2 HZ, 1H), 7.95 (d, J: 3.6 HZ, 1H), 7.69 (dd, J1 = 2 Hz, J2 = 1.6 HZ, 1H), 7.65-7.60 (m, 3H), 7.35 (d, J= 16 HZ, 1H), 6.81 (s, 1H), .40 (m, 4H), 4.57 (d, J= 5.6 HZ, 2H), 2.55-2.50 (m, 3H). LCMS: m/z 418.48 [M+H]+, rR= 1.92 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7—chlor0-5—(4-(morpholinecarbonyl) phenyl)benzo[d] oxazol-Z-yl)methyl)acrylamide (501): ‘3' CI Cl (3; HOD zn’NH4Cl HO:©\ (MeO)3CHCH2Cl Cl on N3 \Ofl NaNa‘ Nal —~—~—~——> ———> *‘<\ < 02N Br Methanol 15—Crown-5 N Br BF3.OEt2_ CHzclz HzN N Br 9 11 12 Pd/C H2 0 Methanol ONE010 \—_ Zinc dust (13 g, 198 mmol) was added to the reaction e followed by dropwise addition of saturated NH4Cl (100 mL) at room temperature (CAUTION: Exothermic reaction was observed). After completion of addition, the reaction e was heated at 50 °C for 1 h.
The reaction mixture was allowed to cool to room temperature, filtered and washed with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4 and trated under reduced pressure to give crude 2-amino bromochlorophenol (10), which was used in the next step without further purification. 1H NMR (400 MHZ, DMSO-dg) 6 8.97—8.85 (bs, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 5.57-5.10 (bs, 2H).
Synthesis of 5-bromochloro-Z—(chloromethyl)benzo[d]oxazole (11): 2- Chloro-1,l,l—trimethoxyethane (0.3 mL, 2.04 mmol) was dissolved in dichloromethane (20 mL) at room temperature and cooled to 0 OC. Borontrifluoride etherate (0.5 mL, 4.09 mmol) was added dropwise followed by 2-aminobromochlorophenol (10) (0.5 g, 2.25 mmol).
The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was transferred into saturated NaHC03 solution and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous NazSO4 and concentrated under d pressure to give crude compound, which was purified by silica gel chromatography (0-20% ethyl acetate/n-hexane) to obtain 5- bromo—7-chloro(chloromethyl)benzo[d]oxazole (11). (Yield: 0.18 g, 19%). 1H NMR (400 MHZ, CDCl3) 6 7.82 (s, 1H), 7.58 (s, 1H), 4.78 (s, 2H).
Synthesis of 2-(azid0methyl)—5-br0m0-7—chlorobenzo[d]oxazole (12): 5- 7—chloro(chloromethyl)benzo[d]oxazole (11) (0.1 g, 0.35 mmol) was dissolved in acetonitrile (2 mL) at room temperature. Sodium azide (0.03 g, 0.42 mmol), 15-Crown—5 (0.010 g) and sodium iodide (0.03 g, 0.177 mmol) were added and the reaction e was heated at 90 0C for 18 h. The reaction mixture was allowed to cool to room temperature, erred into iced water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over ous NaZSO4 and concentrated under reduced pressure to obtain 0.13 g of crude 2—(azidomethyl)bromo chlorobenzo[d]oxazole (12), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 5 8.10 (d, J: 1.6 Hz, 1H), 7.86 (d, J: 2 Hz, 1H), 4.93 (s, 2H).
Synthesis of (5—br0m0-7—chlorobenzo[d] 0xaz01y1)methanamine (13): 2- (Azidomethyl)bromochlorobenzo[d]oxazole (12) (0.3 g, 1.04 mmol) was dissolved in methanol (40 mL) at room ature. The reaction mixture was degassed with N2 gas and % palladium on carbon (0.06 g) was added. The reaction mixture was purged with H2 gas and stirred for 2 h. The reaction mixture was filtered and washed with dichloromethane (3 x 50 mL). The combined organic layers were concentrated under d pressure to give crude (5-bromochlorobenzo[d]oxazolyl) methanamine (13), which was used in the next step without further purification. LCMS: m/z 262.98 [M+H]+, IR = 1.71 min.
Synthesis of (6-aminopyridinyl)—N-((5—brom0-7— chlorobenz0[d]0xaz01—2-yl)methyl) acrylamide (14): (5-Bromochlorobenzo[d]oxazol— ethanamine (13) (0.5 g, 1.91 mmol) was dissolved in romethane (20 mL) at room temperature. The reaction mixture was cooled to 0 °C and (E)(6—aminopyridinyl) acrylic acid (0.37 g, 2.29 mmol), EDCI (0.43 g, 2.29 mmol) and HOBt (0.31 g, 2.29 mmol) were added, followed by DIPEA (0.65 mL, 3.82 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction mixture was transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous NagSO4 and concentrated under d pressure to give the crude t, which was purified by silica gel chromatography (0-5% MeOH in CH2C12) to obtain (E)(6-aminopyridinyl)-N-((5-bromochlorobenzo[d]oxazol yl)methyl)acryl amide (14). (Yield: 0.14 g, 18%). 1H NMR (400 MHZ, DMSO-ds) 6 8.80- 8.77 (m, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.79 (s, 1H), 7.66-7.36 (m, 1H), 7.34 (d, J= 16 Hz, 1H), 6.49—6.35 (m, 4H), 4.71 (d, J: 5.6 Hz, 2H). LCMS: m/z 409.0 , 1R = 1.89 min.
Synthesis of (E)(6-amin0pyridin-3—yl)—N—((7-chloro(4-(m0rpholine carbonyl)phenyl) benzo[d] oxazol-Z-yl)methyl)acrylamide (501): (E)(6~Aminopyridin~ 3-yl)-N-((5-bromochlorobenzo[d]oxazolyl)methyl)acrylamide (14) (0.02 g, 0.049 mmol) was dissolved in THF (2 mL) at room temperature and degassed with N2 gas for 15 min. Bromo(tri—tert—butylphosphine)Pd(I) dimer (1 mg) and 4-(morpholine yl)phenylboronic acid (0.02 g, 0.073 mmol) and KP (0.01 g, 0.15 mmol)were added at room temperature and stirred for 5 min. The reaction mixture was irradiated under microwave for 30 min at 100 °C. The reaction mixture was allowed to cool to room temperature, transferred into iced water and extracted with ethyl e (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under d pressure to give crude nd which was purified by silica gel chromatography (0-6% MeOH in CH2C12) to obtain (E)(6-aminopyridin—‘3-yl)-N-((7- chloro(4-(morpholinecarbonyl)phenyl)benzo[d]oxazolyl)methyl)acrylamide (501).
(Yield: 0.009 g, 36%). 1H NMR (400 MHZ, DMSO-d6) 5 8.83-8.80 (m, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.86-7.83 (m, 3H), .64 (m, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.35 (d, J= 16 Hz, 1H), 6.50—6.44 (m, 4H), 4.74 (d, J= 6 Hz, 1H), 3.63-3.41 (m, 8H). LCMS: m/z 518.24 [M+H]+, 1R: 1.82 min.
Synthesis of (E)(6-amin0pyridin-3—yl)—N—((7—chloro—S-(4-(morpholine carbonyl) phenyl) benzofuran-Z-yl) methyl) acrylamide (502): Cl Cl 0 HQ @Nfi 0 NH 0 l3 NH 0 O HO __ _ \ \ —— Br Pd(PEh3)4. K2003. \ / / 1,4—Dioxane,H20 \ O O N N 8 502 H2N H2N ] (E)(6-Aminopyridinyl)—N-((5-bromochlorobenzofuran-2— yl)methy1)acrylamide (0.20 g, 0.49 mol) (8) was dissolved in 1,4-dioxane (3 mL) at room temperature and degassed with N2 gas for 5 min. Tetrakis(triphenylphosphine)palladium (0) (0.028 g, 0.02 mmol) and 4-morpholinecarbonylphenylboronic acid (0.17 g, 0.73 mmol) were added at room temperature and stirred for 5 min. A degassed solution of K2C03 (0.10 g, 0.73 mmol) in 0.5 mL of water was added and the reaction mixture was irradiated under microwave for l h at 80 °C. The reaction mixture was allowed to cool to room temperature, transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined c layers were washed with brine, dried over anhydrous NaZSO4 and trated under reduced pressure to give crude compound, which was purified by silica gel chromatography (0—6% MeOH in CH2C12) to obtain (E)-3;(6-aminopyridinyl)-N-((7— (4—(morpholinecarbonyl)phenyl)benzofiJranyl)methyl)acrylamide (502).
(Yield: 0.12 g, 47%). 1H NMR (400 MHz, DMSO-dé) 5 8.66-8.63 (m, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.62 (d, J: 11.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.36 (d, J= 16 Hz, 1H), 6.90 (s, 1H), 6.49-6.41 (m, 4H), 4.60 (d, J: 5.6 Hz, 2H), 3.62 (s, 8H). LCMS: m/z 517.98 [M+H]+, tR= 1.88 min.
Synthesis of (6-amin0pyridinyl)-N-((7-chlor0(4-(m0rpholinosulfonyl)phenyl) benzofuran-Z-yl)methyl)acrylamide (504): CI HQ 9 or .3 ,3*N 0 o 0 HO \__/ \ \ Br Pd(PPh3)4, K2003, 1,4-Dioxane, H20 800\ O/ Nfi/ H2N 504 (E)—3-(6—Aminopyridinyl)-N-((7—chloro—5-(4— (morpholinosulfonyl)phenyl)benzofuranyl)methyl)acrylamide (504) was synthesized using General Procedure 2. (Yield: 10 mg, 10%). 1H NMR (400 MHZ, DMSO-ds) 6 8.65 (s, 1H), 8.08 (d, J: 4 Hz, 1H), 8.03-7.99 (m, 3H), 7.82 (t, J: 2 Hz, 3H), 7.62 (d, J: 6 Hz,1H), 7.35 (d, J: 16 Hz, 1H), 6.93 (s, 1H), 6.49 (s, 1H), 6.46 (s, 2H), 6.42 (d, J: 16 Hz, 1H), 4.61 (s, 2H), 3.65 (t, J: 4.4 Hz, 4H), 2.92 (t, J= 4.4 Hz, 4H). LCMS: m/z 553.4 [M+H]+, rR = 1.97 min.
Synthesis of (E)(6-aminopyridin—3—yl)-N-((7-chloro-S-(4—(2—(pyrazin-Z-yl)hydrazine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (505): CI CI 0 NW Pd(PPh3)4, K2003 0 — \ B’O Donane,H20 \ \ / O O O o N 16 ill/H \N l HZN NI / j 505 N/ Br HN\N EDCI'HOBt’ 2- Hydrazino DIPEA, CH2012 Bro" Synthesis of 4—br0m0-N‘-(pyrazinyl)benzohydrazide (15): 4-Bromobenzoic acid (0.5 g, 2.4 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 OC. 2- Hydrazinylpyrazine (0.32 g, 2.9 mmol), EDCI (0.55 g, 2.9 mmol), HOBt (0.39 g, 2.9 mmol) and DIPEA (0.96 g, 7.4 mmol) were added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was transferred into water (100 mL) and extracted with CHZCIZ (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous NazSO4 and concentrated under reduced pressure to give crude product, which was purified by silica gel tography (0-5% MeOH in CH2C12) to obtain o-N'—(pyrazinyl)benzohydrazide (15). (Yield: 0.15 g, 20%).
LCMS: m/z 295.18 [M+2], IR = 1.8 min.
Synthesis of (6-aminopyridinyl)-N-((7-chlor0(4-(2—(pyrazin-Z— yl)hydrazine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (505): (E)—3—(6- aminopyridinyl)-N-((7-chloro(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)benzofuran- 2-yl)methyl)acrylamide (16) (0.25 g, 0.55 mmol) was dissolved in 1,4-dioxane (2 mL) at room temperature and degassed using N2 for 5 min. Tetrakis(triphenylphosphine)palladium (0) (31 mg, 20 mol%) and 4-bromo-N‘—(pyrazinyl)benzohydrazide (0.24 g, 0.82 mmol) were added and d for 5 min. A degassed solution of K2CO3 (0.15 g, 1.1 mmol) in 2 mL of water was added and the reaction mixture was irradiated under microwave for 30 min at -96— 100 OC. The reaction mixture was transferred into iced water and extracted with ethyl e (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give crude product, which was purified by chromatography to obtain (E)(6-aminopyridin—3-yl)-N-((7-chloro—5—(4- (2—(pyrazinyl)hydrazinecarbony1)phenyl)benzofurany1)methyl)acrylamide (505).
(Yield: 0.01 g, 4%). 1H NMR (400 MHz, DMSO-dg) 5 10.58 (s, 1H), 9.07 (s, 1H), 8.66 (t, J= 5.8 Hz, 1H), 8.16 (s, 1H), 8.10-8.07 (m, 2H), 8.03 (d, J= 8.4 Hz, 2H), 7.97 (s, 2H), 7.88 (d, J= 8.4 Hz, 2H), 7.78 (s, 1H), 7.61 (dd, J1, J2 =2.4 Hz, 1H), 7.36 (d, J= 15.6 Hz, 1H), 6.91 (s, 1H), 6.49-6.41 (m, 4H), 4.60 (d, J= 5.6 Hz, 2H). LCMS: m/z 540.18 [M+H]+, m = 1.73 min.
Synthesis of (E)(2-((3-(6—aminopyridinyl)acrylamido)methyl)chlorobenzofuran- -yl)benzamide (506): :NLQQBm—Z—k—Q—e \COO BrOPd ] Synthesis of (E)(6-aminopyridinyl)-N-((7-chlor0(4-(2- morpholinoacetyl)phenyl) benzofuran-Z-yl)methyl)acrylamide (507): (E)-3—(6- Aminopyridin—3—yl)~N-((7-chloro-5—(4,4,5,5—tetramethyl—l,3,2-dioxaborolan—2—yl)benzofuran- 2—yl)methyl)acrylamide ('16) (0.05 g, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL) at room ature and degassed using N2 for 5 min. Tetrakis(triphenylphosphine) palladium (0) (7 mg, 20 mol%) and 1-(4~bromophenyl)morpholinoethanone (0.47 g, 0.16 mmol) were added at room temperature and stirred for 5 min. A degassed solution of K2C03 (0.03 g, 0.22 mmol) in 2 mL of water was added and the reaction mixture was irradiated under microwave for 30 min at 100 OC. The reaction e was allowed to cool to room temperature, transferred into water and extracted with ethyl e (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0-5% MeOH in ) to obtain (E)(6-aminopyridiny1)-N-((7- chloro(4-(2~morpholinoacetyl)pheny1)benzofuran-Z-yl)methyl)acrylamide (507). (Yield: 0.01 g, 10%). 1H NMR (400 MHz, g) 6 8.63 (t, J: 5.8 Hz, 1H), 8.08 (d, J: 4.4 Hz, 3H), 7.96 (d, J: 1.6 Hz,1H), 7.87 (d, J: 8.4 Hz, 2H), 7.77 (d, J: 1.6 Hz, 1H), 7.61 (dd, J1, J2 = 2.4 Hz, 1H), 7.34 (d, J: 16 Hz, 1H), 6.91 (s, 1H), 6.48-6.40 (m, 4H), 4.61 (d, J: 5.6 Hz, 2H), 3.88 (s, 2H) 3.60-3.58 (m, 4H), 3.34—3.32 (m, 4H). LCMS: m/z 531.4 [M+H]+, rR = 1.65 min.
Synthesis of (E)—3-(6-aminopyridin-S—yl)—N-((7—chloro—S—(4-(3,3-diflu0roazetidine carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (508). cu GI JL H0 "0 /N 0X 12. KI. H20 +0 db}, NH3 H20 I Br Pd(PPh3)20'2, Cul Br 0)/-—NH TMG DMF 17 18 XL? F Pd(dppf)C12 K2C03 ,B , 0 mN/DLF dioxane, H20 EDC|.HOBt, N,‘ \ OH DIPEA,DMF \ O F NH«bl/jg: 508 O Synthesis of 4—br0m0chlor0iodophenol (18): ochlorophenol (17) (2.06 g, 10.0 mmol) was dissolved in ammonia (30 mL). KI (0.166 g, 1.0 mmol) in 5 mL of water and iodine (2.54 g, 10.0 mmol) were added at 25 °C and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with water, acidified using concentrated HCl and extracted with ethyl acetate (50 mL x 3). The ed organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure to obtain crude product, which was purified by silica gel chromatography (10-20% ethyl acetate/petroleum ether) to provide 4-bromochloro—6—iodophenol (18) (2.3 g, 70.0% yield) as an off-white solid. LCMS: m/z 332.1 [M+H]+, IR = 1.92 min.
Synthesis of tert-butyl (5-br0m0-7—ch10robenz0furanyl)methylcarbamate (19): 4—Bromochloroiodophenol (18) (500 mg, 1.5 mmol) was dissolved in DMF (10 mL). tert—Butyl propynylcarbamate (233 mg, 1.5 mmol) and tetramethylguanidine (TMG) (345 mg, 3.0 mmol), CuI (28.8 mg, 0.15 mmol) and Pd(PPh3)2C12 (105 mg, 0.15 mmol) were added at 25 °C under nitrogen atmosphere and stirred at 40 °C for 16 h. The reaction mixture was transferred into iced water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over ous , and concentrated under reduced pressure to obtain crude product, which was purified by silica gel chromatography % ethyl acetate/petroleum ether) to provide utyl (5-bromo chlorobenzofuranyl)methylcarbamate (19) (240 mg, 44.4% yield). LCMS: m/z 3 81.9 [M+Na]+, 7R = 2.05 min.
] Synthesis of tert—butyl (7-chlor0(4-(3,3-diflu0r0azetidinecarb0nyl) ) benzofuran-Z-yl)methylcarbamate (21): tert—Butyl (7-chloro(4—(3,3— difluoroazetidine-l-carbonyl)phenyl)benzofuranyl)methylcarbamate (21) was synthesized using General ure 2. Yield (60%). LCMS: m/z 477.0 [M+H]+, tR= 1.91min.
Synthesis of (4-(2-(aminomethyl)chlorobenzofuran-S-yl) phenyl)(3, 3- difluoroazetidin-l-yl) methanone (22): (4-(2-(Aminomethyl)chlorobenzofuran yl)phenyl)(3,3-difluoroazetidinyl)methanone was synthesized using General Procedure 3 (see below, conversion of 24 to 25). Yield (89%). LCMS: m/z 377.0 [M+H]+, tR= 1.36 min.
Synthesis of (E)—3-(6-aminopyridin—3-yl)—N-((7-chlor0(4—(3,3- ‘ difluoroazetidine-l-carbonyl)phenyl)benzofuranyl)methyl)acrylamide (508): (E)—3-(6— Aminopyridin—3 -yl)—N—((7-chloro-5 -(4—(3 ,3 -difluoroazetidine-1—carbonyl)phenyl)benzofiiran- —100— 2—yl)methyl)acrylamide (508) was synthesized using General Procedure 1. Yield (12%). 1H NMR (400 MHz, CD3OD) 5 .65 (m, 8H), 7.51-7.36 (m, 2H), 6.95—6.52 (m, 3H), 4.60 (s, 4H), 4.45 (s, 2H). LCMS: m/z 523.1 [M+H]+, IR: 1.39 min.
Synthesis of (E)—3-(6-aminopyridinyl)-N-((7—chlor0-5—(4-(3,3—difluoroazetidine carbonyl)phenyl)benzo[d]oxazol-Z-yl)methyl)acrylamide (509): XL? F NELF C! c: CI H N BocHN o Pd(dppf)Clz BocHN o 2 o \_<\fl 80020 \_<\ _K.C~O_. \—<\N O F N N 2 3 Br Br , EtsN,CHZCI2 dioxaneszO O N/jF 13 23 24 O CHZCIZ Nil—«N O H N o 2 o F EDCI,HOBt \ +—-—-—-— <\ O F _ O N’j‘F DIPEA,DMF N/ \ 509 o .
Synthesis of tert-butyl (5—bromo-7—chlorobenzo[d]oxazol-Z- yl)methylcarbamate (23): (5-Bromochlorobenzo[d]oxazol-2—yl)methanamine (13) (640 mg, 2.46 mmol) was dissolved in romethane (20 mL). Di-tert-butyl dicarbonate (638 mg, 2.95 mmol) and triethylamine (496 mg, 4.92 mmol) were added at 0 OC. The on mixture was stirred at room temperature for 4 h. The on mixture was transferred into iced water and extracted with dichloromethane (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude tert—butyl(5-bromo—7- chlorobenzo[d]oxazolyl)methylcarbamate (23), which was used without further purification in the next step. LCMS: m/z 305.0 +, IR = 1.87.
] Synthesis of tert—butyl (7-chloro(4-(3,3-difluoroazetidine-l- carbonyl)phenyl)benzo[d]oxazol-Z-yl)methylcarbamate (24): A mixture of tert-butyl (5- bromo-7—chlorobenzo[d]oxazol—2—yl)methylcarbamate (23) (310 mg, 0.86 mmol), morpholino(4—(4,4,5,5—tetramethyl—l,3,2-dioxaborolan—2-yl)phenyl)methanone (20) (278 mg, 0.86 mmol), Pd(dppf)C12 (63 mg, 0.086 mmol) and K2C03 (237 mg, 1.72 mmol) in 15 mL of dioxane and 3 mL of H20 were stirred at 85 0C under nitrogen atmosphere for 3 h. The —101- reaction mixture was extracted with EtOAc (20 mL X 3). The ed organic layers were washed with brine, dried over anhydrous , and the solvents were removed under reduced pressure to give the crude product, which was d by silica gel chromatography (20% EtOAc/petroleum ether) to give tert-butyl(7-chloro(4—(3,3-difluoroazetidine—1- yl)phenyl)benzo[d]oxazol—2-yl)methylcarbamate (24) as a yellow solid (yield: 180 mg, 44%) LCMS: m/z 422 [M-55]; tR =1.77 min Synthes1s 0f (4-(2-(aminomethyl)chl0r0benzo[d]oxazol-S-yl)phenyl)(3,3- difluoroazetidinyl)methan0ne (25): .
General Procedure 3. Boc Deprotection.
Cl CI BocHN O O H2 0 \ F TFA _<\ F N N O [0039 1] tert-Butyl (7—chloro-5 -(4-(3,3—difluoroazetidine— 1 - carbonyl)phenyl)benzo[d]oxazolyl)methylcarbamate (24) (100 mg, 0.21 mmol) was ved in CHzClz (10 mL). TFA (3 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure to give crude (4-(2- (aminomethyl)chlorobenzo [djoxazol-S -y1)phenyl)(3 ,3 -difluoroazetidin- 1 — y1)methanone (25), which was used without further purification in the next step. Yield (100%). LCMS: m/z 378.1 [M+H]+; m = 1.69 min.
Synthesis of (6-amin0pyridin-3—yl)—N—((7-chloro—5—(4-(3,3-diflu0r0azetidine carbonyl)phenyl)benzo[d] oxazolyl)methyl)acrylamide (509): HZN o ' <\N O F N/l \ OH EDCIHOBt O N/j\F + \ HZN DIPEA DMF (4-(2-(Aminomethyl)chlorobenzo[d]oxazol-S-yl)phenyl)(3,3-difluoroazetidin- 1-yl)methanone (25) (100 mg, 0.265 mmol) was dissolved in DMF (5 mL) and (E)(6— aminopyridinyl)acrylic acid (44 mg, 0.65 mmol) was added at 0 oC. EDCl (100 mg, 0.53 mmol) and HOBt (72 mg, 0.53 mmol) were added at 0 °C followed by DIPEA (68 mg, 0.53 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and —102- stirred for 2 h. The reaction mixture was transferred into iced water (20 mL) and extracted with EtOAc (25 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced pressure to give crude product, which was purified by chromatography to afford (E)(6-aminopyridin—3-yl)—N-((7-chloro(4— (3 ,3 -difluoroazetidinecarbony1)phenyl)benzo[d]oxazolyl)methyl)acrylamide (509).
Yield (46 mg, 33%). 1H NMR (400 MHz, fi) 5 8.09-8.08 (m, 1H), 7.92 (d, J= 1.5 Hz, 1H), 7.82-7.77 (m, 6H), 7.5 (d, J= 15.6 Hz, 1H), 6.63 (d, J: 8.9 Hz, 1H), 6.54 (d, J = 15.7 Hz, 1H), 4.85—4.83 (m, 4H), 4.63-4.51 (m, 2H). LCMS: m/z 524.2[M+H]+;1‘R =1. min.
Synthesis of (E)—3—(6-amin0pyridinyl)-N-((5—(4-(m0rpholinecarbonyl)phenyl)—7— (trifluoromethyl)benzofuran-Z—yl)methyl)acrylamide (510): o ,0 NHBoc 13—0430% CF3 CFa (j CF3 / CFa OH (0:1) —»K"'2 O" m 3...me W" 0 ——"—’ ( a) 2 \ Br H20 pf)Clz,KOAC \ O Br I EtaN dioxane, H20 0 (\o 26 27 23 29 NJ CHZCIZ \ / NH2 00 O EDCI, HOB’: Nd DIPEA, DMF 30 sis of oiod0(trifluoromethyl) phenol (27): A mixture of 4- bromo—2—(trifluoromethyl)pheno1 (26) (8 g, 33.3 mmol), KI (16 g, 99.9 mmol) and 12 (8.5 g, 33.3 mmol) in 50 mL ofNH3OH and 50 mL of H20 was stirred at 30 0C for 16 h. HCl was added to the solution to reach a pH of 7. The reaction mixture was extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 4—bromoiodo- 6-(trifluoromethyl)phenol (27) as a white solid (yield: 8 g, 67%). LCMS: IR = 1.53 min.
Synthesis of tert-butyl (S-bromo(trifluoromethyl)benzofuran yl)methylcarbamate (28). A mixture of o—2-iodo—6-(trifluoromethyl)phenol (27) (l g, 2.7 mmol), rerr~buty1 prop—2-ynylcarbamate (500 mg, 3.24 mmol), Pd(PPh3)C12(118 mg, 0.27 mmol) and CuI (51 mg, 0.27 mmol) in 20 mL oftriethylamine was stirred at 80 0C under nitrogen atmosphere for 2 h. The reaction mixture was extracted with EtOAc (50 mL X 3).
The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give tert—butyl mo (trifluoromethyl)benzofuranyl)methylcarbamate (28) as a white solid (yield: 600 mg, 57%). LCMS: m/z 417.9 [M+Na]+; 1R = 2.04 min.
Synthesis of tert-butyl (5-(4—(morpholinecarbonyl)phenyl) (trifluoromethyl)benzofuran-Z-yl)methylcarbamate (29): A mixture of tert—butyl (5- bromo(trifluoromethyl)benzofurany1)methy1carbamate (28) (200 mg, 0.51 mmol), morpholino(4-(4,4,5 ,5 -tetramethyl—1 ,3,2-dioxaborolan—2-yl)phenyl)methanone (193 mg, 0.61 mmol), Pd(dppt)C12 (38 mg, 0.051 mmol) and KOAc (100 mg, 1.02 mmol) in 8 mL of dioxane and 2 mL of H20 was stirred at 85 0C under nitrogen atmosphere for 2 h. The mixture was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over ous NazSO4, and concentrated under reduced pressure to give the crude product, which was d by silica gel chromatography (40% EtOAc/petroleum ether) to give tert—butyl (5-(4—(morpholine-4—carbonyl)phenyl)—7- (trifluoromethyl)benzofuran—2—yl)methylcarbamate 7 as a white solid. : 150 mg, 47%).
LCMS: m/Z 505.0 [M+H]+; 1R = 1.85 min. ] sis of (Amin0methyl)-7—(triflu0romethyl)benz0furan yl)phenyl)(morpholin0)methan0ne (30): tert—Butyl (5-(4—(morpholine—4-carbonyl)phenyl)- 7-(trifluoromethyl)benzofuran—2-yl)methylcarbamate 29 (120 mg, 0.24 mmol) was dissolved in CH2C12 (4 mL). TFA (1 mL) was added at 0 °C. The reaction e was stirred at room temperature for 2 h, and concentrated under reduced pressure to give crude (4—(2- (aminomethyl)-7—(trifluoromethyl)benzofiiranyl)pheny1)(morpholino)methanone (30), which was used without further purification in the next step. Yield (100%). LCMS: m/z 405.0[M+H]+; 1R = 1. 316 min.
Synthesis of (6-aminopyridinyl)-N-((5-(4-(m0rpholine carbonyl)phenyl)(triflu0r0methyl)benzofuran-2—yl)methyl)acrylamide (510): (4-(2-I (Aminomethyl)(trifluoromethyl)benzofiirany1)phenyl)(morpholino)methanone (30) (crude product from previous step, 0.24 mmol) was dissolved in DMF (3 mL) and (E)—3-(6- aminopyridinyl)acrylic acid (39 mg, 0.24 mmol). The reaction mixture was cooled to 0 °C. EDCI (55 mg, 0.28 mmol) and HOBt (32 mg, 0.24 mmol) were added to this reaction -104— mixture at 0 OC followed by DIPEA (93 mg, 0.72 mmol) dropwise. The reaction mixture was allowed to warm to room ature and d further for 2 h. The on e was transferred into water (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced pressure to give crude product, which was purified by preparative HPLC to afford (E)-3 -(6-aminopyridin—3 —yl)-N-((5 -(4-(morpholinecarbonyl)phenyl) (trifluoromethyl)benzofi1ran—2-yl)methy1)acrylamide (yield: 68 mg, 52%). 1H NMR (400 MHZ, DMSO'd6) 5 8.89 (t, J= 5.7 Hz, 1H), 8.25-8.21 (m, 4H), 8.11 (dd, J= 2.0 Hz, J= 9.2 Hz, 1H), 7.87-7.82 (m, 3H), 7.64 (d, J= 8.2 Hz, 1H), 7.44 (d, J= 15.8 Hz, 1H), 7. 00—6 96 (m, 2H), 6. 62 (d, J: 15. 8 Hz, 1H), 4.64 (d, J: 5.7 Hz, 1H), 3.41-3.32 (m, 8H). LCMS: m/z 551. 1 [M+H]+; IR —1.423 min Synthesis of (E)—3-(6-amin0pyridinyl)-N—((7—tert-butyl-S-(4-(m0rpholine—4- carb0nyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (511).
NHBoc 0" K‘ ‘2 OH -—> W" BocH o Pd(PPh3)C12 B NH3OHBr Pd(dppf)C]2 KOAC \ O r E'SN Br dioxane, H20 |/\O 31 34 NJ CHZCIZ \ _N H2 0 O <—-——————— EDCI, HOB! DIPEA, DMF O |/\O 4—Bromotert—butyliodophenol (32) was synthesized in accordance with the procedure described above for the conversion of 26 to 27. Yield (37%). 1H NMR (400 MHz, CDCl3) 5 7.66 (d, J: 2.5 Hz,1H), 7.36 (d, J = 2.2 Hz,1H), 5.51 (s, 1H), 1.39 (s, 9H). tert-Butyl (5-bromotert-butylbenzofuran-Z-y1)methylcarbamate (33) was synthesized in accordance with the procedure bed above for the conversion of 27 to 28.
Yield (27%). LCMS: rR = 1.427 min. utyl (7—tert-butyl—5—(4—(morpholine—4—carbonyl)phenyl)benzofuran—2— yl)methylcarbamate (35) was synthesized using General Procedure 2. Yield (59%). LCMS: m/Z 493.2 [M+H]+; rR = 1.945 min. —105— (4-(2-(Aminomethyl)—7—lert—butylbenzofi1ran—5-yl)phenyl)(morpholino)methanone was synthesized using General Procedure 3. Yield (100%). LCMS: m/z 393.1 [M+H]+; IR = 0.874 min.
((E)-3 -(6—Aminopyridin-3 -yl)-N—((7—tert-butyl-5 -(4-(morpholine—4-carbonyl) phenyl) benzofuranyl)methyl)acrylamide (511) was synthesized using l Procedure 1. Yield (40%). 1H NMR (400 MHZ, DMSO-d6) 5 8.79 (t, J= 6.2 Hz, 1H), 8.21 (s, 1H), 8.15-8.08 (m, 2H), 7.75-7.73 (m, 3H), 7.51-7.44 (m, 3H), 7.37 (d, J: 1.8 Hz, 1H), 6.97 (d, J= 9.4 Hz, 1H), 6.76 (s, 1H), 6.61 (d, J= 16 Hz,1H), 4.61 (d, J= 5.9 Hz,1H), 3.71- 3.40 (m, 8H), 1.50 (s, 9H). LCMS: m/z 539.2 [M+H]+; {R = 1.477 min.
Synthesis of (E)(6-aminopyridin—3-yl)’-N—(2-(7-chloro(4-(morpholine carbonyl)phenyl)benzHofuran-Z-prr0panyl)acrylamide (512).
CI CI \ NaNa, K2C03 Pd (PPh3)C|2 Br E13N CHZCI2 —> Br I Br DMF Cul EtaN DMF 3., 18 36 Cl DAR0 Cl BocHN N3 0 Raney Ni HZN o (Boc)20 c H5OH, H2 Br 2 H\ [ Et N CH3 2CI2 f)CI2 38 B KOAc dioxane, H20 Cl 0 BocHN O H2N O 0 \ \ WW/ TFA ‘/\O HZN N CH2CI2 0 My —"‘"* 42 EDCI, HOBt o DIPEA, DMF Synthesis of 2-(5-br0mochlorobenzofuran-Z-yl)propan-Z-ol (36). 2-(5- Bromo-7~chlorobenzofuran—2—yl)propanol (36) was synthesized was synthesized in accordance with the procedure bed above for the sion of 27 to 28. Yield (71%).
LCMS: m/z=27l.0 [MOH]; tR =1 l92min. —106- Synthesis of 2-(5-br0m0ch10r0benzofuran-Z-yl)propan-Z-yl methanesulfonate (37). 2-(5-Bromochlorobenzofuranyl)propan-2—ol (36) (500 mg, 1.74 mmol) was ved in dichloromethane (15 mL). Methane sulfonyl chloride (299 mg, 2.08 mmol) and triethylamine (263 61 mmol) were added at 0 °C and the reaction mixture was allowed to warm to room temperature and stirred for 4 h. The on mixture was transferred into iced water and extracted with romethane (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give crude 2-(5-bromochlorobenzofuran y1)propany1methanesulfonate (37), which was used in the next step without further purification. LCMS: m/z 270.9 [M-OMs] +-, in = 1.38 min.
Synthesis of 2-(2-azid0propanyl)-5—br0m0ehlorobenzofuran (38). 2-(5- Bromochlorobenzofuran—2—yl)propanyl methanesulfonate (37) (crude, l.74 mmol) was dissolved in DMF (5 mL). Sodium azide (226 mg, 3.48 mmol) was added at room temperature. The reaction mixture was refluxed at 80 0C for 2 h. After cooling to room temperature, the e was transferred into iced water, and extracted with ethyl e (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give 450 mg crude 2—(2-azidopropan— 2—y1)—5-bromo-7—chlorobenzofuran (38), which was used in the next step without further purification. LCMS: m/z 270.9 [M-Ng] +; tR = 1.37 min.
Synthesis of 2-(5-bromoehlor0benzofuran-Z—yl)propan-Z-amine (39). 2—(2- Azidopropan—2-yl)—5-bromo-7—chlorobenzofuran (38) (100 mg, 0.32 mmol) was ved in methanol (2 mL). Raney Ni (100 mg, wet) was added under hydrogen atmosphere and the mixture was stirred at room ature for l h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 70 mg of crude 2-(5-bromo chlorobenzofuran-2—yl)propanamine (39), which was used without further purification in the next step. LCMS: m/z 271 [M—NH2]+; tR = 0.87 min. sis of tert-butyl 2-(5-brom0chlorobenzofuran-Z-y1)propan-Z- ylcarbamate (40). 2-(5—Bromo—7-chlorobenzofuranyl)propanamine (39) (220 mg, 0.77 mmol) was dissolved in dichloromethane (5 mL) and de-tert-butyl dicarbonate (184 mg, 0.847 mmol) was added at 0 °C. Triethylamine (116 mg, 1.15 mmol) was added into the on mixture and stirred at room temperature for 4 h. The reaction mixture was transferred into iced water and extracted with dichloromethane (50 mL X 3). The combined —107- organic layers were washed with brine, dried over anhydrous Nast4, and concentrated under reduced pressure to give the crude product, which was purified by chromatography (0- 10% ethyl acetate/n-hexane) to give Iert—butyl 2-(5-bromochlorobenzofuran—Z- yl)propany1carbamate 57. Yield (100 mg, 87%). LCMS: m/z 410.0 [M+Na]+; tR = 1.33 min.
Synthesis of tert-butyl 2-(7-chloro—5-(4-(morpholine carbonyl)phenyl)benzofuranyl)pr0panylcarbamate (41). tert-Butyl 2-(7-chloro(4- (morpholinecarbonyl)phenyl)benzofuranyl)propanylcarbamate (41) was synthesized using General Procedure 2. Yield (78%). LCMS: m/z 499.1 [M+H]+, rR = 1.90 min.
Synthesis of (4-(2-(2-aminopropan-2—yl)chlorobenzofuran-S- nyl)(morpholino)methanone (42). (4-(2-(2—Aminopropanyl)-7—chlorobenzofuran— -yl)phenyl)(morpholino)methanone (42) was synthesized using General Procedure 3. Yield (100%). LCMS: m/z 382.0 [M-NH2]+, {R = 1.337 min.
Synthesis of (6-amin0pyridinyl)-N-(2-(7-chlor0—5—(4-(m0rpholine carbonyl)phenyl)benzofuran—2-yl)propan-2—yl)acrylamide (512). (E)-3—(6-Aminopyridin- 3—yl)—N-(2—(7-chloro(4-(morpholinecarbonyl)pheny1)benzofuran—2-yl)propan—2— yl)acrylamide (512) was synthesized using General ure 1. Yield (11%). 1H NMR (400 MHz, DMSO-dg) 5 8.51 (s, 1H), 8.12 (d, J: 1.6 Hz, 1H), 7.99 (d, J: 9.9 Hz, 2H), 7.87 (d, J=1.6 Hz, 1H), 7.78 (d, J: 8.3 Hz, 2H), 7.67 (d, J=1.6 , 7.52 (d, J: 8.3 Hz, 2H), 7.25 (d, J= 15.6 Hz, 1H), 6.93 (d, J= 9.0 Hz, 1H), ), 6.84 (s, 1H), 6.61 (d, J: .8 Hz, 1H), .55 (m, 8H), 1.72 (s, 6H). LCMS: m/z 545.1 [M+H]+, tR = 1.498 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-chloro(2-methyl-l-oxoisoindolin-S- yl)benzofuran-Z-yl)methyl)acrylamide (513).
BocHN 7:388 BocHN O Pd(dppf)Cl2 B\ 11 M OH : e H3 OH Br/CEEkO/N Br/qO/CBDV/k0 EtOH 30012 BPO CCI4 0 CI 43. Pd(dppf)Cl2, K2003 BocHN O TFA N" —-——————-——> O —> Br dioxane, H20 CHzclz H N O H N 000 49 0 "PW.EDCI HOBt Synthesis of tert—butyl loro—S-(4,4,5,5-tetramethyl-l,3,2-di0xab0rolan—2— yl)benzofuranyl)methyl)carbamate (43). tert—Butyl ((7-chloro(4,4,5,5-tetramethyl— 1,3,2-dioxaborolanyl)benzofuran—2-yl)methy1)carbamate (43) was synthesized in accordance with the procedure described below for the synthesis of (tert—Butyl (5-(4,4,5,5- tetramethyl— 1 ,3 ,2-dioxaborolanyl)(trifluoromethyl)benzofiiran-Z—yl)methylcarbamate (60).
Synthesis of methyl 4—brom0-2—methylbenzoate (45): 4—Bromo methylbenzoic acid (44) (2.5 g, 11.6 mmol) was dissolved in methanol (30 mL). SOC12 (4069 mg, 34.2 mmol) was added at 0 0C. After the addition, the mixture was refluxed overnight.
The mixture was trated to obtain crude methyl 4-bromomethylbenzoate 45, which was used in the next step without further purification.Yield (75.5%). LCMS: m/z 229 , m = 1.91 min.
] Synthesis of methyl 4—bromo-Z-(bromomethyl)benzoate (46): A solution of methyl 4-bromo-2—methylbenzoate 45 (2000 mg, 8.77 mmol), N-bromosuccinimide (NBS) (3035 mg, 17.54 mmol), benzoyl peroxide (BPO) (1061 mg, 4.39 mmol) in CC14 (20 mL) was refluxed overnight under nitrogen atmosphere. After cooling to room temperature, the —109- mixture was washed with brine (20 mL X 2) and dried over anhydrous NaZSO4. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (2-5% EtOAc/petroleum ether) to give methyl o (bromomethyl)benzoate 46 as a white solid (yield: 1.8 g, 67%). LCMS: m/z 308.7 [M+H]+; z‘R = 1.88 min.
] Synthesis of 5-bromo-2—methy1is0indolin-l-one (47): A solution of 4-bromo (bromomethyl)benzoate 46 (1000 mg, 3.27 mmol) in 30% ammonia in ethanol (10 mL) was heated at reflux overnight. The solvent was removed under reduced pressure and the residue was poured into 10 mL of water and ted with ethyl e (15 mL X 3). The combined organic layers were dried over anhydrous NaZSO4. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (30% EtOAc / petroleum ether) to give 5-bromo-2—methylisoindolin—1—one 47 as a white solid (yield: 400 mg, 54%). LCMS: m/z 226.7 [M+H]+; tR = 1.49 min.
Synthesis of tert-butyl (7-chlor0(2-methyl—l-0x0isoindolinyl)benzofuran- 2-yl)methylcarbamate (48): tert- Butyl (7—chloro-5—(2-methyl—l-oxoisoindolin~5- zofuran—2—yl)methylcarbamate (48) was synthesized using l Procedure 2. Yield (79%). LCMS: m/Z 427 [M+H]+, rR = 1.20 min.
Synthesis of 5-(2-(amin0methyl)chlor0benzofuranyl)methylis0ind01in0ne (49): 5-(2—(Aminomethyl)chlorobenzofuran—S-yl)~2-methylisoindolin—1—one (49) was synthesized using General Procedure 3. Yield (70%). LCMS: m/z 327 [M+H]+; IR = 1.17 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((7-chlor0(2-methyl indOlinyl)benzofuran-Z-yl)methyl)acrylamide (513) :1 (E)-3~(6-Aminopyridin—3- y1)-N- ((7-chloro-5 -(2—methyl—l ~oxoisoindolin—5-y1)benzofuran—2-yl)methyl)acrylamide (5 13) was synthesized using General Procedure 1. Yield (13.8%). 1H NMR (400 MHZ, DMSO-ds) 8.67-8.64 (t, J= 5.6 Hz, 1H), 8.08 (s, 1H), 7.94-7.93 (m, 2H), 7.82-7.61 (m, 5H), 7.36 (d, J==15.6 Hz, 1H), 6.91 (s, 1H), 6.49-6.41 (m, 3H), 4.61-4.52 (m, 4H), 3.10 (s, 3H).
LCMS: m/Z 473.7 ; tR = 1.55 min.
Synthesis of (E)(6-aminopyridin—3-yl)—N-((7-chlor0(2-methyl-1,3-di0xoisoindolin yl)benzofuran-Z-yl)methyl)acrylamide (514). -110— \ Cl c: . l N— Cl / BOCHN BocHN o 5' O o HzN O O \ TFA O 8’0 —> \ N_ CH CI 1 :_< Pdd(PP)fCl.KCO 2 2 2 2 a 50 O 43 0 dioxane, H20 0 N1. 0 01 O \ / \ NH \O cozH EDCI. HOBt N \ / 514 DIPEA, DMF tert-Butyl(7-chloro—5-(2-methyl-1,3-dioxoisoindolinyl)benzofuran yl)methylcarbamate (50) was synthesized using General Procedure 2. Yield (63%). LCMS: m/Z 463.7 [M+Na]+, 7R: 1.90 min. 5—(2—(Aminomethyl)—7—chlorobenzofuranyl)—2—methylisoindoline-l ,3-dione (51) was synthesized using General Procedure 3. Yield (65%). LCMS: m/z 324 [M-NH2]+; [R = 1.22 min.
] (E)~3~(6—Aminopyridin—3-yl)—N—((7—chloro—5—(2—methyl—1,3—dioxoisoindolin—5— yl)benzofurany1)rnethyl)acrylarnide (514) was synthesized using General ure 1.
Yield (35%). 1H NMR (400 MHz, DMSO-dg) 6 8.66—8.34 (t, J= 5.6 Hz, 1H), 8.17-8.05 (m, 4H), 7.94-7.87 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.36 (d, J=15.6 Hz, 1H), 6.91 (s, 1H), 6.49-6.41 (m, 3H), 4.61 (d, J=5.6 Hz, 2H), 3.07 (s, 3H). LCMS: m/z 488.7 [M+H]+; IR = 1.79 min.
Synthesis of (S,E)(6-amin0pyridinyl)-N-((7-chlor0(4-(3-methylm0rpholine—4- carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (515). —1_11- BocHN \0)K© O )K©\B(QH)2 BocHN \ \000 B r Pd(dPP)f)Cl2 KCO2 a CHZCIZ 19 dioxane H20 O \ T NH o / \ / NH2 LiOH O OH N —> N— O THF H o2 \ / 55 EDC|,HBOt HATU DMF Methyl (tert-butoxycarbonylamino)methyl)chlorobenzofuran-S- yl)benzoate (52): Methyl 4-(2-((tert-butoxycarbonylamino)methyl)chlorobenzofuran yl)benzoate (52) was synthesized using General Procedure 2. Yield (60%). LCMS: m/z :438 [M+Na]+, IR: 1.95 min.
Methyl 4-(2-(aminomethyl)—7—chlorobenzofuran-S-yl)benzoate (53): Methyl 4- (2—(aminomethyl)chlorobenzofi1ran—5-yl)benzoate (53) was synthesized using l Procedure 3. Yield (79%). LCMS: m/z:299 [M-NH2]+; IR = 1.01 min.
(E)-Methyl 4-(2-((3-(6-amin0pyridinyl)acrylamido)methyl) chlor0benzofuran-S-yl)benzoate (54): (E)-Methyl 4-(2—((3-(6-aminopyridin yl)acrylamido)methyl)chlorobenzofuran—5-yl)benzoate (54) was synthesized using General Procedure 1 Yield (47.8%) LCMS: m/z:4627 [M+H]; IR = 1. 35 min.
(E)(2-((3-(6-Amin0pyridinyl)acrylamido)methyl) chlor0benzofuran-S-yl)benzoic acid (55): thy1 4-(2-((3-(6-aminopyridin yl)acrylamido)methy1)chlorobenzofuran—S-yl)benzoate (54) (350 mg, 0.759 mmol) was dissolved in 5 mL THF and 5 mL H20. LiOH (64 mg, 1.52 mmol) was added at 0°C. Then reaction e was stirred at room temperature for 4 h. The reaction mixture was transferred into water and neutralized with dilute HCl (1N, until pH 3). The mixture was extracted with ethyl acetate (50 mL X 3). The combined organic layers were washed with -112— brine, dried over anhydrous Na2$O4 and concentrated under reduced pressure to obtain (E)(2-((3-(6—aminopyridin-3—yl)acrylamido)methyl)chlorobenzofuranyl)benzoic acid (55). Yield (300 mg, 88%). LCMS: 7.7 [M+H]+; IR = 1.29 min.
Synthesis of (S,E)(6-aminopyridinyl)-N-((7-chloro—5—(4—(3— methylmorph01inecarbonyl)phenyl)benzofuranyl)methyl)acrylamide (515).,»(E)-4— (2-((3-(6-Aminopyridinyl)acrylamido)methyl)chlorobenzofuran-S-yl)benzoic acid (55) (60 mg, 0.134 mmol) was dissolved in DMF (2 mL) and (S)methylmorpholine (16 mg, 0.161 mmol) was added at 0 °C. HATU (102 mg, 0.268 mmol) was added to this reaction mixture at 0 °C. The reaction mixture was d to warm to room ature and stirred overnight. The mixture was directly purified by chromatography to afford (S, E)- 3-(6-aminopyridin—3—yl)—N-((7-chloro—5-(4—(3—methylmorpholine—4- carbonyl)phenyl)benzofuran—2~yl)methy1)acrylamide (515). Yield (12 mg, 14%). 1H NMR (400 MHz, MeOD-ds) 6 865 (s, 1H), 8.08—7.34 (m, 9H) 6. 89 (s, 1H), 6.41 (s, 4H) 4.60 (s 2H) 3. 81—3 35 (m, 7H) 125 (s 3H) LCMS: m/z 531.2 ; tR= 1. 72 min.
Synthesis of (R,E)(6-aminopyridinyl)—N—((7—chloro(4-(3-methylmorpholine carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (516).
NH \O ""60 .— 0 OH_.__.
— HATU DMF N O \ / 55 no (R,E)(6-Aminopyridinyl)-N-((7-chloro(4-(3—methylmorpholine carbonyl)phenyl)benzofuran—2-yl)methyl)acrylamide (516) was synthesized in accordance with the procedure described above for the synthesis of (S, E)(6—aminopyridinyl)-N—((7- chloro(4-(3-methylmorpholinecarbonyl)phenyl)benzofuranyl)methyl)acrylamide (515). Yield (17%). 1H NMR (400 MHz, DMSO-d6) 5 8.64 (t, J= 4.8 Hz, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.80—7.72 (m, 4H), 7.62 (d, J= 8.8 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.35 (d J= 15.6H2 1H) 690 (s, 1H), 6.49—6.41 (m 4H), 460 (d J=5.2Hz 1H), 3. 80- 3. 31 (m 7H) 1.27 (d, J: 7. 20 Hz, 3H). LCMS: m/z 5312 [M+H]; IR: 1.74 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((5—(4—(3,3-dimethylmorpholine—4- carbonyl)phenyl)~7-(trifluoromethyl)benzofuran—2-yl)methyl)acrylamide (517).
BOCHN\—‘<:©\ H0\‘©_ Synthesis of methyl 4-(2-(aminomethyl)(trifluoromethyl)benzofuran yl)benzoate (57). Methyl (terz-butoxycarbonylamino)methyl)—7- (trifluoromethyl)benzofuranyl)benzoate (56) (2.4 g, 5.5 mmol) was dissolved in CH2C12 (20 mL). TFA (6 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under d pressure to give crude methyl 4—(2- (aminomethyl)(trifluoromethyl)benzofuran-5—y1)benzoate (57), which was used without further purification1n the next step. Yield (100%) LCMS: m/z 367.0 [M+H]+; IR— 0.71 min. Yield (100%). LCMS: m/z 333.0 [M-NH2]+, tR= 1.49 min. —114— Synthesis of thyl (3-(6-amin0pyridinyl)acrylamid0)methyl)- 7—(triflu0r0methyl)benzofuran-S-yl)benzoate (58). The crude methyl 4—(2— (aminomethyl)—7—(trifluoromethyl)benzofuranyl)benzoate (57) (crude mixture from previous step, 5.5 mmol) was dissolved in DMF (20 mL) and (E)-3—(6-aminopyridin yl)acrylic acid (918 mg, 5.6 mmol) was added at 0 °C. EDCI (1.3 g, 6.7 mmol) and HOBt (756 mg, 5.6 mmol) were added to this on mixture at 0 °C followed by DIPEA (2.2 g, 16.8 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The crude mixture was purified by preparative-HPLC without workup to afford (E)-methyl (3-(6-aminopyridin-3 -yl)acrylamido)methyl) (trifluoromethyl)benzofuran—5-yl)benzoate (58). Yield (1.5 g, 55%). LCMS: m/z 496.0 , m = 0.99 min. sis of (E)(2—((3—(6-amin0pyridinyl)acrylamid0)methyl) (triflu0romethyl)benzofuran-S-yl)benz0ic acid (59). (E)—Methyl 4—(2—((3-(6— aminopyridinyl)acry1amido)methyl)—7-(trifluoromethyl)benzofi1ran—5-yl)benante 5 (1.0 g, 2 mmol) was dissolved in THF (4 mL), LiOH (169 mg, 4 mmol) and water (1 mL) was added to this mixture. The mixture was stirred at room temperature for 8 h, then 1N HCl solution was added and the pH adjusted to pH 6. (E)(2—((3-(6-Aminopyridin—3— yl)acrylamido)methyl)—7-(trifluoromethyl)benzofiiranyl)benzoic acid (59) was collected by filtration.Yield (600 mg, 83%). LCMS: m/z 482.0 , tR= 1.29 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((5—(4-(3,3-dimethylmorpholine-4— carbonyl)phenyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (517). (E)-4—(2- ((3-(6-Aminopyridinyl)acrylamido)methyl)(trifluoromethyl)benzofilran-S—yl)benzoic acid (59) (60 mg, 0.12 mmol) was dissolved in DMF (2 mL) and 3,3-dimethylmorpholine (14 mg, 0.12 mmol) was added at 0 °C. HATU (57 mg, 0.15 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (31 mg, 0.24 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 4 h. The reaction mixture was transferred into water (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2$O4 and concentrated under d pressure to give crude product, which was purified by preparative-HPLC to afford (517). (Yield: 20 mg, 27%). 1H NMR (400 MHZ, CD3OD) 5 8.19 (dd, J: 2 Hz, J= 9.2 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J= 1.6 Hz, 1H), 7.80—7.75 (m, 3H), 7.56 (d, J: 8 Hz, 2H), 7.49 (d, J: 15.6 Hz, 1H), 7.05 (d, J: 9.2 Hz, 1H), 6.93 (s, —115- 1H), 6. 65 (d, J: 15 6 Hz, 1H), 4. 73 (s, 2H), 378 (t, J=4. 8 Hz, 2H), 3.52 (s, 2H), 3.46 (t, J= 5. 2 -,Hz 2H), 1. 54 (s, 6H). LCMS: m/z 5793 [M+H]+; 1R =1.85 min Synthesis of (E)(6-amin0pyridinyl)-N-((5-(4-(2-(pyridin yl)hydrazinecarbonyl)phenyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (518). l'jl‘NHz \OD | ——-—'—> COzH O HATU DIPEA DMF (E)—3~(6-Aminopyridin—3~y1)-N—((5-(4-(2-(pyridin yl)hydrazinecarbonyl)phenyl)-7—(trifluoromethyl)benzofuran~2-y1)methy1)acry1amide (518) was Synthesized according to General Procedure 1 using the indicated reagents. Yield (31%). 1H NMR (400 MHz, CD3OD) 5 8.16 (s, 1H), .06 (m, 4H), 7.85~7.83 (m, 3H), 7.76 (dd, J: 2.4 Hz, J: 8.8 Hz, 1H), 7.66-7.62 (m, 1H),7.50 (d, J: 15.6 Hz, 1H), 6.94-6.83 (m, 3H), .47 (m, 2H), 4.73 (s, 2H). LCMS: m/z 573.3 [M+H]+;1‘R = 1.70 min.
Synthesis of (E)(6—amin0pyridinyl)-N-((5-(4-(2-(pyrazin yl)hydrazinecarbonyl)phenyl)(trifluoromethyl)benz0furanyl)methyl)acrylamide (519). aC02H HATU DIPEA DMF (E)(6-Aminopyridinyl)-N—((5-(4-(2-(pyrazin-2— yl)hydrazinecarbonyl)phenyl)(trifluoromethyl)benzofurany1)methy1)acrylamide (519) was synthesized according to General Procedure I using the indicated reagents. Yield (9.8%). 1H NMR (400 MHz, CD3OD) 5 8.16 (s, 2H), .06 (m, 4H), 7.96 (d, J= 2.8 Hz, 1H),7.87—7.77 (m, 3H), 7.76 (dd, J: 2.4 Hz, J: 8.8 Hz, 1H), 7.50 (d, J: 15.6 Hz, 1H), 6.92 (d, J== 14 Hz, 1H), 6.61 (d, J: 8.4 Hz, 1H), 6.49 (d, J: 15.6 Hz, 1H), 4.73 (s, 2H). LCMS: m/z 574.2 [M+H]+; rR = 1.63 min.
Synthesis of (E)-\3-(6-aminopyridinyl)-N-((5-(4-(3,3-difluoroazetidine-l- carbonyl)phenyl)—7-(triflu0r0methyl)benzofuranyl)methyl)acrylamide (520).
CI:a o O \09 0 \ _ O :><:NHC’ COH2 N/ \ HoBt DIPEA DMF (E)-3 -(6-Aminopyridin—3 -yl)-N—((5-(4-(3 ,3 -difluoroazetidinecarbonyl)phenyl)- 7-(trifluoromethyl)benzofuranyl)methyl)acrylamide (520) was synthesized using General Procedure 1. Yield (32%). 1H NMR (400 MHZ, CD30D) 5 8.14 (s, 1H), 8.07 (s, 1H), 7.82— 7.74 (m, 7H), 7.50 (d, J: 16 Hz, 1H), 6.93 (s, 1H), 6.61 (d, J: 8.8 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), .59 (m, 6H). LCMS1m/z 557.2 [M+H]+; tR = 1.80 min.
Synthesis of (E)(6-amin0pyridinyl)—N-((5-(5—(morpholine—4-carbonyl)pyridinyl)— 7-(triflu0romethyl)benzofuran-Z-yl)methyl)acrylamide (521).
O\._/N _ CF CF3 3 BocHN\_ Synthesis of (6-(2-(aminomethyl)—7—(trifluoromethyl)benzofuranyl)pyridin- 3-yl)(m0rpholin0)methanone (62). (6—(2-(Aminornethyl)—7-(trifluoromethyl)benzofuran y1)pyridin—3—yl)(morpholino)methanone (62) was synthesized using General Procedure 3.
Yield (100%). LCMS: m/z 406.0 [M+H]+, tR= 1.13 min.
Synthesis of (E)(6-‘amin0pyridinyl)—N—((5-(5-(m0rpholine carb0nyl)pyridinyl)-7—(trifluoromethyl)benzofuranyl)methyl)acrylamide (521): (E)—3—(6—Arninopyridinyl)—N—((5-(5-(morpholine—4-carbonyl)pyridin—2—yl)—7- (trifluoromethyl)benzofuran—2-y1)rnethyl)acrylamide (521) was synthesized using General Procedure 1. Yield (5%). 1H NMR (400 MHz, MeOD) 6 8.77-8.76 (m, 1H), 8.54 (s, 1H), 8.35 (s, 1H), .07 (m, 2H), 8.01—7.99(m,1H), 7.76 (dd, J= 2.2 Hz, J= 8.7 Hz, 1H), 7.50 (d, J: 16.0 Hz, 1H), 6.97 (s, 1H), 6.62 (d, J: 8.9 Hz, 1H), 6.49 (d,>J= 15.6 Hz, 1H), 4.73 (s, 2H), 3.81-3.71 (m, 8H). LCMS: m/z 552.2 [M+H]+, IR: 1.65 min.
Synthesis of 3-(6-aminopyridinyl)-N-((5-(4-(3-flu0r0pyrrolidine carb0nyl)phenyl)(triflu0romethyl)benzofuranyl)methyl)acrylamideF(522).
DC02H 0‘ HATU N/ DIPEA DMF 3—(6-Aminopyridin—3-yl)—N—((5—(4—(3—fluoropyrrolidinecarbonyl)pheny1)— 7—(trifluorornethyl)benzofuran-Z—yl)methyl)acrylarnide (522) was synthesized according to General Procedure 1 using the indicated reagents. Yield (15%). 1H NMR (400 MHz, CD3OD) 5 8.06 (d, J: 12 Hz, 2H), 7.78—7.64 (m, 6H), 7.48 (d, J: 15.6 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J: 8.8 Hz, 1H), 6.47 (d, J=15.6 Hz, 1H), 5.44-5.31 (m, 1H), 4.70 (s, 2H), 3.90-3.67 (m, 4H), 2.29-2.04 (m, 2H). LCMS: m/z 553.3 ; tR = 1.76 min.
Synthesis of (R,E)(6-aminopyridin-3~yl)-N-((7-chloro-S-(4-(3-flu0r0pyrrolidine carb0nyl)phenyl)benz0furan-2—yl)methyl)acrylamide (523).
N/ \ 55 _ (R,E)(6-Aminopyridinyl)-N—((7-chloro(4-(3-fluoropyrrolidine carbonyl)phenyl)benzofuran-2—yl)methyl)acrylamide (523) was synthesized according to General Procedure 1 using the indicated reagents. Yield (11%). 1H NMR (400 MHz, MeOD- d6) 5 8.15 (dd, J: 2.0 Hz, J: 9.2 Hz,1H), 8.06 (s, 1H), 7.81-7.76 (1’1'1, 3H), .63 (m, 3H), 7.50 (d, J: 15.6 Hz, 1H), 6.99 (d, J= 9.2 Hz,1H),6.89(s,1H), 6.63 (d, J: . 6 Hz 1H) 4.72 (s 2H), 3.92—3.78 (m, 4H),2.33-2.178 (m, 2H). LCMS: m/z 519.7 [M+H]; tR— 1.61 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((5-(4-(3-fluor0azetidine-l-carb0nyl)phenyl)- 7-(triflu0r0methyl)benzofuran-2—yl)methyl)acrylamide (524). 9% o 0 \ 0 FQNH HCI NH F _ 0 N7 002H —"_—’N/ \ 524 0 (6—Aminopyridinyl)-N-((5-(4-(3-fluoroazetidinecarbonyl)pheny1)—7- (trifluoromethyl)benzofuranyl)methyl)acrylamide (524) was synthesized according to General Procedure 1 using the indicated ts. Yield (34%). 1H NMR (400 MHz, CD3OD) 6 8.12 (d, J: 0.8 Hz, 1H), 8.06 (d, J: 2.4 Hz, 1H), 7.81-7.73 (m, 6H), 7.49 (d, J= 15.6 Hz, 1H), 6.92 (s, 1H), 6.61 (d, J: 8.4 Hz,1H), 6.48 (d, J: 15.6 Hz, 1H), 5.52- .34 (m, 1H), 4.84 (s, 2H), 4.72-4.23 (m, 4H). LCMS: m/z 539.3 [M+H]+; IR = 1.75 min. —119- Synthesis of (S,E)—3-(6-aminopyridinyl)-N-((5-(4-(3-fluoropyrrolidine carb0nyl)phenyl)—7-(triflu0r0methyl)benzofuran-Z-yl)methyl)acrylamidCFe(525).
HATU DIPEA, DMF (S, E)—3 -(6-Aminopyridinyl)—N-((5-(4—(3—fluoropyrrolidinecarbonyl)phenyl)— 7—(trifluoromethyl)benzofuran~2-yl)methyl)acrylamide (525) was synthesized ing to General Procedure 1 using the indicated reagents. Yield (17%). 1H NMR (400 MHZ, CD30D) 6 8.10-8.05 (m, 2H), 7.80-7.65 (m, 6H), 7.49 (d, J= 15.6 Hz, 1H), 6.91 (s, 1H), 6. 60 (d, J: 8 8 Hz, 1H), 648 (d, J: 15. 6 Hz, 1H), 5.45—5. 32 (m, 1H), 4.88 (s, 2H), 3. 91—3. 65 (m, 4H) 2.28—2. 05 (m, 2H) LCMS: m/z 553. 3 [M+H]; IR: 1.76 min.
Synthesis of (E)(6-aminopyridin—3-yl)-N-((5-(4—(3,3-dimethylazetidine 1 carbonyl)phenyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (526).
CF3 o ‘ 0 O \ O O \ O NH NH O ><:NH HCI — N/3A _ —___.
COZH N/ \ 526 o / \ N 59 — — DIPEA, DMF (E)—3 —(6—Aminopyridin—3 -yl)-N-((5 -(4-(3 ,3-dimethylazetidine-1 -carbonyl)phenyl)— fluoromethyl)benzofuranyl)methyl)acrylamide (526) was synthesized according to General Procedure 1 using the indicated reagents. Yield (28%). 1H NMR (400 MHZ, CD3OD) 6 8.66 (s, 1H), 8.24 (s, 1H), 8.08 (d, J: 1.6 Hz, 1H), 7.86-7.73 (m, 5H), 7.62 (dd, J: 2 Hz, J= 8.8 Hz, 1H), 7.35 (d, J= 16 Hz, 1H), 6.94 (s, 1H), 6.49-6.41 (m, 3H) 4.61 (d, J.= 3.6 Hz, 2H), 4.05-4.02 (m, 3H),3.75 (s, 2H), 1.25 (s, 6H). LCMS: m/z 549.3 ; 1R = 1.87 min.
Synthesis of (R,E)(6-amin0pyridinyl)~N-((7—chlor0(4-(3-flu0ropyrrolidin ylsulfonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (527). -l20- Br EN) fiéiom NHBoc CI ; O F \ O BocHN TFA "m—* O\ 53b cl’séo EtaN F’d(dppf)C|2 K2C03 OS,,0 "—’CHCI2 2 CH2C|2 dioxane H20 i: 65 0/] ‘0.qu a" Ewe... '0 \ O _ o o // _ s.
// N 6/8 HATU N\ 0 O F DIPEA DMF 527 sis of (R)(4-hromophenylsulfonyl)—3-flu0r0pyrrolidine (64): (R) Fluoropyrrolidine hydrochloride (125 mg, 1 mmol) was dissolved in 10 mL CHZClz. The mixture was cooled to 0 0C and to this mixture were added Et3N (202 mg, 2 mmol) and obenzene—1—sulfonyl chloride (63) (255 mg, 1 mmol). The resulting mixtue was d to warm to room temperature and d for 1 h. The mixture was washed with H20 (10 mL X 2), dried over anhydrous NaZSO4 and concentrated to give 308 mg of (R)- 1—(4-bromophenylsulfonyl)-3~fluoropyrrolidine (64) (100% yield) as a white solid.
LCMS: m/z 307.9 [M+H]+; tR = 1.74 min.
Synthesis of (R)-tert-butyl (7-chloro—5-(4-(3-_flu0r0pyrrolidin-1— ylsulfonyl)phenyl)benzofuran-Z-yl)methylcarbamate (65): (R)-tert—Butyl (7-chloro-5—(4— (3—fluoropyrrolidin-l-y1sulfonyl)phenyl)benzofi1ran—2-yl)methylcarbamate (65) was synthesized using General Procedure 2. Yield (68%). LCMS: m/z 509.2 [M+H]+; IR = 2.10 min.
Synthesis of (R)-(7-chlor0-5—(4-(3-flu0r0pyrr01idin ylsulfonyl)phenyl)benzofuran-Z-yl)methanamine (66). (R)-(7-Chloro(4-(3- fluoropyrrolidin-l-ylsulfonyl)phenyl)benzofuranyl)methanamine (66) was synthesized using General Procedure 3. Yield (100%). LCMS: m/z 409.2 [M+H]+; tR = 1.83 min.
Synthesis of 3-(6-aminopyridin-S-yl)-N—((7-chloro-S-(4-(3- fluoropyrrolidinylsulfonyl)phenyl)benz0furanyl)methyl)acrylamide (527). (R,E)—3— (6—Aminopyridiny1)—N—((7—chloro(4-(3-fluoropyrrolidin ylsulfonyl)phenyl)benzofuran-2—yl)methyl)acrylamide (527) was synthesized using General Procedure 1. Yield (15%). 1H NMR (400 MHz, CD3OD) 5 8.84 (t, J= 5.6 Hz, 1H), 8.19 (s, 1H), 8.19—7.88(1n, 8H), 7.79 (d, J= 1.6 Hz, 1H), 7.43 (d, J: 13.2 Hz, 1H), 6.96-6.93 (m, 2H), 6.59 (d, J: 15.6 Hz, 1H), 5.29-5.16 (m, 1H), 4.62 (d, J= 5.6 Hz, 2H), .15 (m, 4H), 2.08-2.01 (m, 2H). LCMS: m/z 555.1 [M+H]+, IR: 1.70 min.
Synthesis of (S,E)(6-aminopyridin-S-yl)-N—((7-chloro—5—(4-(3-fluoropyrrolidine—1- carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (528). ,5«50,0HATUWPEA,DMF ' ] (S, E)—3 -(6-Aminopyridin-3 -y1)—N—((7-chloro(4-(3 -fluoropyrrolidine carbonyl)pheny1)benzofurany1)methy1)acrylamide (528) was synthesized according to General Procedure 1 using the indicated reagents. Yield (26%). 1H NMR (400 MHz, DMSO'dfi) 6 8.64(t, J: 5.6 Hz,1H), 8.08 (d, J: 2.4 Hz,1H), 7.92(d, J: 1.6 Hz,1H), 7.79 (d, J= 8.4 Hz, 2H), 7.73 (d, J=1.6 Hz, 1H), 7.67-7.61(1n, 3H), 7.36 (d, J: 15.6 Hz ,1H,) 6 90 (s, 1H), 6.49—6.41 (m, 4H),4.60 (d, J: 6.0 Hz, 2H), 3.79-3.56 (m, 4H),2.16— 203 (m, 2H) LCMS: m/z 519.7 [M+H]; tR= 1. 63 min.
Synthesis of (E)(6-aminopyridinyl)—N-((7-chloro—5-(4-(3,3-dimethylazetidine carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (529).
O O \ O \ O «b NH O NH D< O HC' NH — N C02H N/ \ 529 HATU O N/ \ 55 ._ mPEA,DMF — HgN (E)-3 -(6-Aminopyridin-3 -yl)-N-((7-chloro(4-(3 ,3 -dimethylazetidine carbony1)pheny1)benzofurany1)methy1)acry1amide (529) was synthesized according to General Procedure 1 using the indicated reagents. Yield (25%). 1H NMR (400 MHz, DMSO'dfi) 5 8.64 (t, J: 5.6 Hz, 1H), 8.08 (d, J: 2.4 Hz, 1H), 7.91 (d, J: 1.6 Hz, 1H), .60 (m, 6H), 7.35 (d, J: 15.6 Hz, 1H), 6.90 (s, 1H), 6.49-6.40(1n,4H), 4.60 (d, J —122- = 5.6 Hz, 2H), 4.03 (s, 2H), 3.75 (s, 2H), 1.26 (s, 6H). LCMS: m/Z 515.7 [M+H]+; 1R — 1.74 min.
Synthesis of (E)(6-aminopyridin-3—yl)-N-((5-(4-(2,2-dimethylmorpholine-4— yl)phenyl)(trifluoromethyl)benzofuranyl)methyl)acrylamideF(530).
HATU DIPEA, DMF (E)(6-Amin0pyridin—3-yl)-N—((5—(4-(2,2—dimethylm0rph01ine-4— carbony1)pheny1)—7-(trifluoromethy1)benzofi1ran-2—y1)methy1)acrylamide (530) was synthesized according to General Procedure 1 using the indicated reagents. Yield (27%). 1H NMR (400 MHZ, CD3OD) 5 8.11 (s, 1H), 8.06 (d, J: 2.4 Hz, 1H), 7.80-7.73 (m, 4H), 7.56 (s, 2H), 7.49 (d, J= 15.6 Hz, 1H), 6.92 (s, 1H), 6.61 (d, J: 8.8 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 4.72 (s, 2H), 4.63 (s, 2H), 3.82—3.49 (m, 4H), 1.31-1.16 (s, 6H). LCMS: m/Z 579.2 [M+H]+; rR = 1.68 min.
Synthesis of (E)-3—(6—aminopyridinyl)—N-((5—(4-(m0rph01in0sulf0nyl)phenyl) (trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide0(531). 9 ""u Br*‘©*8-01——"** m—Q:—©N9/—\" " N/—\U0 E13N CHZCIZ KOAc Pd(dppficlz o O O dioxane 69 O CFs BocHN 28\ Br TFA BocHN —-——* \ 0 CHM HZN (Pdd f)C| KCO OD "0 O 0 P9 2 2 3 // dioxane H20 70 6’ONK/jo 71 élstK/O HO \ O —~ N" 0 NH — 0 ,0 \ / 2 3’ EDCI, HOBt. DIPEA. DMF 531 —123— Synthesis of 4-(4-br0mophenylsulfonyl)morpholine (68). 4—(4— Bromophenylsulfonyl)morpholine (68) was synthesized in ance with the procedure described above for the synthesis of (R)(4-bromophenylsulfonyl)fluoropyrrolidine (64).
Yield (100%). LCMS: m/z 306.0 [M+H]+, {R = 1.06 min.
Synthesis of 4-(4-(4,4,5,5-tetramethyl—1,3,2-di0xab0rolan yl)phenylsulf0nyl)morpholine (69): A mixture of 4-(4-bromopheny1sulfonyl)morpholine (68) 6.0 g, 19.7 mmol), 4,4,4‘,4‘,5,5,5',5‘-octamethyl-2,2’—bi(1,3,2-dioxaborolane) (5.0 g, 19.7 mmol ), Pd(dppf)C12 (1.6 g, 1.97 mmol) and AcOK (3.8 g, 39.4 mmol) in 100 mL of dioxane was stirred at 90 0C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel tography (10% EtOAc/petroleum ether) to give 5.2 g of 4-(4-(4,4,5,5-tetramethyl—1,3,2-dioxaborolan—2— yl)phenylsulfonyl)morpholine (69) as a yellowish solid (yield: 75%). LCMS: m/z 354.0 [M+H]+, rR = 1.89 min.
Synthesis of tert-butyl (5—(4-(morpholinosulfonyl)phenyl)—7- (trifluoromethyl)benzofuran—Z-yl)methylcarbamate (70): tert—Butyl (5—(4— (morpholinosulfonyl)phenyl)(trifluoromethyl)benzofuranyl)methylcarbamate (70) was synthesized using General ure 2. Yield (47%). LCMS: m/z 541.0 [M+H]+; IR = 1.97 min.
Synthesis of (5-(4-(m0rpholinosulfonyl)phenyl)-7— (trifluoromethyl)benzofuran—Z-yl)methanamine (71). (5-(4-(Morpholinosulfonyl)phenyl)— 7-(trifluoromethyl)benzofuran—2~yl)methanamine (71) was synthesized using l Procedure 3. Yield (88%). LCMS: m/z 441.1 [M+H]+; IR = 1.29 min.
] Synthesis of (E)(6-aminopyridinyl)-N-((5-(4- 01inosulfonyl)phenyl)(triflu0mmethyl)benzofuranyl)methyl)acrylamide (531). (E)-3—(6-Aminopyridiny1)-N-((5-(4-(morpholinosulfonyl)phenyl) (trifluoromethyl)benzofuran—Z-yl)methyl)acrylamide (531) was synthesized using General Procedure 1. Yield (77%). 1H NMR (400 MHz, CD30D) 5 .95 (m, 5H), 7.85—7.36 (m, 5H), 6.83—6.35 (m, 3H), 4.61 (s, 2H), 3.63—6.22 (m, 4H), 2.92-2.90 (m, 4H). LCMS: m/z 587.0 [M+H]+; rR = 1.47 min.
Synthesis of (6-aminopyridinyl)-N—(2-(7—chloro—5-(4-(morpholine—4— carbonyl)phenyl)benzofuran—Z—yl)ethyl)acrylamide (532). ~124— Cl CI HO MsCI Et3N o NaNa, DMF h3CI2 \ Br CHZCIZ 85°C I Br Br EtaN DMF 18 73 0@BO 0' CI (‘5 \ \ Br lat—’OH H2N B, BocHN Br Pd4,chos CH2012 76 Dioxane, H20 CI Cl NH2 '0 0 HOWN\ \ O \ O BocHN O (\o TEA, HZN o N} CHzclz 0 QZ EDCI, HOBt 77 78 DIPEA CHZCIZ HN 00’ Synthesis of 2-(5—br0m0chlor0benzofuranyl)ethanol (72). A mixture of 4- bromo—2-iodo(trifluor0methyl)phenol (18) (6.8 g, 20.48 mmol), tert—butyl prop ynylcarbamate (1.48 g, 20.48 mmol), Pd(PPh3)C12 (710 mg, 1.02 mmol) and Cul (503 mg, 2.66 mmol) in 20 mL of Et3N was stirred at 80 °C under nitrogen atmosphere for 4 h. The mixture was extracted with EtOAc (50 mL x 3). The ed c layers were washed with brine, dried over anhydrous NaZSO4, and the solvents were removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to give 2 8 g of 2-(5-bromochlorbbenzofuran—2-yl)ethanol (72) as a white solid (yield: 50%). LCMS: m/z 256 8 [M-17]; IR—— 1.79 min.
Synthesis of 2-(5-br0m0chlorobenzofuran-2—yl)ethyl methanesulfonate (73): 2-(5-Bromochlorobenzofuranyl)ethanol (72) (500 mg, 1.83 mmol) was dissolved in dichloromethane (8 mL). Methane sulfonyl chloride (416 mg, 3.66 mmol) and triethylamine (370 mg, 3.66 mmol) were added at 0 °C. The reaction mixture was allowed to warm to room temperature and d for 4 h. The reaction mixture was transferred into iced water and extracted with romethane (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under d pressure to give 600 mg crude 2—(5-bromo-7—chlorobenzofuran—2-y1)ethylmethanesulfonate —125— 92, which was used in the next step without further purification. LCMS: m/z 376 [M+Na]+, m = 1.85 min. sis of 2-(2-azid0ethyl)br0m0—7—chlorobenzofuran (74): 2—(5—Bromo— 7—chlorobenzofuranyl)ethy1 methanesulfonate (73) (600 mg, 1.71 mmol) was ved in DMF (10 mL). Sodium azide (222 mg, 3.42 mmol) was added at room temperature. The reaction mixture was stirred at 80 0C for 8 h. After cooling to room temperature, the mixture was transferred into iced water and extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, and trated under reduced pressure to give 600 mg of the crude product, which was purified by chromatography (0-10% ethyl acetate/n-hexane) to obtain 2—(2-azidoethy1)—5— 7—chlorobenzofuran 93 (yield: 400 mg, 80%). LCMS: m/z 300 [M+H]+, tR= 1.96 min.
Synthesis of 2-(5-br0mochl0r0benz0furan-2—yl)ethanamine (75): 2-(2— Azidoethy1)—5—bromo—7—chlorobenzofuran (74) (100 mg, 0.34 mmol) was dissolved in ethanol (8 mL). 1.0% Pd/C (50% wet (10 mg)) was added and the reaction flask was purged with hydrogen gas. The mixture was stirred at room temperature for 1 h. The reaction e was filtered and the filtrate was concentrated under reduced pressure to give 60 which was used mg of the crude 2—(5~bromo—7-chlorobenzofuranyl)ethanamine (75), t further purification in the next step. LCMS: m/z 274 [M+H]+, IR = 1.32 min.
Synthesis of tert-butyl 2-(5-brom0chlor0benzofuranyl)ethy1carbamate (76): (2—(5—Bromo—7-chlorobenzofuran—2—yl)ethanamine (75) (250 mg, 0.92 mmol) was dissolved in romethane (10 mL) and di-tert-butyl dicarbonate (400 mg, 1.84 mmol) was added at 0 °C. Then triethylamine (185 mg, 1.84 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was transferred into iced water and extracted with dichloromethane (15 mL x 3). The combined c layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give 300 mg crude tert-butyl 2-(5-bromochlorobenzofuran—2— yl)ethylcarbamate (76), which was used without further purification in the next step. LCMS: m/Z 395 [M+Na]+, tR = 2.11.
Synthesis of tert—butyl 2-(7-chlor0(4—(m0rph01ine carbonyl)phenyl)benzofuran-Z-yl)ethylcarbamate (77): tert—Butyl 2—(7—ch10ro—5—(4— —126— (morpholinecarbonyl)phenyl)benzofuran—2-yl)ethylcarbamate (77) was synthesized using General Procedure 2. Yield (77%). LCMS: m/z 485 [M+H]+, tR = 2.02.
Synthesis of (4-(2-(2-aminoethyl)chlorobenzofuran-S- yl)phenyl)(morpholino)methanone (78): ((4-(2-(2-aminoethyl)chlorobenzofuran—S— yl)phenyl)(morpholino)methanone (78) was synthesized using General Procedure 3. Yield (72%), LCMS: m/z 385 [M+H]+, {R = 1.28.
Synthesis of (E)(6-aminopyridinyl)-N-(2-(7-chloro-S-(4—(morpholine yl)phenyl)benzofuranyl)ethyl)acrylamide (532): (6-Aminopyridinyl)-N- (2-(7-chloro(4-(morpholine-4carbonyl)phenyl)benzofuranyl)ethyl)acrylamide (532) was synthesized using General Procedure 1. Yield (47%). 1H NMR (400 MHz, DMSO'dé) 6 8.14 (t, J: 5.6 Hz, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.86 (d, J: 1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.67 (d, J=l.6 Hz, 1H), 7.58 (dd, J=2.4Hz, J: 8. 8Hz 1H), 7. 50 (d, J=8.4 Hz, 2H) 7.28 (d, J=15.6 Hz 1H), 6. 84 (s 1H), 6.46-630 (m 4H), 3. 6.03. 55(m, 8H) 3.04 (t J: 56Hz, 2H). LCMS: m/z:531.7 [M+H]; tR= 1.71 min. sis of (E)(6-aminopyridin-3—yl)-N-((7—chlor0(4-(3-fluoroazetidin-1— ylsulfonyl)phenyl)benzofuranyl)methyl)acrylamide (533).
O\\ /C| _NH HCl Q‘S\\ON©/F BOCHN BIO O O OS" 0 \ F BocHN .._, Br Et3N,CHZC|2Pd(,dppf)C12 K2003 §_N F 79 dioxane H20 31 n "mm;\/ NH _ O‘3 CH2C12 IOI _~.—i~._, __ fi-N (8')N F EDCIHOBt DMF N\ 533 / o Synthesis of 1-(4-bromophenylsulfonyl)fluoroazetidine (80): l-(4- Bromophenylsulfony1)—3—fluoroazetidine (80) was synthesized in accordance with the ure described above for the synthesis of (R)-l—(4-b1'omophenylsulfonyl)—3- fluoropyrrolidine (64). Yield (90%). LCMS: m/z 294.0 [M+H]+, tR = 1.08 min. ~127- sis of tert-butyl (7-chloro(4-(3—flu0r0azetidin ylsulfonyl)phenyl)benzofuran—Z-yl)methylcarbamate (81): tert—Butyl (7-chloro(4-(3- fluoroazetidin-1—ylsulfonyl)phenyl)benzofuranyl)methylcarbamate (81) was synthesized using l Procedure 2. Yield (73%). LCMS: m/z 517.0 [M+Na]+, IR = 1.82 min.
Synthesis of (7-chloro-5—(4-(3-fluoroazetidin ylsulfonyl)phenyl)benzofuran-Z-yl)methanamine (82). (7—Chloro(4-(3-fluoroazetidin- 1-ylsu1fony1)phenyl)benzofuran-Z-yl)methanamine (82) was synthesized using General Procedure 3 Yield (100%). LCMS: m/z 395.1 [M+H], tR= 1 28 min Synthesis of (E)(6-aminopyridinyl)-N—((7-chloro(4-(3-fluoroazetidin- 1 ylsulfonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (533): (E)(6-Aminopyridin ((7-chloro(4-(3 -fluoroazetidin-1 ylsulfonyl)phenyl)benzofuran yl)methyl)acrylamide (533) was synthesized using General Procedure 1. Yield (35%). 1H NMR (400 MHz, CD30D) 6 8.18 (dd, J: 9.6 Hz J: 2 Hz, 1H), 8.07 (d, J: 1.6 Hz, 1H), 7.97 (s, 4H), 7.89 (d, J: 1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.51 (d, J: 15.6 Hz, 1H), 7.04 (d, J: 9.6 Hz, 1H), 6.92 (s, 1H), 6.65 (d, J: 15.6 Hz, 1H), 5.25-5.22 (m, 1H), 5.11- .08 (m, 1H), 4.73 (s, 2H), 4.18-4.09 (In, 2H), 3.91-3.82 (m, 2H). LCMS: m/z 541.0 [M+H]+, 2R = 1.48 min.
Synthesis of (E)—3-(6-aminopyridinyl)-N—((7—chloro(5-(morpholine—4- carbonyl)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (534): 051%} wN/fi0 Cl NH O — \ Pd(PPh3)4 K2003 N/ \ I 14-Dioxane H20 \ H2N 534 o Nfi (E)(6-Aminopyridin-3—yl)-N—((7—chloro—5-(5-(morpholinecarbonyl)pyridin- 3-yl)benzofurany1)methyl)acrylamide (534) was sized using General Procedure 2.
(Yield: 0.06 g, 22 %). 1H NMR (400 MHz, DMSO-dg) 5 9.02 (d, J= 4 Hz, 1H), 8.67-8.62 (m, 2H), 8.18 (t, J: 2Hz, 1H), 8.09 (d, J: 4 Hz,1H), 8.01 (s, 1H), 7.84 (d, J: 4 Hz, 1H), 7.62 (dd, J1, J2 = 4 Hz, 1H), 7.35 (d, J: 16 Hz, 1H), 6.91 (s, 1H), 6.49 (s, 1H), 6.46 (s, 2H), 6.42 (d, J: 16 Hz, 1H), 4.61 (d, J: 8 Hz, 2H), 3.68 (s, 4H), 3.58 (s, 2H), 3.41 (s, 2H). LCMS: m/Z 518.4 [M+H]+, 1R: 1.70 min. -128— Synthesis of (E)-N-((7-chlor0(4-(m0rpholinecarbonyl)phenyl)benzofuran-Z-yl) methyl)(pyridinyl)acrylamide (535): 0 Cl CIH_H2N o I\ \ 0H NH 0 \ O N / M \ O f ' N EDCI,HOBt, \ / O NJ’ DIPEA.CH2C|2 N 84 o 535 0 (E)-N-((7-Chloro(4-(morpholinecarb0nyl)pheny1)benzofuranyl)methyl)— 3-(pyridiny1)acry1arnide (535) was synthesized using General ure 1. : 0.01 g, 37%). 1H NMR (400 MHz, DMSO-d6) 5 9.01 (t, J= 6.0 Hz, 1H), 8.62 (d, J= 6 Hz, 2H), 7.92 (d J: 1.6 Hz 1H) 7.80 (s 1H) 7.78 (s 1H), 7.73 (d J: 1.6 Hz 1H) 7.56-7.47 (m 5H) 6. 95-6. 91 (m, 2H), 4. 65 (s 1H), 464 (s 1H), 3 62- 3. 38 (m 8H). LCMS: m/z 502. 63 [M+H], tR=1 90 min.
