Substituted benzofurans, benzopyrroles, benzothiophenes, and structurally related complement inhibitors

Abstract

To provide further complement inhibitors which have therapeutic potential in the treatment of numerous disorders.SOLUTION: Disclosed are compounds of formulae I and II, and pharmaceutically acceptable salts and prodrugs thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 654,108, filed April 6, 2018. [Background technology]

[0002] The complement system is part of the body's immune system, enhancing the ability of antibodies and phagocytes to destroy and eliminate foreign substances (e.g., pathogens) within the body. The complement system comprises a group of plasma proteins that interact to attack the extracellular structures of pathogens, inducing a series of inflammatory responses that help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to a specific pathogen or by antibody binding to the pathogen. Activation of complement proteins triggers a cascade, with one complement protein in turn inducing the activation of the next. The activation of a small number of complement proteins at the start of the pathway is enormously amplified by each subsequent enzymatic reaction, resulting in a rapid, disproportionately large complement response (Non-Patent Document 1). Healthy organisms have regulatory mechanisms to prevent unregulated complement activation.

[0003] Once activated, complement proteins can bind to pathogens, opsonizing them for uptake by phagocytes bearing complement receptors. Small fragments of some complement proteins then act as chemoattractants, recruiting more phagocytes to the site of complement activation and further activating these phagocytes. Complement proteins then form holes or pores in the invading organism, leading to its destruction. Complement plays an important role in defending the body against foreign substances but can also destroy healthy cells and tissues. Inappropriate activation of complement is associated with many disease states affecting the immune, renal, cardiovascular, and nervous systems (Non-Patent Document 2). Therefore, there is a need for the development of additional complement inhibitors that are therapeutically effective in treating many disorders. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Marrides, S.Pharmacological Reviews 1998,Vol.50,pages 59-88 [Non-patent document 2] Morgan,B.Eur J Clin Invest 1994,Vol.24,pages219-228 Summary of the Invention [Means for solving the problem]

[0005] In certain aspects, the present invention provides compounds having the structure of Formula (I), and pharmaceutically acceptable salts and prodrugs thereof: [ka] (In the formula, TIFF0007720376000002.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, TIFF0007720376000003.tif22115 is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, TIFF0007720376000004.tif22115 is aryl or heteroaryl, R ais independently, for each occurrence, halogen, cyano, hydroxy, -NH, -NH(Ac), -NH(alkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), -NH(aryl), -NH(heteroaryl), -N(alkyl), -NHC(O)(alkyl), -CH(alkyl)NH, -CH(hydroxyalkyl)NH, -CH(haloalkyl)NH, -CH(cycloalkyl)NH, -CH(heterocycloalkyl)NH, -CH(aryl)NH, -CH(heteroaryl)NH, -CHNHC(O)(alkyl) ), —C(O)NH, —C(O)(alkyl), —SO NH, —SO (cycloalkyl), —SO (heterocycloalkyl), —SO (alkyl), —SO (aryl), or —SO (heteroaryl), or selected from the group consisting of substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; R b are independently, for each occurrence, halogen, cyano, -CH2(OCH2CH2) q OCH3, -alkylene- (branched or unbranched polyethylene glycol), -alkylene-O- (branched or unbranched polyethylene glycol), or -NR j R k or a substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl, hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, (heteroarylalkoxy)alkyl, (arylalkoxy)alkyl, (aryloxy)alkyl, ((cycloalkyl)alkoxy)alkyl, ((heterocycloalkyl)alkoxy)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkylene-NR j R k, tosyl, -SO2(alkyl), -SO2(cycloalkyl), -CO(alkyl), -CO(aryl), -CO(heteroaryl), -CO(cycloalkyl), -CO(heterocycloalkyl), -CONH(alkyl), -CONH(arylalkyl), -CONH(heteroarylalkyl), -CON(alkyl), -CONH(heterocycloalkyl), and -CONH(cycloalkyl); R c are independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, alkyl, cycloalkyl, and heterocycloalkyl; R 1 is selected from the group consisting of -NH, -COOH, -CHCOOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(arylalkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CH(NH(CO)(aryl substituted cycloalkyl))COOH, -CH(NH(CO)(heteroaryl substituted cycloalkyl))COOH, -CH(S(alkyl))COOH, -CO(NH)CH(substituted or unsubstituted aryl), -CO(NH)CH(substituted or unsubstituted heteroaryl), -CO(NH)(substituted or unsubstituted aryl), -CO(NH)(substituted or unsubstituted heteroaryl), and -CH(tetrazolyl); n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is an integer from 1 to 20, J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, -CH(cycloalkyl)-, -N((C(O)O)arylalkyl)-, -N((C(O)O)heteroarylalkyl)-, or -N(C(O)arylalkyl)-; K is —C(O)—, —NH—, —CH—, —O—, —S—, —S(O)—, —SO—, —N(alkyl)-, —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-, —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-; wherein at least one of J and K is —C(O)—, —CH—, or —CH(alkyl)-; L is a bond, -CH2-, -CH2CH2-, or -CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )-, -C(=CHR L )—, —S(O)—, and —S(O)—; where R L is H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2 is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl; R j and R k are each independently H or selected from the group consisting of substituted or unsubstituted alkyl, aminoalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CO(aryl), —CO(arylalkyl), —CO(heteroarylalkyl), and —CO((heterocycloalkyl)alkyl); U is N or CR 3 and R 3 is H, halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, haloalkyl, -CN, -CONH2, -CO2H, -CH2CO2H, -NH2, hydroxyalkyl, aminoalkyl, -OH, -NH(alkyl), -N(alkyl)2, thioalkyl, or -S(alkyl); V is N, CH, C(halogen), or C(alkyl); The stereochemical configuration at any chiral center is R, S, or a mixture of R and S).