Synthesis of (B-N—(U-chloro(4-(morpholinecarb0nyl)phenyl)benzofuran—Z-yl) methyl)(6-(trifluoromethyl)pyridin-3—yDacrylamide (536): 0 C! CIHH2N NH 0 \00 —— F30Won—q (\0 __ (\O EDCI HOBt \ / Nd DIPEA,CHZCIZ N F3 0 (E)—N—((7-Chloro(4-(morpholinecarbonyl)phenyl)benzofurany1)methy1)- 3-(6-(trifluorornethyl)pyridinyl)acry1arnide (536) was synthesized using General Procedure 1. (Yield: 0.02 g, 13%). 1H NMR (400 MHZ, DMSO'd6) 6 9.03-8.99 (m, 2H), 8.31—8.28 (m, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.92 (d, J=1.6 Hz,1H), 7.80(s,1H), 7.78 (s, 1H), 7.73 (d, J: 1.6 Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 6.98-6.94 (m, 2H), 4.66 (s, 1H), 4.65 (s, 1H), .62 (m, 8H). LCMS: m/z 570.39 [M+H]+, 2 min.
Synthesis of (E)-N-((7-chlor0(4-(morpholinecarbonyl)phenyl)benz0furan-2—yl) methyl)(6-chloropyridinyl)acrylamide (537): CWOH 0 NH O 0 CIHH2N " \ 00Q fi EDCI HOBt, \ / DIPEACH20|2 -l29— (E)—N—((7-Chloro-5—(4-(morpholine—4-carbonyl)phenyl)benzofuranyl)methyl)- 3—(6—chloropyridinyl)acrylamide (537) was synthesized using General Procedure 1. (Yield: 0.01 g, 7%). 1H NMR (400 MHz, DMSO-a’6) 5 8.93 (t, J: 5.6 Hz, 1H), 8.64 (d, J= 2.4 Hz, 1H), 8.09 (dd, J1, J2 = 2.4 Hz, 1H), 7.92 (d, J: 1.6 Hz, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.73 (d, J: 1.6 Hz, 1H), 7.60-7.51 (m, 4H), 6.94 (s, 1H), 6.83 (d, J: 16 Hz, 1H), 4.64 (d, J: 5.6 Hz, 2H), 3.63-3.16 (m, 8H). LCMS: m/z 536.20 [M]+, tR = 2.22 min. sis of ((E)-N-((7-chlor0(4-(m0rph0linecarbonyl)phenyl)benzofuran yl)methyl)(pyridinyl)acrylamide (538): Ho J Cl 13%" Cl Boc—Nl\-l_<)/\©\ Hd o Boo—NH o \ Pd Tetrakis(triphenylphosphine)palladium (0) (0.25 g, 0.21 mmol) and 4-(morpholine—4- carbonyl) phenylboronic acid (0.83 g, 3.55 mmol) were added at room temperature and d for 5 min. A degassed solution of K2C03 (0.65 g, 4.71 mmol) in water (2 mL) was added and the reaction mixture was irradiated under microwave for 30 min at 90 °C. The reaction mixture was transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over ous NagSO4 and concentrated under reduced pressure to give crude nd, which was purified by silica gel chromatography (0—90% ethyl acetate/n-hexane) to obtain tert—butyl (7—chloro-5— (4-(morpholine-4—carbony1)phenyl)benzofuran-2—yl)methylcarbamate (83). (Yield: 0.50 g, 45%). 1H NMR (400 MHz, DMSO-d6) 6 7.91 (s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.10 (d, J: 1.6 Hz, 1H), 7.54—7.50 (m, 2H), 6.83 (s, 1H), 4.34 (s, 1H), 4.33 (s, 1H), 3.42-3.37 (m, 8H), 1.42 (s, 9H). sis of (4-(2-(aminomethyl)—7-chlorobenzofuran-S- yl)phenyl)(m0rph01in0)methanone hydrochloride (84): rerrgButyl(7-chloro(4- (morpholinecarbony1)phenyl)benzofuranyl)methylcarbamate (83) (0.5 g, 1.06 mmol) was dissolved in dichloromethane (15 mL) at room ature. The reaction mixture was cooled to 0 OC and HCl in dioxane (5 mL) was added dropwise. The reaction mixture was slowly d to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated under reduce pressure and the crude product was crystallized with diethyl ether and dried under reduced pressure to obtain (4-(2-(aminomethyl)chlorobenzofuran yl)phenyl)(morpholino)methanone hydrochloride (84). : 0.33 'g, 85%). 1H NMR (400 MHz, DMSO—dg) 5 8.72 (bs, 3H), 8.03 (d, J: 1.6 Hz, 1H), .80 (m, 3H), 7.55 (s, 1H), 7.51 (s, 1H), 7.21 (s, 1H), 4.35 (s, 2H), 3.63-3.41 (m, 8H).
Synthesis of (E)—N-((7-chloro-S-(4-(morpholine carbonyl)phenyl)benz0furanyl) )(pyridinyl)acrylamide (538): (4-(2— (Aminomethyl)-7—chlorobenzofuran—5~yl)phenyl)(morpholino)methanonehydrochloride (84) (0.1 The g, 0.26 mmol ) was dissolved in dichloromethane (10 mL) at room temperature. reaction mixture was cooled to 0 °C and (E)—3—(pyridinyl) acrylic acid (0.06 g, 0.40 mmol), EDCI (0.077 g, 0.40 mmol) and HOBt (0.054 g, 0.4 mmol) were added, followed by DIPEA (0.05 mL, 0.53 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was transferred into iced water and extracted with ethyl acetate (3 x 25 mL). The ed organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced pressure to give crude product, which was d by silica gel chromatography (0-5% MeOH in CHZClz) to obtain (E)-N-((7-chloro(4-(morpholinecarbonyl)pheny1)benzofuranyl)methyl) (pyridinyl)acrylamide (538). (Yield: 0.01 g, 7%). 1H NMR (400 MHz, DMSO-d6) 6 8.92 (t, J= 5.6 Hz, 1H), 8.79 (d, J= 1.6 Hz,1H), 8.57 (dd, J1= 1.6 Hz, J2 = 1.2 Hz, 1H), 8.03—7.92 (m, 1H), 7.92 (d, J: 1.6 Hz,1H), 7.80(s,1H),7.78(s, 1H), 7.73 (d, J: 1.6 Hz, 1H),7.54 (s, 1H), 7.53-7.44 (m, 3H), 6.94 (s, 1H), 6.83 (d, J: 15.6 Hz, 1H), 4.65 (s, 1H), 4.63 (s, 1H), 3.63—3.49 (m, 8H). LCMS: m/z 502.63 [M+H]+, IR: 196 min. -131— Synthesis of (E)—N—((7-chlor0(4-(morpholinecarb0nyl)phenyl)benzofuran-2— yl)methyl) (pyridin—2-yl)acrylamide (539): 0 CI \ N — / \ K — f0 N EDCI, HOBt, \ N DIPEA, CH2C12 0 539 0 ] (E)-N-((7-Chloro(4-(morpholinecarbonyl)phenyl)benzofuranyl)methyl)- 3-(pyridinyl)acrylamide (539) was sized using General Procedure 1. (Yield: 0.015 g, 11 %). 1H NMR (400 MHz, DMSO-d5) 6 9.02 (t, J= 5.8 Hz, 1H), 8.63 (d, J= 3.6 Hz, 1H), 7.91 (d, J: 1.6 Hz, 1H). 7.87—7.78 (m, 3H), 7.73 (d, J: 1.6 Hz, 1H), 7.61 (d, J:- 7.6 Hz, 1H), 7.55-7.50 (m, 3H), 7.39—7.36 (m, 1H), 7.16 (d, J: 15.6 Hz, 1H), 6.93 (s, 1H), 4.65 (s, 1H), 4.64 (s, 1H), 3.62—3.38 (m, 8H). LCMS: m/z 502.38 [M+H]+, tR=2.06 min.
Synthesis of (E)-N-((7-chlor0(4-(m0rpholine-4—carb0nyl)phenyl)benzofuran yl)methyl)-3—(pyridazinyl)acrylamide (540): CIHH2N NH 0 \00 \ HEDCI HOBtDIPEACH2C|2 540 (ED—N—((7—Ch100r0—5—(4-(morpholinecarbonyl)phenyl)benz0furan-2—yl)methy1)— 3—(pyridazin—3-yl)acrylamide (540) was sized using General Procedure 1. (Yield: 0.02 g, 13 %). 1H NMR (400 MHz, DMSO-ds) (3 9.20 (dd, J1, J2 = 1.6 Hz, 1H), 9.15 (t, J: 11.2 Hz, 1H), 7.99-7.91 (m, 3H), 7.81-7.76 (m, 4H), 7.52 (s, 1H), 7.50 (s, 1H), 7.29 (d, J =16 Hz 1H) 6. 96 (s 1H) 4.68 (s, 1H), 4.66 (s, 1H), 3.62-3.35 (m, 8H). LCMS: m/z 503.43 [M+H]Jr IR=194 min.
Synthesis of (E)-N-((7-chlor0(4-(morpholinecarbonyl)phenyl)benzofuranyl) methyl)-3—(3,5-dimethylis0xazol-4—yl)acrylamide (541): CIHIH2N o \ O N;i/\rif O O o EDCI HOBt O 00 DIPEACHZCIZ 84 '0 —132- (E)—N—((7-Chloro(4-(morpholine—4—carbonyl)phenyl)benzofuranyl)methyl)- 3—(3,5—dirnethylisoxazolyl)acrylamide (541) was synthesized using l Procedure 1.
(Yield: 0.012 g, 9 %). 1H NMR (400 MHz, DMSO-dé) 5 8.83 (t, J: 11.6 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.81 (s, 1H), 7.79 (s, 1H), 7.74 (d, J: 1.6 Hz, 1H), 7.52 (d, J: 8.4 Hz, 2H), 7.28 (d, J: 16.4 Hz, 1H), 6.94 (s, 1H), 6.51 (d, J: 16 Hz, 1H), 4.63 (d, J: 5.6 Hz, 2H), 3.63-3.35 (m, 8H), 2.49 (s, 3H), 2.34 (s, 3H). LCMS: m/z 520.4 [M+H]+, tR=2.l9 min.
Synthesis of (E)-N-((7-chloro(4-(morpholinecarbonyl)phenyl)benzofuran-Z-yl) )(thiazolyl)acrylamide (542):O CIH,H2N o (NN NH o \ \ 0 NJK S EDCI HOB! DIPEA0142012 84 o DON (E)-N—((7-Chloro(4-(morpholinecarbonyl)phenyl)benzofuranyl)methyl)— 3—(thiazol—2-yl)acrylamide (542) was synthesized using l Procedure 1. (Yield: 0.02 g, %). 1H NMR (400 MHz, DMSO‘db) 5 9.18 (d, J= 1.2 Hz, 1H), 8.96 (t, J: 10.4 Hz, 1H), 8.02 (d, J: 2 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.54—7.51 (m, 3H), 6.94 (d, J: 14.4 Hz, 2H), 4.63 (d, J: 5.6 Hz, 2H), 3.63-3.35 (m, 8H). LCMS: m/z 508.33 [M+H]+, tR=2.07 min.
Synthesis of (E)(6-amin0pyridinyl)-N—((7-chloro-S—(3-(morpholinecarbonyl) phenyl)benzofuran-Z-yl)methyl)chrylamOide (543): NH O Pd(PPh3)4 K2003 14-Dioxane H20 (E)(6-Aminopyridin—3 -yl)-N—((7-chloro(3-(morpholine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (543) was synthesized using General Procedure 2. : 0.05 g, 20%). 1H NMR (400 MHz, DMSO-d6) 5 8.65 (t, J= 6 Hz, 1H) 8.08 (d. J: 4 Hz 1H) 7.91 (d J: 4 Hz 1H) 7.80 (dd J1, J2 = 4 Hz 1H) 7.72 (d J: 4Hz, 2H) 7.61 (dd J1,J2= 4H2 1H), 7.,54(t J= 8H2, 1H), 739(d, J: 8Hz, 1H), 7.35 (d, J: 16 Hz, 1H), 6.89 (s, 1H), 6.47 (d, J: 8 Hz, 1H), 6.45 (s, 2H), 6.42 (d, J: 16 -l33— Hz, 1H), 4.60 (d, J= 4 Hz, 2H), 3.65-3.38 (m, 8H). LCMS: 177/2 517.63 [M+H]+, IR = 1.84 min.
Synthesis of (6—amin0pyridinyl)-N—((7-chloro-S-(S-fluoro(m0rph01ine carb0nyl)pyridinyl)benzofuran-Z-yl)methyl)aerylamide (544): Br F CI | (\0 CI 0 0 — \ 0 \ /o F _ \ _ I? l (\O \ / / O Pd(PPh3)4, K2003 \ / Nd N 16 . N N Dloxane, H20 (E)—3—(6—Aminopyridin-3~y1)~N~((7—chlor0—5-(5-flu0ro(m0rpholine—4- carbonyl)pyridinyl)benzofuran—2-yl)methyl)acrylamide (544) was synthesized using General Procedure 2. (Yield: 0.02 g, 18%). 1H NMR (400 MHz, DMSO-de) 5 8.88 (t, J: 4 Hz, 1H), 8.66 (t, J: 4 Hz, 1H), 8.30 (dd J1, J2 = 4 Hz, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.63 (dd, J1, J2: 2 Hz,1H), 7.36 (d, J: 16 Hz, 1H), 6.92 (s, 1H), 6.51 (d, J = 4 Hz, 1H), 6.49 (s, 2H), 6.43 (d, J= 16 Hz,1H), 4.61 (d, J: 4 Hz, 2H), 3.69-3.29 (m, 8H). LCMS: m/z 536.43 [M+H]+, 7R: 1.77 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-chlor0-5—(4—(2—m0rpholino-Z-oxoacetyl) phenyl)benzofuran-Z-yl)methyl)acrylamideO(545): ‘ .ONUQéLBO,0 \OD Pd(PPh3)4, K2003 Dioxane, H20 HZN 16 NO ] (E)(6—Aminopyridinyl)-N—((7-chloro(4-(2—morpholino oxoacetyl)phenyl)benzofuranyl)methyl)acrylamide (545) was synthesized using General Procedure 2. (Yield: 0.02 g, 12%). 1H NMR (400 MHz, DMSO-dg) 6 8.65 (t, J= 5.8 Hz, 1H), 8.09 (d, J= 2 Hz, 1H), 8.01-7.96 (m, 5H), 7.81 (d, J= 1.6 Hz, 1H), 7.62 (dd, J1 = 2.0 Hz, J2 = 2.4 Hz, 1H), 7.35 (d, J= 15.6 Hz, 1H), 6.93 (s, 1H), 6.49-6.40 (m, 4H), 4.61 (d, J: 5.6 Hz, 2H), 3.73—3.67 (m, 4H), .54 (m, 2H), .32 (m, 2H). LCMS: m/z 545.29 [M+H]+, 7R: 1.87 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((7-chlor0(2-(m0rpholinecarbonyl) pyrimidin-S-yl)benzofuran-Z-yl)methyl)acrylamide (546): -134— *Hiwgg \N (\O Pd LCMS: m/Z 519.03 , tR= l69 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((7—chloro-S-(2,5-diflu0r0(morpholine carb0nyl)phenyl)benz0furan-2—yl)m:thyl)acrylamide (547): EffiflPd (PPh3)4, K2CO3 Dioxane, H20 OOON (E)(6-Amin0pyridinyl)-N-((7-chlor0(2,5-difluoro(morpholine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (547) was synthesized using l Procedure 2. (Yield: 0.02 g, 11%), 1H NMR (400 MHz, DMSO'd6) 5 8.65 (t, J: 4 Hz, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.65-7.62 (m, 3H), 7.51-7.48 (m, 1H), 7.36 (d, J: 16 Hz, 1H), 6.92 (s, 1H), 6.48 (d, J= 8 Hz, 1H), 6.46 (s, 2H), 6.43 (d, J: 16 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 3.66 (s, 4H), 3.57 (s, 2H), 3.34 (s, 2H). LCMS: m/z 553.39 [M+H]+, 1R: 1.89 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-chloro(2,3-difluoro(morpholine—4— carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (548): 0 O CI F F O — \ B\/0 Br \ F (\O _. O \ O O Nd hf \ PngPh3)4,K2CO3 N 548 16 Dloxane, H20 H2N H2N o -l35- (E)—3—(6—Aminopyridiny1)—N—((7-chloro-5—(2,3-difluoro(morpholine—4- carbonyl)phenyl)benzofilranyl)methyl)acrylamide (548) was synthesized using General Procedure 2. (Yield: 0.02 g, 11%). 1H NMR (400 MHz, g) 6 8.65 (t, J: 5.8 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.63-7.61 (m, 2H), 7.51-7.48 (m, 1H), 7.37-7.32 (m, 2H), 6.93 (s, 1H), 6.49-6.40 (m, 4H), 4.61 (d, J: 5.6 Hz, 2H), 3.67 (s, 4H) 3.56-3.55 (m, 2H), 3.34—3.32 (m, 2H). LCMS: m/z 554.21 [M+H]+, IR: 1.86 min.
Synthesis of (E)(6-aminopyridin-S-yl)—N—((7-chloro(3-fluoro(morpholine yl)phenyl)benzofuranyl)methyl)acrylamide (549): Cl 0 CI 0 O _ \ 3,") Br \ F — o \7 \ N/ N Pd(PPh3)4. K2C03 D G) N 549 16 Dioxane, H20 H2N HzN 0 (E)—3-(6—Aminopyridin—3—yl)—N—((7—chloro—5—(3—fluoro(morpholine—4- carbonyl)phenyl)benzofuran-2—y1)methyl)acrylamide (549) was synthesized using l ure 2. (Yield: 0.02 g, 12%). 1H NMR (400 MHz, DMSO-dg) 6 8.64 (t, J: 6.0 Hz, 1H), 8.08 (d, J: 1.6 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.79 (d, J: 1.6 Hz, 1H), 7.73— 7.61 (m, 3H), 7.61—7.49 (m, 1H), 7.35 (d, J: 15.6 Hz, 1H), 6.90 (s, 1H), 6.49—6.40 (m, 4H), 4.61 (d, J: 5.2 Hz, 2H), 3.67 (s, 4H), 3.56—3.54 (m, 2H), 3.30—3.28 (m, 2H).
LCMS: m/Z 535.13 [M+H]+, 1R: 1.85 min.
Synthesis of (E)(4-aminophenyl)-N-((7-chloro(4-(morpholinecarbonyl) phenyl) ' uran-Z-yl)methyl)acrylamide (550): c1 CI CIHIH2N o O H2N©_\\—/ LCMS: m/Z 545.44 [M]+, rR= 1.90 min. sis of (E)—3-(6-aminopyridinyl)-N—((7-chloro(6-(morpholine carbonyl)pyridazin-3—yl)benzofur:n—2—yl)methyl)acrylamide (552).
—ON\H—<:; Synthesis of (6-aminopyridinyl)-N-((7-chloro(4-(2-morpholino-Z-oxoethyl) phenyl)benzofuran-Z-yl)methyl)acrylamide (553): Pd(PPh3)O4, K2003 Dioxane, H2O (E)—3—(6-Amin0pyridinyl)—N—((7-chloro-5—(4-(2-morpholino yl)phenyl)benzofuranyl)methyl)acrylamide (553) was synthesized using General Procedure 2. (Yield: 0.01 g, 4%). 1H NMR (400 MHz, DMSO-dg) 5 8.63 (t, J= 5.8 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.85 (d, J= 1.6 Hz, 1H), 7.66-7.60 (m, 4H), 7.37-7.31 (m, 3H), 6.88 (s, 1H), .40 (m, 4H), 4.60 (d, J: 5.2 Hz, 2H), 3.77 (s, 2H), 3.55-3.51 (m, 4H), 3.48-3.30 (m, 4H). LCMS: m/z 531.28 [M]+, IR: 1.87 min.
Synthesis of (E)—3-(6-amin0pyridinyl)—N—((7-methwry(4- (morpholinesulfonyl)phenyl) benzofuran-Z-yl)methyl)acrylamid: (554): O/ o/ OH Br/\n’ O Mesyl Chlroride,15-—-crown5 0 1M LAH in THF \ Triethylamine DMSO ACN K2CO3DMF /—0 THF H0 CHZCIZ NaN3 Br Br 87 89 Ethanol, Zn dust, H30 ted NH4Cl H o WNW; o N— \ Pd((PP,h3)4 K2003 EDCl, HOBt DIPEA 03:0 1 ,-4Dioxane, Water CH20I2 554 E:1 Synthesis of ethyl 4-br0m0meth0xybenzofuran-Z-carboxylate (86): 6- Bromohydroxymethoxybenzaldehyde (85) (10 g, 43.2 mmol) was dissolved in DMF (100 mL) at room temperature. K2CO3 (14.92 g, 108.0 mmol) and ethyl bromoacetate (7.47 mL, 64.9 mmol) were added and the reaction mixture was heated at 100 °C for 6 h. The reaction mixture was allowed to cool to room temperature, transferred into iced water and ted with ethyl acetate (3 X 200 mL). The combined organic layers were washed with brine solution, dried over anhydrous NaZSO4 and concentrated under reduced re to give crude product, which was purified by silica gel chromatography (O—5% ethyl acetate in hexane) to obtain ethyl 4-bromomethoxybenzofiJran—2-carboxylate (86). Wield: 6.7 g, —138- 52%). 1H NMR (400 MHz, CDCl3) 6 7.54 (s, 1H), 7.49 (d, J: 8 Hz, 1H), 7.09 (d, J: 8.4 Hz, 1H), 4.34—4.40 (m, 2H), 3.96 (s, 3H), 1.36-1.33 (m, 3H). LCMS: m/z 299.12 [M]+, zR =2.72 min.
Synthesis of (4-br0m0—7-meth0xybenz0furan-Z-yl)methanol (87): Ethyl 4- bromo—7-methoxybenzofuran—2-carboxylate (86) (1.7 g, 5.6 mmol) was dissolved in THF (40 mL) at room temperature. The reaction mixture was cooled to 0 °C and l M LAH in THF (3.9 mL, 002 mmol) was added dropwise at the same temperature and stirred for 15 min. The reaction mixture was transferred into iced water and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine solution, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give crude product, which was crystallized using n-pentane to obtain (4-bromo—7—methoxybenzofuran-2—yl) methanol (8 7).
(Yield: 1.40 g, 97%). 1H NMR (400 MHz, DMSO‘d6) 6 7.35 (d, J = 8.8 Hz, 1H), 6.89 (d, J: 8.4 Hz, 1H), 6.88 (s, 1H), 5.59—5.56(m,1H), 4.58 (d, J = 6.4 Hz, 2H), 3.92 (s, 3H).
] Synthesis of Synthesis of (4—br0m0—7—meth0xybenzofuran-Z—yl)methyl methanesulfonate (88) : (4-Bromomethoxybenzofuran—2-yl)methanol (87) (1.48 g, 5.7 mmol) was dissolved in romethane (20 mL) at room temperature. The reaction mixture was cooled to 0 °C and methane sulphonyl chloride (0.54 mL, 6.9 mmol) was added dropwise followed by addition of triethylamine (1.19 mL, 8.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was transferred into iced water and extracted with CH2C12 (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to obtain crude (4—bromomethoxybenzofuran—2-yl) methyl methanesulfonate (88), which was used in the next step without further purification.
Synthesis of 2-(azid0methyl)—4-br0m0meth0xybenzofuran (89): (4-Bromo- 7—methoxybenzofuranyl)methyl esulfonate (88) (1.55 g, 4.6 mmol) was dissolved in acetonitrile (ACN) (20 mL) at room temperature. Sodium azide (0.60 g, 9.2 mmol), DMSO (0.48 mL, 6.9 mmol) and wn-5 (0.15 g, 0.70 mmol) were added to the reaction mixture, which was heated at 95 °C for 30 min. The reaction mixture was allowed to cool to room ature, erred into iced water and extracted with ethyl acetate (3 x 100 mL). The ed organic layers were washed with brine on, dried over ous NaZSO4 and concentrated under reduced pressure to give crude 2-(azidomethyl)—4~bromo methoxybenzofuran (89), which was used in the next step without further purification. ~139— Synthesis of m0meth0xybenzofuranyl) methanamine (90): 2— (Azidomethyl)—4—bromo—7—methoxybenzofuran (89) (1.4 g, 4.96 mmol) was dissolved in ethanol (15 mL) and water (7 mL) at room temperature. Ammonium de (0.618 g, 115.6 mmol) and zinc dust (0.42 g, 6.50 mmol) were added to the reaction mixture, which was heated at 90 °C for 1 h. The reaction mixture was allowed to cool to room temperature, transferred into ethyl acetate (20 mL with 0.2 mL ammonia solution). The reaction mixture was filtered through Celite and the filtrate was trated under reduced pressure to give crude (4-bromo—7-methoxybenzofuran—2-yl)methanamine (90), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-dg) 5 7.32 (d, J = 8.4 Hz 1H), 6.85 (d, J: 8.4 Hz, 1H), 6.63 (s, 1H), 3.93 (s, 3H), 3.80 (s, 2H).
Synthesis of (E)(6-aminopyridinyl)—N—((4-br0m0tert—butyl-2,3- dihydrobenzofuran-Z-yl)methyl)acrylamide (91): (4—Bromo—7—methoxybenzofuran-2— yl)methanamine (90) (1.05 g, 4.09 mmol) was dissolved in dichloromethane (10 mL) at room temperature. (6—aminopyridinyl)acrylic acid (1.00 g, 6.14 mmol), EDCI (0.94 g, 4.91 mmol), HOBt (0.66 g, 4.91 mmol) and DIPEA (2.1 mL, 12.2 mmol) were added at 0 OC. The reaction mixture was allowed to warm to room temperature and stirred for 2 h, erred into iced water and extracted with CH2C12 (3 x 50 mL). The combined organic layers were washed with brine solution, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give crude product, which was purified by silica gel column tography (0— 3% MeOH in ) to obtain (E)—3—(6—aminopyridin-3—y1)—N—((4—bromo—7— methoxybenzofuran—2—yl)methyl)acrylamide (91) (Yield: 1.5 g, 91%) 1H NMR (400 MHZ, DMSO-dg) 5 8.63 (t, J: 5.8 Hz,1H), 8.08 (d, J= 2 Hz, 1H), 7.65 (dd, J]: 2.4 Hz, J; z 2 Hz, 1H), 7.36 (d, J: 8.8 Hz, 1H), 7.33 (s, 1H), 6.90 (d, J: 8.8 Hz, 1H), 6.66 (s, 1H), 6.60 (bs, 2H), 6.52 (d, J= 8.8 Hz, 1H), 6.43 (d, J: 16 Hz, 1H), 4.54 (d, J= 5.6 Hz, 2H), 3.89 (s, 3H). LCMS m/z 403.24 [M+H]+ =1.87 min. , tR Synthesis of (E)(6-amin0pyridinyl)-N—((7-meth0xy(4— (morpholinesulfonyl)phenyl) benzofuranyl)methyl)acry1amide (554): (E)—3 —(6- Aminopyridiny1)-N-((4-bromomethoxybenzofurany1)methyl)acrylamide (91) (0.3 g, 0.74 mmol) was dissolved in 1,4—dioxane (5 mL) at room temperature. (4— (Morpholinesulfonyl)phenyl)boronic acid (0.30 g, 1.11 mmol) and a degassed solution of K2CO3 (0.20 g, 1.48 mmol) in 1 mL of water were added at room ature and degassed using N2 for 10 min. Tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.03 mmol) was -140— added and the reaction mixture was irradiated under microwave for l h at 80 OC. The reaction e was allowed to cool to room temperature, transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under d pressure to give crude compound, which was purified by preparative HPLC to obtain (E)-3—(6—aminopyridin—3-yl)- methoxy—4-(4—(morpholinosulfonyl)phenyl)benzofuran—2-yl)methyl)acrylamide (554).
(Yield: 0.18 g, 44%). 1H NMR (400 MHz, DMSO-de) 5 8.57 (t, J= 5.8 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.88-.7.82 (m, 4H), 7.60 (dd, J1= 2.4 Hz, J2 = 2 Hz 1H), 7.42 (d, J= 8 Hz,1H), 7.33 (d, J= 15.6 Hz, 1H), 7.08 (d, J= 8.4 Hz,1H), 6.95 (s, 1H), 6.47-6.38 (m, 4H), 4.53 (d, J: 5.6 Hz, 2H), 3.98 (s, 3H), 3.66 (t, J: 8.8 Hz, 4H), 2.93 (t, J: 4.4 Hz, 4H). LCMS: m/Z 549.61 [M+H]+, zR= 1.90 min.
Synthesis of (E)(6-amin0pyridin-3—yl)—N—((7-chlor0(4-(3,3-dimethylazetidin—1- ylsulfonyl)phenyl)benzofuran—2—yl)methyl)acrylamide (555).
AC\O >§V€§JO NHBoc AC\NOO8’9 N8/9 08‘ NHBoc .5 \ o’ TFA o .
Pd(dppf)Clz. K2003. Cl CH2C|2 dioxiane, H20 94 EDCI HOBt o DIPEA DMF 0 95 555 Synthesis of tert—butyl (7-chloro—5-(4-(3,3-dimethylazetidin—1— onyl)phenyl)benzofuran—2—yl)methylcarbamate (94): tert—Butyl (7-chloro-5—(4-(3,3- dimethylazetidin- l —ylsulfonyl)phenyl)benzofuran—2-yl)methylcarbamate (94) was synthesized using l Procedure 2. Yield (64%). LCMS: m/z 505.1 [M+H]+; tR = 1.30 min.
Synthesis of (7-chloro(4—(3,3—dimethylazetidin—1- ylsulfonyl)phenyl)benzofuran—2~yl)methanamine (95): (7—chloro—5—(4-(3 ,3—dimethylazetidin— 1 —y-1sulfonyl)phenyl)benzofuran—2-yl)methanamine (95) was sized using General Procedure 3. Yield (100%). LCMS: m/z 405. 1 [M+H]; tR— 0.95 min. —141— Synthesis of (E)(6-aminopyridin—3-yl)-N-((7-chloro-5—(4—(3,3- dimethylazetidin—1-y1sulfonyl)phenyl)benzofi1ran-2—y1)methy1)acrylamide (5 55): (6- Aminopyridinyl)-N-((7-chloro—5 —(4-(3,3 -dimethylazetidin— 1 - ylsulfonyl)phenyl)benzofuran—2-yl)methyl)acrylamide (555) was synthesized using General Procedure 1. Yield (31%). 1H NMR (400 MHz, CD3OD) 6 8.07 (s, 1H), 7.97-7.88 (m, 5H), 7.76—7.74 (m, 1H), 7.69 (s, 1H), 7.50 (d, J: 16 Hz, 1H), 6.89 (s, 1H), 6.60 (d, J: 9 Hz, 1H), 6.48 (d, J= 16 Hz, 1H), 4.71 (s, 2H), 3.50 (s, 4H), 1.07 (s, 6H). LCMS: m/z 551.2 [M+H]+; rR = 1.92 min. sis of (E)(2-((3-(6-aminopyridinyl)acrylamid0)methyl)chlor0benzofuran- -yl)phenyl morpholinecarboxylate (556). l/\ J? O//\NJ CH2012 —‘"** E j 0 O 93 EDCI.HOBt. o 0 (3| DIPEA,DMF CI Synthesis of tert-butyl (7—chloro-5—(4~hydroxypheny1)benzofuran—2— y1)methylcarbamate (96): tert—butyl (7—chloro—5-(4~hydroxyphenyl)benzofuran yl)methylcarbamate (96) was synthesized using General Procedure 2. Yield (92%). LCMS: m/Z 396.0 [M+Na]+; rR = 1.88 min.
Synthesis of 4~(2-((z‘ert—butoxycarbonylamino)methyl)chlorobenzofi1ran yl)phenyl morpholinecarboxylate (97): utyi (7-chloro—5-(4- hydroxyphenyl)benzofurany1)methylcarbamate (96) (311 mg, 0.83 mmol) was disolVed in mL of CHzClz. MN—dimethylpyridinamine (97 mg, 0.83 mmol), Et3N (167 mg, 1.66 mmol), and morpholinecarbonyl chloride (148 mg, 1 mmol) were added succesively. The reaction mixture was stirred at room temperature for 1 h, quenched with water (20 mL), extracted with CH2C12 (20 mL X 2). The combined organic ts were washed with brine (20 mL), dried over anhydrous NazSO4, and concentraed to s to give 298 mg of 4—(2— ((tert—butoxycarbonylamino)methyl)—7—chlorobenzofuran—S-yl)phenyl morpholine—4— carboxylate (97), which was used directly without further purification. Yield (74%). LCMS: m/Z 487.0 ; rR = 1.98 min.
Synthesis of 4-(2-(aminomethyl)—7-chlorobenzofuran—5-yl)phenyl morpholine carboxylate (98): 4—(2—(aminomethyl)—7-chlorobenzofuran—5—yl)phenyl morpholine—4— carboxylate (98) was synthesized using General Procedure 3. Yield (100%). LCMS: m/z 387.0 [M+H]+; IR = 1.29 min. sis of (E)(2-((3 -(6-aminopyridinyl)acrylamido)methyl)—7~ chlorobenzofuran-S-y1)phenyl morpholinecarboxylate (556): (E)(2-((3-(6- aminopyridiny1)acry1amido)methyl)—7-chlorobenzofurany1)pheny1 morpholine carboxylate (556) was synthesized using General Procedure 1. Yield (51%). 1H NMR (400 MHz, CD30D) 8 6.69-6.59 (m, 1H), 8.05 (d, J: 2 Hz, 1H), .45 (m, 5H), 7.29-7.20 (m, 2H), 7.04 (d, J= 9 Hz, 1H), 6.86 (s, 1H), 6.65 (d, J: 16 Hz, 1H), 4.71 (s, 2H), 3.82—3.52 (m, 8H). LCMS: m/z 533.2 ; IR = 1.31 min.
Synthesis of (E)(6-aminopyridinyl)-N—((7—(diflu0r0methyl)—5—(4-(m0rpholine—4— carb0nyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (557).
Br NHBoc NHBoc NIS —/NHBoc \ DAST OH DMF Cul, Pd(PPh3)2C|2 O CH2C12 E13N DMF / CW 3000 0 "N O NHBoc fl 0d NH2 Pd(dppf)CI2 K200a CH2012 Oo e H20 F F EDCI HOBt DIPEA DMF "jg?; Synthesis of 5-bromo-2—hydroxyiodobenza1dehyde (100): 5-Bromo-2— hydroxybenzaldehyde (99) (10 g, 50 mmol) was dissolved in DMF (100 mL). NIS (11 g, 50 mmol) was added at room temperature and the reaction mixture was stirred for 48 h. The reaction mixture was transferred into iced water and extracted with ethyl acetate (100 mL X —143— 3). The ed organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give 14 g of 5-bromohydroxy-3— iodobenzaldehyde (100), which was used in next step without r purification (85% yield). LCMS: IR = 1.93 min.
Synthesis of tert—butyl (5-bromoformylbenzofuran—2—y1)methy1carbamate (101): A mixture of 5-bromohydroxy—3-iodobenzaldehyde (100) (3.3 g, 10 mmol), tert- butyl propynylcarbamate (1.6 g, 10 mmol), Pd(PPh3)2C12 (700 mg, 1 mmol) and CuI (191 mg, 1 mmol) in 3 mL of Et3N and 20 mL ofDMF was degassed and heated at 80 0C under nitrogen atmosphere for 2 h. After cooling down to room ature, the reaction mixture was diluted with 20 mL of water, extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 22 g of tert—butyl (5—bromoformylbenzofi1ran-2—yl) methylcarbamate (101) as a yellow solid (yield: 63%). LCMS: m/z 378.0 [M+H]+; IR = 1.18 min.
Synthesis of tert—butyl (5~bromo-7—(difluoromethyl)benzofuran yl)methylcarbamate (102): tert~Butyl (5~bromo—7~formylbenzofuran—2-yl) carbamate (101) (353 mg, 1 mmol) was dissolved in dichloromethane (10 mL). DAST (386 mg, 2.4 mmol) was added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature where it was stirred for 2 h. The reaction mixture was transferred into iced water and extracted with dichloromethane (20 mL X 3). The combined c layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (15% EtOAc/petroleum ether) to give 200 mg of tert—butyl (5-bromo(difluoromethyl)benzofuran—2- yl)methylcarbamate (102) (53% yield). LCMS: m/z 375.9 [M+H]+, IR = 1.89 min.
Synthesis of tert-butyl (7-(difluoromethyl)(4-(morpholine carbonyl)phenyl)benzofuranyl)methylcarbamate (103): tert-Butyl (5-bromo (difluoromethyl)benzofuran—2-yl)methylcarbamate (102) (375 mg, 1 mmol) and morpholino(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan—2-yl)phenyl)methanone (317 mg, 1 mmol) was dissolved in e (10 mL) and ed for 5 min. Pd(dppi)C12 (82 mg, 0.1 mmol), K2C03 (276 mg, 2 mmol) and 1 mL of water were added. The reaction mixture was heated at 90 °C for 2 h. The reaction mixture was transferred into water (20 mL), extracted —144— with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and d by chromatography (1 O-20% ethyl acetate/petroleum) to give tert—butyl (7-(difluoromethyl)~5-(4-(morpholinecarbonyl)phenyl)benzofuran-2 —yl)methylcarbamate 103 (200 mg, 41% yield) as yellowish solid. LCMS: m/z 487.2 [M+1]+, IR = 1.73 min.
Synthesis of (4-(2-(aminomethyl)-7—(difluoromethyl)benzofuran-S- yl)phenyl)(morpholino)methanone (104): tert-Butyl fluoromethyl)(4-(morpholine carbonyl)pheny1)benzo-furanyl)methylcarbamate (103) (200 mg, 0.41 mmol) was dissolved in CH2C12 (6 mL). TFA (1 mL) was added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced re to give the crude (4-(2-(aminomethyl) (difluoromethyl)benzofuranyl)phenyl)(morpholino)methanone (104), which was used in the next step without further purification. (120 mg, 76% yield). LCMS: m/z 387.2 [M+H]+; tR = 1.20 min.
Synthesis of (E)—3—(6-aminopyridinyl)—N—((7-(difluoromethyl)(4- olinecarbonyl)phenyl)benzofuran-2—yl)methyl)acrylamide (557): (4-(2- methyl)—7-(difluoromethyl)benzofuran-S-yl)phenyl)(morpholino)methanone (1 04) (120 mg, 0.31 mmol ) was dissolved in DMF (5 mL) and (E)(6-aminopyridinyl)acrylic acid (51 mg, 0.31 mmol) was added at 0 °C. EDCI (60 mg, 0.31 mmol) and HOBt hydrate (42 mg, 0.31 mmol) were added followed by DIPEA (80 mg, 0.62 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The reaction mixture was purified by Prep-HPLC without work up to afford (E)(6- aminopyridinyl)-N-((7-(difluoromethyl)(4-(morpholinecarbonyl)phenyl)benzofuran- 2-yl)methyl)acrylamide (5 5 7) as White solid (80 mg, 49% yield). 1H NMR (400 MHZ, g) 6 8.90 (t, J= 6 Hz, 1H), 8.46-8.19 (m, 2H), 8.15-8.09 (m, 2H), .76 (m, 3H), 7.58-7.37 (m, 4H), 7.01 (d, J= 9 Hz, 1H), 6.91 (s, 1H), 6.64 (d, J= 16 Hz, 1H), 4.63 (d, J= 5 Hz, 2H), 3.68-3.43 (m, 9H). LCMS: m/z 533.3 [M+H]+; IR = 1.29 min.
Synthesis of (E)(2—((3-(6-aminopyridinyl)acrylamid0)methyl)-7— (trifluoromethyl)benzofuran-S-yl)phenyl morpholinecarb0xylate (558) —145— H0 (\NAO 0 Br @ammi 0 «#11401/\ 0d \ —> NHBoc O \ _> 0 Pd(dppf)C|2,K2603, DMAP- 513110112012 0 NHBOC 0 \ dioxane,H20 O CF31 CF3 26 105 106 CF3 j: o O A _ 0 "who 0 0 \ /N O OH O NH: O \ O HN 107 EDCI, HOBt, CF3 DIPEA, DMF ch Synthesis of tert-Butyl (5-(3-hydroxyphenyl)—7-(trifluoromethyl)benzofuran—2- yl)methylcarbamate (105): tert~Butyl (5—(3-hydroxyphenyl)-7—(trifluoromethyl)benzofuran—2— y1)methylcarbamate (105) was synthesized using l Procedure 2. Yield (96%). LCMS: m/z 430.1 [M+Na]+; {R = 1.80 min.
Synthesis of 3—(2—((tert—butoxycarbonylamino)methyl)—7— (trifluoromethyl)benzofuran—5-y1)phenyl morpholine—4—carboxylate (106): tert—Butyl (5—(3— hydroxyphenyl)(trifluoromethyl)benzofuran—2—yl)methylcarbamate (105) (268 mg, 0.66 mmol) was disolVed in 20 mL of . N,N—dimethylpyridinamine (80 mg, 0.66 mmol), Et3N (132 mg, 1.32 mmol), and morpholine—4—carbonyl chloride (196 mg, 1.31 mmol) were added iVely. The reaction e was stirred at room temperature for 1 h, quenched with water (20 mL), ted with CH2C12 (20 mL X 2). The combined c solvents were washed with brine (20 mL), dried over anhydrous NaZSO4, and concentraed to dryness to give 279 mg of 3—(2-((tert-butoxycarbonylamino)methyl)-7—(trifluoromethyl)benzofuran-5— yl)phenyl morpholine—4—carboxy1ate (106), which was used directly without further purification. Yield (82%). LCMS: m/Z 521.1 [M+H]+; R = 1.26 min.
Synthesis of 3—(2-(aminomethyl)—7—(trifluoromethyl)benzofuran—5-yl)pheny1 morpholinecarboxy1ate (1 07): 3-(2-(aminomethyl)—7-(trifluoromethyl)benzofuran—5— yl)pheny1morpholinecarboxylate (107) was synthesized using General ure 3. Yield (100%). LCMS: m/z 421.3 [M+H]+; zR = 1.27 min.
Synthesis of (E)(2-((3~(6-aminopyridin-3~y1)acrylamido)methyl) (trifluoromethyl)benzofuran-5~yl)phenyl morpholine—4—carboxy1ate (558): (E)-3—(2—((3—(6— aminopyridin—3-yl)acrylamido)methyl)(trifluoromethyl)benzofuran-S-yl)phenyl morpholinecarboxylate (55 8) was synthesized using General Procedure 1. Yield (60%). 1H NMR (400 MHz, CD3OD) 5 8.20 (d, J: 9 Hz, 1H), 8.07 (d, J= 13 Hz, 2H), 7.79 (s, 1H), 7.60—7.43 (m 4H), 7.18(d J=8Hz 1H), 705 (d, J=9Hz, 1H), 6.93 (s, 1H) 6.66 (d,J= 16 Hz, 1H) 4.73 (s 2H) 3. 803.55 (m 8H) LCMS: m/z 567.2 [M+H]' R: 135 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(4—(morpholine—4- carbonyl)phenyl)benzofuranyl)methyl)acrylamide (559). '1) 0’ / \ 8’0 Br QN h 0 / Cl Br N b HO NW / 0 032003 \ // 0 O —-————> ——-—> o _—> :N 0\ choa. CH3CN 0\ CHsoN 30°C Pd(dppf)Clz K2003 dioxane, H20 UN 111 108 109 Raney Ni, H2 (NO EtOH 0—) EDCI HOBt \/MW\ 2 NH2 DIPEA, DMF 112 559 Synthesis of 2-(2-Bromoformylphenoxy)acetonitrile (109): 3—bromo hydroxybenzaldehyde (108) (1.2 g, 6 mmol) was disolved in 30 mL of CH3CN. 2- Chloroacetonitrile (450 mg, 6 mmol) and K2C03 (1 .66g, 12 mmol) were added. The reaction mixture was stirred at room ature for 16 h. After completion, 30 mL of H20 was added to this mixture. The mixture was ted with EtOAc ( 40 mL X 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaZSO4, concentrated, and purified by silica gel chromatography (10% ethyl acetate/petroleum ether) to give 1.28 g of 2—(2-bromoformylphenoxy)acetonitrile (109). Yield (91%). LCMS: m/z 239.9 [M+H]+; IR = 1.56 min.
Synthesis of 7-Bromobenzofuran-Z-carbonitrile (110): 2—(2-Bromo phenoxy)acetonitrile (109) was disolved in CH3CN. C82CO3 (5.7 g, 17.6 mmol) was added. The reaction mixture was d at 80 0C for 16 h. After cooling to room ature, mL of H20 was added, the reaction mixture was extracted with EtOAc (40 mL X 3). The combined organic solvents were washed with brine (20 mL), dried over anhydrous NaZSO4, concentrated and purified by silica gel chromatography (10% ethyl acetate/petroleum ether) to give 210 mg of 7-bromobenzofuran-Z-carbonitrile (110). Yield (11%). LCMS: IR = 1.78 min.
] Synthesis of 7—(4-(Morpholine—4-carbonyl)phenyl)benzofuran-Z-carbonitrile (111): A mixture of morpholino(4—(4,4,5,S—tetramethyl-l ,3,2-dioxaborolan—2— yl)phenyl)methanone (301 mg, 0.95 mmol), 7—bromobenzofuran—2-carbonitrile (110) (210 —147— mg, 0.95 mmol), Pd(dppf)C12 (73 mg, 0.1 mmol) and K2C03 (262 mg, 1.95 mmol) in 10 mL of e and 2 mL of H20 was stirred at 90 °C under nitrogen atmosphere for 3 h. The mixture was extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and the solvents were removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (30% EtOAc/petroleum ether) to give 185 mg of 7-(4-(morpholine' carbonyl)pheny1)benzofurancarbonitrile (111). Yield (58%). LCMS: m/z 333.1 [M+H]+; ZR = 1.62 min. sis of (4-(2-(Aminomethyl)benzofuran y1)phenyl)(morpholino)methanone (112): 7-(4-(Morpholine—4-carbonyl)phenyl)benzofuran carbonitrile (111) (154 mg, 0.46 mmol) was disolved in 15 mL of EtOH. 100 mg of Raney Ni was added. The mixture was stirred under H2 atmosphere for 20 min. The mixture was d, the filtrate was trated and purified by LC (50% EtOAc/petroleum ether) to give 132 mg of (aminomethyl)benzofuran—7— y1)pheny1)(morpholino)methanone (112). Yield (85%). LCMS: m/z 337.2 [M+H]+; tR = 0.83 min.
Synthesis of (E)(6-aminopyridin—3—yl)-N—((7—(4-(morpholine carbony1)phenyl)benzofuranyl)methyl)acrylamide (559): (4—(2- (aminomethy1)benzofuran—7-y1)phenyl)(morpholino)methanone (112; 100 mg, 0.3 mmol) was dissolved in DMF (5 mL) and (E)(6-aminopyridin—3-yl)acry1ic acid (49 mg, 0.3 mmol) was added at 0 0C. EDCI (84 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) were added to this reaction mixture at 0 °C followed by DIPEA (77 mg, 0.6 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 4 h. The reaction mixture was transferred into water (20 mL) and ted with EtOAc (25 mL X 3).
The ed organic layers were washed with brine, dried over anhydrous NazSO4 and concentrated under reduced pressure to give crude product which was purified by Prep- HPLC to afford (E)(6-aminopyridinyl)-N-((7-(4-(morpholine carbonyl)pheny1)benzofuran—2-yl)methyl)acrylamide (559) (43 mg, yield: 30%). 1H NMR (400 MHZ, CD30D) 8 8.22—8.18 (m, 1H), 8.07—7.99 (m, 3H), 7.61-7.46 (m, 5H), 7.38-7.32 (m, 1H), 7.05 (d, J: 9 Hz, 1H), 6.82 (s, 1H), 6.63 (d,J= 16 Hz, 1H), 4.71 (s, 2H), 3.83-3.53 (m, 8H). LCMS: m/Z 483.1 [M+H]+; rR = 1.22 min.
Synthesis of (E)~3—(6—aminopyridin—3—yl)—N-((7-chlor0(5-(m0rph01ine-4— carbonyl)pyridinyl)benzofuran—Z—yl)methyl)acrylamide (560). c. Q N_ N / \ TFA — \ / 0 CH CI B0°HN \ 2 2 300"" Pd(dppf)012 K2003 dioxane H2O Cl (3 2Wm N- \ / \ / —N H2NW"0\ E001, HOBt, 114 DIPEA, DMF Synthesis of utyl (7-chloro-S-(S—(morpholinecarbonyl)pyridin—2— yl)benzofuran—2—yl)methylcarbarnate (1 1 3): tert-Butyl (7—chloro—5—(5-(morpholine carbonyl)pyridin—2—yl)benzofiiran—2—yl)methylcarbamate (113) was synthesized using General Procedure 2. Yield (69%). LCMS: m/z: 472.0 [M+H]+, tR= 1.70 min.
Synthesis of (6—(2—(Aminomethyl)~7—chlorobenzofuran—5—yl)pyridin—3- yl)(morpholino)methanone (114): (6—(2-(Aminomethyl)—7—chlorobenzofuran—5-yl)pyridin-3— yl)(morpholino)methanone (114) was synthesized using General Procedure 3. Yield (100%).
LCMS: m/Z: 372.0 [M+H]+, rR = 0.78 min.
Synthesis of (E)-3—(6—aminopyridinyl)—N—((7-chloro(5—(morpholine—4— carbonyl)pyridin—2—yl)benzofuran—2-yl)methyl)acrylarnide (560): (6—aminopyridin~3— yl)—N—((7-chloro—5—(5—(rnorpholine—4—carbonyl)pyridin—2—yl)benzofuran—2— yl)methyl)acrylamide (5 60) was synthesized using General Procedure 1. Yield (69%). 1 NMR (400 MHz, DMSO-dé) 5 8.85 (t, J: 6 Hz, 1H), 8.72 (d, J: 2 Hz, 1H), 8.37 (d, J: 2 Hz, 1H), 8.27-7.92 (m, 7H), 7.44 (d, J: 16 Hz, 1H), 7.01-6.93 (m, 2H), 6.60 (d, J: 16 Hz, 1H), 4.63 (d, J: 6 Hz, 2H), 3.78—3.36 (m, 8H). LCMS: m/z 518.2 [M+H]+; tR = 1.26 min.
Synthesis of (E)-3—(6-amin0pyridinyl)-N-((5-(4-(4-methylpiperazine-l- carb0nyl)phenyl)(triflu0r0methyl)benz0furan-Z-yl)methyl)acrylamide (561).
F30 F30 O NH N— 0 H2" /' " "2" WMH /I H \ HATU, DIPEA, DMF N\ N \ / N3 0 O 561 N\ sis of (E)—3—(6—arninopyridin—3—yl)—N—((5-(4-(4—rnethylpiperazine—1- carbonyl)phenyl)—7—(trifluoromethyl)benzofuran—2-yl)methy1)acrylamide (56 1 ). ~149— General ure 4: Amide coupling using HATU.
(E)—4—(2—((3—(6-aminopyridin~3-yl)acrylamido)methyl)—7- (trifluoromethyl)benzofuran-5—yl)benzoic acid (59) (60 mg, 0.12 mmol) was dissolved in DMF (2 mL) and l-methylpiperazine (12 mg, 0.12 mmol) was added at 0 °C. HATU (68 mg, 0.18 mmol) were added to this reaction mixture at 0 °C followed by DIPEA (31 mg, 0.24 mmol) dropwise. The reaction mixture was allowed to warm to room ature and stirred for 4 h. The reaction mixture was transferred into water (20 mL) and extracted with EtOAc (25 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced re to give crude t which was purified by Prep-HPLC to afford (E)-3~(6—aminopyridinyl)-N—((5-(4—(4-methylpiperazine-1— carbonyl)phenyl)—7—(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (561). Yield (9%). 1H NMR (400 MHz, CD30D) 6 8.03-7.93 (m, 3H), 7.73—7.61 (m, 5H), 7.49—7.35 (m, 4H), 6. 81 (s, 1H), 650 (d, J: 9 Hz, 1H), 637 (d J: 16 Hz, 1H), 4.61 (s, 2H), 3.77-3.38 (m, 4H), 2. 51-2. 30 (m, 4H). LCMS: m/z 5643 [M+H]; IR: 171 min sis of (E)(6-amin0pyridinyl)—N—((7-chlor0(4-flu0r0(m0rpholine carbonyl)phenyl)benzofuran—Z-yl)methyl)acrylamide (562).
Bp W Bb CH C1 B cHN 2 2 BocHN Pd(dppf)C[2 K2003, :10 O: e, H20 Cl N o w o 0:3 o F M..." HZN \ EDCI, HOBt, 116 DIPEA, DMF Synthesis of tert—Butyl (7~chloro—5-(4-fluoro(morpholine carbonyl)phenyl)benzofuranyl)methylcarbamate (115): Iert-Butyl (7-chloro(4-fluoro (morpholinecarbonyl)phenyl)benzofuranyl)methylcarbamate (115) was synthesized using General Procedure 2. Yield (60%). LCMS: m/z: 489.1 [M+H]+, tR= 1.72 min.
Synthesis of (5-(2—(aminomethyl)chlorobenzofuranyl)—2— fluorophenyl)(morpholino)methanone (1 16): (5-(2—(aminomethyl)—7—chlorobenzofuranyl)- 2-fluorophenyl)(morpholino)methanone (116) was synthesized using General Procedure 3.
Vield (100%). LCMS: IR: 1.26 min.
Synthesis of (E)(6-aminopyridin-3—yl)-N-((7-chloro(4—fluoro—3~(morpholine- 4—carbonyl)phenyl)benzofuranyl)methyl)acrylamide (562): (E)(6-aminopyridin~3—yl)-N- ((7-chloro(4-fluoro(morpholinecarbonyl)phenyl)benzofuranyl)methyl)acrylamide (5 62) was synthesized using General Procedure 1. Yield (23%). 1H NMR (400 MHz, CD30D) 8 8.15-8.06 (m, 1H), 7.93 (s, 1H), .34 (m, 5H), 7.25-7.16 (m, 1H), 6.95 (d, J: 9 Hz 1H) 6.75 (s 1H) 654 (d J: 16 Hz, 1H), 4.60 (s, 2H), 3.75-3.52 (m, 6H), 3.36-3.29 (m, 2H) LCMS: m/z 535.2 [M+H];tR=1 .73 min.
Synthesis of (E)(6-aminopyridin—3-yl)-N-((5-(4-fluoro(morpholine carbonyl)phenyl)(triflu0r0methyl)benzofuranyl)methyl)acrylamide (563). &/O:é——>O©F (2301010? TFA B —> o \ BOCHN °° \ Pd((dppOClz K2003 dioxane H20 0 /—\ F30 U 00 Op 0 0 OF M "mm"N H2N \ EDCI, HOBt, 118 DIPEA DMF sis of tert—Butyl (5-(4-fluoro-3 -(morpholine—4-carbonyl)phenyl) (trifluorornethyl)benzofuran-2—yl)methylcarbamate (1 17): tert—Butyl (5-(4—fluoro (morpholinecarbonyl)pheny1)-7—(trifluoromethyl)benzofuranyl)methylcarbamate (1 17) was synthesized using General Procedure 2. Yield (70%). LCMS: m/z: 523.2 [M+H]+, IR — 1.91 min.
Synthesis of (aminomethyl)(trifluoromethyl)benzofuranyl)-2— fluorophenyl)(morpholino)methanone (118): (5—(2-(aminomethy1)~7- (trifluoromethyl)benzofuranyl)fluorophenyl)(morpholino)methanone (118) was synthesized using General Procedure 3. Yield (100%). LCMS: m/z: 423.0 [M+H]+, IR = 0.90 min.
Synthesis of (E)(6—aminopyridiny1)-N-((5—(4-fluoro(morpholine yl)phenyl)—7—(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (563): (E)(6- aminopyridinyl)—N—((5-(4-fluoro—3—(morpholineCarbonyl)phenyl) (trifluoromethyl)benzofuran—2-yl)methy1)acrylamide (563) was synthesized using General —151- Procedure 1. Yield (23%). 1H NMR (400 MHZ, CD3OD) 5 8.06 (s, 2H), 7.85-7.69 (m, 4H), 7.49 (d, J: 16 Hz, 1H),7.38-7.30(m,1H), 6.91 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.48 (d, J: 16 Hz, 1H), 4.71 (s, 2H), .75 (m, 4H), 3.70—3.65 (m, 2H), 3.47-3.40 (m, 2H). LCMS: m/z 569.2 [M+H]+, m = 1.66 min.
Synthesis of (6-aminopyridinyl)-N-((5-(4-(piperazine-l—carbonyl)phenyl) (trifluoromethyl)benzofurany1)methyl)acrylamide (564).
F3C F30 0 NH NH 0 HN2 fl HM ——-2 4 HM\__/ HN N\ N 0" \ HATU,D|PEA,DMF N\ N \ / / o 0 bNH 59 564 sis of (E)—3-(6-amin0pyridin—3-yl)—N—((5-(4—(piperazinecarbony1)pheny1)~7— (trifluoromethy1)benzofuran-2—y1)methy1)acry1amide (564): (E)—3—(6—amin0pyridin—3—y1)— N-((5 —(4-(piperazine-1—carbony1)phenyl)—7-(trifluoromethy1)benzofuran—Z- y1)methy1)acrylamide (564) was synthesized using general procedure 4. Yield (9%). 1H NMR (400 MHz, CD3OD) 5 8.02-7.94 (m, 2H), 7.72—7.61 (m, 4H), 7.47-7.35 (m, 3H), 6.81 (s, 1H), 6.50 (d, J: 9 Hz, 1H), 6.37 (d, J: 16 Hz,_1H), 4.60 (s, 2H), 3.70—3.61 (m, 2H), 3.44- 3.32 (m, 2H), 2.87—2.64 (m, 4H). LCMS: m/z 550.2 [M+H]+, tR=1.51 min. 4.
Synthesis of (E)—3-(6-amin0pyridinyl)—N—((5-(5-(4-methylpiperazine carbonyl)pyridin-Z-yl)(triflu0romethyl)benzofuranyl)methyl)acrylamide (565). —152- 0 o \ \ BocHN BocHN Br nCI2 Pd After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (5—20% EtOAc/petroleum ether) to yield 143 g of tert—butyl (5—(4,4,5,5— ethyl-l ,3 ,2~dioxaborolan—2-yl)(trifluoromethy1)benzofuran—2—yl)methylcarbamate (119) as a yellow solid (90% yield). 1H NMR (400 MHZ, CDC13) 6 8.10 (s, 1H), 7.88 (s, 1H), 6.59 (s, 1H), 4.97 (s, 1H), 4.42 (d, J: 5 Hz, 2H), 1.40 (s, 9H), 1.30 (s, 12H). LCMS: m/z 464.1 [M+Na]+, rR = 2.05 min.
Synthesis of methyl 6-(2-((terr-butoxycarbonylamino)methy1) (trifluoromethyl)benzofuran—5—yl)nicotinate (120): A mixture of tert-butyl (5—(4,4,5,5— tetramethyl- 1 ,3 ,2-dioxaborolanyl)—7-(trifluoromethyl)benzofuran-2—y1)methylcarbamate (119) (2.4 g, 5.52 mmol), methyl 6-bromonicotinate (1 g, 4.6 mmol), Pd(dppf)C12 (337 mg, 0.46 mmol) and K2C03 (1.26 g, 9.2 mmol) in 20 mL of dioxane and 4 mL of H20 was stirred at 85 0C under nitrogen atmosphere for 2 h. The mixture was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and trated under reduced pres sure to give the crude product, which was purified by silica gel chromatography (40% EtOAc/petroleum ether) to give 2 g of methyl 6—(2-((tert- butoxycarbonylamino)methyl)(trifluoromethyl)benzofuran—5-yl)nicotinate (120) as a yellow solid. Yield (96%). LCMS: m/z 451.1 [M+H]+, :11: 1.88 min.
] Synthesis of methyl 6-(2—(aminomethyl)—’7—(trifluoromethyl)benzofuran—5- yl)nicotinate (121): Methyl 6-(2-((tert-butoxycarbonylamino)methy1) (trifluoromethyl)benzofuran-S-yl)nicotinate (120) (2 g, 4.4 mmol) was dissolved in CH2C12 (20 mL). TFA (6 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure to give the crude methyl 6—(2— (aminomethyl)(trifluoromethyl)benzofuran—5—yl)nicotinate (121), which was used without further purification in the next step. Yield (100%). LCMS: m/z 351.0 [M+H]+; {R = 0.89 min.
Synthesis of (E)—methyl (3—(6-aminopyridin—3—y1)acrylamido)methyl)—7— oromethyl)benzofuran—S—yl)nicotinate (122): The crude methyl aminomethyl)—7- (trifluoromethyl)benzofuran-S-yl)nicotinate (121) (crude mixture from previous step, 4.4 mmol) was dissolved in DMF (8 mL) and (E)—3—(6—aminopyridin-3—yl)acrylic acid (722 mg, 4.4 mmol) was added at 0 °C. HATU (2.5 g, 6.6 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (1.13 g, 8.8 mmol) dropwise. The reaction mixture was allowed to warm to room ature and stirred for 4 h. The crude mixture was purified by Prep— HPLC without workup to afford 800 mg of (E)-methyl 6-(2-((3-(6—aminopyridin—3- yl)acrylamido)methyl)-7—(trifluoromethyl)benzofuran—5-yl)nicotinate (122). Yield (36%).
LCMS: m/z 497.1 [M+H]+, 1R = 1.38 min.
Synthesis of (E)(2-((3-(6-aminopyridinyl)acrylamido)methy1) (trifluoromethyl)benzofuran-5—yl)nicotinic acid (123): (E)-methy1 6—(2-((3-(6-amin0pyridin— 3-yl)acrylamido)methyl)—7-(trifluoromethyl)benzofuran-5—yl)nicotinate (122) (800 mg, 1.6 mmol) was dissolved in THF (10 mL). LiOH (98 mg, 2.4 mmol) and water (2 mL) were added to this mixture. The mixture was d at room temperature for 8 h, 1N HCl solution was added and ed to pH ~ 6. 700 mg of (E)—6-(2—((3—(6—aminopyridin—3— yl)acrylamido)methyl)—7—(trifluoromethyl)benzofiiran—S—yl)nicotinic acid (123) was collected by filtration and dried in vacuuineld (90%). LCMS: m/z 483.1 [M+H]+, 1R = 1.34 min. —154— ] Synthesis of (E)(6-aminopyridinyl)-N—((5-(5-(4—methylpiperazine carbonyl)pyridin—2—y1)(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (565): (ED—3— (65aminopyridin-3—yl)-N-((5-(5-(4-methylpiperazinecarbony1)pyridin—2—yl)—7— (trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (565) was synthesized using the indicated reagents according to general procedure 4. (10 mg; Yield: 14%). 1H NMR (400 MHz, CD3OD) 6 .73 (m, 1H), 8.49 (d, J: 1 Hz, 1H), 8.31 (s, 1H), 8.07—8.06 (m, 2H), 7.98-7.95 (m, 1H), 7.75-7.72 (m, 1H), 7.49 (d, J= 16 Hz, 1H), 6.94 (s, 1H), 6.60 (d, J= 9 Hz, 1H), 6.48 (d, J= 16 Hz, 1H), 4.72 (s, 2H), 3.83 (s, 2H), 3.57 (s, 2H), .49 (m, 4H), 2.35 (s, 3H). LCMS: m/z 565.2 [M+H]+; :R = 1.53 min.
Synthesis of (E)—3-(6-aminopyridinyl)-N-((5-(4-(4,4—diflu0ropiperidine-l- carbonyl)phenyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (566).
F3C F30 HCIO LCMS: m/z 585. 3 [M+H]+; tR = 1 81 min. sis of (E)-3—(6-aminopyridinyl)-N-((5-(4-(4-flu0r0piperidine carbonyl)phenyl)—7—(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (567).
F3C F3C H:O / 00 0 ° OW: I H HATU DIPEA DMF N\ N \ / <" 567 2 (E)—3—(6-aminopyridiny1)-N—((5-(4-(4-fluoropiperidinecarbony1)phenyl) (trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (567) was synthesized using the indicated reagents according to general procedure 4. Yield (55%). 1H NMR (400 MHz, DMSO—d6) 6 8.66 (t, J: 6 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J: 2 Hz, 1H), 7.87—7.82 (m, 3H), 7.64—7.61 (m, 1H), 7.53 (d, J: 8 Hz, 2H), 7.36 (d, J: 16 Hz, 1H), 6.95 (s, 1H), —155- 6.49-6.41 (m, 4H), 5.00-4.85 (m, 1H), 4.02 (d, J: 6 Hz, 2H), 3.68-3.47 (m, 4H), 1.96- 1.75 (m, 4H). LCMS: m/z 567.2 [M+H]+; Q; = 1.70 min. sis of (E)(6-amin0pyridin—3-yl)—N-((7—(4-flu0rophenyl)(5-(morpholine carb0nyl)pyridinyl)benzofuranyl)methyl)acrylamide (568). 0 FQBWH» 0 O \ TFA \ N BocHN "k BocHN O —» l ‘ / O Hummus». P0313. K3P04. / Ny 0H20I2 dloxane. H20 83 o 124 O O HZN /N \ OH \ O N HZN _ \ O H2N / / Nd HOBt, EDCI, , DMF ‘ 125 568 ] Synthesis of tert—butyl (7—(4-fluorophenyl)—5-(5-(morpholinecarbonyl)pyridin- 2«yl)benzofuran-2—yl)methylcarbamate (124): tert—Butyl (7—chloro-5—(5—(morpholine—4- carbonyl)pyridin-2—yl)benzofuran—2—yl)methylcarbamate (83) (140 mg, 0.3 mmol), 4~ fluorophenylboronic acid (125 mg, 0.9 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol), lohexylphosphine (17 mg, 0.06 mmol) and K3PO4 (201 mg, 0.9 mmol) were added to 10 mL of dioxane and 1 mL of water. The reaction mixture was degassed and heated at 130 0C under nitrogen atmosphere for 12 h. The reaction mixture was cooled down to room temperature, poured into 5 mL of water, extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under d pressure to give the crude product which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to give tert-butyl (7—(4—fluorophenyl)—5-(5-(morpholine-4— carbony1)pyridinyl)benzofuranyl)methylcarbamate (124) as white solid (100 mg, 63% yield). LCMS: m/z 532.1 [M+H]+; rR = 1.78 min.
Synthesis of (6—(2-(aminomethyl)—7-(4—fluorophenyl)benzofuran—S-yl)pyridin—3- yl)(morpholino)methanone (125): tert—Butyl (7—(4-fluorophenyl)—5-(5-(morpholine—4— carbonyl)pyridin—2-yl)benzofuran—2-yl)methylcarbamate (124) (110 mg, 0.21 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added dropwise at 0 °C. The reaction mixture —156— was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give (6—(2-(aminomethyl)(4—fluorophenyl)benzofuran—5-yl)pyridin yl)(morpholino)methanone (125), which was used without further purification in the next step (80 mg, 89% yield). LCMS: m/z 432.1 [M+H]+; {R = 0.87 min.
Synthesis of (E)—3-(6—aminopyridinyl)—N-((7-(4—fluorophenyl)—5-(5- oline—4—carbonyl)pyridinyl)benzofuranyl)methyl)acrylamide (568): (6—(2- (Aminomethyl)—7—(4—fluorophenyl) benzofuran-S-yl)pyridiny1)(morpholino)methanone (125) (80 mg, 0.2 mmol), (E)(6-aminopyridin—3-yl)acry1ic acid (35 mg, 0.2 mmol), HOBt hydrate (40 mg, 0.3 mmol), EDCI (55 mg, 0.3 mmol) and DIPEA (74 mg, 0.6 mmol) were added in DMF (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The on mixture was diluted with water (10 mL), extracted with EtOAc (10 mL X 3). The ed organic layers were washed with brine, dried over anhydrous Na2804, concentrated under reduced pressure to give the crude t which was purified by Pre-HPLC to give (E)(6-amin0pyridin—3—yl)-N—((7—(4—fluorophenyl)—5—(5- (morpholinecarbonyl)pyridin-2—yl)benzofuranyl)methyl)acrylamide (568) (36 mg, 34% yield) as white solid. 1H NMR (400 MHz, DMSO—d6) 6 8.82 (s, 1H), 8.73 (s, 1H), 8.38 (s, 1H), .94 (m, 9H), 7.50—7.36 (m, 3H), 7.01-6.91 (m, 2H), 6.60 (d, J: 16 Hz, 1H), 4.62 (d, J: 5 Hz, 2H), 3.94—3.42 (m, 8H). LCMS: m/z 578.2 [M+H]+, tR= 1.32 min.
Synthesis of (E)(6-aminopyridin—3-yl)-N-((5-(5-(3,3-dimethylm0rpholine yl)pyridin~2-yl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (569).
F3C \/[ F30 N" O N— O H N2 "N\_/0 H N / 2 / 1, 0 H \ / #—> 0 \ / OH l H N\ N \ N\ N \ / HATU, DIPEA, DMF / m 0 0 0 123 569 (E)—3-(6—aminopyridinyl)—N—((5-(5-(3,3-dimethylmorpholine carbonyl)pyridinyl)-7—(trifluoromethyl)benzofuranyl)methyl)acrylamide (569) was synthesized using the indicated reagents according to general procedure 4. Yield (49%). 1H NMR (400 MHz, DMSO-ds) c3 8.73-8.66 (m, 3H), 8.38 (s, 1H), 8.18 (d, J= 8 Hz, 1H), 8.08 (s, 1H), 7.98-7.95 (m, 1H), 7.63—7.61 (m, 1H), 7.36 (d, J= 16 Hz, 1H), 7.00 (s, 1H), 6.48-6.41 (m, 4H), 4.62 (d, J: 6 Hz, 2H), 3.71-3.69 (m, 2H), 3.44 (s, 2H), 3.33 (s, 2H), 1.44 (s, 6H). LCMS: m/z 580.0 [M+H]+; {R = 1.37 min.
Synthesis of (S,E)—3—(6—aminopyridin-3—yl)—N—((5-(5-(3-flu0r0pyrrolidine carbonvl)pyridin-Z—yl)(trifluoromethyl)benz0furanyl)methyl)acrylamide (570). -157~ F36 HN F36 N_ o _ HZN / KlF O MN H2N / l H \ / —’ o | H S/ \ HATU, DIPEA, DMF N \ N \ / gF O O 123 570 [0054 1] (S,E)-3 -(6-arninopyridin-3 -yl)-N-((5 -(5-(3 ~fluoropyrrolidine- l -carbonyl)pyridin- 2-yl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (570) was synthesized using the te reagents according to l procedure 4. Yield (22%). 1H NMR (400 MHz, DMSO'dé) c3 8.89-8.85 (m, 1H), 8.70-8.65 (m, 2H), 8.40 (s, 1H), 8.22-8.08 (m, 3H), .61 (m, 1H), 7.36 (d, J= 16 Hz, 1H), 7.00 (s, 1H), 6.49-6.41 (m, 4H), 5.48-5.29 (m, 1H), 4.62 (d, J: 6 Hz, 2H), 3.80-3.60 (m, 4H), 2.19-2.17 (m, 2H). LCMS: m/z 554.2 [M+H]+; m = 1.31 min.
Synthesis of (E)(6-aminopyridin-3—yl)—N-((5—(4—(4—hydroxymethylpiperidine carbonyl)phenyl)—7-(triflu0r0methyl)benzofuran-Z-yl)methyl)acrylamide (571). ______>H2N / O I H HATU DIPEA DMF N\ N \ 571 Q (E)—3 -(6-arninopyridin—3 -yl)—N—((5-(4-(4-hydroxy—4~rnethylpiperidine— l — carbonyl)phenyl)-7—(trifluorornethyl)benzofuranyl)methyl)acrylarnide (57 l) was synthesized using the indicated reagents according to general procedure 4. Yield (45%). 1H NMR (400 MHz, CD30D) 6 7.98-7.94 (m, 2H), .62 (m, 4H), 7.43—7.36 (rn, 3H), 6.80 (s, 1H), 6.49 (d, J: 5 Hz, 1H), 6.37 (d, J: 16 Hz, 1H), 4.67-4.51 (m, 2H), 4.17- 4.14 (rn 1H) 3.43—3.21 (m, 3H), 1.60-1.47 (m, 4H), 1.17 (s, 3H). LCMS: m/z 579.3 [M+H]+; IR— l69 min.
Synthesis of (E)(6-aminopyridin—3—yl)-N-((5-(4—(3,3-dimethylpiperazine—l- carbonyl)phenyl)(triflu0romethyl)benzofuranyl)methyl)acrylamide (572).
F30 F30 N HN\__/ H N HATU D!PEA. DMF (E)-3 -(6-aminopyridin-3 -((5-(4-(3,3-dimethylpiperazine— l — carbonyl)phenyl)(trifluoromethyl)benzofurany1)methyl)acrylamide (572) was synthesized using the indicated reagents according to general procedure 4. Yield (52%). 1H —158- NMR (400 MHz, CD3OD) 5 8.11 (s, 1H), 8.06 (d, J= 2 Hz, 1H), 7.80—7.74 (m, 4H), 7.54-7.48 (m, 3H), 6.92 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.49 (d, J: 4 Hz, 1H), .64 (m 4H) 3. 74—3. 45 (m, 2H), 2.85—2.76 (m, 2H), 1.23 (s, 3H), 1.06 (s, 3H). LCMS: m/z 5783 [M+H]+; tR—— 1.63 min.
Synthesis of (E)-N-((5-(4-(1,4-diazepanecarb0nyl)phenyl) (trifluoromethyl)benzofuran—2—yl)methyl)(6-amin0pyridinyl)acrylamide (573).
F30 F3C HNme-SCL HATU DIPEA DMF W"? o 1"o)- (E)-N—((5 —(4—(1,4—diazepane-1—carbonyl)phenyl)(trifluoromethyl)benzofuran—2- yl)methyl)-3~(6-aminopyridin—3—yl)acrylamide (573) was synthesized using the indicated reagents according to l procedure 4. Yield (24%). 1H NMR (400 MHZ, CD30D) 6 8.12—8.04 (m, 2H), 7.84—7.74 (m, 4H), 7.61-7.46 (m, 3H), 6.92 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), 4.72 (s, 2H), 3.87~3.77 (m, 2H), 3.63—3.53 (m, 2H), 3.13—2.87 (m, 4H), 2.00—1.78 (m, 2H). LCMS: m/z 564.2 [M+H]+, z‘R: 1.19 min.
Synthesis of (E)-N—((5-(4-(1,4-0xazepanecarb0nyl)phenyl) (trifluoromethyl)benzofuran-Z-yl)Inethyl)-3—(6-amin0pyridinyl)acrylamide (574).
F30 "NA F30 H N2 V H N2 I H HATU DIPEA DMF N\ N \ 0 L/ONW (E)—N—((5—(4—(1,4—oxazepanecarbonyl)phenyl)(trifluoromethyl)benzofuran—2— yl)methy1)—3—(6—aminopyridin—3-yl)acry1amide (574) was synthesized using the indicated reagents according to general procedure 4. Yield (51%). 1H NMR (400 MHz, DMSO-ds) 5 8.69 (t, J: 6.0 Hz, 1H), 8.25 (s, 1H), 8.08 (d, J: 2 Hz, 1H), 7.86-7.81 (m, 3H), 7.65- 7.63 (m, 1H), 7.51 (d, J: 8 Hz, 2H), 7.36 (d, J: 16 Hz, 1H), 6.95 (s, 1H), 6.50-6.41 (m, 4H), 4 61 (d J= 5 Hz, 2H), 3.75-3.59 (m, 8H), 1.91-1.73 (m, 2H). LCMS: m/z 565.2 [M+H]; t—R— 1. 62 min sis of (E)—3-(6—aminopyridinyl)—N—((5-(4-(2,2-dimethylpiperazine-l- carbonyl)phenyl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (575). ~159— (:6 CF: CF3 >H(—NBacN_) HATU. DIPEA DMF 00‘ I;\ ] Synthesis of (E)(6—aminopyridin—3~yl)—N—((5-(4~(2,2—dimethylpiperazine—1— carbonyl)phenyl)~7—(trifluoromethyl)benzofiiran-Z—yl)methyl)acrylamide (575): (E)—3-(6— yridin-3—yl)-N—((5—(4—(2,2—dimethylpiperazine—1-carbonyl)phenyl)—7— (trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (575) was synthesized using the indicated reagents according to general procedure 3. Yield (14%). 1H NMR (400 MHz, DMSO-ds) 5 8.77 (t, J: 6 Hz, 1H), 8.26-8.08 (m, 3H), 7.86-7.92 (m, 2H), 7.50 (d, J: 8 Hz, 1H), 6.94 (s, 1H), 6.55—6.31 (m, 5H), 5.80 (d,J= 13 Hz, 1H), 4.62—4.56 (m, 2H), 3.20—3.17 (m, 4H), 2.76-2.74 (m, 2H), 2.62 (s, 2H), 1.44 (s, 6H). LCMS: m/z 578.3 [M+H]+, IR: 1.59 min.
Synthesis of (E)(6-aminopyridinyl)-N—((7-chlor0-5—(4—(4—methylpiperazine carbonyl)phenyl)benzofuran—Z-yl)methyl)acrylamide (576). w 675 TFA \ ——————-> BM" B Br °°HN octz. K2003, (N) CHzc'z 19 dioxane, H20 127 N\ «061280;? "WUngEDCI, HOBt,DIPEA, DMF N\ Synthesis of tert—Butyl (7-chloro-5~(4—(4-methylpiperazine carbonyl)phenyl)benzofuran~2-yl)methylcarbamate (127): tert—Butyl (7-chloro(4—(4- -160— methylpiperazinecarbonyl)phenyl)benzofuranyl)methylcarbamate (127) was synthesized using the indicated reagents according to General ure 2. Yield (87%).
LCMS: m/z 484.1 ; 1R = 1.39 min.
Synthesis of (4—(2-(Aminomethyl)—7-chlorobenzofuranyl)phenyl)(4- methylpiperazin—l-yl)methanone (128): (4—(2-(Aminomethyl)—7—chlorobenzofuran-5— yl)phenyl)(4amethylpiperazinyl)methanone (128) was synthesized using the indicated reagents according to l Procedure 3. Yield (100%). LCMS: m/z 385.2 [M+H]+; tR — 1. 54 min.
Synthesis of (E)(6—aminopyridin—3-yl)-N-((7-chloro(4-(4-methylpiperazine- l-carbonyl)phenyl)benzofuran—2-yl)methyl)acrylamide (576): (E)—3 ~(6—aminopyridin—3-yl)—N~ ((7-chloro—5~(4—(4—methylpiperazine-l -carbonyl)phenyl)benzofuran-2—yl)rnethyl)acrylarnide (576) was synthesized using the indicated reagents according to General Procedure 1. Yield (100%). 1H NMR (400 MHz, DMSO—d6) 6 8.64 (t, J: 6 Hz, 1H), 8.08-7.61 (m, 6H), 7.48 (d, J: 8.0 Hz, 2H), 7.36 (d, J: 16 Hz, 1H), 6.90 (s, 1H), 6.49—6.41 (m, 4H), 4.61— 4.59 (m, 2H), 3.78—3.54 (m, 4H), .33 (m, 4H), 2.20 (s, 3H). LCMS: m/z 530.2 [M+H]+; 1R = 1.54 min.
Synthesis of (S,E)(6-aminopyridinyl)—N—((5-(5-(3-flu0r0pyrrolidine carbonyl)pyridinyl)—7—(trifluoromethyl)benzofuranyl)methyl)acrylamide (577). mam]N/—<;©\L)\n/OH_—.HNCNBncHATU DIPEA DMF [426%%05ac mg}:14%0HCH20I2 Synthesis of (ID—tert-Butyl 4-(6-(2:((3-(6-aminopyridinyl)acrylamido)rnethyl)- 7—(trifluoromethyl)benzofuranyl)nicotinoyl)piperazinecarboxylate (129): rt—Butyl 4-(6—(2'((3-(6-aminopyridinyl)acrylamido)methyl)—7-(trifluoromethyl)benzofuran otinoyl)piperazinecarboxylate (136) was synthesized using the indicated reagents according to General Procedure 4. (52% yield). LCMS: m/z 651.2 [M+H]+; tR = 1. 73 min.
Synthesis of (E)(6-aminopyridinyl)-N—((5-(5-(piperazine carbonyl)pyridinyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (577): (E) (6-aminopyridin—3-yl)—N—((5 -(5 —(piperazine—l -carbonyl)pyridin—2-yl)—7- (trifluoromethyl)benzofuran-2—yl)rnethyl)acrylamide (577) was synthesized using the ted reagents according to General Procedure 3. Yield (50%). 1H NMR (400 MHz, CD3OD) 5 8.74 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.10—7.93 (m, 4H), 7.50 (d, J: 16 Hz, 1H), 6.95 (d, J== 13 Hz, 1H), 6.66-6.51 (m, 1H), 6.47-6.37 (m, 1H), 4.73—4.67 (m, 2H), 3.79-3.50 (m, 4H), 2.94-2.86 (m, 4H). LCMS: m/z 551.2 [M+H]+; tR = 1.45 min. sis of (E)—3—(6-amin0pyridin—3—yl)-N-((7-chlor0—5—(5—((3,5-dimethylisoxazol yl)(hydr0xy)methyl)thi0phen—2-yl)benzofuran—Z—yl)methyl)acrylamide (578).
BocHNWB’O0 BrA; / 43 (371< BocHN N’ 0 / / 9 ———> l / q n-BuLi THF HO ’N Pdcu K2003. dioxane. H20 8 /N 130 131 132 HZN / TFA MW; O / __ l q CHZCIZ 3 /N EDCI HOBt DIPFJ-\, DMF H0 HZNwHO/C Synthesis of (5—bromothiophen—2—yl)(3,5—dimethylisoxazolyl)methanol (131): 4-Iodo-3,5-dimethylisoxazole (130) (3.35 g, 15 mmol) was dissolved in 45 mL of THF. The mixture was degassed and cooled to -78 0C. n-BuLi (6.6 mL, 16.5 mmol, 2.5 N in hexanes) was added slowly. After stirring for l h at -78 °C, 5-bromothiophenecarba1dehyde (3.15 g, 16.5 mmol) was added. The mixture was stirred at —78 0C for additional 1 h, and then allowed to warm up to 0 °C slowly. 10 mL ofNH4Cl aqueous on was added to quench the reaction and the mixture was extracted with EtOAc (35 mL X 3). The ed organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated and purified by silica gel chromatography (10%-20% EtOAc/petroleum ether) to give 455 mg of (5— bromothiophenyl)(3,5-dimethylisoxazolyl)methanol (131) as yellow oil (yield: 8%).
LCMS: m/z 290.0 [M+H]+; tR = 1.66 min.
Synthesis of tert-butyl (7-chloro(5-((3,5-dimethylisoxazol—4— yl)(hydroxy)methyl)thiophen-2—yl)benzofuran—2-yl)methylcarbamate (132): (5- Bromothiophenyl)(3,5-dimethylisoxazoly1)methanol (131) (160 mg, 0.55 mmol) and tert-butyl oro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzofuran yl)methylcarbamate (203 mg, 0.5 mmol) was dissolved in dioxane (6 mL) and ed.
Pd(dppf)C12 (40 mg, 0.05 mmol), K2C03 (138 mg, 1 mmol) and 0.6 mL of water were added.
The on mixture was heated at 100 °C for 2 h. The reaction mixture was transferred into water and extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give the crude product which was purified by chromatography (20-30% ethyl e/petroleum ether) to give tert—butyl (7-chloro(5-((3,5-dimethylisoxazol yl)(hydroxy)methyl)thiophen—2-yl)benzofuranyl)methylcarbamate (132) (160 mg, 66% yield) as yellowish solid. LCMS: m/z 489.1 [M+H]+, IR = 1.85 min.
Synthesis of (5-(2-(aminomethyl)chlorobenzofuranyl)thiophen—2-yl)(3,5- dimethylisoxazol—4-yl)methanol (133): tert-Butyl (7-chloro(5—((3,5-dimethy1isoxazol—4- yl)(hydroxy)methyl)thiophen—2—yl)benzofuranyl)methylcarbamate (132) (80 mg, 0.16 mmol) was dissolved in CH2C12 (4 mL). TFA (1 mL) was added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and d for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude (5-(2—(aminomethyl)—7- chlorobenzofuran—S—yl)thiophen—2-yl)(3,5-dimethylisoxazol-4—yl)methanol (133), which was used in the next step without further purification (80 mg, Yield: 100%). LCMS: m/z 371.1 [M+H]+; 1R = 1.38 min.
Synthesis of (6~aminopyridin—3—yl)—N—((7—chloro—5—(5—((3,5— dimethylisoxazol—4—yl)(hydroxy)methy1)thiophen—2-yl)benzofuran—2—yl)methyl)acrylamide (578): (5—(2—(Aminomethyl)—7—chlorobenzofuran—5—yl)thiophen—2—yl)(3,5—dimethylisoxazol—4- yl)methanol (133) (80 mg, 0.16 mmol) was dissolved in DMF (3 mL) and (6— aminopyridin—3—yl)acrylic acid (32 mg, 0.19 mmol) was added at 0 OC. EDCI (37 mg, 0.19 mmol) and HOBt (26 mg, 0.19 mmol) were added to this reaction mixture at 0 OC followed by DIPEA (41 mg, 0.32 mmol) dropwise. The reaction e was allowed to warm to room temperature and stirred for 18 h. The crude mixture was purified by Prep—HPLC to afford (E)—3—(6-aminopyridin—3~yl)—N—((7-chloro~5—(5-((3,54dimethylisoxazol—4— yl)(hydroxy)methyl)thiophen—2-yl)benzofuranyl)methyl)acrylamide (5 78) (6 mg, 7% yield). 1H NMR (400 MHZ, CD3OD) 8 8.07 (d, J: 2 Hz, 1H), 7.78-7.72 (m, 2H), 7.57-7.48 (m, 2H), 7.27 (d, J: 4 Hz, 1H), 6.88 (m, 1H), 6.81 (s, 1H), 6.61 (d, J= 9 Hz, 1H), 6.48 (d, J = 16 Hz, 1H), 6.00 (s, 1H), 4.68 (s, 2H), 2.43 (s, 3H), 2.21 (s, 3H). LCMS: m/z M+H]+, rR= 1.64 min.
Synthesis of (E)(6-aminopyridinyl)—N—((5-(5-fluoro(morpholine carbonyl)pyridinyl)(trifluor0methyl)benzofuranyl)methyl)acrylamide (579). ~163— O \M/ F é\ N N/ \o BocHN / o 3 / \ o / O \ / F W» TFA, DCM BocHN O N Pd2(dba)a. PCya, K3PO4, dioxane. H20 r'\ —’ F30 N o CFa \_/ so 134 O 0 HZN / _ WNWN/ \ OH / / :ac \N / Ema \_/ EDCI, HOBt. DIPEA, DMF O HZNWMWFHF30 N O 135 579 Synthesis of tert-butyl (5-(5-fluoro(morpholinecarbonyl)pyridin—2-y1) (trifluoromethyl)benzofuran—2-yl)methylcarbamate (134): (5—(5-fluoro(morpholine carbonyl)pyridiny1)(trifluoromethyl)benzofuran—2-yl)methylcarbamate (1 34) was synthesized using the indicated reagents according to l Procedure 2. Yield: 68%.
LCMS: m/Z 524.2 [M+H]+; m = 1.78 min.
Synthesis of (6-(2-(aminornethyl)—7—(trifluoromethyl)benzofuran—5-y1) fluoropyridin—2-y1)(morpholino)rnethanone (135): (6—(2—(aminomethy1) (trifluoromethyl)benzofuran-S—yl)-3~fluoropyridin—2—yl)(morpholino)methanone (135) was synthesized using the indicated reagents ing to General ure 3. Yield: 75%.
LCMS: m/z 424.0 [M+H]+; m = 1.22 min.
Synthesis of (E)(6-aminopyridin—3-yl)~N~((5-(5-fluoro—6—(morpholine carbonyl)pyridin-2—yl)(trifluorornethyl)benzofuran-2~yl)methyl)acry1amide (579): (E) (6-aminopyridin-3~y1)-N—((5-(5-fluoro(morpholine—4-carbonyl)pyridin—2-yl) (trifluoromethyl)benzofuran—2-yl)methyl)acrylamide (579) was synthesized using the indicated reagents according to l Procedure 1. Yield: 38%. 1H NMR (400 MHz, DMSO'dé) 8 8.86 (t, J= 6 Hz, 1H), 8.61 (s, 1H), 8.34-7.98 (In, 7H), 7.44 (d, J: 16 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J: 9 Hz, 1H), 6.60 (d, J: 16 Hz, 1H), 4.64 (d, J: 6 Hz, 2H), 3.75-3.56 (m, 8H). LCMS: m/z 570.2 [M+H]+, tR= 1.32 min.
Synthesis of (E)(6-aminopyridinyl)—N-((5-(5-flu0r0(m0rpholine carbonyl)pyridinyl)(triflu0romethyl)benzofuranyl)methyl)acrylamide (580). ~164- O _ B°°HN BocHN \ N HO -————————> B EDCI H081 Pd(dr>r>f)0|:a K2003. dioxane, H20 136 DIPEA CH2612 TFA HEN / \ CHEC'Z \N / F EDCI HOB! DIPEA DMF F3C HNWHO; Synthesis of (2-bromo-5~fluoropyridin~4~yl)(morpholino)methanone (137): 2- Bromo—5—fluoroisonicotinic acid (136) (1.0 g, 4.6 mmol) was dissolved in DCM (20 mL) and morpholine (0.4 g, 4.6 mmol) was added at 0 °C. EDCI (1.3 g, 6.8 mmol) and HOBt hydrate (0.9 g, 6.8 mmol) were added to this reaction mixture followed by DIPEA (1.2 g, 9.0 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 4 h. The reaction mixture was washed with water (10 mL), brine, dried over Na2804, concentrated under reduced pressure to give the crude product, which was d by silica gel choramatagraphy (15% EtOAc/petroleum ether) to give 1.2 g of (2-bromo-5— fluoropyridin—4-yl)(morpholino)methanone (137). Yield (90%). LCMS: m/z 289.0 [M+H]+, IR = 1.50 min Synthesis of tert—butyl fluoro-4—(morpholine—4-carbonyl)pyridin—2—yl)—7— (trifluoromethyl)benzofuranyl)methy1carbamate (138): A mixture of (2-bromo fluoropyridin—4-yl)(morpholino)methanone (137) (100 mg, 0.34 mmol), tert—butyl (7— (trifluoromethyl)benzofuran-2—yl)methylcarbamate (60) (150 mg, 0.34 mmol), Pd(dppt)C12 (25 mg, 0.034 mmol) and K2CO3 (94 mg, 0.68 mmol) in 5 mL of dioxane and 1 mL of H20 was degassed. The reaction mixture was heated at 85 0C under en atmosphere for 2 h.
After cooling down to room temperature, the reaction mixture was poured into iced water (10 mL), ted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over ous Na2S O4, and concentrated under reduced pressure to give the crude product, which was d by prep—TLC (30% EtOAc/petroleum ether) to give 124 mg of tert-butyl (5-(5-fluoro(morpholine~4~carbonyl)pyridinyl)—7- (trifluoromethyl)benzofuran-2—yl)methylearbamate (138) as a white solid. Yield (70%).
LCMS: m/Z 524.2 [M+H]+, zR = 1.89 min. -165— Synthesis of (2-(2-(aminomethyl)(trifluoromethyl)benzofuranyl) fluoropyridinyl)(morpholino)methanone (139): tert-Butyl (5-(5-fluoro—4—(morpholine-4— carbonyl)pyridin—2—yl)(trifluoromethyl)benzofuranyl)methylcarbamate (138) ( 90 mg, 0.17 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added at 0 °C (ice bath). The on mixture was allowed to warm to room temperature and stirred for 2 h. The on mixture was concentrated under reduced pressure to give 75 mg of the crude (2-(2- (aminomethyl)(trifluoromethyl)benzofuranyl)fluoropyridin yl)(morpholino)methanone (139), which was used without further purification in the next step. Yield (100%). LCMS: m/z 424.0 [M+H]+; tR = 1.63 min.
Synthesis of (E)—3-(6—aminopyridiny1)—N-((5—(5-fluoro—4-(morpholine—4— carbonyl)pyridiny1)(trifluoromethyl)benzofuranyl)methyl)acrylamide (580): (2-(2- (Aminomethyl)(trifluoromethyl)benzofurany1)fluoropyridin—4— yl)(morpholino)methanone (139) (75 mg, 0.17 mmol) was dissolved in DMF (5mL) and (E)— 3—(6-aminopyridin—3—yl)acrylic acid (31 mg, 0.19 mmol) was added at 0 °C (ice bath). ED Cl (54 mg, 0.28 mmol) and HOBt hydrate (38 mg, 0.28 mmol) were added to this reaction mixture at 0 °C followed by DIPEA (49 mg, 0.38 mmol) se. The reaction mixture was allowed to warm to room temperature and stirred further for 4 h. The crude mixture was purified by Prep—HPLC without workup to afford 23 mg of (E)—3—(6-aminopyridin—3-yl)—N— ((5 oro-4—(morpholine—4-carbonyl)pyridinyl)(trifluoromethyl)benzofuran-2— yl)methyl)acrylamide (580). Yield (20%). 1H NMR (400 MHz, CD3OD) 5 8.57 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.99-7.94 (m, 2H), 7.64 (d, J: 9 Hz, 1H), 7.38 (d, J: 16 Hz, 1H), 6.83 (s, 1H), 6.50 (d, J: 9 Hz, 1H), 6.37 (d, J= 16 Hz, 1H), 4.61 (s, 2H), 3.75-3.66 (m, 4H), 3.59- 3.55 (m, 2H), 3.34-3.30 (m, 2H). LCMS: m/z 570.2 [M+H]+, tR=1.63 min.
Synthesis of (6—amin0pyridinyl)-N-((7-chloro(5-flu0ro(m0rpholine carb0nyl)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (581).
/ CI HN\/:>O \ i / F \ OH CI N —, N o O HATU, DIPEA, CH20I2 O 140 141 /? :fih‘u/—\O BOCHN / \ / F TFA, DCM BOCHN N . Pd2(dba)3 PCya K3PO4 dioxane H20 CI N/ \O —’ O \_/ 43 142 o 0 :l\OH WM / H _ \ O \N / F EDCl H031 DIPEA DMF CI N/ ‘0 O \_/ Synthesis of (6—chlorofluoropyridin—2—yl)(morpholino)methanone (141): 6— Chloro—3-fluoropicolinic acid (140) (700 mg, 4.0 mmol) was dissolved in DCM (20 mL).
Morpholine (348 mg, 4.0 mmol), HATU (1.5 g, 4.0 mmol) and DIPEA (774 mg, 6.0 mmol) were added at room temperature. The reaction mixture was d at room temperature for 16 h. The reaction mixture was washed with water (20 mL), brine, dried over anhydrous Na2804 and concentrated under reduced re to give 694 mg of (6-chloro~3-fluoropyridin-2— yl)(morpholino)methanone (141) as white solid, which was used in the next step without further purification. Yield (60%). LCMS: m/z 245.1 [M+H]+; tR = 1.56 min.
Synthesis of tert—butyl (7-chloro(5-fluoro(morpholinecarbonyl)pyridin—2— zofi1ranyl)methylcarbamate (142): A mixture of tert—butyl (7-chloro(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)benzofiiranyl)methy1carbamate (43) (322 mg, 0.79 mmol), (6—chloro—3—fluoropyridinyl)(morpholino)methanone (141) (193 mg, 0.79 mmol), Pd2(dba)3 (56 mg, 0.08 mmol), PCy3 (45 mg, 0.16 mmol) and K3PO4 (335 mg, 1.58 mmol) in 8 mL of dioxane and 2 mL of H20 was degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture was d and the filtrate was concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (25% EtOAc/petroleum ether) to give 160 mg of tert-butyl (7—chloro-5—(5—fluoro(morpholine—4—carbonyl)pyridin- enzofuranyl)methylcarbamate (142) as an oil. Yield (70%). LCMS: m/z 490.2 [M+H]+, m = 1.85 min.
Synthesis of (6-(2-(aminomethyl)—7-chlorobenzofuranyl)—3-fluoropyridin—2- yl)(morpholino)methanone (143): tert-Butyl (7-chloro(5-fluoro(morpholine-4— carbonyl)pyridinyl)benzofuranyl)methylcarbamate (142) (160 mg, 0.33 mmol) was ved in CH2C12 (5 mL). TFA (0.5 mL) was added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction e was concentrated under d pressure to give crude (6-(2—(aminomethyl)—7- chlorobenzofuran-S-yl)fluoropyridin—2-yl)(morpholino)methanone (143), which was used without further purification in the next step. Yield (130 mg, 100%). LCMS: m/z 390.0 [M+H]+; 1R = 1.29 min.
Synthesis of (E)(6-aminopyridin—3—yl)—N—((7-chloro—5—(5-fluoro-6—(morpholine- 4-carbonyl)pyridin—2—yl)benzofuran—2-yl)methyl)acrylamide (581): (6—(2-(Aminomethyl) chlorobenzofuran-S-yl)—3-fluoropyridin—2—yl)(morpholino)methanone (143) (370 mg, 0.95 mmol) was dissolved in DMF (8 mL) and (E)(6—aminopyridin—3-yl)acrylic acid (7; 156 mg, 0.95 mmol) was added at 0 °C (ice bath). EDCI (274 mg, 1.42 mmol) and HOBt hydrate (192 mg, 1.42 mmol) were added to this reaction mixture followed by DIPEA (245 mg, 1.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NazSO4, and concentrated under reduced pressure to give the crude t, which was purified by pre-HPLC to give 33 mg of (E)(6-aminopyridinyl)-N-((7-chloro—5—(5— fluoro—6-(morpholinecarbonyl)pyridinyl)benzofuranyl)methyl)acrylamide (581) as white solid. Yield (83%). 1H NMR (400 MHz, DMSO-dfi) 5 8.84 (t, J: 6 Hz, 1H), 8.31-7.94 (m, 8H), 7.43 (d, J= 16 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J= 9 Hz, 1H), 6.59 (d, J: 16 Hz, 1H), 4.63 (d, J= 6 Hz, 2H), 3.71 (s, 4H), .56 (m, 2H), 3.35—3.32 (m, 2H). LCMS: m/z 536.2 [M+H]+, rR=1.21 min.
Synthesis of (E)-N-(4-(2-((3-(6-aminopyridinyl)acrylamido)methyl) chlorobenzofuran-S-yl)phenyl)morpholinecarboxamide (582). —168- / My!2 lei BucHN / omN—< BocHN / ammo —> 000"sz °MNHH Pd(dppf)C|2,K2003 DMAP.Et3N, )7" o 1.4-di0xane, H20 cu DOM \——/ CI 0 19 144 145 W0" 0 / \ T" We" N / - |\\ ~H m H 00 O / NH DOM />—N —,o HZN N EDCI H08: DIF'EA DMF . , . )f—Nmo Cl o 146 582 Synthesis of tert-butyl (5-(4-aminophenyl)—7—chlorobenzofuran y1)methylcarbamate (144): A mixture of tert-butyl (5-bromochlorobenzofuran y1)methy1carbamate (19) (360 mg, 1 mmol), ,5,5—tetramethy1-1,3,2-dioxaborolan—2— yl)benzenamine (219 mg, 1 mmol), Pd(dppf)C12 (82 mg, 0.1 mmol) and K2C03 (276 mg, 2 mmol) in 10 mL of e and 1 mL of H20 was degassed. The reaction e was heated at 100 0C under nitrogen atmosphere for 1 h. After cooling down to room temperature, the mixture was poured into iced water (10 mL), extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NazSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (25% EtOAc/petroleum ether) to give 300 mg of tert—butyl (5-(4— aminophenyl)—7—chlorobenzofuran-2—y1)methy1carbamate (144) as yellow solid. Yield: (81%).
LCMS: m/Z 373.1 [M+H]+, rR= 1.66 min.
Synthesis of tert—butyl (7-chloro—5—(4-(morpholine carboxamido)pheny1)benzofuranyl)methy1carbamate (145): A mixture of lert—butyl (5—(4- aminophenyl)—7-chlorobenzofuran-2—yl)methylcarbamate (144) (300 mg, 0.8 mmol) was dissolved in 15 mL of CHzClz. Morpholine—4—carbony1 chloride (120 mg, 0.8 mmol), DMAP (98 mg, 0.8 mmol) and Et3N (162 mg, 1.6 mmol) were added at room ature. The reaction e was refluxed for 48 h. After cooling down to room temperature, the on mixture was washed with H20 (15 mL), brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (50% EtOAc / petroleum ether) to give 280 mg of tert-butyl (7-chloro (4-(morpholine—4—carboxamido)phenyl)benzofuranyl)methylcarbamate (145) as yellow solid. Yield: (72%). LCMS: m/z 486.2 [M+H]+, tR =2.30 min.
Synthesis ofN—(4—(2-(aminomethy1)chlorobenzofuran-5—y1)pheny1)morpholine— 4-carboxamide (146): utyl (7—chloro—5—(4—(morpholine—4— ~169— carboxamido)phenyl)benzofuran—2—y1)methylcarbamate (145) (280 mg, 0.58 mmol) was dissolved in CH2C12 (10 mL). TFA (1 mL) was added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The on mixture was concentrated under reduced pressure to give 230 mg of the crude N—(4-(2-(aminomethyl)—7- chlorobenzofuranyl)phenyl)morpholine-4—carboxamide (146), which was used without further purification in the next step. Yield: (100%). LCMS: m/z 386.1 [M+H]+; tR = 1.22 min. sis of (E)-N-(4-(2-((3-(6—aminopyridinyl)acrylamido)methyl)—7— chlorobenzofuran-S-yl)phenyl)morpholinecarboxarnide (582): N—(4-(2-(aminomethyl)—7- chlorobenzofuran-S~yl)phenyl)morpholinecarboxamide (146) (220 mg, 0.57 mmol) was dissolved in DMF (8 mL) and (E)(6-aminopyridinyl)acrylic acid (94 mg, 0.57 mmol) was added at 0 °C (ice bath). EDCI (163 mg, 0.85 mmol) and HOBt hydrate (115 mg, 0.85 mmol) were added to this reaction mixture followed by DIPEA (147 mg, 1.14 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was poured into water (20 mL) and ted with EtOAc (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by prep— HPLC to give 53 mg of (E)—N—(4—(2-((3-(6-aminopyridiny1)acry1amido)methy1) chlorobenzofuran-S-y1)phenyl)morpholine-4—carboxamide (582) white solid. Yield: (17%). 1H NMR (400 MHz, é) 8 8.85 (t, J: 6 Hz, 1H), 8.67 (s, 1H), .06 (m, 4H), 7.81 (s, 1H), 7.67-7.56 (m, 5H), 7.44 (d, J= 16 Hz, 1H), 6.99 (d, J: 9 Hz, 1H), 6.88 (s, 1H), 6.61 (d, J: 16 Hz, 1H), 4.61 (d, J: 6 Hz, 2H), 3.67-3.58 (m, 4H), .41 (m, 4H).
LCMS: m/z 532.2 [M+H]+, rR=1.23 min.
Synthesis of (E)—3-(6-aminopyridin-3—yl)-N-((7-chloro-S-(S-(morpholine carb0nyl)pyrimidinyl)benzofuran-Z—yl)methyl)acrylamide (583). >%01 O—/ O/B NHBDC \ 0H\/—— The on e was cooled down to room temperature, diluted with iced water (50 mL), extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under d pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 370 mg of ethyl 2-(2-((tert—butoxycarbonylamino)methyl)chlorobenzofuran—5-yl)pyrimidine carboxylate (147) as white solid. Yield (35%). LCMS: m/z 432.1 [M+H]+, tR= 2.02 min.
Synthesis of ethyl 2-(2-(aminomethyl)chlorobenzofuranyl)pyrimidine carboxylate (148): Ethyl 2-(2-((tert-butoxycarbonylamino)methyl)chlorobenzofuran-S- yl)pyrimidinecarboxy1ate (147) (370 mg, 0.86 mmol) was dissolved in CHzClz (5 mL).
TFA (0.5 mL) was added at 0 °C (ice bath). The reaction e was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude ethyl 2-(2-(aminomethyl)chlorobenzofuran—5-yl)pyrimidine carboxylate (148), which was used without further purification in the next step. Yield (290 mg, 100%). LCMS: m/z 3320 [M+H]; tR—— 1.98 min. sis of (E)—ethy1 2-(2-((3-(6-amin0pyridiny1)acry1amido)methyl)~7— chlorobenzofuran-S-y1)pyrimidinecarboxylate (149): Ethyl 2—(2—(aminomethyl)—7— —171— chlorobenzofuran—5~yl)pyrimidinecarboxylate (148) (150 mg, 0.34 mmol) was dissolved in DMF (5 mL) and (6-aminopyridinyl)acrylic acid (55 mg, 0.34 mmol) was added at 0 OC (ice bath). HATU (155 mg, 0.41 mmol) was added followed by DIPEA (87 mg, 0.68 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction e was poured into an iced—water (10 mL), ted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure to give the crude product, which was d by silica gel chromatography (50% EtOAc/petroleum ether) to afford 120 mg of (E)-ethy1 2-(2-((3 -(6-aminopyridin-3 -yl)acrylamido)methyl)chlorobenzofuran yl)pyrimidine-5~carboxylate (149). Yield (75%). LCMS: m/z 478.2 [M+H]+, IR = 1.92 min.
Synthesis of (E)(2-((3-(6—aminopyridinyl)acrylamido)methyl)-7— chlorobenzofuran-S~yl)pyrimidine—5-carboxylic acid (150): (E)-ethyl 2-(2-((3-(6- aminopyridin—3-yl)acrylamido)methyl)—7-chlorobenzofuranyl)pyrimidine—5—carboxylate (149) (120 mg, 0.25 mmol) was dissolved in THF (4 mL). LiOH (32 mg, 0.75 mmol) and water (1 mL) were added at room temperature. The reaction mixture was d at room temperature for 2 h. The reaction mixture was cooled down to 0 °C (ice bath), 2N HCl aqueous solution was added and adjusted to pH = 6. The mixture was extracted with EtOAc (20 mL X 3). The ed organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure to afford 100 mg of (E)(2-((3-(6- aminopyridin—3—yl)acrylamido)methyl)—7—chlorobenzofuran—5—yl)pyrimidinecarboxylic acid (150). Yield (89%). LCMS: m/z 450.1 [M+H]+, 1R: 1.28 min.
Synthesis of (E)(6-aminopyridin—3-yl)-N-((7-chloro—5-(5-(morpholine—4— carbonyl)pyrimidin—2-yl)benzofuranyl)methyl)acrylamide (583): (E)—2-(2-((3—(6- aminopyridin—3-yl)acrylamido)methyl)chlorobenzofuran—5-yl)pyrimidine—5—carboxylic acid (150) (50 mg, 0.11 mmol) was ved in DMF (3 mL). Morpholine (10 mg, 0.11 mmol), HATU (84 mg, 0.22 mmol) and DIPEA (28 mg, 0.22 mmol) were added at room temperature. The reaction mixture was stirred at room temperature further for 2 h. 15 mL of EtOAc and 10 mL of H20 were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (15 mL X 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous NaZSO4, concentrated and ed by Prep-HPLC to afford 15 mg of (E)(6—aminopyridin—3-yl)-N—((7-chloro-5—(5-(morpholine carbonyl)pyrimidin—2-yl)benzofuranyl)methyl)acrylamide (583). Yield (26%). 1H NMR -l72- (400 MHZ, DMSO—d6) 8 9.02—8.97 (m, 2H), 8.65 (t, J: 4 Hz, 2H), 8.39 (d, J: 2 Hz, 1H), 8.08 (d, J: 2 Hz, 1H), 7.64-7.59 (m, 1H), 7.36 (d, J: 16 Hz, 1H), 7.01 (s, 1H), 6.50-6.39 (m, 4H), 4.61 (d, J: 6 Hz, 2H), 3.73—3.43 (m, 8H). LCMS: m/z 519.2 [M+H]+, IR: 1.62 min. sis of (E)(6-aminopyridinyl)-N—((7-chloro-5—(5—(4-methylpiperazine—1- carbonyl)pyridinyl)benzofuranyl)methyl)acrylamide (584). 0 0%)?"mNHBoc Cl N_ O HO / N Cl 43 \' o \ / EDCIHOBt N Br Pdwppm'z K2003 B0°HN \ DIPEA CH20|2 151 152 dioxane, H20 153 O Cl "Ck/T11"!INNH2/ \ N~ o TFA 2 o \ / CHzc'z HZN \ O EDCI HOBt 70 154 N\ DIPEA DMF Synthesis of (6-bromopyridiny1)(4-methylpiperazin-l-yl)methanone (152): 6- icotinic acid (151) (500 mg, 2.5 mmol) was ved in CH2C12 (15 mL) and l- methylpiperazine (274 mg, 2.7 mmol) was added at 0 °C. EDCI (573 mg, 3 mmol) and HOBt (402 mg, 3 mmol) were added to this reaction mixture at 0 OC followed by DIPEA (642 mg, 5 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was transferred into water (20 mL) and ted with CH2C12 (30 mL X 3). The combined c layers were washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give (6- bromOpyridin-3—yl)(4-methylpiperazin—l-yl)methanone (152). Yield (400 mg, 52%). LCMS: m/z 285.1 M+H]+; IR = 1.35 min.
Synthesis of tert—butyl (7-chloro—5-(5-(4-methylpiperazine—1—carbonyl)pyridin~2- yl)benzofuran—2-yl)methylcarbamate (153): tert-Butyl (7-chloro(5-(4-methylpiperazine-l- carbonyl)pyridinyl)benzofuranyl)methylcarbamate as synthesized using the indicated reagents according to General Procedure 2. Yield (47%). LCMS: m/z 485.2 [M+H]+; m = 1.26 min.
Synthesis of (6-(2-(aminomethy1)—7-chlorobenzofuran—5~yl)pyridin-3—yl)(4- methylpiperazin—1-yl)methanone (154): (6-(2-(aminornethyl)—7—chlorobenzofuran—S— yl)pyridin—3—yl)(4—methylpiperaziny1)methanone (154) was synthesized using the indicated -l73- reagents according to General Procedure 3. Yield (100%). LCMS: m/z 385.1 [M+H]+; tR = 1. 45 min.
Synthesis of (E)(6-aminopyridin—3-yi)-N—((7-chloro(5-(4-rnethylpiperazine- l-carbonyl)pyridinyl)benzofuran-2—yl)methyl)acrylamide (584): (E)~3-(6—Arninopyridin—3— y1)-N-((7-chloro(5—(4—methylpiperazine-1 -carbonyl)pyridinyl)benzofuran—2- yl)methyl)acrylamide (584) was synthesized using the indicated reagents according to General Procedure 1. Yield (52%). 1H NMR (400 MHz, DMSO-d6) 6 8.72-8.64 (m, 2H), 8.35 (s, 1H), .07 (m, 3H), 7.97-7.90 (m, 1H), 7.66-7.60 (m, 1H), 7.36 (d, J= 16 Hz, 1H), 6.95 (s, 1H), 6.51-6.39 (m, 4H), 4.60 (d, J= 6 Hz, 2H), 3.64 (s, 4H), 2.41-2.29 (m, 4H), 2.20 (s, 3H). LCMS: m/z 531.2 [M+H]+, 5R = 1.05 min Synthesis of (6-amin0pyridin-3—yl)—N—((5—(5-(4,4-diflu0r0piperidine carbonyl)pyridin-Z-yl)(triflu0romethyl)benzofuran-2—yl)methyl)acrylamide (585).
F30 F30 N.— o HNC> Synthesis of (E)(6-amin0pyridinyl)—N—((7-chloro-S-(S-(piperazine carbonyl)pyrimidinyl)benzofuranyl)methyl)acrylamide (586).
CI CI N— O N— O H N HN\_/N—- 2 H2N / O \ :/>_/< / j i 0 \ :/>_/< H H N 0" N N \ N \ HATU, DIPEA, DMF N \ N \ / / <55 0 o N 150 586 \ (ID-3—(6-Aminopyridin—3-yl)-N-((7-chloro—5-(5-(piperazinecarbony1)pyrimidin- 2-yl)benzofuranyl)methyl)acrylamide (5 86) was synthesized using the indicated reagents ing to General Procedure 4. Yield: 17%. 1H NMR (400 MHz, DMSO-dg) 6 8.97 (s, 2H), 8.66 (s, 2H), 8.39 (s, 1H), 8.09 (s, 1H), 7.62 (d, J: 8 Hz, 1H), 7.36 (d, J: 16 Hz, 1H), —174— 7.01 (s, 1H), 6.52-6.38 (m, 4H), 4.61 (d, J: 5 Hz, 2H), .60 (m, 2H), 3.49-3.42 (m, 2H), 2.42-2.29 (m, 4H), 2.21 (s, 3H). LCMS: m/z 532.3 [M+H]+, tR= 1.61 min.
Synthesis of (6-aminopyridinyl)-N—((5-(4-(3~fluoromethylazetidine carbonyl)phenyl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (587).
F30 F30 O: .HN:>(H<:I O a o O O HATU DIPEA DMF N\ N \ O i 537 I: (E)-3—(6—Aminopyridinyl)-N-((5-(4—(3—fluoromethylazetidine- l - yl)phenyl)-7—(trifluoromethyl)benzofuran—2-yl)methyl)acrylamide (587) was synthesized using the indicated reagents according to l procedure 4. Yield (1 8%). 1H NMR (400 MHz, DMSO—d6) 8 8.67 (t, J: 6 Hz, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.91-7.75 (m, 5H), 7.66~7.61 (m, 1H), 7.36 (d, J: 16 Hz, 1H), 6.95 (s, 1H), 6.51—6.39 (m, 4H), 4.62 (d, J: 6 Hz, 2H), 4.57-4.07 (m, 4H), 1.61 (d, J: 22 Hz, 3H). LCMS: m/z 553.2 , IR— l.39 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-chloro~5-(5-fluoro-4—(m0rpholine carbonyl)pyridin-2—yl)benzofuranyl)methyl)acorylamide (588). 6%: BocHngi:§< O BocHN TFA H2N / CH20'2 F Pd(()Clgdppf choa \N / dloxane H20 CI EDCI HOBt DIPEA DMF ""2 W Synthesis of tert-butyl (7-chloro(5-fluoro(morpholinecarbony1)pyridin-2— yl)benzofuran-2—yl)methylcarbamate (155): tert-Butyl (7—chloro(5-fluoro(morpholine- 4-carbonyl)pyridiny1)benzofuranyl)methylcarbamate (155) was synthesized using the indicated reagents according to General Procedure 2. Yield: 44%. LCMS: m/z 490.2 [M+H]+, rR = 1.85 min.
Synthesis of (2—(2—(aminomethyl)-7—chlorobenzofuran—5—yl)—5—fluoropyridin yl)(morpholino)methanone (156). (2—(2—(Aminomethyl)—7—chlorobenzofuran-S-yl)-5— fluoronvridin—4-yl)(morpholino)methanone (156) was synthesized using the indicated -l75- reagents according to l Porcedure 3. Yield: 100%. LCMS: m/z 390.1 [M+H]+; tR = 1.30 min.
Synthesis of (E)(6-aminopyridin—3-y1)-N-((7-chloro(5-fluoro(morpholine- 4-carbonyl)pyridin—2-yl)benzofuran—2-yl)methyl)acrylamide (588): (E)(6-Aminopyridin~3— yl)-N—((7—chloro-5—(5—fluoro—4-(morpholine—4—carbonyl)pyridin—2-yl)benzofuran-2— yl)methyl)acrylamide (5 88) was synthesized using the indicated reagents according to General Procedure 1. Yield: 23%. 1H NMR (400 MHz, DMSO'dG) 5 8.86 (t, J = 6 Hz, 1H), 8.77 (s, 1H), 8.37-8.06 (m, 7H), 7.44 (d, J= 16 Hz, 1H), 6.98 (d, J= 9 Hz, 1H), 6.95 (s, 1H), 6.61 (d, J: 16 Hz, 1H), 4.63 (d, J= 6 Hz, 2H), 3.78-3.48 (m, 8H). LCMS: m/z 536.1 [M+H]+, r2 = 1.28 min.
Synthesis of (6—aminopyridinyl)-N~((7—chlor0-5—(5—(piperazine—1- carbonyl)pyridinyl)benzofuran—Z-yl)methyl)acrylamide (589).
NHBoc i?—8:? QLOB NHB°C 12' K; Pd(PPh3)C|2 OH m.
NH3 H2001 Cul EtsN Pd(dppf)C|2 Cl AcOK dioxane 157 158 160 ——»B°CHN Pd(dppf)C|2 K2C03 CH2CI2 HATU, DIPEA DMF dioxane H2O N_ O H N2 L‘OHI (I t} ‘1 \ / —* / / THF, H20 0 163 164 HATU, m DIPEA DMF N_ O "\ /O" \539 QH :3 N Boc sis of 4-Bromochloroiodophenol (158): 4-Bromochloro enol (158) was synthesized using the indicated reagents similar procedure of intermediate (1 8). Yield (63%).
Synthesis of tert—Butyl (5-bromo—7-chlorobenzofuranyl)methylcarbamate ( 159): tert—Butyl (5-bromochlorobenzofuran—2-yl)methylcarbamate (159) was synthesized —176— using r procedure of ediate (19). Yield (75%). LCMS: m/Z 306.0 [M—55]+; IR = 2.07 min.
Synthesis of tert—Butyl (7-chloro(4,4,5,5-tetramethyl-l,3,2-dioxaborolan—2— yl)benzofuran—2—yl)methylcarbamate (160): tert—Butyl (7~chloro—5~(4,4,5,5-tetramethyl-1,3,2~ dioxaboroIanyl)benzofuranyl)methylcarbamate (160) was sized using the indicated reagents similar procedure of intermediate (20). Yield (92%). LCMS: m/z 352.1 [M-55]+; 1R = 2.15 min.
Synthesis of methyl 6-(2-((tert-butoxycarbonylamino)methyl)—7- chlorobenzofuran-S-yl)nicotinate (161): Methyl 6-(2-((tert-butoxycarbonylamino)methyl) chlorobenzofuran—5-yl)nicotinate (161) was synthesized using the indicated reagents according to General Procedure 2. Yield (96%). LCMS: m/z 417.1 [M+H]+; IR = 2.16 min.
Synthesis of methyl 6—(2—(aminomethyl)—7-chlorobenzofuran—5—yl)nicotinate (162): Methyl aminomethyl)—7-chlorobenzofuran—5—yl)nicotinate (162) was synthesized using the ted reagents according to General Procedure 3. Yield (100%). LCMS: m/z 317.1 [M+H]+; 1R = 1.83 min.
] Synthesis of (E)—methyl 6~(2—((3—(6—aminopyridinyl)acrylamido)methyl)—7— chlorobenzofuran—5—yl)nicotin'ate (163): (E)-methyl 6-(2-((3—(6—aminopyridin—3— yl)acrylamido)methyl)-7—chlorobenzofuranyl)nicotinate (163) was synthesized using the ted reagents according to General Procedure 4. Yield (89%). LCMS: m/z 463.1 [M+H]+; 1R = 1.81 min.
Synthesis of (E)—6—(2-((3—(6-aminopyridin—3-yl)acrylamido)methyl)—7— chlorobenzofuranyl)nicotinic acid (164): (E)—6-(2—((3-(6-Aminopyridin—3- yl)acrylamido)methyl)—7-chlorobenzofuranyl)nicotinic acid (164) was synthesized using the indicated reagents according tosimilar procedure of ediate (55). Yield (78%).
LCMS: m/z 449.1 [M+H]+; zR = 1.25 min.
Synthesis of (E)-tert-butyl 4-(6-(2-((3-(6-aminopyridinyl)acrylamido)methyl)- 7-chlorobenzofuranyl)nicotinoyl)piperazinecarboxylate (1 65): (E)-tert-Butyl 4-(6-(2- ((3-(6-aminopyridinyl)acrylamido)methyl)—7-chlorobenzofuran—5- otinoy1)piperazine~1-carboxylate (165) was synthesized using the indicated reagents according to General Procedure 4. Yield (37%). LCMS: m/z 617.2 [M+H]+; IR = 1.70 min Synthesis of (E)—3—(6—aminopyridin—3-y1)—N—((7-chloro—5—(5—(piperazine carbonyl)pyridin~2-yl)benzofuran—2—yl)methyl)acrylamide (5 89): (E)—3 —(6—aminopyridin-3 — —l77— yl)-N—((7—chloro—5 —(5 razine— 1 -carbonyl)pyridin—2-yl)benzofuran—2- yl)methy1)acrylamide (589) was sized using the indicated reagents according to General Procedure 3. Yield (61%). 1H NMR (400 MHz, DMSO-d6) 5 8.68—8.62 (m, 2H), 8.36 (s, 1H), 8.17-8.08 (m, 4H), 7.93—7.91 (m, 1H), .60 (m, 1H), 7.35 (d, J: 16 Hz, 1H), 6.95 (s, 1H), 6.49-6.40 (m, 4H), 4.60 (d, J: 6 Hz, 2H), 3.58—3.56 (m, 2H), 2.76—2.65 (m, 6H). LCMS: m/z 517.2 [M+H]+; 1R = 1.50 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(piperazinecarb0nyl)pyrimidin yl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (590). 8p i::—/C'—<\ NW0N— o 80‘ 0 BocHN BocHN \ :34: Pd(,dppf)Clz C52C03 ‘\ CHzclz ’\ e, H20 166 HZN 167 N// OH HATU, DlPEA, DMF "IQ/Ag"HE‘QS—{ZH HzoHOH, THF HN@VyHHE‘QZH \_‘/ HATU, DIPEA, DMF HZN / TFA, CH20|2 N\ H O\ \NNj>_/ Synthesis of ethyl 2-(2-(aminomethyl)—7-(trifluoromethyl)benzofiiran yl)pyrimidine—5-carboxylate (167): Ethyl 2-(2-((tert—butoxycarbonylamino)methyl)-7— (trifluoromethyl)benzofuranyl)pyrimidinecarboxylate (166) (0.75 g, 1.6 mmol) was dissolved in CH2C12 (20 mL). TFA (5 mL) was added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude ethyl 2-(2-(aminomethyl) oromethyl)benzofuran—5—yl)pyrimidine—5-carboxylate (167), which was used Without further purification in the next step Yield (06 g, 100%). LCMS: m/z 366.1 ; IR = 1.31 min. sis of (E)-ethyl 2—(2—((3—(6-aminopyridin—3—yl)acry1amido)methyl)-7— (trifluoromethyl)benzofuran—5-yl)pyrimidine—5«carboxylate (168): Ethyl 2-(2-(aminomethyl)- 7-(trifluoromethyl)benzofuranyl)pyrimidine—5—carboxylate (167) (0.6 g, 1.6 mmol) was dissolved in DMF (15 mL) and (6—aminopyridin—3-yl)acrylic acid (0.3 g, 1.8 mmol) was added at 0 °C (ice bath). HATU (0.71 g, 1.8 mmol) was added followed by DIPEA (0.4 g, 3.1 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction e was poured into an ater (50 mL), extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NazSO4, concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to afford 700 mg of (E)-ethyl 2-(2-((3 -(6-aminopyridin—3-yl)acrylamido)methyl)—7-(trifluoromethy1)benzofiiran- -yl)pyrimidinecarboxylate (168). Yield (88%). LCMS: m/z 512.2 , tR= 1.36 min.
Synthesis of (E)(2-((3-(6-aminopyridinyl)acrylamido)methyl) (trifluoromethyl)benzofuran-5~y1)pyrimidine—5-carboxylic acid (169): (E)-ethy1 2-(2—((3—(6- aminopyridinyl)acrylamido)methyl)(trifluoromethyl)benzofuran—5-yl)pyrimidine carboxylate (168) (630 mg, 1.2 mmol) was dissolved in THF (10 mL). LiOH (150 mg, 3 mmol) and water (2.5 mL) were added at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled down to 0 °C (ice bath), 2N HCl solution was added and adjusted to pH = 6. The mixture was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , concentrated under reduced pressure to afford 550 mg of (E)—2-(2—((3-(6- —179— aminopyridinyl)acrylamido)methyl)-7—(trifluoromethyl)benzofuranyl)pyrimidine carboxylic acid (169). Yield (92%). LCMS: m/z 484.1 [M+H]+, IR: 1.22 min.
] Synthesis of (E)-tert—butyl 4-(2-(2-((3-(6-aminopyridin—3-yl)acrylamido)methyl)— 7—(trifluoromethyl)benzofuranyl)pyrimidinecarbonyl)piperazine— 1 -carboxylate (1 70): (E)(2-((3—(6-aminopyridinyl)acrylamido)methy1)(trifluoromethyl)benzofuran-5 - yl)pyrimidinecarboxylic acid (169) (20 mg, 0.04 mmol) was dissolved in DMF (3 mL). tert-Butyl piperazine-l-carboxylate (8 mg, 0.04 mmol), HATU (30 mg, 0.08 mmol) and DIPEA (10 mg, 0.08 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The crude mixture was purified by Prep-HPLC t workup to afford 20 mg of (E)—tert—butyl 4—(2-(2—((3-(6—aminopyridin—3— yl)acrylamido)methyl)~7—(trifluoromethyl)benzofuran—5-y1)pyrimidine—5- carbonyl)piperazine-1—carboxylate (170). Yield (60%). LCMS: m/z 652.7 [M+H]+, 1R: 1.89 min.
Synthesis of (E)—3-(6—aminopyridin—3-yl)—N—((5—(5~(piperazine carbonyl)pyrimidin—2—yl)—7—(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (590): (E)— tert—butyl 4-(2—(2-((3-(6-aminopyridin—3—yl)acrylamido)methyl)—7— oromethyl)benzofuran—5-y1)pyrimidine—5-carbonyl)piperazine— 1 —carboxylate (l 70) (20 mg, 0.03 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added at 0 OC (ice bath).
The on mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude t, which was purified by Prep—HPLC to afford 18 mg of (E)(6-aminopyridinyl)—N—((5—(5- (piperazine- l —carbonyl)pyrimidin—2—yl)(trifluoromethyl)benzofuran—2— hyl)acrylamide (590) as white solid. (90% yield). 1H NMR (400 MHz, DMSO'dé) 8 9.07—8.97 (m, 4H), 8.65—8.67 (m, 3H), 8.10-8.07 (m, 1H), 7.64-7.60 (m, 1H), 7.39—7.32 (m, 1H), 7.07 (s, 1H), 6.50-6.39 (m, 3H), 4.67-4.59 (m, 2H), 3.16-3.09 (m, 4H), 1.35—1.13 (m, 4H). LCMS: m/z 552.2 ; IR = 1.48 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-chloro(5-(4,4-difluoropiperidine-l- carbonyl)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (591).
HZNmHfl—WOH—w»N— 0 F?©NH N \ N \ / HNmNW o HATU, DIPEA, DMF —l80- (E)-3~(6—aminopyridinyl)-N-((7-chloro(5-(4,4—difluoropiperidine-1— carbonyl)pyridinyl)benzofi1ranyl)methyl)acrylamide (591) was synthesized using the indicated reagents according to General Procedure 4. Yield (16%). 1H NMR (400 MHz, DMSO-dé) 5 8.75 (s, 1H), 8.66-8.63 (m, 1H), 8.37 (d, J: 2 Hz, 1H), 8.17-8.03 (m, 3H), 8.01-7.98 (m, 1H), 7.63-7.61 (m, 1H), 7.36 (d, J: 16 Hz,1H), 6.95 (s, 1H), 6.49-6.41 (m, 4H), 4.61 (d J=‘6 Hz, 2H), .49 (m, 4H), 2.08—2.07 (m, 4H). LCMS: m/z 552.2 ; m = 165 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-methoxy(4-(morpholine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (592).
Nk©\ ’0 Br —0 O B‘ ,2 K, Pd(PPh3)C|2 O / \ —> 0 31' > NH3' H20 CuI,Et3N BOCHN \ Pd(dppf)C|2, /° K2003, 171 172 dioxane, H HN ______._____, BocHN CH2C|2 0:00 Q O EDCI HOBtHDIPEA DMF 2 qN o O O N\ N \ / ® 0 0 Synthesis of 4-bromoiodomethoxyphenol (171): 4-Bromomethoxyphenol (1; 14.5 g, 71.8 mmol) was dissolved in 500 mL ofNH4OH. A solution KI (36.0 g, 220 mmol) and 12 (18.2 g, 71.8 mmol) in 120 mL of H20 was added to this mixture and the on mixture was stirred at 30 0C for 4 h. HCl was added to the reaction mixture till pH = 7. The mixture was extracted with EtOAc (200 mL X 3). The ed c layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 12.0 g of 4-bromoiodomethoxyphenol (171) as a yellow solid (yield: 52%). LCMS: tR = 1.83 min.
Synthesis of tert-butyl (5-bromo—7-methoxybenzofi1ranyl) methylcarbamate (172): A mixture of 4-bromoiodo—6-methoxyphenol (171) (12.0 g, 36.6 mmol), tert—butyl propyny1carbamate (6.84 g, 44.1 mmol), Pd(PPh3)2C12(1.56 g, 3.66 mmol) and CuI (695 mg, 3.66 mmol) in 100 mL of Et3N was stirred at 80 0C under nitrogen atmosphere for 2 h.
After cooling to room temperature, the mixture was poured into iced water and extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over ous Na2804, and concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 6.7 g of tert- butyl (5-bromomethoxybenzofuranyl) carbamate (172) as a white solid (yield: 51%). LCMS: m/z 380.0 [M+Na]+, rR = 1.92 min.
Synthesis of utyl (7-methoxy(4-(morpholine carbonyl)pheny1)benzofuran—2—yl)methylcarbamate (173): A mixture of utyl (5-bromo- 7-rnethoxybenzofurany1) carbamate (172) (200 mg, 0.56 mmol), morpholino(4- (4,4,5,5—tetramethyl—1,3,2—dioxaborolanyl)phenyl)methanone (213 mg, 0.67 mmol), Pd(dppi)C12 (44 mg, 0.06 mmol) and K2C03 (155 g, 1.1 mmol) in 6 mL of dioxane and 0.6 mL of H20 was stirred at 100 0C under nitrogen atmosphere for 2 h. The mixture was extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (25%-50% EtOAc/petroleum ether) to give 140 mg of tert—butyl (7-methoxy(4-(morpholine—4— carbonyl)phenyl)benzofuran—2-y1)methylcarbamate (173) as a yellow solid. Yield (95%).
LCMS: m/z 467.1 [M+H]+, tR= 1.68 min.
] Synthesis of (4-(2-(aminomethyl)—7-methoxybenzofuran yl)phenyl)(morpholino)methanone (174): tert—Butyl (7-methoxy(4-(rnorpholine carbonyl)phenyl)benzofurany1)methy1carbamate (173) (140 mg, 0.3 mmol) was dissolved in CHzClz (5 mL). TFA (1 mL) was added at 0 °C. The reaction mixture was stirred at room ature for 2 h, and concentrated under reduced pressure to give the crude (4-(2- (aminomethyl)methoxybenzofuran—5-yl)phenyl)(morpholino)methanone (174), which was used without further purification in the next step. Yield (100%). LCMS: m/z 367.2 [M+H]+; IR = 1.17 min.
Synthesis of (E)-3—(6—aminopyridin—3-yl)-N—((7-methoxy-5—(4—(morpholine-4— carbonyl)phenyl)benzofuran—2-yl)methyl)acry1amide (592): (4-(2-(Aminomethyl) methoxybenzofuran—5—y1)phenyl)(morpholino)methanone (174) (110 mg, 0.3 mmol) was dissolved in DMF (3 mL) and (E)(6-aminopyridin—3-y1)acry1ic acid (74 mg, 0.45 mmol) was added at 0 °C. EDCI (86 mg, 0.45 mmol) and HOBt (61 mg, 0.45 mmol) were added to this reaction mixture at 0 °C followed by DIPEA (77 mg, 0.6 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The crude mixture was purified by Prep-HPLC to afford (E)—3—(6-aminopyridin—3—yl)—N—((7-methoxy(4- (morpholinecarbonyl)phenyl)benzofurany1)methy1)acry1amide (592) (5 mg, yield: 3%). 1H NMR (400 MHz, CD3OD) 6 8.18 (d, J= 9 Hz, 1H), 8.05 (s, 1H), 7.76 (d, J= 8 Hz, 2H), 7.55-7.42 (m, 4H), 7.13 (s, 1H), 7.03 (d, J= 9 Hz, 1H), 6.77 (s, 1H), 6.64 (d, J= 16 Hz, 1H), 4.68 (s, 2H), 4.06 (s, 3H), 3.82-3.53 (m, 8H). LCMS: m/z 513.2 [M+H]+, IR: 1.18 min.
Synthesis of (E)(6-amin0pyridinyl)-N—((5—(5—(m0rph01inecarb0nyl)pyrimidin (triflu0r0methyl)benzofuran—Z-yl)methyl)acrylamide (593).
F30 F30 N_ o o /—\ / \ O NH 0 \ / < LiOH H20 u — N 0 . THF, H20 HATU, DIPEA, DMF 166 5%OH ——-—-—> NHBoc NHBoc NHBoc 176:>%Q HO H2" / F3C \:/>—/(N— 0 l N\ OH N— 0 / H2N / TFA o o N N I H \:/>—/( \ N\ N \ CH Cl HzN 2 2 L / OBt,DlPEA,DMF LNT) 177 0 O 593 0 ] Synthesis of 2-(2-((rert—butoxycarbonylamino)methyl) (trifluoromethyl)benzofuranyl)pyrimidinecarboxylic acid (175 ): Ethyl (tert- butoxycarbonylamino)methyl)(trifluoromethyl)benzofuran—5-yl)pyrimidinecarboxylate (166) (300 mg, 0.82 mmol) was dissolved in THF (6 mL), LiOH (103 mg, 2.46 mmol) and water (1.5 mL) was added to this mixture. The reaction mixture was stirred at room temperature for 2 h. 1N HCl solution was added and adjusted to pH = 3. 250 mg of 2-(2- ((tert-butoxycarbonylamino)methyl)(trifluoromethyl)benzofuranyl)pyrimidine carboxylic acid (175) was collected by filtration (90% yield). LCMS: m/z 43 8.1 [M+H]+; tR = 1.3min.
Synthesis of tert—butyl (5-(5-(morpholinecarbonyl)pyrimidin—2-yl) (trifluoromethyl)benzofuran—Z-yl)methylcarbamate (176): 2-(2-((tert- Butoxycarbonylamino)methyl)—7-(trifluoromethyl)benzofuran—5—yl)pyrimidine-5 -carboxylic acid (175) (200 mg, 0.46 mmol) was ved in DMF (3 mL). Morpholine (40 mg, 0.46 —l83— mmol), HATU (348 mg, 0.92 mmol) and DIPEA (119 mg, 0.92 mmol)) were added at room temperature. The reaction mixture was stirred at room temperature further for 2 h. 15 mL of EtOAc and 10 mL of H20 were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (15 mL X 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2804, concentrated and purified by silica gel chromatography (50% EtOAc/petroleum ether) to afford 70 mg of tert—butyl (5-(5- (morpholinecarbony1)pyrimidin—2-yl)—7—(trifluoromethyl)benzofuran yl)methylcarbamate (176). Yield (30%). LCMS: m/z 507.1 [M+H]+, tR = 1.84 min.
Synthesis of (2-(2-(aminomethyl)—7-(t1ifluoromethyl)benzofuran—5-yl)pyrimidin- morpholino)methanone (177): tert—Butyl (5—(5—(morpholine-4~carbonyl)pyrimidin yl)-7—(trifluoromethyl)benzofuran—2-yl)methylcarbamate (176) (70 mg, 0.14 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give crude (2-(2-(aminomethyl) (trifluoromethyl)benzofuran—5~yl)pyrimidin—5—yl)(morpholino)methanone (177), which was used without further purification in the next step (80 mg). Yield (100%). LCMS: m/z 407.1 [M+H]+, rR = 1.55 min.
Synthesis of (6-aminopyridin—3—yl)—N—((5—(5~(morpholine—4— yl)pyrimidin—2—yl)—7-(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (5 93): (2—(2— (Aminomethyl)—7-(trifluoromethyl)benzofi1ranyl)pyrimidin—5—yl)(morpholino)methanone (177) (20 mg, 0.05 mmol) was dissolved in DMF (5 mL) and (E)—3—(6—aminopyridin—3— yl)acrylic acid (9 mg, 0.05 mmol) was added at 0 °C. EDCI (14 mg, 0.075 mmol) and HOBt (10 mg, 0.075 mmol) were added to this reaction mixture at 0 °C ed by DIPEA (13mg, 0.10 mmol) dropwise. The reaction mixture was allowed to warm to room ature and stirred further for 18 h. The reaction mixture was purified by Prep-HPLC without workup to afford (E)(6-aminopyridin-3 -y1)-N-((5 -(5-(morpholine—4-carbonyl)py1imidinyl) (trifluoromethyl)benzofuranyl)methyl)acrylamide (593) (10 mg, yield: 36%). 1H NMR (400 MHz, CD3OD) 6 8.88-8.84 (m, 3H), 8.63 (s, 1H), 7.95 (s, 1H), .60 (m, 1H), 7.38 (d, J: 16 Hz, 1H), 6.86 (s, 1H), 6.50 (d, J: 9 , 6.37 (d, J: 16 Hz, 1H), 4.61 (s, 2H), 3.72-3.46 (m, 8H). LCMS: m/z 553.2 [M+H]+, tR= 1.57 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((5~(5-(4-methylpiperazine carbonyl)pyrimidinyl)—7-(triflu0romethyl)benzofuran—Z-yl)methyl)acrylamide (594).
—— N— /| H N N Oi:>:\N:>_-/<:H ——> N:>—/< / HATU DIPEA DMF o §:><\/ ] (E)-3 -(6-aminopyridin-3 -yl)-N-((5-(5-(4-methylpiperazinecarbonyl)pyrimidin— 2—y1)—7-(trifluoromethyl)benzofuranyl)methy1)acrylamide (594) was synthesized using the indicated reagents according to General Procedure 4. Yield (50%). 1H NMR (400 MHz, CD3OD) 8 8.84 (s, 3H), 8.62 (s, 1H), 7.95 (s, 1H), 7.67-7.60 (m, 1H), 7.38 (d, J= 16 Hz, 1H), 6.85 (s, 1H), 6.49 (d, J: 9 Hz, 1H), 6.37 (d, J= 16 Hz, 1H), 4.61 (s, 2H), 3.75-3.46 (m, 4H), 2.50—2.36 (m, 4H), 2.25 (s, 3H). LCMS: m/z 566.2 , IR: 1.55 min.
Synthesis of (E)(6-aminopyridinyl)—N-((5—(4—(piperidine—l-carbonyl)phenyl) uoromethyl)benzofuran-Z—yl)methyl)acrylamide (595).
HZN / I o N\ N N HATU DIPEA DMF \ / < > (E)—3—(6—aminopyridin—3 -((5-(4—(piperidine— l —carbony1)phenyl)—7— (trifluoromethy1)benzofuranyl)methyl)acrylamide (595) was synthesized using the indicated reagents according to General Procedure 4. Yield (79%). 1H NMR (400 MHz, DMSO—ds) 8 8.86 (t, J: 6 Hz, 1H), 8.30—7.77 (III, 8H), 7.55—7.39 (m, 3H), 7.01—6.90 (m, 2H), 6.60 (d, J: 15.8 Hz, 1H), 4.64 (d, J: 6 Hz, 2H), 3.65-3.54 (m, 4H), 1.69-1.45 (m, 6H).
LCMS: m/Z 549.3 [M+H]+; rR = 1.33 m Synthesis of (E)—3-(6—aminopyridin-3~yl)—N—((7-chlor0(4-(4,4-diflu0r0piperidine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (596). o F H N H N HCI HN 2 / 2 O / O F I H i N H OH —> N \ N \ N \ \ / / HATU. DIPEA, DMF o F (E)(6-aminopyridinyl)-N-((7-chloro(4-(4,4-difluoropiperidine carbonyl)phenyl)benzofurany1)methy1)acry1amide (596) was synthesized using the indicated reagents according to General ure 4. Yield (37 mg, 43% yield) as white solid. 1H NMR (400 MHz, DMSO-dg) 8 8.87 (t, J: 6 Hz, 1H), 8.34—8.07 (m, 4H), 7.92 (d, J = 2 Hz, 1H), 7.80 (d, J: 8 Hz, 2H), 7.74 (d, J: 2 Hz, 1H), 7.56 (d, J: 8 Hz, 2H), 7.45 (d, J =16 Hz, 1H), 6.99 (d, J= 9 Hz, 1H), 6.92 (s, 1H), 6.62 (d, J: 16 Hz, 1H), 4.63 (d, J: 6 Hz, 2H), .66 (m, 4H), 2.14-1.97 (m, 4H). LCMS: m/z 551.2 [M+H]+; tR = 1.31 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-chloro(4-(4~fluoropiperidine carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (598).
WHMOM/\~/ ""3 mwig HzNN 55 0H HATU DIPEA DMF (ED(6-aminopyridinyl)-N—((7-chloro—5-(4-(4-fluoropiperidine yl)phenyl)benzofuran—Z—yl)rnethyl)acrylamide (598) was synthesized using the indicated reagents according to l Procedure 4. Yield (32%).]H NMR (400 MHz, DMSO‘d6) 6 8.87 (t, J= 6 Hz, 1H), 8.36—8.06 (m, 4H), 7.94-7.70 (m, 4H), 7.56—7.40 (m, 3H), 7.03~6.89 (m, 2H), 6.62 (d, J: 16 Hz, 1H), 5.04-4.83 (m, 1H), 4.64 (t, J= 9 Hz, 2H), 3.75- 3.64 (m, 4H), 2.02—1.64 (m, 4H). LCMS: m/z 533.2 [M+H]+; tR = 1.28 min.
Synthesis of (E)(6—aminopyridinyl)—N-((7-chloro(4-(3-fluor0methylazetidine- 1-carbonyl)phenyl)benzofuranyl)methyl)acrylamide (599).
(Wm / / \ / o >c~++HCI o \ o Wm\ O HEN N O O HZN N O O 55 OH N HATU, DIPEA, DMF 599 CI CI q\ [006 15] (E)~3 -(6-aminopyridin—3 -((7-chloro(4-(3 -fluoromethylazetidine- 1 ~ carbonyl)phenyl)benzofuranyl)methyl)acrylamide (599) was synthesized using the ted reagents according to General Procedure 4. Yield (10%). 1H NMR (400 MHz, DMSO'd6) 8 8.65 (t, J: 6 Hz, 1H), 8.10—8.08 (m, 1H), 7.96-7.92 (m, 1H), 7.84—7.73 (m, 6H), 7.66-7.59 (m, 1H), 7.39-7.32 (m, 1H), 6.90 (s, 1H), 6.49-6.40 (m, 3H), 4.60 (d, J: 6 Hz, 2H), 4.54—4.40 (m, 2H), 4.20—4.11 (m, 2H), 1.61 (d, J: 22 Hz, 3H). LCMS: m/z 519.3 [M+H]+, tR = 1.65 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((7-chlore(4-(piperidine—l- carbonyl)phenyl)benzofuran~2~yl)methyl)acrylamide (600).
HO UVH/ \ N / O HZN N OH HATU DIPEA DMF 0| (N > (E)—3 ~(6-aminopyridin-3 -((7-chloro(4-(piperidine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (600) was synthesized using the indicated reagents according to General procedure 4. Yield (70%). 1H NMR (400 MHz, DMSO'dé) 8 8.84 (t, J: 6 Hz, 1H), 8.24-7.97 (m, 4H), 7.91 (d, J: 2 Hz, 1H), 7.81-7.70 (m, 3H), .39 (m, 3H), 6.97-6.89 (m, 2H), 6.60 (d, J: 16 Hz, 1H), 4.62 (d, J: 6 Hz, 2H), 3.64-3.55 (m, 4H), 1.68-1.42 (m, 6H). LCMS: m/z 515.2 ; tR = 1.31 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-(piperazine-l-carbonyl)phenyl) (trifluoromethyl)benzofuran-Z—yl)methyl)acrylamide (601). 8:)ch +1wale20 0: 1 HATU DIPEA DMF WED 19 0° (E)(6-aminopyridin—3-y1)~N—((5-(4—(piperazine~1—carbonyl)phenyl)~7- (trifluoromethyl)benzofuranyl)methy1)acrylamide (601) was synthesized using the indicated reagents according to General Procedures 4 and 3. Yield (90%). 1H NMR (400 MHz, CD30D) 8 7.96-7.91 (m, 1H), 7.69-7.61 (m, 4H), 7.50—7.35 (m, 4H), 6.74 (s, 1H), 6.49 (d, J: 9 Hz, 1H), 6.37 (d, J: 16 Hz, 1H), 4.58 (s, 2H), 3.76-3.34 (m, 4H), 2.92-2.71 (m, 4H). LCMS: m/Z 516.3 [M+H]+, 1R = 1.17 min. sis of (E)(6-aminopyridinyl)-N-((7—chloro-S-(4-(4-hydroxy methylpiperidinecarbonyl)phenyl)benzofuranyl)methyl)acrylamide (602). 0 0 H N2 \N 55 \ /> < "Mic OH HATU DIPEA DMF 19 00") (E)(6-aminopyridin—3-yl)-N-((7-chloro(4-(4-hydroxymethy1piperidine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (602) was synthesized according to General Procedure 4. Yield (47%). 1H NMR (400 MHz, CD3ODV) 5 8.13-8.04 (m, 1H), 7.98- 7.90 (m, 1H), 7.72-7.60 (m, 3H), 7.50 (d, J: 2 Hz, 1H), 7.44—7.32 (m, 3H), 6.93 (d, J= 9 Hz, 1H), 6.76 (s, 1H), 6.54 (d, J: 16 Hz, 1H), 4.60 (s, 2H), 4.20-4. 10 (m, 1H), 3.49-3.25 (m, 3H),165- 1.40 (m, 4H), 1 17 (s, 3H). LCMS: m/z 545.2 [M+H]; tR— 1. 21 min.
Syntheis of (6-amin0pyridinyl)-N-((5-(4-(3,3-difluor0pyrrolidine—1- mrhonvl)phenyl)—7-(trifluor0methyl)benzofuran-2—yl)methyl)acrylamide (603). —187- F30 T F30 00 OO o HN "2" / o O O OH ——> | H N N \ N \ HATU, DIPEA, DMF F 0 603 F (E)—3-(6-aminopyridin—3—yl)-N-((5-(4—(3,3-difluoropyrrolidine—1- carbonyl)phenyl)—7-(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (603) was synthesized using the indicated reagents according to General ure 4. Yield (49%). 1H NMR (400 MHz, CD3OD) 8 8.13-7.90 (m, 3H), .52 (m, 5H), 7.38 (d, J: 16 Hz, 1H), 6.95 (d, J= 9 Hz, 1H), 6.82 (s, 1H), 6.55 (d, J: 16 Hz, 1H), 4.61 (s, 2H), 3.94—3.65 (m, 4H), .28 (m, 2H). LCMS: m/Z 571.2 [M+H]+; IR = 1.32 min.
Synthesis of (E)(6-aminopyridinyl)—N-((5-(4-(4—flu0r0-4—methylpiperidine-l- carbonyl)phenyl)—7-(triflu0r0methyl)benzF0furanyl)methyl)acrylamide (604).FSC ><:/\NH F3C HATU DIPEA DMF ] (E)—3—(6—aminopyridin—3—yl)—N-((5—(4—(4—fluoro—4—methylpiperidine— l - carbonyl)phenyl)—7-(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (604) was synthesized using the indicated reagents according to General Procedure 4. Yield (4%). 1H NMR (400 MHz, CD3OD) 8 8.14—7.91 (m, 3H), 7.73-7.62 (m, 3H), 7.52-7.34 (m, 3H), 6.96 (d, J: 9 Hz, 1H), 6.82 (s, 1H), 6.55 (d, J: 16 Hz, 1H), 4.62 (s, 2H), 4.41—3.27 (m, 4H), 2.09- 1.50 (m, 4H), 1.36—1.15 (m, 3H). LCMS: m/z 581.2 [M+H]+; IR = 1.07 min.
Synthesis of (E)—3-(6-amin0pyridin—3-yl)—N—((7—(trifluoromethyl)(4-(4- (trifluoromethyl)piperidinecarbonyl)phenyl)benzofuranyl)methyl)acrylamide (605).
F300 F304<: F30 "2" / o O O N H N HATU DIPEA DMF \ / < > 0 605 (E)—3—(6—aminopyridin—3—yl)-N—((7—(trifluoromethyl)-5—(4—(4— (trifluoromethyl)piperidinecarbonyl)phenyl)benzofuran—2—yl)methyl)acrylarnide (605) was synthesized using the indicated reagents according to General Procedure 4. Yield (46%). 1H ~188- NMR (400 MHz, CD3OD) 8 8.04-7.93 (m, 2H), 7.71-7.62 (m, 4H), 7.48-7.34 (m, 3H), 6.81 (s, 1H), 6.50 (d, J= 9 Hz, 1H), 6.37 (d, J: 16 Hz, 1H), 4.60 (s, 2H), 4.56-4.47 (m, 1H), 3.88— 373 (m, 1H), 3.15-3.04 (m 1H) 287—2.73 (m, 1H), 2.52-2.37 (m, 1H), 1.99-1.72 (m, 2H), 1. 56— 1 35 (m, 2H). LCMS: m/z 617. 3 [M+H]; IR: 1 94 min.
Synthesis of (E)—3-(6-aminopyridin-3~yl)-N-((5-(4-(3-hydroxy (trifluoromethyl)pyrrolidine—l-carbonyl)phenyl)(trifluoromethyl)benzofuran-2— yl)methyl)acrylamide (606).
F30 880% F30 "Own: H N . 00 O .
N\ N \ OH HATU DIPEA, DMF / O 805 (E)(6-aminopyridinyl)—N—((5-(4-(3-hydroxy(trifluoromethyl)pyrrolidine- 1-carbonyl)phenyl)—7-(trifluoromethyl)benzofuranyl)methyl)acrylamide (606) was synthesized using the indicated reagents according to General ure 4. Yield (42%). %). 1H NMR (400 MHz, CD3OD) 8 8.14-7.90 (m, 3H), 7.76-7.53 (m, 5H), 7.38 (d, J: 16 Hz, 1H), 6.95 (d, J: 9 Hz, 1H), 6.83 (s, 1H), 6.55 (d, J: 16 Hz, 1H), 4.62 (s, 2H), 3.87-3.41 (m, 4H), 2.34-1.92 (m, 2H). LCMS: m/z 619.2 [M+H]+; tR = 1.30 min.
Synthesis of (E)-3—(6-aminopyridinyl)-N:((5-(4-(4-chloropiperidine—1— carbonyl)phenyl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (607).
F30 F30 00 Q: HN2 /, o O O H N N‘ N \ HATU DIPEA, DMF / < > O 607 ] (E)(6-aminopyridin—3-yl)-N—((5~(4-(4-chloropiperidinecarbonyl)phenyl)-7— (trifluoromethyl)benzofuranyl)methyl)acrylamide (607) was synthesized using the indicated reagents according to General ure 4. Yield (52%). 1H NMR (400 MHz, CD30D) 5 8.10-7.94 (m, 3H), 7.70-7.36 (m, 6H), 6.95-6.53 (m, 3H), 4.62 (s, 2H), 4.32- 4.26 (m, 1H), .20 (m, 4H), 2.10-1.70 (m, 4H). LCMS: m/z 583.2 [M+H]+; IR = 1.46 min.
Synthesis of (E)—3-(6-aminopyridin—3-yl)-N—((5-(4-(3—fluoromethylpyrrolidine-l— carbonyl)phenyl)(trifluor0methyl)benzofuran—2-yl)methyl)acrylamide (608). —189— F30 F30 ml] :HF0 HATU DIPEA DMF (E)(6—aminopyridiny1)-N-((5—(4-(3 -fluoro-3—methylpyrrolidine carbonyl)phenyl)(trifluoromethyl)benzofurany1)methyl)acrylamide (608) was synthesized using the ted reagents according to General Procedure 4. Yield (8%). 1H NMR (400 MHZ, CD3OD) 8 8.03-7.93 (m, 2H), 7.74-7.50 (m, 6H), 7.38 (d, J= 16 Hz, 1H), 6. 81 (s, 1H) 6. 51 (d, J= 9 Hz, 1H), 638 (d, J= 16 Hz, 1H), 4.61 (s, 2H), 3.82-3.48 (m, 4H), 2.21- 1. 95 (m 2H) 1. 56- 1. 35 (m, 3H). LCMS: m/z 567 3 [M+H]; tR= 1. 83 min Synthesis of (E)(6-aminopyridin-3—yl)-N—((5-(4-(4-hydr0xy-4— (trifluoromethyl)piperidine-l-carb0nyl)phenyl)(trifluoromethyl)benz0furan yl)methyl)acrylamide (609).
F30 F30 O / I O O N \ ("OHO N H O\ HATU DIPEA, DMF \ / O 609 HO CF3 ] (E)-3—(6-a1ninopyridin—3-y1)-N-((5-(4-(4-hydroxy(trifluoromethyl)piperidine-1— carbony1)pheny1)(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (609) was synthesized using the indicated reagents according to General Procedure 4. Yield (39%). 1H NMR (400 MHz, DMSO-d6) 8 8.73 (t, J= 6 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J: 2 Hz, 1H), 7.94-7.71 (m, 4H), 7.55 (d, J= 8 Hz, 2H), 7.39 (d, J: 16 Hz, 1H), 7.03-6.93 (m, 3H), 6.64 (d, J: 9 Hz, 1H), 6.49 (d, J= 16 Hz, 1H), 6.17 (s, 1H), 4.62 (d, J: 5 Hz, 2H), 4.54-4.42 (m, 1H), 3.68-3.52 (m, 1H), 3.23—2.93 (m, 2H), 1.84-1.58 (m, 4H). LCMS: m/z 633.2 [M+H]+; tR = 1.70 min.
Synthesis of (S,E)—3-(6-aminopyridinyl)-N—((5-(4-(3-chloropyrrolidine-1— carbonyl)phenyl)(trifluor0methyl)benzofuranyl)methyl)acrylamide (610).
F30 F30 "2" / o O Q: - O Q I N N \ HATU. DIPEA, DMF \ N / Q<31 0 610 ] (S,E)—3-(6—aminopyridinyl)-N—((5—(4-(3—chloropyrrolidinecarbony1)phenyl)- fluoromethy1)benzofuran-2—yl)methyl)acrylamide (610) was synthesized using the indicated reagents according to General Procedure 4. Yield (21%). 1H NMR (400 MHz, MeOD—d6) 8 7.99—7.90 (m, 2H), 7.71—7.49 (m, 6H), 7.36 (d, J: 16 Hz, 1H), 6.78 (s, 1H), 6.48 —l90— (d, J: 9 Hz, 1H), 6.36 (d, J: 16 Hz, 1H), 4.68-4.48 (m, 3H), .46 (m, 4H), 2.43-2.07 (m, 2H). LCMS: m/z 569.2 [M+H]+; IR = 1.83 min.
Synthesis of (E)~N—((5-(4-(2-oxaazaspiro[3.3]heptanecarb0nyl)phenyl)—7— (trifluoromethyl)benzofuran—Z-yl)methyl)(6-aminopyridinyl)acrylamide (611).
F30 F30 H2N HNOCO MN H2N / /‘ Hflc@_[<0OH\ OW"mm?\ HATU,DIPEA, DMF O D 59 611 N% (E)-N-((5-(4-(2-oxaazaspiro[3.3]heptanecarbony1)phenyl)—7- (trifluoromethyl)benzofiiranyl)methyl)(6-aminopyridin—3-y1)acrylamide (611) was synthesized using the ted reagents according to l Procedure 4. Yield: 24%. 1H NMR (400 MHZ, DMSO—dg) 8 8.90—8.83 (m, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.12-8.04 (m, 3H), 7.92-7.81 (m, 3H), 7.73 (d, J: 8 Hz, 2H), 7.45 (d, J: 16 Hz, 1H), .90 (m, 2H), 6.60 (d, J: 16 Hz, 1H), 4.70 (s, 4H), 4.64 (d, J: 6 HZ, 2H), 4.53 (s, 2H), 4.24 (s, 2H).
LCMS: m/Z 563.2 [M+H]+, tR=1.33 min.
Synthesis of (E)-3~(6—aminopyridinyl)—N—((5-(5-(3,3-difluoropyrrolidine carb0nyl)pyridinyl)—7-(triflu0r0methyl)benzofuran-Z-yl)methyl)acrylamide (612).
F3C F3C M"| H OH | H N \ N\ N \ HATU, DIPEA. DMF / Ow: O 0 F 123 612 (E)-3—(6—aminopyridiny1)—N—((5-(5-(3,3-difluoropyrrolidinecarbonyl)pyridin- 2-yl)(trifluoromethyl)benzofuran-2—yl)methyl)acrylamide (612) was synthesized using the indicated reagents according to General ure 4. Yield (42%). 1H NMR (400 MHz, CD3OD) 5 8.75-8.07 (m, 3H), 7.98—7.92 (m, 4H), 7.39—6.53 (m, 4H), 4.62 (s, 2H), 3.93- 3.74 (m, 4H), 2.41-2.37 (m, 2H). LCMS: m/z 572.1 [M+H]+; tR = 1.28 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((5-(5-(3-hydroxy (trifluoromethyl)pyrrolidinecarb0nyl)pyridinyl)(triflu0r0methyl)benzofuran yl)methyl)acrylamide (613).
F30 F3C N— o N— o H N HNQ40H H N 2 / 2 0 \ / / —_~_) 0 \ / l OH l N N \ H \ N \ H \ / HATU, DIPEA, DMF / @0133 O 0 123 513 OH (E)(6-aminopyridin—3-yl)—N-((5-(5-(3-hydroxy(trifluoromethyl)pyrrolidine— 1-carbonyl)pyridinyl)(trifluoromethyl)benzofuran—2-y1)methyl)acrylamide (613) was ~191- synthesized using the indicated reagents according to General Procedure 4. Yield (48%). 1H NMR (400 MHZ, CD3OD) 6 8.81-8.71 (m, 1H), 8.41 (s, 1H), 8.24-7.87 (m, 4H), 7.38 (d, J: 16 HZ, 1H), 6.95 (d, J: 9 H2, 1H), 686 (s, 1H), 655 (d, J: 16 HZ, 1H), 4.61 (s, 2H), 3.96- 3. 44 (m, 4H), 2. 32— 1.94 (m, 2H) LCMS: m/z 620.1 [M+H]; 1R: 1.26 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4-chloropiperidine carbonyl)pyridinyFl)(trifluoromethyl)benzofuranyl)methyl)acrylamide F30H N N— o 2 / o l H \ / N‘ N \ HATU DIPEA DMF / < > 0 614 (6—aminopyridin—3~yl)~N-((5—(5—(4—chloropiperidine-l-carbonyl)pyridin—2- yl)—7-(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (614) was synthesized using the indicated reagents according to General Procedure 4. Yield (33%). 1H NMR (400 MHZ, CDgOD) 5 8.64-8.09 (m, 4H), 7.98-7.86 (m, 3H), 7.40-6.53 (m, 4H), 4.63 (s, 2H), 4.33— 4.28 (m, 1H), 3.96-3.20 (m, 4H), 2.11—1.77 (m, 4H). LCMS: m/z 584.1 [M+H]+; IR = 1.40 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-(trifluoromethyl)—5-(5-(4- oromethyl)piperidine—1-carbonyl)pyridinyl)benzofuranyl)methyl)acrylamide (615).
O—ca F30 N_ o H N2 / O l H \ l/ N N \ HATU DIPEA DMF \ / <"‘ 0 615 2 (E)—3—(6—aminopyridin—3-yl)-N—((7-(trifluoromethyl)(5-(4- (trifluorornethyl)piperidine—1—carbonyl)pyridinyl)benzofi1ranyl)methyl)acrylamide (615) was synthesized using the indicated reagents according to l Procedure 4. Yield (16%). 1H NMR (400 MHZ, DMSO-d6) 6 8.77-8.61 (m, 3H), 8.39 (s, 1H), 8.20 (d, J= 8 HZ, 1H), 8.09 (d, J: 2 Hz, 1H), 8.03-7.95 (m, 1H), 7.65-7.59 (m, 1H), 7.36 (d, J: 16 HZ, 1H), 700 (s, 1H), 6. 9 (m 4H) 4 69-4.53 (m, 3H), 3.71 (s, 1H), 3.24-3. 14 (m, 1H), 2.94- 260 (m, 2H), 200— 172 (m, 2H), 155140 (m, 2H) LCMS: m/z 6183 [M+H], IR=1. 87 min. ‘ Synthesis of (E)(6-aminopyridinyl)—N-((5-(5—(4-hydroxy—4- (trifluoromethyl)piperidine-1—carbonyl)pyridin-2—yl)—7-(trifluoromethyl)benzofuran yl)methyl)acrylamide (616).
N— 380%. N— o \ / 2 / O ‘ H \ / N\ N \ HATU DIPEA DMF / O 616 01:3 (E)-3 -(6-aminopyridin—3-yl)—N—((5-(5-(4-hydroxy(trifluoromethyl)piperidine carbony1)pyridinyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (611) was synthesized using the indicated reagents according to General Procedure 4. Yield (23%). 1H NMR (400 MHZ, DMSO'dé) 5 8.83— 8.60 (m, 3H), 8.39 (s, 1H), 8.24-7.97 (m, 3H), 7.66-7.63 (m, 1H), 7.38 (d, J= 15.7 Hz, 1H), 7.01 (s, 1H), .39 (m, 4H), 6.21 (s, 1H), 4.70—4.42 (m, 3H), 3.71- 3.52 (m, 1H), 3.22—2.94 (m, 2H), 1.89—1.57 (m, 4H). LCMS: m/z 634.2 [M+H]+; 1R = 1.62 min. sis of (E)(6-aminopyridinyl)-N—((5-(5-(3-flu0r0methylpyrrolidine carb0nyl)pyridinle)(trifluoromethyl)benz0furanyl)methyl)acrylamide (617).F30N— N_ o \ / 2 / o I H \ / N \ N \ HATU, DIPEA DMF / O %F (E)-3 -(6-aminopyridin—3 —yl)—N-((5-(5—(3 -fluoro-3 -methylpyrrolidine carbonyl)pyridinyl)(trifluoromethyl)benzofuran—2—yl)rnethyl)acrylamide (617) was synthesized using the indicated reagents according to General Procedure 4. Yield (14%). 1H NMR (400 MHZ, CD30D) 8 8.74 (d, J: 8 Hz, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.03-7.90 (m, 3H), 7.69-7.61 (m, 1H), 7.38 (d, J= 16 Hz, 1H), 6.86-6.82 (m, 1H), 6.51 (d, J: 9 Hz, 1H), 6.38 (d, J: 16 Hz, 1H), 4.61 (s, 2H), 3.85-3.47 (m, 4H), 2.20-1.94 (m, 2H), .38 (m, 3H). LCMS: m/z 568.2 [M+H]+; IR = 1.76 min. sis of (S,E)(6-aminopyridiny1)-N-((5-(5-(3-chlor0pyrrolidine carbonyl)pyridinyl)(trifluor0methyl)benzofuranyl)methyl)acrylamide (618).
N_ 0 N- o H N2/1Hyo&:>—<\J— Synthesis of (E)(2-((3-(6-aminopyridinyl)acrylamido)methyl) (trifluoromethyl)benzofuranyl)-N—(1-(trifluoromethyl)cyclopropyl)nicotinamide (619).
F30 MOB F3C N o /N o NH2HCI H2N / H2N / \ o CF3 1 H /_\ 1 HN — N OH HATU.DIPEA,DMF Nx / \ N\ / H \ fi (E)—6—(2—((3—(6—aminopyridin—3~y1)acry1amido)methy1) (trifluoromethy1)benzofuran— 5 —y1)—N—( 1 -(trifluoromethy1)cyclopropy1)nicotinamide (6 19) was sized using the indicated reagents according to l Procedure4. Yield (28%). 1H NMR (500 MHZ, CD3OD) 5 9.10 (d, J: 2 Hz, 1H), 8.57 (s, 1H), 8.39-8.31 (m, 2H), 8.25 (dd, J: 9 Hz, 2 Hz,1H), 8.12 (d, J: 9 Hz,1H), 8.07 (s, 1H), 7.51 (d,J=16 Hz, 1H), 7.08 (d, J: 9 Hz, 1H), 7.00 (s, 1H), 6.67 (d, J= 16 Hz, 1H), 4.75 (s, 2H), 1.43 (t, J: 7 Hz, 2H), 1.30- 1.25 (m, 2H). LCMS: m/Z 590.2 [M+H]+, 1R: 1.26 min.
Synthesis of (E)-3—(6—amin0pyridin-3—yl)-N—((5-(5-(4-hydr0xy—4—methylpiperidine-l— carbonyl)pyridin—Z-yl)-7—(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (620).
N o HN2 / \ 0/ Synthesis of (E)—3-(6-amin0pyridin—3—yl)—N—((5-(5-(3-hydroxymethylazetidine—1— carbonyl)pyridinyl)(trifluoromethyl)benzofuran—Z-yl)methyl)acrylamide (621). —194— F F N O fl/W H2N / / \ HATU DIPEA DMF W" N O #OH [0063 7] (E)(6-amin0pyridinyl)-N—((5-(5-(3 -hydroxy-3—methylazetidine-l - carbonyl)pyridiny1)-7—(trifluoromethyl)benzofuranyl)methyl)acrylamide (621) was synthesized using the indicated reagents according to General Procedure 4. Yield (6%). 1H NMR (500 MHz, CD3OD) 6 8.95 (s, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 8.27-8.02 (m, 4H), 7.50 (d, J= 15 Hz, 1H), 7.11-6.94 (m, 2H), 6.67 (d, J= 15 Hz, 1H), 4.75 (s, 2H), 4.40-4.06 (m, 4H), 1.55 (s, 3H). LCMS: m/z 552.2 [M+H]+, IR: 1.36 min.
Synthesis of (S,E)—3-(6-aminopyridiny1)-N-((7-(triflu0r0methyl)—5-(5-(2- uoromethyl)pyrrolidine—l—carbonyl)pyridinyl)benzofuran yl)methyl)acrylamide (622).
(OF3 HN " Fac N o O HzN /N\ H2N / / \ / | 0 O _ .CFa l W"—’ ‘ H N —~ N\ [I] \ N OH \ N \ / / HATU.D|PEA,DMF 123 622 (S,E)~3—(6-aminopyridinyl)-N—((7-(trifluorornethyl)—5-(5-(2— (trifluoromethyl)pyrrolidine-1 -carbonyl)pyridin—2-yl)benzofuran—2-yl)methyl)acrylamide (622) was synthesized using the indicated reagents according to General Procedure 4. Yield (40%). 1H NMR (500 MHz, DMSO-d6) 8 8.88 (s, 1H), .65 (m, 2H), 8.41 (s, 1H), 8.23 (d, J= 8 Hz, 1H), 8.16-8.07 (m, 2H), 7.64 (dd, J: 9 Hz, 2 Hz, 1H), 7.38 (d, J: 16 Hz, 1H), 7.01 (s, 1H), 6.51—6.42 (m, 4H), 5.17-5.04 (m, 1H), 4.64 (d, J: 5 Hz, 2H), 3.77—3.47 (m, 2H), 2.30-2.17 (m, 1H), 2.08—1.85 (m, 3H). LCMS: m/z 604.2 [M+H]+, tR= 1.80 min.
Synthesis of (E)-N-((5—(5-(3-azabicyclo[3.1.0]hexanecarbonyl)pyridinyl)—7- (trifluoromethyl)benzofuranyl)methyl)(6-aminopyridinyl)acrylamide (623).
HZNWHES N O N\ N \ HATU. DIPEA, DMF O (E)-N—((5-(5-(3-azabicyclo[3.1.0]hexane—3—carbonyl)pyridin—2—yl)—7— (trifluoromethyl)benzofuran—2-y1)methyl)—3—(6-aminopyridin—3—yl)acrylamide (623) was svnthesized using the te ts according to General Procedure 4. Yield (8%). 1H —195— NMR (500 MHZ, DMSO—d6) 5 8.83 (d, J= 2 HZ, 1H), 8.77-8.70 (m, 2H), 8.44 (s, 1H), 8.23 (d, J: 8 HZ, 1H), 8.14 (d, J: 2 HZ, 1H), 8.07 (dd, J: 8 HZ, 2 HZ, 1H), 7.68 (dd, J= 8 HZ, 2 HZ, 1H), 7.41 (d, J: 16 HZ, 1H), 7.05 (s, 1H), 6.56-6.36 (m, 4H), 4.67 (d, J: 6 HZ, 2H), 4.00 (d, J: 12 HZ, 1H), 3.86—3.78 (m, 1H), 3.51—3.43 (m, 2H), 1.69-1.58 (m, 2H), 0.72 (dd, J = 12 HZ, 7 HZ, 1H), 0.25-0.18 (m, 1H). LCMS: m/z 548.3 [M+H]+, tR= 1.73 min.
Synthesis of (R,E)(6-amin0pyridin-3—yl)—N—((7-(triflu0r0methyl)(5-(2- (triflu0r0methyl)pyrrolidinecarbonyl)pyridinyl)benzofuran yl)methyl)acrylamide (624).
(R,E)—3 -(6-aminopyridin-3 —yl)—N—((7-(trifluoromethyl)-5 -(5 -(2- (trifluoromethyl)pyrrolidine- 1 ~carbonyl)pyridin-2—yl)benzofurany1)methyl)acrylamide (624) was synthesized using the indicated reagents accroding to General Procedure 4. Yield (17%). 1H NMR (500 MHZ, DMSO—ds) 5 8.87 (s, 1H), .66 (m, 2H), 8.39 (d, J: 16 HZ, 1H), 8.23 (d, J= 8HZ, 1H), 815807(m, 2H), 7.63 (dd, J1: 9HZ, J2=2HZ, 1H), 7.,37(d J =16 HZ, 1H), 7.01 (s, 1H), 6.51-6.40 (m, 4H), 5.17—5.02 (m, 1H), 4.63 (d, J: 6 HZ, 2H), 3.77—3.45 (m, 2H), .15 (m, 1H), 2.07-1.84 (m, 3H). LCMS: m/z 604.2 [M+H]+, IR: 1.39 min.
Synthesis of (E)-N-((5-(5-(2-0xa—6—azaspiro[3.3]heptane—6-carbonyl)pyridinyl) u0r0methyl)benzofuran-Z-yl)methyl)-3~(6-amin0pyridinyl)acrylamide (625).
FFF HN FF HEN /_\ N O /| o / \ H O HzN / HATU. DMF / 0 % 123 625 (E)-N-((5-(5-(2-oxaazaspiro[3.3]heptanecarbony1)pyridiny1) oromethyl)benzofuranyl)methyl)(6-aminopyridinyl)acrylamide (625) was synthesized using the indicated reagents according to General procedure 4. Yield (36%). 1H NMR (500 MHZ, DMSO-d6) 6 8.90 (d, J=2 HZ, 1H), 8.73-8.65 (m, 2H), 8.41 (s, 1H), 8.22 (d,J=8HZ,1H),8.15—8.,06(m 2H), 763 (dd, J1: 9HZ, , 1H), 7.,36(d J=16HZ, —196- 1H), 7.00 (s, 1H), 6.51-6.40 (m, 4H), 4.70 (q, J= 7 Hz, 4H), 4.62 (d, J: 6 Hz, 2H), 4.58 (s, 2H), 4.26 (s, 2H). LCMS: m/z 564.2 [M+H]+; tR = 1.25 min.
Synthesis of ((5—(5-(6-oxaazabicyclo[3.1.1]heptane-3—carb0nyl)pyridinyl) (trifluoromethyl)benzofuran-Z-yl)methyl)(6—aminOpyridinyl)acrylamide (626).
Q o Fac\ I HN o Ho—§ F30 N OH N_ (Nj H2N / HN . 2 \ / / \ / o H HATU,DIPEA,DMF | o O\ / HJ\\o4 / N\ N o o 123 626 (E)-N-((5—(5-(6-oxa—3-azabicyclo[3.1.1]heptanecarbonyl)pyridinyl)—7- (trifluoromethyl)benzofuran—2-yl)methyl)-3~(6-aminopyn'dinyl)acrylamide (626) was synthesized using the ted reagents according to l Procedure 4. Yield (42%). 1H NMR (500 MHz, 6) 8 8.84 (s, 1H), 8.74-8.65 (m, 2H), 8.40 (s, 1H), 8.21 (d, J: 8 Hz, 1H), 8.14—8.06 (m, 2H), 7.63 (d, J= 8 Hz, 1H), 7.36 (d, J: 16 Hz, 1H), 7.00 (s, 1H), 6.52-6.31 (m, 4H), 4.70—4.47 (m, 4H), 4.04-3.97 (m, 1H), 3.89-3.80 (m, 1H), 3.65-3.53 (m, 2H), 3.34-3.32 (m, 1H), 3.12—3.04 (m, 1H). LCMS: m/z 563.9 [M+H]+; IR = 1.77 min.
Synthesis of (E)—3—(6—amin0pyridin-3—yl)—N—((5—(5-(3-hydr0xy—3—methylpyrrolidine-1— carb0nyl)pyridin—Z—yl)—7—(triflu0romethyl)benz0furan—2-yl)methyl)acrylamide (627).