[0006] In certain embodiments, the present invention provides compounds having the structure of formula (II-g), and pharmaceutically acceptable salts and prodrugs thereof: [ka] (In the formula, TIFF0007720376000006.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, TIFF0007720376000007.tif22115 is aryl or heteroaryl, R a is independently, for each occurrence, halogen, cyano, hydroxy, -NH, -NH(Ac), -NH(alkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), -NH(aryl), -NH(heteroaryl), -N(alkyl), -NHC(O)(alkyl), -CH(alkyl)NH, -CH(hydroxyalkyl)NH, -CH(haloalkyl)NH, -CH(cycloalkyl)NH, -CH(heterocycloalkyl)NH, -CH(aryl)NH, -CH(heteroaryl)NH, -CHNHC(O)(alkyl) ), —C(O)NH, —C(O)(alkyl), —SO NH, —SO (cycloalkyl), —SO (heterocycloalkyl), —SO (alkyl), —SO (aryl), or —SO (heteroaryl), or selected from the group consisting of substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; T 1 are N, CH, and NR T1 , or CRT1 and T 2 is NR T2 or CR T2 and T 3 are N, CH, and NR T3 , or CR T3 and where: (a)T 1 is CR T1 Or NR T1 and R T1 and R T2 together with the intervening atoms form an optionally substituted cycloalkyl, aryl, or heteroaryl ring; T 3 is N or CH, or (b)T 3 is CR T3 Or NR T3 and R T3 and R T2 together with the intervening atoms form an optionally substituted heteroaryl ring; T 1 is N or CH, (a)T 2 But NR T2 (b) T 3 is N, or (c) T 1 But NR T1 There is at least one thing that R 1is selected from the group consisting of -NH, -COOH, -CHCOOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(arylalkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CH(NH(CO)(aryl substituted cycloalkyl))COOH, -CH(NH(CO)(heteroaryl substituted cycloalkyl))COOH, -CH(S(alkyl))COOH, -CO(NH)CH(substituted or unsubstituted aryl), -CO(NH)CH(substituted or unsubstituted heteroaryl), -CO(NH)(substituted or unsubstituted aryl), -CO(NH)(substituted or unsubstituted heteroaryl), and -CH(tetrazolyl); n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, -CH(cycloalkyl)-, -N((C(O)O)arylalkyl)-, -N((C(O)O)heteroarylalkyl)-, or -N(C(O)arylalkyl)-; K is —C(O)—, —NH—, —CH—, —O—, —S—, —S(O)—, —SO—, —N(alkyl)-, —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-, —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-; R c are independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, alkyl, cycloalkyl, and heterocycloalkyl; L is a bond, -CH2-, -CH2CH2-, or -CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )-, -C(=CHR L )—, —S(O)—, and —S(O)—; where R Lis H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2 is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl; V is N or CH; The stereochemical configuration at any chiral center is R, S, or a mixture of R and S).

[0007] In a further aspect, the present invention provides compounds having the structure of formula (II), and pharmaceutically acceptable salts and prodrugs thereof: [ka] (In the formula, TIFF0007720376000009.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, R a is independently, at each occurrence, selected from the group consisting of halogen, cyano, hydroxy, —NH, —NH(Ac), —NH(alkyl), —N(alkyl), —NHC(O)(alkyl), —CHNHC(O)(alkyl), —C(O)NH, —C(O)(alkyl), optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; T 1 are N, CH, and NR T1 , or CR T1 and T 2 is NR T2 or CR T2 and T 3 are N, CH, and NR T3 , or CR T3 and where: (a)T 1 is CRT1 Or NR T1 and R T1 and R T2 together with the intervening atoms form an optionally substituted cycloalkyl, aryl, or heteroaryl ring; T 3 is N or CH, or (b)T 3 is CR T3 Or NR T3 and R T3 and R T2 together with the intervening atoms form an optionally substituted heteroaryl ring; T 1 is N or CH, (a)T 2 But NR T2 (b) T 3 is N, or (c) T 1 But NR T1 There is at least one thing that R 1 is selected from the group consisting of -NH, -CHCOOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CO(NH)CHaryl, -CO(NH)CHheteroaryl, -CO(NH)aryl, and -CO(NH)heteroaryl; p is 0, 1, or 2; J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, or -CH(alkyl)-; K is —C(O)—, —NH—, —O—, —CH—, —S—, —S(O)—, —SO—, —N(alkyl)-, or —CH(alkyl)-; wherein at least one of J and K is —C(O)—, —CH—, or —CH(alkyl)-; W is N, CH, or CR c and X is N, CH, or CR c and Y is N, CH, or CR c and Z is N, CH, or CR c and R c are independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, and alkyl; L is a bond, -CH2-, -CH2CH2-, or -CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )- and -C(=CHR L )-, where R L is H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2 is alkyl, hydroxyalkyl, or haloalkyl; V is N or CH; The stereochemical configuration at any chiral center is R, S, or a mixture of R and S).

[0008] In certain aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

[0009] In certain aspects, the present invention relates to a method of treating a disease or condition characterized by abnormal complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof. In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immunological disorder. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome. DETAILED DESCRIPTION OF THE INVENTION

[0010] Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in treating disorders of the immune, renal, cardiovascular, and nervous systems. Provided herein are compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts and prodrugs thereof, that are useful for treating or preventing diseases or conditions characterized by abnormal activity of the complement system.

[0011] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0012] The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or are oxygen, nitrogen, or sulfur.

[0013] As used herein, the term "alkyl" is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C for straight chain). 30 , C3 to C for branched chains 30 ), or having about 20 or less, or 10 or less carbon atoms. In certain embodiments, the term "alkyl" refers to a C1-C 10 In certain embodiments, the term "alkyl" refers to a C1 to C6 alkyl group, for example, a C1 to C6 straight chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3 to C6 alkyl group, for example, a C1 to C6 straight chain alkyl group. 12 It refers to a branched chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3 to C8 branched chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0014] The term "cycloalkyl" refers to monocyclic, bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Some cycloalkyls have from 5 to 12 carbon atoms in their ring structure, and some have 6 to 10 carbons in the ring structure. Preferably, cycloalkyl is a (C3-C7)cycloalkyl, which refers to a monocyclic saturated carbocyclic ring having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings are rings in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form -(CH2) w - (where w is 1, 2, or 3) bridging group). Representative examples of bicyclic systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. Bridged or fused bicyclic cycloalkyls are attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group is optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0015] The term "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a cycloalkylalkyl group is a cyclohexylmethyl group.