F F F F F Ho«pNH F N o N o H2N / / \ _ HZN / / \ o o l H 0" l H N\ N \ HATU,DIPEA.DMF N\ H \ / / 0 o UVOH (E)—3 -(6-aminopyridin-3 -yl)—N—((5 -(5-(3 -hydroxy—3 ~methylpyrrolidine carbonyl)pyridin—2—yl)-7—(trifluoromethyl)benzofuran—2-yl)rnethyl)acrylamide (627) was synthesized using the ted reagents according to General Procedure 4. Yield (16%). 1H NMR (500 MHz, CDgOD) 8 8.77-8.69 (m, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 8.00-7.92 (m, 3H), 7.63 (dd, J1: 9 Hz, J2 = 2 Hz, 1H), 7.38 (d, J= 16 Hz, 1H), 6.84 (s, 1H), 6.49 (d, J: 9 Hz, 1H), 6.37 (d, J= 16 Hz, 1H), 4.61 (s, 2H), 3.78-3.48 (m, 3H), 3.35 (dd, J]: 43 Hz, J2 =12 Hz, 1H), 1.95-1.83 (m, 2H), 1.37-1.27 (m, 3H). LCMS: m/Z 566.2 [M+H]+; IR = 1.23 min.
Synthesis of of (E)(6-aminopyridinyl)—N—((5-(5-(3-flu0r0—4-meth0xypyrr0lidine—l— carbonyl)pyridinyl)—7-(triflu0r0methyl)benzofuran-2—yl)methyl)acrylamide (628).
F F HN F N O ' N o HZN / / \ HATU DIPEA DMF I N\ H \ / ‘ 0 : 628 F (E)-3~(6-aminopyridin—3-yl)-N-((5-(5-(3-fluoromethoxypyrrolidine— 1 - carbonyl)pyridinyl)—7—(trifluoromethyl)benzofi1ran—2-yl)methyl)acrylamide (628) was synthesized using the indicated reagents according to General Procedure 4. Yield (50 mg, 17% . 1H NMR (500 MHz, DMSO-d6) 6 8.93-8.85 (m, 1H), 8.71 (s, 1H), 8.66 (t, J= 6 Hz, 1H), 8.41 (s, 1H), .06 (m, 3H) 7.63 (d J=9Hz, 1H), 7.37 (d, J= 16 Hz 1H), 701 (s, 1H), 6.52- 6.39(rn, 4H) 5.28 (dd, J1: 50Hz, J2=30Hz, 1H), 4.63 (d, J: 5Hz, 2H), 4. 15-3. 53 (m, 5H), 3.38 (s, 3H). LCMS: m/z 5842 [M+H]; IR: 132 min.
Synthesis of (E)(2-((3-(6-aminopyridinyl)acrylamido)methyl) (trifluoromethyl)bFenzofuran-S-yl)-N-(4,4-difluorocyclohexyl)nic0tinamide (629).F F F N o N o HzNm"; HzN / / \ 0W" O F HATU, DIPEA DMF \ HN‘<:> Synthesis of (E)(2-((3-(6-aminopyridinyl)acrylamido)methyl) (trifluoromethyl)beanofuran-S-yl)-N-(pyridinylmethyl)nicotinamide (630). mpg HATU. DIPEA, DMF HN'E:> —198- ] (E)—6-(2-((3-(6-arninopyridinyl)acrylamido)methyl) (trifluoromethyl)benzofuranyl)-N-(pyridinylmethyl)nicotinamide (630) was synthesized using the indicated reagents according to General Procedure 4. Yield (26%). 1H NMR (500 MHz, DMSO'dfi) 8 9.48-9.40 (m, 1H), 9.17 (s, 1H), 8.93-8.84 (m, 1H), 8.79-8.70 (m, 2H), 8.68-8.61 (m, 1H), 8.44-8.34 (m, 3H), 8.29-8.18 (m, 3H), 8.15-8.09 (m, 2H), 7.73-7.64 (m, 1H) 7.46 (d, J= 16 Hz 1H), 7.03 (s, 1H), 7.00 (d, J=9 Hz 1H), 6.62 (d,J= 16 , 4. 68-4 58 (m 4H). LCMS: m/z 573. 3 [M+H]; tR = 1.63 min. sis of (E)(6-aminopyridinyl)-N-((5-(5-(6,6-dimethyl azabicyclo[3.1.0]hexanecarbonyl)pyridinyl)(trifluoromethyl)benzofuran yl)methyl)acrylamide (631).
N - o HCI HN F3C HzN / / \ , N_ N l 0 H ~— HZN Nx 0H N \ HATU.D|PEA.DMF.RT o / /‘ \ / 2:: o N\ / 123 631 (E)(6-aminopyridin—3-yl)-N—((5—(5—(6,6—dimethyl-3 -azabicyclo[3.1.0]hexane carbonyl)pyridinyl)(trifluoromethyl)benzofuran—2-yl)methyl)acrylamide (631) was synthesized using the indicated reagents according to General Procedure 4. Yield (35 mg, 38% yield). 1H NMR (500 MHz, 6) 8 8.79 (d, J= 2 Hz, 1H), 8.70-8.63 (m, 2H), 8.39 (s, 1H), 8.18 (d, J: 8 Hz, 1H), 8.09 (d, J: 2 Hz,1H), 8.03 (dd, J: 8 Hz, 2 Hz,1H), 7.63 (dd, J: 8 Hz, 2 Hz, 1H), 7.37 (d, J: 16 Hz, 1H), 7.00 (s, 1H), 6.51-6.40 (m, 4H), 4.63 (d, J = 6 Hz, 2H), 3.88—3.82 (rn, 1H), 3.69-3.59 (m, 2H), 3.27 (d, J: 11 Hz, 1H), 1.50-1.42 (m, 2H), 1.02 (s, 3H), 0.90 (s, 3H). LCMS: m/z 576.3 [M+H]+, IR: 1.86 min.
Synthesis of (E)-N-((5-(5-(8-oxaazabicyclo[3.2.1]0ctanecarb0nyl)pyridin—2—yl) (trifluoromethyl)benzofuranyl)methyl)—3-(6-aminopyridinyl)acrylamide (632).
HCI N_ N "2" / o \ / l H o HATU DIF’EA DMF, RT N\ N \ ] (E)~N—((5-(25-(8-oxa—3-azabicyclo[3.2.1]octane—3-carbony1)pyridin—2-yl)—7- (trifluoromethyl)benzofurany1)methyl)(6-aminopyridin—3—yl)acry1arnide (632) was synthesized using the indicated reagents according to General Procedure 4. Yield (54%). 1H NMR (500 MHz, DMSO-d6) 8 8.73 (s, 1H), 8.69 (s, 1H), 8.66 (t, J: 6 Hz, 1H), 8.39 (s, 1H), 8.20 (d, J: 8 Hz, 1H), 8.09 (s, 1H), 7.98 (d, J= 8 Hz, 1H), 7.63 (d, J: 9 Hz, 1H), 7.36 (d, J = 16 Hz, 1H), 7.00 (s, 1H), 6.50-6.40 (m, 4H), 4.63 (d, J: 6 Hz, 2H), 4.46-4.37 (m, 1H), 4.28—4. 15 (m, 2H) 3. 53-3.43 (m 1H), 3.30-3.24 (m, 1H), 3.09-2.99 (m, 1H), 1.89-1.60 (m, 4H) LCMS: m/z 578.2 [M+H]; IR—— 1. 67 min Synthesis of (E)—N-((5-(5-(2-0xa—5-azabicyclo[2.2.1]heptane-S~carb0ny1)pyridin-2—y1)—7- (trifluoromethy1)benzofuran-Z-yl)methyl)(6-amin0pyridinyl)acrylamide (633).
F F N\ N o HzN / / \ HATU DIPEA DMF l N\ H \ i / Q)o ] (E)-N—((5-(5-(2-oxaazabicyclo[2.2.1]heptanecarbonyl)pyridiny1)-7— (trifluoromethy1)benzofuran-2—y1)methyl)-3~(6—amin0pyridiny1)acrylamide (633) was synthesized using the indicated reagents accoeding to l Procedure 4. Yield (9%). 1H NMR (500 MHz, DMSO-d6) 5 .82 (m, 1H), 8.72—8.64 (m, 2H), 8.41 (d, J= 6 Hz, 1H), 8.22(t,J=9Hz,1H),814—8.02(m 2H), 763 (dd, J1: 9Hz, J2=2Hz, 1H), 7.,36(d J: 16 Hz 1H), 7.01 (s, 1H), 6. 53—6. 37 (m, 4H), 4.92-4.45 (m, 4H), 4.00-3.52 (m, 4H), 1.98—1.75 (m, 2H). LCMS: m/z 564. 3 [M+H]+; tR— 1.62 min.
Synthesis of (E)-N—((5—(5—(1-0xaazaspir0[3.3]heptane—6—carb0ny1)pyridin—2-yl) (trifluoromethyl)benzofuran-2—yl)methyl)(6-amin0pyridin—3-yl)acrylamide (634).
N / \ | fl 0/ — OH HN \ 2 / 123 N 0 0 _TFA_.. F03 £0 / . N/ \ l H _ N CH2CI2 \ O HN \ / HATU, DIPEA, DMF 2 x N o (E)—N—((5-(5—(1—oxaazaspiro[3.3]heptanecarbonyl)pyridin—2-yl)—7- (trifluoromethyl)benzofuran—2-y1)methy1)(6-aminopyridinyl)acrylamide (634) was synthesized using the indicated reagents ding to General Procedures 3 and 4. Yield (21%).1H NMR (400 MHz, 6) 5 8.92 (d, J= 2 Hz, 1H), 8.71 (s, 1H), 8.67 (t, J= 6 Hz, 1H), 8.41 (s, 1H), 8.21 (d,J= 8 Hz, 1H), 8.17-8.12 (m, 1H), 8.09 (d, J= 2 Hz,1H),7.66- 7.59 (m, 1H), 7.36 (d, J: 16 Hz, 1H), 7.00 (s, 1H), 6.51-6.39 (m, 4H), 4.67-4.54 (m, 4H), 4.47-4.33 (m, 3H), 4.21-4.12 (m, 1H), 2.86 (t, J: 8 Hz, 2H). LCMS: m/z 564.3 [M+H]+; tR = 1.65 min. —200- Synthesis of (E)—3—(6—aminopyridinyl)-N—((7-methoxy(4- (morpholinosulfonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (635).
OB 9 /‘\ S—N o n \_/ NOMO TFA NHBoc O O NHBoc ———> CHZCIZ Pd(dppt)C12 K2003, e H20 0 HATU, DIPEA CHZCIZ Synthesis of tert-butyl (7-meth0xy—5-(4- (morpholinosulfonyl)phenyl)benzofuran-Z-yl)methylcarbamate (178): tert—butyl (7— methoxy-S-(4-(morpholinosulfonyl)phenyl)benzofuranyl)methylcarbamate (178) was synthesized using the indicated reagents according to General Procedure 2. Yield (54%).
LCMS: m/z 503 l [M+H]; tR~ 170 min Synthesis of (7-methoxy(4-(morpholinosulfonyl)phenyl)benzofuran yl)methanamine (179): (7-methoxy—5-(4—(morpholinosulfonyl)pheny1)benzofuran—2— yl)methanarnine (179) was syntheized using the indicated reagents according to General Procedure 3. Yield (100%). LCMS: m/z 403.2 [M+H]+; Q; = 1.10 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-meth0xy(4- (morpholinosulfonyl)phenyl)benzofuran-2—yl)methyl)acrylamide (635): (E)(6- aminopyridin-3~yl)-N—((7-methoxy-5~(4-(morpholinosulfonyl)phenyl)benzofiiran-Z- yl)methyl)acrylamide (635) was synthesized using the indicated reagents according to General ure 4. Yield (4%). 1H NMR (400 MHz, CDCl3) 8 .20 (m, 1H), 7.83- 7.74 (m, 4H), .52 (m, 3H), 7.36-7.34 (m, 1H), 6.99-6.97 (m, 1H), 6.74 (s, 1H), 6.50 (d, J= 8 Hz, 1H), 6.25 (d, J= 16 Hz, 1H), 4.75 (d, J= 6 Hz, 2H), 4.67 (s, 2H), 4.09 (s, 3H), 3.79-3.76 (m, 4H), 3.07-3.04 (m, 4H). LCMS: m/z 549.2 [M+H]+, tR= 1.32 min. sis of (E)(6-amin0pyridin-3—yl)-N-((7—chlor0-5—(4-flu0r0—3- (morpholin0sulfonyl)phenyl)benzofuranyl)methyl)acrylamide (636).
B NHBoc F o NH F o \_/ 9 43 m Cl obs ——-—> 0 N38‘ _____________, o EtaN. CH2CI2 \—/ o f)C|2, K2003, Br Br dioxane, H20 180 181 / o5 o HO |\ (‘3' N NH2 NHz —. 0 \ H /N1 N \ \ EDCLHOBt, 0' O DMF o Synthesis of 4-(5-Br01110flu0r0phenylsulfonyl)morpholine (181): Morpholine (0.64 g, 7.3 mmol) was ved in 20 mL of CH2C12. Et3N (0.74 g, 7.3 mmol) and 5-bromo—2-fluorobenzene—1-sulfony1 chloride (1.0 g, 3.67 mmol) were added at 0 OC. The mixture was allowed to warm up to room ature and stirred for 3 h. The mixture was poured into iced water, extracted with CH2C12 (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 4—(5-bromo—2—fluorophenylsulfonyl)morpholine (181) as a white solid (1.18 g, Yield: 100%). LCMS: m/z 324 [M+H]+; tR = 1.63 min.
Synthesis of tert-Butyl (7-chlor0(4-fluoro (morpholin0sulf0nyl)phenyl)benzofuranyl)methylcarbamate (182): tert—Butyl (7- chloro—S-(4-fluoro-3 -(morpholinosulfonyl)phenyl)benzofi1rany1)methy1carbamate (182) was sized using the indicated reagents according to General Procedure 2. Yield (77%).
LCMS: m/Z 547.1 [M+Na]+; rR = 1.78 min.
Synthesis of (7-Chlor0(4-flu0r0(m0rpholinosulfonyl)phenyl)benzofuran- 2-yl)methanamine (183): (7-Chloro(4-fluoro—3 -(morpholinosulfonyl)phenyl)benzofuran- 2-yl)methanamine (183): was synthesized using the indicated reagents according to General Procedure 3. Yield (100%). LCMS: m/z 426.0 [M+H]+; IR = 1.72 min. sis of (6-amin0pyridinyl)-N-((7-chlor0(4-fluoro (morpholin0sulf0nyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (636): (E)(6— aminopyridiny1)-N-((7-chloro—5-(4—fluoro(morpholinosulfony1)pheny1)benzofuran-Z- y1)methy1)acry1amide (636): was synthesized using the indicated reagents according to General Procedure 1. Yield (31%). 1HNMR (400 MHZ, CD3OD) 5 8.08 (d, J = 9 Hz, 1H), 7.97-7.81 (m, 3H), 7.64 (s, 1H), 7.48-.30 (m, 3H), 6.94 (d, J: 9 Hz, 1H), 6.76 (s, 1H), 6.54 (d, J: 16 Hz, 1H), 4.60 (s, 2H), 3.66-3.58 (m, 4H), 3.12-3.03 (m, 4H). LCMS: m/z 571.1 [M+H]+, IR = 1.40 min.
Synthesis of (E)—3-(6-aminopyridinyl)-N—((7-methoxy(4-(piperazine carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (637). 0— Ho ‘0 \o (HO)ZB‘©_§ /0 TFA ——>0000—4 o o .
B°°HN \ CHZC'Z H2" \ / \ Pd Synthesis of methyl amin0methyl)meth0xybenzofuranyl)benzoate (185). Methyl 4-(2-((tert-butoxycarbonylamino)methyl)-7—methoxybenzofuran—5- yl)benzoate (184); (2.3 g, 5.6 mmol) was dissolved in CHZCIZ (50 mL). TFA (10 mL) was —203- added at 0 °C. The on mixture was stirred at room temperature for 1 h, and trated under reduced re to give the crude methyl 4—(2—(aminomethyl) methoxybenzofuranyl)benzoate (185), which was used without further purification in the next step. Yield (100%). LCMS: m/z 334.0 [M+Na]+; IR = 1.23 min.
Synthesis of (E)-methyl 4-(2-((3-(6-amin0pyridin-3—yl) acrylamido) methyl)methoxybenzofuran-S-yl) benzoate (186): The crude methyl methyl 4—(2~ methyl)methoxybenzofuranyl)benzoate (185); crude mixture from previous step, .6 mmol) was dissolved in DMF (50 mL) and (E)—3-(6-aminopyridinyl)acrylic acid (1.1 g, 6.6 mmol) was added at 0 °C. HATU (2.5 g, 6.6 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (1.4 g, 11.2 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , and concentrated under reduced pressure to give 1.64 g crude product, which was used without further purification in the next step. Yield (64%). LCMS: tR = 1.30 min.
Synthesis of (E)(2-((3-(6-amin0pyridin-3—yl) mido) methyl)—7- methoxybenzofuran-S-yl) benzoic acid (187): (E)—Methyl 4—(2-((3-(6—aminopyridin yl)acrylamido)methyl)methoxybenzofuran-5—yl)benzoate (186); (200 mg, 0.44 mmol) was dissolved in THF (10 mL). LiOH (30 mg, 1.3 mmol) and water (2.5 mL) were added to this mixture. The mixture was stirred at room ature for 2 h, 1N HCl solution was added and adjusted to pH = 6. 180 mg of (E)(2—((3-(6-aminopyridin yl)acrylamido)methyl)—7-methoxybenzofurany1)benzoic acid (187) was collected by filtration. Yield (90%). LCMS: m/z 444.3 [M+H]+, IR: 1.17 min.
Synthesis of rt-butyl 4-(4-(2-((3-(6-aminopyridin yl)acrylamid0)methyl)meth01q1benzofuran-S-yl)benzoyl)piperazinecarboxylate (188): (E)—4-(2-((3-(6-aminopyridin~3—yl)acrylamido)methyl)~7—methoxybenzofuran—5— yl)benzoic acid (187); (180 mg, 0.4 mmol) was dissolved in DMF (10 mL) and tert-butyl piperazine-l-carboxylate (89 mg, 0.48 mmol) was added at 0 °C. HATU (180 mg, 0.48 mmol) were added to this reaction mixture at 0 °C followed by DIPEA (31 mg, 0.22 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was transferred into water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give 200 mg crude product which was -204— used without further purification in the next step. Yield (81%). LCMS: m/z 612.3 [M+H]+, tR = 1.33 min.
Synthesis of (E)(6-aminopyridin-3—yl)—N-((7-meth0xy—5-(4-(piperazine carb0nyl)phenyl)benz0furan-Z-yl)methyl)acrylamide (637): (E)-tert—Butyl 4-(4—(2-((3—(6— aminopyridin—3—yl)acrylamido)methyl)—7-methoxybenzofuran—5—yl)benzoyl)piperazine— 1 - carboxylate (188); (0.2 g, 0.33 mmol) was dissolved in CH2C12 (10 mL). TFA (2 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 h, and concentrated under reduced pressure to give the crude product which was purified by Prep- HPLC without workup to afford 16 mg of (E)(6-aminopyridiny1)-N-((7-meth0xy—5- (4-(piperazine—1—carbonyl) phenyl) benzofuran—2-yl)methyl)acrylamide (637). Yield (10%). 1H NMR (400 MHz, CD3OD) 5 8.07-8.00 (m, 1H), 7.93 (s, 1H), 7.67 (d, J: 8 Hz, 2H), 7.47 (d, J: 8 Hz, 2H), 7.37 (d, J: 16 Hz, 1H), 7.32-7.29 (m, 1H), 7.01 (s, 1H), 6.89 (d, J: 9 Hz, 1H), 6.65 (s, 1H), 6.52 (d, J: 16 Hz, 1H), 4.56 (s, 2H), 3.94 (s, 3H), .67 (m, 4H), 3.27-3.22 (m, 4H). LCMS: m/z 512.3 [M+H]+, IR=1.06 min.
Synthesis of (E)—3-(6—aminopyridinyl)—N—((7-meth0xy—5-(5-(m0rpholine—4— yl)pyrimidinyl)benzofuran-Z-yl)methyl)acrylamide (638).
N_ _ —o \ (HO)ZB—<\% N_ o O N O @ ::>—<:—> O \ / O N 0 BOGHN CHzClz H N \ Pd(dppf)C|2.C82003 / BOCHN Br dioxane. H20 172 190 0 ~o tH2 ._ / ~. 0 \N / LiOH HN H \W —’ Hsz/Y :H: /| N OH THF H20 Nx N \ HATU, DIPEA, DMF O .
HN o — w——.
HATU. DIPEA, DMF 9833WE (6-aminopyridi'n-3~yl)—N-((7—meth0xy—5-(5-(morpholine-4— carbony1)pyrimidinyl)benzofuran—2-yl)methyl)acrylamide (638) was synthesized in a similar fashion as example 637 using the ts indicated. Yield (10%). 1H NMR (400 MHz, CD3OD) 5 8.82 (s, 2H), 8.23 (s, 1H), 8.12—8.05 (m, 1H), 7.97—7.91 (m, 2H), 7.37 (d, J —205 - =16 HZ, 1H), 6.94 (d, J= 9 Hz, 1H), 6.71 (s, 1H), 6.53 (d, J: 16 Hz, 1H), 4.58 (s, 2H), 3.96 (s, 3H), 3.76—3.44 (m, 8H). LCMS: m/z 515.2 [M+H]+, tR= 1.14 min.
Synthesis of (6-aminopyridinyl)-N-((7-meth0xy(5-(piperazine carb0nyl)pyrimidin—2—yl)benzofuranyl)methyl)acrylamide (639).
H/—\N \_/NBoc / a}? 1HATU DIPEA DMF HZN O" /| )‘wo 2. TFA CH2C|2 N\ H N / NW (E)-3 -(6-amin0pyridin—3—y1)—N—((7—meth0xy(5-(piperazine— 1- carbony1)pyrimidin—2—y1)benzofurany1)methy1)acrylamide (639) was synthesized using the ted reagents according to General Procedures 2 and 3. Yield (31%). 1H NMR (400 MHZ, CD30D) 8 8.83 (s, 2H), 8.19 (s, 1H), .03 (m, 1H), 7.91-7.87 (m, 2H), 7.34 (d, J =16 Hz, 1H), 6.92 (d, J: 9 Hz,1H), 6.69 (s, 1H), 6.52 (d, J= 16 Hz, 1H), 4.57 (s, 2H), 3.94 (s, 3H), 3.92—3.76 (m, 4H), 3.31—3.23 (m, 4H). LCMS: m/z 514.2 [M+H]+, tR= 1.04 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-meth0xy(5-(m0rpholine carb0nyl)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (640). "/o\ lo QL‘; _ o— N 0 Br — NHBoc o’ ""300 31W fl ,B—B\ \ \0 0 N o o \ / o —>BOCHN O ——> \ /O o Pd(dPPf)C|2, 0\ Pd(dppf)C|2. K2003.
ACOK, dioxane dioxane, H20 172 193 194 .20 _ / N" o N- O HZN \ / OH H2N / TFA O \ / LiOH _. o \ / N—, 0W" O \ / /o —.
CHzc'z HEN \ / HATU, DIPEA, DMF THF, H20 195 196 —O —O N— O HN O N o HzN \_/ HZN / / o 1 \ / o — \‘/ OH N N n \ NJ 1 \ \ / HATU,D|PEA,DMF / O o o 0 (E)—3—(6—aminopyridiny1)—N—((7—meth0xy-5—(5—(m0rph01ine—4— carbony1)pyridin—2—y1)benzofuran—2-yl)methy1)acry1arnide (640) was prepared in a —206— similar fashion as example 565 using the indicated reagents. Yield (50%). 1H NMR (400 MHz, CD3OD) 5 8.62 (s, 1H), 8.10—7.87 (m, 4H), 7.66 (s, 1H), 7.45 (s, 1H), 7.34 (d, J: 16 Hz, 1H), 6.92 (d, J: 9 Hz, 1H), 6.68 (s, 1H), 6.51 (d, J: 16 Hz, 1H), 4.57 (s, 2H), 3.95 (s, 3H), 3.76—3.39 (m, 8H). LCMS: m/z 514.1 [M+H]+, tR= 1.15 min.
Synthesis of (6-aminopyridinyl)-N-((7-methoxy(5-(piperazine-l-carb0nyl) pyridinyl)benzofuran-Z-yl)methyl)acrylamide (641).
CNBDC 0/ N O HNNQVWHmi 1HATU, DlPEA, DMF HzN , \ 2 TFA CH2C|2 %H \ LNHN’» (6—aminopyridin—3—yl)—N—((7—methoxy(5 —(piperazine- l -carbonyl) n- 2-yl)benzofuranyl)methyl)acrylamide (641) was synthesized using the indicated reagents according to General Procedures 2 and 3. Yield (50%). 1H NMR (400 MHz, CD30D) 5 8.65 (s, 1H), 8.08 (d, J: 9 Hz, 1H), 7.96-7.87 (m, 3H), 7.70 (s, 1H), 7.50 (s, 1H), 7.36 (d, J= 16 Hz, 1H), 6.94 (d, J: 9 Hz, 1H), 6.69 (s, 1H), 6.53 (d, J: 16 Hz, 1H), 4.57 (s, 2H), 3.96 (s, 3H), 3.91—3.70 (m, 4H), 3.30—3.22 (m, 4H). LCMS: m/z 513.2 [M+H]+, 1R: 1.05 min.
Synthesis of (E)(6-aminopyridinyl)—N-((7—chlor0(4—(3,3—diflu0roazetidin-l- ylsulfonyl)phenyl)benzofuran—2—yl)methyl)acrylamide (642). 0 CI oO FjgNH NHB..
HCI >§r§ NHBoc 0. O 0\\Ob NQ‘s/GB :5\ 0'73" TEA DCM Ff: W FjC/N ‘o O Pd(dPPf)C|2. K2003. dloxane, H20‘ TFA 0‘30ij WWW WNJ<_2:<:H [=be 200 VC/O EDCI HOBt DIPEA DMF Synthesis of l-(4-Br0mophenylsulfonyl)-3,3-difluoroazetidine (198): 1-(4- Bromophenylsulfonyl)-3,3—difluoroazetidine (198) Was synthesized using similar to procedure of intermediate (199). Yield (92%). LCMS: m/z 311.9 [M+H]+, IR = 1.85 min.
Synthesis of tert-Butyl (7—chlor0—5—(4—(3,3—diflu0r0azetidin onyl)phenyl)benzofuranyl)methylcarbamate (199): Synthesis of utyl (7- chloro— 5 -(4-(3 ,3 —difluoroazetidin—1-y1sulfonyl)phenyl)benzofuran—2—yl)methylcarbamate —207- (199) was synthesized using General ure 2. Yield (53%). LCMS: m/z 513.0 [M+H]+, tR = 1.98 min.
Synthesis of (7-Chloro-S-(4—(3,3—diflu0roazetidin-1— ylsulfonyl)phenyl)benzofuranyl)methanamine (200): (7-Chloro(4-(3,3- difluoroazetidin-l-ylsulfonyl)phenyl)benzofuran—2-yl)rnethanarnine (200) was synthesized using General Procedure 3. Yield (100%). LCMS: m/z 413.7 [M+H]+, IR = 1.29 min.
Synthesis of (E(6-aminopyridin-S-yl)-N—((7—chloro—S-(4-(3,3- difluoroazetidinylsulf0nyl)phenyl)benzofuranyl)methyl)acrylamide (642): (E) (6-aminopyridin-3 -yl)-N-((7-chloro- 5-(4-(3 ,3 roazetidin-1 - ylsulfonyl)phenyl)benzofuran—2-yl)methyl)acrylamide (642) was synthesized using General Procedure 4. Yield (25%). 1H NMR (400 MHz, CD3OD) 5 7.95 (s, 1H), 7.91-7.84 (m, 4H), 7.77 (s, 1H), 7.64 (d, J: 9 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J: 16 Hz, 1H), 6.78 (s, 1H), 6.50 (d, J: 9 Hz, 1H), 6.37 (d, J: 16 Hz, 1H), 4.60 (s, 2H), 4.13 (t, J: 12 Hz, 4H). LCMS: m/z 559.1 [M+H]+, 1R: 1.85 min.
Synthesis of (S,E)(6-amin0pyridin-3—yl)—N-((7-chlor0(4-(3-flu0r0pyrr01idin ylsulfonyl)phenyl)benzofuran-2—yl)m'ethyl)acrylamide (643). 00 ° Br m / Br HCIHNQ‘F 0‘0 / NHBoc NHBoo \ 0.? O O Q. ——» N180 >§f° 43 fsi c|/S\\ M o _ N ‘o o Pd(dppf)C|2, K2003, 201 202 dioxane,H20 F CI 0 0 O 0 / O HN / W11 O — TFA 0" NH2 \ "ZN ,8 o 0 N .\ i) / _—_.... N Q!‘b EDCI, HOBt, DIPEA, DMF 203 643 NHZ (S,E)(6-aminopyridin-3 -yl)—N—((7-chloro- 5-(4-(3 -fluoropyrrolidin ylsulfonyl)phenyl)benzofuranyl)methyl)acrylamide (643) was synthesized in a similar fashion as example 642 using the indicated reagents. Yield (12%). 1H NMR (400 MHZ, CD3OD) 5 8.07 (d, J= 2 Hz, 1H), 7.97-7.84 (m, 5H), .73 (m, 1H), 7.67 (d, J= 2 Hz, 1H), 7.50 (d, J: 16 Hz, 1H), 6.88 (s, 1H), 6.62 (d, J: 9 Hz, 1H), 6.49 (d, J: 16 Hz,1H), .18 (d, J: 52 Hz, 1H), 4.71 (s, 2H), 3.65-3.43 (m, 4H), 2.19-1.90 (m, 2H). LCMS: m/z 555.2 [M+H]+, 1R: 1.81 min. sis of (E)(6-aminopyridinyl)-N-((5-(4-(3,3-diflu0roazetidin—l- ylsulfonyl)phenyl)(triflu0r0methyl)benz0furanyl)methyl)acrylamide (644). mNHBoc Kiss CF3 Oxs/Q/Br 0O / NHBoc FjC/NO Pd(dppf)C|2 K2003 (3‘s 0 CHZCIZ F dioxiane H20 FjC/N "O 204 - O / ct O F\,C/N,s\\ EDCE HOBl, 0 DIPEA, DMF 205 {—22 F NHZ [006 73] (FD-3 -(6-aminopyridiny1)-N—((5 -(4-(3,3-difluoroazetidinylsulfonyl)phenyl)- fluoromethyl)benzofuranyl)Inethyl)acrylamide (644) was synthesized in a similar fashion as example (643) using the indicatd reagents. Yield (27%). 1H NMR (400 MHz, CD30D) 6 8.21 (s, 1H), .06 (In, 5H), 7.89 (s, 1H), 7.77-7.74 (In, 1H), 7.50 (d, J: 16 Hz, 1H), 6.95 (s, 1H), 6.62 (d, J: 9 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), 4.77-4.73 (In, 2H), 4.28-4.22 (In, 4H). LCMS: m/z 593.2 [M+H]+; tR = 1.89 min.
(E)(6-amin0pyridinyl)—N—((5-(5-(3,3-diflu0r0azetidine—1-carb0nyl)pyridinyl)—7- (trifluoromethyl)benzofuran—Z-yl)methyl)acrylamide (645).
F F F F F HN<>74? 1 O—B NHBoc [ \ /N / HN N 0 2 | |\ HCHO.HCOOH / |\ GI 43 \N NHBoc TFA N/ Br N/ Br CH20l2 Pd(dppf)C|2. K2003, 0 dioxane, H20 1 \ NH2 /N/ \l i HOOC N NH2 EDCI HOBt DIPEA O CHQCIQ Synthesis of (E)—3-(6-aminopyridin-3—yl)—N—((7-chlor0-5—(5- (dimethylamin0)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (646): (E)-3—(6— aminopyridiny1)-N—((7-chioro—5—(5-(dimethylamino)pyridin—2-y1)benzofuran—2— y1)methy1)acry1arnide (646) in a similar fashion as example (644) using the ted reagents. 1H NMR (400 MHZ, DMSO-d6) 6 8.62 (t, J: 6 Hz, 1H), 8.21-8.07 (m, 3H), 8.00 (s9 1H), 7.84 (d, J: 9 Hz, 1H), 7.65-7.58 (rn, 1H), 7.35 (d,J= 16 Hz, 1H), 7.22-7.14 (rn, 1H), 6.88 (s, 1H), .36 (m, 4H), 4.58 (d, J: 6 Hz, 2H), 2.99 (s, 6H). LCMS: m/z 448.2 [M+H]+, [R = 1.70 min.
Synthesis of (E)(6-aminopyridin—3—yl)—N-((5-(5-(4-flu0rophenyl)—3-methylisoxazol yl)(triflu0romethyl)benzofuranyl)methyl)acrylaniide (648). 212 648 (6-aminopyridiny1)-N-((5-(5-(4-fluoropheny1)-3—methy1isoxazol—4-y1) (trifluoromethy1)benzofuran—2-y1)methyl)acry1amide (648) was synthesized using the indicated reagents according to General Procedure 1. Yield: 41%. 1H NMR (400 MHz, CD3OD) 8 7.91 (s, 1H), 7.72-7.58 (m> 2H), 7.44—7.31 (m, 4H), 7.03-6.91 (m, 2H), 6.76 (s, 1H), 6.48 (d, J= 9 Hz, 1H), 6.41-6.29 (m, 1H), 4.59 (s, 2H), 2.11 (s, 3H). LCMS: m/z 537.2 [M+H]+, IR = 1.83 min.
Synthesis of (6-amin0pyridinyl)-N-((7-chlor0(5-(piperazine—1- carbonyl)pyrimidinyl)benzofuran-Z-yl)methyl)acrylamide (649).
C/M\ HN\_/NBoc ::>_/ Synthesis of (E)—3-(6-amin0pyridinyl)—N-((7-chloro-S-(S-(Z—hydroxypropan yl)thiophenyl)benzofuran-Z-yl)methyl)acrylamide (650).
TFA CH M3 g Br //8 NHBOC NH DCM 0\ HZN // HATU, DIPEA, DMF Synthesis of 1-(5-(2-(aminomethyl)chlorobenzofuran-S-yl)thi0phen yl)ethanone (214): tert—Butyl (5-(5~acetylthiophen—2-yl)—7-chlorobenzofuran-2— hylcarbamate (213; 200 mg, 0.49 mmol) was dissolved in CHzClz (5 mL) and TFA (1 mL) was added se at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by Prep-TLC (5% CM) to give 120 mg of 1- (5-(2—(aminomethyl)—7-chlorobenzofuranyl)thiophenyl)ethanone (214) (80% yield).
LCMS: m/z 306.0 [M+H]+; IR = 0.97 min.
Synthesis of 2-(5-(2-(aminom‘ethyl)chlor0benzofuran-S-yl)thiophen—2- yl)pr0panol (2 1 5): 1—(5 —(2— (Aminomethyl)chlorobenzofuran—5 —yl)thiophen-2— —211~ anone (214); (200 mg, 0.65 mmol) was dissolved in THF (10 mL) and CHgMgBr (1.8 mL, 5.2 mmol, 3M in THF) was added dropwise at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was cooled down to 0 °C (ice bath), sat. NaHCO3 aqueous solution (10 mL) was added to the reaction mixture and extracted with dichloromethane (15 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC to give 100 mg of 2—(5-(2-(aminomethyl)-7—chlorobenzofuranyl)thiophenyl)propanol (215) (48% yield). LCMS: m/z 344.9 [M+Na]+; rR = 1.34 min.
Synthesis of (E)(6-amin0pyridinyl)—N-((7-chloro-S-(S—(Z- hydroxypr0panyl)thi0phenyl)benzofuranyl)methyl)acrylamide (650). 2-(5-(2- (Aminomethyl)—7-chlorobenzofuranyl)thiopheny1)propan—2—ol (215); (100 mg, 0.3 mmol) was dissolved in DMF (2 mL) and (E)—3—(6-arninopyridin—3~yl)acrylic acid (49 mg, 0.3 mmol), HATU (136 mg, 0.36 mmol), DIPEA (77 mg, 0.6 mmol)) were added at room temperature. The reaction mixture was d at room temperature for 4 h and purified by Prep—HPLC without work up to give 9 mg of (E)—3—(6—aminopyridin—3-yl)—N-((7—chloro(5- (2-hydroxypropanyl)thiophen—2—yl)benzofi1ran-2—yl)methyl)acrylamide (650). Yield 6%. 1HNMR (400 MHz, CD3OD) 5 8.07 (s, 1H), .69 (m, 2H), 7.58-7.45 (m, 2H), 7.21 (d, J = 4 Hz, 1H), 6.94 (d, J: 4 Hz, 1H), 6.81 (s,1H), 6.62 (d, J: 9 Hz, 1H), 6.48 (d, J: 16 Hz, 1H), 4.68 (s, 2H), 1.65 (s, 6H). LCMS: m/z 468.0 [M+H]+, tR= 1.74 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5—(4,4-difluorepiperidine carbonyl)pyridinyl)methoxybenzofuranyl)methyl)acrylamide (651). oc N NHBoc w, F /.
CH2012 F \ Pd((dppfiCl2K2003 dioxane H20 /o :45HATU.DIPEA. DMF (E)-3 -(6-aminopyridin-3—yl)-N—((5—(5-(4,4—difluoropiperidinecarbonyl)pyridin- 7-(trideuteromethoxy)benzofuran—2—yl)methyl)acry1amide (651) was synthesized in a —212- similar fashion as example (640) using the indicated reagents. 1H NMR (400 MHZ, DMSO- d6) 8 8.77-8.71 (m, 1H), 8.64-8.54 (m, 1H), 8.15-7.92 (m, 4H), 7.70 (s, 1H), 7.65-7.58 (m, 1H), 7.36 (d, J: 16 HZ, 1H), 6.82 (s, 1H), 6.49-6.40 (m, 4H), 4.56 (s, 2H), 4.03 (s, 3H), 3.83— 3.43 (m, 4H), .00 (m, 4H). LCMS: m/z 548.0 , tR = 1.37 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4,4-difluoropiperidine carbonyl)pyrimidinyl)(triflu0romethyl)benzofuranyl)methyl)acrylamide (652).
F30 ""3F F30 H2N / F N o H2N / I /:\>_/_/< N\ H N‘ OH \ HATU,D|PEA.DMF WE N_ Q 0 o F 169 552 (E)-3 —(6—aminopyridin—3 —yl)—N—((5-(5—(4,4-difluoropiperidine— 1 - carbonyl)pyrimidinyl)—7—(trifluoromethyl)benzofuran—2-yl)methyl)acrylamide (652) was synthesized using the indicated reagents according to General Procedure 4. Yield 83%. 1H NMR (400 MHZ, CD3OD) 6 8.91—8.82 (m, 3H), 8.63 (s, 1H), 8.10 (d, J: 9 HZ, 1H), 7.97— 7.91 (m, 1H), 7.38 (d, J: 16 HZ, 1H), 6.95 (d, J: 9 HZ, 1H), 6.88 (s, 1H), 6.55 (d, J: 16 HZ, 1H), 4.63 (s, 2H), 3.90—3.50 (m, 4H), 2.11—1.94 (m, 4H). LCMS: m/z 587.1 [M+H]+, IR: 1.30 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((5-(5-(3,3-diflu0ropyrrolidine-l- carbonyl)pyrimidin-Z—yl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (653).
F30 7 HN N 0 0" HATU, DIPEA DMF le N_ N \ / OTFN (ID(6-aminopyridin-3—yl)—N—((5-(5—(3,3-difluoropyrrolidine carbonyl)pyrimidin—2-yl)—7—(trifluoromethyl)benzofi1ran—2—yl)methyl)acrylamide (652) was synthesized using the ted reagents according to General ure 4. Yield 50%. 1H NMR (400 MHZ, CD30D) 8 8.84 (s, 3H), 8.62 (s, 1H), 7.95 (s, 1H), 7.67-7.60 (In, 1H), 7.38 (d, J= 16 HZ, 1H), 6.85 (s, 1H), 6.49 (d, J= 9 HZ, 1H), 6.37 (d, J= 16 HZ, 1H), 4.61 (s, 2H), 3.75-3.46 (m, 4H), 2.50-2.36 (m, 4H), 2.25 (s, 3H). LCMS: m/z 566.2 [M+H]+, IR= 1.55 min.
Chiral resolution of (E)—3-(6-aminopyridinyl)-N—((5-(5—(3-flu0r0methylpyrrolidine- 1-carb0nyl)pyridinyl)(triflu0r0methyl)benzofuranyl)methyl)acrylamide (617). —213- 120 mg of Compound 617 was resolved under the following chiral HPLC conditions to afford a crude mixture of cis—trans isomers 654 and 656 and a crude mixture of cis—trans isomers 655 and 657: Column: AD-H (250*4.6mm X 5pm) Mobile Phase: n-hexane(0.1%DEA):EtOH(0.1%DEA) = 10:90 Flow: 1.0 mL/minute Temperature: 40 °C Wavelengths: 214 nm and 254 nm Instrument: SHIMADZU.
Cis, single enantiomer 656 was formed during the concentration of trans, single enantiomer 654, and cis, single enantiomer 657 was formed during the tration of trans, single enantiomer 655. 654 and 656 were uently separated from each other via ative TLC (6% MeOH/CHzClg) to give trans (or E), single enantiomer 654 and cis (or Z), single omer 656. 10 mg of 654 and 10 mg of 656 was obtained. 655 and 657 were also separated from each other via preparative TLC (6% MeOH/CHzClz) to give trans, single enantiomer 655 and cis, single enantiomer 657. 7 mg of 655 and 11 mg of 657 was obtained.
The absolute configuration of nds 654, 655, 656 and 657 has not been determined. Therefore, each of 654, 655, 656 and 657, as used herein in nce to a particular compound, refers to a compound having the indicated analytical data and the indicated retention time in the chiral preparative HPLC method described above for the chiral resolution of Compound 617. The analytical data and retention times for each of Compounds 654, 655, 656 and 657 are indicated below. (654) (IR = 19.46 s by chiral preparative HPLC). 1H NMR (400 MHZ, CD30D) 8 8.77-8.69 (m, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 8.01-7.89 (m, 3H), 7.65-7.58 (m, 1H), 7.37 (d, J: 16 Hz, 1H), 6.82 (s, 1H), 6.48 (d, J: 9 Hz, 1H), 6.36 (d, J: 16 Hz, 1H), 4.60 (s, 2H), 3.85-3.49 (m, 4H), 2.23-1.92 (m, 2H), 1.55-1.37 (m, 3H). LCMS: m/z 568.2 [M+H]+, rR = 1.27 min. (655) OR = 30.74 minutes by chiral preparative HPLC). 1H NMR (400 MHz, CD30D) 8 8.94—8.78 (m, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.13-8.05 (m, 3H), .69 (m, 1H), 7.50 (d, J: 16 Hz, 1H), 6.95 (s, 1H), 6.61 (d, J: 9 Hz,1H), 6.49 (d, J: 16 Hz, 1H), 4.73 (s, 2H), 3.98-3.60 (m, 4H), 2.31-2.06 (m, 2H), 1.67-1.48 (m, 3H). LCMS: m/z 568.2 [M+H]+, m = 1.31 min. -214— (657) (tR = 7.51 minutes by chiral preparative HPLC). 1H NMR (400 MHZ, CD3OD) 6 8.76—8.70 (m, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 8.03—7.94 (m, 3H), 7.87—7.79 (m, 1H), 6.81 (s, 1H), 6.51 (d, J: 12 Hz, 1H), 6.26 (d, J: 9 Hz, 1H), 5.81 (d, J: 12 Hz, 1H), 4.54 (s, 2H), 3.86—3.48 (m, 4H), 2.23-1.89 (m, 2H), 1.55— 1.35 (m, 3H). LCMS: m/z 568.2 [M+H]+, m = 1.26 min. ] (656) (tR = 8.16 minutes by chiral preparative HPLC). 1H NMR (400 MHZ, CD3OD) 5 8.78-8.67 (m, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 8.02-7.89 (m, 3H), 7.86-7.79 (m, 1H), 6.78 (s, 1H), 6.51 (d, J= 13 Hz, 1H), 6.26 (d, J= 9 Hz, 1H), 5.80 (d, J= 13 Hz, 1H), 4.54 (s, 2H), 3.84-3.49 (m, 4H), 2.21-1.91 (m, 2H), 1.55- 1.36 (m, 3H). LCMS: m/z 568.2 [M+H]+, m = 1.30 min.
(R,E)(6-aminopyridin—3-yl)—N—((5—(5-(3-flu0r0methylpyrr01idine—1~ carbonyl)pyridinyl)—7-(trifluoromethyl)benzofuran—2-yl)methyl)acrylamide, (R,Z)(6- aminopyridin-3—y1)-N-((5-(5-(3-flu0r0-3~methylpyrrolidinecarb0nyl)pyridinyl)-7~ (trifluoromethyl)benzofuranyl)methy1)acrylamide, 3~(6-amin0pyridin—3-yl)-N-((5- (5-(3 -fluoro-3 —methylpyrrolidine- l —carbony1)pyridin—2—yl)-7—(triflu0r0methy1)benzofurarr yl)methyl)acrylamide and (S,Z)(6-aminopyridin-3~yl)-N-((5-(5-(3-flu0ro—3- methylpyrrolidine- l ~carb0nyl)pyridinyl)(trifluoromethyl)benzofuran—2— yl)methyl)acrylamide can be depicted as follows: F F F F o H2N O F \ —: O NH \ / l\\l I \ _ _ N / N NH \ 6 _ 1 / \ N / N — o HzN F F F o F F O F H2N NH \ O I 6 / \ o F~ —‘ N / N \ _ NH \ N/ \ —— | o N / N respectively.
Synthesis of (E)—3-(6-aminopyridinyl)—N—((5-(5-(4,4-difluoropiperidine—l- carb0nyl)pyridinyl)furo [2,3—b] pyridin-Z—yl)methyl)acrylamide (658).
BUG I \ NHBoc Br \ NHBoc PinZBz | —> I \ ___________+ OH DMF 50 0C N/ Pd(PPh3)ZC|2, Cul, O N/ O Pd(dppf)Clz, KOAC.
Et3N. DMF, 90 00 dloxane, 100- oC 218 219 9L FF 0 6 SB — N NHB00 BocHN / (:5 O m E" ‘ — N \ / O LA / N O \ / \ / N O N N O CHZCIZ Pd(dPPf)CI2. chost dioxane 100 0C 220 , H20, 222N sis of 5-bromoiodopyridinol (218): S-Bromopyridin—Z-ol (1.74 g, mmol) was dissolved in DMF (40 mL) and N18 (2.7 g, 12 mmol) was added at room temperature. The reaction mixture was heated at 50 0C for 6 h. The reaction mixture was cooled down to room temperature, poured into 50 mL of water, ted with EtOAc (60 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , and trated under reduced pressure to give 5—bromo-3~iodopyridin—2-ol (218) as yellow solid (1.0 g, 33% yield). LCMS: m/z 301.9 [M+H]+; IR = 1.34 min.
Synthesis of tert—butyl (5-bromofuro[2,3-b]pyridin—Z-yl) methylcarbamate (219): 5-Bromo—3-iodopyridin—2—ol (218); (200 mg, 0.67 mmol), tert—butyl prop ynylcarbamate (104 mg, 0.67 mmol), Pd(PPh3)2C12 (47 mg, 0.07 mmol), CuI (13 mg, 0.07 mmol), and ylamine (135 mg, 1.34 mmol) were added in 10 mL of DMF and degassed.
The reaction mixture was heated at 90 0C under nitrogen atmosphere for 3 h. After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, Which was purified by silica gel chromatography (30% EtOAc/petroleum ether) to yield 150 mg of tert—butyl (5- bromofuro[2,3-b]pyridinyl) methylcarbamate (219) as a yellow solid (69% yield). LCMS: m/z 329.0 ; rR = 1.76 min.
Synthesis of tert—butyl (5-(4,4,5,5~tetramethyl-1,3,2~di0xab0rolan o[2,3-b]pyridin-Z-yl)methylcarbamate (220): tert—Butyl (5-bromofuro[2,3~b]pyridin— 2-yl) methylcarbamate (219); (600 mg, 1.8 mmol), 4,4,4’,4',5,5,5’,5'—octamethy1—2,2'—bi(1,3,2— dioxaborolane) (460 mg, 1.8 mmol), Pd(dppf)C12 (147 mg, 0.18 mmol), and potassium —216- acetate (353 mg, 3.6 mmol) were added in 10 mL of dioxane and degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture was d. The filtrate was concentrated under reduced re to give the crude product, which was purified by silica gel chromatography (5—20% EtOAc/petroleum ether) to yield 300 mg of tert—butyl (5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2—yl)furo[2,3—b]pyridin—2-yl)methylcarbamate (220) as a yellow solid (45% yield). LCMS: m/z 375.2 [M+H]+, tR= 1.36 min. sis of tert—butyl (5-(5-(4,4-difluoropiperidine-l-carbonyl)pyridin yl)furo[2,3-b]pyridin-Z-yl)methylcarbamate (221): (6-Bromopyridinyl)(4,4- difluoropiperidin—1—y1)methanone (83 mg, 0.27 mmol), tert—butyl 4,5,5-tetramethyl— 1,3,2—dioxaborolan—2-yl)fi1ro[2,3-b]pyridin—2—yl)methylcarbamate (220); (100 mg, 0.27 mmol), Pd(dppf)C12 (22 mg, 0.03 mmol), and K2C03 (75 mg, 0.54 mmol) were added in a mixture of (10:1) e (10 mL) and water (1 mL) and degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 3 h. The reaction e was cooled down to room temperature and filtered. The solids ted were rinsed with ethyl acetate and discarded. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel tography (30% EtOAc/petroleum ether) to yield 100 mg of tert—butyl (5—(5—(4,4—difluoropiperidine—1-carbonyl)pyridin-2—yl)furo[2,3—b]pyridin—2— yl)methy1carbamate (221) as off-white solid (yield 39%). LCMS: m/z 473.2 [M+H]+, tR = 1.65 min.
Synthesis of (6—(2-(amin0methyl)fur0[2,3-b]pyridin-S-yl)pyridin-3—yl)(4,4- difluoropiperidinyl)methan0ne (222). tert-Butyl (5-(5-(4,4-difluoropiperidine—1- carbonyl)pyridin—2—yl)furo[2,3-b]pyridin-2—yl)methylcarbamate (221); (47.2 mg, 0.1 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was trated under reduced pressure to give (6-(2-(aminomethyl)furo[2,3-b]pyridin—5-yl)pyridin y1)(4,4-difluoropiperidinyl)methanone (222), which was used without further purification in the next step (35 mg, yield 85%). LCMS: m/z 373.2 [M+H]+; [R = 1.21 min.
Synthesis of (E)—3—(6—aminopyridin—3—yl)—N—((5-(5-(4,4-difluoropiperidine—1— carbonyl)pyridin—2—yl)furo[2,3—b]pyridin—2-y1)methyl)acry1amide (658): (6-(2- (Aminomethyl)furo[2,3 -b]pyridin—5—y1)pyridinyl)(4,4-difluoropiperidin- 1-y1)methanone (222); (37.2 mg, 0.1 mmol), (E)—3—(6—aminopyridin—3—yl)acrylic acid (16.4 mg, 0.1 mmol), ~217— PLATU (38 mg, 0.1 mmol), and triethylamine (21 mg, 0.2 mmol) were added in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , and concentrated under reduced pressure to give the crude product which was purified by Pre- HPLC to give (E)(6-aminopyridin-3~yl)-N-((5-(5-(4,4-difluoropiperidine-l- carbonyl)pyridinyl)furo[2,3-b]pyridin—2-yl)methyl)acrylamide (658) (30 mg, yield 57%). 1H NMR (400 MHZ, DMSO-d6) 6 9.00 (t, J= 2 Hz, 1H), 8.83-7.98 (m, 6H), 7.67-7.31 (m, 1H), 6.90 (s, 1H), 6.58-5.77 (m, 5H), 4.65-4.52 (m, 2H), .48 (m, 4H), 2.18-2.01 (m, 4H). LCMS: m/z 519.2 [M+H]+, IR: 1.50 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-cyclopropyl-S-(S-(4,4-difluoropiperidine- 1-carbonyl)pyridin-2—yl)benzofuran-Z-yl)methyl)acrylamide (659).
F >—B OH( )2 F \ NHB°° / F l NHBoc —>TFA N /N Pd(PPh3)4 PCYa, K3PO4, DCM dixoane H20, MW 223 224 0 \NM F / OH \ NH2 —————> F i HATU DIPEA DMF N /N Synthesis of utyl (7-cyclopropyl-S-(S-(4,4-difluoropiperidine—l— carbonyl)pyridinyl)benzofuranyl)methylcarbamate (224). tert—Butyl (7-chloro(5- (4,4-difluoropiperidine-1 -carbonyl)pyridin—2-yl)benzofi1ranyl)methylcarbamate (223); (300 mg, 0.6 mmol), cyclopropylboronic acid (155 mg, 1.8 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), PCy3 (40 mg, 0.12 mmol), and potassium phosphate (407 mg, 1.8 mmol) were added in a mixture of dioxane (5 mL) and H20 (0.5 mL) and ed. The reaction mixture was heated at 140 0C under ave condition for 1 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate was concentrated under d pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to yield 150 mg of tert—butyl (7-cyclopropyl—5-(5—(4,4— ~218- difluoropiperidine-l-carbonyl)pyridin—2-yl)benzofuran—2-yl)methy1carbamate (224) as a white solid (5 0% yield). LCMS: m/z 512.3 [M+H]+, 1R = 1.84 min.
Synthesis of (6-(2-(aminomethyl)—7—cyclopropylbenzofuran-S-yl)pyridin yl)(4,4-difluoropiperidinyl)methanone (225): tert—Butyl (7-cyclopropyl(5-(4,4- difluoropiperidine— 1 -carbonyl)pyridin—2-yl)benzofuran—2-yl)methylcarbamate (224); (1 00 mg, 0.2 mmol) was dissolved in CH2C12 (12 mL). TFA (2 mL) was added dropwise at 0 °C.
The reaction e was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give (6-(2-(aminomethyl)—7- cyclopropylbenzofurany1)pyridiny1)(4,4-difluoropiperidiny1)methanone (225), which was used without further purification in the next step (80 mg, 100% yield). LCMS: m/z 412.2 [M+H]+; 1R = 1.35 min. .
Synthesis of (E)(6-amin0pyridinyl)-N—((7-cyclopropyl—S-(S-(4,4- difluoropiperidine-l-carb0nyl)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (659). (6-(2-(Aminomethyl)—7—cyclopropylbenzofuran—5—y1)pyridin—3-y1)(4,4-difluoropiperidin— 1 — y1)methanone (225); (80 mg, 0.19 mmol) was ved in DMF (3 mL) and (6— aminopyridin—3-yl)acrylic acid (34 mg, 0.21 mmol) was added at 0 OC. HATU (87 mg, 0.23 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (74 mg, 0.57 mmol) dropwise. The on mixture was allowed to warm to room temperature and stirred further for 1 h. The reaction e was purified by Prep—HPLC to afford 40 mg of (6- aminopyridinyl)-N-((7-cyclopropyl(5—(4,4-difluoropiperidine-l—carbonyl)pyridin-2— y1)benzofuran—2-yl)methy1)acrylamide (659) (38% yield). 1H NMR (400 MHz, DMSO—d6) 8 8.81 (t, J= 6 Hz, 1H), 8.72 (d, J= 2 Hz, 1H), 8.33-8.05 (m, 6H), 7.95 (dd, J1= 8 Hz, J2 = 2 Hz,1H), 7.62 (d, J= 2 Hz,1H), 7.45 (d,J= 16 Hz,1H), 7.00 (d, J= 9 Hz, 1H), 6.82 (s, 1H), 6.62 (d, J= 16 Hz, 1H), 4.61 (d, J= 5 Hz, 2H), 3.83-3.42 (m, 4H), 2.35-2.27 (m, 1H), 2.16- 2.00 (m, 4H), 1.12-0.96 (m, 4H). LCMS: m/z 558.2 [M+H]+, 1R: 1.32 min.
Synthesis of (E)(6-aminopyridinyI)-N-((5-(5-(4,4-difluoropiperidine-l- carbonyl)pyridinyl)(methoxy-d3)benzofuranyl)methyl)acrylamide (660). -2l9- ~ /~ F \‘ NHBoc decanel ,0": NHB°° CDal K2003 NHBoc CH30N O tBuoK O 226 227 OH 225 o\ 0003 \ /N N / N TFA F | F HFQO: o CHZCI2 o HATU DIPEA DMF 0ch3 00030 Synthesis of tert-butyl (4,4-difluoropiperidinecarbonyl)pyridin yl)hydroxybenzofuran-Z-yl)methylcarbamate (227): lert-Butyl (5-(5-(4,4- difluoropiperidinecarbonyl)pyridin—2-yl)methoxybenzofuran—2-yl)methylcarbamate (226); (1 g, 2 mmol) was dissolved in 15 mL of DMF. Decanethiol (521 mg, 3 mmol) and t- BuOK (336 mg, 3 mmol) were added to this mixture. The mixture was heated to 110 °C and stirred for 1.5 h. After g to room temperature, the mixture was poured into 20 mL of H20, and extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NazSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10—20% ethyl acetate/petroleum ether) to afford 300 mg of tert—butyl (5—(5—(4,4-difluoropiperidine—1- carbonyl)pyridinyl)-7—hydroxybenzofuran—Z-yl)methylcarbamate (227) (31% yield).
LCMS: m/z 488 l [M+H]; 1R— 1.58 min ] Synthesis of tert-butyl (5-(5—(4,4-difluoropiperidine-l-carb0nyl)pyridinyl)— 7-(trideuter0methoxy)benzofuran—2—yl)methylcarbamate (228). tert-Butyl (5—(5—(4,4- difluoropiperidinecarbonyl)pyridinyl)hydroxybenzofurany1)methylcarbamate (5; 20 mg, 0.05 mmol) was disolved in 5 mL of CH3CN. K2CO3, (14 mg, 0.1 mmol) and CD31 (15 mg, 0.1 mmol) were added at room temperature. The mixture was stirred room temperature for 18 h. 3 mL of H20 was added and the mixture was extracted with ethyl acetate (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NazSO4, and concentrated under reduced re to give the crude product, which was purified by silica gel chromatography (20% ethyl acetate/petroleum ether) to give 10 mg of tert-butyl (5—(5-(4,4-difluoropiperidine—1-carbonyl)pyridin-2—yl) (trideuteromethoxy)benzofuran—2-yl)methylcarbamate (228) (50% yield). LCMS: m/z 505.1 [M+H]; tR— 168 min.
Synthesis of (6-(2—(amin0methyl)(trideuter0methoxy)benzofuran yl)pyridinyl)(4,4-difluor0piperidin-l—yl)methan0nc (229): tert—Butyl (5-(5-(4,4- difluoropiperidinecarbonyl)pyridinyl)—7—(trideuteromethoxy)benzofuran yl)methylcarbamate (228); (100 mg, 0.2 mmol) was dissolved in CH2C12 (5 mL) and TFA (1 mL) was added dropwise at room temperature. The on mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used without further purification in the next step (60 mg, 75% yield) LCMS: m/z 405 2 [M+H]+; tR = 1. 28 min ] Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4,4-difluoropiperidine—l- carb0nyl)pyridinyl)—7—(meth0xy-d3)benz0furanyl)methyl)acrylamide (660): (6~(2- (aminomethyl)(trideuteromethoxy)benzofuran-S—yl)pyridiny1)(4,4-difluoropipen'din—1- y1)methanone (229); (60 mg, 0.15 mmol) was ved in DMF (3 mL) and (E)—3-(6- aminopyridin—3~yl)acrylic acid (25 mg, 0.15 mmol), HATU (113 mg, 0.3 mmol), DIPEA (39 mixture was stirred at room mg, 0.3 mmol)) were added at room temperature. The reaction temperature for 18 h. The reaction mixture was purified by Prep-HPLC without work up to give 30 mg of (E)(6—aminopyridin—3-y1)~N-((5-(5-(4,4-difluoropiperidine carbonyl)pyridin~2-yl)—7-(methoxy—d3)benzofuran—2—yl)methy1)acrylamide (660). Yield (37%). 1H NMR (500 MHz, DMSO-d6) 8 8.83 (s, 1H), 8.74 (s, 1H), 8.49-8.07 (m, 5H), 8.03- 7.93 (m, 2H), 7.69 (s, 1H), 7.46 (d, J: 16 Hz, 1H), 7.03 (d, J: 9 Hz, 1H), 6.84 (s, 1H), 6.61 (d, J: 16 Hz, 1H), 4.59 (d, J= 5 Hz, 2H), 3.82-3.43 (m, 4H), 2.14~2.02 (m, 4H). LCMS: m/z 551.2 [M+H]+, 1R: 1.82 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(6,6-difluoro-2—azaspiro[3.3]heptane- 2—carbonyl)pyridin-2—yl)(trifluoromethyl)benzofuranyl)methyl)acFrylamide (661).
N o /EN: HATU DIPEA DMF HNWH; fiFF ] (E)—3-(6-aminopyridinyl)-N—((5-(5-(6,6-difluoro-2—azaspiro[3.3]heptane carbony1)pyridin—2-y1)—7-(trifluoromethy1)benzofuranyl)methyl)acrylamide (661) was synthesized using the ted reagents according to General Procedure 4. 1H NMR (500 MHZ, CD3OD) 5 8.82 (d, J: 2 Hz, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.07-8.03 (m, 1H), 7.99~ 7.93 (m, 2H), 7.66-7.61 (m, 1H), 7.38 (d, J: 16 Hz, 1H), 6.84 (s, 1H), 6.49 (d, J: 9 Hz, 1H), 6.37 (d, J: 16 Hz, 1H), 4.61 (s, 2H), 4.46 (s, 2H), 4.20 (s, 2H), 2.78-2.73 (m, 4H). LCMS: m/z 598.2 [M+H]+; tR = 1.25 min.
Synthesis of (E)—3-(6-amin0pyridin—3—yl)-N-((5-(5-(4,4—difluoropiperidine-l- carbonyl)pyridinyl)—7-(1,3,4—0xadiazolyl)benz0furanyol)methyl)acrylamide (662). \ o \ o O 0% \0 Na] _\NHBoc / \ / \ HO Br > HO BI’ Chiaroamine-T, Pd(PPh3)2C|2. BocHN Pd(("PPDCb. BocHN DMF Cu} Et3N AcOK, e 1\N HZNHN NHZNH? TsOH (cat) Pd((dppnciz K2003 BOCHN ET" BOCHN triethyl orthoformate dioxane H20 N o o /_\ BocHN \ FFN CHZC‘Z N \ HATU, DIPEA. DMF Synthesis of methyl S-bromohydr0xy—3-i0dobenzoate (230): Methyl 5— bromo—2-hydroxybenzoate (10 g, 43.3 mmol) and NaI (7.8 g, 52 mmol) were added to 200 mL of DMF. The mixture was cooled to 0 0C and chloroamine-T hydrate (14.7 g, 52 mmol) was added. The reaction mixture was stirred at 0 0C for 5 h, quenched with 200 mL of H20, extracted with EtOAc (500 mL X 3). The combined organic layers were washed with sat. sodium bisulfite and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography (20% EtOAc/petroleum ether) to give LCMS: m/Z 356.2 [M- g of methyl o—2—hydroxy-3—iodobenzoate (230) (55% yield). 55]; tR— 1.95 min.
Synthesis of methyl 5-brom0((tert— carbonylamin0)methyl)benzofurancarboxylate (231): A mixture of methyl 5 — bromohydroxy—3-iodobenzoate (230) (7.5 g, 21 mmol), utyl -yny1carbamate (3.6 g, 23 mmol), Pd(PPh3)2C12 (1.5 g, 2.1 mmol), CuI (800 mg, 4.2 mmol) in 80 mL of Eth was heated at 90 °C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture Was filtered and the filtrate was concentrated under reduced silica gel chromatography (33%— pressure to give the crude product, which was purified by 59% EtOAc/petroleum ether) to give 6.1 g of methyl 5—bromo((tert— butoxycarbonylamino)methyl)benzofuran—7—carboxylate (231) as a yellowish solid (76% yield). LCMS: m/Z 408.0 [M+Na]+; IR = 1.82 min.
Synthesis of methyl 2-((tert—butoxycarbonylamino)methyl)(4,4,5,5- tetramethyl-l,3,2-di0xaborolan-Z-yl)benzofuran-7—carb0xylate (232): A mixture of methyl 5-bromo—2—((z‘ert—butoxycarbonylamino)methyl)benzofiirancarboxylate (231) (5 g, 13 mmol), 4,4,4‘,4’,5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.6 g, 18 mmol), Pd(dppt)C12 (913 mg, 1.3 mmol) and AcOK (2.6 g, 26 mmol) in 50 mL of e was degassed and heated at 100 0C under nitrogen atmosphere for 6 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced re to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to give 4.65 g of methyl 2-((tert- butoxycarbonylamino)methyl)—5 —(4,4,5 ,5 —tetramethyl-l ,3 ,Z-dioxaborolan-Z-yl)benzofuran—7- ylate (232) as a yellow solid (83% yield). LCMS: m/z 453.9 [M+Na]+, tR= 2.12 min.
Synthesis of methyl 2-((tert—but0xycarbonylamin0)methyl)—5—(5-(4,4- difluoropiperidine-l-carb0nyl)pyridinyl)benzofurancarb0xylate (233): A ' mixture of (6-bromopyridinyl)(4,4-difluoropiperidinyl)methanone (3.1 g, 10 mmol), methyl 2-((tert-butoxycarbonylamino)methyl)—5-(4,4,5 ,5 -tetramethyl— 1 ,3 ,2-dioxaborolan yl)benzofurancarboxylate (232) (4.3 g, 10 mmol), Pd(dppi)C12 (702 mg, 1 mmol) and K2CO3 (2.8 g, 20 mmol) in 50 mL of dioxane and 5 mL ofH20 was degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 6 h, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to remove most of the solvent and 50 mL water was added. The ing e was extracted with EtOAc (30 mL X 3). The combined c layers were washed with brine, dried over anhydrous NaZSO4, and trated under reduced pressure to give the crude product, which was purified by silica gel chromatography (50%—70% EtOAc/petroleum ether) to give 3.2 g of methyl 2—((z‘ert-butoxycarbonylamino)methyl)-5—(5-(4,4-difluoropiperidine-1 - carbonyl)pyridin—2-y1)benzofurancarboxylate (233) as a yellow solid. (60% .
LCMS: m/z 530.2 [M+H]+, tR = 1.92 min. sis of tert-butyl (5-(5-(4,4-difluoropiperidinecarbonyl)pyridin yl)(hydrazinecarb0nyl)benzofuran-Z-yl)methylcarbamate (234): Methyl 2-((tert- butoxycarbonylamino)methyl)-5 -(5—(4,4—difluoropiperidine-1—carbonyl)pyridin yl)benzofuran-7—carboxylate (233); (1 g, 1.9 mmol) was dissolved in 9 mL of EtOH. —223 - Hydrazine hydrate (3 mL) was added at room temperature. The reaction mixture was heated at 100 0C for 2 h. After cooling down to room temperature, the precipitate was Collected by filtration and dried under reduced pressure to afford 0.81 g of tert-butyl (5— (5 ~(4,4-difluoropiperidinecarbonyl)pyridiny1)(hydrazinecarbonyl)benzofuran yl)methylcarbamate (234). (68% yield). LCMS: m/z 530.2 [M+H]+, tR= 1.71 min.
Synthesis of tert-butyl (5-(5-(4,4-diflu0ropiperidine-l-carbonyl)pyridin yl)(1,3,4-0xadiazolyl)benzofuran-Z-yl)methylcarbamate (235): tert—Butyl (5-(5- (4,4-difluoropiperidinecarbonyl)pyridiny1)—7-(hydrazinecarbonyl)benzofuran—2- yl)methylcarbamate (234); (423 mg, 0.8 mmol) was added to 26 mL of yl orthoformate. 4-Methylbenzenesulfonic acid (7 mg, 0.04 mmol) was added. The reaction mixture was heated at 125 0C for 2 h. The solvent was removed under reduced pressure and the re was purified by silica gel chromatography (50% EtOAc/petroleum ether) to give 215 mg of tert—butyl (5 —(5 —(4,4-difluoropiperidinecarbonyl)pyridin—2—y1)—7—(1,3 ,4-oxadiazol yl)benzofuran-2—yl)methylcarbamate (235) (50% yield). LCMS: m/z 540.3 [M+H]+, IR: 1.83 min.
Synthesis of (6—(2—(amin0methyl)—7-(1,3,4-0xadiazol—2-yl)benzofuran yl)pyridinyl)(4,4—difluor0piperidin-l-yl)methanone (236): tert—Butyl (5~(5~(4,4- difluoropiperidine- 1 —carbonyl)pyridin—2~yl)~7—(1 ,3 ,4—oxadiazol—2—yl)benzofuran—2- yl)methylcarbamate (235); (162 mg, 0.3 mmol) was dissolved in CH2C12 (4 mL). TFA (1 mL) was added at 0 OC (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction e was concentrated under d pressure to give 167 mg of crude (6-(2—(aminomethyl)-7—(1,3,4-oxadiazolyl)benzofuran~ ~yl)pyridinyl)(4,4—difluoropiperidinyl)methanone (236), which was used without r purification in the next step. (100% yield). LCMS: m/z 440.2 [M+H]+; IR = 1.54 min.
] Synthesis of (E)(6-aminOpyridinyl)-N-((5-(5-(4,4-difluoropiperidine-l- carbonyl)pyridinyl)(1,3,4-oxadiazolyl)benzofuranyl)methyl)acrylamide (662). (6-(2-(Aminomethyl)( 1 ,3 ,4-oxadiazol-Z-yl)benzofi1ranyl)pyridin-3 ,4- difluoropiperidinyl)methanone (236) (167 mg, 0.3 mmol) was dissolved in DMF (4 mL) and (E)—3—(6—aminopyridin—3-yl)acrylic acid (59 mg, 0.36 mmol) was added at 0 °C. HATU (148 mg, 0.39 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (77 mg, 0.6 mmol) dropwise. The reaction e was allowed to warm to room temperature and stirred for 4 h. 20 mL ofEtOAc and 10 mL of water were added to this mixture. The -224— aqueous phase was separated and extracted with EtOAc (15 mL X 2). The combined c layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (50% EtOAc/petroleum ether to 5% MeOH/EtOAc) to give 40 mg of (E)-3—(6-aminopyridinyl)-N-((5-(5—(4,4-difluoropiperidine-1—carbonyl)pyridin—2-yl)—7-(1,3 ,4-oxadiazol yl)benzofuranyl)methyl)acrylamide (662) as a yellow solid (23% yield). 1H NMR (500 MHz, CD3OD) 5 9.20 (s, 1H), 8.80 (d, J= 2 Hz, 1H), 8.73 (d, J= 2 Hz, 1H), 8.52 (d, J: 2 Hz, 1H), 8.11 (d, J= 8 Hz, 1H), .02 (m, 2H), .74 (m, 1H), 7.50 (d, J: 16 Hz, 1H), 6.97 (s, 1H), 6.61 (d, J= 9 Hz, 1H), 6.50 (d, J=16 Hz, 1H), 4.78 (s, 2H), 3.99-3.63 (m, 4H), 2.23-2.05 (m, 4H). LCMS: m/z 586.2 [M+H]+, IR: 1.23 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((5-(5-(4,4-diflu0r0piperidine carbonyl)pyridin-Z-yl)—7-(trifluoromethoxy)benzofuran—2-yl)methyl)acrylamide (663).
F300 Br F300I? LBr NHBOC 0 I Kl / NHBoc Ja’ \ NH 'H o 0 HO 3 2 HO Pd(PPh3)2CI2, Cul. Pd(dppf)C|2, KOACx ' OCF3 am, 35 "c dioxane, 100 0c 237 238 N O NHBoc / F \ O / \ Br N F o TFA __ N O ——.——————————> BOCHN \ CH2C|2 OCF3 Pd(dppf)CI2. K2603. 239 dioxane,H20, 100°C 240 F F3CO F300 O W014 N o ‘] / \ H2N H2" / o | wH .— — N N N N \ H2" \ HATU,DIPEA, OVY Q DMF 0 QF F F 241 F 663 Synthesis of 4-bromo-2—iodo(trifluoromethoxy)phenol (237): 4-Bromo oromethoxy)phenol (3.2 g, 12 mmol) was dissolved in 100 mL ofNH4OH. A solution of K1 (6.2 g, 37 mmol) and 12 (3.3 g, 13 mmol) in 50 mL ofH20 was added to the reaction mixture and stirred at room temperature up to 5 h. The reaction e was cooled down to 0 0C (ice bath), neutralized with HCl (conc.) until pH ~ 6-7; extracted with EtOAc (150 mL X 3). The combined c layers were washed with sat. aq. sodium bisulfite solution, brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give 4 g of 4— bromoiodo(trifluoromethoxy)phenol (237) as a yellow solid (85% yield). LCMS: tR = 1.79 min.
Synthesis of tert-butyl (5-br0mo(trifluor0methoxy)benzofuran yl)methylcarbamate (238): 4-Bromoiodo—6-(trifluoromethoxy)phenol (237) (4 g, 15.7 mmol), tert-butyl propynylcarbamate (2.9 g, 18.8 mmol), Pd(PPh3)2C12 (0.73 g, 1.6 mmol), CuI (0.6 g, 3.1 mmol) were added in 50 mL of triethylamine and degassed. The reaction mixture was refluxed at 85 0C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced re to give the crude product, which was purified by silica gel chromatography (5% EtOAc/petroleum ether) to yield 3.6 g of tert-butyl (5-bromo—7— (trifluoromethoxy)benzofuran—2—yl)methylcarbamate (238) as a pale yellow solid (82% yield). LCMS: m/z 354.0 [M—ssr, rR = 1.88 min.
Synthesis of tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2—dioxaborolanyl) (triflu0mmeth0xy)benzofuran—Z-yl)methylcarbamate (239): tert—Butyl mo-7— oromethoxy)benzofuran-2~yl)methylcarbamate (238) (4.7 g, 11 mmol), 4,4,4’,4',5,5,5',5'-octamethyl-2,2'—bi(1,3,2-dioxaborolane) (5.8 g, 22 mmol), Pd(dppt)C12 (0.9 g, 1.2 mmol), and potassium acetate (2.3 g, 22 mmol) were added in 50 mL of dioxane and degassed. The reaction e was heated at 100 0C under nitrogen atmosphere for 2 h.
After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to yield 5.1 g of tert—butyl (5-(4,4,5,5- ethyl-l ,3 ,2-dioxaborolanyl)—7-(trifluoromethoxy)benzofuranyl)methylcarbamate (239) as a white solid (96% yield). LCMS: m/z 480.2 [M+Na]+, tR = 1.93 min.
] Synthesis of tert-butyl (4,4-difluoropiperidinecarb0nyl)pyridinyl)— 7-(triflu0rometh0xy)benzofuranyl)methylcarbamate (240): tert-Butyl (5-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan—2-yl)(trifluoromethoxy)benzofuranyl)methylcarbamate (239) (5 g, 11 mmol), (6-bromopyridinyl)(4,4-difluoropiperidinyl)methanone (3.7 g, 12 mmol), Pd(dppi)C12 (0.8 g, 1.1 mmol), and K2CO3 (3 g, 22 mmol) were added in a mixture of dioxane (50 mL) and water (5 mL) and degassed. The reaction mixture was heated at 100 0C under nitrogen here for 5 h. The reaction e was cooled down to room temperature, filtered and the filtrate was concentrated under d pressure to give the crude product, which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to yield 4.7 g of tert—butyl (5-(5~(4,4-difluoropiperidine-l-carbonyl)pyridinyl) (trifluoromethoxy)benzofuranyl)methylcarbamate (240) as a white solid (yield 78%).
LCMS: m/Z 556.2 [M+H]+, IR = 2.06 min. sis of (6-(2-(amin0methyl)(trifluor0meth0xy)benzofuran yl)pyridin—3-yl)(4,4-diflu0ropiperidin-l-yl)methan0ne (241): tert—Butyl (5—(5—(4,4— difluoropiperidine— 1 -carbonyl)pyridinyl)—7-(trifluoromethoxy)benzofiiran yl)methy1carbamate (240) (3.7 g, 6.7 mmol) was dissolved in CH2C12 (30 mL). TFA (3 mL) was added dropwise at room ature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude (6-(2-(aminomethyl)-7—(trifluoromethoxy)benzofuranyl)pyridin—3-yl)(4,4- difluoropiperidin—l-yl)methanone (241), which was used without further purification in the next step (3 g, 100% yield). LCMS: m/Z 456.1 [M+H]+, tR= 1.83 min.
Synthesis of (E)(6—aminOpyridinyl)—N—((5-(5-(4,4-diflu0r0piperidine carb0nyl)pyridin-Z-yl)—7-(trifluoromethoxy)benzofuran-Z—yl)methyl)acrylamide (663). (6—(2-(Aminomethyl)(trifluoromethoxy)benzofi1ran—5-yl)pyridinyl)(4,4— difluoropiperidin-l-yl)methanone (241) (2.2 g, 4.8 mmol) was dissolved in DMF (40 mL) and (E)-3—(6—aminopyridin—3—y1)acrylic acid (0.9 g, 5.3 mmol) was added at 0°C. HATU (3.7 g,' 9.7 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (12 g, 96 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 4 h. The reaction mixture was poured into iced water (100 mL), extracted with EtOAc (100 mL X 3). The combined c layers were washed with brine, dried over Na2804, concentrated under d pressure to give crude product which was purified by silica gel chromatography (10% MeOH/EtOAc) to afford 1 g of (E)(6-aminopyridin—3-yl)- N—((5 -(5-(4,4—difluoropiperidine— 1 —carbonyl)pyridiny1)-7—(trifluoromethoxy)benzofuran yl)methyl)acrylamide (663) (34% . 1H NMR (400 MHZ, DMSO—ds) 5 8.77 (d, J = 2 Hz, 1H), 8.65 (t, J= 6 Hz, 1H), 8.43 (d, J=1Hz, 1H), 8.17 (d, J: 8 Hz,1H),8.15—8.07(m, 2H), 8.05-7.99 (m, 1H), .60 (m, 1H), 7.36 (d, J= 16 Hz, 1H), 6.97 (s, 1H), 6.52-6.38 (m, 4H), 4.61 (d, J= 6 Hz, 2H), 3.83-3.43 (m, 41-1), 2.17-2.00 (m, 4H). LCMS: m/z 602.4 [M+H]+; rR = 1.80 min. sis of (E)(6-amin0pyridinyl)-N-((5-(5-(4,4—difluoropiperidine-l— carb0nyl)pyridinyl)-6e(trifluoromethyl)benzofuranyl)methy1)acrylamide (664).
CF CF3 3 \B~B’O CF3 0’ ‘0 0 Br Km2 r///\NHBoc 0 CFa o B: ‘—‘—> "" \ m’ 0 BccHN \ HO B°°HN NH4OH Pd(PPh3)2C|2.Cul. Br HO Pd(dppf)C|2,KOAc, EtaN. 85 oC e, 100A o 242 243 244 \ o Br N r\OVF N F F9 I N \ / TFA | ______—> N \ ——> F / Pd(dppf)C|2. mom CHZC'Z N F \ 0 NHBoc dioxane‘ 0 F30 O , H20, 100 C F30 NH: \ 0 NH N|\ 2 / N \ H2N F70 ' \ /N _._____, N F \ __ IPEA,DMF FC 0 HN ] Synthesis of 4-brom0—2-iodo-S—(trifluoromethyl)phenol (242): 4-Bromo (trifluoromethyl)phenol (2 g, 8.3 mmol) was dissolved in 100 mL ofNH4OH. A solution of Kl (4.1 g, 25 mmol) and 12 (2.1 g, 8.3 mmol) in 50 mL ofH20 was added to the reaction mixture and stirred at room temperature up to 2 h. The reaction mixture was cooled down to 0 0C (ice bath), neutralized with HCl (conc.) until pH ~ 6-7; extracted with EtOAc (150 mL X 3). The combined organic layers were washed with sat. aq. sodium bisulfite solution, brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give 2.1 g of 4- bromo—2-iodo—5—(trifluoromethyl)phenol (242) as a yellow solid (70% yield). LCMS: tR = 1.22 min.
Synthesis of tert-butyl (5-brom0(trifluoromethyl)benzofuran yl)methylcarbamate (243): oiodo—5-(trifluoromethyl)phenol (242) (2.1 g, 5.7 mmol), rert-butyl propynylcarbamate (0.93 g, 6 mmol), Pd(PPh3)2C12 (0.42 g, 0.6 mmol), CuI (0.1 g, 0.05 mmol) were added in 50 mL of ylamine and degassed. The on mixture was refluxed at 85 0C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under d pressure to give the crude product, which was purified by silica gel chromatography (5% EtOAc/petroleum ether) to yield 2.2 g of tert-butyl (5-bromo(trifluoromethyl)benzofuran— 2-yl)methy1carbamate (243) as a pale yellow solid (95% yield). 1H NMR (400 MHZ, CDClg) —228— 7.85 (s, 1H), 7.79 (s, 1H), 6.60 (5, 1m, 4.47 (d, J: 6 Hz, 2H), 1.47 (s, 9H). LCMS: m/z 339.9 +; 1R = 1.95 min.
] Synthesis of tert-butyl 4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—6- uoromethyl)benzofuranyl)methylcarbamate (244): tert-Butyl (5-bromo (trifluoromethyl)benzofuranyl)methylcarbamate (243) (1 g, 2.5 mmol), 4,4,4',4',5,5,5',5'- octamethyl—2,2’-bi(1,3,2-dioxaborolane) (2.8 g, 11 mmol), Pd(dppi)C12 (0.3 g, 0.42 mmol), and ium e (1.1 g, 11 mmol) were added in 50 mL of dioxane and degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to yield 240 mg of terI-butyl (5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan—2—yl)(trifluoromethyl)benzofuran—2-yl)methylcarbamate (244) as a white solid (22% yield). LCMS: tR = 2.02 min.
Synthesis of tert-butyl (5-(5-(4,4-diflu0ropiperidine-l-earb0nyl)pyridinyl)- 6-(trifluoromethyl)benzofuran-Z-yl)methylcarbamate (245): tert-Butyl (5-(4,4,5,5- tetramethyl- 1 ,3 ,2—dioxaborolan-2—yl)(trifluoromethyl)benzofuran—2-yl)methy1carbamate (244) (200 mg, 0.45 mmol), (6-bromopyridin—3-yl)(4,4-difluoropiperidin—1-yl)methanone (130 mg, 0.5 mmol), Pd(dppi)C12 (48 mg, 0.05 mmol), and K2C03 (124 mg, 0.9 mmol) were added in a mixture of dioxane (10 mL) and water (1 mL) and degassed. The reaction mixture was heated at 100 0C under nitrogen here for 5 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to yield 135 mg of tert—butyl (5-(5—(4,4-difluoropiperidine carbonyl)pyridin—2-yl)(trifluoromethyl)benzofuran-2—yl)methylcarbamate (245) as a white solid (yield 56%). LCMS: m/z 540.2 [M+H]+, IR: 1.33 min.
Synthesis of (aminomethyl)(trifluoromethyl)benzofuran-S-yl)pyridin- 3-yl)(4,4-difluoropiperidinyl)methanone (246): Iert-Butyl (5—(5-(4,4-difluoropiperidine- 1-carbonyl)pyridinyl)(trifluoromethyl)benzofuran—2-y1)methylcarbamate (245) (135 TFA (1.5 mL) was added dropwise at mg, 0.25 mmol) was dissolved in CH2C12 (10 mL). room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude (6—(2-(aminomethyl)—6- (trifluoromethy1)benzofuran— 5-yl)pyridin—3-yl)(4,4-difluoropiperidinyl)methanone (246), which was used without further purification in the next step (110 mg, 100% yield). LCMS: m/z 440.1 , tR= 1.36 min.
Synthesis of (E)—3—(6—aminopyridin—3—yl)—N-((5-(5—(4,4-difluoropiperidine—l— carbonyl)pyridinyl)—6—(trifluoromethyl)benzofuran-2—yl)methyl)acrylamide (664). (6— (2-(Aminomethyl)—6-(trifluoromethyl)benzofuran—5—yl)pyridin—3 —yl)(4,4-difluoropiperidin—1 - yl)methanone (246) (50 mg, 0.10 mmol ) was dissolved in DMF (3 mL) and (E)—3—(6— yridinyl)acrylic acid (18 mg, 0.10 mmol) was added at 0 OC. HATU (46 mg, 0.12 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (65 mg, 0.50 mmol) dropwise. The reaction e was allowed to warm to room temperature and stirred further for 1 h. The reaction mixture was purified by Prep-HPLC to afford 15 mg of (E)—3-(6- aminopyridin~3~yl)—N—((5~(5—(4,4-difluoropiperidine—1-carbonyl)pyridin—2-yl) (trifluoromethyl)benzofurany1)methyl)acrylamide (664) (26% yield). 1H NMR (400 MHz, DMSO-d6) 5 8.75-8.71 (m, 1H), 8.68~8.62 (m, 1H), 8.12 (s, 1H), 8.08 (d, J= 2 Hz, 1H), 8.02- 7.98 (m, 1H), 7.78 (s, 1H), 7.64—7.58 (m, 2H), 7.36 (d, J: 16 Hz, 1H), 6.91 (s, 1H), 6.49— 6.39 (m, 4H), 4.63 (d, J= 6 Hz, 2H), 3.82-3.70 (m, 2H), 3.53—3.44 (m, 2H), 2.19—2.03 (m, 4H). LCMS: m/z 586.2 [M+H]+, rR= 1.63 min.
Synthesis of (E)(6-aminopyridin—3-yl)—N—((5-(5—(4,4-diflu0r0piperidine-l- yl)pyridinyl)—7-(4-flu0r0phenyl)benzofuranyl)methyl)acrylamide (665). _—~—>BocHN Pd(PPh3)4 PCy3 K3PO4, dioxane H20 248 F ] (ED—3-(6-aminopyridin-3~yl)-N~((5-(5-(4,4~difluoropiperidine—1-carbonyl)pyridin- 2-yl)(4—fluorophenyl)benzofuranyl)rnethyl)acrylamide (665) was synthesized in a similar fashion as example (659) using the indicated reagents. 1H NMR (400 MHz, DMSO- 0105 8.86—8.79 (m, 1H), 8.76 (d, J: 2 Hz, 1H), 8.38 (d, J: 2 Hz, 1H), 8.28—8.16 (m, 3H), —230- 808-7.97 (m 4H), 7.48-7. 35 (m, 3H), 7.30—689 (m, 4H), 6. 64—6. 54 (m 1H) 4.62 (d, J: 6 Hz, 2H), 3. 82- 3.68 (m 4H), 2.15—2.03 (m, 4H). LCMS: m/z 612.2 [M+H]; tR= 1.44 min Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4,4-diflu0r0piperidine—l- carb0nyl)pyridinyl)(pyridinyl)benzofuranyl)methyl)acrylamide (666). _ o o \ NQ13(0H)2 N N —_.._._..__> BocHN \ Pd(PPh3)4. PCS/3. K3PO4. 223 dioxane. H20 N . . 9FN 250 9F 666 (E)-3 ~(6-aminopyridin-3 -y1)—N—((5-(5-(4,4—difluoropiperidine— 1 -carbony1)pyridin— 2—y1)—7—(pyridin—4—y1)benzofuran—2-y1)methyl)acrylamide (666) was synthesized in a similar fashion as example (659) using the indicated reagents. 1H NMR (500 MHZ, DMSO-dg) 8 .83 (m, 3H), 8.79 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.35-8.18 (m, 6H), 8.12 (d, J= 8 Hz, 1H), 8.04 (d, J: 10 Hz, 1H), 7.48 (d,J= 16 Hz, 1H), 7.04—6.96 (m, 2H), 6.62 (d, J: 16 Hz, 1H), 4.67 (d, J= 6 Hz, 2H), 3.84-3.43 (m, 4H), 2.17-2.02 (m, 4H). LCMS: m/z 595.2 [M+H]+, 1R = 1.65 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4,4-difluoropiperidine-l- carbon0thi0yl)pyridinyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (667). 0 ~ o N— N —————3———> N —-—> \ \ CHZC‘Z NHBoc NHBoc F F F3C HzN[N\ / \ o , // COOH N_ N HATU DIPEA DMF 253 HN%N6{/334be Synthesis of tert—butyl (5-(5-(4,4-diflu0ropiperidine—l—carbonothioyl)pyridin- 7-(trifluoromethyl)benzofuran-2—yl)methylcarbamate (252): tert—Butyl (5-(5-(4,4- difluoropiperidinecarbonyl)pyridinyl)—7-(trifluoromethyl)benzofuran yl)methylcarbamate (251) (200 mg, 0.37 mmol) and Lawesson’s t (105 mg, 0.26 mmol) were added in 10 mL of ne. The reaction mixture was heated at 80 0C for 12 h.
After cooling down to room temperature, the reaction mixture was concentrated under d pressure to give the crude product, which was purified by Prep-HPLC to afford 55 mg of tert-butyl (5 -(5 -(4,4-difluoropiperidine—1 -carbonothioy1)pyridinyl) (trifluoromethyl)benzofuranyl)methylcarbamate (252) as a pale yellow solid (27% yield). ). LCMS: m/z 556.2 [M+H]+; tR = 1.82 min.
Synthesis of (6-(2—(aminomethyl)—7—(triflu0r0methyl)benzofuran-S-yl)pyridin- 3-yl)(4,4-difluoropiperidin—l-yl)methanethi0ne (253): tert-Butyl (5-(5-(4,4- opiperidinecarbonothioyl)pyridin—2-yl)(trifluoromethyl)benzofuran-2— yl)methylcarbamate (252) (55 mg, 0.10 mmol) was dissolved in CH2C12 (10 mL). TFA (1.5 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude (6-(2- (aminomethyl)—7-(trifluoromethyl)benzofuran-5 -yl)pyridin—3 ,4—difluoropiperidin— 1 — yl)methanethione (253), which was used t further purification in the next step (45 mg, 100% yield). LCMS: m/z 456.1 [M+H]+; tR = 1.37 min.
Synthesis of (E)(6-aminopyridinyl)-N—((5-(5—(4,4-difluoropiperidine carbonothioyl)pyridinyl)(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (667): (6-(2-(Aminomethyl)—7-(trifluoromethy1)benzofuran-5—yl)pyridin—3—yl)(4,4- difluoropiperidin—l-y1)methanethione (253); (45 mg, 0.10 mmol ) was dissolved in DMF (3 mL) and (Z)(6—aminopyridin-3—yl)acrylic acid (16 mg, 0.10 mmol) was added at 0 °C.
HATU (46 mg, 0.15 mmol) was added at 0 0C followed by DIPEA (39 mg, 0.30 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The reaction mixture was purified by Prep-I-IPLC without workup to afford mg of (E)(6-aminopyridiny1)-N-((5-(5-(4,4-difluoropiperidine carbonothioyl)pyridin-2—y1)—7-(trifluoromethyl)benzofuran—2-y1)methyl)acrylamide (667) : 42%). 1H NMR (500 MHZ, DMSO-d6) 6 8.90—8.84 (m, 1H), 8.72-8.66 (m, 2H), 8.38 (s, 1H), 8.20 (s, 1H), 8.17 (d, J: 8 Hz, 1H), 8.12-8.05 (m, 1H), 7.93 (dd, J: 8 Hz, 2 Hz, 1H), 7.46 (d, J: 16 Hz, 1H), 7.02 (s, 1H), 6.95 (d, J: 8 Hz, 1H), 6.60 (d, J: 16 Hz, 1H), 4.65 (d, —232- J: 5 Hz, 2H), 4.48-4.41 (m, 2H), 3.75-3.70 (In, 2H), 2.32-2.11 (m, 4H). LCMS: m/z 602.2 [M+H]+; 7R = 1.46 min.
Synthesis of (E)(6-amin0pyridinyl)-N—((5'-(5-(4,4-diflu0r0piperidine carbonyl)pyridinyl)-2,7'-bibenzofuran-2'-yl)methyl)acrylamide (668). _ o o \ / «{0tho N N BocHN \ _——————’ BocHN Pd(PPhs)4. PCYs. K3P04, 223 72 dioxane. H20 255 F (E)—3—(6-arninopyridiny1)~N-((5'-(5~(4,4-difluoropiperidinecarbony1)pyridin— 2,7’-bibenzofuran—2'—y1)rnethy1)acrylamide (668) was synthesized in a similar fashion as example (659) using the indicated reagents. 1H NMR (400 MHZ, DMSO-d6) 5 8.82 (d, J = 2 Hz, 1H), 8.70 (d, J: 2 Hz, 2H), 8.43 (d, J= 2 Hz,1H), 8.21 (d, J: 8 Hz,1H), 8.11 (d, J: 2 Hz, 1H), 8.03 (dd, J1 = 8 Hz, J2 = 2 Hz, 1H), 7.80-7.74 (m, 3H), 7.64 (dd, J]: 8 Hz, J2 = 2 Hz, 1H), 7.46—7.29 (m, 3H), 6.97 (s, 1H). 6.51-6.41 (m, 4H), 4.71 (d, J: 6 Hz, 2H), 3.86— 3.44 (m, 4H), .03 (m, 4H). LCMS: m/z 634.5 ; tR é 1.86 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4,4-difluoropiperidine carbonyl)pyridin-Z-yl)—7-(pyridinyl)benzofuran-Z-yl)methyl)acrylamide (669).
CI NH BocHN Pd(PPh3)4i PCVs. K3P04. dloxane, H20 (E)(6-aminopyridin—3-yl)-N—((5-(5-(4,4—difluoropiperidine-1—carbonyl)pyridin- 2-yl)—7-(pyridinyl)benzofuran—2—yl)methyl)acrylamide (669) was synthesized in a similar fashion as e (659) using the inidcated reagents. 1H NMR (400 MHZ, DMSO-d6) 5 9.24-9.14 (m, 1H), 8.77 (s, 1H), 8.69—8.63 (m, 1H), 8.45 (s, 2H), 8.43—7.95 (m, 6H), 7.66- 7.53 (m, 2H), 6.94 (s, 1H), 6.56-6.36 (m, 3H), 6.36-6.26 (m, 1H), 4.64—4.50 (m, 2H), 3.83- 3.67 (m, 2H), 3.60-3.46 (m, 2H), 2.15-2.03 (m, 4H). LCMS: m/z 595.6 [M+H]+; tR = 1.66 min.
Synthesis of (E)(3-amin0isoquin0linyl)-N-((5-(5-(4,4-difluoropiperidine yl)pyridin-Z-yl)(triflu0romethyl)benzofuran-Z-yl)methyl)acrylamide (670). o 0 Br /\£[/ O\/ \ o/\ \ LiOH OH | )2,P(2—MePh)3 / l THF,H20 l HzN N DMF,D|PEA,100 ac HZN N/ HZN N/ 258 259 260 F F @014 FF N O 211 F 670 Synthesis of (IQ-ethyl 3-(3-amin0is0quinolinyl)acrylate (259): 7— Bromoisoquinolinamine (258) (450 mg, 2.0 mmol), ethyl acrylate (300 mg, 3.0 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), trio-tolylphosphine (122 mg. 0.4 mmol), and DIPEA (516 mg, 4.0 mmol) were added in DMF (4 mL) and degassed. The reaction mixture was heated at 100 0C for 3 h under nitrogen atmosphere. After cooling down to room temperature, the reaction mixture was poured into iced water (20 mL), extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over ous Na2804, concentrated under reduced pressure to give the crude product, which was purified by column tography on silica gel (10% EtOAc/petroleum ether) to give (E)-ethyl 3-(3— aminoisoquinolinyl)acrylate (259) as White solid (400 mg, 83% yield ). LCMS: m/z 243.2 [M+H]+; tR = 1.34 min.
Synthesis of (E)(3-aminoisoquinolinyl)acrylic acid (260): (E)-ethyl 3—(3- aminoisoquinolin—7-yl)acrylate (259); (400 mg, 1.7 mmol) and LiOH (200 mg, 8.3 mmol) were added in a mixture of THF (10 mL) and H20 (1 mL) at room ature. The reaction mixture was heated at 70 0C for 3 h. The reaction mixture was concentrated under reduced —234— pressure to remove THF, diluted with water (10 mL), neutralized with 2N HCl until pH = 3, extracted with CH2C12 (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , and concentrated under reduced pressure to give 200 mg of (E)(3-aminoisoquinolin—7-yl)acrylic acid (260) as white solid, which was used without further purification in the next step (57% yield). LCMS: m/z 215.1 [M+H]+; tR = 1.09 min.
Synthesis of (E)(3-aminoisoquinolinyl)-N—((5-(5-(4,4-diflu0r0piperidine- 1-carb0nyl)pyridinyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (670): (6-(2-(Aminomethyl)(trifluoromethyl)benzofuranyl)pyridinyl)(4,4-difluoropiperidin- l-yl)methanone (211) (75 mg, 0.17 mmol) was dissolved in DMF (3 mL) and (E)(3- aminoisoquinolinyl)acrylic acid (260) (35 mg, 0.16 mmol) was added at 0 OC. HATU (122 mg, 0.32 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (62 mg, 0.48 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred r for l h. The reaction mixture was purified by Prep-HPLC to afford 53 mg of (E)(3- aminoisoquinolin-7—yl)—N—((5-(5—(4,4-difluoropiperidine—l-carbonyl)pyridin—2—yl)—7- (trifluoromethyl)benzofuran—2~y1)methyl)acrylamide (670) (52% yield). 1H NMR (500 MHz, DMSO—d6) 8 8.93 (s, 1H), 8.88 (s, 1H), 8.81-8.69 (m, 4H), 8.41 (s, 1H), 8.23 (d, J: 8 Hz, 1H), 8.06-8.01 (m, 2H), 7.77 (d, J: 9 Hz, 1H), 7.65 (d, J= 9 Hz, 1H), 7.58 (d, J= 16 Hz, 1H), 7.04 (s, 1H), 6.86-6.80 (m, 1H), 6.75 (d, J=16 Hz, 1H), 4.67 (d, J: 5 Hz, 2H), 3.81— 3.71 (m, 2H), 3.55-3.44 (m, 2H), 2.15-2.03 (m, 4H). LCMS: m/z 636.2 [M+H]+; tR = 1.46 min.
Synthesis of ((5-(5-(4,4-diflu0r0piperidine—l-carb0nyl)pyridinyl)—7- (trifluoromethyl)benz0furanyl)methyl)(pyridinyl)acrylamide (671). 0H F F F FF F — / N- 0 0 \ / 0 N / o \ / N _‘—._. | N N \ \ H HZN / HATU, DIPEA, DMF 671 F 211 F F ((5-(5-(4,4-difluoropiperidinecarbonyl)pyridiny1)—7— (trifluoromethy1)benzofuranyl)methyl)(pyridinyl)acrylamide (671) was synthesized using the indicated reagents according to General Procedure 4. Yield: 75%. 1H NMR (400 MHz, CD30D) 6 8.79 (s, 1H), 8.67 (d, J: 2 Hz, 1H), 8.56 (d, J: 5 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J: 8 Hz, 1H), 8.24 (s, 1H), 8.01-7.88 (m, 2H), 7.69-7.62 (m, 1H), 7.58 (d, J: 16 Hz, —235- 1H), 6.89 (s, 1H), 6.80 (d, J= 16 Hz, 1H), 4.65 (s, 2H), 3.87-3.49 (m, 4H), 2.11—1.91 (m, 4H). LCMS: m/z 571.2 [M+H]+, IR: 1.50 min.
Synthesis of (E)—3~(6—aminopyridinyl)-N-((5-(5-(4,4-diflu0ropiperidine-l- carb0nyl)pyridin-2—yl)—7-(is0quinolinyl)benz0furanyl)methyl)acrylamide (672). o \ / (HO)ZB N N ——‘—"—’ BocHN \ BocHN Pd(PPh3)4, PCY3, K3P04. 223 dioxane. H20 262 672 F F (E)-3 - nopyridin-3 -yl)—N—((5—(5—(4,4-difluoropiperidine—1-carbonyl)pyridin— 2-yl)(isoquinolin—6—yl)benzofuranyl)methyl)acrylamide (672) was synthesized in a similar fashion as example (658). 1H NMR (400 MHZ, DMSO-d6) 5 9.67-9.59 (m, 1H), 8.89- 8.73 (m, 3H), 8.68-8.61 (m, 1H), 8.54-8.42 (m, 5H), 8.30-8.00 (m, 6H), 7.48 (d, J: 16 Hz, 1H), 7.02-6.95 (m, 2H), 6.62 (d, J== 16 HZ, 1H), 4.68 (d, J: 5 Hz, 2H), 3.82-3.46 (m, 4H), 2.18-2.03 (m, 4H). LCMS: m/z 645.3 ; IR = 1.70 min.
Synthesis of (E)-N—((5-(5-(4,4-diflu0ropiperidine—1-carb0nyl)pyridinyl)-7—(pyridin yl)benzofuran-Z-yl)methyl)(pyridinyl)acrylamide (673).
O \ / O N / N —-——-——+ l N HZN / HATU, DIPEA, DMF 257 673 F F F ((5-(5-(4,4-difluoropiperidinecarbonyl)pyridinyl)-7—(pyridin—3- yl)benzofuranyl)methyl)(pyridinyl)acrylamide (673) was synthesized using the indicated reagents according to General Procedure 4. Yield: 17%. 1H NMR (400 MHz, DMSO'dfi) 5 9.21 (d, J: 2 Hz, 1H), 8.91 (d, J: 5 Hz, 1H), 8.81-8.75 (m, 2H), 8.69-8.64 (m, 1H), 8.59—8.53 (m, 1H), 8.46 (d, J: 2 Hz,1H), 8.38 (d, J: 8 Hz, 1H), 8.32 (d, J: 2 Hz, 1H), 8.26 (d, J: 8 Hz, 1H), 8.05-7.96 (m, 2H), 7.63-7.57 (m, 1H), 7.55 (d, J: 16 Hz, 1H), 7.49- —236- 7.42 (m, 1H), 6.98 (s, 1H), 6.82 (d, J= 16 Hz, 1H), 4.65 (d, J= 5 Hz, 2H), 3.81-3.46 (m, 4H), .01 (m, 4H). LCMS: m/z 580.2 [M+H]+, tR= 1.71 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5—(4,4-difluoropiperidine—1- carbonyl)pyridinyl)(pyridinyl)benzofuranyl)methyl)acrylamide (674).
N _____. N\l N < 2 HATU, DIPEA. DMF 250 F F 674 (E)-3 -(6-aminopyridiny1)-N-((5—(5-(4,4-difluoropiperidinecarbony1)pyridin- 2-y1)(pyridinyl)benzofurany1)methyl)acry1amide (674) was synthesized using the indicated reagents according to General Procedure 4. Yield: 10%. 1H NMR (400 MHz, DMSO'dfi) 5 8.94-8.88 (m, 1H), 8.81-8.73 (m, 4H), 8.60—8.47 (m, 2H), 8.40 (s, 1H), 8.26 (d, J: 8 Hz, 1H), .96 (m, 4H), 7.56 (d, J= 16 Hz, 1H), 7.50-7.41 (m, 1H), 6.99 (s, 1H), 6.83 (d, J: 16 Hz, 1H), 4.67 (d, J: 6 Hz, 2H), 3.82—3.45 (m, 4H), 2.09 (s, 4H). LCMS: m/z 580.2 [M+H]+, rR= 1.70 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((5-(5—((4,4-diflu0ropiperidin-l- yl)methyl)pyridin—2-yl)(trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (675).
\ N \ OH 30012 \ CI HN/\:> I / / Br N F Br N CH20I2 BF N HCI K2003, CH3CN, Kl, F 253 45 00 264 H20, 90 "c r.t. 266 675 —237— Synthesis of 2-br0mo(chloromethyl)pyridine hydrochloride (264): (6— Bromopyridin—3—yl)methanol (1) (1.0 g, 5.3 mmol) was dissolved in CH2C12(15 mL), SOClz (3 mL, 42 mmol) was added dropwise at room temperature. The on mixture was d at room temperature for 2 h and concentrated under reduced pressure to give 2-bromo—5— (chloromethyl)pyridine hydrochloride (263) as white solid (13 g, 98% yield). LCMS: m/z 205.1 [M+H]+; 1R = 1.78 min. sis of 2-bromo-S-((4,4-diflu0ropiperidinyl)methyl)pyridine (264): 2- Bromo(chloromethy1)pyridine hydrochloride (263) (1.3 g, 5.2 mmol), 4,4-difluoro piperidine (692 mg, 5.7 mmol), K2C03 (3.6 g, 26 mmol) and K1 (86 mg, 0.52 mol) were added in CH3CN (15 mL). The reaction mixture was heated at 45 0C for 6 h. LC—MS analysis showed the completion of reaction. After cooling down to room temperature, the reaction mixture was diluted EtOAc (100 mL), washed with H20 (100 mL), brine, dried over anhydrous NazSO4, concentrated under reduced pressure to give 2—bromo—5—((4,4— difluoropiperidin—l —y1) methyl)pyridine (264) as white solid, which was used in next step without further purification (1.3 g, 85% yield). LCMS: m/z 291.1 [M+H]+; IR = 1.77 min.
Synthesis of tert—butyl (5-(5-((4,4-difluoropiperidin-l-yl)methyl)pyridin-2—yl)— 7—(trifluor0methyl)benzofuranyl)methylcarbamate (265): o—5—((4,4- difluoropiperidin—l—y1)methy1)pyridine (264) 190 mg, 0.65 mmol), tert—buty1(5—(4,4,5,5~ tetramethyl— 1 ,3 ,2~dioxaborolan~2~yl)—7~(trifluoromethyl)benzofuran—2—y1)methylcarbamate (300 mg, 0.68 mmol), Pd(dppt)C12 (48 mg, 0.065 mmol), and K2C03 (180 mg, 1.3 mmol) were added in a mixture of dioxane (15 mL) and H20 (03 mL) and degassed. The reaction mixture was heated at 90 0C under nitrogen here for 16 h. LC-MS analysis showed the completion of reaction. After g down to room temperature, the reaction e was diluted with water (20 mL), ted with EtOAc (50 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na2804, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (30% EtOAc/petroleum ether) to give tert-butyl (5-(5-((4,4-difluoropiperidin—1-y1)methy1)pyridin— 2-y1)(trifluoromethy1)benzofuran y1)methylcarbamate (265) as white solid (40 mg, 24% yield). LCMS: m/z 526.1 ; :R = 1.48 min.
] Synthesis of (5-(5-((4,4-difluoropiperidin—1~yl)methyl)pyridin—Z—yl) (trifluoromethyl)benzofuran-Z-yl)methanamine (266): tert-Buty1(5—(5—((4,4— difluoropiperidin— 1 ~yl)methyl)pyridinyl)~7-(trifluor0methyl)benzofuran ~2— y1)methylcarbamate (264) (40 mg, 0.076 mmol) was dissolved in CH2C12 (3 mL), and TFA (1 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1h. TLC showed the completion of reaction. The reaction mixture was concentrated under reduced pressure to afford (5-(5—((4,4-difluoropiperidin-l- yl)methyl)pyridinyl)(trifluoromethyl)benzofuran—2-yl)methanamine (266), which was used without further cation in the next step (35 mg, 99% . LCMS: m/z 426.2 [M+H]+; zR = 1.81 min.
Synthesis of (E)(6-aminopyridinyl)-N—((5-(5-((4,4-difluoropiperidin yl)methyl)pyridin—2-yl)(trifluor0methyl)benzofuran-Z-yl)methyl)acrylamide (675): ((4,4-Difluoropiperidin-1—yl)methy1)pyridin-2—yl)(trifluoromethyl)benzofuran hanamine (266) (35 mg, 0.076 mmol), (E)(6-aminopyridin-3—yl) acrylic acid (16 mg, 0.1 mmol), HATU (0.11 mol), and DIPEA (59 mg, 0.46 mmol) were added in DMF (2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction e was purified by Prep-HPLC without work up to give (E)-3—(6-aminopyridin—3-y1)-N—((5-(5—((4,4- difluoropiperidinyl)methy1)pyridin—2—y1)(trifluoromethy1)benzofuran—2- y1)methyl)acrylamide (675) as white solid (10 mg, 23% yield). 1H NMR (500 MHz, DMSO— d6) 5 .60 (m, 3H), 8.34 (s, 1H), 8.11-8.06 (m, 2H), 7.86 (d, J= 8 Hz, 1H), 7.63 (d, J: 9 Hz, 1H), 7.36 (d, J: 16 Hz, 1H), 6.98 (s, 1H), 6.51—6.40 (m, 4H), 4.62 (d, J= 6 Hz, 2H), 3.64 (s, 2H), 2.56-2.51 (m, 4H), 2.03-1.92 (m, 4H). LCMS: m/z 572.5 [M+H]+; [R = 1.90 min.
Synthesis of (E)-3—(4-aminofluor0phenyl)-N-((5-(5-(4,4-diflu0ropiperidine-l- carbonyl)pyridin—2—yl)(triflu0r0methyl)benzofuran-Z-yl)methyl)acrylamide (676).
' NOV HZNFDBr o / O\/ Pd(OAc)2, P(2-MePh)3 F DMF, DIPEA, 100 °C o 269 676 Synthesis of (E)—ethyl 3-(4-amin0fluorophenyl)acrylate (267): (E)-ethyl 3— (4-aminofluoropheny1)acrylate (267) was synthesized in a similar fashion as intermediate (259). Yield: 95%. LCMS: m/z 210.2 [M+H]+; tR = 1.59 min. —239- Synthesis of (E)(4-amin0flu0r0phenyl)acrylic acid (268): (E)(4-amino— 3-fluorophenyl)acrylic acid (268) was sized in a similar fashion as intermediate (260).
Yield: 87%. LCMS: m/z 182.1 [M+H]; IR—— 130 min.
Synthesis of (E)—3-(4—aminoflu0r0phenyl)—N—((5-(5-(4,4-diflu0r0piperidine- 1-carbonyl)pyridin-Z-yl)(triflu0r0methyl)benzofuran—2—yl)methyl)acrylamide (676): (E)—3—(4-amino—3-fluorophenyl)-N—((5-(5-(4,4-difluoropiperidine—1-carbonyl)pyridin—2—yl) (trifluoromethyl)benzofurany1)methyl)acrylamide (676) was synthesized using the ted reagents according to General Procedure 4. Yield: 6%. 1H NMR (500 MHz, DMSO-ds) 6 8.78 (d, J= 2 Hz, 1H), 8.70 (s, 1H), 8.67 (t, J= 6 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J: 8 Hz,1H), 8.05-8.01 (m, 1H), 7.34 (d, J: 16 Hz, 1H), 7.24 (d, J: 11 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.00 (s, 1H), 6.75 (t, J: 9 Hz, 1H), 6.43 (d, J= 16 Hz, 1H), 4.62 (d, J: 6 Hz, 2H), 3.80—3.72 (m, 2H), 3.53-3.44 (m, 2H), 2.14-2.04 (m, 4H). LCMS: m/z 603.3 [M+H]+; IR = 1.90 min.
Synthesis of (E)—3—(6-amin0pyridin—3—yl)-N-((5—(5-(4,4-diflu0mpiperidine-l- carb0nyl)pyridinyl)-3—methyl(triflu0r0methyl)benzofuranyl)methyl)acrylamide (677).
F Br/VN HobBrFbfi Br Br —D> Br > HO Br WH N//\O TFA THF CHZCI2 cho3 DMF o /0 Bfi K2003 0 3b N\\ CHQCN N\\ Pd(dppr2COa)CI2 N PdC|2(dppf))KOAc dixoane dioxane H20 HszOOH H2N Raney Ni. H2 / —’HZN EtOH (NOEF 0 HATU DIPEA. DMF Synthesis of 5-br0m0hydr0xy(trifluor0methyl)benzaldehyde 4- Bromo(trifluoromethyl)phenol (20 g, 83 mmol) was disolved in H (100 mL), hexamethylenetetramine (23.2 g, 166 mmol) was added in portions over 10 min. The mixture was stirred at 90°C under nitrogen atmosphere for 18 h. The mixture was cooled to room temperature. H20 (100 mL) was added followed by 50% H2804 (60 mL), the mixture was —240— stirred for 2h. H20 (100 mL) was added, the resulting precipitate was collected by filtration to afford crude 5-bromohydroxy—3—(trifluoromethyl)benzaldehyde (270) as yellow solid (12.5 g, 56% , which was used directly. LCMS: m/z 271.1 [M+H]+; IR = 1.58 min.
Synthesis of 4-br0m0(1-hydr0xyethyl)(triflu0r0methyl)phen01 (271): 5- Bromo—2—hydroxy(trifluoromethyl)benzaldehyde (270) (12.5 g, 46 mmol) was dissolved in THF (100 mL), CH3MgBr (38.3 mL, 115 mmol, 3M in diethyl ether) was added dropwise at 0°C under nitrogen atmosphere. The reaction e was stirred at room temperature for 1h, quenched with NH4Cl aqueous solution (100 mL), extracted with EtOAc (200 mL X 2). The combined organic layers were dried over anhydrous NaZSO4, filtered, trated and purified by silica gel chromatography (6% EtOAc/petroleum ether) to afford o-2—(1— hydroxyethyl)~6—(trifluoromethyl)phenol (271) as yellow solid (7.5 g, 57% yield). LCMS: m/z 269.2 [M—OHT; zR =1.70 min.
Synthesis of 1—(5—br0m0hydr0xy(triflu0r0methyl)phenyl)ethan0ne (272): PDC (11.8 g, 315 mmol) was added to a stirred on of 4—bromo-2—(1-hydroxyethyl)—6- (trifluoromethyl)phenol (271) (6.0 g, 21 mmol) in CH2C12 (260 mL), the mixture was stirred at room ature for 2h, and filtered. The filtrate was concentrated and purified by silica gel chromatography (6% EtOAc/petroleum ether) to give 1-(5—bromo—2—hydroxy—3- (trifluoromethyl) phenyl) ethanone (272) as white solid (300 mg, 6% yield). LCMS: m/z 285.0 [M+H]+; rR =1.70 min.
Synthesis of 2-(2-acetylbrom0-6—(triflu0r0methyl)phenoxy)acet0nitrile (273): 1-(5-Bromohydroxy(trifluoromethyl) phenyl) ethanone (271); (300 mg, 1.06 mmol) was ved in DMF (4 mL). K2C03 (293 mg, 2.1 mmol) and 2—bromoacetonitrile (0.1 mL, 1.4 mmol) were added. The mixture was stirred at 40°C under nitrogen atmosphere for 2h. The mixture was poured into water (10 mL), extracted with EtOAc (50 mL X 2), dried over anhydrous Na2804, concentrated, and d by silica gel chromatography (6% EtOAc/petroleum ether) to give 2-(2-acetylbromo(trifluoromethyl)phenoxy) acetonitrile (268) as white solid (150 mg, yield 44%). LCMS: m/z 322.0 [M+H]+; IR =1.66 min.
] Synthesis of S-br0m0methyl(trifluor0methyl)benzofurancarbonitrile (274): 2—(2-Acetyl—4—bromo(trifluoromethyl)phenoxy)acetonitrile (273); (150 mg, 0.46 mmol) was dissolved in CH3CN (4 mL). K2CO3 (254 mg, 1.84 mmol) was added. The mixture was stirred at 95°C for 18 h, concentrated, and purified by silica gel chromatography (6% EtOAc/petroleum ether) to give 5—bromomethyl(trifluoromethyl)benzofuran—2~ —241- carbonitrile (274) as white solid (60 mg, 43% yield). 1H NMR (500 MHZ, DMSO-d6) 6 8.54 (s, 1H), 8.17 (s, 1H), 2.48 (s, 3H).
Synthesis of 3-methyl(4,4,5,5-tetramethyl-1,3,2-di0xaborolan-2—yl)(triflu oromethyl) benzofuran-Z-carbonitrile (275): 5-Bromomethyl—7- (trifluoromethyl)benzofuran—2-carbonitrile (274); (60 mg, 0.2 mmol), 4,4,4',4',5,5,5’,5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (76 mg, 0.3 mmol), Pd(dppf)C12 (15 mg, 0.02mmol), and potassium acetate (39 mg, 0.4 mmol) were added in 3 mL of dioxane and degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 3 h. After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced re to give the crude product, which was purified by silica gel tography (20% EtOAc/petroleum ether) to yield 60 mg of 3—methyl(4,4,5,5-tetramethyl—l ,3,2- dioxaborolan—2-yl)—7—(trifluoromethyl) benzofuran—Z—carbonitrile (275) as white solid (85% yield). LCMS: m/z 352.1 [M+H]+; rR = 2.01 min.
] Synthesis of 5-(5-(4,4-difluoropiperidine—l—carbonyl)pyridinyl)-3—methyl-7— (trifluoromethyl)benzofuran-Z-carbonitrile (276): 3—Methyl-5—(4,4,5,5-tetramethyl-l ,3 ,2- dioxaborolanyl)-7—(trifluoromethyl) benzofuran—2—carbonitrile (275) (60 mg, 0.17 mmol), (6-bromopyridin—3—yl)(4,4-difluoropiperidin—l—yl)methanone (61 mg, 0.2 mmol), Pd(dppf)C12 (13 mg, 0.02 mmol), and K2CO3 (47 mg, 0.34 mmol) were added in a mixture of dioxane (3 mL) and water (0.2 mL) and degassed. The reaction mixture was heated at 1000C under en atmosphere for 3 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was concentrated under d pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to yield 40 mg of 5—(5—(4,4-difluoropiperidinecarbonyl)pyridinyl)methyl‘(trifluoromethyl) benzofuran—2-carbonitrile (276) as white solid (yield 53%). LCMS: m/z 450.1 [M+H]+; tR = 1.81 min.
Synthesis of (aminomethyl)methyl(trifluoromethyl)benzofuran-S- yl) pyridinyl)(4,4-diflu0ropiperidin-l-yl)methadone (277): A solution of 5-(5-(4,4- difluoropiperidine- 1 nyl)pyridinyl)-3 ~methyl(trifluoromethyl) benzofuran carbonitrile (276) (40 mg, 0.09 mmol), Raney Ni (5 mg) in C2H50H (5 mL) was d under hydrogen atmosphere at room temperature for 2h. The mixture was filtered, the filtrate was concentrated to give (6—(2—(amino methyl)—3—methy1~7-(trifluoromethyl)benzofuran—5— —242— yl)pyridin—3—yl)(4,4—difluoropipe ridin—l—yl)methadone (277) as white solid (20 mg, yield * 50%). LCMS: m/z 454.2 [M+H]+; rR =1.83 min.
Synthesis of (E)—3-(6-amin0pyridinyl)—N-((5-(5—(4,4-difluor0piperidine—1- carb0nyl)pyridinyl)methyl(trifluor0methyl)benzofuran-2—yl)methyl)acryl amide (677): (6-(2-(Aminomethyl)methyl(trifluoromethyl)benzofuranyl)pyridinyl) (4,4- difluoropiperidin—l-yl)methadone (277) (20 mg, 0.04 mmol) was ved in DMF (3 mL) and (E)(6-aminopyridiny1)acrylic acid (8 mg, 0.05 mmol) was added at 0 °C. HATU (23 mg, 0.06 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (8 mg, 0.08 mmol). The on mixture was allowed to warm to room temperature and stirred further for 2 h. The reaction mixture was purified by Prep-HPLC without workup to give 5 mg of ((E-3—(6-aminopyridin—3-yl)—N-((5-(5—(4,4-difluoropiperidine-1—carbonyl)pyridin yl)methyl-7—(trifluoromethyl)benzofuran—2—yl)methyl)acryl amide (677). Yield : 21%. 1H NMR (500 MHZ, 6) 5 8.83-8.76 (m, 2H), 8.68 (s, 1H), 8.42 (s, 1H), 8.31 (d, J= 8 Hz, 1H), 8.17 (s, 1H), 8.07-8.01 (m, 2H), 7.42 (d,J= 16 Hz, 1H), 6.93 (d, J: 9 Hz, 1H), 6.54 (d, J: 16 Hz, 1H), 4.60 (d, J: 6 Hz, 2H), 3.80-3.72 (m, 2H), 3.53—3.44 (m, 2H), 2.37 (s, 3H), 2.15-2.03 (m, 4H). LCMS: m/z 600.2 [M+H]+; IR = 1.43 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5—(5-(4,4-diflu0r0piperidine-l- carb0n0thi0yl)pyridin-Z-yl)-7—(triflu0romethyl)benz0furanyl)methyl)pr0p-2— enethioamide (678).
F F N O HzN / L t / \ awesson's reagen W" HzN — N \ e reflux mNi 585 FF -(6-aminopyridin—3—yl)-N-((5-(5-(4,4-difluoropiperidinecarbonyl)pyridin—2-yl)(tri fluoromethyl)benzofuranyl)methyl)acrylamide (585) (293 mg, 0.5 mmol) and Lawesson’s reagent (404 mg, 1 mmol) was dissolved in toluene (10 mL). The reaction mixture was heated to reflux for 16 h. The mixture was concentrated under reduced pressure, which was purified by Prep-HPLC to afford 3 mg of (E)—3~(6-aminopyridinyl)-N-((5-(5- (4,4—difluoropiperidine— 1 —carbonothioyl)pyridin—2—yl)~7—(trifluoromethyl)benzofuran—Z- yl)methyl)prop—2-enethioamide (678). Yield: 1%. 1H NMR (400 MHz, CD3OD) 6 8.67—7.34 (m, 8H), 7.01-5.97 (m, 3H), 5.20 (s, 2H), 4.55—4.87 (m, 2H), .76 (m, 2H), 2.34-2.01 (m, 2H), 2.12-2.05 (m, 2H). LCMS: m/z 618.2 [M+H]+, IR: 2.00 min. —243— Synthesis of (E)-3—(6—aminopyridin—3-yl)—N—((5-(4-((4,4-difluoropiperidin-l- yl)sulf0nyl)phenyl)(triflu0r0methyl)benzofuran—Z-yl)methyl)acrylamide (679). o F3C 30201 F NHHCI o=§—NC> HN \ O 2 HATU, DIPEA, DMF Synthesis of 1-(4-br0mophenylsulfonyl)—4,4-difluoropiperidine (278): 4- Bromobenzene-l—sulfonyl chloride (2.5 g, 10 mmol) was dissolved in DCM (30 mL) and triethylamine (3 g, 30 mmol) was added. 4,4-Difluoropiperidine hydrochloride (1.8 g, 12 mmol) was added at 0 0C (ice bath). The reaction mixture was allowed to warm to room temperature and d for 1 h. The reaction mixture was diluted with DCM (100 mL), washed with water, brine, dried over anhydrous NaZSO4, and concentrated under reduced to give 2.9 g of 1-(4-bromophenylsulfonyl)-4,4-difluoropiperidine (278), which was . pressure used in next step without further purification (87% yield). LCMS: m/z 340.0 [M+H]+, Q; = 1.73 min.
] Synthesis of tert-butyl (5-(4-(4,4-diflu0r0piperidinylsulf0nyl)phenyl)—7- (trifluoromethyl)benzofuran-Z-yl)methylcarbamate (279): 1-(4-Bromophenylsulfonyl)- fluoropiperidine (278) (1.5 g, 4.4 mmol), tert—butyl (5—(4,4,5,5-tetramethyl~1,3,2- dioxaborolan—Z—yl)(trifluoromethyl)benzofuran-Z—yl)methylcarbamate (2.1 g, 4.8 mmol), Pd(dppf)C12 (0.36 g, 0.44 mmol), and K2CO3 (1.8 g, 13.2 mmol) were added to a mixture of dioxane (30 mL) and water (6 mL) and degassed. The reaction mixture was heated at 90 0C under nitrogen atmosphere for 6 h. The reaction mixture was cooled down to room ature, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10-30% petroleum ether) to yield 1.5 g of z‘ert—butyl (5-'(4-(4,4—difluoropiperidin—1-ylsulfonyl)phenyl) (trifluoromethyl)benzofuranyl)methylcarbamate (279) as a white solid (58% yield).
LCMS: m/z 575.1 [M+H]+, 1R: 1.86 min. -244— Synthesis of (5-(4-(4,4-diflu0r0piperidin-l-ylsulfonyl)phenyl)—7— (trifluoromethyl)benzofuran-Z-yl)methanamine (280): tert-Butyl (5-(4-(4,4- difluoropiperidin— 1 —ylsulfonyl)phenyl)(trifluoromethyl)benzofuran—2-yl)methylcarbamate (279) 1 g, 3.1 mmol) was dissolved in CH2C12 (20 mL). TFA (5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced re to give (4,4-difluoropiperidin-1— ylsulfonyl)phenyl)(trifluoromethyl)benzofuranyl)methanamine (280), which was used without further purification in the next step (580 mg, 70% yield). LCMS: m/z 475.1 [M+H]+, rR = 1.44 min.
Synthesis of (E)—3—(6—amin0pyridin-3—yl)—N—((5-(4-((4,4-diflu0ropiperidin-l- yl)sulfonyl)phenyl)-7—(triflu0romethyl)benzofuran-Z—yl)methyl)acrylamide (679): (5-(4- (4,4-Difluoropiperidin— l -ylsulfonyl)phenyl)(trifluoromethyl)benzofuran—2-y)methanamine (280) (250 mg, 0.53 mmol) was dissolved in DMF (4 mL) and (E)(6-aminopyridin—3— yl)acrylic acid (95 mg, 0.58 mmol) was added at 0 OC. HATU (222 mg, 0.58 mmol) was added to this on mixture at 0 °C followed by DIPEA (205 mg, 1.6 mmol) dropwise.
The reaction mixture was allowed to warm to room temperature and stirred r for 2 h.
The reaction mixture was d Prep-HPLC to afford 70 mg of (E)(6-aminopyridin yl)-N—((5 —(4-((4,4-difluoropiperidin—1—y1)su1fonyl)phenyl)-7~(trifluoromethyl)benzofuran-Z- hyl)acrylamide (679) (21% yield). 1H NMR (500 MHz, DMSO—dg) 6 8.88—8.82 (m, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 8.09—7.84 (m, 8H), 7.45 (d,J= 16 Hz, 1H), 7.02—6.90 (m, 2H), 6.60 (d, J: 16 Hz, 1H), 4.68—4.61 (m, 2H), 3.19~3.07 (m, 4H), 2.16-2.03 (m, 4H).
LCMS: m/Z 621.2 [M+H]+, tR= 1.91 min.
Synthesis of (E)-N-((5—(4-((4,4-diflu0ropiperidin-1—yl)sulfonyl)phenyl) (trifluoromethyl)benzofuran-Z-yl)methyl)(pyridin-3—yl)acrylamide (680).
|\ F30 F30 N / / OH ' o 00 O "Q9 F \ _ o o . H O O Myi F F N / / N \ HzN \ O HATU,D|PEA,DMF 275 530 (E)—N—((5-(4-((4,4-difluoropiperidiny1)sulfonyl)phenyl)—7- (trifluoromethyl)benzofuranyl)methyl)(pyridinyl)acrylamide (680) was synthesized in a similar fashion as example (677). Yield: 24%. 1H NMR (500 MHZ, DMSO-dg) 5 8.99— 8.94 (m, 1H), 8.86 (s, 1H), 8.68-8.60 (m, 1H), 8.34 (s, 1H), 8.20-8.14 (m, 1H), 8.10-8.03 (m, —245— 2H), 7.97 (s, 1H), 7.92-7.87 (m, 2H), 7.62-7.55 (m, 2H), 7.01 (s, 1H), 6.87 (d, J= 16 Hz, 1H), 4.68 (d, J= 5 Hz, 2H), 3.18-3.11 (m, 4H), 2.14-2.06 (m, 4H). LCMS: m/z 606.2 [M+H]+, rR = 1.96 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((5-(5-(4,4-difluoropiperidine-l- carbonyl)pyridinyl)-6,7-difluorobenzofuran-Z-yl)methyl)acrylamide (681).
F O\ /O LIE/Br : \ /B‘B\ F Br Br l2 Kl NHBoc NHBOC O O —-——-——————> ———_———> NH; H20 rt HO Pd(PPh3)°2CI2. Cul, F O Pd(dppf)C|2,AcOK, NEta, 80 C F dioxane. 100°C 231 232 odd GF as .
FmB o’ NHBoc F/fl: TFA KoAc Pd(dppf)C|2 N_ BocHN CHZCIZ F dloxane, H20 283 284 F 14sz F F (j N\ COOH H2N / \ N" O HATU, DlPEA DMF H2N \ 235 WHO: Synthesis of 4—bromo-2,3-difluor0i0d0phenol (281): 4-Bromo-2,3- ophenol (2 g, 9.7 mmol) was dissolved in 100 mL ofNH4OH. A solution of K1 (4.8 g, 29 mmol) and 12 (2.5 g, 9.7 mmol) in 50 mL of H20 was added to the reaction mixture and stirred at room ature up to 1 h. The reaction mixture was cooled down to 0 OC (ice bath), neutralized with HCl (cone) until pH ~ 6-7; extracted with EtOAc (200 mL X 3). The combined organic layers were washed with sat. aq. sodium bisulfite solution, brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give 2.8 g of 4-bromo- 2,3-difluoroiodophenol (281) as a yellow solid (85% yield). LCMS: m/z IR = 1.31 min.
Synthesis of tert-butyl mo-6,7-difluorobenzofuran—2- yl)methylcarbamate (282): 4-Bromo-2,3-difluoroiodophenol (281) (2 g, 5.9 mmol), tertbutyl prop—2—ynylcarbamate (1.1 g, 7.1 mmol), Pd(PPh3)2Clz (0.6 g, 0.9 mmol), Cul (0.17 g, 0.9 mmol) were added in 30 mL of triethylamine and degassed. The on mixture was refluxed at 80 0C under nitrogen here for 2 h. After cooling down to room temperature, the reaction mixture was d. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (5% EtOAc/petroleum ether) to yield 1.7 g of rert-butyl (5—bromo-6,7—difluorobenzofiiran-2— yl)methylcarbamate (282) as a pale yellow solid (80% yield). LCMS: m/z 3 84.3 [M+Na]+, tR = 2.13 min.
Synthesis of tert-butyl (6,7-difluoro-S-(4,4,5,5—tetramethyl-1,3,2-dioxaborolan- 2—yl)benzofuran-Z-yl)methylcarbamate (283): tert—Butyl (5-bromo-6,7-difluorobenzofuran- 2-yl)methylcarbamate (282) (500 mg, 1.4 mmol), 4,4,4’,4',5,5,5',5'-octarnethyl-2,2'-bi(1,3,2- dioxaborolane) (534 mg, 2.2 mmol), Pd(dppi)C12 (190 mg, 0.2 mmol), and potassium acetate (280 mg, 2.8 mmol) were added in 10 mL of e and degassed. The reaction e was heated at 100 0C under nitrogen atmosphere for 2 h. After cooling down to room ature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to yield 0.4 g of tert—butyl (6,7—difluoro—5—(4,4,5,5—tetramethyl-1,3,2— dioxaborolanyl)benzofuran—2-yl)methylcarbamate (283) as a white solid (70% yield).
LCMS: m/Z IR = 1.87 min.
Synthesis of tert-butyl (5-(5—(4,4-difluoropiperidine—1-carb0nyl)pyridinyl)— 6,7-difluorobenzofuran-Z-yl)methylcarbamate (284): tert—Butyl (6,7-difluoro—5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan—2-yl)benzofuran—2-yl)methylcarbamate (283) (0.4 g, 0.96 mmol), (6—bromopyridinyl)(4,4—difluoropiperidin-l-yl)methanone (0.29 g, 0.96 mmol), Pd(dppf)C12 (0.11 g, 0.14 mmol), and K2CO3 (0.26 g, 1.92 mmol) were added in a mixture of dioxane (10 mL) and water (1 mL) and degassed. The on mixture was heated at 100 0C under nitrogen here for 5 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was trated under reduced pressure to give the crude t, which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to yield 0.38 g of tert—butyl (4,4-difluoropiperidinecarbonyl)pyridin—2—yl)—6,7- difluorobenzofuranyl)methylcarbamate (284) as a white solid (yield 80%). LCMS: m/z 508.1 [M+H]+, IR: 1.96 min. sis of (6-(2-(aminomethyl)-6,7-difluorobenzofuranyl)pyridin yl)(4,4—difluoropiperidin—1-yl)methan0ne (285): tert—Butyl (5—(5-(4,4—difluoropiperidine-1 - carbonyl)pyridin—2—yl)-6,7—difluorobenzofi1ranyl)methylcarbamate (284) (100 mg, 0.2 mmol) was dissolved in CHzClz (5 mL). TFA (1 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction —247- mixture was trated under reduced pressure to give the crude (6-(2-(aminomethyl)-6,7- difluorobenzofuran-S-yl)pyridinyl)(4,4-difluoropiperidinyl)methanone (285) which was used without r purification in the next step (81 mg, 100% yield). LCMS: m/z 408.1 [M+H]+, 1R = 1.22 min.
Synthesis of (E)(6-aminopyridinyl)-N—((5-(5-(4,4-difluoropiperidine—l— carbonyl)pyridin-Z-yl)-6,7-diflu0robenzofuran-Z-yl)methyl)acrylamide (681): (6-(2- (Aminomethyl)-6,7-difluorobenzofuran-S-yl)pyridin-3 -y1)(4,4-difluoropiperidin yl)methanone (285) (81 mg, 0.2 mmol) was dissolved in DMF (2 mL) and (E)(6- aminopyridinyl)acrylic acid (33 mg, 0.2 mmol) was added at 0 °C. HATU (152 mg, 0.4 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (52 mg, 0.4 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 2 h. The reaction mixture was purified by Prep-HPLC to afford 23 mg of (E)(6- aminopyridin—3—yl)—N—((5-(5—(4,4-difluoropiperidinecarbonyl)pyridinyl)-6,7- difluorobenzofuranyl)methyl)acrylamide (681) (20% yield). 1H NMR (500 MHz, DMSO— d6) 5 .76 (m, 2H), .82 (m, 7H), 7.45 (d, J: 16 Hz, 1H), 7.08-6.89 (m, 2H), 6.60 (d, J: 16 Hz, 1H), 4.68-4.58 (m, 2H), .71 (m, 2H), 3.56-3.42 (m, 2H), .02 (m, 4H). LCMS: m/z 554.2 [M+H]+; {R = 1.71 min. sis of (E)—N—((5-(4-(4,4-difluoropiperidinecarb0nyl)phenyl)—7- (trifluoromethyl)benzofuran-Z-yl)methyl)(pyridin—3~yl)acrylamide (682).
F F F F F F o N/ I \ OH 0 / \ / o / o _ o N | H N HzN —2_.
\ N\ N \ HATU, DIPEA, DMF 211 682 F F F F [0 0768] (E)—N-((5—(4-(4,4-difluoropiperidinecarbonyl)phenyl)—7- (trifluoromethyl)benzofuranyl)methyl)(pyridinyl)acry1amide (682) was synthesized using the indicated reagents according to General Procedure 4. Yield: 31%. 1H NMR (400 MHz, DMSO-dé) 8 8.94 (t, J= 6 Hz, 1H), 8.79 (d, J= 2 Hz, 1H), 8.62-8.53 (m, 1H), 8.27 (s, 1H), 8.06-8.00 (m, 1H), 7.91-7.81 (m, 3H), 7.61-7.52 (m, 3H), 7.49-7.43 (m, 1H), 6.99 (s, 1H), 6.84 (d, J: 16 Hz, 1H), 4.66 (d, J: 6 Hz, 2H), 3.78-3.43 (m, 4H), 216-196 (In, 4H).
LCMS: m/z 569.9 [M+H]+, zR = 2.03 min.
Synthesis of (E)(6—aminopyridin-3—yl)-N-((5-(4-(4,4-difluoropiperidine—l-carbonyl)—2- fluorophenyl)(trifluoromethyl)benzofuran—Z-yl)methyl)acrylamide (683).
QLOI03 NHBoc F I:><:>NHHCI Br Om OH O NHBoc EDCI HOBt DIPEA Pd(dppf)c|2 O CHZCIZ K2C03 CF3 2" 1 4-dioxane H20 237 M O \0 "Mn TFA i/NNH2 NS Q Q N NH? CHZCKZ g > F CF3 HATU. DIPEA, DMF F (E)-3 -(6-aminopyridiny1)-N-((5-(4-(4,4-difluoropiperidinecarbony1) fluorophenyl)(triflu0r0methy1)benzofuran-Z—yl)methy1)acry1amide as synthesized in a similar fashion as example (538). 1H NMR (400 MHz, CD3OD) 5 8.98 (s, 1H), 8.74 (s, 1H), 8.63—8.55 (m, 1H), 8.07 (s, 1H), .86 (m, 1H), 7.78-7.65 (m, 3H), 7.46-7.38 (m, 2H), 7.01-6.91 (m, 2H), 4.78 (s, 2H), 3.98-3.81 (m, 2H), 3.73—3.57 (m, 2H), 2.20—1.99 (m, %DLCM&m&&B2flMHTJyflA4mm Synthesis of ((5-(4-(4,4-difluoropiperidine—l-carb0nyl)flu0r0phenyl)—7- (trifluoromethyl)benzofuran-Z-yl)methyl)(pyridin—3-yl)acrylamide (684).
F7000 HO__8:__.IN\/ % Fg\nH2 HATU DIPEA, DMF F 684 (E)-N—((5—(4-(4,4-difluoropiperidinecarbonyl)fluoropheny1)—7— (trifluoromethyl)benzofuran—2-y1)methyl)—3—(pyridinyl)acry1amide (684) was sized using the indicated reagents accoeding to General Procedure 4. Yield: 37%. 1H NMR (400 MHZ, DMSO-d6) 8 9.02-8.84 (m, 2H), 8.70-8.61 (m, 1H), 8.29-8.12 (m, 2H), 7.79 (s, 1H), 7.72 (t, J= 8 Hz, 1H), 7.68-7.55 (m, 2H), 7.50 (d, J: 11 Hz, 1H), 7.44-7.38 (m, 1H), 7.01 (s, 1H), 6.92-6.83 (m, 1H), 4.67 (d, J: 6 Hz, 2H), 3.82-3.65 (m, 2H), 3.54-3.35 (m, 2H), 2.15— 1.99 (m, 4H). LCMS: m/z 588.2 [M+H]+, IR: 1.58 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4,4-difluoropiperidine carbonyl)thiophenyl)(trifluor0methyl)benzofuranyl)methyl)acrylamide (685). —249- \ o ><:NH HCI B cHN /0 ° 8 o \ o W#—’ so 0 3 BocHN \ / Br OH N EDCI HOBt DIPEA.
"W Pd(dPPf)C|2. K2903, Dioxane, H20 290 F WFF HATU DIPEA DMFCS} (ID-3 ~(6-amin0pyridinyl)—N—((5-(5—(4,4-diflu0r0piperidine carbonyl)thi0phenyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (685) was synthesized in a similar fashion as example (521). 1H NMR (400 MHZ, CD30D) 8 8.15 (s, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.76 (d, J: 9 HZ, 1H), 7.53-7.45 (m, 3H), 6.91 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.48 (d, J: 16 Hz, 1H), 4.71 (s, 2H), .89 (m, 4H), 2.18-2.07 (m, 4H). LCMS: m/z 591.2 [M+H]+, tR= 1.84 min.
Synthesis of (E)(6—amin0pyridinyl)—N-((5-(4-(4,4-diflu0r0piperidine carbonyl)phenyl)(triflu0r0methoxy)benzofuranyl)methyl)acrylamide (686). (‘3 N F3CO ,B F O omNHBoc ..
F 00 O TFA O —-—> BocHN \ W- CHzc‘Z 0cm Pd(dPPf)Cl2. K2003. dioxane,H20.100°C 292 F 239 F H NWOH 0HO 2 N 200, .o O 0Q "ZN \ < 2 HATU DIPEA DMF 293 F 686 (E)—3 -(6—amin0pyridin-3 —((5 -(4~(4,4—diflu0r0piperidine- l -carb0nyl)phenyl)— 7—(trifluoromethoxy)benzofuran-Z-yl)methyl)acrylamide (688) was synthesized in a similar fashion as example (663) using the indicated reagents. 1H NMR (400 MHZ, DMSO-dg) 5 8.65 (t, J: 6 Hz, 1H), 8.08 (d, J: 2 Hz, 1H), 7.99 (d, J: 2 Hz, 1H), 7.83-7.77 (m, 2H), 7.68—7.54 —250— (In, 4H), 7.35 (d, J: 16 Hz, 1H), 6.92 (s, 1H), 6.53-6.31 (m, 4H), 4.60 (d, J: 6 Hz, 2H), 3.79—3.42 (m, 4H), 2.13—1.98 (In, 4H). LCMS: m/z 601.3 [M+H]+, IR: 1.84 min.
Synthesis of (E)-N-((5-(4-(4,4-diflu0r0piperidine—1-carb0nyl)phenyl)—7- (trifluor0methoxy)benzofuranyl)methyl)—3-(pyridinyl)acrylamide (687).
F3CO \ F200 ° U481 ° o O O | N M N n ‘1O 0 N H2" \ \ IPEA,DMF / 293 687 F (E)—N-((5-(4-(4,4-difluoropiperidine- 1 —carb0nyl)pheny1) (trifluoromethoxy)benzofuran—2-yl)methyl)—3—(pyridin-3—yl)acry1amide (687) was synthesized using the indicated reagent saccording to Genral Procedure 4. Yield: 27%. 1H NMR (400 MHZ, DMSO-ds) 5 8.92 (t, J: 6 Hz, 1H), 8.79 (d, J: 2 Hz, 1H), .53 (In, 1H), 8.05—7.98 (In, 2H), 7.84-7.77 (m, 2H), 7.67 (s, 1H), 7.60-7.43 (m, 4H), 6.96 (s, 1H), 6.82 (d, J: 16 Hz, 1H), 4.64 (d, J: 6 Hz, 2H), 3.79-3.41 (m, 4H), 2.14-1.97 (m, 4H). LCMS: m/z 586.2 [M+H]+, rR= 1.88 min.
Synthesis of (E)-N-((5-(4—(2-0xa—6—azaspir0[3.3]heptane—6-carbonyl)phenyl) (trifluoromethyl)benzofuran—2~yl)methyl)—3-(pyridin—3—yl)acrylamide (688).
NH2 ——-—————N—--—> °O O:W_ HATU THF H20 DIPEA DMF HATU DIPEA DMF (E)-N-((5—(4-(2-oxaazaspiro[3.3]heptanecarbonyl)pheny1) (trifluoromethyl)benzofuran-Z-y1)methyl)—3—(pyridiny1)acry1arnide (688) was sized using the indicated reagents in a similar fashion as example (517). 1H NMR (400 MHz, DMSO—d6) 5 9.03-8.85 (m, 2H), 8.66 (s, 1H), 8.30—8.18 (m, 2H), 7.89 (s, 1H), 7.84 (d, J: 8 Hz, 2H), 7.73 (d, J= 8 Hz, 2H), 7.68-7.55 (m, 2H), 6.99 (s, 1H), 6.89 (d, J: 16 Hz, 1H), .63 (m, 6H), 4.53 (s, 2H), 4.24 (s, 2H). LCMS: m/z 548.2 [M+H]+, tR= 1.39 min.
Synthesis of (E)-N-((5-(5-(2-oxaazaspiro[3.3]heptanecarbonyl)pyridin—2—yl) (triflu0r0methyl)benzofuran-Z-yl)methyl)(pyridinyl)acrylamide (689).
\ \ O __ \ O<><:NH O H% \ / N N N HATU DlPEA DMF % CF3 ] (E)-N-((5-(5-(2-oxaazaspiro[3.3]heptanecarbonyl)pyridinyl) (trifluoromethyl)benzofurany1)methy1)(pyridiny1)acry1arnide (689) was synthesized using the indicated reagents ing to General Procedure 4. Yield (22%). 1H NMR (400 MHz, DMSO'd6) 6 8.98—8.88 (m, 2H), 8.79 (d, J: 2 Hz, 1H), 8.72 (s, 1H), 8.60—8.53 (m, 1H), 8.41 (s, 1H), 8.22 (d, J: 8 Hz, 1H), 8.14-8.10 (m, 1H), 8.02 (d, J= 8 Hz, 1H), 7.56 (d, J = 16 Hz, 1H), 7.50-7.43 (m, 1H), 7.04 (s, 1H), 6.84 (d, J: 16 Hz, 1H), 4.75-4.62 (m, 6H), 4.58 (s, 2H), 4.26 (s, 2H). LCMS: m/z 549.2 [M+H]+, tR= 1.61 min.
Synthesis of (E)(6-aminopyridinyl)-N—(2—(5-(5-(4,4-difluoropiperidine-l- carbonyl)pyridinyl)—7-(trifluoromethyl)benzofuran-Z-yl)ethyl)acrylamide (690).
HO \/\OH i233"Bii O NQ _.________'HO 0 B \ HO r Pd((PPI13)2z:I2 Cul EtaN Pd(dppf)0|2 KOAc. e Br 3/0 fl—’Pd((,dppficlz K2003 297 dioxane H20 CFa CF3 H0 0 M50 0 M56] 0 _..__> NaN3 \ F CHCl22. EIN \ I 3 FF 299 o 3O1N wHEN \0 HW000" W "'60" \ F 1 HATU DlPEA DMF "MN 302 0 Synthesis of 2-(5-br0m0(triflu0romethyl)benzofuranyl)ethanol (297): 4- Bromoiodo(trifluoromethyl)phenol (20 g, 55 mmol), butynol (3.9 g, 55 mmol), Pd(PPh3)2C12 (3.9 g, 5.5 mmol), CuI (1.1 g, 5.5 mmol) were added in 400 mL of triethylamine and degassed. The reaction e was refluxed at 80 0C under nitrogen atmosphere for 2 h.
After cooling down to room temperature, the on mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica —252— gel chromatography (10% EtOAc/petroleum ether) to yield 13.5 g of 2-(5-hromo-7— (trifluoromethyl)benzofuran—2—yl)ethanol (297) as a pale yellow solid (80% yield). LCMS: tR = 1.94 min.
Synthesis of 2-(5—(4,4,5,5-tetramethyl-l,3,2—dioxab0rolan-Z-yl)—7- (trifluoromethyl)benzofuran-Z-yl)ethanol (298): romo—7— (trifluoromethyl)benzofuran—2—yl)ethanol (297) (10 g, 32.5 mmol), 4,4,4',4',5,5,5',5’- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.4 g, 48.8 mmol), Pd(dppi)C12 (2.4 g, 3.3 mmol), and potassium acetate (6.4 g, 65 mmol) were added in 200 mL of dioxane and degassed. The reaction mixture was heated at 80 0C under en atmosphere for 2 h. After g down to room ature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to yield 9 g of 2-(5-(4,4,5,5-tetramethy1—1,3,2-dioxaborolan-2— yl)—7—(trifluoromethyl)henzofuran-Z-yl)ethanol (298) as a white solid (80% yield). LCMS: m/z 357.1, tR=1.86 min.
Synthesis of (4,4—diflu0r0piperidinyl)(6—(2-(2—hydr0xyethyl) (trifluoromethyl)benzofuranyl)pyridinyl)methanone (299): 2—(5—(4,4,5,5— Tetramethyl—l ,3,2—dioxaborolan—Z—yl)—7—(trifluoromethyl)benzofuran-2—yl)ethanol (298) (8 g, 22.5 mmol), (6—hromopyridinyl)(4,4—difluoropiperidin—1—y1)methanone (6.9 g, 22.5 mmol), Pd(dppt)Clz (1.6 g, 2.3 mmol), and K2CO3 (3.5 g, 25 mmol) were added in a mixture of dioxane (150 mL) and water (15 mL) and degassed. The reaction mixture was heated at 80 0C under nitrogen here for 2 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to yield 9 g of (4,4—difluoropiperidin—1-y1)(6-(2-(2—hydroxyethyl)—7— (trifluoromethyl)benzofuran-S-y1)pyridinyl)methanone (299) as a white solid (yield 90%).
LCMS: m/z 455.1 , ZR = 1.82 min.
Synthesis of 2-(5-(5-(4,4-diflu0r0piperidine—1-carb0nyl)pyridinyl) (trifluoromethyl)benz0furan-Z-yl)ethyl methanesulfonate (300): (4,4-Difluoropiperidin yl)(6—(2-(2~hydroxyethyl)—7-(trifluoromethyl)benzofuran—5—yl)pyridin-3—yl)methanone (299); (3 g, 6.6 mmol) was dissolved in DCM (50 mL) and triethylamine (1.3 g, 13.2 mmol) was added. Methanesulfonyl chloride (0.75 g, 6.6 mmol) was added dropwise at 0 0C (ice bath) over 10 min. The on mixture was allowed to warm to room ature and stirred for 1 —253- h. The reaction mixture was diluted with DCM (100 mL), washed with water, brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to giVe 3 .3 g of 2—(5—(5- (4,4—difluoropiperidinecarbonyl)pyridin—2-yl)(trifluoromethyl)benzofuran-2—yl)ethyl methanesulfonate (300), which was used in next step without further ation (95% yield).
LCMS: m/z 533.1 [M+H]+, 1R: 1.67 min.
Synthesis of (6-(2-(2-azidoethyl)—7-(trifluoromethyl)benzofuranyl)pyridin- 3-yl)(4,4-difluoropiperidin—l-yl)methanone (301): 5-(4,4-Difluoropiperidine carbonyl)pyridiny1)(trifluoromethy1)benzofurany1)ethy1methanesulfonate(300; 1 g, 1.9 mmol) was dissolved in 20 mL of DMF. NaN3 (0.4 g, 5.7 mmol) and K2CO3 (0.5 g, 3.7 mmol) were added. The reaction mixture was heated at 60 0C for 2 h, cooled down to room temperature, poured into iced water (50 mL), extracted with EtOAc (50 mL X 3), washed with brine (50 mL), dried over NaZSO4, and concentrated under reduced re to afford 0.8 g of (6-(2-(2-azidoethyl)(trifluoromethyl)benzofuranyl)pyridinyl)(4,4— difluoropiperidin—1-yl)methanone (301) as yellow solid, which was used without further purification in the next step (90% yield). LCMS: m/z 480.1 [M+H]+; IR = 1.80 min.
Synthesis of (6-(2-(2-aminoethyl)-7—(triflu0r0methyl)benzofuran-S-yl)pyridin- 3-yl)(4,4-diflu0r0piperidinyl)methanone : (6—(2-(2-Azidoethyl) (trifluoromethyl)benzofuran-5—yl)pyridin-3 ~yl)(4,4~difluoropiperidinyl)methanone (30 1; 200 mg, 0.42 mmol) was ved in methanol (10 mL). 10% Raney Ni (50% wet) (0.3 g) was added and hydrogen gas was purged at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under d pressure to give 170 mg of (6—(2-(2-aminoethyl)(trifluoromethyl)benzofuranyl)pyridinyl)(4,4—difluoropiperidin- 1-yl)methanone (302), which was used without r purification in the next step (90% yield). LCMS: m/z 454.1 ; {R = 1.33 min.
Synthesis of (E)(6-aminopyridinyl)—N-(2-(5-(5-(4,4-difluoropiperidine yl)pyridinyl)(triflu0r0methyl)benz0furan-2—yl)ethyl)acrylamide (690). (6- (2-(2-Aminoethyl)(trifluoromethy1)benzofurany1)pyridiny1)(4,4-difluoropiperidin yl)rnethanone (302; 50 mg, 0.11 mmol) was dissolved in DMF (2 mL) and (E)—3-(6- aminopyridin—3-y1)acrylic acid (18 mg, 0.11 mmol) was added at 0 OC. HATU (84 mg, 0.22 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (28 mg, 0.22 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 2 h. The reaction mixture was purified Prep-HPLC to afford 38 mg of (E)-3—(6- —254— aminopyridin—3 —(2—(5 -(5 -(4,4-difluor0piperidine-1—carbonyl)pyridin—2-yl)—7- (trifluoromethyl)benzofuran—2—yl)ethyl)acrylamide (690) (58% yield). 1H NMR (400 MHZ, CD30D) 8 8.82-8.76 (m, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.19 (d, J= 9 Hz, 1H), 8.13—8.00 (m, 3H), 7.43 (d, J= 16 Hz, 1H), 7.06 (d, J: 9 Hz, 1H), 6.87 (s, 1H), 6.57 (d, J= 16 Hz, 1H), 4.00-3.87 (m, 2H), 3.77 (t, J: 7 Hz, 2H), 3.71-3.61 (m, 2H), 3.19 (t, J: 7 Hz, 2H), 2.21-2.03 (m, 4H). LCMS: m/Z 600.1 [M+H]+, 1R: 1.40 min.
Synthesis of (E)(6-aminopyridinyl)-N-(2-(5-(4-(4,4-difluoropiperidine—l- carbonyl)phenyl)(triflu0romethyl)benzofuran-Z-yl)ethyl)acrylamide (691).
F3C F30 Q 0 0 K2003. PdClz(dPPf) 0 Br + 0/8 0 \ dioxane, H20 \ HO HO 297 303 Q 304 QF F F MsCI \O 0Q Raney Ni H2 NaN3 Mao" E13N CHZCIZ K2003, DMF HATU DIPEA, DMF ] (E)-3—(6-amin0pyridin—3—yl)—N—(2-(5—(4-(4,4-difluoropiperidine carbonyl)phenyl)(trifluoromethyl)benzofuran—2-yl)ethyl)acrylamide (691) was prepared using the indicated reagents in a r fashion as example (690). 1H NMR (400 MHz, DMSO-dg) 8 8.41—8.15 (m, 5H), 8.09 (d, J: 9 Hz, 1H), 7.87-7.79 (m, 3H), 7.58 (d, J: 8 Hz, 2H), 7.38 (d, J: 16 Hz, 1H), 6.99 (d, J: 9 Hz,1H), 6.91 (s, 1H), 6.51 (d, J: 16 Hz, 1H), 3.80-3.45 (m, 6H), 3.08 (t, J: 7 Hz, 2H), 2.15-1.98 (m, 4H). LCMS: m/z 599.1 [M+H]+, tR= 1.47 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(4-fluoropheny1)(4- (trifluoromethyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (692). ~255— D..om .. oi: cF o O O a BocHN CLO O Pd((dppf)C12 K2C03 [(3)304 Pd((PPh3)4 BocHN BocHN \ Cng, dioxane, H20 dioxane H20 308 309 WW" / TFA O O O CFa N HzN \ CH2C'2 HATU DIPEA DMF Synthesis of tert-Butyl (7-chloro(4-(trifluoromethyl)phenyl)benzofuran-Z- yl)methylcarbamate (308): tert-Butyl (7-chloro(4-(trifluoromethyl)phenyl)benzofuran yl)methylcarbamate (308) was sized using General Procedure 2. Yield: 91%. LCMS: m/z 448.1 [M+Na]+, IR: 1.95 min.
Synthesis of utyl (7-(4-flu0r0phenyl)—5-(4— (trifluoromethyl)phenyl)benzofuran-Z—yl)methylcarbamate (309): tert—Butyl (7—(4— fluorophenyl)(4-(trifluoromethyl)phenyl)benzofuranyl)methylcarbarnate (309) was synthesized using the indicated reagents according to l Procedure 2 Yield: 61%.
LCMS: m/z 508.1 [M+Na]+, IR: 1.99 min.
Synthesis of (7-(4-Flu0r0phenyl)—5-(4-(triflu0romethyl)phenyl)benzofuran yl)methanamine (310): (7-(4-Fluorophenyl)—5-(4-(trifluoromethyl)phenyl)benzofuran yl)methanarnine (310) was synthesized using the indicated reagents according to General ure 3. Yield: 98%. LCMS: m/z 369.0 [M—NH2]+, tR= 1.56 min.
Synthesis of (E)(6-aminopyridin—3-yl)—N-((7-(4-flu0r0phenyl)—5-(4- (trifluoromethyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (692): (E)-3—(6— yridin-3—yl)-N—((7—(4-fluorophenyl)-5—(4-(trifluoromethyl)phenyl)benzofuran-2— yl)methyl)acrylamide (692) was synthesized using the indicated ts according to General Procedure 4. Yield: 45%. 1H NMR (400 MHz, DMSO-dg) 5 8.62 (t, J = 6 Hz, 1H), 8.11-7.99 (m, 5H), 7.96 (d, J= 2 Hz, 1H), 7.86-7.76 (m, 3H), 7.64-7.58 (m, 1H), 7.44-7.31 (m, 3H), 6.88 (s, 1H), 6.50-6.39 (m, 4H), 4.60 (d, J= 6 Hz, 2H). LCMS: m/z 532.2 [M+H]+, IR = 2.05 min.
Synthesis of (E)(6—aminopyridin—3—yl)—N—((7-(4—fluor0phenyl)(4- (methylsulfonyl)phenyl)benzofuran-Z—yl)methyl)acrylamide (693). -256— 0 0H K2003. PdIQ TFA o M%~——* 1 O / CH CI u HATU. DlPEA, DMF EocHN \ O 2 2 H2N \ 0 an 314 693 Synthesis of tert-butyl (7-chlor0(4-(methylsulfonyl)phenyl)benzofuran-Z- yl)methylcarbamate (312): tert-Butyl (5jbromochlorobenzofuranyl)methylcarbamate (19, 500 mg, 1.9 mmol), 4—(methylsulfonyl)phenylboronic acid (311, 460 mg, 2.3 mmol), Pd(dppf)C12 (163 mg, 0.2 mmol) and K2CO3 (787 mg, 5.7 mmol) were added in a mixture of dioxane (30 mL) and H20 (6 mL). The reaction mixture was stirred at 95°C under en atmosphere for 12 h. LCMS showed the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with EtOAc (30 mL), washed with water, brine, dried over anhydrous Na2SO4, and concentrated under d pressure to give the crude t, which was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to give tert-butyl (7-chloro(4-(methylsulfonyl)phenyl)benzofuran—2-yl)methylcarbamate (312), (450 mg, 54% yiled) as yellowish solid. LCMS: m/z 458.0 [M+23]+, IR: 1.73 min.
Synthesis of utyl (7-(4-fluorophenyl)(4- (methylsulfonyl)phenyl)benzofuranyl)methylcarbamate (313): tert—Butyl (7—chloro (4-(methylsulfonyl)pheny1)benzofuran—2-yl)methylcarbamate (312, 220 mg, 0.5 mol), 4- fluorophenylboronic acid (84 mg, 0.6 mmol), Pd(PhP3)4 (58 mg, 0.05 mmol), PCy3(14 mg, 0.05mmol) and K3PO4 (320 mg, 1.5 mmol) in a mixture of dioxane (2 mL) and H20 (0.2 mL). The mixture was heated to 140°C under microwave for 1.5 h. The reaction mixture was cooled down to room ature, diluted with EtOAc (30 mL), washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to give tert-butyl (7-(4-fluorophenyl)(4-(methylsulfonyl)phenyl)benzofuran—2- hylcarbamate (313), (200 mg, 80% yiled) as te solid. LCMS: m/z 518.0 [M+23]+, 1R: 1.79 min.
Synthesis of (7-(4—flu0r0phenyl)—5—(4-(methylsulf0nyl)phenyl)benzofuran-Z— hanamine (314): tert—Butyl (7—(4—fluorophenyl)—5—(4- —257— (methylsulfonyl)phenyl)benzofuran-2—yl)methylcarbamate (313, 200 mg, 0.4 mmol) was dissolved in CHzClz (20 mL). TFA (4 mL) was added at 0 °C. The reaction mixture was stirred at 15°C for 2 h, and concentrated under reduced pressure to give the crude (7-(4- fluorophenyl)—5-(4~(methylsulfonyl)phenyl)benzofuranyl)methanamine (314), (160 mg, 100% yield), which was used without further purification in the next step. LCMS: m/z 396.1 ; 1R = 1.33 min.
] Synthesis of (E)(6-aminopyridinyl)-N—((7-(4-fluorophenyl)(4- lsulfonyl)phenyl)benzofuranyl)methyl)acrylamide (693): (7-(4-Fluoropheny1)- methy1sulfony1)phenyl)benzofuranyl)methanamine (314, 80 mg, 0.20 mmol), (E) (6-aminopyridinyl)acrylic acid (36 mg, 0.22 mmol) and HATU (84 mg, 0.22 mmol) was dissolved in DMF (3 mL) and DIPEA (78 mg, 0.60 mmol) was added slowly. The reaction mixture was stirred at 20°C for 2 h. The mixture was purified by Pre-HPLC to give (E)(6- aminopyridin-3—yl)-N—((7-(4-fluorophenyl)—5—(4—(methylsulfonyl)phenyl)benzofuran—2- yl)methyl)acrylamide (693) as white solid (40 mg, 37% yield). 1H NMR (400 MHZ, DMSO- dg) 8 8.81 (t, J: 6 Hz, 1H), 8.20 (s, 1H), 8.11—7.96 (m, 10H), 7.82 (d, J= 2 Hz, 1H), 7.48- 7.36 (m, 3H), 6.94 (d, J: 9 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J: 16 Hz, 1H), 4.62 (d, J: 6 Hz, 2H), 3.28 (s, 3H). LCMS: m/z 542.2 [M+H]+, tR= 1.40 min.
Synthesis of (E)(6-amin0pyridinyl)—N-((5-(3,5—dimethylisoxazolyl)(4- fluorophenyl)benzofuran-Z-yl)methyl)acrylamide (694).
CI B—%%:fi 0' pH 0 F4< >—B /:,fi 13H 3°CHN \\ BUCHN K3PO4 Pd(PPhgl Pd(dppf))CI2 cho3 Cng dioxane, H20 BOCHN dioxane H20 \ OH / H N2 TFA H2" N CH2012 HgN HATU. DIPEA. DMF 317 694 (E)(6—aminopyridin—3-yl)—N-((5—(3,5-dimethylisoxazol-4—yl)—7—(4- fluorophenyl)benzofuranyl)methyl)acrylamide (694) was synthesized using the indicated reagents in a similar fashion as example (693). 1H NMR (400 MHZ, DMSO—d6) 8 8.07 (s, 1H), 8.01-7.84 (m, 4H), 7.65 (d, J: 9 Hz, 1H), 7.57 (s, 1H), 7.46-7.20 (m, 5H), 6.87-6.77 (m, -258— 1H), 6.53-6.37 (m, 2H), 4.57 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H). LCMS: m/z 483.2 [M+H]+, tR = 1.84 min.
Synthesis of (6-amin0pyridinyl)-N-((5-(2-(4,4—difluoropiperidine carb0nyl)cyc10pr0pyl)—7-(triflu0r0methyl)benzofu:anyl)methyl)acrylamide (695).
Br ®s\(9" | / \AOA i "—'—* BocHN o BocHN BocHN _.________, NaH DMso CF3 Pd(OAc)2,—P(2—MePh) 28 DIPEA DMF ..0c N BocHN 0.5193, LiOH C—>HCl2 2 THF HATU DIPEA DMF W3W QMWQ HATU DIPEA ow Synthesis of (E)-ethyl 3-(2-((tert—butoxycarbonylamin0)methyl) (trifluoromethyl)benz0furan-5—yl)acrylate (318): A mixture of tert—butyl (5—bromo (trifluoromethyl)benzofuranyl)methylcarbamate (28; 2.0 g, 5.1 mmol), ethyl acrylate (1.02 g, 10.2 mmol), Pd(OAc)2 (228 mg, 1.02 mmol), olylphosphine (620 mg, 2.04 mmol) DIPEA (1.32 g, 10.2 mmol) in 30 mL ofDMF was stirred at 100°C under nitrogen atmosphere for 16 h. The mixture was extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NagSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 0.7 g of hyl 3-(2-((tert— butoxycarbonylamino)methyl)(trifluoromethyl)benzofiiranyl)acrylate (318) as a yellow liquid. Yield: 30%. LCMS: m/z 357.9 [M—55]+, tR = 2.29 min.
Synthesis of ethyl (tert—butoxycarbonylamin0)methyl) (trifluoromethyl)benzofuran-5yl)cyclopropanecarboxylate (319): Sodium e (20 mg, 0.5 mmol, 60% in mineral oil) was added to a stirred solution of hyl sulfoxonium iodide (198 mg, 0.86 mmol) in 10 mL ofDMSO at 0°C. The mixture was stirred at 0°C for one hour. (E)-ethyl 3-(2—((rert-butoxycarbonylamino)methyl)(trifluoromethyl)benzofuran- -yl)acrylate (318; 206 mg, 0.5 mmol) in 2 mL of DMSO and 2 mL of THF was added to the reaction mixture. After completion of the reaction, 1 N HCl was added and the reaction mixture extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed —259— with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 50 mg of ethyl 2—(2—((tert-butoxycarbonylamino)methyl)—7- (trifluoromethyl)benzofuran—5yl)cyclopropanecarboxylate (319) as a yellow liquid. Yield: 23%. LCMS: m/z 450.1 [M+Na]+, 7R = 1.71 min. sis of 2-(2-((tert-butoxycarbonylamino)methyl)-7— (trifluoromethyl)benzofuranyl)cyclopropanecarboxylic acid (320): Ethyl 2-(2-((tert- butoxycarbonylamino)methyl)(trifluoromethyl)benzofuran-5yl)cyclopropanecarboxylate (319; 150 mg, 0.35 mmol) was dissolved in THF (5 mL). LiOH (30 mg, 0.7 mmol) and water (2 mL) were added to this mixture. The mixture was d at room temperature for 16 h, 1N HCl solution was added and adjusted to pH ~ 6. The reaction mixture extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give 110 mg of 2-(2—((z‘ert— butoxycarbonylamino) methyl)(trifluoromethyl)benzofuran—5 -yl)cyclopropanecarboxylic acid (320) as a yellowish solid. Yield: 79%. LCMS: m/z 422.1 [M+Na]+, IR = 1.66 min.
Synthesis of tert-butyl (5-(2-(4,4—difluor0piperidine-1—carbonyl)cyclopropyl)- 7-(trifluoromethyl)benzofuran-2—yl)methylcarbamate (321): 2—(2—((tert— butoxycarbonylamino) methyl)—7—(trifluoromethyl)benzofuran-5—yl)cyclopropanecarboxylic acid (320; 40 mg, 0.1 mmol) and 4,4—difluoropiperidine hydrochloride (1 6 mg, 0.1 mmol) was dissolved in DMF (5 mL) at 0 °C. HATU (38 mg, 0.1 mmol) was added to this reaction mixture followed by DIPEA (26 mg, 0.2 mmol). The reaction mixture was d for 4 h.
The reaction mixture was transferred into water (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NazSO4 and concentrated under reduced pressure to give 30 mg of tert—butyl (5-(2-(4,4- difluoropiperidinecarbonyl)cyclopropyl)(trifluoromethyl)benzofuran yl)methy1carbamate (321), which was used in next step directly without any purification.
Yield: 60%. LCMS: m/z 503.1 [M+H]+, :R = 1.77 min.
Synthesis of (aminomethyl)(triflu0r0methyl)benzofuran yl)cyclopropyl)(4,4-diflu0ropiperidin-l-yl)methanone (322): tert-Butyl (5-(2—(4,4- difluoropiperidine-l -carbonyl)cyclopropyl)—7—(trifluoromethyl)—benzofuran—2- hylcarbamate (321; 50 mg, 0.1 mmol) was ved in CH2C12 (6 mL). TFA (1 mL) 2 h, and was added at 0 OC. The on mixture was d at room temperature for —260- concentrated under d pressure to give 40 mg of (2-(2-(aminomethyl) (trifluoromethyl)benzofuran-5—yl)cyclopropy1)(4,4-difluoropiperidin— 1 —yl)methanone (322), which was used without further purification in the next step. Yield: 99%. LCMS: m/z 403.1 [M+H]+; rR = 1.30 min.
Synthesis of (E)(6—aminopyridinyl)—N-((5-(2-(4,4-difluoropiperidine carbonyl)cyclopropyl)(trifluoromethyl)benzofuranyl)methyl)acrylamide (695): (2- (2-(Aminomethyl)(trifluoromethyl)benzofurany1)cyclopropyl)(4,4-difluoropiperidin— 1 - yl)methanone (322; 40 mg, 0.1 mmol) and (6-aminopyridin—3-yl)acry1ic acid (16.4 mg, 0.1 mmol) was dissolved in DMF (5 mL) at 0 °C. HATU (38 mg, 0.1 mmol) was added to this on mixture at 0 °C followed by DIPEA (26 mg, 0.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The on mixture was transferred into water (20 mL) and ted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give crude product which was purified by Prep—HPLC to afford 30 mg of (E)(6-aminopyridin-3—yl)-N—((5—(2-(4,4-difluoropiperidine—l-carbonyl)cyclopropyl)— 7-(trifluoromethyl)benzofuran—2-yl)methyl) acrylamide (695). Yield: 55%. 1H NMR (400 MHz, CDgOD) 8 8.10 (d, J: 9 Hz, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.37 (d, J: 16 Hz, 1H), 7.28 (s, 1H), 6.95 (d, J= 9 Hz, 1H), 6.70 (s, 1H), 6.53 (d, J: 16 Hz, 1H), 4.57 (s, 2H), 3.78- 3.57 (m, 4H), 2.51-2.44 (m, 1H), 2.29-2.22 (m, 1H), 1.98-1.80 (m, 4H), 1.52-1.45 (m, 1H), 1.36-1.28 (m, 1H). LCMS: m/z 549.1 [M+H]+, tR= 1.38 min.
Synthesis of (E)(6-aminopyridinyl)-N—((5-(4-(4,4-difluor0piperidine-l- carbonyl)phenyl)(3-fluor0pyridinyl)benzofuranyl)methyl)acrylamide (696).
O — OH 0 ______.__.
BocHN \ Q precatalyst,K3PO4(0.5 M), BocHN THF. 40 °C 323 F 324 F catalyst = 0' ,P‘d-NHZ XPhos / \ OH 325 696 —261— ] Synthesis of utyl (5-(4—(4,4-diflu0r0piperidinecarbonyl)phenyl)-7—(3- fluoropyridinyl)benzofuranyl)methylcarbamate (324): tert—Butyl (7—chloro—5—(4— (4,4-difluoropiperidine—l-carbonyl)phenyl)benzofuranyl)methylcarbamate (323; 200 mg, 0.4 mmol), 3-fluoropyridinylboronic acid (85 mg, 0.6 mmol), st (31 mg, 0.04 mmol) and K3PO4 (2 mL, 1 mmol, 0.5 M) were added in THF (4 mL) and degassed. The reaction mixture was heated at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give tert-butyl (5 -(4-(4,4-difluoropiperidine-1 -carbonyl)phenyl)- 7-(3 -fluoropyridinyl)benzofuranyl)methylcarbamate (324) (200 mg, 88% yield).
LCMS: m/z 566.2 ; tR = 1.97 min.
Synthesis of (4-(2-(aminomethyl)—7-(3-flu0r0pyridinyl)benzofuran-S— yl)phenyl)(4,4—diflu0ropiperidin—l-yl)methan0ne (325): tert-Butyl (5—(4—(4,4— difluoropiperidine— 1 —carbonyl)phenyl)—7—(3 —fluoropyridinyl)benzofuran—Z— hylcarbamate (324; 200 mg, 0.35 mmol) was ved in CH2C12 (5 mL). TFA (1 mL) was added se at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixtUre was concentrated under reduced pressure to give (aminomethyl)—7—(3 —fluoropyridin—4—yl)benzofuran—5—yl)phenyl)(4,4— difluoropiperidin—1—yl)methanone (325), which was used without further purification in the next step (200 mg, 100% yield). LCMS: m/z 466.1 [M+H]+; IR = 1.74 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-(4,4-difluor0piperidine carbonyl)phenyl)(3-flu0r0pyridinyl)benzofuranyl)methyl)acrylamide (696): (4— (2—(Aminomethyl)—7—(3-fluoropyridinyl)benzofuranyl)phenyl)(4,4—difluoropiperidin— 1 — yl)methanone (325; 200 mg, 0.34 mmol) was dissolved in DMF (2 mL). (E)(6- aminopyridin-3—yl)acrylic acid (85 mg, 0.52 mmol), HATU (260 mg, 0.68 mmol), and DIPEA (220 mg, 1.7 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by Pre-HPLC to give (E)(6-aminopyridin~3—yl)-N—((5-(4-(4,4-difluoropiperidinecarbonyl)phenyl)(3- fluoropyridin—4-yl)benzofuran-Z-yl)methyl)acrylamide (696) (75 mg, 36% yield) as white solid. 1HNMR (400 MHz, DMSO—d6) 6 8.84—8.74 (m, 2H), 8.61 (d, J: 5 Hz, 1H), 8.37-8.01 (m, 5H), 7.91—7.73 (m, 4H), 7.60—7.54 (m, 2H), 7.43 (d, J: 16 Hz, 1H), 6.99 (d, J= 9 Hz, 1H), 6.91 (s, 1H), 6.59 (d, J: 16 Hz, 1H), 4.58 (d, J: 5 Hz, 2H), 3.78-3.47 (m, 4H), 2.15- 1.97 (m, 4H). LCMS: m/z 612.3 [M+H]+; tR = 1.38 min. —262- Synthesis of (6-aminopyridin-3—yl)-N~((5-(4-(4,4-difluoropiperidine-lcarbonyl l)(2,4,6-trif1u0r0phenyl)benzofuranyl)methyl)acrylamide (697). or B\ 0 O O —F—» BocHN \ catalyst,K3PO4(0.5 M), BocHN THF,40°C 323 F 327 697 (E)(6-aminopyridiny1)-N-((5-(4-(4,4-difluoropiperidine carbony1)pheny1)(2,4,6-trifluorophenyl)benzofuran-Z—y1)methy1)acrylamide (697) was synthesized using the indicated reagents in a similar fashion as example (696). 1H NMR (400 MHz, DMSO-d6) 8 8.62-8.53 (m, 1H), 8.10—8.01 (m, 2H), 7.80 (d, J: 8 Hz, 2H), 7.69- 7.52 (m, 4H), 7.43 (t, J: 9 Hz, 2H), 7.33 (d, J: 16 Hz, 1H), 6.86 (s, 1H), 6.50-6.35 (m, 4H), 4.52 (d, J: 6 Hz, 2H), 3.77-3.45 (m, 4H), 2.15-1.97 (m, 4H). LCMS: m/z 647.3 [M+H]+; tR = 1.86 min.