[0016] The term "heterocycloalkyl," as used herein, refers to radicals of non-aromatic ring systems, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, having 3 to 12 atoms including at least one heteroatom such as nitrogen, oxygen, or sulfur, and which may be fully saturated or contain one or more units of unsaturation (for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system). For illustrative purposes, and not to be construed as limiting the scope of the invention, examples of heterocycles are listed below: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl , isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, trithianyl, and 2-azobicyclo[3.1.0]hexane. Heterocycloalkyl groups are optionally substituted with one or more substituents, as described below.

[0017] As used herein, the term "(heterocycloalkyl)alkyl" refers to an alkyl group substituted by one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0018] The term "alkenyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) in an alkenyl group can be located at any position in the moiety and can have either the (Z) or (E) configuration about the double bond(s).

[0019] The term "alkynyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0020] The term "alkylene" is art-recognized and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from an alkyl group, as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with a substituent such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, or the like. That is, in one embodiment, "substituted alkyl" is "alkylene."

[0021] The term "amino" is a term of art and as used herein refers to both unsubstituted and substituted amines, for example, those of the general formula: [ka] (In the formula, R a , R b , and R c are each independently hydrogen, alkyl, alkenyl, -(CH2) x -R d or R a and R b together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure, and R d represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl, and x is zero or an integer ranging from 1 to 8. In certain embodiments, R a or R b Only one of R a , R b and nitrogen together do not form an imide. a and R b(and optionally R c ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d In certain embodiments, the term "amino" refers to -NH2.

[0022] In certain embodiments, the term "alkylamino" refers to --NH(alkyl).

[0023] In certain embodiments, the term "dialkylamino" refers to -N(alkyl)2.

[0024] The term "amide," as used herein, means -NHC(=O)-, where the amide group is attached to the parent molecular moiety through a nitrogen. Examples of amides include alkylamides such as CHC(=O)N(H)- and CHCHC(=O)N(H)-.

[0025] The term "acyl" is a term of art and, as used herein, refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0026] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group, i.e., -CHNH.

[0027] The term "aminoacyl" is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

[0028] The term "aminothionyl" as used herein refers to the analog of aminoacyl in which the O of RC(O)-- is replaced by sulfur, thus the form RC(S)--.

[0029] The term "phosphoryl" is a term of art and as used herein generally refers to a group having the formula: [ka] where Q50 represents S or O, and R59 represents hydrogen, lower alkyl, or aryl, such as -P(O)(OMe)- or -P(O)(OH). For example, when used to substitute an alkyl, the phosphoryl group of the phosphorylalkyl has the general formula: [ka] wherein Q50 and R59 are each independently defined above, and Q51 represents O, S, or N, for example, -OP(O)(OH)OMe or -NH-P(O)(OH). When Q50 is S, the phosphoryl moiety is a "phosphorothioate."

[0030] The term "aminophosphoryl," as used herein, refers to a phosphoryl group substituted with at least one amino group, as defined herein, for example, -P(O)(OH)NMe2.

[0031] The terms "azide" or "azido" as used herein refer to an -N3 group.

[0032] The term "carbonyl" as used herein refers to -C(=O)-.

[0033] The term "thiocarbonyl" as used herein refers to -C(=S)-.

[0034] The term "alkylphosphoryl," as used herein, refers to a phosphoryl group substituted with at least one alkyl group, as defined herein, e.g., -P(O)(OH)Me.

[0035] The term "alkylthio" as used herein refers to alkyl-S-. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0036] The term "carboxy" as used herein means a -CO2H group.

[0037] The term "aryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, including, for example, benzene, naphthalene, anthracene, and pyrene. Typically, aryl groups contain 6 to 10 carbon ring atoms (i.e., (C6-C8) 10 ) aryl). Aromatic rings can be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings (the rings are "fused rings"), at least one of the rings is aromatic hydrocarbon, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group.

[0038] The term "heteroaryl" is a term of art and as used herein refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms and including one or more heteroatoms, such as nitrogen, oxygen, or sulfur, in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. "Heteroaryl" refers to a group in which one or more ring positions can be substituted with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings (the rings are "fused rings"), at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0039] The term "aralkyl" or "arylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with an aryl group, where the moiety is attached to the parent molecule through the alkyl group.

[0040] The term "heteroaralkyl" or "heteroarylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through an alkyl group.

[0041] The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0042] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0043] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein, represented by -C(=O)-. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0044] The term "alkylcarbonyl," as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0045] The term "arylcarbonyl," as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0046] The terms "alkylcarbonyloxy" and "arylcarbonyloxy" as used herein mean an alkylcarbonyl group or an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to, phenylcarbonyloxy.

[0047] The terms "alkenoxy" or "alkenoxyl" mean an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propene-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-).

[0048] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0049] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0050] The term "carbocyclyl," as used herein, means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms and which is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0051] The term "cyano" is a term of art and as used herein refers to --CN.

[0052] The term "halo" is a term of art and as used herein refers to -F, -Cl, -Br, or -I.

[0053] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with halogen atoms.

[0054] The term "hydroxy" is a term of art and as used herein refers to --OH.

[0055] The term "hydroxyalkyl," as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0056] The term "silyl," as used herein, includes hydrocarbyl derivatives of the silyl (HSi-) group (i.e., (hydrocarbyl)Si-), where the hydrocarbyl group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl group may be a combination of different groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM), and can be varied to provide multiple silyl groups.