Synthesis of (E)—3-(6-aminopyridinyl)-N-((7-(5-chloro-Z,4-diflu0r0phenyl)—5—(4- (4,4-diflu0ropiperidinecarbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (698). —263- _—_.
N N BocHN \ catalyst. K3PO4(0.5 M), BocHN \ CHzCIz THF,40°C F F 323 F 328 F (E)-3—(6-amin0pyridiny1)-N—((7-(5-ch10r0~2,4—dif1u0r0pheny1)~5~(4—(4,4- difluoropiperidine-1—carbony1)pheny1)benzofuran—2—y1)methy1)acry1amide (698) was synthesized using the indicated reagents in a r fashion as example (696). 1H NMR (400 MHZ, DMSO-d6) 5 8.58 (t, J: 5 Hz, 1H), 8.10—7.98 (m, 3H), 7.88—7.81 (m, 2H), 7.76 (t, J: 9 Hz, 1H), 7.68 (s, 1H), 7.63—7.52 (m, 3H), 7.34 (d, J: 16 Hz, 1H), 6.86 (s, 1H), 6.50-6.36 (m, 4H), 4.54 (d, J: 5 Hz, 2H), 3.75—3.46 (m, 4H), 2.14-1.97 (m, 4H).
LCMS: m/Z 663.2 [M+H]+; IR = 1.91 min.
Synthesis of (E)(6—amin0pyridinyl)—N—((5'-(4-(4,4—difluoropiperidine yl)phenyl)-2,7'—bibenzofuran-2'-yl)methyl)acrylamide (699).
BocHN \ catalyst, K3PO4 (0.5 M), THF, 40 "c 323 F 330 331 699 (E)-3 —(6—aminopyridin—3 -yl)—N—((5'—(4—(4,4-diflu0ropiperidine carbonyl)pheny1)~2,7'-bibenzofuran—2‘—y1)methyl)acrylamide (699) was synthesized using the —264- indicated reagents in a similar fashion as example (696). 1H NMR (400 MHz, CD3OD) 5 8.20—8.16(m, 1H), 8.09 (s, 1H), .84 (m, 3H), 7.81-7.75 (m, 1H), 7.74-7.68 (m, 2H), 7.66-7.59 (m, 3H), 7.56 (d, J: 16 Hz,1H), .26 (m, 2H), 6.91 (s, 1H), 6.62 (d, J: 9 Hz, 1H) 654 (d J: 16 Hz 1H) 4.82 (s, 2H), 3.96-3.64 (m, 4H), 2.21—2.01 (m, 4H). LCMS: m/z 633. 3 [M+H]+; tR~ 1. 94 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((7-(3,5-dichlor0phenyl)(4-(4,4- difluoropiperidine-l-carbonyl)phenyl)benzofuranyl)methyl)acrylamide (700). m33~00 400 D \ L", F O\ o "803 NHBoc O NHBoc Pd(()dppfC|2 K2003, netlmMF dioxane H2O OMe OH 332 333 CI Cl N Q 430 B(°H)2 TFA szo F NHBOc ———+ __... F ___.—» EtaN, CHZCIZ O \ CHzclz o NHBOC Pd(PPh;,)4, PCya, 334 K3P04, dioxane, H20 OTf 335 0 Cl CI 4.0 0 WU‘ o F O \ o O NH: |PEA,DMF O‘ O N o. HWO/NHz\ /N or Cl 0' O o 336 CI 700 ] Synthesis of utyl (5-(4-(4,4-difluoropiperidinecarbonyl)phenyl)—7- methoxybenzofuran-Z-yl)methylcarbamate (332).: A mixture of (4-bromophenyl)(4,4— difluoropiperidin—l-yl)methanone (4.1 g, 14.6 mmol), tert—butyl (7-methoxy(4,4,5,5- tetramethyl-l,3,2-dioxaborolan—2-yl)benzofuranyl)methylcarbamate (193; 5 g, 12.4 mmol), Pd(dppt)Cl2 (0.91 g, 1.2 mmol) and K2C03 (3.4 g, 24.8 mmol) in 50 mL of dioxane and 5 mL of H20 was stirred at 90 0C for 4 h. After cooling down to room temperature, the reaction mixture was transferred into water (50 mL), extracted with ethyl acetate (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give the crude t, which was purified by silica gel chromatography (0—50% ethyl acetate/petroleum ether) to give 1.75 g of tert- butyl (5—(4—(44-difluoropiperidine- l —carbonyl)phenyl)-7—methoxybenzofuran—2- yl)methylcarbamate (332) (30% yield) LCMS: m/z 501.1 [M+H]; tR = 1.72 min. —265- Synthesis of utyl (5-(4-(4,4-diflu0r0piperidine-1—carb0nyl)phenyl)—7— hydroxybenzofuranyl)methylcarbamate (333): tert—Butyl (4,4-difluoropiperidine- l-carbonyl)phenyl)—7-methoxybenzofuran—2-yl)methylcarbamate (332; l g, 2 mmol) was dissolved in 20 mL of DMF. Decanethiol (521 mg, 3 mmol) and t-BuOK (336 mg, 3 mmol) were added to this e. The mixture was heated to 110 0C and stirred for 4 h. After g to room ature, the mixture was poured into 20 mL of H20, and extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, and trated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10-20% ethyl acetate/petroleum ether) to afford 500 mg of tert-butyl (5-(4-(4,4—difluoropiperidinecarbonyl)phenyl) hydroxybenzofuran—2-yl)methylcarbamate (333) (31% yield). LCMS: m/z 487.1 [M+H]+; tR = 1.63 min.
Synthesis of 2—((tert—butoxycarbonylamin0)methyl)—5-(4-(4,4- difluoropiperidine—l-carb0nyl)pheny])benz0furan-7—yl trifluoromethanesulfonate (334): tert—Butyl (5 -(4-(4,4-difluoropiperidine-1—carbonyl)phenyl)hydroxybenzofuran—2- yl)methylcarbamate (333; 500 mg, 1.03 mmol) was sisolved in 20 mL of CH2C12. Et3N (312 stirred at mg, 3.1 mmol) and szO (348 mg, 1.23 mmol) were added at 0 0C. The mixture was room temperature for 1 h, diluted with 20 mL of H20, extracted with CH2C12 (20 mL X3).
The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (20% ethyl acetate/petroleum ether) to yield 210 mg of 2-((tert—butoxycarbonylamino)methyl)(4-(4,4-difluoropiperidine-1— carbonyl)phenyl)benzofiiranyl trifluoromethanesulfonate (334). Yield: 40%. LCMS: m/z 619.1 [M+H]+; m = 1.80 min.
Synthesis of tert-butyl (7-(3,5-dichlor0phenyl)(4-(4,4-dif1u0r0piperidine-1— carbonyl)phenyl)benz0furanyl)methylcarbamate (335): 2-((tert— butoxycarbonylamino)methyl)(4-(4,4-difluoropiperidinecarbonyl)phenyl)benzofuran—7 - yl trifluoromethanesulfonate (334; 40 mg, 0.07 mmol), 3,5-dichlorophenylboronic acid (37 0.02 mmol) mg, 0.19 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol), tricyclohexylphosphine (5 mg, and K3PO4 (28 mg, 0.13 mmol) were added to a mixture of dioxane (2 mL) and water (0.2 mL) and degassed. The reaction mixture was heated under ave irradiation at 140 °C for 2 h. The reaction e was cooled down to room temperature, poured into 5 mL of water, extracted with EtOAc (10 mL X 3). The combined organic layers were washed with —266- brine, dried over anhydrous Na2804, concentrated under reduced pressure to give the crude product which was purified by Prep-TLC (50% EtOAc/petroleum ether) to give tert—butyl (7- (3 ,5 —dichlorophenyl)(4-(4,4-difluoropiperidine—1-carbonyl)phenyl)benzofuran-2— yl)methylcarbamate (335) as white solid (30 mg, 75% yield). LCMS: m/z 615.1 [M+H]+; tR = 1.93 min.
Synthesis of (4-(2-(aminomethyl)(3,5-dich10rophenyl)benzofuran yl)phenyl)(4,4-difluoropiperidin-l-yl)methanone (336): tert-Butyl (7-(3,5- rophenyl)(4 -(4,4-difluoropiperidine-1 nyl)phenyl)benzofuran hylcarbamate (335; 30 mg, 0.05 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added dropwise at 0 °C. The reaction mixture was d to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give (4-(2—(aminomethyl)—7-(3 ,5-dich1orophenyl)benzofuran—5 -yl)pheny1)(4 ,4-difluoropiperidin— 1 — yl)methanone (336), which was used without further purification in the next step (25 mg, 100% yield). LCMS: m/Z 515.0 [M+H]+; tR = 1.50 min.
Synthesis of (E)—3—(6-amin0pyridinyl)-N~((7-(3,5-dichlor0phenyl)(4-(4,4- difluoropiperidine—1-carb0nyl)phenyl)benzofuranyl)methyl)acrylamide (700): (4—(2- (Aminomethyl)—7—(3 ,5-dichlorophenyl)benzofuran—5-yl)phenyl)(4,4-difluoropiperidin— 1 - yl)methanone (336; 25 mg, 0.05 mmol) was dissolved in DMF (3 mL). (E)-3—(6— aminopyridin—3—yl)acrylic acid (10 mg, 0.06 mmol), HATU (37 mg, 0.1 mmol), and DIPEA (13 mg, 0.1 mmol) were added at room temperature. The reaction mixture was d at room temperature for 1 h. The crude mixture was purified by Pre—HPLC to give (E)—3—(6- aminopyridin-3 -y1)—N—((7-(3 ,5 -dichlorophenyl)(4—(4,4-difluoropiperidine carbonyl)phenyl)benzofuranyl)methyl)acrylamide (700) (3 mg, 10% yield) as white solid. 1H NMR (400 MHZ, CDgOD) 6 8.11 (d, J= 9 Hz, 1H), .83 (m, 6H), 7.75 (s, 1H), 7.60- 7.50 (m, 5H), 6.90 (s, 1H), 6.61 (d, J: 16 Hz, 1H), 4.74 (s, 2H), 3.99-3.60 (m, 4H), 2.18- 2.01 (m, 4H). LCMS: m/z 661.0 [M+H]+; rR = 1.57 min.
Synthesis of (6-aminopyridinyl)-N-((5-(4-(4-fluorophenoxy)phenyl)—7-(4- fluorophenyl)benzofuranyl)methyl)acrylamide (701). —267- Cl F F Jig)» \oB’ i C' BocHN \ Q F‘Q‘WOW NaNOz,AcOH 43 o o O O —’ H NQO Cuar, HBr dioianea); 0Pd PPh ,PC3120 03c,K PO4 , 2 P‘dwppflcb' K2CO3‘ donane. H20 1 2 i 338 339 F . W" 0 — O O / \ be".
QO O N N \ CH2C|2 O O O HATU,D1PEA, DMF / BocHN \ HZN \ o 340 341 701 Synthesis of 1-br0m0(4-flu0r0phenoxy)benzene (338): 4-(4- Fluorophenoxy)aniline (337; 200 mg, 1 mmol) was dissolved in 10 mL of AcOH, the mixture was cooled to 0 OC and degassed. NaNOz (76 mg, 1.1 mmol) was added. After stirring for 0.5 h, CuBr (240 mg, 1.5 mmol) and HBr aqueous solution (5 mL) was added. The mixture was stirred at 70 0C for 3h. After cooling to room temperature, the mixture was d with 20 mL of H20, extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, concentrated and purified by silica gel tography to give 200 mg of 1-bromo(4-fluorophenoxy)benzene (338) as white solid. Yield: 80%. LCMS: tR= 1.86 min.
] Synthesis of tert-butyl (7-ch10r0—5-(4—(4—flu0r0phen0xy)phenyl)benzofuran-Z- yl)methylcarbamate (339): A mixture of 1—bromo(4-fluorophenoxy)benzene (338; 300 mg, 1.12 mmol), tert—butyl (7-chloro-5—(4,4,5,5-tetramethy1-1,3,2-dioxaborolan—2- yl)benzofuranyl)methylcarbamate (456 mg, 1.12 mmol), Pd(dppi)C12 (82 mg, 0.12 mmol) and K2C03 (309 mg, 2.24 mmol) in 10 mL of dioxane and 1 mL of H20 was stirred at 100 0C under nitrogen atmosphere for 2 h. The mixture was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the ts were removed under reduced re to give the crude product, which was purified by silica gel chromatography (40% EtOAc/petroleum ether) to give 400 mg of tert—butyl (7- chloro(4-(4-fluorophenoxy)pheny1)benzofurany1)methy1carbamate (339) as a white solid. Yield (80%). LCMS: m/z 490.1 +, IR= 2.3 min.
Synthesis of tert—butyl (5-(4-(4-flu0r0phenoxy)phenyl)(4- fluorophenyl)benzofuran-Z-yl)methylcarbamate (340): tert-Butyl (7-chloro(4-(4— fluorophenoxy)phenyl)benzofuran—2-yl)methylcarbamate (339; 150 mg, 0.32 mmol), 4- fluorophenylboronic acid (90 mg, 0.64 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), tricyclohexylphosphine (27 mg, 0.1 mmol) and K3PO4 (136 mg, 0.64 mmol) were added to a mixture of dioxane (5 mL) and water (0.5 mL) and degassed. The reaction mixture was heated under microwave irradiation at 140 °C for 2 h. The reaction mixture was cooled down to room temperature, poured into 5 mL of water, extracted with EtOAc (10 mL X 3). The combined c layers were washed with brine, dried over anhydrous Na2804, concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (17-50% EtOAc/petroleum ether) to give tert—butyl (5—(4-(4- fluorophenoxy)phenyl)(4-fluorophenyl)benzofuranyl)methylcarbamate (340) as white solid (130 mg, 80% yield). LCMS: m/z 550.1 [M+H]+; IR = 1.99 min. sis of (5-(4-(4-fluorophen0xy)phenyl)(4-fluorophenyl)benzofuran yl)methanamine (341): tert-Butyl (5—(4—(4-fluorophenoxy)phenyl)(4- henyl)benzofuran—2—yl)methylcarbamate (340; 100 mg, 0.19 mmol) was dissolved in CH2C12 (5 mL). TFA (2 mL) was added dropwise at 0 CC. The reaction mixture was allowed to warm to room temperature and d for 4 h. The reaction mixture was concentrated under reduced pressure to give (5—(4-(4—fluorophenoxy)phenyl)—7-(4- fluorophenyl)benzofuranyl)methanamine (341), which was used without further purification in the next step (80 mg, 100% yield). LCMS: m/z 411.0 [M—NH2]+; tR = 1.56 min.
Synthesis of (E)(6-aminopyridinyl)—N—((5-(4-(4-flu0r0phen0xy)phenyl)- 7-(4-flu0r0phenyl)benz0furanyl)methyl)acrylamide (701): (5-(4-(4- phenoxy)phenyl)(4-fluorophenyl)benzofuran—2-yl)methanamine (341; 80 mg, 0.19 mmol) was dissolved in DMF (3 mL). (E)(6-aminopyridin—3-yl)acrylic acid (46 mg, 0.28 mmol), HATU (108 mg, 0.28 mmol), and DIPEA (49 mg, 3.8 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 h. The crude mixture was purified by Pre-HPLC without workup to give (E)—3—(6-aminopyridinyl)-N- ((5-(4-(4-fluorophenoxy)phenyl)-7—(4-fluorophenyl)benzofi1ran-2—yl)methyl)acrylamide (701) (5 mg, 5% yield) as yellow solid. 1H NMR (400 MHZ, CD3OD) 8 8.06 (s, 1H), 8.01- 7.89 (m, 2H), 7.80-7.62 (m, 5H), 7.50 (d,J= 16.0 Hz, 1H), 7.30-7.02 (m, 8H), 6.83 (s, 1H), 6.61 (d, J= 9 Hz, 1H), 6.48 (d, J= 16 Hz, 1H), 4.70 (s, 2H). LCMS: m/z 574.2 ; IR = 2.18 min. sis of (E)(6—aminopyridinyl)-N—((7-(4—(4,4-diflu0r0piperidine-l- carb0nyl)phenyl)-5—(triflu0r0methyl)benzofuran—2-yl)methyl)acrylamide (702). —269- 0»B/Q/(N Br Br //\NHBoc 9 I / 2. KI .
HO CF > HO CF O CF3 \ / 3 >\ / 3 NHSIHZO Pd(PPh3)2CI2. Cul, BocHN \ K2003. Pd(dppf)C|2, Eth dioxane, H20 342 343 F F < S H2N / N N I O O O N\ 0H O O Q —. Q ————~ CHzclz HATU,D|PEA,DMF H2" / 0 CF?» 0 0 ca O OF: M" \ BocHN \ HZN 344 345 702 Synthesis of 2-brom0i0d0(triflu0r0methyl)phenol (342): 2—Bromo (trifluoromethyl)phenol (3 g, 12.4 mmol) was dissolved in 100 mL of NH4OH. A solution of K1 (6 g, 37.2 mmol) and 12 (3.2 g, 12.4 mmol) in 200 mL of H20 was added to this mixture and the reaction mixture was stirred at 20 0C for 6 h. The mixture was cooled to O 0C, HCl (conc.) was added to the reaction mixture till pH = 7. The e was extracted with EtOAc (300 mL X 2). The combined organic layers were washed with sat. sodium bisulfite and brine, dried over anhydrous Na2804, and trated under reduced re to give 2-bromo-6—iodo(trifluoromethy1)phenol (342), (4.5 g, 99% yield) as a yellow solid which was used without further purification in the next step.
LCMS: tR = 1.76 min.
Synthesis of tert—butyl (7-bromo(trifluor0methyl)benzofuran yl)methylcarbamate (343): A mixture of 2-bromoiodo(trif1uoromethy1)phenol (342, 4.5 g, 12.3 mmol), tert-butyl prop-2—yny1carbamate (2.1 g, 13.5 mmol), Pd(PPh3)2C12 (882 mg, 1.2 mmol), and CuI (228 mg, 1.2 mmol) in 100 mL of ylamine was stirred at 70 0C under nitrogen here for 2 h. After g to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EtOAc/petroleum ether 0~15%) to give tert—butyl (73-bromo oromethy1)benzofuranyl)methylcarbamate (343), (1.7 g, 35% yield) as orange solid. LCMS: m/z 340 [M-55]+; tR = 1.86 min.
Synthesis of tert—butyl (7-(4-(4,4-difluoropiperidinecarb0nyl)phenyl) (trifluoromethyl)benz0furanyl)methylcarbamate (344): tert-Butyl (7-bromo—5- —270- (trifluoromethyl)benzofuran-2—yl)methylcarbamate (343, 420 mg, 1.1 mmol), (4,4— difluoropiperidin—l ~yl)(4—(4,4,5,5—tetramethyl-1 ,3 ,2-dioxaborolan-2— yl)phenyl)methanone (420 mg, 1.2 mmol), Pd(dppf)C12 (82 mg, 0.1 mmol) and K2CO3 (455 mg, 3.3 mmol) were added in a mixture of dioxane (20 mL) and H20 (4 mL). The reaction mixture was stirred at 95°C under nitrogen atmosphere for 16 h. LCMS showed the on was complete. The on mixture was cooled down to room temperature, d with EtOAc (30 mL), washed with water, brine, dried over anhydrous Na2804, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0-3 0% petroleum ether) to give terI-butyl (7—(4- (4,4—difluoropiperidine— l -carbonyl)phenyl)(trifluoromethyl)benzofuran—2— yl)methylcarbamate (344), (480 mg, 85% yiled) as white solid. LCMS: m/z 483.1 [M— 5512 rR= 1.81 min.
Synthesis of (4-(2-(amin0methyl)(trifluor0methyl)benz0furan yl)phenyl)(4,4-difluoropiperidin-l-yl)methan0ne (345): (7-(4—(4,4-Difluoropiperidine- 1-carbonyl)phenyl)-5—(trifluoromethyl)benzofuran—2—yl)methylcarbamate (344, 95 mg, 0.18 mmol) was dissolved in CH2C12 (10 mL). TFA (1 mL) was added at 0 OC. The reaction mixture was d at 15°C for 3 h, and trated under reduced pressure to give the crude (4—(2—(aminomethyl)-5—(trifluoromethyl)benzofuran—7—yl)phenyl)(4,4— difluoropiperidin—l~y1)methanone (345), (77 mg, 100% yield), which was used without further purification in the next step. LCMS: m/z 439.1 [M+H]+; IR = 1.41 min.
Synthesis of (E)(6-aminopyridinyl)-N—((7-(4-(4,4-difluoropiperidine- 1-carb0nyl)phenyl)—5-(triflu0romethyl)benz0furanyl)methyl)acrylamide (702): (4-(2-(Aminomethyl)-5—(trifluoromethyl)benzofuranyl)phenyl)(4,4-difluoropiperidin— 1-yl)methanone (345, 95 mg, 0.18 mmol), (E)—3-(6-aminopyridin—3-yl)acrylic acid (33 mg, 0.2 mmol) and HATU (76 mg, 0.2 mmol) was dissolved in DMF (3 mL) and DIPEA (70 mg, 0.54 mmol) was added slowly. The on mixture was stirred at 20°C for 2 h.
The mixture was purified by Pre-HPLC to give (E)(6-aminopyridiny1)-N-((7-(4- (4,4-difluoropiperidine- l -carbony1)pheny1)(trifluoromethy1)benzofuran yl)methy1)acry1amide (702) as white solid (40 mg, 39% yield). 1H NMR (400 MHZ, DMSO-dé) 6 8.88-8.79 (m, 1H), 8.22-7.96 (m, 7H), 7.83 (s, 1H), 7.63 (d, J= 8.1 Hz, 2H), 7.44 (d, J=16 Hz,1H), 6.98 (s, 1H), 6.93 (d, J= 9 Hz, 1H), 6.58 (d, J: 16 Hz, 1H), 4.64 (d, J: 5 Hz, 2H); .38 (m, 4H), 2.20-1.92 (m, 4H). LCMS: m/z 584.8 , m = 2.02 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(5-(4-fluorobenzoyl)pyridinyl) (4-flu0r0phenyl)benzofuranyl)methyl)acrylamide (703) and (E)(6- aminOpyridin-3—yl)-N-((7-(4-flu0r0phenyl)(5-((4- flu0r0phenyl)(hydroxy)methyl)pyridin-Z-yl)benzofuran-Z-yl)methyl)acrylamide (704).
N as0,3 NHBOC \ 0 /( \ ° ° \ «N M B N | 0Br Br cI 0 \ NHBoc /I" F O \ F \ o . THF F Br PdtdpPOCIz. K2003. 346 34a dioxane, H20 CI NH300 TFA HzN\IN a_____k, Pd(PP,h3)4 Pcya eszco3 DOM HATU DMF dioxane H20,140°C 703 704 Synthesis of (6-bromopyridinyl)(4-fluorophenyl)methanone (348): 6- Bromo-N—methoxy—N-methylnicotinamide (347; 2 g, 8.1 mmol) was dissolved in THF (10 mL). (4-Fluorophenyl)magnesium bromide (346; 4.5 mL, 9 mmol, 2 M in THF) was added dropwise over 5 min at 0 0C (ice bath). The reaction mixture was allowed to warm to room ature and'stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL), extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, trated under reduced pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 1 7 g of (6-bromopyridinyl)(4-fluoropheny1)methanone (348) as white Solid (75% yield) LCMS: m/z 280 1 [M+H]+; IR: 193 min Synthesis of tert—butyl (7-chl0r0(5-(4-fluorobenzoyl)pyridin-Z— zofuran—Z-yl)methylcarbamate (349): tert— Butyl (7—chloro(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)benzofuran—2—yl)methylcarbamate (1.8 g, 4.3 mol), (6- bromopyridinyl)(4-fluorophenyl)methanone (348; 1 g, 3.6 mmol), Pd(dppt)C12 (0.29 g, 0.4 mmol), and K2C03 (1 g, 7.2 mmol) were added in a mixture of (10:1) dioxane (10 mL) and water (1 mL) and degassed. The reaction mixture was heated at 80 0C under nitrogen atmosphere for 2 h. The reaction mixture was cooled down to room temperature, diluted with water (10 mL), extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, concentrated under reduced pressure to give 1.4 g of tert-butyl (7-chloro(5-(4-fluorobenzoyl)pyridin—2-yl)benzofuran hylcarbamate (349), which was used in next step without further ation (81% yield). LCMS: m/z 481.1 [M+H]+; rR = 1.88 min.
Synthesis of tert-butyl (4-fluorobenzoyl)pyridinyl)(4- fluorophenyl)benz0furan—2—yl)methylcarbamate (350): tert—Butyl (7—chloro(5-(4— fluorobenzoyl)pyridinyl)benzofuran—2-yl)methylcarbamate (349; 200 mg, 0.42 mmol), 4- fluorophenylboronic acid (175 mg, 1.25 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), tricyclohexylphosphine (35 mg, 0.08 mmol) and C32C03 (410 mg, 1.25 mmol) were added to a e of dioxane (5 mL) and water (0.5 mL) and ed. The reaction mixture was heated under microwave irradiation at 140 °C for 2 h. The reaction mixture was cooled down to room temperature, poured into 10 mL of water, ted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to give utyl (4- fluorobenzoyl)pyridinyl)(4~fluorophenyl)benzofuran~2-yl)methylcarbamate (350) as white solid (120 mg, 54% yield). LCMS: m/z 541.2 [M+H]+; tR = 2.21 min.
Synthesis of (amin0methyl)(4-flu0r0phenyl)benzofuran-S-yl)pyridin- 3-yl)(4-flu0r0phenyl)methanone (351): tert-Butyl (5-(5-(4-fluorobenzoyl)pyridin—2-yl)—7- (4-fluorophenyl)benzofuranyl)methylcarbamate (350; 120 mg, 0.22 mmol) was dissolved in CHzClz (5 mL). TFA (1 mL) was added dropwise at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give (6—(2-(aminomethyl)(4- fluorophenyl)benzofuran—5—yl)pyridin—3-yl)(4-fluorophenyl)methanone (351), which was used without further purification in the next step (70 mg, 72% yield). LCMS: m/z 441.2 [M+H]+; zR = 2.21 min.
Synthesis of (E)(6—amin0pyridinyl)—N—((5—(5-(4-flu0r0benz0yl)pyridin yl)(4-flu0r0phenyl)benzofuran-Z-yl)methyl)acrylamide (703): (Aminomethyl)-7— rophenyl)benzofuran-5—yl)pyridiny1)(4-fluorophenyl)methanone (351; 70 mg, 0.18 mmol) was dissolved in DMF (5 mL). (E)-3—(6-aminopyridin-3—yl)acrylic acid (30 mg, 0.18 mmol) and HATU (116 mg, 0.31 mmol) were added at room temperature. The reaction e was stirred at room temperature for 2 h. The reaction mixture was purified by Pre- HPLC to give (E)(6-aminopyridin—3-y1)—N—((5—(5—(4-fluorobenzoyl)pyridin—2—y1)(4- fluorophenyl)benzofuranyl)methyl)acry1amide (703) (60 mg, 57% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.99 (s, 1H), 8.66-8.59 (m, 1H), 8.46 (s, 1H), 8.37-8.28 (m, 2H), 8.26—8.18 (m, 1H), 8.09 (s, 1H), 8.06-7.91 (m, 4H), 7.62 (d, J: 10 Hz, 1H), 7.50-7.33 (m, 6H), 6.94 (s, 1H), 6.51-6.38 (m, 3H), 4.61 (d, J: 5 Hz, 2H). LCMS: m/z 587.2 [M+H]+; IR = 1.97 min.
Synthesis of (E)(6-aminopyridin-3—yl)—N—((7—(4-flu0r0phenyl)(5-((4- fluorophenyl)(hydroxy)n1ethyl)pyridin-Z-yl)benzofuranyl)methyl)acrylamide (704): (E)-3—(6—aminopyridin—3—yl)—N—((5~(5~(4-fluorobenzoyl)pyridin-2—yl)~7-(4- fluorophenyl)benzofuran-2—yl)methyl)acrylamide (703; 40 mg, 0.07 mmol) was dissolved in THF (5 mL) and MeOH (5 mL). Sodium borohydride (5 mg, 0.14 mmol) was added at room temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by Pre—HPLC to give (E)—3-(6— aminopyridinyl)—N—((7-(4—fluorophenyl)—5-(5-((4-fluorophenyl)(hydroxy)methyl)pyridin— 2-yl)benzofuranyl)methyl)acrylamide (704). (5 mg, 12% yield) as white solid. 1H NMR (400 MHz, CD3OD) 5 8.62 (s, 1H), 8.12-7.99 (m, 4H), 7.96-7.85 (m, 4H), .34 (m, 3H), 7.16 (t, J: 9 Hz, 2H), 7.02 (t, J: 9 Hz, 2H), 6.94 (d, J= 9 Hz, 1H), 6.81 (s, 1H), 6.53 (d, J: 16 Hz, 1H), 5.89 (s, 1H), 4.62 (s, 2H). LCMS: m/z 589.0 [M+H]+; IR = 1.44 min. sis of (E)(6-aminopyridin-3—yl)-N-((5-(4-(4,4-diflu0r0piperidine carb0n0thi0yl)phenyl)(pyridin-4—yl)benzofuranyl)methyl)acrylamide (705).
Lawesson's reagent O Pd(PPhs)4. PCYa. KaPoi. toluene \ dioxane. H20 354 705 Synthesis of tert-butyl (5-(4-(4,4-difluoropiperidinecarb0nyl)phenyl)—7— (pyridinyl)benz0furan-2—yl)methylcarbamate (352):Iert—Butyl (7-chloro-5—(4-(4,4- opiperidinecarbonyl)phenyl)benzofuran-2—yl)methylcarbamate (323; 250 mg, 0.5 mmol), pyridiny1boronic acid (183 mg, 1.5 mmol), Pd(PPh3)4 (57 mg, 0.05 mmol), tricyclohexylphosphine (42 mg, 0.15 mmol) and K3PO4(210 mg, 1 mmol) were added to a mixture of dioxane (3 mL) and water (0.3 mL) and degassed. The reaction mixture was heated under microwave irradiation at 140 °C for 2 h. The reaction mixture was cooled down to room temperature, poured into 5 mL of water, extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, trated under reduced pressure to give the crude product which was purified by silica gel chromatography % EtOAc/petroleum ether) to give tert-butyl (4,4- difluoropiperidine- 1 —carbonyl)phenyl)—7-(pyridinyl)benzofuranyl)methylcarbamate (352) as white solid (209 mg, 71% yield). LCMS: m/z 548.3 [M+H]+; IR = 1.92 min.
] Synthesis of tert-butyl (4,4-difluoropiperidine—1-carb0n0thioyl)phenyl)— 7-(pyridinyl)benzofuranyl)methylcarbamate (353): tert—Butyl (5-(4-(4,4- difluoropiperidine-l—carbonyl)phenyl)—7—(pyridiny1)benzofu.ranyl)methylcarbamate (352; 209 mg, 0.38 mmol) and Lawesson’s reagent (170 mg, 0.42 mmol) were added in 30 mL of toluene. The reaction mixture was heated at 100 0C for l h. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10-25% EtOAc/petroleum ether) to give 145 mg of tert—butyl (5~(4—(4,4—difluoropiperidinecarbonothioyl)phenyl)—7- —275- (pyridinyl)benzofuranyl)methylcarbamate (353) as a yellow solid. Yield: 67%. LCMS: m/Z 564.3 [M+H]+; m = 2.04 min.
Synthesis of (4-(2-(aminomethyl)(pyridin-4—yl)benzofuran-S- yl)phenyl)(4,4-diflu0r0piperidin-l-yl)methanethione (354): tert-Butyl (5-(4-(4,4- difluoropiperidine- l —carbonothioyl)phenyl)(pyridinyl)benzofuran hylcarbamate (353; 159 mg, 0.28 mmol) was dissolved in CH2C12 (10 mL). TFA (2 mL) was added dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give (4-(2-(aminomethyl)(pyridinyl)benzofuranyl)phenyl)(4,4- difluoropiperidin—1-yl)methanethione (354), which was used without further purification in the next step (168 mg, 100% yield). LCMS: m/z 464.2 [M+H]+; tR = 1.82 min.
Synthesis of (6—amin0pyridin—3-yl)-N—((5-(4—(4,4-difluoropiperidine-l- 0thioyl)phenyl)(pyridinyl)benzofuran-Z-yl)methyl)acrylamide (705). (4-(2—(Aminomethyl)~7-(pyridinyl)benzofuran—5-yl)phenyl)(4,4-difluoropiperidin—1 - yl)methanethione (354; 138 mg, 0.30 mmol) was dissolved in DMF (3 mL). (E)(6- aminopyridin—3-yl)acrylic acid (49 mg, 0.3 mmol), HATU (110 mg, 0.36 mmol), and DIPEA (192 mg, 1.49 mmol) were added at room temperature. The reaction mixture was d at room temperature for 1 h. The crude mixture was ed by Pre-HPLC without workup to give (E)(6-aminopyridinyl)-N-((5-(4-(4,4-difluoropiperidine-l -carbonothioyl)phenyl)- 7-(pyridin—4-yl)benzofuranyl)methyl)acrylamide (705) (22 mg, 11% yield) as yellow solid. 1H NMR (400 MHz, DMSO—d6) 8 8.73 (d, J: 6 Hz, 2H), 8.64 (t, J: 6 Hz, 1H), 8.11-8.00 (m, 4H), 7.95-7.93 (m, 1H), 7.84 (d, J: 8 Hz, 2H), 7.65-7.59 (m, 1H), 7.48 (d, J2 8 Hz, 2H), 7.37 (d, J= 16 Hz, 1H), 6.89 (s, 1H), 6.52-6.37 (m, 4H), 4.62 (d, J: 5 Hz, 2H), 4.51-4.39 (m, 2H), .63 (m, 2H), 2.30-2.06 (m, 4H). LCMS: m/z 610.2 [M+H]+; tR = 1.81 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(2,4-diflu0r0phenyl)(4-(4,4- difluoropiperidinecarbonothioyl)phenyl)benzofuranyl)methyl)acrylamide (706).
Lawesson's t —__, —> O Pd(PPh3)4. F’Cya‘ K3P04. toluene \ dioxane‘ H20 F F 357 706 (E)—3-(6-aminopyridin—3—yl)—N—((7-(2,4—difluorophenyl)(4-(4,4- difluoropiperidine—l-carbonothioyl)phenyl)benzofuran—Z—yl)methyl)acrylamide (706) was synthesized using the indicated reagents in a similar fashion as example (705). 1H NMR (500 MHZ, é) 5 8.57 (t, J: 6 Hz, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.84-7.75 (m, 3H), 7.64- 7.57 (m, 2H), 7.51-7.42 (m, 3H), 7.37-7.25 (m, 2H), 6.85 (s, 1H), 6.55-6.34 (m, 4H), 4.59- 4.39 (m, 4H), 3.75-3.62 (m, 2H), 2.29-2.05 (m, 4H). LCMS: m/z 645.3 [M+H]+, tR= 1.98 min. sis of (E)—3-(6-amin0pyridinyl)-N—((5—(5-(4,4-diflu0r0piperidine-l- carbon0thioyl)pyridin-Z—yl)—7-(pyridinyl)benzofuran-Z-yl)methyl)acrylamide (707).
Lawesson's reagent Pd(PPh3)4‘ PCya, K3P04, toluene \ dioxane, H20 360 701 (E)(6—aminopyridin-3—yl)—N-((5—(5—(4,4—difluoropiperidine—l- carbonothioyl)pyridin-2—yl)—7-(pyridin—4—y1)benzofuran—2-y1)methyl)acrylamide (707) was synthesized using the indicated s in a similar fashion as example (705). 1H NMR (400 MHZ, CD30D) 5 8.61—8.54 (m, 3H), 8.26—8.20 (m, 2H), 802—789 (m, 4H), 7.81-7.76 (m, -277— 1H), 7.67—7.63 (In, 1H), 7.40 (d, J: 16 Hz, 1H), 6.82 (s, 1H), 6.51 (d, J: 9 Hz, 1H), 6.38 (d, J: 16 Hz, 1H), 4.63 (s, 2H), 4.48-4.38 (m, 2H), 3.77-3.70 (In, 2H), 2.23—1.96 (In, 4H).
LCMS: m/z 611.3 [M+H]+, 1R =1.90 min.
Synthesis of (E')(6-aminopyridinyl)-N-((7—(2,4-diflu0r0phenyl)(5-(4,4- opiperidinecarbonothioyl)pyridin-Z-yl)benzofuranyl)methyl)acrylamide (708). >C~° 1&3 F \ N Lawesson's reagent Pd(FPh3)4. Peyar K3P04. "We" \ dioxane, HZO NHBoc CI 0 F 363 708 (E)(6—arninopyridin—3-y1)-N—((7-(2,4—difluorophenyl)(5-(4,4— difluoropiperidinecarbonothioy1)pyridin—2-y1)benzofuran—2-yl)methy1)acrylamide (708) was synthesized using the indicate reagents in a similar fashion as example (706). 1H NMR (500 MHZ, DMSO—ds) 5 8.66 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.14—8.05 (m, 3H), 7.91—7.75 (In, 2H), 7.60 (d, J= 8 Hz, 1H), 7.52—7.44 (m, 1H), 7.37-7.26 (In, 2H), 6.90 (s, 1H), .35 (In, 4H), 4.54 (d, J: 5 Hz, 2H), 4.47—4.39 (s, 2H), 3.77-3.69 (In, 2H), .11 (In, 4H).
LCMS: m/z 646.2 [M+H]+, (R: 1.91 min.
Synthesis of (E)—3-(6-aminopyridinyl)-N-((5-(4-(ethylsulf0nyl)phenyl)(4- fluorophenyl)benzofuranyl)methyl)acrylamide (709).
Q3"Q9 C. 9 @‘B"2°" 9 o O 01 -O O 1 Pd(dppf)C|2 K2003. BocHN \ 0—\ Pd((PP,h3)4 PCy; K3P04 BocHN \ BocHN dioxane H20 dioxane H20 O 0%"/ O TFA 9 - iosi_\ / - O O s CHgCIZ N H \ a? HzN HATU, DlPEA, DMF / 366 709 —278— Synthesis of tert-butyl oro-S-(4—(ethylsulfonyl)phenyl)benzofuran yl)methylcarbamate (364): A mixture of 4—(ethylsulfony1)pheny1boronic acid (300 mg, 1.4 mmol), utyl (7-chlor0(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan—2—y1)benzofi1ran yl)methy1carbamate (43) (500 mg, 1.4 mmol), Pd(dppf)C12 (100 mg, 0.14 mmol) and K2CO3 (380 mg, 2.8 mmol) in 20 mL of dioxane and 1 mL of H20 was heated at 100 °C under nitrogen atmosphere for 5 h. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to give 600 mg of tert—butyl (7-chloro(4-(ethylsulfonyl)phenyl)benzofuran-2—yl)methylcarbamate (364) as white solid. Yield (96%). LCMS: m/z 394.0 [M—55]+, IR = 2.01 min.
Synthesis of tert-butyl (5-(4-(ethylsulfonyl)phenyl)-7—(4- flu0r0phenyl)benzofuran-2—yl)methylcarbamate (365): tert—Butyl (7—chloro(4— sulfonyl)phenyl)benzofuran—2—yl)methylcarbamate (364; 200 mg, 0.44 mmol), 4- fluorophenylboronic acid (187 mg, 1.32 mmol), Pd(PPh3)4 (51 mg, 0.05 mmol), tricyclohexylphosphine (25 mg, 0.10 mmol) and K3PO4 (280 mg, 1.32 mmol) were added to a mixture of dioxane (3 mL) and water (0.3 mL) and degassed. The reaction mixture was heated under microwave irradiation at 140 °C for 2 h. The on mixture was cooled down to room temperature, poured into 5 mL of water, extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NagSO4, concentrated under reduced re to give the crude t, which was purified by silica gel chromatography (50% EtOAc/petroleum ether) to give 220 mg of tert—butyl (5 -(4- (ethylsulfonyl)phenyl)-7—(4-fluorophenyl)benzofuran—2-y1)methy1carbamate (365) as white solid (98% yield). LCMS: m/z 410.1 [M+H—100]+; IR = 2.08 min.
Synthesis of (5-(4-(ethylsulfonyl)phenyl)(4-fluor0phenyl)benzofuran-Z- yl)methanamine (366): utyl (5-(4—(ethy1sulfony1)phenyl)-7—(4- fluorophenyl)benzofuranyl)methylcarbamate (365; 220 mg, 0.43 mmol) was dissolved in CH2C12 (5 mL). TFA (5 mL) was added dropwise at 0 °C (ice bath). The reaction mixture was allowed to warm to room ature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give (5-(4-(ethylsulfonyl)phenyl)-7—(4— fluoropheny1)benzofiiran—2-y1)methanamine (366), which was used without further purification in the next step (175 mg, 100% yield). LCMS: m/z 410.2 [M+H]+; tR = 1.86 min.
Synthesis of (E)(6-aminopyridinyl)—N—((5-(4-(ethylsulf0nyl)phenyl)(4- henyl)benzofuran-Z-yl)methyl)acrylamide (709): (5-(4-(Ethylsulfonyl)phenyl)—7— (4-fluorophenyl)benzofuran—2-yl)methanamine (366; 175 mg, 0.43 mmol) was dissolved in DMF (5 mL). (E)—3—(6—aminopyridinyl)acry1ic acid (78 mg, 0.48 mmol), HATU (245 mg, 0.64 mmol), and DIPEA (166 mg, 1.30 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The on mixture was purified by Pre-HPLC to give (E)(6-aminopyridinyl)-N-((5-(4-(ethylsulfonyl)phenyl)-7—(4- fluorophenyl)benzofuranyl)methy1)acrylamide (709) (120 mg, 50% yield) as white solid. 1H NMR (400 MHZ, CD3OD) 6 8.20 (d, J= 9 Hz, 1H), 8.07-7.93 (m, 7H), 7.88 (d, J= 2 Hz, 1H), 7.75 (s, 1H), 7.49 (d, J: 16 Hz, 1H), 7.26 (t, J: 9 Hz, 2H), 7.05 (d, J: 9 Hz, 1H), 6.89 (s, 1H), 6.65 (d, J: 16 Hz, 1H), 4.73 (s, 2H), 3.27 (q, J= 7 Hz, 2H), 1.28 (t, J: 7 Hz, 3H).
LCMS: m/z 556.1 [M+H]+; tR = 1.42 min. sis of (E)-3—(6-aminopyridin-3—yl)—N-((7-(2,4-diflu0r0phenyl)(5-(4,4- difluoropiperidinecarb0nyl)pyridinyl)benzofuran-Z-yl)methyl)acrylamide (710).
F B(OH)2 N o B°°HN \ Pd Synthesis of (E)—3-(6-amin0pyridin—S-yl)—N-((7-(3-chlorofluor0phenyl)—5-(4-(4,4— difluoropiperidine—l—carbonyl)phenyl)benzofuranyl)methyl)acrylamide (71 1). c: O B o O:NO OH o O O BocHN \ N BocHN 2 Pd(PPh3)4, PCy3 K3PO4, CH26|2 dioxane H20 140 DC F F F F 369 0 OO o HNO/VLOH 0Q 0 N —--—> HATU DIPEA DMF (E)(6-aminopyridin—3-y1)—N—((7-(3-ch10r0—4—fluorophenyl)(4-(4,4- difluoropiperidine— 1 -carbonyl)pheny1)benz0furan-2—y1)methy1)acrylamide (71 1) was synthesized using the indicated ts in a similar fashion as example (699). 1H NMR (400 MHz, DMSO—ds) 8 8.61 (t, J: 5 Hz, 1H), 8.25-8.20 (m, 1H), 8.11-8.00 (m, 2H), 7.97-7.79 (m, 4H), 7.65—7.52 (m, 4H), 7.36 (d, J: 16 Hz, 1H), 6.87 (s, 1H), .38 (m, 4H), 4.60 (d, J: 5 Hz, 2H), 3.77-3.42 (m, 4H), 2.14-1.98 (m, 4H). LCMS: m/z 645.3 [M+H]+; rR = 1.91 min.
Synthesis of (E)(6-aminopyridin—3-yl)-N-((6-chlor0(4-(4,4-diflu0r0piperidine—1- carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (713). —281 - CI Cl \ "fir I SQ NBS, AIBN B OH 3/\n/0 6' I" N.-Nd thl | K2C03, DMF Ie yam Ine CC14 1 374aB 374bCl CI B r NaN3 ch03 f PPha + S N3 N3 THF, H20 375218 1575bCI Br CI 376a 37Gb 0 Cl 0 Br BocHN BocHN Eth CHZCIZ Br Cl 377a 377b 3783 378b F o 0 Cl F 3 0 Cl \ \ BOCHN O N B/o o C' 04/ <:> ‘0 O TFA \ —> O BOCHN Pdd( PP)fCI2 KCO, 2 3 _ O N CHZCIZ dioxane, H20 OVF Br O NQ}: 378a 379 F 380 o 0 CI — / 0 \ O H2N \ / OH NH N _ .—r.~——» _ HATU,D|PEA,DMF O Synthesis of ochloro—5-(2-chloroallyloxy)benzene (373): o chlorophenol (13.4 g, 64.6 mmol) was dissolved in 100 mL of DMF. 2,3—Dichloropropene (14.4 g, 129.2 mmol) and K2C03 (17.8 g, 129.2 mmol) were added. The mixture was stirred at 110 0C for 4 h. The mixture was cooled to room temperature, diluted with H20 (100 mL), extracted with EtOAc (30 mL X 3). The combined organic solvents were dried over anhydrous Na2804, concentrated and purified by silica gel chromatography (petroleum ether) to give 15.5 g of 1-bromochloro(2-chloroallyloxy)benzene (373) as colorless liquid.
Yield (85%). 1H NMR (400 MHZ, CDC13) 8 7.17-7.16 (m, 1H), 7.01-7.00 (m, 1H), 6.89—6.88 (m 1H), .56 (m, 1H), 5.50 (s, 1H), 4.57 (s, 2H).
Synthesis of 4-br0m0chloro-Z-methylbenzofuran (374a) and 6-bromo —Z-methylbenzofuran (374b): 1-Bromochloro—5-(2-chloroallyloxy)benzene (373; 22 g, 78 mmol) was dissolved in 100 mL ofN,N—diethylaniline. The mixture was heated to —282- 220°C for 32 h. After cooling to room temperature, 500 mL of EtOAc was added. The e was washed with 2N HCl aqueous solution (200 mL X 3), brine (60 mL), dried over anhydrous Na2804, concentrated and purified by silica gel chromatography (petroleum ether) to afford 1.4 g of mixture 4-bromo—6-chloro-2—methylbenzofuran (374a) and o chloromethylbenzofuran (374b) as a white solid. Yield (7%). LCMS: IR = 2.01 min.
Synthesis of 4-br0m0(bromomethyl)chlorobenzofuran (375a) and 6- br0m0(bromomethyl)chlor0benzofuran (375b). 4-Bromochloro methylbenzofuran (374a) and 6-bromochloromethylbenzofuran (374b) (500 mg, 2 mmol) was dissolved in 20 mL of CC14. NBS (399 mg, 2.2 mmol) and AIBN (66 mg, 0.4 mmol) were added. The mixture was degassed and stirred for 5 h, cooled to room ature and filtered, the filtrate was concentrated to give 650 mg of 4-bromo-2—(bromomethyl) chlorobenzofuran (375a) and 6—bromo—2-(bromomethyl)chlorobenzofuran (375b), which was used directly to next step. Yield (98%). LCMS: IR = 1.95 min.
] Synthesis of 2-(azid0methyl)-4—br0m0chlor0benzofuran (376a) and 2- (azidomethyl)br0m0-4—chlor0benz0furan (376b): 4-Bromo(bromomethyl)—6— chlorobenzofuran (375a) and 6-bromo-2—(bromomethyl)chlorobenzofuran (375b) (650 mg, 2 mmol) was dissolved in 10 mL of DMF. NaN3 (195 mg, 3 mmol) and K2CO3 (553 mg, 4 mmol) were added. The mixture was d at room temperature for 2h, diluted with H20 (20 mL), extracted with EtOAc ( 10 mL X 3), washed with brine (10 mL), dried over Na2804, concentrated to afford 550 mg of domethy1)—4-bromo—6-chlorobenzofuran (376a) and 2—(azidomethyl)bromo—4—chlor0benzofi1ran (376b) as yellow solid, which was used directly. Yield (96%). LCMS: tR = 1.91 min.
Synthesis of (4-br0m0chlorobenzofuran-Z-yl)methanamine (377a) and (6- bmm0chlor0benzofuran-Z-yl)methanamine (377b): 2—(Azidomethyl)-4—bromo-6— chlorobenzofuran (376a) and 2-(azidomethyl)br0mochlorobenzofi1ran (376b) (500mg, 1.7 mmol) was disolved in 20 mL of THF. PPh3 (668 mg, 2.5 mmol) was added. The mixture was stirred at room temperature for 1 h, and H20 (10 mL) was added. The mixture was stirred at 60 °C for 4 h, cooled to room temperature, concentrated and purified by silica gel chromatography (EtOAc) to afford 360 mg of mo—6-chlorobenzofuran—2- yl)methanamine (377a) and (6-br0mochlorobenzofuranyl)methanamine . Yield (62%). LCMS: m/z 244.9 [M-NH2]+; {R = 1.27 min.
Synthesis of tert-butyl (4-br0m0chlorobenzofuran-Z-yl)methylcarbamate (378a) and tert-butyl (6-br0m0chlor0benzofuranyl)methylcarbamate (378b): (4- Bromochlorobenzofuran—2-yl)methanamine (377a) and (6-bromochlorobenzofuran—2- yl)methanamine (377b) (310 mg, 1.2 mmol) was dissolved in dichloromethane (15 mL). Di- utyl dicarbonate (523 mg, 2.4 mmol) and triethylamine (3 64 mg, 3.6 mmol) were added at 0 °C and the reaction mixture was stirred at room temperature for 18 h. The on mixture was concentrated and purified by silica gel chromatography (10% ethyl acetate/petroleum ether) to give 360 mg of tert-butyl (4-bromochlorobenzofuran yl)methylcarbamate (378a) and tert-butyl (6-bromochlorobenzofuran yl)methylcarbamate (378b) (84% yield). LCMS: m/z 388.9.7 [M+Na]+; IR = 1.87 min.
The two compouds were seperated from each other by chiral HPLC (AD-H column) to give 100 mg of tert-butyl (4—br0m0chl0r0benzofuran—2-yl)methylcarbamate 374a and 100 mg of tert-butyl (6-bromochlorobenzofuran-2—yl)methylcarbamate 374b. sis of tert-butyl (6—chlor0—4—(4—(4,4—diflu0r0piperidine-l- carbonyl)phenyl)benzofuran-Z-yl)methylcarbamate (375): A mixture of tert—butyl (4- bromochlorobenzofuran—2-yl)methylcarbamate (378a; 50 mg, 0.14 mmol), (4,4- difluoropiperidin—1—yl)(4-(4,4,5 , 5 -tetramethyl-1,3 ,2—dioxabor0lan—2-yl)phenyl)methanone (73 mg, 0.21 mmol), Pd(dppi)C12 (10 mg, 0.01 mmol) and K2C03 (38 g, 0.28 mmol) in 10 mL of dioxane and 2 mL of H20 was stirred at 100 0C under nitrogen atmosphere for 2 h. The e was trated and d by Prep-TLC (33% EtOAc/petroleum ether) to give 60 mg of tert—butyl (6-chloro(4—(4,4-difluoropiperidine- l —carbonyl)phenyl)benzofuran yl)methylcarbamate (379) as a white solid. Yield (83%). 1H NMR (400 MHZ,CD3OD) 5 7.72 (d, J: 8 Hz, 2H), 7.62 (d, J= 8 Hz, 2H), 7.54 (s, 1H), 7.36 (s, 1H), 6.78 (s, 1H), 4.39 (s, 2H), 3.92-3.54 (m, 4H), 2.01-2.20 (m, 4H), 1.47 (s, 9H). LCMS: m/z 449.0 [M-55]+, tR= 1.82 min. sis of (4-(2-(aminomethyl)chlorobenzofuran-4—yl)phenyl)(4,4- opiperidinyl)methanone (380): tert-Butyl (6-chloro(4-(4,4-difluoropiperidine- 1-carbonyl)phenyl)benzofuranyl)methylcarbamate (379; 60 mg, 0.1 mmol) was dissolved in CHzClz (10 mL). TFA (2 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure to give 47 mg of (4-(2- (aminomethyl)chlorobenzofuran—4-yl)phenyl)(4,4-diflu0ropiperidin-1 -y1)methanone (380), which was used t further purification in the next step. Yield (98%). LCMS: m/z 405.1 [M+H]+; IR—— 1. 37 min.
Synthesis of (E)(6-aminopyridinyl)-N-((6-chloro-4—(4-(4,4- difluoropiperidine—l-carbonyl)phenyl)benzofuran-Z—yl)methyl)acrylamide (713): (4-(2- (Aminomethyl)—6-chlorobenzofuran-4—yl)phenyl)(4,4—difluoropiperidin—1-yl)methanone (380; 47 mg, 0.1 mmol) was dissolved in DMF (2 mL) and (E)(pyridinyl)acrylic acid (25 mg, 0.15 mmol) was added at 0 °C. HATU (57 mg, 0.15 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (38 mg, 0.3 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The crude e was purified by Prep-HPLC without workup to yield 25 mg of (E)-3—(6—aminopyridin—3-yl)—N— ((6-chloro—4-(4-(4,4-difluor0piperidine—1—carbonyl)phenyl)benzofuran-2— yl)methyl)acrylamide (713). Yield (39%). 1H NMR (400 MHz, 6) 5 8.56 (t, J = 6 Hz, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.73 (d, J: 8 Hz, 2H), 7.64-7.57 (m, 3H), 7.46 (d, J: 2 Hz, 1H), 7.33 (d, J= 16 Hz, 1H), 6.91 (s, 1H), 6.50-6.34 (m, 4H), 4.58 (d, J= 5 Hz, 2H), 3.82-3.44 (m, 4H), 2.19-1.97 (m, 4H). LCMS: m/z 551.2 [M+H]+, 1R: 1.85 min.
Synthesis of (E)(5-aminopyridinyl)-N-((4-chlor0(4-(4,4-diflu0r0piperidin yl)phenyl)benz0furan-2—yl)methyl)acrylamide (714).
FF?)N 0 Br 02 <:> ‘0 BocHN \0 TFA o o~ F \ -—"—‘—> Pd(dppf)C|2, K2003; 2 2 0' e, H20 Cl 378b 381 \0 O O O @FF "NW; NW" \ F /~ 0 o @F Cl HATU, DEPEA. DMF 382 714 (E)—3 -(5-aminopyridinyl)-N—((4-chloro(4-(4,4-difluoropiperidin— l - yl)phenyl)benzofuran—Z—yl)methyl)acrylamide (714) was synthesized using the indicated reagents in a r fashion as example (713). Yield (16%). 1H NMR (400 MHZ, DMSO-d5) 8.62 (t, J: 5 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.85 (d, J: 8 Hz, 2H), 7.71 (s, 1H), 7.66— 7.53 (m, 3H), 7.36 (d, J: 16 Hz, 1H), 6.83 (s, 1H), .34 (m, 4H), 4.67-4.56 (m, 2H), 3.83-3.39 (m, 4H), 2.20-1.95 (m, 4H). LCMS: m/z 551.2 , IR: 1.79 min.
Chiral resolution of Compound (608). 200 mg of Compound (608) was ed using the following conditions to afford 27 mg of single omer 715 and 40 mg of single enantiomer 716: Column: As-H (250* 4.6 mm, 5 uM) Mobile Phase; HexaneszMethanol (0.1%DEA) (70:30) Flow: 3 mL/min Temp: 40 0C Wavelengths: 214 nm and 254 mm.
Under these chiral HPLC conditions, the retention time for Compound 715 was 5.09 minutes and the retention time for Compound 716 was 5.99 minutes.
The absolute configuration of Compounds 715 and 716 has not been determined.
Therefore, 715, as used herein in reference to a particular compound, refers to a compound having the indicated analytical data and a retention time of 5.09 minutes in the chiral HPLC method described above for the chiral resolution of Compound 608. 716, as used herein in reference to a particular compound, refers to a compound having the indicated analytical data and a retention time of 5.99 minutes in the chiral HPLC method described above for the chiral tion of Compound 608. The analytical data for Compounds 715 and 716 are indicated below. 715: 1H NMR (400 MHz, CD30D) 8 8.12 (s, 1H), 8.07 (s, 1H), 7.84-7.64 (m, 6H), 7.50 (d, J2 16 Hz, 1H), 6.93 (s, 1H), 6.62 (d, J= 9 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), 4.72 (s, 2H), 3.93-3.59 (m, 4H), 2.34-2.01 (m, 2H), 1.67-1.48 (m, 3H). LCMS: m/z 567.3 [M+H]+; IR = 1.38 min. 716: 1H NMR (400 MHz, CD3OD) 8 8.12 (s, 1H), 8.07 (d, J= 2 Hz, 1H), 7.83- 7.64 (m, 6H), 7.50 (d, J= 16 Hz, 1H), 6.92 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), 4.72 (s, 2H), 3.94-3.60 (m, 4H), 2.35-2.01 (m, 2H), 1.66-1.48 (m, 3H). LCMS: m/z 567.3 [M+H]+; 2‘}; = 1.38 min.
(R,E)—3-(6-aminopyridinyl)—N-((5 -(4-(3-fluoro-3 -methylpyrrolidine carbonyl)phenyl)—7-(trifluoromethyl)benz0furan—2-yl)methyl)acrylamide and (S,E)—3-(6- yridinyl)-N-((5—(4-(3-flu0ro-3 lpyrr01idinecarbonyl)phenyl)—7- (trifluoromethyl)benzofuran—2-yl)methyl)acrylamide can be depicted as follows: -286— F F F F F F O O O 0 \ 0 "‘F \ O ' F NH NH N — _... N N/ \ o N/ \ H2N and H2" , respectively.
Synthesis of (6-aminopyridinyl)-N-((5-(3-(morpholine-4—carbonyl)phenyl) (trifluoromethyl)benzofuran-Z-yl)methyl)acrylamide (717).
B(OH)2 F c3 O NHBoc Qo PdWPPDC'z, K2003, Br dioxane, H20 F c3 O 0 NH2 \ HO \ l I / / N NH2 N EDCl, HOBt, J (7N 384 DIPEA, DMF 717 0 J sis of tert-butyl (5-(3-(m0rpholine—4-carbonyl)phenyl) (trifluoromethyl)benzofuran-Z-yl)methylcarbamate (383): utyl (5-(3-(morpholine—4- carbonyl)phenyl)-7—(trifluoromethyl)benzofuran-2~y1)methy1carbamate (383) was synthesized using the indicated reagents according to General Procedure 2. Yield: 67%.
LCMS: m/z 504.9 [M+H]+; tR = 1.81 min.
Synthesis of (3-(2-(aminomethyl)(triflu0r0methyl)benzofuran yl)phenyl)(morpholino)methanone (384): (3-(2-(aminomethy1)—7- (trifluoromethyl)benzofuranyl)phenyl)(morpholino)methanone (384) ws synthesized using the indicated reagent according to General Procedure 3. Yield (100%). LCMS: m/z 404.8 [M+H]+; 1R = 1.27 min.
Synthesis of (E)—3-(6-aminopyridinyl)—N—((5-(3-(m0rpholine yl)phenyl)(trifluoromethyl)benzofuran—Z-yl)methyl)acrylamide (717): (E)(6- aminopyridinyl)-N—((5-(3—(morpholine~4—carbonyl)phenyl)—7—(trifluoromethyl)benzofuran- 2-yl)methyl)acrylarnide (717) was synthesized using the indicated reagents according to General Procedure 4. (45 mg, yield:48%). 1H NMR (400 MHz, DMSO-d6) 5 8.86-8.83 (m, 1H), 8.26—7.42 (m, 11H), 6.96 (s, 1H), 6.91 (d, J: 10 Hz, 1H), 6.58 (d, J: 16 Hz, 1H), 4.64 (d, J: 6 Hz, 2H), 3.65-3.40 (m, 8H). LCMS: m/z 550.8 [M+H]+, 1R: 1.35 min.
Synthesis of (E)(6-aminopyridiny1)-N-((6-(5-(4,4-diflu0ropiperidine-l- carb0nyl)pyridin-Z-yl)benzofuranyl)methyl)acrylamide (718).
\ \ O" O HzN \0 N \ \ N _ "I o \ "— 0 / I/ H \ / HM2 H2N \ / N QN _________—. N HATU, DIPEA, DMF 211 F 713 QN F F F (E)(6—Aminopyridin—3-yl)—N-((6—(5-(4,4-difluoropiperidinecarbonyl)pyridin- 2—yl)benzofuran-Z—yl)methyl)acrylarnide (718) was synthesized using the indicated reagents accrding to General Procedure 4. Yield: 46%. 1H NMR (400 MHz, DMSO-d6) 5 8.85 (t, J = 6 Hz, 1H), 8.75 (s, 1H), .20 (m, 4H), .04 (m, 3H),7.98 (dd, J: 8 Hz, 2 Hz, 1H), 7.71 (d, J: 8 Hz, 1H), 7.45 (d, J: 16 Hz, 1H), 7.02 (d, J: 9 Hz, 1H), 6.83 (s, 1H), 6.62 (d, J = 16 Hz, 1H), 4.61 (d, J: 5 Hz, 2H), 3.81-3.45 (m, 4H), 2.15-2.02 (m, 4H). LCMS: m/z 518.2 [M+H]+, 1R: 1.27 min.
Synthesis of (E)-N-((5-(5-(4,4-difluoropiperidine-l-carbonyl)pyridinyl)-7—(4- fluorophenyl)benzofuran-Z-yl)methyl)(pyridinyl)acrylamide (719).
F O /I \ OH N \N O. HATU. DIPEA. DMF N \ (E)—N-((5-(5-(4,4-difluoropiperidinecarbonyl)pyridin—2-y1)(4- fluorophenyl)benzofuran-Z—yl)methyl)(pyridinyl)acrylarnide (719) was synthesized using the indicated ts ing to General Procedure 4. Yield: 18%. 1H NMR (400 MHz, 6) 6 8.94—8.87 (m, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.64-8.56 (m, 1H), 8.39 (s, 1H), 8.27-7.95 (m, 6H), 7.62—7.49 (m, 2H), 7.44-7.35 (m, 2H), 6.95 (s, 1H), 6.84 (d, J: 16 Hz, 1H), 4.64 (d, J= 5 Hz, 2H), 3.81-3.46 (m, 4H), 2.18-2.01 (m, 4H). LCMS: m/z 597.2 [M+H]+, 1R = 1.53 min. —288- Synthesis of (E)-N-((5-(5-(4,4-diflu0r0piperidine—l-carb0nyl)pyridinyl)(3- henyl)benzofuran—Z-yl)methyl)—3-(pyridin—3-yl)acrylamide (720). {3m F BocHN BocHN CHZCIZ Pd(PPh3)4 PCY3 K3PO4, dioxane H20 385 F / \ OH \N / N ———————-—> I N HATU, DIPEA, DMF 386 F 720 F F (E)-N—((5-(5-(4,4-difluoropiperidine—1-carbonyl)pyridin—2—yl)—7-(3- fluorophenyl)benzofuran—2-yl)methyl)—3—(pyridin—3-yl)acrylamide (720) was synthesized using the indicated ts in a similar fashion as example (699). Yield: 52%. 1H NMR (500 MHz, DMSO-d6) 6 8.97-8.90 (m, 1H), 8.90-8.85 (m, 1H), 8.80—8.74 (m, 1H), 8.68—8.62 (m, 1H), 8.44 (s, 1H), 8.32—8.16 (m, 3H), 8.04—7.98 (m, 1H), 7.88-7.80 (m, 2H), 7.65-7.55 (m, 3H), .27 (m, 1H), 6.98 (s, 1H), 6.88 (d, J: 16 Hz, 1H), 4.69-4.62 (m, 2H), 3.82- 3.45 (m, 4H), 2.16-2.02 (m, 4H). LCMS: m/z 597.2 [M+H]+, tR= 1.53 min.
Synthesis of (E)-N—((5'-(5-(4,4—difluoropiperidine—l-carb0nyl)pyridin—2-yl)-[2,7'— bibenzofuran]-2'-yl)methyl)—3-(pyridinyl)acrylamide (721).
HATU DIPEA, DMF NH2 255 O 721 (E)—N-((5'-(5-(4,4-difluoropiperidine—1-carbony1)pyridin~2-yl)—[2,7'- bibenzofuran]-2'-yl)methyl)(pyridiny1)acrylamide (721) was synthesized using the indicated reagents according to General ure 4. Yield: 40%. 1H NMR (400 MHZ, CD30D) 6 9.02-8.94 (m, 1H), 8.82 (s, 1H), .68 (m, 1H), 8.65 (s, 1H), 8.56 (d, J= 8 Hz, 1H), 8.29 (s, 1H), 8.17—8.03 (m, 2H), 7.87 (s, 1H), 7.79—7.68 (m, 3H), 7.63 (d, J: 8 Hz, 1H), 7.42-7.27 (m, 2H), 7.04—6.94 (m, 2H), 4.86 (s, 2H), 4.00—3.63 (m, 4H), 2.22—2.05 (m, 4H).
LCMS: m/z 619.2 [M+H]+, tR=1.61 min.
Synthesis of (E)—3~(6—amin0pyridinyl)-N-((5-(4-(4,4-difluoropiperidine—1- carbonyl)phenyl)(pyridinyl)benzofuran-Z-yl)methyl)acrylamide (722). 1 TFA CH20|2 2 HATU, DIPEA, DMF N\ 352 722 (E)(6-aminopyridiny1)~N—((5-(4-(4,4-difluoropiperidinecarbonyl)phenyl)- 7-(pyridiny1)benzofuranyl)methyl)acrylamide (722) was synthesized using the indicated reagents according to General Procedures 3 and 4. Yield: 40%. 1H NMR (400 MHZ, DMSO- d6) 5 8.73 (d, J: 6 Hz, 2H), 8.63 (t, J: 6 Hz, 1H), 8.11—8.01 (m, 4H), 7.96-7.86 (m, 3H), 7.65-7.54 (m, 3H), 7.37 (d, J: 16 Hz, 1H), 6.90 (s, 1H), 6.53-6.38 (m, 4H), 4.62 (d, J: 5 Hz, 2H), 3.78-3.44 (m, 4H), .01 (m, 4H). LCMS: m/z 594.2 [M+H]+, tR= 1.68 min.
Synthesis of(E)-N-((5-(4-(4,4-difluoropiperidine—l-carbonyl)phenyl)(pyridin yl)benzofuran-Z-yl)methyl)(pyridinyl)acrylamide (723).
CO 00 1TFA, 0112012 BocHN \ big}: 2 HATU DIPEA, DOMF MH (E)-N~((5—(4~(4,4-difluoropiperidine—1-carbonyl)phenyl)—7-(pyridin zofuran-2—yl)methyl)(pyridinyl)acrylamide (723) was sized using the indicated reagents according to General Procedures 3 and 4. Yield: 48%. 1H NMR (400 MHZ, DMSO-dg) 8 8.90 (t, J: 6 Hz, 1H), 8.82-8.71 (m, 3H), 8.57 (d, J: 4 Hz, 1H), 8.09- 7.99 (m, 4H), 7.97-7.86 (m, 3H), 7.62-7.52 (m, 3H), 7.49-7.42 (m, 1H), 6.94 (s, 1H), 6.83 (d, J: 16 Hz, 1H), 4.66 (d, J: 5 Hz, 2H), .43 (m, 4H), 2.14—1.99 (m, 4H). LCMS: m/z 579.2 [M+H]+, 1R: 1.72 min.
Synthesis of (E)(6-aminopyridinyl)-N—((5-(4-(4,4-difluoropiperidine carbonyl)phenyl)(pyridinyl)benzofuran-Z-yl)methyl)acrylamide (724). o \ / ( )2 o O O ———~—+ BocHN \ (N 2 Pd(PPh3)4. PCYa. K3P04. dioxane, H20. 140 °c 388 724 (E)-3 -(6-aminopyridiny1)-N-((5-(4-(4,4-difluoropiperidinecarbonyl)phenyl)- 7-(pyridin—3-yl)benzofuran—Z-yl)methyl)acrylamide (724) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHz, DMSO-dg) 5 9.24 (s, 1H), 8.86-8.79 (m, 1H), .65 (m, 1H), 8.50-8.41 (m, 1H), 8.20 (s, 1H), 8.13-8.06 (m, 1H), 8.02-7.98 (m, 1H), 7.93-7.86 (m, 2H), 7.68-7.52 (m, 3H), 7.45 (d, J= 16 Hz, 1H), 6.97 (d, J: 9 Hz, 1H), 6.91 (s, 1H), 6.59 (d, J: 16 Hz, 1H), 4.63 (d, J: 5 Hz, 2H), 3.60-3.43 (m, 4H), 2.16-1.98 (m, 4H). LCMS: m/z 594.2 [M+H]+, tR = 1.34 min.
Synthesis of (E)N~((5-(4-(4,4-difluor0piperidine—l-carbonyl)phenyl)(pyridin yl)benzofuranyl)methyl)(pyridinyl)acrylamide (725).
/ \ OH ——————~——-————> / HATU, DIPEA, DMF W" 888 F 725 F ] (E) —N—((5 —(4-(4,4-difluoropiperidine- 1 nyl)phenyl)(pyridin-3 — yl)benzofuran—2-yl)methyl)—3—(pyridin—3-yl)acry1amide (725) was synthesized using the indicated reagents according to General Procedure 4. Yield: 20%. 1H NMR (400 MHZ, DMSO-dg) 8 9.32 (d, J: 2 Hz, 1H), 8.93 (t, J: 6 Hz, 1H), .84 (m, 1H), 8.78-8.72 (m, 1H), 8.67-8.60 (m, 2H), 8.21-8.15 (m, 1H), 8.03 (d,J= 2 Hz, 1H), 7.96-7.87 (m, 3H), 7.81- 7.74 (m, 1H), 7.63-7.54 (m, 4H), 6.95 (s, 1H), 6.86 (d, J= 16 Hz, 1H), 4.66 (d, J= 6 Hz, 2H), 3.78-3.45 (m, 4H), 2.13—1.99 (m, 4H). LCMS: m/z 579.2 [M+H]+, tR= 1.74 min.
Synthesis of (E)—3-(6-amin0pyridin—3-yl)—N—((5-(4—(4,4-diflu0r0piperidine—1— carbonyl)phenyl)(3-flu0r0phenyl)benzofuran-Z-yl)methyl)acrylamide (726). 00 o BocHN \ Pd(PPh3)4,PCy3.K3PO4. dioxane, H20, 140 "c 323 F 389 F F O / \ OH | O o O 00 o O OO HZN QHZHATU DIPEA DMF N; 390 F F F F (E36 —(6—aminopyridin-3—yl)-N—((5-(4-(4,4-difluoropiperidine- l -carbonyl)phenyl)- 7—(3~fluorophenyl)benzofuran—2-yl)methyl)acry1amide (726) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, DMSO—d6) 5 8.81 (t, J: 6 HZ, 1H), 8.20 (s, 1H), .03 (m, 1H), 7.96 (d, J: 2 Hz, 1H), 7.92—7.81 (m, 6H), 7.63-7.54 (m, 4H), 7.44 (d, J: 16 Hz, 1H), 7.33-7.24 (m, 1H), 6.95 (d, J: 9 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J: 16 Hz, 1H), 4.63 (d, J: 6 Hz, 2H), 3.81-3.60 (m, 4H), .01 (m, 4H). LCMS: m/z 611.3 [M+H]+, 1R = 1.79 min.
Synthesis of (E)-N-((5-(4-(4,4-difluor0piperidine—l-carb0nyl)phenyl)(3- fluorophenyl)benzofuran—Z-yl)methyl)-3—(pyridinyl)acrylamide (727). o O O HzN \ HATU DIPEA DMF 390 )‘F (E)-N—((5-(4-(4,4-difluoropiperidinecarbonyl)phenyl)-7—(3- fluorophenyl)benzofuran—2—yl)methyl)(pyridinyl)acry1amide (727) was synthesized using the indicated reagents according to General Procedure 4. Yield: 39%. 1H NMR (400 MHZ, DMSO-d6) 6 8.88 (t, J= 6 Hz, 1H), 8.78 (d, J= 2 Hz, 1H), 8.59-8.53 (m, 1H), 8.01 (d, J= 8 Hz, 1H), 7.96 (d, J= 2 Hz, 1H), .81 (m, 5H), 7.63-7.51 (m, 4H), 7.49-7.42 (m, 1H), 7.32-7.25 (m, 1H), 6.91 (s, 1H), 6.82 (d, J= 16 Hz, 1H), 4.65 (d, J= 6 Hz, 2H), 3.81- 3.44 (m, 4H), 2.14—2.00 (m, 4H). LCMS: m/z 596.3 [M+H]+, 1R: 2.11 min, Synthesis of (E)—3-(6—aminopyridin-3—yl)—N—((5-(4-(4,4-difluoropiperidine carbonyl)phenyl)—7—(4-fluorophenyl)benzofuran—2—y])methyl)acrylamide (728). o F@B(OH)2 o 0 fl. 0 __, N N BocHN \ Pd(PPh3)4. PCY3, K3P04, BocHN \ CH20I2 dioxane. H20, 140 00 F F 323 F 391 F F F O / \ 0.. 1 O 000 HzN N o "—49% .000 HzN \ N; HATU, DIPEA. DMF N\/N \ F QF F F 392 728 ] (E)-3—(6-aminopyridinyl)-N—((5-(4-(4,4-difluoropiperidinecarbonyl)pheny1)- 7-(4-fluorophenyl)benzofurany1)methyl)acrylamide (728) was synthesized using the indicated reagents in a similar n as example (699). 1H NMR (400 MHz, fi) 5 8.83 (t, J= 6 Hz, 1H), 8.27—8.15 (m, 2H), 8.13-8.00 (m, 3H), 7.92 (d, J: 2 Hz, 1H), 7.87 (d, J: 8 Hz, 2H), 7.82-7.71 (m, 2H), 7.61-7.52 (m, 2H), 7.49-7.33 (m, 3H), 6.99 (d, J: 9 Hz, 1H), 6.88 (s, 1H), 6.60 (d, J: 16 Hz, 1H), 4.62 (d, J: 6 Hz, 2H), 3.80-3.40 (m, 4H), 2.14- 1.98 (m, 4H). LCMS: m/z 611.3 [M+H]+, tR= 1.88 min.
Synthesis of (E)—3-(6-aminopyridin-3—yl)—N-((5-(4—(4,4-difluoropiperidine carb0nyl)phenyl)(4-flu0r0phenyl)benzofuran-Z-yl)methyl)acrylamide (729).
F F O / \ OH I O o N o o O O ~—‘——> / o O O HzN \ Q HATU.DIPEA,DMF N\l H \ F DF F F 392 729 (E)(6-arninopyridinyl)-N-((5-(4-(4,4-difluoropiperidinecarbonyl)phenyl)— 7-(4-fluorophenyl)benzofuranyl)methyl)acrylamide (729) was synthesized using the ed reagents according to General Procedure 4. Yield: 19%. 1H NMR (400 MHz, DMSO‘dé) 5 8.88 (t, J= 6 Hz, 1H), 8.78 (d, J= 2 Hz, 1H), 8.59-8.54 (m, 1H), 8.08-7.98 (m, 3H), 7.93 (d, J: 2 Hz, 1H), 7.87 (d, J: 8 Hz, 2H), 7.77 (d, J: 2 Hz, 1H), 7.60-7.51 (m, 3H), 7.48-7.43 (m, 1H), 7.42-7.34 (m, 2H), 6.90 (s, 1H), 6.82 (d, J: 16 Hz, 1H), 4.63 (d, J: 5 Hz, 2H), 3.79-3.44 (m, 4H), 2.14-2.01 (m, 4H). LCMS: m/z 596.3 [M+H]+, tR= 1.92 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(5-chloromethoxyphenyl)(4-(4,4- difluoropiperidine-l-carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (730). on?"1 \ Pd(PPh3)4. PCVa. K3P04. dioxane. H20, 140 °C 393 F 394 730 (6-aminopyridin—3—yI)-N—((7—(5-chloromethoxypheny1)—5-(4—(4,4— difluoropiperidine—l —carbony1)pheny1)benzofuran—2-yl)methy1)acry1amide (73 0) was sized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHz, DMSO-dg) 8 8.54 (t, J: 6 Hz, 1H), 8.07 (d, J: 2 Hz,1H), 7.91 (d, J= 2 Hz, 1H), 7.81 (d, J: 8 Hz, 2H), 7.62—7.46 (m, 6H), 7.33 (d, J= 16 Hz, 1H), 7.22 (d, J: 9 Hz, 1H), 6.82 (s, 1H), 6.49—6.36 (m, 4H), 4.52 (d, J: 6 Hz; 2H), 3.76 (s, 3H), .44 (m, 4H), 2.13-1.99 (m, 4H). LCMS: m/z 657.3 [M+H]+, rR= 1.89 min.
Synthesis of (E)(6-aminopyridin-3—yl)—N—((5-(4-(4,4—difluoropiperidine carbonyl)phenyl)(3-(trifluoromethyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (731).
BocHN. 1:33ng Pd(PPh3)4 PCy3 K3PO4 dioxane H20,14O°C 395 F o 0 "———». ..2 o / O H O O | \ {1:2 HATU,DIPEA.DMF HZN N\ N \ F QF F F 396 731 (E)—3-(6—aminopyridin—3-y1)—N-((5—(4—(4,4—difluoropiperidine—1—carbony1)pheny1)— 7—(3~(trifluoromethy1)phenyl)benzofuran—2—y1)methyl)acry1amide (731) was synthesized —294- using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHz, DMSO-d6) 8 8.82 (t, J: 6 Hz, 1H), 8.34-8.06 (m, 6H), 7.99 (d, J: 2 Hz, 1H), 7.93-7.85 (m, 3H), 7.84-7.75 (m, 2H), 7.57 (d, J: 8 Hz, 2H), 7.45 (d, J= 16 Hz, 1H), 6.99 (d, J: 9 Hz, 1H), 6.91 (s, 1H), 6.60 (d, J= 16 Hz, 1H), 4.63 (d, .1: 6 Hz, 2H), 3.79-3.42 (m, 4H), 2.14- 1.97 (m, 4H). LCMS: m/z 661.2 [M+H]+, tR= 1.54 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(3-cyanophenyl)—5-(4-(4,4- difluoropiperidine-l-carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (732).
N. B. 0 Cl 0OH O O o —. o _, N N BocHN \ Pd(PPh3)4.PCy3,K3p04, BocHN \ CHZCIZ e, H20, 140 "C F F 323 F 397 F CN CN O W o o HgN N o O O ———~—> / o O O HzN \ Q HATU,D|PEA,DMF N\l fl \ F DF 398 732 ] (E)(6-amin0pyridin—3-yl)—N-((7-(3—cyan0phenyl)(4-(4,4-difluoropiperidine- 1-carb0ny1)phenyl)benzofuran—2—yl)methy1)acrylamide (732). 1H NMR (400 MHz, DMSO- d6) 8 8.66-8.59 (m, 1H), 8.48 (s, 1H), 8.38 (d, J= 8 Hz, 1H), 8.10—8.06 (m, 1H), 8.01-7.96 (m, 1H), 7.96-7.87 (m, 4H), 7.76 (t, J: 8 Hz, 1H), .53 (m, 3H), 7.37 (d, J: 16 Hz, 1H), 6.89 (s, 1H), 6.54-6.38 (m, 4H), 4.61 (d, J: 5 Hz, 2H), 3.81-3.46 (m, 4H), 2.16—1.99 (m, 4H). LCMS: m/z 618.2 [M+H]+, rR= 1.81 min.
Synthesis of (E)(6-amin0pyridinyl)—N-((5-(4-(4,4-difluoropiperidine—l- carbonyl)phenyl)(4-(trifluoromethyl)phenyl)benzofuranyl)methyl)acrylamide (733). —295— 3* O o O O Jab—fl o O O —» N N BocHN \ pd(Pph3)4lpr3'Kapo4i BocHN \ CHZCIZ dioxane, H20, 140 °c F F 323 F 399 F FSC F30 o WNW" o o O O o HzN \ Q HATU, DIPEA, DMF F 0QF F F (E)-3—(6-amin0pyridinyl)-N-((5-(4-(4,4-diflu0r0piperidine—1—carbonyl)phenyl)— 7-(4-(trifluoromethyl)phenyl)benzofuranyl)methyl)acrylamide (733) was synthesized using the indicated reagents in a r fashion as example (699). 1H NMR (400 MHZ, DMSO-d5) 8 8.61 (t, J: 6 Hz, 1H), 8.26-8.18 (m, 2H), 8.08 (s, lH),'7.99 (s, 1H), 7.95—7.83 (m, 5H), 7.64—7.53 (m, 3H), 7.36 (d, J: 16 Hz, 1H), 6.89 (s, 1H), 6.49-6.30 (m, 4H), 4.60 (d, J: 5 Hz, 2H), 3.80—3.43 (m, 4H), 2.13—1.99 (m, 4H). LCMS: m/z 661.3 [M+H]+, IR: 1.93 min.
Synthesis of (6-aminopyridinyl)-N—((7-(3,5-diflu0r0phenyl)(4-(4,4- difluoropiperidinecarb0nyl)phenyl)ben:0furanyl)methyl)acrylamide (734). 0 F\<‘jr O N 0\ N BocHN \ Q Pd(PPh3)4, PCy3 K3PO4 BocHN < 2 CH20'2 dioxane H20 140 "c F F 323 F F F0 /| \ 0.. PO o HZN N o o O O ————> / o O O HZN \ Q HATU.D|PEA.DMF MNl \ F QF F F 402 734 (E)(6—amin0pyridinyl)-N-((7-(3,5-difluor0phenyl)(4-(4,4— difluoropiperidine- 1 nyl)phenyl)benzofurany1)methyl)acrylamide (734) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHz. DMSO—d6) 5 8.63 (t, J: 5 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.94—7.87 (m, 3H), 7.84— —296- 7.77 (m, 2H), 7.65-7.53 (m, 3H), .29 (m, 2H), 6.92-6.85 (m, 1H), 6.50—6.32 (m, 4H), 4.62 (d, J: 5 Hz, 2H), 3.80—3.44 (m, 4H), 2.15—2.01 (m, 4H). LCMS: m/z 629.3 [M+H]+, IR = 1.89 min. sis of (E)(6-amin0pyridin—3-yl)-N—((5-(4—(4,4-diflu0r0piperidine-l- carbonyl)phenyl)(6-flu0r0pyridinyl)benzofuran-Z—yl)methyl)acrylamide (735).
/ OH Cl i O 0 F \N o —» BocHN \ Pd(PPh3)4.PCy3.K3PO4. BocHN dioxane. H20. 140 °C 323 F / \OH HzN N HgN / HATU. DIPEA, DMF W" 404 735 [0 08 76] (E)-3 -(6-aminopyridin-3 -y1)-N-((5-(4—(4,4-difluoropiperidine— 1 -carb0nyl)phenyl)— 7-(6-flu0r0pyridiny1)benzofuran—2-yl)methyl)acrylamide (735) was synthesized using the indicated reagents in a similar fashion as example . 1H NMR (400 MHZ, DMSO-dg) 8 8.90 (d, J= 2 Hz, 1H), 8.84 (t, J: 5 Hz, 1H), 8.65-8.58 (m, 1H), 8.23-8.03 (m, 4H), 7.99 (d, J: 2 Hz, 1H), 7.93-7.86 (m, 3H), 7.60-7.54 (m, 2H), 7.48-7.37 (m, 2H), 6.96 (d, J: 9 Hz, 1H), 6.91 (s, 1H), 6.59 (d, J: 16 Hz, 1H), 4.63 (d, J: 5 Hz, 2H), 3.80-3.45 (m, 4H), 2.15- 1.99 (m, 4H). LCMS: m/z 612.3 [M+H]+, 1R = 1.78 min.
Synthesis of (E)(6-amin0pyridinyl)—N-((7-(2,4-diflu0r0phenyl)(4-(4,4- difluoropiperidine-l-carbonyl)phenyl)benzofuranyl)methyl)acrylamide (736). —297— o QIROH o O O BOCHN \ ’\ 2 Pd(PPh3)4, PCyg, K3PO4, e, H20, 140 °C 323 F 406 736 (E)(6-amin0pyridiny1)-N—((7-(2,4—diflu0r0phenyl)—5—(4-(4,4- difluoropiperidine-1—carb0ny1)phenyl)benzofuran-Z—yl)methyl)acry1amide (736) was sized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, DMSO-dg) 5 8.63-8.57 (m, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.85-7.76 (m, 3H), 7.64— 7.43 (m, 5H), 7.37—7.25 (m, 2H), 6.85 (s, 1H), 6.50—6.36 (m, 4H), 4.53 (d, J: 6 Hz, 2H), 3.80-3.43 (m, 4H), 2.13—1.98 (m, 4H). LCMS: m/z 628.9 [M+H]+, tR=2.02 min.
Synthesis of (E)—3—(6-amin0pyridinyl)-N-((7—(3,4—difluorophenyl)—5-(4-(4,4- difluor0piperidine-l-carb0nyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (737). 3°CHN \ Pd(PPh3)4. Pol/3, K3P04. BocHN dioxane, H20, 140 °c 323 F 408 737 (E)(6-Aminopyridiny1)-N-((7-(3,4-diflu0r0phenyl)—5-(4-(4,4- difluoropiperidine-l-carb0nyl)phenyl)benzofi1ran—2—yl)methyl)acrylamide (737) ) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, DMSO-dg) 8 8.62 (t, J: 6 Hz, 1H), .06 (m, 2H), 7.97—7.79 (m, 5H), 7.65—7.53 -298— (m, 4H), 7.36 (d, J= 16 Hz, 1H), 6.87 (s, 1H), 6.50-6.39 (m, 4H), 4.61 (d, J: 6 Hz, 2H), .42 (m, 4H), 2.16—1.96 (m, 4H). LCMS: m/z 629.3 [M+H]+, IR = 1.88 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(2-chlorofluorophenyl)(4-(4,4- opiperidinecarbonyl)phenyl)benzofuranyl)methyl)acrylamide (738).
B\ Oc O 0 F Cl TFA O ————-————> O —> N N BocHN \ Pd(PPh3)4. F’Cys. K3PO4. BocHN \ CHzolz dioxane, H20. 140 °C F F 323 F 409 F O WWW DO0. O o O O / H2N \ Q HATU DIPEA DMF F 0QF F F (E)(6-aminopyridin—3-y1)-N—((7-(2—chlor0-4—flu0r0pheny1)—5—(4-(4,4- difluoropiperidinecarbony1)pheny1)benzofuran—Z—yl)methy1)acrylamide (738) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, CD3OD) 8 8.08 (d, J: 9 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.73—7.65 (m, 2H), 7.51- 7.42 (m, 3H), 7.42-7.27 (m, 3H), 7.16-7.08 (m, 1H), 6.94 (d, J: 9 Hz, 1H), 6.76 (s, 1H), 6.50 (d, J: 16 Hz, 1H), 4.53 (s, 2H), 3.85-3.45 (m, 4H), .84 (m, 4H). LCMS: m/z 645.2 [M+H]+, rR = 1.50 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(4-chlorofluorophenyl)—5-(4-(4,4— difluorOpiperidine-l-carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (739).
BocHNV \ Pd(PPh3)4.PCy3.K3P04, Bod-IN dioxane, H20, 140 °c 323 F —299- (B(6-amin0pyridinyl)—N—((7-(4—chlor0flu0r0phenyl)-5—(4—(4,4— difluoropiperidine— l -carb0nyl)phenyl)benzofuran—2—y1)methy1)acrylamide (739) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, CD30D) 5 8.21 (d, J: 9 HZ, 1H), 8.05 (s, 1H), 7.91 (d, J: 2 Hz, 1H), 7.84-7.55 (m, 9H), 7.47 (d, J: 16 Hz, 1H), 7.42—7.35 (m, 2H), 7.07 (d, J: 9 HZ, 1H), 6.88 (s, 1H), 6.63 (d, J= 16 HZ, 1H), 4.68 (s, 2H), 3.94-3.60 (m, 4H), 2.19-1.97 (m, 4H). LCMS: m/z 645.3 [M+H]+, xR = 1.92 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(2,5-difluorophenyl)(4-(4,4- difluoropiperidine-l-carbonyl)phenyl)benzofuranyl)methyl)acrylamide (740).
BocHN. j:ocim Pd(PPh3)4 Pczy3 K3PO4 dioxane HZO,14O°C 413 F (E)(6-amin0pyridinyl)—N—((7—(2,5-diflu0r0phenyl)(4-(4,4- difluoropiperidine-l-carbonyl)pheny1)benzofurany1)methyl)acrylamide (740) was synthesized using the indicated reagents in a similar n as example (699). 1H NMR (400 MHZ, é) 5 1H NMR (400 MHZ, DMSO) 8 8.59 (t, J: 6 Hz, 1H), 8.09-7.97 (m, 2H), 7.87—7.82 (m, 2H), 7.72—7.28 (m, 8H), 6.86 (s, 1H), 6.56-6.31 (m, 4H), 4.60—4.49 (m, 2H), 3.84—3.41 (m, 4H), 2.18-1.94 (m, 4H). LCMS: m/z 629.3 [M+H]+, 1R: 1.88 min. sis of (6-aminopyridinyl)-N-((7—(3-chlor0phenyl)(4-(4,4- difluoropiperidine-l-carbonyl)phenyl)benzofuranyl)methyl)acrylamide (741). —300— Cl@B\OH 0 O O O W» O —> N N BocHN \ Pd o O O H2N \ Q HATU.D|PEA,DMF N\| H \ F QF F F 416 741 (E)-3—(6-amin0pyridin—3~yl)—N—((7—(3—ch10r0phenyl)—5—(4—(4,4-difluoropiperidine- l—carb0nyl)pheny1)benzofuranyl)methyl)acrylamide (741) was synthesized using the indicated reagents in a r fashion as example (699). 1H NMR (400 MHz, DMSO'dG) 8 8.65-8.56 (m, 1H), 8.13-7.77 (m, 7H), 7.70—7.48 (m, 5H), 7.36 (d, J: 16 Hz, 1H), 6.87 (s, 1H), 6.56-6.36 (m, 4H), .48 (m, 2H), 3.84-3.40 (In, 4H), 2.18—1.96 (m, 4H). LCMS: m/z 627.1 [M+H]+, rR= 1.91 min.
Synthesis of (E)(6-aminopyridinyl)-N-((7-(4-chlorophenyl)(4-(4,4- difluoropiperidine—1—carbonyl)phenyl)benzofuran-Z-yl)methyl)acrylamide (742). 0H 0 ©B\ O o _, QN BocHN Pd(PPh3)4 PCya. K3PO4 BocHN \ CHzolz e H20 140°C . F 417 F HEN \ QHNHATU DIPEA DMF / 418 742 (6-aminopyridinyl)-N—((7-(4-ch10r0phenyl)(4-(4,4-diflu0r0piperidine- 1—carbonyl)phenyl)benzofuran—2—yl)methyl)acrylamide (742) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, DMSO-dg) 8 8.66- 8.58 (m, 1H), 8.13-7.51 (m, 12H), 7.36 (d, J=16 Hz, 1H), 6.87 (s, 1H), 6.57-6.31 (m, 4H), 4.68-4.51 (m, 2H), .42 (m, 4H), 2.19-1.96 (m, 4H). LCMS: m/z 627.2 [M+H]+, tR = 1.94 min.
Synthesis of (E)(6-amin0pyridin-3—yl)-N—((5-(4-(4,4-diflu0r0piperidine carbonyl)phenyl)(6-flu0r0methylpyridinyl)benzofuran-Z-yl)methyl)acrylamide (743).
/ \ CI — O B(OH)2 o O O —» BocHN \ Pd(PPh3)4.PCy3.K3PO4, BocHN dioxane, H20, 140 °c 323 F N /| \ 0H o HzN N ___._—> HZN / HZN N; HATU, DEPEA, DMF W" 420 743 (E)-3—(6—Aminopyridiny1)—N-((5-(4—(4,4-difluoropiperidine carbony1)phenyl)-7—(6—flu0r0methy1pyridin—3—yl)benzofuran—2—y1)methyl)acrylamide (743) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, DMSO-de) 6 8.82-8.76 (m, 1H), .00 (m, 5H), 7.84 (d, J: 8.2 Hz, 2H), 7.60-7.52 (m, 4H), 7.42 (d, J: 16 Hz, 1H), 7.29 (s, 1H), 6.97 (d, J: 9 Hz, 1H), 6.89 (s, 1H), 6.56 (d, J: 16 HZ, 1H), 4.55 (d, J: 5 Hz, 2H), 3.77-3.44 (m, 4H), 2.28 (s, 3H), 2.10-2.00 (m, 4H). LCMS: m/z 626.2 [M+H]+, rR= 1.41 min.
Synthesis of (E)-3—(6—amin0pyridinyl)-N-((5-(4—(4,4-diflu0r0piperidine carbonyl)phenyl)(4-methylpyridinyl)benzofuran-Z-yl)methyl)acrylamide (744).
CI N/ ‘OH O 1 o O O ———————-+ BOCHN \ Pd(PPh3)4. PCVa, K3PO4, e. H20, 140 °C 323 F 421 F (E)-3 -(6-amin0pyridin-3—yl)-N—((5 -(4-(4,4-diflu0ropiperidine—1-carbonyl)phenyl)- 7-(4-methylpyridin—3—yl)benzofuran—2-y1)methy1)acry1amide (744) was synthesized using the indicated reagents in a similar fashion as example (699). Yield: 51%. 1H NMR (400 MHZ, DMSO-dg) 6884—869 (m, 3H), 8.39-8.04 (m, 5H), 7.88—7.54 (m, 6H), 7.42 (d, J: 16 Hz, 1H), 7.00 (d, J: 9 Hz, 1H), 6.91 (s, 1H), 6.58 (d, J: 16 Hz, 1H), 4.56 (s, 2H), 3.84-3.38 (m, 4H), 2.36 (s, 3H), 2.14-1.99 (m, 4H). LCMS: m/z 608.1 , tR = 1.30 min. sis of (E)—3—(6—aminopyridin-S-yl)—N—((5-(5—(4-flu0r0phenoxy)pyridinyl)(4- fluorophenyl)benzofuran-Z-yl)methyl)acrylamide (745).
BocHN. 1:24:58: H2NQBFN F@OH NaNOz, HBr W, Br CuBr AcOH Pd(dppf))CI2 K2003 dioxane H20 Cul, 082003, dioxane. HzN‘Q’ C. Q FQBW N BOCHN \ Pd(PPh3)4, XPhos, K3P04, BOCHN dioxane, H20 HZN / N\ OH HATU. DIPEA, DMF / 428 745 Synthesis of 5-(4-flu0r0phenoxy)pyridin—2-amine (424): 5-Bromopyridin—2- amine (423; 1 g, 5.8 mmol) was dissolved in dioxane (20 mL). 4-Fluorophenol (0.7 g, 5.8 mmol). CuI (0.1 g, 0.6 mmol) and C52CO3 (3.8 g, 11.6 mmol) were added at 25 0C. The —303— reaction mixture was heated at 110 0C for 16 h. After cooling down to room temperature, the reaction mixture was poured into water (20 mL), ted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over ous , concentrated under reduced pressure to give the crude t, which was purified by silica gel tography (20% EtOAc/petroleum ether) to give 150 mg of 5—(4— fluorophenoxy)pyridin—2-amine (424) as white solid (13% yield). LCMS: m/z 205.1 [M+H]+; tR = 1.23 min.
Synthesis of 2-bromo-S-(4-fluorophenoxy)pyridine (3): 5-(4- Fluorophenoxy)pyridinamine (424; 200 mg, 1 mmol) was dissolved in 5 mL of AcOH, the mixture was cooled down to 0 OC and degassed. NaNOz (76 mg, 1.2 mmol) was added. After stirring for 0.5 h, CuBr (170 mg, 1.2 mmol) and HBr aqueous solution (2 mL) was added.
The mixture was stirred at 25 0C for 2 h. The reaction mixture was diluted with 20 mL of H20, extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over NaZSO4, concentrated and purified by silica gel tography (20% EtOAc/petroleum ether) to give 100 mg of 2—bromo—5—(4—fluorophenoxy)pyridine (425) as white solid (37% yield). LCMS: m/z 270.0 [M+H]+; tR = 1.73 min.
Synthesis of tert-butyl (7—chloro-5—(5-(4—flu0rophenoxy)pyridin-2— yl)benzofuran—Z—yl)methylcarbamate (426): A mixture of 2-bromo—5-(4— fluorophenoxy)pyridine (425; 135 mg, 0.5 mmol), tert—butyl (7—chloro—5~(4,4,5,5—tetramethyll ,3,2-dioxaborolan—2-yl)benzofuran—2-yl)methylcarbamate (203 mg, 0.5 mmol), i)C12 (41 mg, 0.05 mmol) and K2CO3 (138 mg, 1 mmol) in 5 mL of dioxane and 0.5 mL of H20 was stirred at 100 0C under nitrogen atmosphere for 2 h. After cooling down to room temperature, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and the solvents were removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 170 mg of tert-butyl (7-chloro(5-(4-fluorophenoxy)pyridinyl)benzofuran hylcarbamate (426) as a white solid (71% yield). LCMS: m/z 469.1 [M+H]+, IR = 1.89 min.
Synthesis of tert-butyl (5-(5-(4-flu0r0phen0xy)pyridinyl)—7-(4- fluorophenyl)benzofuran-Z-yl)methylcarbamate (427): utyl (7-chloro(5-(4— fluorophenoxy)pyridinyl)benzofuranyl)methylcarbarnate (426; 180 mg, 0.4 mmol), 4— —304— fluorophenylboronic acid (60 mg, 0.4 mmol), Pd(PPh3)4 (42 mg, 0.04 mmol), XPhos (36 mg, 0.08 mmol) and K3PO4 (170 mg, 0.8 mmol) were added to a mixture of dioxane (5 mL) and water (0.5 mL) and degassed. The reaction mixture was heated at 110 °C for 2 h. The on mixture was cooled down to room temperature, filtered and the filtrate was concentrated under reduced re to give the crude product, which was purified by silica gel chromatography (30% EtOAc/petroleum ether) to give 100 mg of tert—butyl (5-(5-(4- fluorophenoxy)pyridinyl)(4-fluorophenyl)benzofuranyl)methylcarbamate (427) as white solid (47% . LCMS: m/z 529.2 [M+H]+; IR = 1.92 min.
Synthesis of (5-(5-(4-fluorophen0xy)pyridinyl)—7-(4- fluorophenyl)benzofuran-Z-yl)methanamine (428): tert—Butyl (5-(5-(4- fluorophenoxy)pyridin—2—y1)(4-fluorophenyl)benzofuranyl)methylcarbamate (427; 100 mg, 0.19 mmol) was dissolved in CHzClz (5 mL). TFA (1 mL) was added se at 0 oC.
The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was trated under reduced pressure to give (5-(5-(4- fluorophenoxy)pyridin—2-yl)—7-(4-fluorophenyl)benzofuran—2-yl)methanamine (428), which was used without further purification in the next step (80 mg, 100% yield). LCMS: m/z 429.1 ; 1R = 1.49 min.
Synthesis of (E)(6—amin0pyridinyl)-N-((5-(5-(4-flu0r0phen0xy)pyridin- 2-yl)(4-flu0r0phenyl)benzofuranyl)methyl)acrylamide (745): (5-(5—(4— Fluorophenoxy)pyridinyl)(4—fluorophenyl)benzofuran—2-yl)methanamine (428; 80 mg, 0.19 mmol) was dissolved in DMF (3 mL). (E)—3-(6—aminopyridin-3 -yl)acrylic acid (31 mg, 0.19 mmol), HATU (72 mg, 0.19 mmol), and DIPEA (50 mg, 0.38 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 h. The crude mixture was purified by Pre—HPLC without workup to give (E)(6-aminopyridinyl)—N— ((5-(5-(4-fluorophenoxy)pyridin-2—yl)—7-(4-fluorophenyl)benzofuran-Z-yl)methyl)acrylamide (745) (45 mg, 41% yield) as white solid. 1H NMR (400 MHz, CD3OD) 8 8.23 (d, J = 3 Hz, 1H), 7.94-7.76 (m, 6H), 7.64-7.57 (m, 1H), 7.40-7.32 (m, 2H), 7.15-6.99 (m, 6H), 6.72 (s, 1H), 6.48 (d, J= 9 Hz, 1H), 6.35 (d, J= 16 Hz, 1H), 4.57 (s, 2H). LCMS: m/z 575.2 , m = 2.01 min.
Synthesis of (E)(6-aminopyridinyl)—N-((5-(4—(4,4—diflu0r0piperidine carbonyl)phenyl)(pyridin—2—yl)benzofuran—Z—yl)methyl)acrylamide (746). _____________, BocHN \ catalyst, K3PO4 (0.5 M), THF, 4o 00 323 F 429 Q.N HATU DIPEA, DMF m)" F 0QFN ] (E)—3 —(6-Aminopyridin-3 —yl)-N-((5 -(4—(4,4—difluoropiperidine- l - carbonyl)phenyl)(pyridin—2-yl)benzofi1ran—2—yl)methy1)acrylamide (746) was synthesized using the indicated reagents in a similar fashion as example (699). 1H NMR (400 MHZ, CD3OD) 8 8.76—8.69 (m, 1H), 8.40-8.34 (m, 1H), 8.25 (d, J: 2 Hz, 1H), 8.09-7.98 (m, 2H), 7.94 (s, 1H), 7.90—7.85 (m, 2H), 7.75 (d, J: 9 Hz, 1H), 7.63-7.57 (m, 2H), 7.54—7.42 (m, 2H), 6.92-6.85 (m, 1H), 6.61 (d, J: 9 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), 4.75 (s, 2H), 3.95-3.61 (m, 4H), .04 (m, 4H). LCMS: m/z 594.2 [M+H]+; tR = 1.74 min.
Synthesis of (E)—3-(6-aminopyridin—3-yl)-N—((5-(5-(3-hydr0xy (trifluoromethyl)azetidinecarb0nyl)pyridin—2—yl)(trifluoromethyl)benzofuran yl)methyl)acrylamide (747). o (1) , TBAF, THF CFgH OH (1) Pd/C, H2, MeOH CT ————-——> HN 0sz (2) TBAF, THF 0sz (2) 1M HCI H01 431 432 433 &2. 61%,3.
HATU DIPEA, DMF Synthesis of benzyl 3—hydroxy—3-(trifluoromethyl)azetidinecarb0xylate (432): Benzyl 3-oxoazetidine-l—Carboxylate (431, 1.0 g, 6.1 mmol) was dissolved in THF (20 mL). TMSCF3 (2.2 g, 9.1 mmol) was added dropwise at 0 °C (ice bath) over 5 min followed —306- by TBAF (156 mg, 0.6 mmol). The reaction mixture was stirred at 0 °C for 20 min. A solution of TBAF (1.6 g, 6.1 mmol) in THF (5 mL) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. The on e was diluted with ethyl acetate (20 mL), washed with water (20 mL), brine (30 mL), dried over Na2S04 and concentrated under reduced re to give benzyl 3-hydroxy—3— (trifluoromethyl)azetidinecarboxylate (432) (1.1 g, 82% yield) as white solid, which was used in next step without further purification. 1H NMR (500 MHz, CD30D) 8 7.50—7.27 (m, 5H), 5.13 (s, 2H), 4.24 (s, 2H), 3.98 (s, 2H).
Synthesis of 3-(trifluoromethyl)azetidinol hydrochloride (433): Benzyl 3- hydroxy(trifluoromethyl)azetidine-l—carboxylate (432, 500 mg, 1.9 mmol) was dissolved in methanol (40 mL). Palladium on carbon (10% Pd, 100 mg) was added. The reaction e was stirred under H; atmosphere at room temperature for 1 h. The reaction e was filtered and the filtrated was treated with HCl (2 mL, 1N aqueous solution). The reaction mixture was stirred at room temperature for 1 h and trated under reduced pressure to give 3-(trifiuoromethyl)azetidin—3-ol hydrochloride (433) (340 mg, 100% yield), which was used in the next step without r purification.
Synthesis of (E)—3~(6-aminopyridinyl)—N—((5—(5—(3-hydroxy (trifluoromethyl)azetidine~1-carbonyl)pyridin-2—yl)(trifluoromethyl)benzofuran—2- yl)methyl)acrylamide (747): (E)(6—aminopyridin-3—yl)—N-((5—(5-(3-hydroxy—3- (trifluoromethyl)azetidine— 1 -carbonyl)pyridin~2-yl)(trifluoromethyl)benzofuran—2- yl)methyl)acrylamide (747) was sized using the indicated reagents according to General Procedure 4. (50 mg, 22% yield). 1H NMR (500 MHz, DMSO-d6) 8 8.97 (s, 1H), 8.92—8.86 (m, 1H), 8.73 (s, 1H), 8.43 (s, 1H), 8.27-8.17 (m, 4H), 8.13 (d, J= 9 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J: 16 Hz, 1H), 7.05-6.98 (m, 2H), 6.62 (d, J: 16 Hz, 1H), 4.71 (d, J: 10 Hz, 1H), 4.65 (d, J: 5 Hz, 2H), 4.41 (d, J: 9 Hz, 1H), 4.34 (d, J: 10 Hz, 1H), 4.12 (d, J= 11 Hz, 1H), 2.93 (s, 1H). LCMS: m/z 606.2 [M+H]+, IR=1.40 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-(4,4-difluoropiperidinecarbonyl) fluorophenyl)(pyridinyl)benzofuranyl)methyl)acrylamide (748).
QL‘?, B NH 800 F F \ F F Br >CNHHCI Br 0 F F (:1 43 OH _, N o EDCI, HOBt, DIPEA o Pd(dppf)Clz. K2C03.
CHZCIZ 434 435 1,4—dioxane, H20 CI N._ N\ / 0 QM")? 0 O O O o O O l B°°HN \ CHZC'Z BOCHN \ F {:2 Pd(PPh3)4.PCy3,K3PO4, F dioxane, H20, 140 °C {:2 436 F 437 F F F HO /| \ N NH2 0 / o O O N l Q N N n HATU, DIPEA, DMF \ \ / F 0 Q:F 438 F 748 Synthesis of (4-bromofluorophenyl)(4,4-diflu0r0piperidinyl)methanone (435). 4—Bromofluorobenzoic acid (434; 2.2 g, 10 mmol) was dissolved in CHZCIZ (40 mL) and 4,4-difluoropiperidine hydrochloride (1.6 g, 10 mmol) was added at 0 °C (ice bath).
EDCI (2.3 g, 12 mmol) and HOBt hydrate (1.6 g, 12 mmol) were added to this reaction mixture at 0 °C followed by DIPEA (2.6 g, 20 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred r for 2 h. The on e was diluted with CHzClz (100 mL), washed with water (50 mL), brine, dried over anhydrous NaZSO4, concentrated under reduced pressure to give (4—bromofluorophenyl)(4,4- difluoropiperidin—1—yl)methanone (435), which was used in next step without further purification (3 g, 93% yield). LCMS: m/z 322.1 [M+H]+, tR= 1.63 min.
Synthesis of tert—butyl (7-chloro-S-(4—(4,4-difluoropiperidinecarb0nyl) fluor0phenyl)benzofuranyl)methylcarbamate (436): (4—Bromofluorophenyl)(4,4- difluoropiperidin-l-yl)methanone (435; 786 mg, 2.45 mmol), tert-butyl (7-chloro—5—(4,4,5 ,5 - tetramethyl—1,3,2-dioxaborolanyl)benzofuranyl)methylcarbamate (43; l g, 2.45 mmol), Pd(dppf)Clz (204 mg, 0.25 mmol), and K2C03 (676 mg, 4.9 mmol) were added in a mixture of dioxane (20 mL) and water (2 mL) and degassed. The reaction mixture was heated at 95 0C under nitrogen atmosphere for 2 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was concentrated and purified by silica gel chromatography (20% petroleum ether) to yield 1.0 g of tert-butyl (7—chloro—5—(4- (4,4-difluoropiperidine- 1 nyl)-2—fluoropheny1)benzofuranyl)methylcarbamate (436) as a white solid (78% yield). LCMS: m/z 523.1 [M+H]+, rR = 2.06 min.
Synthesis of tert-butyl (5-(4-(4,4-difluor0piperidine-1~carb0nyl) fluorophenyl)(pyridinyl)benzofuranyl)methylcarbamate (437): tert-Butyl (7- chloro-5—(4-(4,4-difluoropiperidinecarbonyl)fluoropheny1)benzofuran yl)methylcarbamate (436; 500 mg, 0.96 mmol), pyridin—3-y1boronic acid (177 mg, 1.4 mmol), Pd(PPh3)4 (222 mg, 0.19 mmol), tricyclohexylphosphine (81 mg, 0.29 mmol) and K3PO4 (248 mg, 1.9 mmol) were added to a mixture of dioxane (10 mL) and water (2 mL) and degassed. The reaction mixture was heated under microwave irradiation at 140 °C for 2 h. The reaction mixture was cooled down to room temperature, poured into 10 mL of water, extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , concentrated and purified by silica gel chromatography (50% EtOAc/petroleum ether) to give tert-butyl (5—(4—(4,4—difluoropiperidine-l-carbonyl) fluorophenyl)(pyridinyl)benzofuranyl)methylcarbamate (437) as white solid (240 mg, 44% yield). LCMS: m/z 566.2 [M+H]+; 1R = 1.59 min.
Synthesis of (4-(2-(aminomethyl)(pyridin-3—yl)benzofuran—S-yl) fluorophenyl)(4,4-difluoropiperidin-l-yl)methan0ne (438): tert-Butyl (5-(4—(4,4- opiperi dine- l -carbonyl)fluoropheny1)-7—(pyridin-3 —yl)benzofuran yl)methylcarbamate (437; 240 mg, 0.43 mmol) was dissolved in CH2C12 (5 mL). TFA (1 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under d pressure to give (4- inomethyl)(pyridin-3 -yl)benzofuran—5-yl)fluorophenyl)(4,4-difluoropiperidin- 1-yl)methanone (438), which was used without further purification in the next step (250 mg, 100% yield). LCMS: m/z 466.1 [M+H]+, IR = 1.56 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-(4,4-difluoropiperidine-l- carbonyl)fluor0phenyl)(pyridinyl)benzofuranyl)methyl)acrylamide (748): (4- (2-(Aminomethyl)—7—(pyridin-3—yl)benzofuran—5—yl)—3—f1uorophenyl)(4,4—difluoropiperidin-1 - yl)methanone (438; 250 mg, 0.43 mmol) was dissolved in DMF (4 mL) and (E)(6- yridin-3 -yl)acrylic acid (84 mg, 0.51 mmol) was added at 0 °C. HATU (194 mg, 0.51 mmol) was added to this reaction e at 0 °C followed by DIPEA (111 mg, 0.86 mmol) —309- dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The reaction mixture was purified Prep—HPLC to afford 38 mg of (E)-3~(6- aminopyridin-3 -yl)-N—((5 -(4-(4,4—difluoropiperidinecarbonyl)fluorophenyl)(pyridin— 3—yl)benzofuranyl)methyl)acrylamide (748) (15% yield). 1H NMR (400 MHZ, DMSO-dg) 8 9.18 (d, J: 2 Hz, 1H), 8.69-8.59 (m, 2H), 8.38-8.30 (m, 1H), 8.08 (d, J: 2 Hz, 1H), 7.87 (s, 1H), .71 (m, 2H), 7.64-7.54 (m, 2H), 7.48 (d,J= 11 Hz, 1H), 7.41 (d, J: 8 Hz, 1H), 7.35 (d, J= 16 Hz, 1H), 6.91 (s, 1H), 6.51-6.36 (m, 4H), 4.61 (d, J= 6 Hz, 2H), 3.82-3.64 (m, 2H), 3.58-3.40 (m, 2H), 2.14-2.00 (m, 4H). LCMS: m/z 612.2 [M+H]+, tR= 1.72 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-(4,4-difluoropiperidine—1-carbonyl) fluorophenyl)—7-(4-(triflu0r0methyl)phenyl)benz0furanyl)methyl)acrylamide (749).
C, F < S F30@B(OH)2 o O O O Pd(PPh3)4. PCYS: K3P04.
B°°HN \ BocHN dioxane, H20, 140 "c [0090 1] (E)—3 inopyridin-3—yl)—N—((5-(4-(4,4-difluoropiperidine-1—carbonyl)—2— fluoropheny1)—7—(4-(trifluoromethyl)phenyl)benzofuranyl)methyl)acrylamide (749) was sized using the indicated reagents in a similar fashion as example (748). Yield: 43%. 1H NMR (400 MHZ, DMSO-dg) 8 8.62 (t, J: 5 Hz, 1H), 8.22-8.14 (m, 2H), 8.09 (s, 1H), .85 (m, 3H), .71 (m, 2H), 7.65-7.59 (m, 1H), 7.49 (d, J: 11 Hz, 1H), 7.44-7.33 (m, 2H), 6.91 (s, 1H), 6.52-6.38 (m, 4H), 4.61 (d, J: 5 Hz, 2H), 3.79-3.43 (m, 4H), 2.16-1.99 (m, 4H). LCMS: m/Z 679.2 [M+H]+, IR: 1.95 min.
Synthesis of (E)(6-amin0pyridinyl)-N-((7-(4-chlorophenyl)(4-(4,4- difluoropiperidine-l-carbonyl)fluorophenyl)benzofuran-Z-yl)methyl)acrylamide (750).
Cl F < S CI@B(OH)2 —___, 0 O O o Pd(PPh)4 PCy3 . 3: KP043 ' BocHN \ dioxane. H20. 140 0C (ED(6—amin0pyridiny1)—N—((7—(4—chlor0phenyl)—5—(4-(4,4-difluoropiperidine— 1-carbonyl)fluorophenyl)benzofuran—2-yl)methyl)acrylamide (750) was synthesized using the indicated reagents in a similar fashion as example (748). 1H NMR (400 MHZ, DMSO-dg) 8 8.63 (t, J: 6 Hz, 1H), 8.09 (s, 1H), 8.02-7.95 (m, 2H), 7.83 (s, 1H), 7.75 (t, J: 8 Hz, 1H), 7.68—7.56 (m, 4H), 7.48 (d, J: 11 Hz, 1H), 7.44—7.32 (m, 2H), 6.89 (s, 1H), 6.51—6.39 (m, 4H), 4.59 (d, J: 6 Hz, 2H), 3.79-3.42 (m, 4H), .00 (m, 4H). LCMS: m/z 645.2 [M+H]+, tR= 1.51 min. sis of (E)-3—(6-amin0pyridinyl)-N-((5-(4-(4,4-diflu0ropiperidine-l-carb0nyl) fluorophenyl)(4-flu0r0phenyl)benzofuran—Z-yl)methyl)acrylamide (751).
F—QB(0H)2 Pd(PPh3)4. PCYa. K3P04.
BOCHN dioxane, H20. 140 °C (E)(6-aminopyridiny1)-N-((5-(4-(4,4-difluoropiperidine-1—carbonyl)-2— fluorophenyl)(4—fluorophenyl)benzofuranyl)methyl)acrylamide (751) was synthesized using the indicated reagents in a similar fashion as example (748). 1H NMR (400 MHZ, DMSO-dg) 6 8.63 (t, J: 6 Hz, 1H), 8.09 (s, 1H), 8.02—7.95 (m, 2H), 7.83 (s, 1H), 7.75 (t, J= 8 Hz, 1H), 7.68-7.56 (m, 4H), 7.48 (d, J: 11 Hz, 1H), 7.44-7.32 (m, 2H), 6.89 (s, 1H), 6.51- -3ll - 6.39 (m, 4H), 4.59 (d, J: 6 Hz, 2H), 3.79—3.42 (m, 4H), .00 (m, 4H). LCMS: m/z 645.2 [M+H]+, IR: 1.51 min.
Synthesis of (E)-N-((5-(5-(4,4-diflu0r0piperidine-l-carb0nyl)pyridinyl) (trifluoromethoxy)benzofuran—Z-yl)methyl)(pyridinyl)acrylamide (752).
F360 \ F300 wo "I \ OH __. N»~ o N 110""_ H —" N ...___. a N N N \ HN \ \ 2 / HATU, DIPEA, DMF 241 F 752 F (E)-N-((5-(5-(4,4-difluoropiperidinecarbonyl)pyridinyl) (trifluoromethoxy)benz0furan—2—yl)methyl)—3-(pyridin—3—yl)acrylamide (752) was synthesized using the indicated ts according to General Procedure 4. Yield: 27%. 1H NMR (400 MHz, DMSO—d6) 6 8.93 (t, J: 6 Hz, 1H), 8.81-8.74 (m, 2H), 8.60-8.54 (m, 1H), 8.45 (d, J= 2 Hz, 1H), 8.20-8.11 (m, 2H), 8.05—7.98 (m, 2H), 7.55 (d, J: 16 Hz, 1H), 7.49— 7.43 (m, 1H), 7.01 (s, 1H), 6.83 (d? J: 16 Hz, 1H), 4.65 (d, J: 6 Hz, 2H), 3.79—3.44 (m, 4H), 2.15—2.02 (m, 4H). LCMS: m/z 587.2 [M+H]+, IR: 1.82 min.
Synthesis of (E)-3—(6—amin0pyridin—3-yl)—N-((7~(2,4—diflu0r0phenyl)(4-(4,4- difluoropiperidine—l—carbonyl)—2—fluorophenyl)benzofuran-Z—yl)methyl)acrylamide (753).
F F BOCHNMO F N B(OH)2 o O O catalyst, K3PO4 (0.5 M), BocHN THF. 40 °c st = O O 446 753 Synthesis of terr—butyl (7-(2,4-difluorophenyl)—5—(4-(4,4-difluoropiperidine yl)~2—fluorophenyl)benzofuran—2—yl)methylcarbamate (445): tert—Butyl (7-chloro—5—(4- (4,4—difluoropiperidinecarbonyl)~2-fluorophenyl)benzofuran—2—yl)methylcarbamate (43 6; 150 mg. 0.29 mmol), 2,4-difluorophenylb0r0nic acid (68 mg, 0.43 mmol), catalyst (23 mg, —312— 0.03 mmol) and K3PO4 (1.2 mL, 0.6 mmol, 0.5 M) were added in THF (4 mL) and degassed.
The reaction mixture was heated at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0—30% EtOAc/petroleum ether) to give tert—butyl 4-difluorophenyl) (4-(4,4-difluoropiperidine—1-carbonyl)—2-fluorophenyl)benzomranyl)methylcarbamate (445) (160 mg, 92% yield). LCMS: m/z 601.2 ; {R = 1.82 min.
Synthesis of (4-(2-(aminomethyl)(2,4—difluorophenyl)benzofuran—5-y1) fluorophenyl)(4,4-difluoropiperidinyl)methanone (446): Iert-Butyl (7-(2,4- difluorophenyl)—5 - (4-(4,4-difluoropiperidinecarbonyl)fluorophenyl)benzofuran yl)methylcarbamate (445; 160 mg, 0.27 mmol) was dissolved in CH2C12 (5 mL). TFA (3 mL) was added at 0 °C (ice bath). The reaction mixture was stirred at room temperature for 1 h, and concentrated under reduced pressure to give 133 mg of (4—(2-(aminomethyl)(2,4— difluorophenyl)benzofuran~5~yl)-3 -fluorophenyl)(4,4-difluoropiperidin— 1 —yl)methanone (446), which was used without further purification in next step (100% yield). LCMS: m/z 501.1 [M+H]+; 1R = 1.27 min.
Synthesis of (E)-3—(6-aminopyridin-3—yl)—N-((7—(2,4-difluorophenyl)(4-(4,4— difluoropiperidine-1—carbonyl)—2-fluorophenyl)benzofuran—2-yl)methyl)acrylamide (753): (4— (2-(Aminomethyl)—7-(2,4-difluorophenyl)benzofuran—5-yl)—3-fluorophenyl)(4,4- difluoropiperidin-l-yl)methanone (446; 130 mg, 0.25 mmol) was dissolved in DMF (5 mL) and (E)-3—(pyridinyl)acrylic acid (46 mg, 0.28 mmol) was added at 0 °C. HATU (148 mg, 0.39 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (100 mg, 0.78 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and d further for 1 h. The crude mixture was d by Prep-HPLC without workup to yield 60 mg of (E)—3—(6-aminopyridinyl)-N—((7-(2,4-difluorophenyl)—5-(4-(4,4-difluoropiperidine- 1-carbonyl)fluorophenyl)benzofuranyl)methyl)acrylamide (753). Yield (36%). 1H NMR (400 MHZ, CD3OD) 6 8.06 (d, J= 2 Hz, 1H), 7.82 (s, 1H), 7.77-7.66 (m, 3H), 7.52 (s, 1H), 7.48 (d, J= 16 Hz, 1H), 7.42-7.36 (m, 2H), 7.18—7.09 (m, 2H), 6.86 (s, 1H), 6.61 (d, J= 9 Hz, 1H), 6.46 (d, J= 16 Hz, 1H), 4.67 (s, 2H), .58 (m, 4H), 2.20-1.99 (m, 4H).
LCMS: m/Z 647.2 , tR = 1.88 min.
Synthesis of (E)—3-(6-amin0pyridinyl)-N-((5-(4—(4,4-diflu0ropiperidine—l- carbonyl)phenyl)—7—(2,6-diflu0r0pyridinyl)benzofuran-Z-yl)methyl)acrylamide (754).
F F ° \ / / \ N_ \ o o O catalyst, K3PO4 (0.5 M), BocHN \ 435 ‘F THF.40°C -N o \ / F /[ \ 0 O 0 ~ HZN \ < > HATU DIPEA DMF HZNfl/HTN 443 754 (E)—3 -(6-amin0pyridin—3 -yl)-N-((5 ,4—difluoropiperidinecarbony1)phenyl)- 7-(2,6-difluor0pyridin—3-yl)benz0furan—Z-yl)methyl)acrylamide (754) was synthesized using the indicated reagents in a similar fashion as example (753). Yield: 28%. 1H NMR (400 MHz, 6) 5 8.62-8.51 (m, 2H), .00 (m, 2H), 7.87—7.80 (m, 2H), 7.74 (s, 1H), 7.62- 7.53 (m, 3H), 7.43—7.38 (m, 1H), 7.34 (d, J: 16 Hz, 1H), 6.88 (s, 1H), 6.50-6.36 (m, 4H), 4.55 (d, J: 5 Hz, 2H), 3.77-3.41 (m, 4H), 2.14-1.97 (m, 4H). LCMS: m/z 630.3 [M+H]+, tR = 1.81 min.
Synthesis of (E)(6-amin0pyridin—3—yl)-N—((5—(4—(4,4-difluoropiperidinecarb0nyl)—2- flu0r0pheny1)-7—(3-fluorophenyl)benzofuran-Z-yl)methyl)acrylamide (755). 6 GB" BocHN Pd((,PPh3)4 PCy3 K3PO4 dioxane H20 140 0C _.—_.H2N HATU. DIPEA. DMF 450 755 (E)—3-(6-aminopyridinyl)-N~((5-(4-(4,4-difluoropiperidinecarbonyl) fluorophenyl)(3-flu0r0phenyl)benzofuran-Z-yl)methyl)acrylamide (755) was synthesized using the indicated reagents in a simialr fashion as example (753). Yield: 34%. 1H NMR (400 MHz, DMSO-d6) 5 8.83 (t, J: 6 Hz, 1H), 8.24-8.03 (m, 4H), 7.86-7.38 (m, 9H), 7.29 (t, J: —314- 9 Hz, 1H), 6.96 (d, J= 9 Hz, 1H), 6.91 (s, 1H), 6.60 (d, J: 16 Hz, 1H), 4.64 (d, J: 6 Hz, 2H), 3.77-3.44 (m, 4H), 2.15-2.00 (m, 4H). LCMS: m/z 629.2 [M+H]+, tR= 1.47 min.
Synthesis of (E)(6-aminopyridin—3-yl)-N-((7-(3-chlor0phenyl)~5-(4-(4,4- diflu0r0piperidine-l-carb0nyl)-2—flu0r0phenyl)benzofuran-Z-yl)methyl)acrylamide (756).
C G 0' (0H)2 O\CIO 300 BocHN catalyst K3PO4 (0 5 M) BOCHN THF. 40°C 452 755 (E)(6-aminopyridinyl)—N—((7-(3-chlorophenyl)-5—(4—(4,4-difluoropiperidine- 1-carbonyl)fluorophenyl)benzofuran—2—y1)methyl)acrylamide (756) was synthesized using the indicated reagents in a similar fashion as example (753). Yield: 15%. 1H NMR (400 MHz, CD3OD) 5 .05 (m, 1H), 7.95-7.92 (m, 1H), 7.85 (d, J= 8 Hz, 1H), 7.82-7.78 (m, 1H), 7.77-7.69 (m, 2H), 7.66-7.62 (m, 1H), .47 (m, 2H), 7.45-7.37 (m, 3H), 6.87 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.49 (d, J: 16 Hz, 1H), 4.73 (s, 2H), 3.94-3.60 (m, 4H), 2.20-2.03 (m, 4H). LCMS: m/Z 645.2 [M+H]+, rR= 1.93 min.
Synthesis of (E)(6-aminopyridinyl)-N—((7-(3-chlor0flu0r0phenyl)(4-(4,4- difluoropiperidinecarb0nyl)fluor0phenyl)benzofuranyl)methyl)acrylamide (757). —315— G <3... o O O BocHN catalyst, K3PO4 (0 5 M) THF, 40 0c 454 757 (E)—3-(6—amin0pyridin—3—yl)—N—((7—(3—chloro—4—fluorophenyl)~5-(4-(4,4- difluoropiperidine-l -carb0nyl)-2—flu0r0phenyl)benzofuran—Z—yl)methyl)acrylamide (757) was synthesized using the indicated reagents in a similar fashion as example (753). Yield: 8%. 1H NMR (400 MHz, DMSO~d6) 6 8.61 (t, J: 5 Hz, 1H), .l4 (m, 1H), 8.10-8.05 (m, 1H), 8.03-7.96 (m, 1H), 7.84 (s, 1H), 7.77 (t, J: 8 Hz, 1H), 7.70 (s, 1H), 7.64-7.56 (m, 2H), 7.47 (d, J= 11 Hz, 1H), 7.40 (d, J: 8 Hz, 1H), 7.36 (d, J=16 Hz, 1H), 6.89 (s, 1H), 6.49-6.38 (m, 4H), 4.61 (d, J: 5 Hz, 2H), 3.79-3.43 (m, 4H), 2.15-1.99 (m, 4H). LCMS: m/z 663.2 [M+H]+, IR = 1.90 min.
Synthesis of (E)(6-amin0pyridinyl)—N—((5-(4-(4,4-diflu0ropiperidine—l- othioyl)—2-flu0rophenyl)—7-(4-fluorophenyl)benzofuran—2-yl)methyl)acrylamide (758).
Lawesson's reagent toluene. reflux HATU. DIPEA, DMF 456 758 (E)-3 —(6—amin0pyridin—3 —((5 —(4—(4,4—difluoropiperidine— l nothioyl) fluorophenyl)—7-(4~flu0r0phenyl)benzofuran—2—yl)methyl)acrylamide (758) was synthesized using the indicated reagents in a similar fashion as example (705). 1H NMR (400 MHz, DMSO-d6) 6 8.61 (t, J: 6 Hz, 1H), 8.09 (s, 1H), 8.04—7.96 (m, 2H), 7.80 (s, 1H), 7.69 (t, J: -316— 8 Hz, 1H), 7.66—7.58 (m, 2H), 7.42-7.27 (m, 5H), 6.88 (s, 1H), 6.52-6.38 (m, 4H), 4.60 (d, J: 6 Hz, 2H), 4.48-4.38 (m, 2H), .66 (m, 2H), 2.33-2.09 (m, 4H). LCMS: m/z 645.3 [M+H]+, rR = 1.99 min.
Synthesis of (E)(6-amin0pyridin-3—yl)—N-((7-(2,4-difluorophenyl)-5,5"-bibenzofuran- 2-yl) )acrylamide (759).
F‘QiNOH); -0 0 o —» BocHN K2C03 dppf) BocHN catalyst, K3PO4(0.5 M). dioxane H20 THF. 40 DC catalyst = Pd-NH2 XPhos H2N\(\ N / / OH HATU, DlPEA. DMF sis of tert-butyl (7-chloro-5,5'-bibenzofuranyl)methylcarbamate (457): tert— Butyl (7-chloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2-yl)benzofuran—2- yl)methylcarbamate (43; 1.2 g, 3 mmol), 5-bromobenzofuran (500 mg, 2.5 mmol), Pd(dppt)C12 (200 mg, 0.25 mmol), and K2C03 (1 g, 7.5 mmol) were added in a e of (10: 1) dioxane (20 mL) and water (2 mL) and degassed. The reaction mixture was heated at 90 0C under nitrogen atmosphere for 16 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% EtOAc/petroleum ether) to yield 720 mg of tert—butyl (7-chloro-5,5'—bibenzofuranyl)methylcarbamate (457) = 1.91 min. as colorless oil (yield 71%). LCMS: m/z 420.0 [M+Na]+, 1R Synthesis of tert-butyl (7-(2,4-diflu0rophenyl)—5,5'-bibenzofuran yl)methylcarbamate (458): tert—Butyl (7—chloro-5,5’—bibenzofuran—2-yl)methylcarbamate —317- (457 ; 500 mg, 1.3 mmol), 2,4-difluorophenylboronic acid (300 mg, 1.9 mmol), st (76 mg, 0.13 mmol) and K3PO4 (7.6 mL, 3.8 mmol, 0.5 M) were added in THF (20 mL) and degassed. The reaction e was heated at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0—10% EtOAc/petroleum ether) to give tert-butyl (7-(2,4- difluorophenyl)-5,5'-bibenzofuranyl)methylcarbamate (458) (470 mg, 56% yield). LCMS: m/z 498.0 [M+Na]+; m = 1.92 min.
Synthesis of (7-(2,4-diflu0r0phenyl)-5,5'-bibenzofuranyl)methanamine (459): utyl (7-(2,4-difluorophenyl)-5,5'-bibenzofurany1)methylcarbamate (458; 150 mg, 0.32 mmol) was dissolved in CHzClz (10 mL). TFA (2 mL) was added at 0 °C (ice bath).
The reaction mixture was stirred at room ature for 1 h, and concentrated under reduced pressure to give 118 mg of (7-(2,4-difluorophenyl)-5,5’-bibenzofuran-2— yl)methanamine (459), which was used without further purification in next step (100% yield). LCMS: m/z 359.0 [M-NH2]+', 13; = 1.45 min.
Synthesis of (E)—3-(6-aminopyridinyl)—N—((7-(2,4—difluor0phenyl)-5,5'- bibenzofuranyl)methyl)acrylamide (759): (7-(2,4-Difluorophenyl)-5,5'-bibenzofuran-2— yl)methanamine (459; 118 mg, 0.31 mmol) was dissolved in DMF (3 mL) and (E) (pyridinyl)acrylic acid (56 mg, 0.34 mmol) was added at 0 OC. HATU (130 mg, 0.34 mmol) was added to this reaction e at 0 °C followed by DIPEA (120 mg, 0.93 mmol) se. The reaction mixture was allowed to warm to room temperature and d further for l h. The crude mixture was purified by Prep-HPLC without workup to yield 45 mg of (E)-3—(6-aminopyridiny1)-N-((7-(2,4-difluorophenyl)—5,5'-bibenzofuran yl)methyl)acrylamide (759). Yield (27%). 1H NMR (400 MHz, DMSO'd6) 5 8.56 (t, J = 5 Hz, 1H), 8.07 (s, 1H), 8.04 (d, J: 2 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.83-7.77 (m, 1H), 7.70-7.57 (m, 4H), 7.49-7.41 (m, 1H), 7.34 (d, J: 16 Hz, 1H), 7.31-7.24 (m, 1H), 7.01 (d, J = 2 Hz, 1H), 6.85 (s, 1H), 6.49-6.36 (m, 4H), 4.54 (d, J: 5 Hz, 2H). LCMS: m/z 522.2 [M+H]+, IR: 1.99 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-(l-(4,4-difluoropiperidin-l- yl)ethyl)phenyl)-7—(4-flu0r0phenyl)benz0furanyl)methyl)acrylamide (760). -3l8— HCI HN O CHaMgBr soot2 C> Br Br H THF 0H Cl 460 461 432 . M I OH o FQB: \ ..at 00 Q 0..
’ N BocHN \ catalyst, K3P04 (0.5 M), BocHN KZCOEI PdWPPUC'z: THF, 40 0C dioxane, H20 FF catalyst = ' C HAT N / DIPE 466 F A, Synthesis of 1-(4-brom0phenyl)ethanol (461): 4—Bromobenzaldehyde (460; 3 g, 16.2 mmol) was ved in THF (100 mL). The mixture was cooled down to 0 OC (ice bath). Methylmagnesium bromide (8.1 mL, 24.3 mmol, 3 M in ether) was added dropwise over 30 min. The reaction mixture was stirred at 0 0C for 2 h, quenched with saturated NH4Cl aqueous solution (20 mL), extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , concentrated under reduced pressure and purified by silica gel chromatography (0—20% EtOAc/petroleum ether) to give 2.6 g of l- mophenyl)ethanol (461) as colorless oil (80% yield).
Synthesis of 1-br0m0(1-chlor0ethyl)benzene (462): l—(4— Bromophenyl)ethanol (461; 1.1 g, 5.5 mmol) was dissolved in CH2C12 (50 mL). The mixture was cooled down to 0 0C (ice bath). SOC12 (10 mL) was added dropwise over 10 min. The reaction was d to warm to room temperature, and then heated at 50 0C for 2 h. The reaction mixture was concentrated under d pressure to give a residue, which was dissolved in EtOAc (150 mL). The mixture was washed with saturated NaHCO3 aqueous solution (100 mL), brine, dried over anhydrous NaZSO4, trated to give 940 mg of 1- bromo(1-chloroethyl)benzene (462) as colorless oil (78% yield).
Synthesis of 1-(1—(4-br0mophenyl)ethyl)—4,4-difluoropiperidine (463): l— 4-(l-chloroethyl)benzene (462; 1.4 g, 6.2 mmol) was dissolved in acetonitrile (80 mL). 4,4-Difluoropiperidine hydrochloride (1.2 g, 7.4 mmol), K2CO3 (2.6 g, 18.6 mmol) and K1 (100 mg, 0.6 mmol) were added at 25 0C. The reaction mixture was heated at 80 0C for 6 —319- h. After cooling down to room temperature, the reaction mixture was diluted with water (60 mL), extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure and purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to give 1.5 g of 1-(1-(4- bromophenyl)ethyl)-4,4-difluoropiperidine (463) as colorless oil (79% . LCMS: m/z 304.0 [M+H]+,tR=1.29 min.
] Synthesis of tert-butyl (7-chlor0(4-(l-(4,4-diflu0r0piperidin yl)ethyl)phenyl)benzofuran-Z-yl)methylcarbamate (464): A mixture of 1—(1—(4— bromophenyl)ethy1)-4,4-difluoropiperidine (463; 740 mg, 2.4 mmol), tert—butyl (7—chloro (4,4,5,5-tetramethy1—l,3,2—dioxaborolan-Z—yl)benzofiaran—2—yl)methylcarbamate (43; 1.2 g, 2.9 mmol), Pd(dppi)C12 (195 mg, 0.2 mmol) and K2C03 (1 g, 7.2 mmol) in 20 mL ofdioxane and 2 mL ofH20 was heated at 100 0C under nitrogen atmosphere for 16 h. After cooling down to room temperature, the reaction e was filtered. The filtrate was trated under reduced pressure to give the crude product, which was d by silica gel chromatography (0-30% EtOAc/petroleum ether) to give 800 mg of tert—butyl (7-chloro(4— (1 -(4,4-difluoropiperidinyl)ethy1)phenyl)benzofuran—2—yl)methy1carbamate (464) as colorless oil (65% yield). LCMS: m/z 505.1 [M+H]+, tR = 1.53 min.
Synthesis of tert—butyl (5-(4-(1—(4,4-difluoropiperidin—1-y1)ethyl)pheny1)—7-(4- fluorophenyl)benzofuran—2-yl)methylcarbamate (465): tert—Butyl (7-chloro-5—(4-(1—(4,4- opiperidin—1—y1)ethyl)phenyl)benzofurany1)methy1carbamate (464; 320 mg, 0.63 mmol), 4-fluorophenylboronic acid (132 mg, 0.95 mmol), catalyst (35 mg, 0.06 mmol) and K3PO4 (3.8 mL, 1.9 mmol, 0.5 M) were added in THF (10 mL) and degassed. The reaction mixture was heated at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (0—30% petroleum ether) to give tert—butyl (5—(4-(1-(4,4-difluoropiperidinyl)ethyl)phenyl)- 7—(4-fluoropheny1)benzofurany1)methylcarbamate (465) (350 mg, 98% yield). LCMS: m/z 444.2 [M-120]+; rR = 2.37 min.
Synthesis of (5-(4-(1-(4,4-diflu0r0piperidinyl)ethyl)phenyl)(4- fluorophenyl)benzofuran-Z—yl)methanamine (466): utyl (5-(4—(1—(4,4- difluoropiperidin— 1 -y1)ethyl)phenyl)—7—(4-fluoropheny1)benzofi1ran—2-y1)methylcarbamate (465; 140 mg, 0.25 mmol) was dissolved in CHZClz (10 mL). TFA (2 mL) was added at 0 °C (ice bath). The reaction mixture was stirred at room temperature for 2 h, and concentrated -320— under reduced pressure to give 115 mg of (5-(4-(1-(4,4-difluoropiperidin—1- y1)ethyl)phenyl)—7—(4—fluoropheny1)benzofuranyl)methanamine (466), which was used without r purification in next step (100% yield). LCMS: m/z 344.1 [M—120]+; IR = 1.27 min.
Synthesis of (E)(6—amin0pyridin-3—yl)-N—((5-(4-(l-(4,4-diflu0r0piperidin—1 - yl)ethy1)phenyl)—7-(4-flu0rophenyl)benzofuranyl)methyl)acrylamide (760): (5—(4-(l -(4,4- Difluoropiperidin— l -y1)ethyl)pheny1)(4-fluorophenyl)benzofuran-Z-yl)methanamine (466; 115 mg, 0.25 mmol) was dissolved in DMF (3 mL) and (E)(pyridinyl)acry1ic acid (46 mg, 0.28 mmol) was added at 0 °C. HATU (110 mg, 0.28 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (97 mg, 0.75 mmol) se. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The crude mixture was purified by Prep—HPLC without workup to yield 12 mg of (6—amin0pyridin—3—yl)-N— ((5—(4—( l —(4,4-difluoropiperidin— 1 —yl)ethyl)phenyl)-7—(4—flu0r0phenyl)benzofuran yl)methyl)acrylamide (760). Yield (7%). 1H NMR (400 MHZ, CD3OD) 8 8.06 (s, 1H), 8.00- 7.93 (m, 2H), .63 (m, 5H), 7.53-7.41 (m, 3H), 7.25 (t, J: 8 Hz, 2H), 6.83 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.48 (d, J: 16 Hz, 1H), 4.70 (s, 2H), 3.64 (q, J: 6 Hz, 1H), 2.71—2.54 (m, 4H), 2.07-1.91 (m, 4H), 1.47 (d, J: 6 Hz, 3H). LCMS: m/z 611.3 [M+H]+, IR = 2.11 min.
Synthesis of (E)—3-(6—aminopyridin-3—yl)—N—((4—(5—(4,4—difluoropiperidine—1— carbonyl)pyridin—2-yl)—6-(trifluoromethyl)benzofuran—2—yl)methyl)acrylamide (76 l ).
CFa CF Q l SQCICl NBS, AIBN Cl N,~Ndiethylaniline Br OH Br r CCI4 K2C03 DMF 467 469a 46% NaN3 K2003 3L THF, H20 4701-1847013CF 471384711)CF31 0 CF3 0 BF BocHN BocHN EtaN Cchlz 472aB 472nm: Br CFs 473a 473b 0 CFa BocHN BocHN N/ 0 N— l BocHN \ Pd((dppf)Clg KOAC Pd(dppflClz choa' l dioxane 474% O N dioxane, H 02 473a 475 OH: O CFa o o \ — / 0 \ H2N H2N \ / 0H NH TFA N m ‘ __,._, _, _ CHzciz \ HATU, \ / DIPEA, DMF O N H2N 476 761 Synthesis of 1~bromo(2-chlor0allyloxy) ifluor0methyl)benzene (468): 3-Bromo(trifluoromethyl)phenol (467; 5 g, 20.7 mmol) was dissolved in 50 mL of DMF. 2,3-Dichloropropene (4.6 g, 41.4 mmol) and K2C03 (5.7 g, 41.4 mmol) were added. The reaction mixture was heated at 100 0C for 2 h. The reaction mixture was cooled down to room temperature, diluted with H20 (100 mL), extracted with EtOAc (100 mL X 3). The combined csolvents were washed with brine, dried over anhydrous N32804, concentrated and purified by silica gel tography (petroleum ether) to give 6.4 g of 1-bromo(2- chloroallyloxy)(trifluoromethyl)benzene (468) as colorless liquid. Yield (98%). 1H NMR (400 MHz,CDC13):8 7.42 (s, 1H), 7.28 (s, 1H), 7.12 (s, 1H), 5.58 (s, 1H), 5.52 (s, 1H), 4.63 (s, 2H).
Synthesis of 4-bromomethyl-6—(trifluoromethyl)benzofuran (469a) and 6- bromomethyl(trifluoromethyl)benzofuran (469b): 1-Bromo(2—chloroallyloxy) (trifluoromethyl)benzene (468; 6.4 g, 20.3 mmol) was dissolved in 20 mL ofMN— diethylaniline. The on mixture Was heated at 220 °C for 15 h. After cooling down to room temperature, 100 mL of EtOAc was added. The mixture was washed with 2 N HCl aqueous solution (100 mL X 3), brine (60 mL), dried over anhydrous , trated and purified by silica gel chromatography (petroleum ether) to afford a mixture of 4-bromo- 2-methyl(trifluoromethyl)benzofuran (469a) and 6-bromomethyl (trifluoromethyl)benzofuran (46%) as a white solid (2.8 g, 49% yield). LCMS: tR = 1.95 min.
Synthesis of 4-bromo(bromomethyl)(trifluoromethyl)benzofuran (470a) and 6-bromo(bromomethyl)(trifluoromethyl)benzofiiran (47Gb): A mixture of 4-bromo —6—(trifluoromethyl)benzofuran (469a) and 6-bromo—2—methyl (trifluoromethyl)benzofuran (46%) (1 g, 3.6 mmol) were dissolved in 40 mL of CCl4. NBS (770 mg, 4.3 mmol) and AIBN (118 mg, 0.7 mmol) were added. The on mixture was degassed and heated at 80 0C for 5 h. The reaction mixture was cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a mixture of 4-bromo(bromomethyl)(trifluoromethyl)benzofuran (470a) and 6-bromo—2- (bromomethyl)—4—(trifluoromethyl)benzofuran (470b), which was used without further ation in next step (1.2 g, 86% yield). LCMS: tR = 1.92 min.
Synthesis of 2—(azidomethyl)—4-bromo(trifluoromethyl)benzofuran (471a) and 2-(azidomethyl)bromo—4-(trifluoromethyl)benzofuran (471b): A mixture of 4—bromo (bromomethyl)-6—(trifluoromethyl)benzofuran (470a) and 6-bromo-2—(bromomethyl)~4- (trifluoromethyl)benzofuran (47Gb) (1.2 g, 3.3 mmol) were dissolved in 50 mL of DMF.
NaN3 (325 mg, 5 mmol) and K2CO3 (926 mg, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 5 h, diluted with H20 (100 mL), ted with EtOAc ( 50 mL X 3), washed with brine (100 mL), dried over Na2804, concentrated under reduced pressure to afford a mixture of 2-(azidomethyl)bromo(trifluoromethyl)benzofuran (471a) and 2-(azidomethyl)-6—bromo(trifluoromethyl)benzofuran (471b) as yellow solid, which was used without further purification in next step (950 mg, 88% yield). LCMS: IR = 1.89 min.
Synthesis of mo—6-(trifluoromethyl)benzofuranyl)methanamine (472a) and (6-bromo—4~(trifluoromethyl)benzofuran-Z—yl)methanamine (472b): 2—(Azidomethyl) bromo-6—(trifluoromethyl)benzofuran (471a) and 2-(azidomethyl)—6-bromo—4- (trifluoromethyl)benzofuran (471b) (950 mg, 2.9 mmol) were disolved in 30 mL of THF. —323— PPh3 (1 .l g, 4.4 mmol) was added. The mixture was stirred at room temperature for l h, and H20 (10 mL) was added. The reaction mixture was heated at 60 0C for 2 h. After cooling down to room ature, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc) to afford a mixture of (4—bromo-6— (trifluoromethyl)benzofuranyl)methanamine (472a) and (6-bromo-4— (trifluoromethyl)benzofuran-Z-y1)methanamine (472b) (800 mg, 91% yield). LCMS: m/z 277.0 [Ni-551+; tR = 1.91 min.
Synthesis of tert—butyl (4—bromo(trifluoromethyl)benzofuran hylcarbamate (473a) and tert-butyl (6-bromo(trifluoromethy1)benzofuran yl)methy1carbamate . (4-Bromo-6—(trifluoromethyl)benzofuran—2—yl)methanamine (472a) and (6—bromo- 4-(trifluoromethyl)benzofuran—2—yl)methanamine (472b) (800 mg, 2.7 mmol) were dissolved in dichloromethane (40 mL). Di—tert—butyl onate (1.2 g, 5.4 mmol) and triethylamine (819 mg, 8.1 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (20% ethyl acetate/petroleum ether) to give a mixture of tert—butyl (4—bromo(trifluoromethyl)benzofuran—2—yl)methylcarbamate (473a) and tert- butyl (6—bromo-4—(trifluoromethyl)benzofuran—Z—yl)methylcarbamate (473b) (900 mg, 84% yield). LCMS: m/z 338.0 [M+Na]+; 1R = 2.18 min. The two compouds were ted from each other by chiral HPLC ((R,R)—Whelk—Ol column) to give 290 mg of tert—butyl (4—bromo(trifluoromethyl)benzofuran—2—yl)methylcarbamate (473a) and 270 mg of tert- butyl (6-bromo-4—(trifluoromethyl)benzofuran—2—y1)methylcarbamate (473b).
Synthesis of tert—butyl (4—(4,4,5,5—tetramethyi—1,3,2-dioxaborolanyl)-6— (trifluoromethyl)benzofuran—Z~yl)methylcarbamate (474): tert—Butyl (4-bromo (trifluoromethyl)benzofuran-2—yl)methylcarbamate (473a; 200 mg, 0.5 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (190 mg, 0.7 mmol), Pd(dppi)C12 (37 mg, 0.05 mmol), and potassium acetate (98 mg, 1 mmol) were added in 20 mL of dioxane and degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 6 h.
After cooling down to room ature, the on mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was d by silica gel chromatography (15% EtOAc/petroleum ether) to yield 200 mg of tert—butyl (4-(4,4,5,5- —324— tetramethyl— 1 ,3 ,2—dioxaborolan—2—yl)—6—(trifluoromethyl)benzofuran-2—yl)methylcarbamate (474) as a yellow solid (85% yield). LCMS: m/z 464.1 [M+Na]+, IR = 1.94 min.
] Synthesis of utyl (4—(5-(4,4-difluoropiperidinecarbonyl)pyridin-2—yl)—6— (trifluoromethyl)benzofuranyl)methylcarbamate (475): A mixture of tert—butyl (4-(4,4,5,5— tetramethyl- 1 ,3 ,2-dioxaborolanyl)(trifluoromethyl)benzofiJranyl)methylcarbamate (474; 200 mg, 0.45 mmol), mopyridin—3—yl)(4,4-difluoropiperidin—1-y1)methanone (213 mg, 0.7 mmol), Pd(dppf)C12 (37 mg, 0.05 mmol) and K2CO3 (124 mg, 0.9 mmol) in 30 mL of dioxane and 5 mL of H20 was heated at 100 °C under nitrogen atmosphere for 4 h. The on mixture was concentrated under d pressure and purified by Prep—TLC (33% EtOAc/petroleum ether) to give 110 mg tert—butyl (4—(5—(4,4—difluoropiperidine-1— carbonyl)pyridin—2—yl)—6—(trifluoromethyl)benzofuran—2—yl)methylcarbamate (475) as a white solid. Yield (45%). 1H NMR (400 3OD) 5 8.84 (s, 1H), 8.06—8.01 (m, 3H), 7.87 (s, 1H), 7.28 (s, 1H), 4.46 (s, 2H), 3.92—3.61 (m, 4H), 2.11 (s, 4H), 1.20 (s, 9H). LCMS: m/z 5402[NHlflitR=201nnn Synthesis of (6-(2—(aminomethyl)-6—(trifluoromethyl)benzofuran—4—yl)pyridin yl)(4,4—difluoropiperidine-1—yl)methanone (476): tert—Butyl (4—(5—(4,4-difluoropiperidine— l — carbonyl)pyridinyl)—6—(trifluoromethyl)benzofuran—2—yl)methylcarbamate (475; 60 mg, 0.15 mmol) was dissolved in CH2C12 (10 mL). TFA (2 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and trated under reduced pressure to give 46 mg of (6—(2—(arninomethyl)—6-(trifluoromethyl)benzofuran-4—yl)pyridin—3—yl)(4,4— difluoropiperidine—l—yl)methanone (476), which was used without further purification in the next step. Yield (94 %). LCMS: m/z 440.1 ; IR = 1.83 min.
Synthesis of (E)(6-aminopyridinyl)-N—((4-(5-(4,4-difluoropiperidine—1— carbonyl)pyridinyl)—6-(trifluoromethyl)benzofiJranyl)methyl)acrylamide (76 1): (6-(2- (Aminomethyl)(trifluoromethyl)benzofuranyl)pyridin—3 -yl)(4,4—difluoropiperidine yl)methanone (476; 46 mg, 0.1 mmol) was dissolved in DMF (2 mL) and (E)(pyridin yl)acrylic acid (25 mg, 0.15 mmol) was added at 0 °C. HATU (57 mg, 0.15 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (38 mg, 0.3 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The crude mixture was purified by Prep-HPLC without workup to yield 6 mg of (E)—3~(6- aminopyridin—3—yl)-N—((4~(5—(4,4—difluoropiperidine—l-carbonyl)pyridin—2—yl)—6- (trifluoromethyl)benzofuran-2—yl)methyl)acrylamide (761). Yield (10 %). 1H NMR (400 —325- MHZ, DMSO—d6) 5 8.90-8.82 (m, 1H), 8.67 (t, J: 6 HZ, 1H), 8.21-8.03 (m, 5H), 7.66-7.58 (m, 1H), 7.43 (s, 1H), 7.35 (d, J: 16 HZ, 1H), 6.52-6.38 (m, 4H), 4.66 (d, J: 6 Hz, 2H), 3.82-3.48 (m, 4H), 2.18-2.00 (m, 4H). LCMS: m/z 586.2 [M+H]+, tR= 1.96 min.
Synthesis of (E)(6-aminopyridin-3—yl)—N—((6-(5-(4,4-diflu0ropiperidine-l- carbonyl)pyridinyl)(triflu0r0methy1)benzofuran-Z-yl)methyl)acrylamide (762).
N'\ U (I) F N \ N O\ /O / Br | 0 Br /B-B\ O 3‘0 F 0 / a}: 0 0 F \ \ _. \ BocHN —————* BocHN BocHN Pd(dppf)C12, K2C o3 CFB Pdd( 322m:Cl ,KOAc CF" CF3 dioxane, H20 473b 477 473 o _ N‘ \ N _ / N\ / F OH o / HZN \ / N \ N TFA N fl F I F _. \ .._._—_, NH O / CH2CI2 H2N o F HATU, DIPEA. DMF \ 479 762 (E)(6—amin0pyridiny1)-N-((6-(5—(4,4—diflu0ropiperidinecarb0ny1)pyridin- 2-y1)-4—(trifluoromethy1)benzofuranyl)methyl)acrylamide (762) was synthesized using the ted reagents in a similar fashion as example (761). 1H NMR (400 MHZ, DMSO-d6) 5 8.79 (s, 1H), 8.69-8.61 (m, 2H), 8.45 (s, 1H), 8.29 (d, J: 8 HZ, 1H), 8.09 (s, 1H), 8.03 (d, J: 8 Hz, 1H), 7.62 (d, J: 9 Hz, 1H), 7.37 (d, J=16 HZ, 1H), 6.93 (s, 1H), 6.50—6.38 (m, 4H), 4.66 (d, J: 6 Hz, 2H), 3.80-3.45 (m, 4H), 2.16-2.01 (m, 4H). LCMS: m/z 586.2 , tR = 1.94 min.
Synthesis of (E)(6-aminopyridinyl)-N-((5-(4-((4,4-difluorocyclohexyl)0xy)phenyl)— 7-(4-fluorophenyl)benzofuran—2-yl)methyl)acrylamide (763). —326- 0/» \ OQO 0 Br OH NaBH_—~4> o ) TFA M oe H / \ DEAD. PPh3 THF Br 0 DCM,H20 Br-QO 482 483 F FC ,OH B\ DAST X-Phos K PO DCM Br© i\/§b\3§3 fl©OF Pd(PPh 3 4 d(dppf)C|2 K2003 dioxane H20 BOCHN dioxaneB):igO TFA 0AM HATU DIPEA DMF BocHN \ HZNQ O 0 O O N \ wN \ Synthesis of oxaspir0[4.5]decanol (481): 1,4—Dioxaspiro[4.5]decan one (480; 10 g, 64 mmol) was dissolved in MeOH (200 mL). The mixture was cooled down to 0 0C (ice bath). NaBH4 (7.3 g, 192 mmol) was added in portions. The reaction mixture was allowed to warm to 25 0C and stirred for 2 h. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (200 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, concentrated under reduced pressure to give 9.2 g of oxaspiro[4.5]decan—8—ol (481) as colorless oil, which was used in next step without further purification (91% yield). LCMS: m/z 159.2 [M+H]+, tR = 1.18 min.
] Synthesis of 8-(4-bromophenoxy)-l,4-dioxaspir0[4.5]decane (482): 1,4- Dioxaspiro[4.5]decanol (481; 4 g, 25 mmol) was dissolved in THF (100 mL). 4- Bromophenol (5.3 g, 30 mmol), DEAD (6.1 g, 30 mmol) and PPh3 (7.9 g, 30 mmol) were added at 25 0.C and stirred for 2 h. The reaction mixture was quenched with saturated NaHC03 aqueous solution (100 mL), extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over ous NaZSO4, concentrated under reduced pressure and purified by silica gel chromatography (5-10% EtOAc/petroleum ether) ~327- to give 4.2 g of 8-(4-bromophenoxy)—1,4—dioxaspiro[4.5]decane (482) as white solid (54% yield). LCMS: m/z 315.0 [M+H]+, rR= 1.83 min.
Synthesis of 4—(4-bromophenoxy)cyclohexanone (483): 8-(4-Bromophenoxy)- 1,4-dioxaspiro[4.5]decane (482; 1.8 g, 5.8 mmol) was dissolved in DCM (10 mL). TFA (1 mL) and water (1 mL) were added. The reaction mixture was stirred at 25 0C for 3 h. The reaction mixture was concentrated under reduced re, diluted with DCM (100 mL), washed with saturated NaHCO3 s solution, brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give 1.4 g of 4-(4-bromophenoxy)cyclohexanone (483) as white solid, which was used in next step without further purification (90% yield).
LCMS: m/Z 269.0 [M+H]+, tR= 1.71 min.
] Synthesis of o(4,4-difluorocyclohexyloxy)benzene (484): 4-(4- Bromophenoxy)cyclohexanone (483; 1.6 g, 6 mmol) was dissloved in DCM (20 mL). The mixture was cooled down to 0 0C and DAST (1.9 g, 12 mmol) was added. The on mixture was allowed to warm to 25 0C and d for 1 h. The reaction mixture was diluted with DCM (100 mL), washed with saturated NaHCO3 aqueous solution, brine, dried over anhydrous , concentrated under reduced pressure and purified by silica gel chromatography (0-5% EtOAc/petroleurn ether) to give 1 g of 1-bromo(4,4- difluorocyclohexyloxy)benzene (484) as white solid (60% yield). LCMS: m/Z not found, tR = 1.87 min. ] tert-Butyl (7-chloro(4-(4,4-difluorocyclohexyloxy)phenyl)benzofuran—2— yl)methylcarbamate (485): (7-chloro—5-(4-(4,4-difluorocyclohexyloxy)pheny1)benzofuran— 2-yl)methylcarbamate (485) was synthesized using the indicated reagents according to General Procedure 2. Yield: 45%. LCMS: m/z 514.1 [M+Na]+, tR= 1.90 min. tert—Buty1(5—(4-(4,4-difluorocyclohexyloxy)phenyl)(4- fluorophenyl)benzofuranyl)methylcarbamate (486): tert-Butyl(5-(4-(4,4- difluorocyclohexyloxy)pheny1)(4-fluorophenyl)benzofuranyl)methylcarbamate (486) was synthesized using the indicated reagents in a similar fashion as Intermediate (445). Yield: 90%. LCMS: m/z 574.1 [M+Na]+, tR= 1.96 min. ] (5-(4-(4,4-Difluorocyclohexyloxy)phenyl)-7—(4—fluorophenyl)benzofuran yl)methanamine (487): (5-(4—(4,4-Difluorocyclohexyloxy)phenyl)—7-(4- fluorophenyl)benzofuran-2—yl)methanamine (487) was synthesized using the indicated —328— reagents ing to General Procedure 3. Yield: 100%. LCMS: m/z 474.1 [M+Na]+, Q; = 1.51 min.
(E)-3~(6—aminopyridin—3-y1)-N-((5-(4-((4,4-difluorocyclohexy1)oxy)pheny1)~7-(4— fuoropheny1)benzofurany1)methy1)acrylamide (763): (6-aminopyridin—3-y1)-N—((5— (4—((4,4—difluorocyclohexyl)oxy)pheny1)(4-fluoropheny1)benzofi1ran y1)methy1)acry1amide (763) was synthesized using the indicated ts according to General Procedure 4.Yie1d: 20%. 1H NMR (400 MHZ, DMSO-de) 5 8.58 (t, J = 5 Hz, 1H), 8.08 (s, 1H), 8.05-7.98 (m, 2H), 7.79 (s, 1H), 7.73-7.57 (m, 4H), 7.41-7.31 (m, 3H), 7.10 (d, J = 9 Hz, 2H), 6.83 (s, 1H), 6.51-6.35 (m, 4H), 4.72-4.62 (m, 1H), 4.58 (d, J: 5 Hz, 2H), 2.17- 1.79 (m, 8H). LCMS: m/z 598.2 [M+H]+, tR=2.09 min.
Synthesis of (E)-3~(6—aminopyridinyl)-N—((5-(5-(4,4-difluoropiperidine—l-carb0nyl)—3— fluoropyridin-Z-yl)(4-flu0r0phenyl)benzofuranyl)methyl)acrylamide (764). 0 Cl F o B: i o F F o O / \ HCI HNO< / \ BocHN \ o ° F Cl < ‘3 / \ — Nw N Cl ~—-~——> N N > BocHN \ N_ OH HOBt, EDCI, DIPEA, K2003, Pd(dppf)Cl2, dioxane. H20 /\ DCM 2 F 433 489 F 490 F catalyst, K3P04(015 M), THF, 40 0c catalyst = Synthesis of (6-chloro-S-fluor0pyridinyl)(4,4-difluoropiperidin hanone (489): 6-Chlorofluoronicotinic acid (488; 875 mg, 5 mmol) was dissolved in DCM (20 mL) and 4,4-difluoropiperidine hydrochloride (942 mg, 6 mmol) was added.
EDCI (1.2 g, 6 mmol), HOBt hydrate (810 mg, 6 mmol) and DIPEA (2 g, 15 mmol) were added. The reaction mixture was d at 25 °C for 16 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL X 3). The combined organic —329- layers were washed with brine, dried over anhydrous Na2S04, concentrated under d pressure and purified by silica gel chromatography (0—30% EtOAc/petroleum ether) to give 790 mg of (6—chloro—5—fluor0pyridin—3—yl)(4,4-difluoropiperidinyl)methanone (489) as colorless oil (57% yield). LCMS: m/z 279.0 [M+H]+, IR = 1.51 min. sis of tert-butyl oro—5—(5—(4,4-difluoropiperidine—1-carbonyl)-3— fluoropyridin—2—yl)benzofuran—2-yl)methylcarbamate (490): A mixture of (6-chloro fluoropyridin—3-yl)(4,4-difluoropiperidin-1—yl)methanone (489; 790 mg, 2.8 mmol), tert-butyl oro—5—(4,4,5,5-tetramethyl-l,3,2—dioxaborolan—2-yl)benzofuran—2-yl)methylcarbamate (43, 1.4 g, 3.4 mmol), f)Clg (245 mg, 0.3 mmol) and K2CO3 (1.2 g, 8.4 mmol) in 20 mL of dioxane and 2 mL of H20 was heated at 100 0C under nitrogen atmOSphere for 3 h.
After cooling down to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0—50% EtOAc/petroleum ether) to give 1.2 g of tert—butyl (7—chloro—5— (5 -(4,4—difluoropiperidine—1—carbony1)-3—fluoropyridin—2—yl)benzofuran—2— yl)methylcarbamate (490) as white solid (81% yield). LCMS: m/z 524.1 [M+H]+, IR = 1.74 min.
Synthesis of tert—butyl (5—(5~(4,4—difluoropiperidine—1—carbonyl)—3—fiuoropyridin- 2—yl)—7—(4-fiuorophenyl)benzofuran-2—yl)methylcarbamate (491): tert—Butyl (7—chloro—5—(5— (4,4—difiuoropiperidine— 1 —carbonyl)—3—fluoropyridin—2—yl)benzofuran-2—yl)methylcarbamate (490; 320 mg, 0.6 mmol), 4—fluorophenylboronic acid (125 mg, 0.9 mmol), catalyst (48 mg, 0.06 mmol) and K3PO4 (3.6 mL, 1.8 mmol, 0.5 M) were added in THF (10 mL) and degassed.
The reaction mixture was heated at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to give Iert—butyl (5-(5-(4,4- opiperidine—l —carbonyl)—3 —fluoropyridin-2—yl)—7—(4—fluorophenyl)benzofuran—2— yl)methylcarbamate (491) (330 mg, 94% yield). LCMS: m/z 584.2 [M+H]+; IR = 1.78 min.
Synthesis of (aminomethyl)—7-(4—fluorophenyl)benzofuranyl) fluoropyridinyl)(4,4-difluoropiperidin—1—yl)methanone (492): terl—Butyl (5-(5-(4,4— difluoropiperidine—1-carbonyl)—3 —fluoropyridin-2—yl)—7—(4-fluorophenyl)benzofuran—2— yl)methylcarbamate (491; 330 mg, 0.57 mmol) was dissolved in CHZClz (20 mL). TFA (3 mL) was added at 0 °C (ice bath). The reaction mixture was stirred at room temperature for 2 h, and trated under reduced pressure to give 270 mg of (6—(2—(aminomethyl)—7—(4— —330— fluorophenyl)benzofurany1)—5-fluoropyridinyl)(4,4-difluoropiperidin—1~yl)methanone (492), which was used t r purification in next step (100% yield). LCMS: m/z 484.1 [M+H]+; tR = 1.36 min.
Synthesis of (ID-3—(6-aminopyridin—3—yl)—N—((5—(5—(4,4-difluoropiperidine—1- carbonyl)—3 ~fluoropyridinyl)(4-fluorophenyl)benzofi1ran-2—yl)methyl)acrylamide (764): (6—(2-(Aminomethyl)(4-fluorophenyl)benzofuranyl)—5—fluoropyridinyl)(4,4- difluoropiperidinyl)methanone (492; 270 mg, 0.56 mmol) was dissolved in DMF (3 mL) and (E)—3-(pyridinyl)acrylic acid (102 mg, 0.62 mmol) was added at 0 °C. HATU (240 mg, 0.62 mmol) was added to this reaction mixture at 0 °C followed by DIPEA (220 mg, 1.7 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The crude mixture was purified by Prep—HPLC without workup to yield 70 mg of (E)—3—(6—aminopyridin—3—yl)-N—((5-(5-(4,4—difluoropiperidine—1—carbonyl)—3- yridin—2—yl)-7—(4~fluorophenyl)benzofuran—2—y1)methyl)acrylamide (764). Yield (20%). 1H NMR (400 MHz, DMSO~d6) 8 8.66 (s, 1H), 8.64—8.59 (m, 1H), 8.19 (s, 1H), 8.11— 7.93 (m, 5H), 7.62 (d, J= 7 Hz, 1H), 7.44-7.33 (m, 3H), 6.95 (s, 1H), 6.51—6.38 (m, 4H), 4.61 (d, J: 5 Hz, 2H), 3.82-3.47 (m, 4H), 2.17—2.04 (m, 4H). LCMS: m/z 630.5 [M+H]+, IR = 1.83 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-chloro-S-(S-(4,4-difluoropiperidine-l- carbonyl) pyridin-Z-yl)benzofuranyl)methyl)acrylamide (766). o 00 OOH OH O /U\ 0 0 j/ Cl fol oocj/ o 0' AIC13 NaOH CI _. _.
EtaN, DCM K2003 aceton EYOH Br Br 900 901 902 903 o o 0 / / 0 Br / N3 / H2N cx 0' KOAC Cl NB Cl NaN3. K2003 PPM ‘S—’ —’ , ACQO Al§C|4 DMF THF, H20 Br N Br Br 905 906 907 908 \/0 /O N O \B BocHN / _B8‘0 BOCHN Cl ,_,_OBI F \ (800)20 F/ Eth,DCM P139131;002 KOAc Pd N?o$l§f) K CO2 3 909 BT 0% BOCHN \ Cl Synthesis of 4-bromo—2-chlorophenyl acetate (901): 4-Bromochlorophenol (900; 15 g, 73 mmol) was dissolved in DCM (300 mL) and triethylamine (15 g, 145 mmol) was added. The mixture was cooled down to O 0C (ice bath) and acetyl de (8.5 g, 109 mmol) was added dropwise. The reaction mixture was stirred at 0 0C for 1 h, then quenched with 1 N HCl (100 mL). The reaction mixture was extracted with DCM (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concnetrated under reduced pressure to give 165 g of 4-bromo—2—chloropheny1 acetate (901), which was used in next step without further purification (92% yield). LCMS: IR = 1.79 min.
] Synthesis of 1-(5-bromochloro-Z-hydroxyphenyl)ethan0ne (902): A mixture of 4-bromochloropheny1 acetate (901; 14.5 g, 58 mmol) and AlC13 (12 g, 88 mmol) was heated at 160 0C for 1 h. After cooling down to room temperature, the reaction mixture was d with DCM (100 mL), poured into diluted HCl aqueous solution (1 N, 100 mL). The mxiture was extracted with DCM (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concnetrated under reduced pressure to give 5.1 g of 1—(5—bromo—3—chloro—2~hydroxyphenyl)ethanone (902), which was used in next step without further purification (35% yield): LCMS: m/z 250.9 [M+H]+, tR = 1.76 min.
Synthesis of ethyl 2-(2-acetylbr0m0ch10r0phen0xy)acetate (903): 1—(5— 3—chlorohydroxyphenyl)ethanone (902; 6 g, 24 mmol) was dissolved in acetone (150 mL) and K2C03 (3.3 g, 24 mmol) was added followed by ethyl 2-bromoacetate (4 g, 24 mmol). The reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced re and purified by silica gel chromatography (0-10% petroleum ether) to give 5.1 g of ethyl 2-(2-acetylbromochlorophenoxy)acetate (903) as White solid (63% yield). LCMS: m/z 337.0 [M+H]+, IR = 1.76 min.
Synthesis of 2-(2-acetylbromochlorophenoxy)acetic acid (904): Ethyl 2- (2-acety1bromo—6—chlorophenoxy)acetate (903; 6.2 g, 18.5 mmol) was dissolved in EtOH (150 mL) and a solution ofNaOH (1.5 g, 37 mmol) in H20 (50 mL) was added. The reaction mixture was stirred at 25 0C for 12 h. The reaction mixture was cooled down to 0 OC, lized with HCl (6 N) to pH = 5 ~ 6, extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous , trated under reduced pressure to give 5.2 g of 2—(2-acety1—4—bromochlorophenoxy)acetic acid (904), which was used in next step t further purification (90% yield). LCMS: m/z 308.9 , rR= 1.53 min.
Synthesis of 5-br0m0chl0r0methylbenzofuran (905): A mixture of 2—(2— acety1—4-bromochlorophenoxy)acetic acid (904; 5.1 g, 16.6 mmol) and KOAc (9.8 g, 100 mmol) in 50 mL of AczO was heated at 150 0C for 1 h. After cooling down to room temperature, the on mixture was poured into saturated NaHCO3 aqueous solution, extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Nags O4, concnetrated under reduced pressure and purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to give 760 mg of 5—bromochloro methylbenzofuran (905) (19% yield). LCMS: tR = 2.24 min.
Synthesis of 5-br0m0(bromomethyl)chlorobenzofuran (906): 5-Bromo— 7-chloromethy1benzofuran (905; 760 mg, 3.1 mmol) was dissolved in 30 mL of CCl4. NBS (830 mg, 4.6 mmol) and AIBN (50 mg, 0.3 mmol) were added. The reaction mixture was degassed and heated at 80 0C for 3 h. The mixture was cooled down to room temperature and filtered, the filtrate was concentrated to give 600 mg of crude 5-bromo—3—(bromomethyl)—7— chlorobenzofuran (906), which was used directly to next step (60% yield). LCMS: Q; = 1.88 min.
Synthesis of 3-(azidomethyl)br0m0-7—chlorobenzofuran (907): 5-Bromo methyl)chlorobenzofuran (906; 600 mg, 1.9 mmol) was dissolved in 10 mL of DMF. NaN3 (240 mg, 3.7 mmol) and K2C03 (510 mg, 3.7 mmol) were added. The reaction mixture was heated at 80 0C for 2 h, cooled down to room temperature, poured into iced water (50 mL), extracted with EtOAc (50 mL X 3). The ed organic phases were washed with brine (50 mL), dried over Na2S04, concentrated and d by silica gel chromatography (10% EtOAc/petroleum ether) to afford 450 mg of 3-(azidomethy1) bromochlorobenzofuran (907) (85% yield). LCMS: {R = 1.74 min.
Synthesis of (S-brom0chlorobenzofuranyl)methanamine (908): 3— (Azidomethyl)bromo—7-chlorobenzofuran (907, 450 mg, 1.6 mmol) was dissolved in THF (10 mL) and PPh3 (825 mg, 3.2 mmol), water (2 mL) was added. The reaction e was heated at 60 0C for 2 h. After cooling down to room temperature, the reaction mixture was poured into iced water, extracted with EtOAc (50 mL X 3). The combined organic phases were washed with brine (50 mL), dried over NaZSO4, concentrated and purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to afford 330 mg of (5-bromo-7— chlorobenzofuran-3—yl)methanamine (908) as pale yellow solid (84% yield). LCMS: m/z 262.0 ; rR = 1.83 min.
Synthesis of tert—butyl (5-br0m0-7—chlorobenzofuranyl)methylcarbamate (909): (5-Bromochlorobenzofiiran—3-yl)methanamine (908; 330 mg, 1.3 mmol) was dissolved in dichloromethane (10 mL). Di-tert—butyl dicarbonate (550 mg, 2.5 mmol) and triethylamine (260 mg, 2.5 mmol) were added at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was transferred into iced water and ted with dichloromethane (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure and purified by silica gel chromatography (0-10% ethyl acetate/petroleum ether) to give 460 mg of tert-butyl mochlorobenzofuranyl)methylcarbamate (909) (100% yield). LCMS: m/z 306.0 [M—55]+; tR = 2.19 min.