[0057] The term "silyloxy" as used herein means a silyl group, as defined herein, appended to the parent molecule through an oxygen atom.

[0058] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention contemplates that all such compounds are within the scope of the present invention, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0059] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0060] It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the valences allowed for the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0061] The term "substituted" is also intended to include all permissible substituents of organic compounds. Broadly speaking, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any way by the permissible substituents of organic compounds.

[0062] As used herein, the term "substituted or unsubstituted," when placed before a list of chemical moieties, means that the list of chemical moieties that follows is substituted or unsubstituted, respectively. For example, "substituted or unsubstituted aryl, heteroaryl, and cycloalkyl" means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0063] The term "protecting group," as used herein, refers to temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals of aldehydes and ketals of ketones, respectively. The field of protecting group chemistry has been extensively reviewed (Greene, TW; Wuts, PGMP Protective Groups in Organic Synthesis, 2004). nd ed.; Wiley: New York, 1991) Protected forms of the compounds of the invention are included within the scope of the invention.

[0064] For purposes of this invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover).

[0065] Other chemical terms herein are used in accordance with conventional usage in the art as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0066] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of salt-containing molecules is not 1:1. For example, a salt may contain two or more inorganic or organic acid molecules per base molecule, such as two hydrochloric acid molecules per compound of Formula I molecule. As another example, a salt may contain less than one inorganic or organic acid molecule per base molecule, such as two tartaric acid molecules per compound of Formula I molecule.

[0067] The term "prodrug" as used herein refers to a compound that can be metabolized in vivo to yield a compound of Formula I or Formula II. Thus, prodrugs include compounds that can be prepared by modifying one or more functional groups in a compound of Formula I or Formula II to give a corresponding compound that can be metabolized in vivo to yield a compound of Formula I or Formula II. Such modifications are known in the art. For example, one or more hydroxyl or amine groups in a compound of Formula I or Formula II can be acylated with an alkyl-C(=O)- group or a residue derived from an amino acid to yield a prodrug.

[0068] Prodrug forms of compounds with various nitrogen-containing functional groups (amino, hydroxyamino, amide, etc.) may include the following types of derivatives, where each R p Groups can individually be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, arylalkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl. (a)-NHC(O)R p Carboxamide represented by (b)-NHC(O)OR p Carbamates represented by (c)NHC(O)OROC(O)R p (Acyloxy) alkyl carbamates represented by the formula (d)-NHCR(=CHCO2R p ) or -NHCR(=CHCONR p R p ) enamine (e)-N=CR p R p A Schiff base represented by (f)RCONHCH2NR p R p Mannich bases (derived from carboximide compounds) represented by

[0069] The preparation of such prodrug derivatives is discussed in various publications (eg Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO0041531, p. 30).

[0070] Prodrug forms of carboxyl-containing compounds are esters (-COR m ), where R m The group corresponds to any alcohol, and the alcohol released into the body via an enzymatic or hydrolytic process is at a pharmaceutically acceptable level. Another prodrug derived from the carboxylic acid form of the present disclosure can be a quaternary salt type structure as described by Bodor et al., J. Med. Chem. 1980, 23, 469.

[0071] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils, and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, and urea. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may also be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, the entire contents of which are incorporated herein by reference.

[0072] As used herein, the term "treating" refers to preventing, halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" refers to halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" refers to reducing at least one objective manifestation of a disease or condition in a subject.

[0073] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0074] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired therapeutic effect.

[0075] As used herein, the term "inhibit" refers to a reduction in an objectively measurable amount or extent. In various embodiments, "inhibit" refers to a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, "inhibit" refers to a 100 percent reduction, i.e., cessation or elimination.

[0076] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0077] compound The present invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts or prodrugs thereof: [ka] (In the formula, TIFF0007720376000014.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, TIFF0007720376000015.tif22115 is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, TIFF0007720376000016.tif22115 is aryl or heteroaryl, R ais independently, for each occurrence, halogen, cyano, hydroxy, -NH, -NH(Ac), -NH(alkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), -NH(aryl), -NH(heteroaryl), -N(alkyl), -NHC(O)(alkyl), -CH(alkyl)NH, -CH(hydroxyalkyl)NH, -CH(haloalkyl)NH, -CH(cycloalkyl)NH, -CH(heterocycloalkyl)NH, -CH(aryl)NH, -CH(heteroaryl)NH, -CHNHC(O)(alkyl) ), —C(O)NH, —C(O)(alkyl), —SO NH, —SO (cycloalkyl), —SO (heterocycloalkyl), —SO (alkyl), —SO (aryl), or —SO (heteroaryl), or selected from the group consisting of substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; R b are independently, for each occurrence, halogen, cyano, -CH2(OCH2CH2) q OCH3, -alkylene- (branched or unbranched polyethylene glycol), -alkylene-O- (branched or unbranched polyethylene glycol), or -NR j R k or a substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl, hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, (heteroarylalkoxy)alkyl, (arylalkoxy)alkyl, (aryloxy)alkyl, ((cycloalkyl)alkoxy)alkyl, ((heterocycloalkyl)alkoxy)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkylene-NR j R k, tosyl, -SO2(alkyl), -SO2(cycloalkyl), -CO(alkyl), -CO(aryl), -CO(heteroaryl), -CO(cycloalkyl), -CO(heterocycloalkyl), -CONH(alkyl), -CONH(arylalkyl), -CONH(heteroarylalkyl), -CON(alkyl), -CONH(heterocycloalkyl), and -CONH(cycloalkyl); R c are independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, alkyl, cycloalkyl, and heterocycloalkyl; R 1 is selected from the group consisting of -NH, -COOH, -CHCOOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(arylalkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CH(NH(CO)(aryl substituted cycloalkyl))COOH, -CH(NH(CO)(heteroaryl substituted cycloalkyl))COOH, -CH(S(alkyl))COOH, -CO(NH)CH(substituted or unsubstituted aryl), -CO(NH)CH(substituted or unsubstituted heteroaryl), -CO(NH)(substituted or unsubstituted aryl), -CO(NH)(substituted or unsubstituted heteroaryl), and -CH(tetrazolyl); n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is an integer from 1 to 20, J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, -CH(cycloalkyl)-, -N((C(O)O)arylalkyl)-, -N((C(O)O)heteroarylalkyl)-, or -N(C(O)arylalkyl)-; K is —C(O)—, —NH—, —CH—, —O—, —S—, —S(O)—, —SO—, —N(alkyl)-, —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-, —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-; wherein at least one of J and K is —C(O)—, —CH—, or —CH(alkyl)-; L is a bond, -CH2-, -CH2CH2-, or -CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )-, -C(=CHR L )—, —S(O)—, and —S(O)—; where R L is H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2 is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl; R j and R k are each independently H or selected from the group consisting of substituted or unsubstituted alkyl, aminoalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CO(aryl), —CO(arylalkyl), —CO(heteroarylalkyl), and —CO((heterocycloalkyl)alkyl); U is N or CR 3 and R 3 is H, halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, haloalkyl, -CN, -CONH2, -CO2H, -CH2CO2H, -NH2, hydroxyalkyl, aminoalkyl, -OH, -NH(alkyl), -N(alkyl)2, thioalkyl, or -S(alkyl); V is N, CH, C(halogen), or C(alkyl); The stereochemical configuration at any chiral center is R, S, or a mixture of R and S).

[0078] In some embodiments, the compound of Formula (I) has the structure of Formula (Ia): [ka] (In the formula, W is N, CH, or CR c and X is N, CH, or CR c and Y is N, CH, or CR c and Z is N, CH, or CR c (It is).

[0079] In certain embodiments, TIFF0007720376000018.tif21115 is naphthyl, indenyl, cyclopentyl, pyrrolidinyl, phenyl, benzofuranyl, thiophenyl, or pyridinyl.

[0080] In certain embodiments, TIFF0007720376000019.tif21115 is phenyl, thiophenyl, or pyridinyl, preferably phenyl.

[0081] In certain embodiments, the compound of Formula (I) has the structure of Formula (Ib): [ka]

[0082] In certain embodiments, p is 1.

[0083] In certain such embodiments, R ais halogen, cyano, hydroxy, —NH, —NH(Ac), —NH(alkyl), —N(alkyl), —NHC(O)(alkyl), —CHNHC(O)(alkyl), —C(O)NH, or —C(O)(alkyl), or is selected from the group consisting of substituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl.

[0084] In other such embodiments, R a is halogen, cyano, —NH 2 , —NH(Ac), —C(O)CH 3 , —C(O)NH 2 , hydroxymethyl, or substituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy, alkyl, or aminoalkyl.

[0085] In other such embodiments, R a is halogen, —NH(Ac), —C(O)CH, or substituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy, alkyl, or aminoalkyl. In further such embodiments, R a is alkyl, cycloalkyl, or halogen.

[0086] Alternatively, in some embodiments, p is 0.

[0087] In certain embodiments, R 1 is -CH2COOH.

[0088] Alternatively, in some embodiments, R 1 is —CO(NH)CH 2 (substituted or unsubstituted aryl).

[0089] In certain embodiments, J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, or -N(C(O)arylalkyl)-; K is —C(O)—, —NH—, —O—, —CH—, —S—, —S(O)—, —SO—, —N(alkyl)-, —CH(alkyl)-, or —N(C(O)arylalkyl)-.

[0090] In some embodiments, -JK- is selected from the group consisting of -C(O)-NH-, -NH-C(O)-, and -CHO-, preferably -CHO-.

[0091] In certain embodiments, U is N or CR 3 and R 3 is H, halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, or haloalkyl.

[0092] In certain embodiments, U is CH. In further embodiments, V is CH.

[0093] Alternatively, in some embodiments, U is CR 3 and R 3 is H, halogen, alkyl, alkoxy, or haloalkyl.

[0094] In some embodiments, the compound of Formula (I) has the structure of Formula (Ic): [ka]

[0095] Alternatively, in some embodiments, the compound of Formula (I) has the structure of Formula (Id): [ka]

[0096] In still further embodiments, the compound of Formula (I) has the structure of Formula (Ie): [ka]

[0097] In still further embodiments, the compound of formula (I) has the structure of formula (If): [ka]

[0098] In any of the preceding embodiments, TIFF0007720376000025.tif22115 can be heteroaryl. For example, in some embodiments, TIFF0007720376000026.tif22115 is furyl, oxazolyl, isoxazolyl, thiophenyl, pyrrolyl, pyrazolyl, or imidazolyl. TIFF0007720376000027.tif22115 is furyl, thiophenyl, or pyrrolyl, preferably furyl.

[0099] In some embodiments, m is 0.

[0100] In alternative embodiments, m is 1. In certain such embodiments, R b are independently, for each occurrence, halogen, cyano, -CH2(OCH2CH2) q OCH3 or -NR j R k or a substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl, hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, (heteroarylalkoxy)alkyl, (arylalkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkylene-NR j R k, tosyl, -SO2(alkyl), -SO2(cycloalkyl), -CO(alkyl), -CO(cycloalkyl), -CONH(alkyl), -CONH(arylalkyl), -CON(alkyl)2, and -CONH(cycloalkyl).

[0101] In certain embodiments, q is an integer from 1 to 5.

[0102] In other such embodiments, R b is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, and (cycloalkyl)alkyl. b is a substituted or unsubstituted -alkylene-NR j R k is.

[0103] In other alternative embodiments, m is 2. In certain such embodiments, each R b is alkyl.

[0104] In certain embodiments, each of W, X, Y, and Z is CH.

[0105] In certain embodiments, at least one of W, X, Y, and Z is CR c For example, Z is CR c and / or Y may be CR c In certain such embodiments, R c is halogen, -OH, -NR j R k In certain preferred embodiments, R c is a halogen, for example, fluoride.