Synthesis of utyl (7-chloro—5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)benzofuranyl)methylcarbamate (910): tert—Butyl (5-bromochlorobenzofuran—3— yl)methylcarbamate (909; 200 mg, 0.55 mmol) was dissolved in dioxane (10 mL) and —334— degassed. Pd(dppt)C12 (44 mg, 0.06 mmol), KOAc (108 mg, 1.1 mmol) and 4,4,4’,4’,5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (211 mg, 0.83 mmol) were added at room temperature. The reaction mixture was heated at 100 0C for 5 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0-10% ethyl acetate/petroleum ether) to give 170 mg of tert-butyl (7-chloro—5—(4,4,5,5—tetramethyl-1,3,2-dioxaborolan yl)benzofuranyl)methylcarbamate (910) as white solid (76% yield). LCMS: m/z 352.0 [M-55]+; rR = 2.28 min.
Synthesis of tert-butyl (7-chlor0(5-(4,4-diflu0ropiperidine carb0nyl)pyridinyl)benzofuranyl)methylcarbamate (911): tert— Butyl (7—chloro (4,4,5,5-tetramethy1-1,3,2—dioxaborolanyl)benzofuranyl)methylcarbamate (910; 176 mg, 0.43 mmol), (6—bromopyridin—3-yl)(4,4—difluoropiperidin—l-yl)methanone (132 mg, 0.43 mmol), Pd(dppf)C12 (13 mg, 0.04 mmol), and K2CO3 (120 mg, 0.86 mmol) were added in a mixture of (10: 1) dioxane (10 mL) and water (1 mL) and degassed. The reaction mixture was heated at 100 0C under nitrogen atmosphere for 4 h. The reaction mixture was cooled down to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced re to give the crude product, which was purified by silica gel chromatography (0-10% petroleum ether) to yield 120 mg of tert-butyl (7—chloro—5-(5-(4,4- difluoropiperidine-l-carbony1)pyridin—2—yl)benzofurany1)methylcarbamate (911) as white solid (55% yield). LCMS: m/z 506.2 [M+H]+, tR=2.03 min.
Synthesis of (6—(3-(amin0methyl)chlorobenzofuranyl)pyridinyl)(4,4- difluoropiperidin—l—yl)methan0ne (912): tert— Butyl ("i-chloro(5—(4,4—difluoropiperidine- 1-carbonyl)pyridinyl)benzofuranyl)methylcarbamate (911; 120 mg, 0.24 mmol) was dissolved in CH2C12 (10 mL). TFA (2 mL) was added se at room temperature. The reaction mixture was stirred at room temperature for 1 h. The on mixture was concentrated under reduced re to give (6-(3-(aminomethy1)chlorobenzofuran-S- yl)pyridinyl)(4,4—difluoropiperidin—l -yl)methanone (912), which was used without r purification in the next step (90 mg, 93% . LCMS: m/z 406.1 , IR = 1.32 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-chlor0-5—(5-(4,4- difluoropiperidinecarbonyl)pyridinyl)benz0furanyl)methyl)acrylamide (766): (6-(3 omethyl)-7—chlorobenzofuran-5—yl)pyridiny1)(4,4—difluoropiperidin— 1 - yl)methanone (912; 90 mg, 0.22 mmol ) was dissolved in DMF (4 mL) and (E)(6- aminopyridinyl)acrylic acid (40 mg, 0.24 mmol) was added at 0 0C. HATU (99 mg, 0.26 mmol) was added to this reaction mixture at 0 0C followed by DIPEA (85 mg, 0.66 mmol) dropwise. The reaction mixture was d to warm to room ature and stirred further for 1 h. The reaction mixture was purified by Prep—HPLC to afford 27 mg of (E)(6- aminopyridinyl)-N—((7-chloro-5—(5—(4,4—difluoropiperidinecarbonyl)pyridin yl)benzofuranyl)methyl)acrylamide (766) (22% yield). 1H NMR (400 MHz, CD30D) 5 8.80-8.69 (m, 1H), 8.38-8.29 (m, 1H), 8.19-8.11 (m, 1H), 8.09-7.89 (m, 4H), 7.76-7.64 (m, 1H), 7.56-7.43 (m, 1H), 6.63-6.53 (m, 1H), 6.49-6.37 (m, 1H), 4.69 (s, 2H), .57 (m, 4H), 2.24-1.97 (m, 4H). LCMS: m/z 552.2 [M+H]+, tR= 1.75 min.
Synthesis of (E)(6-aminopyridinyl)—N—((7-(4-fluorophenyl)(4-(6-flu0r0pyridin yloxy)phenyl)benzofuran-Z-yl)methyl)acrylamide (767).
FU‘" F022 ,0 U" 1:2?"0U0 \ :2:°:~.—~::Br 0°13 K2003 DMF 914 915 CI F o.OB/QSVNHBOC QOH O N QB / \ o b. *‘ ° - O O o PdC|2(dppf) K2003 dioxane H20 BocHN 93‘3"" K3P04(°5M) THF BocHN \ CI ,P‘deN H2 XPhos O F Er\ WQH F F / \ N O \ T_FA- \ — t/ \ H2N /_ / \ // \ N/ O o HATU,DIPEA,DMF | H o o O _ __ \ N \ H2N \ / 920 767 Synthesis of o(4-nitrophenoxy)pyridine (915): 6—Fluoropyridin-3—ol (914; 2 g, 17.7 mmol) was dissolved in DMF (20 mL). 1-Fluoronitrobenzene (2.5 g, 17.7 mmol) and K2CO3 (4.9 g, 35.4 mmol) were added. The on mixture was heated at 80 0C for 2 h. After g down to room temperature, the reaction mixture was poured into iced water, extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under d pressure to give 4 g of 2- fluoro(4-nitrophenoxy)pyridine (915) (97% yield), which was used in next step without further purification. LCMS: m/z 235.1 [M+H]; tR—— 160 min.
Synthesis of 4-(6-flu0r0pyridinyloxy)aniline (916): 2-Fluoro—5-(4- nitrophenoxy)pyridine (915; 4 g, 17.1 mmol) was dissolved in MeOH (50 mL) and Pd/C (400 —336— mg, 10%) was added. The reaction mixture was stirred under H2 atmosphere for 12 h. The reaction e was filtered and the filtrate was concentrated under reduced pressure to give 3.4 g of 4—(6-fluoropyridin—3-yloxy)aniline (916) as white solid, which was used in next step t further purification (98% yield). LCMS: m/z 205.1 [M+H]+; tR = 1.33 min.
Synthesis of 5-(4-bromophenoxy)fluoropyridine (917): luoropyridin- 3-yloxy)aniline (916; 3.4 g, 16.7 mmol) was added to a solution of HBr in AcOH (50 mL, 33% w/w). The mixture was cooled down to 0 0C, and NaNOz (1.7 g, 25 mmol) was added.
After stirring at 0 0C for 0.5 h, CuBr (2.9 g, 20 mmol) was added. The reaction mixture was allowed to warm to room temperature and heated at 80 0C for 3 h. The reaction mixture was cooled down to room temperature, diluted with 50 mL of H20, extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure and purified by silica gel chromatography (0- % EtOAc/petroleum ether) to give 2.7 g of 5-(4-bromophenoxy)fluoropyridine (917) as yellow solid (60% yield). LCMS: m/z 268.0 [M+H]+; IR = 1.77 min.
Synthesis of tert—butyl (7-chlor0(4-(6-fluoropyridin yloxy)phenyl)benzofuran-Z-yl)methylcarbamate (918): A mixture of 5-(4- bromophenoxy)—2-fluoropyridine (917; 500 mg, 1.8 mmol), tert—butyl (7-chloro(4,4,5,5- tetramethyl-l,3,2-dioxaborolan—2-yl)benzofuran—2—yl)methylcarbamate (760 mg, 1.8 mmol), Pd(dppt)C12 (150 mg, 0.2 mmol) and K2C03 (520 mg, 3.7 mmol) in dioxane (10 mL) and water (1 mL) was degassed and heated at 90 0C for 5 h. After cooling down to room temperature, the reaction mixture was d. The filtrate was concentrated under d pressure and d by silica gel chromatography (0-20% EtOAc/petroleum ether) to give 500 mg of tert-butyl (7-chloro(4-(6-fluoropyridin-3—yloxy)phenyl)benzofuran hylcarbamate(918) as white solid (57% . LCMS: m/z 469.1 [M+H]+, tR = 2.22 min.
Synthesis of utyl (7-(4-fluor0phenyl)(4-(6-flu0r0pyridin yloxy)phenyl)benzofuran-Z-yl)methylcarbamate (919) tert—Butyl (7-chloro(4-(6- fluoropyridinyloxy)phenyl)benzofuranyl)methylcarbamate (918; 200 mg, 0.43 mmol), 4—fluorophenylboronic acid (90 mg, 0.64 mmol), catalyst (32 mg, 0.04 mmol) and K3PO4 (1.8 mL, 0.9 mmol, 0.5 M) were added in THF (10 mL) and degassed. The reaction e was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0-3 0% ~337- EtOAc/petroleum ether) to give tert—butyl (7-(4-fluorophenyl)-5~(4-(6-fluoropyridin yloxy)pheny1)benzofuranyl)methylcarbamate (919) (150 mg, 66% yield). LCMS: m/z 551.2 [M+Na]+; 7R = 1.93 min.
Synthesis of (7-(4-fluor0phenyl)—5—(4-(6-flu0r0pyridin yloxy)phenyl)benzofuranyl)methanamine (920): utyl (7-(4-fluorophenyl)—5-(4—(6- yridinyloxy)phenyl)benzofuranyl)methylcarbamate (919; 150 mg, 0.28 mmol) was dissolved in CH2C12 (10 mL). TFA (2 mL) was added at 0 °C (ice bath). The reaction mixture was stirred at room temperature for 1 h, and concentrated under d pressure to give 120 mg of (7-(4-fluorophenyl)(4-(6-fluoropyridinyloxy)phenyl)benzofuran yl)methanamine (920), which was used without further purification in next step (100% . LCMS: m/z 428.1 [M+H}+; IR = 1.20 min.
Synthesis of (E)—3—(6-amin0pyridinyl)—N—((7-(4-flu0r0phenyl)—5—(4—(6— fluoropyridinyloxy)phenyl)benzofuranyl)methyl)acrylamide (767): (7-(4- Fluorophenyl)-5~(4-(6—fluoropyridin—3—yloxy)phenyl)benzofuran-2—yl)methanamine (920; 120 mg, 0.28 mmol) was dissolved in DMF (4 mL) and (E)(pyridinyl)acrylic acid (51 reaction mg, 0.31 mmol) was added at 0 °C. HATU (128 mg, 0.34 mmol) was added to this mixture at 0 °C ed by DIPEA (109 mg, 0.84 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred further for 1 h. The crude e was purified by Prep-HPLC without workup to yield 40 mg of (E)-3~(6-aminopyridin—3-yl)-N— ((7-(4-fluorophenyl)—5-(4-(6-fluoropyridinyloxy)phenyl)benzofuran-2~ yl)methyl)acrylamide (767). Yield (25%). 1H NMR (400 MHz, CD30D) 5 8.06 (s, 1H), 8.01— 7.92 (m, 3H), 7.78-7.61 (m, 6H), 7.49 (d, J: 16 Hz, 1H), 7.24 (t, J: 9 Hz, 2H), 7.18-7.09 (m, 3H), 6.83 (s, 1H), 6.61 (d, J: 9 Hz, 1H), 6.47 (d, J: 16 Hz, 1H), 4.69 (s, 2H). LCMS: m/z 575.2 [M+H]+; m = 2.00 min.
Example 2. MTT Cell Proliferation Assay The MTT cell proliferation assay was used to study the cytotoxic ties of the compounds. The assay was performed according to the method described by Roche Molecular Bioohemicals, with minor modifications. The assay is based on the cleavage of the tetrazolium salt, MTT, in the presence of an on-coupling reagent. The water-insoluble formazan salt produced must be solubilized in an additional step. Cells grown in a 96—well tissue culture plate were incubated with the MTT solution for approximately 4 hours. After this incubation period, a water-insoluble formazan dye formed. After solubilization, the formazan dye was quantitated using a seaming multi-well spectrophotometer (ELISA reader). The absorbance revealed directly correlates to the cell number. The cells were seeded at 10,000 cells in each well of 96-well plate in 100 uL of fresh culture medium and were allowed to attach overnight. The stock solutions of the compounds were diluted in 100 uL cell culture medium to obtain eight concentrations of each test nd, ranging from 1 nM to 30 uM. After incubation for approximately 64—72 hours, 20 uL of CellTiter 96 Aqueous One Solution t (Promega, G358B) was added to each well and the plate was returned to the incubator (37 °C; 5% C02) until an absolute OD of 1.5 was reached for the control cells. All optical densities were measured at 490 nm using a Vmax Kinetic Microplate Reader (Molecular s). In most cases, the assay was performed in duplicate and the results were presented as a mean percent inhibition to the negative controlszE. The following formula was used to calculate the percent of tion: Inhibition (%) = (1- (ODo/OD)) X 100.
The compounds were tested against MS751, Z138 and 3T3 cells. The MS751 cell line is derived from a metastasis to lymph node of human cervix from a patient diagnosed with ous cell carcinoma of the . The 2138 cell line is a mature B-cell acute lymphoblastic leukemia cell line derived from a patient with chronic lumphocytic leukemia. 3T3 cells are standard fibroblast cells; they were originally isolated from Swiss mouse embryo tissue.
The results of the MTT assay are ed in Table 1.
Table 1. MTT Assay (ICso: A = <100 nM; B = 100 nM to <5uM; C = 5 uM to 10 uM; D = >10 uM) Compound Structure 2138 3T3 Compound Name (E)—N—((5—(5-acetylthiophen l yl)-7—chIorobenzofuran-Z- 500 \ o B D W" /S l y|)methy|)-3—(6-aminopyridin- CI 3—y|)acry|amide 0' (E)—3—(6-aminopyridin—3—y|)—N— / o O O ((7—chloro—5~(4—(morpholine—4— 501 I B D N HVK £3N \ carbonyl)p heny|)benzo[d]oxaz /, N oI—2—yl)methy|)acrylamide Compound Structure 2138 3T3 Compound Name (E)-3—(6—aminopyridin—B—y|)—N— ((7—chIoro—S—(4—(morpholine—4— carbonyl)phenyl)benzofuran— 2-y|)methy|)acry|amide (E)—N-((5—(5—acetylthiophen—Z— y|)benzofuran~2-y|)methyl) (6—aminopyridin y|)acrylamide (E)—3—(6-aminopyridin—3-yl)-N- ((7—chloro—5-(4— 504 olinosulfonyl)phenyl)b enzofuran-Z- y|)methyl)acrylamide (E)—3—(6—aminopyridin—3—yI)—N- ((7-chloro—5—(4—(2-(pyrazin—2— 505 y|)hydrazine—1— carbonyl)pheny|)benzofuran- 2-y|)methyl)acry|amide (E)—4—(2—((3—(6—aminopyridin—B— y|)acrylamido)methyI)—7— 506 D chlorobenzofuran—S— __.L__ zamide (E)—3—(6-aminopyridin—B—y|)—N— ((7—chloro—5—(4—(2— morpholinoacetyl)phenyl)benz ofuran—Z—yl)methy|)acrylamide (6—aminopyridin-3—yI)—N— loro—5—(4—(3,3— 508 difluoroazetidine—l— carbonyl)phenyl)benzofuran— 2-yl)methyl)acrylamide (E)—3—(6-am'l no pyridi n—3—yI)—N— ((7-chloro—5—(4—(3,3~ 509 difluoroazetidine—l— carbonyl)pheny|)benzo[d]oxaz oI—2—yl)methy|)acry|amide (E)-3—(6—aminopyridin—3—yI)—N— ((5—(4—(morpholine—4— 510 yl)pheny|)—7— (trifluoromethyl)benzofuran- 2-y|)methyl)acry|amide (E)-3—(6-aminopyridin—B-yl)-N- ((7-(tert—buty|)(4- 511 (morpholine carbonyl)phenyl)benzofuran— 2—y|)methy|)acry|amide (E)-3—(6—aminopyridin—B—yI)—N— (2-(7—chloro—5—(4—(morpholine— 512 4- carbonyl)pheny|)benzofuran— 2—yl)propan—2—y|)acrylamide —340— de MS- Compound Structure 2138 3T3 Compound Name No. 751 .
(E)—3—(6—aminopyridin~3~y|)—N~ ((7-chloro—5—(2—methyl—1— oxoisoindolin—5—yl)benzofuran— 2—y|)methy|)acrylamide (E)—3—(6—aminopyridin—3-y|)-N- |oro~5~(2—methy|—1,3— 514 dioxoisoindolin—S— yI)benzofuran—2- y|)methy|)acrylamide (S,E)-3—(6-aminopyr’ldin-B-yl)- N—((7-ch|oro(4-(3- 515 methylmorpholine carbonyl)phenyl)benzofuran- 2-yl)methy|)acry|amide (R, E)—3—(6—a mi nopyridin—3—yl)- N—((7—chloro—5—(4—(3— 516 methylmorpholine—4— carbonyl)phenyl)benzofuran— 2—yl)methy|)acry|amide (E)—3—(6—aminopyridin—3—y|)—N— ((5-(4—(3,3~ dimethylmorpholine—4- yl)phenyI)—7— (trifluoromethyl)benzofuran— 2—yl)methyl)acry|amide (E)—3—(6—aminopyridin—3—y|)—N— ((5—(4—(2—(pyridin—2— razine—1— carbonyl)phenyl)—7— (trifluoromethyl)benzofuran— ethyl)acry|amide (E)—3—(6—aminopyridin—3-y|)-N— ((5—(4-(2—(pyrazin—2— yl)hydrazine—1— carbonyl)pheny|)—7— (trifluoromethyl)benzofuran- 2—yl)methy|)acrylamide (E)(6—aminopyridin—3—yl)—N- ((5—(4—(3,3—dif|uoroazetidine—l— 520 carbonyl)phenyI)—7- (trifluoromethy|)benzofuran— 2-y|)methy|)acrylamide (E)—3-(6-aminopyridin-3—yI)—N- ((5-(5-(morpholine—4- 521 carbonyl)pyridin-2—yI)—7— (trifluoromethyl)benzofuran— ‘— 2—yl)methy|)acry|amide (R,E)-3—(6—aminopyridin—3—yl)— N—((5-(4—(3~fluoropyrrolidine— 1—carbony|)phenyl)—7— (trifluoromethyl)benzofuran— de MS- Compound Structure Z138 3T3 Compound Name No. 751 2—yl)methyl)acrylamide 3-(6—aminopyridin—3—y|)— N—((7—ch|oro—5—(4—(3— 523 fluoropyrrolidine-l- carbonyl)pheny|)benzofuran— 2-yl)methy|)acrylamide (E)-3—(6-aminopyridin—3-y|)—N— ((5—(4—(3—fluoroazetidine—l— 524 yl)phenyl)—7— (trifluoromethyl)benzofuran- 2—y|)methy|)acrylamide (S,E)-3—(6-aminopyridin-3—y|)— N-((5-(4-(3—f|uoropyrrolidine- 525 1—carbony|)phenyI)—7— (trifluoromethyl)benzofuran— 2—yl)methy|)acry|amide (E)—3—(6-aminopyridin—3—y|)—N— ((5—(4—(3,3~dimethylazetidine— 526 l—carbonyl)pheny|)—7— (trifluoromethy|)benzofuran— 2—y|)methy|)acrylamide (R,E)—3—(6—aminopyridin—3—yl)— N—((7-ch|oro—5~(4—((3— 527 pyrrolidin—l— yl)suIfonyl)phenyl)benzofuran— 2—y|)methy|)acrylamide (S, E)—3—(6-a mi nopyridin—3—yl )— N—((7—chloro—5—(4—(3— 528 fluoropyrrolidine—l— carbonyl)phenyl)benzofuran— 2—y|)methyl)acrylamide (6—aminopyridin—3—y|)—N— ((7—chloro—5—(4—(3,3— 529 dimethylazetidine—l— carbonyl)pheny|)benzofuran— 2-y|)methyl)acry|amide (E)—3—(6~aminopyridin—3—y|)—N- ((5—(4—(2,2— dimethylmorpholine—4— carbonyl)pheny|)-7— (trifluoromethyl)benzofuran- 2—y|)methy|)acrylamide (E)—3—(6-aminopyridin-B-yI)—N— ((5-(4- (morpholinosuIfony|)pheny|)— (trifluoromethy|)benzofuran— 2—y|)methyl)acrylamide —342— de MS- Compound Structure 2138 3T3 Compound Name No. 751 (E)—3—(6—aminopyridin—3—yI)—N— (2—(7—chloro—5-(4—(morpholine— 532 4- carbonyl)phenyl)benzofuran— L 2~yl)ethy|)acry|amide (E)—3—(6—am'lnopyridin—3—yl)—N— loro-5—(4—((3— 533 fluoroazetidin—l— yl)sulfony|)pheny|)benzofuran- 2—y|)methyl)acrylamide (E)(6-aminopyridinyI)-N- ((7-chloro(5-(morphoiine—4- 534 carbonyl)pyridin—3— yl)benzofuran—2— y|)methy|)acrylamide (E)—N—((7~ch|oro—5—(4- (morphol'lne-4— 535 carbonyl)pheny|)benzofuran— 2—yl)methy|)—3—(pyridin—4— yl)acry|amide (E)—N—((7-ch|oro-5—(4— (morpholine-4— ca rbonyl)pheny|)benzofuran— ethy|)—3—(6— uoromethyl)pyridin—3— yl)acry|amide (E)—N—((7—ch|oro—5—(4- (morpholine—4— 537 carbonyl)phenyl)benzofuran— 2—y|)methyl)(6— chloropyridin—3—y|)acrylamide (E)—N—((7—chloro—5-(4- (morpholine-4— 538 ca rbonyl)phenyl)benzofuran- ethyI)—3—(pyridin—3- yl)acry|amide (E)—N—((7—ch|oro—5—(4— (morpholine—4— 539 yl)pheny|)benzofuran— 2—yl)methyI)—3—(pyridin—2— yl)acry|amide (E)-N—((7-chloro(4- (morpholine—4- 540 carbony|)pheny|)benzofuran— Z—yl)methyl)—3—(pyridazin—3— yl)acry|amide (E)—N—((7—ch|oro(4— (morpholine—4— 541 ca rbonyl)pheny|)benzofuran— 2-y|)methyl)—3—(3,5— dimethylisoxazoI-4— —343- Compound Structure Compound Name y|)acry|amide (E)-N—((7—ch|oro—5—(4— (morpholine—4— 542 carbony|)phenyl)benzofuran- 2-yl)methy|)(thiazoI y|amide (E)—3—(6—aminopyridin—3—yI)—N— ((7-chIoro-S-(3-(morpholine carbony|)phenyl)benzofuran- ethyl)acry|amide (E)(6-aminopyridin-B—yI)-N— ((7—chloro—5—(5—fluoro—G— (morpholine-4— carbony|)pyridin—3- zofuran—2— yl)methy|)acrylamide (6—aminopyridin—3—yI)—N— ((7—chIoro—S—(4—(2-morpholino- 545 2- oxoacetyl)ph’enyl)benzofuran— 2-yl)methyl)acrylamide CI (E)—3—(6—aminopyridin—3-yl)—N- ((7—chIoro-S—(Z—(morpholine—4— 546 carbonyl)pyrimidin yl)benzofuran yl)methy|)acrylamide (E)—3—(6-aminopyridin—3—yI)—N- ((7—chloro(2,5—difluore—4— 547 (morpholine—4— carbony|)phenyl)benzofuran- 2—y|)methyl)acrylamide (6—aminopyridin—3—yl)—N— ((7—chloro—5—(2,3—difluore-4— 548 (morpholine—4— carbony|)phenyl)benzofuran— 2-y|)methy|)acry|amide (E)—3-(6-aminopyridin—3—yI)-N- ((7—chloro—5-(3-fluoro—4— 549 (morpholine-4— carbonyl)phenyl)benzofuran- 2—y|)methy|)acrylamide (E)(4—aminophenyI)-N—((7— chIoro-S-(4-(morpholine—4- carbonyl)pheny|)benzofuran— 2—y|)methyl)acry|amide (E)—N—((7-ch|oro—5—(4— (morpholine—4— 551 carbonyl)phenyl)benzofuran- 2—yl)methy|)—3—(6— (dimethylamino)pyridin—3— —344— de MS- nd ure ‘2138 3T3 Compound Name No. 751 y|)acry|amide CI (E)—3-(6—aminopyridin-B-yI)—N- ((7—chIoro-S-(6-(morpholine—4- 552 carbony|)pyridazin-3— y|)benzofuran—2- y|)methy|)acry|amide (E)(6-aminopyridin—3-yI)-N- ((7-chIoro-S-(4—(2-morpholino- 553 2- oxoethyl)pheny|)benzofuran- 2-yl)methy|)acrylamide (E)—3—(6—aminopyridin-3—y|)-N— ((7—methoxy(4— 554 (morpholinosuIfony|)pheny|)b enzofuran-Z— y|)methy|)acrylamide (E)—3-(6—am'lnopyridin-3—y|)—N- ((7-chloro—5-(4-((3,3— 555 dimethylazetidin—l— y|)su|fony|)phenyl)benzofuran— 2—y|)methy|)acrylamide (E)-4—(2—((3—(6—aminopyridin—B- y|)acry|amido)methy|)—7— chIorobenzofuran—S-y|)pheny| line-4—ca rboxyl ate (E)—3-(6—aminopyridin—3—yl)—N— ((7-(difluoromethyl)-5—(4— 557 oline carbonyl)pheny|)benzofuran— 2—y|)methy|)acry|amide (E)—3—(2—((3-(6-aminopyridin-B- y|)acry|amido)methyl)—7— 558 (trifluoromethy|)benzofuran- —yl)pheny| morpholine ca rboxylate (E)—3-(6-aminopyridin—3-y|)-N- ((7-(4-(morpholine—4— carbonyl)pheny|)benzofuran- 2-yl)methy|)acry|amide CI (E)—3—(6—aminopyridin—3—y|)—N— ((7-chIoro—S—(S—(morpholine-4— 560 carbony|)pyridin—2— y|)benzofuran—2— y|)methyl)acry|amide —345— de MS- Compound Structure 2138 3T3 Compound Name No. 751 F F F (E)—3—(6—aminopyridin-B-yI)—N— ((5-(4-(4—methylpiperazine—l— 561 carbonyl)phenyI)—7— uoromethyl)benzofuran— ethyl)acrylamide J (E)—3-(6—aminopyridin—B-yl)—N- ((7—chloro-5—(4—fluoro-3— 562 (morpholine—4- carbonyl)phenyl)benzofuran- 2-yl)methyl)acrylamide (E)—3-(6-aminopyridin—3-y|)—N— ((5—(4-fluoro(morpholine-4— 563 carbonyl)pheny|)—7— (trifluoromethyl)benzofuran~ 2-yl)methyl)acry|amide (E)—3—(6—aminopyridin—S—yI)—N— ((5—(4—(piperazine—1- 564 yl)phenyI)—7— (trifluoromethyl)benzofuran~ 2—yl)methyl)acrylamide (E)—3—(6—aminopyridin—3-yI)-N— ((5—(5—(4-methylpiperazine—l- 565 carbonyl)pyridin-Z—yI)—7— (trifluoromethyl)benzofuran- 2—yl)methyl )acryla mide (E)~3—(6—aminopyridin—B—yl)—N— ((5—(4—(4,4—dif|uoropiperidine— 566 l—carbony|)pheny|)~7— (trifluoromethyl)benzofuran— 2—yl)methy|)acrylamide (E)-3—(6-am'lnopyridin—3—y|)—N- ((5—(4—(4—fluoropiperid‘lne—l— 567 carbonyl)phenyl)—7— uoromethyl)benzofuran- 2—yl)methyl)acrylamide (E)>-3—(6-aminopyridin—3-yl)—N- ((7—(4—fluorophenyl)—5-(5- (morpholine—4— yl)pyridin yl)benzofuran—2- y|)methyl)acrylamide (E)-3—(6—aminopyridin—3—y|)—N— ((5—(5—(3,3— dimethylmorpholine—4— ca rbony|)pyridin—2—yI)-7— (trifluoromethyl)benzofuran— 2—yl)methyl)acry|amide Compound Structure 2138 3T3 Compound Name (S,E)—3—(6—aminopyridin—3—yl)— N—((5—(5—(3—fluoropyrrolidine— 570 HzN 7\ 1-carbonyl)pyridin—Z—yl)—7— (trifluoromethyl)benzofuran— 2—y|)methy|)acrylamide (E)—3—(6—aminopyridin—3—yl)—N~ ((5-(4—(4—hydroxy-4— ItoZ 571 7\ methylpiperidine-1~ \ carbonyl)phenyl) (trifluoromethy|)benzofuran— 2-yl)methy|)acrylamide (E)(6—aminopyridinyI)—N— ((5-(4-(3,3-dimethylpiperazine- 572 1—carbonyl)phenyl)—7— (trifluoromethyl)benzofuran— 2—yl)methy|)acrylamide (E)—N—((5—(4—(1,4—diazepane—1— yl)phenyl)—7— 573 /Z\ (trifluoromethyl)benzofuran— 2—yl)methyl)—3—(6— aminopyridin—3—yl)acry|amide (E)—N-((5-(4—(1,4—oxazepane—4— carbonyl)phenyI)—7— 574 \ (trifluoromethyl)benzofura n— \ 2—yl)methy|)—3—(6— aminopyridin—3—yl)acrylamide m (E)—3—(6—aminopyridin—3—yl)—N- ((5—(4—(2,2—dimethylpiperazine— 575 7\ O O 1—carbonyl)phenyl)—7— 21 (trifluoromethyl)benzofuran— ethyl)acrylamide (E)—3—(6—aminopyridin-3—yl)—N— INZ ((7—chloro—5—(4—(4— \ O f methylpiperazine-l— carbonyl)phenyl)benzofuran— 2—yl)methy|)acrylamide (E)-3—(6—aminopyridin—3—yl)—N— ((5—(5—(piperazine-1— ItoZ 577 7\ carbonyl)pyridin—2—y|)—7- (trifluoromethyl)benzofuran— 2-yl)methy|)acrylamide (6-aminopyridin-B-yl)—N- ((7-chloro(5-((3,5- ylisoxazol-4— droxy)methy|)thiophen— 2—yl)benzofuran—2— yl)methy|)acrylamide —347- de MS- Compound Structure 2138 3T3 Compound Name No. 751 (E)—3~(6-aminopyridin—3—yl)—N- ((5—(5—fluoro—6—(morphol'lne-4— 579 carbonyl)pyridin—Z—yI)—7¥ (trifluoromethy|)benzofuran— 2—yl)methy|)acry|amide (E)—3—(6-aminopyridiny|)-N- ((5—(5-fluoro—4—(morpholine—4- 580 carbonyl)pyridin-Z-yl)—7— (trifluoromethy|)benzofuran- 2-yl)methy|)acrylamide (E)(6—aminopyridiny|)-N- ((7-chloro(5—fluoro—6- (morpholine—4— carbony|)pyridin-2— Cl N 0 y|)benzofuran y|)methy|)acrylamide (E)-N-(4-(2-((3-(6- aminopyridin y|)acrylamido)methyI)—7- chlorobenzofuran—S- y|)phenyl)morpho|ine—4- carboxamide CI (E)—3—(6—aminopyridinyI)—N— ((7-ch|oro—5~(5—(morpho|ine—4— 583 yl)pyrimidin—2— zofuran—2— , y|)methy|)acrylamide (E)—3-(6-aminopyridin~3~yI)—N- ((7—chloro-5—(5—(4- piperazine—l— carbony|)pyridin—2— y|)benzofuran—2~ y|)methy|)acrylamide (6—aminopyrid'm—B—yl)—N— ((5—(5—(4,4—difluoropiperidine- 585 1—carbonyl)pyridin—2-y|) (trifluoromethy|)benzofuran- 2—y|)methy|)acrylamide (E)—3—(6-aminopyridin—3—y|)-N- ((7-chloro—5—(5—(4- methylpiperazine-l— carbony|)pyrimidin-2— y|)benzofuran—2— y|)methy|)acrylamide (E)(6—aminopyridin—3-y|)—N— ((5—(4—(3—fluoro—3— azetidine—l— carbony|)phenyI)—7— (trifluoromethyl)benzofuran— 2-y|)methy|)acrylamide ~348— de MS- Compound Structure 2138 3T3 Compound Name No. 751 (E)—3—(6—aminopyridin—3—y|)—N- ((7-chIoro—S—(S—fluoro—4— (morpholine—4— carbonyl)pyridin-Z- y|)benzofu ran—2— CI y|)methyl)acry|amide (E)—3—(6-aminopyridin—3—yI)—N— ((7—chIoro—S-(S-(piperazine-l— 589 carbonyl)pyridin-Z— y|)benzofuran y|)methyl)acry|amide (E)(6-aminopyridin-S-y|)—N- ((5-(5—(piperazine 590 carbonyl)pyrimidin—Z—yI)—7— (trifluoromethyl)benzofu ran— ethy|)acry|amide (E)—3‘(6—am'mopyridin—3—y|)—N— ((7-chloro—5—(5—(4,4— difluoropiperidine—l— carbonyl)pyridin—Z— y|)benzofuran—2— hyl)acrylamide (E)—3—(6—aminopyrid'm—B—yl)—N— ((7—methoxy—5—(4—(morpholine— 592 4- carbonyl)phenyl)benzofuran— 2—yl)methyl)acrylamide (E)—3—(6—aminopyridin-3—yI)-N— ((5—(5—(morpholine—4— 593 carbonyl)pyrimidin—Z—y|)—7— (trifluoromethyl)benzofuran— 2—yl)methyl)acrylamide (E)-3—(6—aminopyridin-3—yI)—N— ((5-(5-(4—methylpiperazine—l- 594 carbonyl)pyrimidin-Z-y|)—7— uoromethy|)benzofuran- 2—yl)methyl)acrylamide (E)—3-(6-aminopyridin—3-y|)-N— ((5-(4—(piperidine—1— 595 carbonyl)pheny|)—7— (trifluoromethy|)benzofuran- 2-y|)methy|)acrylamide (E)(6-aminopyridin-3—y|)-N- ((7-chloro(4—(4,4- 596 ropiperidine—l— carbonyl)phenyl)benzofuran— 2—yl)methyl)acry|amide (E)—3—(6—aminopyridiny|)—N- ((7-chloro—5—(4—(4- fluoropiperidine—l— carbonyl)phenyl)benzofuran— —349- de MS- Compound Structure 2138 3T3 Compound Name No. 751 2-yl)methy|)acrylamide Cl (E)—3—(6—aminopyridiny|)-N- HN ((7-chIoro—S—(4-(3—fluoro—3— 599 U. H 000 N azetidine—l— N \ N \ / fi carbonyl)phenyl)benzofuran- F 2—y|)methyl)acrylamide CI (E)—3—(6—aminopyridin—3-y|)-N- / loro(4—(piperidine-l— 600 m" O\O O C / ON carbonyl)pheny|)benzofuran- 0 2-yl)methy|)acry|amide Cl (E)-3—(6-aminopyridiny|)-N- ((7—chIoro(4-(piperazine—1- carbonyl)pheny|)benzofuran- 2-yl)methyl)acrylamide (E)-3—(6—aminopyridin—S—yI)—N— ((7—chIoro—S—(4—(4—hydroxy—4— 602 methylpiperid'lne—l— carbonyl)phenyl)benzofuran— 2—y|)methyl)acrylamide 7&3-(6—aminopyridin—3—yI)-N— ((5—(4—(3,3—difluoropyrrolidine— 603 l—carbonyl)phenyI)—7- uoromethyl)benzofuran— 2—yl)methyl)acrylamide (E)—3—(6—aminopyridin—3-y|)-N- ((5-(4—(4—fluoro—4— methylpiperidine—l— carbonyl)phenyI)—7— (trifluoromethyl)benzofuran- 2—y|)methyl)acrylamide (E)—3—(6—aminopyridin—S—yl)—N— rifluoromethyI)—5—(4—(4— 605 (trifluoromethyl)piperidine—l— carbonyl)phenyl)benzofuran— 2-yl)methyl)acrylamide (E)—3—(6—aminopyridin—3—yI)—N— ((5—(4—(3—hydroxy-3— (trifluoromethyl)pyrrolidine—1- carbony|)phenyI)-7— (trifluoromethyl)benzofuran- 2—y|)methy|)acry|amide (E)—3-(6-aminopyridinyl)—N— ((5—(4-(4—chIoropiperidine—l— 607 carbony|)pheny|) (trifluoromethyl)benzofuran— 2—yl)methy|)acrylamide Compound Structure 2138 nd Name FF (E)—3—(6-aminopyridin—3—yI)—N~ F ((5-(4-(3-fluoro O methylpyrrolidine—l— 608 "2'"W" 00 \ Ux’ carbony|)phenyl)-7— (trifluoromethy|)benzofuran- 0 F 2—yl)methy|)acrylamide (6-aminopyridinyI)—N— ((5-(4-(4—hydroxy (trifluoromethy|)piperidine carbony|)pheny|)—7- (trifluoromethy|)benzofuran- 2-yl)methy|)acry|amide (S,E)(6—aminopyridin—3—y|)— N—((5—(4-(3—chIoropyrrolidine— 610 ony|)pheny|)—7— (trifluoromethyl)benzofuran— 2—y|)methy|)acry|amide (E)—N—((5—(4—(2—oxa—6— azaspiro[3.3]heptane—6— carbony|)pheny|)—7— (trifluoromethyl)benzofuran— 2—yl)methyl)-3—(6~ aminopyridin—B—yl)acrylamide (E)-3—(6—aminopyridin—S—y|)—N— ((5-(5—(3,3—difluoropyrrol'ldine— 612 1-carbony|)pyridin—2—yI)—7— (trifluoromethy|)benzofuran- 2-yl)methy|)acry|amide (6—aminopyridin-B—yl)—N— ((5—(5—(3—hydroxy—3- (trifluoromethy|)pyrrolidine—l— carbonyl)pyridin—Z—y|)—7— (trifluoromethyl)benzofuran— 2—y|)methyl)acrylamide (E)—3-(6-am'lnopyridin—B—y|)—N— ((5—(5—(4-chIoropiperidine—l— 614 carbonyl)pyridin—Z—yI)—7— (trifluoromethy|)benzofuran— 2—y|)methy|)acrylamide (E)—3—(6—aminopyridinyl)-N- ((7—(trifluoromethyl)(5-(4— (trifluoromethyl)piperidine-l- 615 carbony|)pyridin-2— y|)benzofuran—2- y|)methyl)acry|amide (E)—3—(6—aminopyridin—3—y|)—N— —(4-hydroxy—4— (trifluoromethyl)piperidine-l— carbonyl)pyridin—2—y|)—7— (trifluoromethyl)benzofuran— 2—yl)methy|)acrylamide —351- de MS- Compound Structure Z138 3T3 Compound Name No. 751 (E)(6-aminopyridin—B-y|)—N- ((5—(5—(3—fluoro—3— methylpyrrolidine—l— carbonyl)pyridin-Z-y|)—7- . (trifluoromethyl)benzofuran- 2—yl)methyl)acry|amide (S,E)—3—(6—aminopyridin-B—y|)— N—((5—(5—(3—chIoropyrrolidine— 618 l-carbonyl)pyridin-Z-yl)—7- (trifluoromethyl)benzofuran- 2-yl)methyl)acrylamide (E)—6-(2-((3-(6-aminopyridin-B- yl)acry|amido)methy|) (trifluoromethy|)benzofuran— —y|)—N—(1— (trifluoromethy|)cyclopropy|)ni cotinamide (E)—3—(6-aminopyridin—B—yI)—N— —(4—hydroxy—4- methylpiperidine—l— carbonyl)pyridin—Z—yI)—7— (trifluoromethy|)benzofuran— 2—yl)methy|)acry|amide j (E)—3—(6—aminopyridin—B—yI)—N— ((5—(5—(3-hydroxy—3- IM methylazetidine—l— carbonyl)pyridin-Z—yI)—7— (trifluoromethyl)benzofuran~ 2—yl)methyl)acry|amide 3—(6—aminopyridin—E-yl)— N—((7-(trif|uoromethyI)—5—(5—(2— (trifluoromethyl)pyrrolidine—1— ca rbonyl ) pyridin—Z- yl)benzofuran y|)methy|)acrylamide (E)-N-((5-(5-(3- yclo[3.1.0]hexane-3— carbonyl)pyridin—2—yl)—7— (trifluoromethyl)benzofuran— 2-yl)methyl)~3—(6— aminopyridin-B-yl)acrylamide 3—(6-aminopyridin—B-yl)- N-((7—(trif|uoromethyl)-5—(5—(2- (trifluoromethyl)pyrrolidine-1— yl)pyridin yl)benzofuran—2— y|)methy|)acry|amide —352— de MS- Compound Structure 2138 3T3 Compound Name (E)—N—((5—(5-(2—oxa—6— azaspiro[3.3]heptane~6— carbonyl)pyridin—Z-yI)-7— (trifluoromethyl)benzofuran— 2—yl)methy|)—3-(6— aminopyridin—3—yl)acrylamide (E)—N-((5-(5-(6-oxa azabicyclo[3.1.1]heptane—3- carbonyl)pyridin-Z-yl)-7— (trifluoromethyl)benzofuran- 2-y|)methyl)(6- yridinyl)acry|amide (E)—3—(6—aminopyridin—3—yI)—N— ((5—(5—(3ghydroxy—3— pyrrolidine—l— carbonyl)pyridin—Z—yl)—7— (trifluoromethyl)benzofuran— 2—y|)methyl)acrylamide 3—(6—aminopyridin—3—yl)—N— ((5—(5—((3R,4R)—3—f| u0r0—4— methoxypyrrolidine—l- yl)pyridin—Z—yl)—7— (trifluoromethyl)benzofuran— 2—yl)methy|)acrylamide (E)—6—(2—((3—(6—aminopyridin—3— y|)acrylam'ldo)methyl)—7— uoromethyl)benzofuran— —yl)—N—(4,4— difluorocyclohexyl)nicotinamid (E)~6—(2—((3—(6—aminopyrid'ln—3— yl)acry|amido)methyl)—7— 630 (trifluoromethyl)benzofuran— —yl)—N—(pyridin—3— ylmethy|)nicotinamide (E)—3—(6—aminopyridin—3~yl)—N— ((5—(5—(6,6—dimethyl—3— azabicyclo[3.1.0]hexane—3— carbonyl)pyridin—Z—yl)—7— (trifluoromethyl)benzofuran— 2—y|)methy|)acrylamide (E)—N-((5-(5-(8-oxa—3— azabicyc|o[3.2.1]octane—3- carbonyl)pyridin-Z-y|)—7- (trifluoromethy|)benzofuran— 2—yl)methyl)—3—(6— aminopyridin—3—yl)acry|amide Compound ure 2138 3T3 Compound Name (E)—N-((5—(5—(2-oxa—5— azabicyc|o[2.211]heptane—S— carbonyl)pyridin—Z—yI)—7— (trifluoromethyl)benzofuran— 2—y|)methyl)—3—(6— aminopyridin—3—yl)acrylamide (E)—N—((5—(5-(1—oxa—6— azaspiro[3.3]heptane—6— carbonyl)pyridiny|) (trifluoromethyl)benzofuran— 2—yl)methy|)(6— aminopyridin—3—yl)acrylamide (E)—3-(6-aminopyridinyl)—N- ((7—methoxy—5—(4— 635 (morpholinosulfonyl)phenyl)b enzofuran—Z— yl)methyl)acry|amide (E)—3—(6—aminopyridin-3—yI)—N— loro—5—(4—fluoro—3— 636 (morpholinosuIfonyl)pheny|)b enzofuran—Z— yl)methy|)acry|amide (E)—3—(6—aminopyridin-3—yI)—N— ((7—methoxy—5—(4~(piperazine— 637 1- carbonyl)phenyl)benzofuran— 2—yl)methy|)acry|amide (E)—3—(6—am'mopyridin—3—yI)—N— thoxy—5—(5—(morpholine— 638 4—carbonyl)pyrimidin—2— yl)benzofuran—2— hyl)acrylamide (E)—3—(6—aminopyridin—3—yI)—N— ((7—methoxy—5-(5—(piperazine— 639 1—carbonyl)pyrimidin—2— yl)benzofuran—2— yl)methyl)acrylamide (6—aminopyridin—3—yI)—N— ((7—methoxy—5—(5-(morpholine— 640 4—carbonyl)pyridin—2— yl)benzofuran-2— y|)methyl)acry|amide (E)—3—(6-aminopyridin-3—y|)-N- ((7—methoxy(5—(piperazine- 641 l—carbonyl)pyridin—2— yl)benzofuran-2— yl)methyl)acrylamide (E)—3—(6—am'lnopyridin-3—yI)—N— ((7—chloro—5—(4—((3,3— difluoroazetidin—l— y|)su|fony|)pheny|)benzofuran— —354— CN:d nd Structure 2138 3T3 Compound Name ‘2-yl)methyl)acrylamide o (S,E)—3-(6-aminopyridin—B—yn— \ o O O SW0, uoropyrrOI In— HEN 3 yl)su|fonyl)pheny|)benzofuran- Cl 2-yl)methy|)acry|amide 0 (E)—3—(6-aminopyridin—3-yI)—N- N/ \ / 1 N O ((5-(4-((3,3-dif|uoroazetidin-l— [I F 644 \ 0 O O M fi'"<> ] Further results of the MTT assay are reported in Table 2.
Table 2. MTT Assay (ICso: A = <100 nM; B = 100 nM to <5uM; C = 5 uM to 30 MM; D = >30 uM; NT = Not tested) nd Number Cell Line 5 2 504 M24 NT B UZOS NT A MMlS NTfi B RPM18226 NT NT NHDF NT A MRC-S B A PC3 NT A DU-145 NT A MDA-MB-231 NT B B MDA-MB-468 NT B HL-60 NT NT Hep G2 B NT HEP 3B B NT DLD—l NTi HCT-IS NT A Colo-205 A Compounds 504, 510, 525 and 585 were further tested against selected solid and hematological cancer cell lines and selected normal cell lines in a 72-hour MTT cell proliferation assay. r results of the MTT assay for Compounds 504 and 510 are reported in Table 3. Further results of the MTT assay for Compound 525 are reported in Table 4. r results of the MTT assay for Compound 585 are reported in Table 5. -371— Table 3. MTT Assay of Compounds 504 and 510 2.138 MTT 0’01 U205 MTT 0.008 -mw- —-mm OLD-1M" 011s 0.22 127 may M TT 0.48 HT-29 M TT M smn 1 on M TT >10 Table 4. MTT Assay of Compound 525 Hm M n- Table 5. MTT Assay of nd 585 can fine Cmpd 585 (UM) Cell Elna Cmpd 585 (UM can una Cm pd 585 (UM) RWFEAMTT 0_OO4 MV~4~11MTT gl" HT1080 MTT 0.21 z-m MT? 009 MTT NCLHSzo-MTT- __ fl 009 RL MTT THP1MTT 002 ou»4475 MTT 0.09 HCC~1143 MTT 0,21 MO?eMTT 0‘02 CA PAN-1MTT HL-SD MTT 0.21 AML-1SS MTT 0.03 ms7s1mn 0 wu-aa MTT , _x 0.22 MOLT4 MTT mmo MTT 0‘11 MSTO-211H MTT 0’25 * w "T" Jurkat M TT Tera-1min 0,12 Hs578T MTT 025 T470 MTT 0.04 SHSYSY MTT 0‘12 U-937 MTT 0.26 Daudi MTT 0.04 HEL.92.1.7 MTT 0.12 LOVO M TT 026 U118MG MT? 005 MRC‘S MTT 0.13 HOT-15 M TT 0,27 OCIAMLS MTT 0.05 P63 MTT 0.14 DB MTT 0.29 Totedo MTT 0,05 Ail-555 MTT 0.14 NON-{2030 M TT 0.05 MCF~10A MTT 0,14 BL-40 MTT SUV-620 MTT - 0714 U-ZSG MTT 0.31 RPMISZZS MTT 0.15 Calu‘s MTT 0.33 KG~1 MTT 0,15 CalU-S MTY 0.35 TF-1MTT {.5480 MTT MCFJZA MTT 0.38 HUCCTv‘lMTT Rep 92 MTT SW—403 MTT 0.38 INCH-1187 MTT Colo-205 MTT HF’AC MTT 0.38 Farage MTT SW-48 M TT 0.17 Net—H1563 MTT 0.39 H EP 33 M‘FT 0‘07 BL-Z MTT 0.18 H5738,$t MTT 0,45 L3.6pIMTT MM1R MTT PA Til-89886 MTT 0.47 NCi-HSS MTT 0.08 N 98 MTT SW~480 MTT 0.48 P tieffer MTT 0‘08 NCI~H28 MTT PATU’SSOZ MTT 0.51 H S« Sultan MTT NChH'165O MTT MOA‘MB-ASS MTT 9.0. MM BT~20 MTT 0.54 Cell line Cmpd 585 (UM) sen line Cm pd 585 (UM) PA TU-SSBST MTT MCI-14508 MTT 1.46 HPAF-HMTT MTT 1.53 Colo-201MTT LN 18 MTT 1.66 A549 MTT HCC-ZO2MTT 1.69 NOI-H747 MTT PBMC MTT {\J N.
SW-B37 MTT CaOV3 MTT 2.22 MCF'I'MTT NCl-H82O MTT 2.84 HCC-4OOG MTT lMR—SOMTT HCC-S27 MTT HOG-2935 MTT 4.39 ARPEJSMTT HCC-1428MTT .3).
NCl-H358 MTT SNU-aes MTT 4'42 Panc-1MTT 00-145 MTT p (O FANG-10.05MTT NCl-H2122 MTT 5.81 MiaPaCazzMTT NHDF MTT 5.82 SW-948 MTT BT‘474 MTT 6.47 NCI-HSZSMTT NCl-HZZS MTT 6.78 DLD-‘lMTT LS-174TMTT CO CO SW-1116 MTT HOT116MTT 9.8 ANBL-G MTT NHEK MTT 10.36 PL’45 MTT M DA -M 8-415 M TT TFKv‘l MTT CA MA-‘lMTT K562 MTT MDA ~MB-23‘1 M TT SK-CO-‘l MTT MDA-MB-361MTT >10 NCl-H217O MTT MH0697H MTT >10 SW-1417 M TT SKOVG MTT >10 HTB-SB MTT >10 Table 5 shows that Compound 585 had an ICso of less than lnM in 72% (91/126) of the cancer cell lines tested. nd 585 had an ICso of less than 500 nM in 91% ) of the hematological cancer cell lines , and an ICso of less than 500 nM in 45% (42/93) of the solid cancer cell lines tested. Hematological cancer cell lines tested included , 2-138, THP-l, MO7E, AML-193, Jurkat, Daudi, Toledo, AML-S, TF-l, Farage, DOHH-2, Pfieffer, HH, MV11, MMIS, Raji, MINO, HEL.92.1.7, KG-l, RPMI 8226, BL- 2, MMIR, HS-Sultan, HL-60, RL, U—937, DB, BL-40, U-266, NCI-H929, ANBL-6 and K562. Solid cancer cell lines tested included NCI-H520, RKO, U118 MG, HeLa, HuCCT—l, CAPAN-l, U2OS, NCI-H889, NCI—H187, L3.6pl, HEP 3B, M8751, NCI—H69, DU—4475, AU—565, SHSY 5Y, Tera—1, SW-620, PC3, LS-180, HepG2, SW-48, NCI-H1299, Colo-205, 8, HCC-1143, HT1080, SHP-77, -468, MSTO—211H, LoVo, HGT-15, -374— 030, Calu—6, SW—403, HPAC, 563, PATU-8988S, A549, HPAF-II, 01, NCI-H747, SW-837, 06, NCI—H358, HCC-827, Panc-l, FANG-10.05, a—Z, SW-948, DLD—l, SW-1116, MDA—MB-23 1 , NCI-H508, BT—549, MCF7, LN—l 8, HCC-202, CaOVS, NCI—H820, HCC-2935, SNU-398, DU145, NCI-H2122, BT-474, NCI-H226, LS- 174T, NCT116, MDA—MB-175, MDA-MB-361, SW-900, NCI—Hl993, HCT116.1, C6, HTB- 38, MHCC97H and SKOV3.
Table 6 also shows that Compound 585 did not inhibit normal cells (n = 10).
Normal cell lines tested included NHDF, 3T3, NHEK, IMR-90, PBMC, ARPE-l9, HS 738st, WI-3 8, MRC-5 and .
Example 3. Target Identification Without being bound by a particular theory, it is believed that the compounds described herein can modulate (e. g. one or more p21 -activated kinases (PAK), for , inhibit) example, one or more of PAKs 1-6. More specifically, and without being bound by a particular theory, it is believed that the compounds described herein can bind to one or more PAKs and function as eric modulators of one or more PAKs. For example, the nds described herein may exert their modulatory effect(s) on one or more PAKs by binding to and destabilizing one or more PAKs or contributing to the degradation of one or more PAKs, thereby modulating (e.g., inhibiting) the effect of one or more PAKs on one or more proteins downstream of the one or more PAK3, for example, growth signaling proteins such as Akt, , p9ORSK, nin, cofilin, p21 and cyclin D1.
In a particular embodiment, one or more of the Group I PAK3 (e. g., PAKI, PAK2, PAK3) is modulated. For example, PAKI is modulated, PAK2 is modulated, PAK3 is modulated or a combination of PAKl , PAK2 and PAK3, such as PAKl and PAK2, PAKl and PAK3, PAK2 and PAK3, or PAKl, PAK2 and PAK3 is modulated. In a particular embodiment, one or more of the group II PAKs (e.g, PAK4, PAK5, PAK6) is modulated.
For example, PAK4 is modulated, PAKS is modulated, PAK6 is modulated or a combination of PAK4, PAKS and PAK6, such as PAK4 and PAKS, PAK4 and PAK6, PAK5 and PAK6 or PAK4, PAKS and PAK6 is modulated. Therefore, the compounds described herein can be useful for treating PAK—mediated disorders.
In r particular embodiment, one or more of the Group I PAKs (e. g. , PAKl, PAK2, PAK3) is inhibited. For example, PAKl is inhibited, PAK2 is inhibited, PAK3 is inhibited or a combination of PAKl, PAK2 and PAK3, such as PAKl and PAK2, PAKl and PAK3, PAK2 and PAK3, or PAKl, PAK2 and PAK3 is inhibited. In a particular embodiment, one or more of the group II PAKs (e.g. , PAK4, PAKS, PAK6) is inhibited. For example, PAK4 is inhibited, PAKS is inhibited, PAK6 is inhibited or a combination of PAK4, PAKS and PAK6, such as PAK4 and PAKS, PAK4 and PAK6, PAKS and PAK6 or PAK4, PAKS and PAK6 is inhibited. Therefore, the nds described herein can be useful for ng PAK-mediated disorders.
PAKs are a family of /threonine kinases that are involved in multiple intracellular signaling pathways. Six human PAKs have been identified to date (PAKs 1-6).
The PAKs can be classified into two subfamilies based on domain structure, sequence homology, and regulation: Group 1, which includes PAKs 1-3, and Group 2, which includes PAKs 4-6 (1).
] Group I PAKs are characterized by an inal region that includes a ved p21 binding domain (PBD) that overlaps with an autoinhibitory domain (AID), and a C- terminal kinase domain. Group I PAKs are known to be involved in regulating normal ar activities and can play a role in disease progression. For example, PAKl plays an important role in cytoskeleton dynamics, cell adhesion, migration, proliferation, apoptosis, mitosis and vesicle-mediated transport processes, and has been shown to be up-regulated in breast, ovary and thyroid cancer. PAKl activity has also been shown to be suppressed in brain lysates from Alzheimer’s disease patients. PAK2 plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis and proliferation. PAK3 plays a role in cytoskeleton regulation, cell migration, and cell cycle regulation.
Group II PAKs are characterized by an N—terminal PBD and a C-terminal kinase domain, but lack other motifs found in the group I PAKs. PAK4 is a pluripotent kinase known to mediate cell ty and logy, eration, embryonic development, cell survival, immune defense, and nic transformation (2), and is a key effector for Cdc42, a subset of the Rho GTPase family, which has been shown to be required for Ras driven tumorigenesis (3). PAKS is unique amongst the PAK family, as it is constitutively zed to the mitochondria, and its localization is independent of kinase activity and Cdc42 binding.
The mitochondrial localization of PAKS is required for it to exert its anti-apoptotic effects and to promote cell survival. One report suggests that PAKS is overexpressed in colorectal —376- cancer and promotes cancer cell invasion. Both PAK4 and PAKS have been linked to the regulation of neurite outgrowth; whereas PAK5 induces e outgrowth, PAK4 inhibits neurite outgrowth. The link of PAK4 and PAK5 to neuronal development suggests that PAK4 and PAK5 may be ed in the progression of ogical disorders, such as Parkinson’ s disease, dementia and brain atrophy. PAK6 has been found to specifically bind to en receptor (AR) and estrogen receptor 0t , and co-translocates into the nucleus with AR in response to androgen. PAK6 sion in adult tissue is mainly restricted to the prostrate and testis. However, PAK6 has been found to be overexpressed in many cancer cell lines, particularly breast and prostate cancers.
Since the PAKs and, in ular, PAK4, are critical hubs of signaling cascades, inhibiting their function can be beneficial for the treatment of cancers, neurodegenerative diseases, and immune system diseases as described herein.
Target Identification using SILAC (Stable Isotope Labeling ofAmino acids in Cells) M8751 cellular proteins are labeled with non—radioactive heavy lysine (L-Lysine- 2HCl, 13C6, 15N2) and arginine (L-Arginine-HCI, 13C6, 15N4) for 7 to 8 ngs. The heaw es are incorporated efficiently with greater than 95% heavy proteins identified by LC- MS. Separate plates of cells are maintained in light amino acids. is a schematic representation of a SILAC experiment, and shows the experimental design.
After successful e labeling, heavy and light plates of MS75 1 cells are collected and lysed in ModRIPA buffer (50 mM Tris-HCl, pH 7.8, 150 mM NaCl, 1% NP-40, 0.1% sodium deoxycholate, 1 mM EDTA), and the protein quantified using Pierce 660 reagent. Two milligrams of light total protein are mixed with a 50-fold excess of soluble competitor (for example, a nd of the invention or a PEGylated compound of the invention) while two milligrams of heavy protein lysate are mixed with an equal amount of e (DMSO). In the second replicate, the heavy and light proteins are flipped. The mixture is ted at 4 °C for 1 h with constant rotation. 30 uL of slurry (for example, 15 nL of 12.5% PEGylated compound of the invention immobilized on resin in 15 uL of PBS) is added to separate tubes with the protein mixtures ofDMSO or soluble competitor, and incubated for 16 to 24 h with constant rotation.
The following day, the beads are collected by quick centrifugation and the supernatant removed. The resin is washed separately twice in ModRIPA buffer with spins after washes. The light (PEGylated compound of the invention) and heavy (DMSO) resins —377- are mixed together then washed twice with ModRIPA, with spins after washes, and prepared for SDS-PAGE.
The lysates are run on a gradient SDS-PAGE gel and stained with Coomassie blue. Six bands from each replicate are cut from the gel, digested with trypsin, desalted, and prepared for LC-MS proteomics.
Samples are run on a Q-Exactive, and the heavy and light peptides are identified using MaxQuan and R Moderated T Test for statistical analysis. The statistical is shows the ment of PAK4 in DMSO samples compared to the soluble competitor samples.
Pull~D0wn ofProteins Using Immobilized Inhibitor ] MS751, U2OS, or HeLa cells are collected and lysed in ModRIPA buffer, and the protein content quantified using Pierce 660 reagent. Two milligrams of total protein is mixed with a 50—fold excess of soluble competitor (for example, a compound of the invention or a PEGylated compound of the invention) or an equal amount ofDMSO in three separate tubes.
The mixture is incubated at 4 °C for 1 h with constant rotation. 30 uL of slurry (for example, uL of 12.5% PEGylated compound of the invention immobilized on resin in 15 uL of PBS) is added to separate tubes with the protein mixtures ofDMSO or soluble competitor and incubated for 16 to 24 h with constant rotation.
The following day, the beads are collected by quick centrifugation and the supernatant d. The resin is washed separately three times in ModRIPA buffer with spins after each wash. Each sample along with input lysate is prepared for GE.
Samples are boiled, run on a 4-20% SDS-PAGE gel and transferred to nitrocellulose membranes for Western blotting. AK4 primary antibody is incubated on the membrane overnight and ed with fluorescent ary antibody. The Western blot shows that PAK4 binds to the resin pre-treated with DMSO but not the resin corresponding to samples pre-treated with soluble itor.
Example 4. Compound 585 induces autophagy.
] UZOS cells were plated in a 6-well plate overnight. The next day, the cells were treated with 1 uM or 10 uM nd 585 for 48 hours, then colleected and lysed in RIPA buffer. The lysate was run on SDS-PAGE and Western blots of PAK4, PUMA, CHOP, p21, cyclin D, MLHl, , AMPK and LC3 were performed. —378- is images of Western blots, and shows the effect of 48-hour treatment with increasing trations of Compound 585 on the levels of markers of autophagy, such as pAMPK, AMPK and LC3, in U208 cells. Treatment for 48 hours with Compound 585 induced markers of stress response and autophagy, as evidenced by increased AMPK phosphorylation and the presence of the short form of LC3 me marker. ent with Compound 585 also reduced cell cycle proteins, p21 and cyclin D1.
Example 5. PAK4 signalling is unchanges in normal cell lines.
Normal human dermal fibroblasts (NHDF) and normal lung cells (IMR—90) were treated with nd 585 for 72 hours, at which time the cells were lysed in RIPA buffer.
The lysates were run on SDS-PAGE and Western blots of phospho-PAK4, PAK4, phospho- cofilin, cofilin, phospho-B-catenin, nin, PARP and caspase-3 were performed. is images of Western blots, and shows that 72-hour treatment with increasing concentrations of Compound 585 had little to no effect on PAK4 signalling in two normal cell lines, NHDF and , as indicated by the levels of phospho—PAK4, PAK4, o-cofilin, cofilin, phospho—B-catenin, B-catenin, PARP and caspase 3.
Example 6. Compound 585 reduces fl-catenin and cofilin signals and ses stress fibers.
U208 cells were grown on coverslips and treated with DMSO or 1 uM Compound 585 for 48 hours, at which time the cells were fixed and stained. The cells were labeled with phospho- or total B-catenin antibodies; phospho- or total cofilin antibodies; or FLUOR® 488 phalloidin. Both phospho- and total B-catenin were reduced by treatment with Compound 585. Both phospho- and total cofilin were reduced by treatment with Compound 585. ALEXA-FLUOR® 488 phalloidin was used to stain F-actin.
Compound 585 caused an se in stress fiber formation.
Example 7. Compound 585 causes cell cycle changes.
U208 cells were treated with DMSO or 1 uM Compound 585 for one, two or three days. At each time point, cells were treated with 10 11M BrdU for 2 hours, and then collected by trypsinization. Cells were subsequently washed, fixed and stained for BrdU and total DNA (7-AAD). BrdU incorporation and cell cycle is was performed using flow -379— cytometry on a BD Fortessa Analyzer. Data was then analyzed using FCS Express 4 software. ] is a cal representation of cell cycle changes observed upon treatment of U208 cells with 1 uM Compound 585 for one, two or three days. Treatment with Compound 585 caused loss of S phase and se in G2 phase at 48-72 hours. Sub-G1 phase d to appear around 48-72 hours.
Example 8. MDA-MB-468 xenogmft in SCID mice. 0] The oncological impact of Compound 504 and Compound 510 were tested using a MDA-MB-468 (triple negative breast ) xenograft model in CB-l7 SCID mice.
MDA-MB-468 (ATCC # HTB—102) breast adenocarcinoma cells were obtained from ATCC.
The cells were grown in high e DMEM supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and 2 mM L—glutamine. Cells were sub-cultured by dilution at a ratio of 1:4. MDA-MB-468 cells were harvested by trypsinization and counted using a hemocytometer. Cells were resuspended in PBS at a 4 X 108 cells per mL. Cells were placed on ice and mixed with an equal volume of Matrigel (BD Biosciences CB-40234). Thirty-two (32) CB-l7 SCID mice were inoculated sub-cutaneously in the left flank with 4 X 107 MDA— MB-468 cells. Treatment was initiated when the tumors reached a mean volume of about 100 mm3. Mice were allocated to four (4) groups of eight (8) mice such that mean tumor volume was about 100 mm3 in each group. Mice were treated with vehicle, standard of care/positive control drug (paclitaxel), Compound 504 or Compound 510. Compound 504 (15 mg/kg) and Compound 510 (15 mg/kg) were given orally (PO) once daily on Monday through Friday each week. Animals’ weights and condition were recorded daily, and tumors were measured on Mondays, Wednesdays, and Fridays. is a graph of mean tumor volume as a function of time, and shows the effect of Compounds 504 and 510 on the volume of MDA-MB—468 xenografts in CB-17 SCID mice. The model demonstrated tumor growth inhibition without major toxicity (minimal or no side effects or weight loss up to 200 mg/kg daily dose).
Mice bearing MDA—MB—468 tumors were treated for three weeks with 30 mg/kg Compound 525 orally every day. Tumors were resected from the mice and fixed in buffered formalin and put into paraffin . The blocks were sectioned and d with antibodies ~380- against Ki67, Apotag, c-Myc, p—S473-Akt1 or p-S450-Aktl. The cells were imaged with a Nikon cope.
There was a reduction in proliferation (Ki67) and an increase in apoptosis (Apotag) upon treatment with Compound 525. There were also overall reductions in c-Myc and PAK4 pathway signaling h Akt (phospho-Aktl).
Example 9. Z-138 xenograft in SCID mice.
The impact of Compound 585 on tumor growth was tested using a Z-l38 mantle cell lymphoma cancer xenograft model in SCID mice. 2-138 (ATCC # CRL-3 001) mantle cell lymphoma cells were obtained from ATCC. These cells were grown in IMEM medium supplemented with 10% horse serum, 1% llin and streptomycin, and 2 mM L- glutamine. Cells were sub-cultured by dilution at a ratio of 1:5 to 1:10. Z-l38 cells were ted by fugation and counted using a hemocytometer. Cells were resuspended in PBS at a 2 X 108 cells per mL. Cells were placed on ice and mixed with an equal volume of Matrigel (BD Biosciences CB-40234). This mixture was kept on ice and injected into the left flank of mice in a volume of 0.2 mL, equivalent to 2 X 107 cells per mouse. Forty (40) CB-l7 SCID mice were inoculated subcutaneously in the left flank with 2 X 107 Z-l38 cells. ent was initiated when the tumors reached a mean volume of 125.2 mm3 . Mice were allocated to five (5) groups of eight (8) mice such that mean tumor volume in each group was within the range of 106.5 to 138.8 mm3. Mice were treated with vehicle, standard of care/positive control drug (cyclophosphamide), or Compound 585. Compound 585 (10, 30, or 60 mg/kg) was given orally (PO) daily beginning on Day 1. Animal weights and conditions were recorded daily, and tumors were measured on Mondays, Wednesdays and Fridays. is a graph of mean tumor volume as a function of time, and shows the effect of varying concentrations of Compound 585 on the volume of Z-138 xenografts in SCID mice. The model demonstrated tumor growth inhibition and even tumor regression without major toxicity al or no side effects or weight loss up to 200 mg/kg daily dose).
Example 10. Hep3B xenograft in SCID mice.
The s of Compound 585 were evaluated on tumor growth using a Hep3B hepatocellular carcinoma xenograft model in SCID mice. Hep 3B (ATCC# HTB- 8064) —38l— hepatocellular carcinoma cells were obtained from ATCC. These cells were grown in DMEM medium supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin. Cells were sub—cultured by dilution at a ratio of 1:4. Hep3B cells were ted by fugation and counted using a hemocytometer. Cells were ended in PBS at a 5 X 107 cells per mL. Cells were placed on ice, then mixed with an equal volume of MatrigelTM (BD Biosciences CB-40234). This e was kept on ice and injected into the left flank of mice in a volume of 0.2 mL, equivalent to 5 x 106 cells per mouse. Thirty-two (32) SCID mice were inoculated subcutaneously in the left flank with 5 x 106 Hep 3B cells.
Treatment was ted when the tumors reached a mean volume of 103.7 mm3 (standard deviation i 30 mm3, range 17—183 mm3). Mice were allocated to four (4) groups of eight (8) mice such that mean tumor volume in each group was within the range of 95 to 104 m3.
Mice were treated with vehicle, standard of care control ubicin), or Compound 585.
With the exception of doxorubicin (which was given IP), all compounds were given by oral gavage. Compound 585 (20 or 60 mg/kg) was given orally (PO) daily. Animal weights and conditions were recorded daily, and tumors were measured on Mondays, Wednesdays and Fridays. is a graph of mean tumor volume as a function of time, and shows the effect of varying concentrations of Compound 585 on the volume of Hep 3B xenografts in SCID mice. The model demonstrated tumor growth inhibition without major toxicity (minimal or no side effects or weight loss up to 200 mg/kg daily dose).
Example 11. MOLT—4 xenograft ih SCID mice.
In this study, the impact of Compounds 667 and 728 on tumor growth was tested using the Molt-4 T-ALL cancer xenograft model in SCID mice. MOLT-4 (CRL-1582) acute lymphoblastic leukemia cells were obtained from ATCC. These cells were grown in RPMI- 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin.
Cells were sub-cultured by transferring floating cells to a new flask and trypsinizing adherent cells before subculturing at a ratio of 1:4. Molt-4 cells were harvested by fugation and d using a hemocytometer. Cells were resuspended in PBS at a 5 x 107 cells per mL.
Cells were placed on ice and mixed with an equal volume of Matrigel (BD Biosciences CB— 40234). This mixture was kept on ice and injected into the left flank of mice in a volume of 0.2 mL, equivalent to 5 x 106 cells per mouse. Twenty—four (24) CB-l7 SCID mice were inoculated subcutaneously in the left flank with the Molt-4 cells. Treatment was initiated when the tumors reached a mean volume of approximately 100 mm3 . Mice were allocated to three (3) groups of eight (8) mice. Mice were treated with vehicle, Compound 667 or Compound 728. Compounds 667 and 728 (100 mg/kg) were given orally (PO) twice daily (BID) beginning on Day 1. Animal weights and conditions were recorded daily, and tumors were measured on Mondays, Wednesdays and Fridays. is a graph of median tumor volume (as a percentage of pre-dose tumor volume) as a function of time, and shows the effect of Compound 667 and Compound 728 on the volume of Molt-4 xenografts in SCID mice. The model demonstrated tumor growth inhibition.
References 1. Arias-Romano, L.E.; Chernoff, J. Biol. Cell, 2008, 100, . 2. a) Dart, A.E.; Wells, C.M. European Journal ofCell Biology, 2013, 92, 129— 138. b) Clairvoyant, F.; Zhu. S. et al. JBiol Chem, 2002, 277, 550—8. c) Cammarano, M.S. et a1. Mol Cell Biol, 2005, 21, 9532-42. d) Wells, C.M. et a1, JCell Sci, 2010, 123, 3. d) Siu, M.K. et al. Proc. Natl. Acad. Sci. USA, 2010, 107(43), 18622-7. 3. a) Guo, C. et al.; J. Med. Chem, 2012, 55, 4728-4739 b) , S.W. et al.
Chemistry & Biology, 2008, 15, 322—331 c) Wells, C.M.; Jones, G. E. Biochem. J., 2010, 425, 465—473.
The teachings of all patents, published applications and nces cited herein are incorporated by reference in their entirety.
While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention assed by the ed claims.

Claims (30)

We Claim :
1. A compound represented by Structural Formula XII: Z6 Z7 R22 q' O R20 N N m' R21 q O (XII), or a ceutically acceptable salt thereof, wherein: m´ is 1 or 2; Z5 is -N- or -C(H)-; R20 is (C1-C4)alkyl, (C1-C4)haloalkyl, -O-(C0-C4 ne)carbocyclyl, -O-(C0-C4 alkylene)heterocyclyl, -C(H)(OH)-carbocyclyl, -C(H)(OH)-heterocyclyl, CH3)-carbo cyclyl, -C(H)(CH3)-heterocyclyl, -C(O)(C1-C4)alkyl, -C(S)(C1-C4)alkyl, C0-C4 alkylene)NR11R12, -C(S)(C0-C4 alkylene)NR11R12, -S(O)2(C1-C4)alkyl, -S(O)2NR11R12 or -C(O)NR13NR11R12, wherein: R11 and R12 are each independently en, (C1-C4) alkyl, carbocyclyl, or heterocyclyl; or R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form an unsubstituted or a substituted heterocyclyl; and R13 is hydrogen or an (C1-C4)alkyl; each R21, if present, is independently halo; q is 0, 1, 2, 3 or 4; each of Z6 and Z7 is independently -N- or -C(H)-, wherein no more than one of Z6 and Z7 is nitrogen; each R22, if present, is independently halo, cyano, (C1-C3)alkyl, halo(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy or halo(C1-C3)alkoxy ; and q´ is 0, 1, 2 or 3, n each substituent on the substituted heterocyclyl formed by R11 and R12 is independently selected from halo, (C1-C3)alkyl, halo(C1-C3)alkyl, hydroxy, (C1- C3)alkoxy, and halo(C1-C3)alkoxy.
2. The compound of Claim 1, wherein q is 0, 1 or 2.
3. The compound of Claim 1 or 2, wherein R21, for each ence and if present, is fluoro.
4. The compound of any one of Claims 1 to 3, wherein R20 is -C(O)(C0-C4 alkylene)NR11R12 or -C(S)(C0-C4 alkylene)NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly ed to form an tituted or substituted (C3-C7)heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulphur.
5. The compound of any one of Claims 1 to 4, wherein the heterocyclyl formed by R11 and R12 taken together with the nitrogen atom to which they are commonly attached is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently ed from halo, hydroxyl, halo(C1-C3)alkyl, )alkyl and (C1-C3)alkoxy.
6. The compound of any one of Claims 1 to 5, wherein Z5 is -C(H)-.
7. The compound of any one of Claims 1 to 5, wherein Z5 is -N-.
8. The compound of Claim 1, wherein the heterocyclyl formed by R11 and R12 taken together with the nitrogen atom to which they are commonly attached is unsubstituted or substituted with 1 or 2 substituents.
9. The compound of Claim 1, represented by Structural Formula XI: Z6 Z7 R22 q' Z5 O N N N m' R21 q F (XI), or a ceutically acceptable salt thereof.
10. A compound ed from Cpd No. Compound Structure N N 500 O 501 O H N N N O O 502 O H N N N O O 503 O N N N N 504 H O O S N O N N HN NH 505 H2N H O N N 506 H O H2N N 507 O H N O N N 508 H N N N O F Cpd No. nd Structure 509 H N N N O F F F 510 O H N N N O O 511 O H N N N O O 512 O H N N N O O N N 513 H O O 514 O H O N N 515 O H N N N O O 516 O H N N N O O F F 517 O H N N N O O Cpd No. nd Structure F F N HN NH 518 H2N H O N N F F N N HN NH 519 H2N H O N N F F 520 O H N N N O F F F N O 521 O H N N N O O F F 522 O H N N N 523 O H N N N F F 524 O H N N N O F F F 525 O H N N N F F 526 O H N N N Cpd No. nd Structure N N F 527 H O O S N 528 O H N N N 529 H N N N F F 530 O H N N N O O N N H O 531 O S N O F F 532 O O N N N N 533 H O O S N F O N 534 N N 535 N O H N O O Cpd No. nd Structure F O 536 F O H N N N O O 537 O H N N N O O 538 O H N N N O O 539 O H N O O 540 O H N N N O O 541 O N H N O O 542 O H N O O O N 543 N N N O 544 O H N N N O O N N 545 H N O Cpd No. nd Structure N O 546 O H N N N N O O Cl F 547 O H N N N O O 548 O H N N N F F O O 549 O H N N N O O 550 O H N O O 551 O H N N N O O N N O 552 O H N N N O O N N H N O 553 O N N O O Cpd No. nd Structure N N 555 H O O S N N N 556 H O O N O Cl O 557 O H N N N O O O N 558 H O H2N N F F 559 O N N N O 560 O H N N N O O F F 561 O H N N N O N O N 562 N N O F Cpd No. nd Structure O N N N 563 H O F F F F F 564 O H N N N O NH F F N O 565 O H N N N O N F F 566 O H N N N F F 567 O H N N N 568 N O H N N N O O F F N O 569 O H N N N O O F F N O 570 O H N N N Cpd No. nd Structure F F 571 O H N N N F F 572 O H N N N O NH F F 573 O H N N N F F 574 O H N N N O O F F 575 O H N N N O NH 576 H N N N O N F F N O 577 O H N N N O NH N N 578 O N H2N O N N 579 O F F N O F F O Cpd No. nd Structure O N N N 580 H O F F F N N 581 O F Cl N O 582 H O NH H2N N N O Cl O N O 583 O H N N N N O O N O 584 H N N N O N F F N O 585 O H N N N N O 586 H N N N N O N F F 587 O H N N N O N 588 N N O F Cpd No. nd Structure N O 589 O H N N N O NH F F N O 590 O H N N N N O NH 591 N N H N N O 592 O H N N N O O F F N O 593 O H N N N N O O F F N O 594 O H N N N N O N F F 595 O H N N N 596 N N H N 598 H N N N Cpd No. nd Structure 599 H N N N 600 O H N N N 601 O H N N N O NH 602 N N H N F F 603 O H N N N O F F F 604 O H N N N F F 605 H N N N F F F F 606 O H N N N F O OH F F F 607 O H N N N Cpd No. nd Structure F F 608 O H N N N O F F F 609 H N N N O OH F F F F 610 O H N N N F F 611 O H N N N F F N O 612 O H N N N O F F F N O 613 O H N N N F O OH F F F N O 614 O H N N N F F N O 615 H N N N F F Cpd No. nd Structure F F N O 616 H N N N O OH F F F F N O 617 O H N N N O F F F N O 618 O H N N N H O F F 619 O F H2N N N HN F F F F N O 620 O H N N N F F N O 621 O H N N N F F N O F H2N F 622 O F H N N N F F N O 623 O H N N N Cpd No. nd Structure F F N O F H2N F 624 O F H N N N F F N O H N N N 625 O F F N O 626 O H N N N F F N O 627 O H N N N O OH F F H2N N 628 O H N N H O 629 O H2N N N HN F F F F N O H2N N 630 O H HN F F N O 631 H N N N Cpd No. nd Structure F F N O 632 O H N N N F F N O 633 O H N N N O O F F N O 634 O H N N N N N H O 635 O S N O O N 636 N N O O F 637 O H N N N O NH N O 638 O H N N N N O O N O 639 O H N N N N O NH N O 640 O H N N N O O Cpd No. nd Structure N O 641 O H N N N O NH N N 642 H O O S N H2N F N N F 643 H O O S N N N H O 644 O S N H2N F F F F F N O 645 O H N N N O F N N 646 H O N 648 N N H O H2N N F F N O 649 O H N N N N O NH N N 650 O Cl OH Cpd No. Compound Structure 651 N N H N N O F F N O 652 O H N N N N F F N O 653 O H N N N N O F F F O F NH ∗ N N N O 654 H2N Enantiomer 1 tR = 19.46 s (chiral HPLC) F F O F NH ∗ N N N O 655 H2N Enantiomer 2 tR = 30.74 minutes (chiral HPLC) F F N O O F NH ∗ 656 N N Enantiomer 1 Cpd No. Compound Structure tR = 8.16 s (chiral HPLC) F F N O O F NH ∗ N N Enantiomer 2 tR = 7.51 minutes (chiral HPLC) N N O H N 658 N N N O 659 O H N N N N N H N 660 O D N O D O F F N O 661 H N N N N O 662 O H N N N F O F N O 663 O H N N N Cpd No. nd Structure F F N O 664 O H N N N N O 665 H2N H N N N N O 666 O H N N N F F N S 667 O H N N N N O 668 H2N H N N N N O 669 O H N N N F F N O 670 O H N N N Cpd No. nd Structure F F N O 671 O H N N N N O 672 H2N H N N N N O 673 O H N N N N O 674 O H N N N F F N N 675 H2N N N F F N O 676 O H N F F N O 677 O H N N N Cpd No. nd Structure F F N S 678 O H N N N N N H O 679 O S N F F N N H O 680 O S N F F F F N O 681 H N N N F F 682 O H N N N F F 683 O H N N N F F 684 O H N N N F F S N 685 O F N N F Cpd No. nd Structure F O F O 686 O H N N N F O F O 687 O H N N N F F 688 O H N N N F F N O 689 O H N N N F F 690 O O N O N N F F 691 O O N N 692 F O F H F N N 693 O O S N N O Cpd No. nd Structure 694 H2N N H O N N 695 N N O F F 696 O H N N N F O 697 H2N H N N N Cl F 698 H2N H N N N 699 H2N H N N N 700 H2N H N N N Cpd No. nd Structure 701 H2N O O N N O F H F N N N O 703 H2N N N N OH 704 H2N N N 705 O H N N N 706 H2N H N N N Cpd No. nd Structure N S 707 O H N N N N S 708 H2N H N N N 709 H2N O SO2Et N N N O 710 H2N H N N N 711 H2N H N N N N N 714 N N H N Cpd No. Compound ure F F O ∗ F N O 715 H2N Enantiomer 1 tR = 5.09 minutes (chiral HPLC) F F O ∗ F N O 716 H2N Enantiomer 2 tR = 5.99 minutes (chiral HPLC) O N N N 717 H F F 718 O N N H N N O N O 719 O H N N N N O 720 O H N N N Cpd No. nd Structure N O 721 O H N N N 722 O H N N N 723 O H N N N 724 O H N N N 725 O H N N N 726 O H N N N 727 O H N N N Cpd No. nd Structure 728 H2N H N N N 729 O H N N N Cl O 730 O H N N N 731 O H N N N 732 O H N N N F F 733 O H N N N 734 H2N H N N N Cpd No. nd Structure 735 H2N H N N N 736 H2N H N N N 737 H2N H N N N 738 H2N H N N N 739 H2N H N N N F F 740 O H N N N 741 O H N N N Cpd No. nd Structure 742 H2N H N N N 743 H2N H N N N 744 O H N N N 745 H2N O O N N 746 O H N N N F F N O 747 O H N N N OH F 748 O H N N N Cpd No. nd Structure F F 749 O H N N N 750 H2N H N N N 751 H2N H N N N F O F N O 752 O H N N N 753 N H O N N 754 H2N H N N N 755 H2N N H O Cpd No. nd Structure 756 H2N N H O 757 N H2N N H O 758 N H2N N H S 759 H2N O O N N 760 H2N H N N N O F O CF3 O N O F N N Cpd No. Compound Structure 763 H2N O O N N 764 H2N H O N N N N O F 766 N N N O Cl 767 H2N H O O N N or a pharmaceutically acceptable salt f.
11. The compound of Claim 1 represented by the following structural formula: H N N N or a pharmaceutically acceptable salt thereof.
12. A compound represented by Structural Formula VII or VIII: O R9a N N O (VII) N N m' R9a or O (VIII), wherein R1a is a phenyl substituted with a substituent selected from halogen, alkyl, haloalkyl, CN, and –OH; R9a is aryl or heteroaryl substituted with -C(O)(C0-C1 alkylene)NR11R12, n R11 and R12 are taken together with the nitrogen atom to which they are commonly ed to form a (C3-C7)heterocyclyl that is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, (C1-C4)alkyl and (C1-C4)haloalkyl, and wherein the aryl or heteroaryl is further optionally substituted with halo; m’ is 1 or 2; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12, wherein R1a is substituted with halogen.
14. The compound of claim 12, wherein R9a is phenyl or a 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and ; substituted at the meta or para position relative to its attachment point with -C(O)(C0-C1 alkylene)NR11R12, wherein R11 and R12 are taken together with the nitrogen atom to which they are commonly attached to form a (C3-C7)heterocyclyl; and further wherein the (C3-C7)heterocyclyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, (C1-C4)alkyl and (C1-C4)haloalkyl.
15. The compound of claim 12, n R9a is selected from 4-(morpholinecarbonyl) , 4-(3,3-difluoroazetidinecarbonyl)phenyl), 4-(4-trifluoromethyl)phenyl, 4- sulfonylphenyl, 4-ethylsulfonylphenyl, rophenoxy, 4,4- difluorocyclohexyloxy, and 4-fluoropyridyloxy.
16. The nd of Claim 10 represented by N N N O N N N N O N N N N O N N N N O N N N or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical ition comprising: (a) a compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of Claim 17 sing a compound represented by the following structural formula: H N N N F , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. Use of a compound of any one of Claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 17 or 18, for the cture of a medicament for treating a PAK-mediated disorder.
20. The use of Claim 19, wherein the diated er is a disorder mediated by PAK1, PAK2 or PAK3, or a combination of the foregoing.
21. The use of Claim 19, wherein the PAK-mediated disorder is a disorder mediated by PAK4, PAK5 or PAK6, or a combination of the foregoing.
22. The use of any one of Claims 19 to 21, wherein the PAK-mediated disorder is cancer, a neurodegenerative disease or an immune system disease.
23. Use of a compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 17 or 18 for the manufacture of a medicament for treating cancer.
24. The use of Claim 23, wherein the cancer is ed from ma, leukemia or
25. The use of Claim 23, wherein the cancer is selected from mantle cell lymphoma, multiple myeloma, cervical cancer, ovarian , osteosarcoma, prostate cancer, breast cancer, colorectal cancer, lung cancer, glioma, liver cancer, extrahepatic bile duct cancer, pancreatic cancer, neuroblastoma, testicular cancer, mesothelioma, and melanoma.
26. The use of Claim 24, wherein the lymphoma is selected from histiocytic lymphoma, mantle cell lymphoma, Burkett lymphoma, and diffuse large B-cell lymphoma.
27. The use of Claim 24, wherein the leukemia is ed from acute myeloid leukemia, acute lymphoblastic leukemia, erythroleukemia, chronic cytic leukemia, and T-cell leukemia.
28. The use of Claim 23, wherein the cancer is cervical cancer.
29. The use of Claim 25, wherein the cancer is mantle cell lymphoma.
30. The use of Claim 25, n the cancer is melanoma. Karyopharm Therapeutics Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: 33333333“\\\“\\\“\\\“\\\“\\\“\\\“\\\“\\\“\\\\\\\3333333333--~»s»\\\\\\\\\\\\\\\\ figgmgasg 3C_.. 303$: xfififiafifi @3333 333 mwmwm 33 333333333333 , 33333333333333.3w3 3333 .3. “33333333333333.3333” 33333333333333. 33!. 3.3333333333333333 33.33.3333 £3 3363» 33333.33? ‘6 3333133 333333333333. 333333333333m3 M333
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