[0106] Alternatively, at least one of W, X, Y, and Z is N. For example, Z can be N. Alternatively, Y can be N.

[0107] In some embodiments, L is a bond, —CH—, —CHCH—, —CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )- and -C(=CHR L )-.

[0108] In some embodiments, L is -CH2-.

[0109] In certain embodiments of compounds of formula (I), TIFF0007720376000028.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, TIFF0007720376000029.tif22115 is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, TIFF0007720376000030.tif22115 is aryl or heteroaryl, R a is independently, at each occurrence, selected from the group consisting of halogen, cyano, hydroxy, —NH, —NH(Ac), —NH(alkyl), —N(alkyl), —NHC(O)(alkyl), —CHNHC(O)(alkyl), —C(O)NH, —C(O)(alkyl), optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; R b are independently, for each occurrence, halogen, cyano, -NR j R k, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl, hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -alkylene-NR j R k , tosyl, -SO2(alkyl), -SO2(cycloalkyl), -CO(alkyl), -CO(cycloalkyl), -CONH(alkyl), -CON(alkyl), and -CONH(cycloalkyl); R c are independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, and alkyl; R 1 is selected from the group consisting of: -NH, -CHCOOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(arylalkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CH(NH(CO)(aryl-substituted cycloalkyl))COOH, -CO(NH)CHaryl, -CO(NH)CHheteroaryl, -CO(NH)aryl, and -CO(NH)heteroaryl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, or -CH(alkyl)-; K is —C(O)—, —NH—, —O—, —CH—, —S—, —S(O)—, —SO—, —N(alkyl)-, or —CH(alkyl)-; wherein at least one of J and K is —C(O)—, —CH—, or —CH(alkyl)-; L is a bond, -CH2-, -CH2CH2-, or -CHR 2-, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )- and -C(=CHR L )-, where R L is H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2 is alkyl, hydroxyalkyl, or haloalkyl; R j and R k are each independently selected from the group consisting of H, alkyl, aminoalkyl, (heterocycloalkyl)alkyl, and heterocycloalkyl; U is N or CR 3 and R 3 is H, halogen, alkyl, alkoxy, or haloalkyl; V is N or CH.

[0110] In certain embodiments, the compound of formula (I) is selected from the compounds in the following table, and pharmaceutically acceptable salts and prodrugs thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0111] In other embodiments, the present invention provides compounds having the structure of formula (II-g), or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, TIFF0007720376000082.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, TIFF0007720376000083.tif22115 is aryl or heteroaryl, R ais independently, for each occurrence, halogen, cyano, hydroxy, -NH, -NH(Ac), -NH(alkyl), -NH(cycloalkyl), -NH(heterocycloalkyl), -NH(aryl), -NH(heteroaryl), -N(alkyl), -NHC(O)(alkyl), -CH(alkyl)NH, -CH(hydroxyalkyl)NH, -CH(haloalkyl)NH, -CH(cycloalkyl)NH, -CH(heterocycloalkyl)NH, -CH(aryl)NH, -CH(heteroaryl)NH, -CHNHC(O)(alkyl) ), —C(O)NH, —C(O)(alkyl), —SO NH, —SO (cycloalkyl), —SO (heterocycloalkyl), —SO (alkyl), —SO (aryl), or —SO (heteroaryl), or selected from the group consisting of substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; T 1 are N, CH, and NR T1 , or CR T1 and T 2 is NR T2 or CR T2 and T 3 are N, CH, and NR T3 , or CR T3 and where: (a)T 1 is CR T1 Or NR T1 and R T1 and R T2 together with the intervening atoms form an optionally substituted cycloalkyl, aryl, or heteroaryl ring; T 3 is N or CH, or (b)T 3 is CR T3 Or NR T3 and RT3 and R T2 together with the intervening atoms form an optionally substituted heteroaryl ring; T 1 is N or CH, (a)T 2 But NR T2 (b) T 3 is N, or (c) T 1 But NR T1 There is at least one thing that R 1 is selected from the group consisting of -NH, -COOH, -CHCOOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(arylalkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CH(NH(CO)(aryl substituted cycloalkyl))COOH, -CH(NH(CO)(heteroaryl substituted cycloalkyl))COOH, -CH(S(alkyl))COOH, -CO(NH)CH(substituted or unsubstituted aryl), -CO(NH)CH(substituted or unsubstituted heteroaryl), -CO(NH)(substituted or unsubstituted aryl), -CO(NH)(substituted or unsubstituted heteroaryl), and -CH(tetrazolyl); n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, -CH(cycloalkyl)-, -N((C(O)O)arylalkyl)-, -N((C(O)O)heteroarylalkyl)-, or -N(C(O)arylalkyl)-; K is —C(O)—, —NH—, —CH—, —O—, —S—, —S(O)—, —SO—, —N(alkyl)-, —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-, —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-; R care independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, alkyl, cycloalkyl, and heterocycloalkyl; L is a bond, -CH2-, -CH2CH2-, or -CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )-, -C(=CHR L )—, —S(O)—, and —S(O)—; where R L is H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2 is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl; V is N or CH; The stereochemical configuration at any chiral center is R, S, or a mixture of R and S).

[0112] In another embodiment, the present invention provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, TIFF0007720376000085.tif21115 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, R ais independently, at each occurrence, selected from the group consisting of halogen, cyano, hydroxy, —NH, —NH(Ac), —NH(alkyl), —N(alkyl), —NHC(O)(alkyl), —CHNHC(O)(alkyl), —C(O)NH, —C(O)(alkyl), optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; T 1 are N, CH, and NR T1 , or CR T1 and T 2 is NR T2 or CR T2 and T 3 are N, CH, and NR T3 , or CR T3 and where: (a)T 1 is CR T1 Or NR T1 and R T1 and R T2 together with the intervening atoms form an optionally substituted cycloalkyl, aryl, or heteroaryl ring; T 3 is N or CH, or (b)T 3 is CR T3 Or NR T3 and R T3 and R T2 together with the intervening atoms form an optionally substituted heteroaryl ring; T 1 is N or CH, (a)T 2 But NR T2 (b) T 3 is N, or (c) T 1 But NR T1 There is at least one thing that R 1-NH2, -CH2COOH, -CH(NH(CO)(alkyl))COOH, selected from the group consisting of -CH(NH(CO)(cycloalkyl))COOH, -CO(NH)CHaryl, -CO(NH)CHheteroaryl, -CO(NH)aryl, and -CO(NH)heteroaryl; p is 0, 1, or 2; J is -C(O)-, -NH-, -CH2-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, or -CH(alkyl)-; K is —C(O)—, —NH—, —O—, —CH—, —S—, —S(O)—, —SO—, —N(alkyl)-, or —CH(alkyl)-; wherein at least one of J and K is —C(O)—, —CH—, or —CH(alkyl)-; W is N, CH, or CR c and X is N, CH, or CR c and Y is N, CH, or CR c and Z is N, CH, or CR c and R c are independently, for each occurrence, halogen, -OH, -NR j R k , alkoxy, and alkyl; L is a bond, -CH2-, -CH2CH2-, or -CHR 2 -, -CF2-, -CFR 2 -, -C(O)-, -C(=NR L )- and -C(=CHR L )-, where R L is H or alkyl, or R L and R c together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R 2is alkyl, hydroxyalkyl, or haloalkyl; V is N or CH; The stereochemical configuration at any chiral center is R, S, or a mixture of R and S).

[0113] In certain embodiments, TIFF0007720376000086.tif21115 is phenyl, thiophenyl, furyl, pyrazole, or pyridinyl, preferably phenyl.

[0114] In certain embodiments, the compound of Formula (II) has the structure of Formula (IIa): [ka]

[0115] In certain embodiments of Formula (II) or Formula (IIa), p is 1. In certain such embodiments, R a is alkyl or alkoxy.

[0116] In certain embodiments, p is 0.

[0117] In certain embodiments, R 1 is -CH2COOH.

[0118] In some embodiments, -JK- is selected from the group consisting of -C(O)-NH-, -NH-C(O)-, and -CHO-, preferably -CHO-.

[0119] In certain embodiments, U is CH. In further embodiments, V is CH.

[0120] In certain embodiments, each of W, X, Y, and Z is CH.

[0121] In certain embodiments, at least one of W, X, Y, and Z is CRc For example, Z is CR c and / or Y may be CR c In certain such embodiments, R c is a halogen, for example, fluoride.

[0122] Alternatively, at least one of W, X, Y, and Z is N. For example, Z can be N. Alternatively, Y can be N.

[0123] In some embodiments, L is -CH2-.

[0124] In certain embodiments of compounds of Formula (II) or Formula (IIa), T 1 is CR T1 and R T1 and R T2 together with the intervening atoms form an optionally substituted heteroaryl ring, such as pyrrole, imidazole, or 1,2,4-triazole.

[0125] In an alternative embodiment of the compound of Formula (II) or Formula (IIa), T 3 is CR T3 and R T3 and R T2 together with the intervening atoms form an optionally substituted heteroaryl ring, such as pyrrole, imidazole, 1,2,4-triazole, or pyridine.

[0126] In certain embodiments, the compound of formula (II) is selected from the compounds in the following table, and pharmaceutically acceptable salts and prodrugs thereof: [ka] [ka] [ka] [ka]

[0127] Pharmaceutical Composition The present invention provides pharmaceutical compositions each comprising one or more compounds of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention (which may include pharmaceutically acceptable salts and / or prodrugs thereof) and a pharmaceutically acceptable carrier.

[0128] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compound of the present invention, which may be an agent useful in the treatment of a disease or condition characterized by abnormal complement system activity.

[0129] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0130] How to use The present invention provides compounds, and pharmaceutically acceptable salts and prodrugs thereof, that are useful for treating or preventing diseases or conditions characterized by abnormal complement system activity.

[0131] In certain aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, for use as a medicament.

[0132] In certain aspects, the present invention provides methods for treating or preventing diseases or conditions characterized by abnormal complement system activity. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, thereby treating or preventing the disease or condition characterized by abnormal complement system activity. By reducing the subject's complement system activity, the disease or condition characterized by abnormal complement system activity is treated.

[0133] Alternatively, in certain embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, for treating a disease or condition characterized by abnormal complement system activity.

[0134] Alternatively, in certain aspects, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for use in the treatment of a disease or condition characterized by abnormal complement system activity.

[0135] As used herein, a "disease or condition characterized by abnormal complement system activity" refers to any disease or condition in which it is desirable to reduce complement system activity. For example, it may be desirable to reduce complement system activity in situations of inappropriate or over-activation of the complement system.

[0136] In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immunological disorder.

[0137] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

[0138] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a kidney disease.

[0139] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

[0140] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

[0141] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

[0142] In certain embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

[0143] In certain embodiments, the disease or condition is atypical hemolytic uremic syndrome.

[0144] In certain embodiments, the disease or condition is organ transplant rejection.

[0145] In certain embodiments, the disease or condition is myasthenia gravis.

[0146] In certain embodiments, the disease or condition is neuromyelitis optica.

[0147] In certain embodiments, the disease or condition is membranoproliferative glomerulonephritis.

[0148] In certain embodiments, the disease or condition is dense deposit disease.

[0149] In certain embodiments, the disease or condition is cold agglutinin disease.

[0150] In certain embodiments, the disease or condition is fulminant antiphospholipid syndrome.

[0151] In other embodiments, the disease or condition characterized by abnormal complement system activity is adult respiratory distress syndrome, myocardial infarction, pneumonia, hyperacute rejection (transplant rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barré syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, organ rejection (transplant), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis.

[0152] In other embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

[0153] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a hematological disorder.

[0154] In another embodiment, the disease or condition characterized by abnormal complement system activity is a visual disorder or an eye disorder.

[0155] In certain embodiments, the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

[0156] Formulation, route of administration, and dosage The compounds of the present invention, and pharmaceutically acceptable salts or prodrugs thereof, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms consistent with the selected route of administration, e.g., oral or parenteral, intravenous, intraperitoneal, intramuscular, topical, or subcutaneous. Additional routes of administration are also contemplated by the present invention.

[0157] Thus, the compounds may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentage of the compositions and preparations may vary and may conveniently be about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0158] Tablets, troches, pills, capsules, etc. may also contain the following diluents and carriers: binders such as gum tragacanth, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavoring agents such as peppermint, wintergreen oil, or cherry flavor. When the unit dosage form is a capsule, in addition to the above-mentioned materials, it may contain liquid carriers such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, etc. Syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavor. Of course, any material used to prepare any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0159] The active compound can also be administered intravenously or intraperitoneally by infusion or injection.The solution of the active compound or its salt can be prepared in water or a physiologically acceptable aqueous solution, and optionally can be mixed with a non-toxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and their mixtures, and in oil.These preparations contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0160] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or powders containing the active ingredient, optionally encapsulated in liposomes, suitable for the preparation of extemporaneous sterile injectable solutions or dispersions. In all cases, the ultimate dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage. Liquid carriers or vehicles can be solvents or liquid dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0161] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients as listed above, and, if necessary, filtering and sterilizing. In the case of sterile powders for preparing sterile injectable solutions, the preparation method can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0162] For topical administration, the compounds can be applied in pure form (i.e., when they are liquids). However, it is generally desirable to administer the compounds to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which can be solid or liquid.

[0163] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol, or glycol, or water-alcohol / glycol blends, in which the compound can be dissolved or dispersed at an effective concentration, optionally with the use of a non-toxic surfactant. Adjuvants such as fragrances and additional antibacterial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-action or aerosol sprayer.

[0164] Thickening agents such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified cellulose or modified inorganic materials may also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps and the like for direct application to the user's skin.

[0165] Examples of useful dermatological compositions that can be used to deliver the compounds of the present invention to the skin are known in the art; see, e.g., Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

[0166] Useful dosages of the compounds of the invention can be determined, at least initially, by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated herein by reference.

[0167] The amount of the compound, or pharmaceutically acceptable salt or prodrug thereof, required for use in therapy will vary depending not only on the particular compound, salt, or prodrug selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.

[0168] In general, however, suitable doses may range from about 0.5 to about 100 mg / kg body weight of recipient / day, e.g., from about 3 to about 90 mg / kg body weight / day, from about 6 to about 75 mg / kg body weight / day, from about 10 to about 60 mg / kg body weight / day, or from about 15 to about 50 mg / kg body weight / day.

[0169] The compounds of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, can be conveniently formulated into unit dosage forms, for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, formulated into such a unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more subdoses per day. The subdose itself may be further divided, for example, into a number of discrete, loosely spaced administrations.

[0170] The compounds of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, can also be administered in combination with other therapeutic agents, such as other agents useful in the treatment or prevention of ischemia, blood loss, or reperfusion injury. In certain embodiments, the compounds of the present invention, and pharmaceutically acceptable salts or prodrugs thereof, can also be administered in combination with one or more other therapeutic agents useful in the treatment or prevention of ocular disorders or eye disorders.

[0171] Other delivery systems may include sustained-release, delayed-release, or sustained-release delivery systems, as are well known in the art. Such systems can avoid repeated administration of active compounds, increasing convenience for patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. The use of long-term sustained-release implants may be desirable. Long-term release, as used herein, means that the delivery system or implant is constructed and arranged to deliver therapeutic concentrations of the active ingredient for at least 30 days, preferably 60 days.

[0172] In certain embodiments, the compounds of the present invention are formulated for intraocular administration, for example, by direct injection or insertion into or in connection with an intraocular medical device. In certain embodiments, the compounds of the present invention are formulated as eye drops. In certain embodiments, the compounds of the present invention can be administered via ocular delivery, for example, by local administration to the eye, including topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, suprachoroidal, or subtenon administration. The compounds of the present invention can be administered via ocular delivery, either alone or in combination with one or more additional therapeutic agents.

[0173] The compounds of the present invention can be formulated for attachment within medical devices, which can include a variety of conventional grafts, stents, including stent-grafts, catheters, balloons, baskets, or any other device that can be placed or permanently implanted within a body lumen. In certain instances, it would be desirable to have devices and methods that can deliver the compounds of the present invention to a body region being treated by an interventional technique.

[0174] In an exemplary embodiment, the compounds of the invention can be deposited within a medical device, such as a stent, and delivered to a treatment site for treatment of a body part.

[0175] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral arteries. Stent designs include those in U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor). Such designs include both metallic and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver drugs to sites of contact with the vascular system, as disclosed, for example, in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and International Patent Applications WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center).

[0176] The term "attached" means that the compound is coated, adsorbed, disposed, or otherwise incorporated into the device by methods known in the art. For example, the compound can be embedded in and released from a polymeric material coating or extending over the medical device ("matrix-type"), or can be surrounded by and released through a polymeric material ("reservoir-type"). In the latter example, the compound can be encapsulated within or bound to the polymeric material using one or more techniques for producing such polymeric materials known in the art. In other formulations, the compound can be linked to the surface of the medical device without the need for a coating, for example, by a detachable bond, and released over time, or removed by active mechanical or chemical processes. In other formulations, the compound can be in a permanently immobilized form, providing the compound at the implantation site.

[0177] In certain embodiments, the compounds may also be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices such as stents. The coatings produced from these components are typically homogeneous and are useful for coating many devices designed for implantation.

[0178] The polymer can be either a biostable polymer or a bioabsorbable polymer, depending on the desired release rate or the degree of polymer stability desired, although bioabsorbable polymers are often preferred for this embodiment because, unlike biostable polymers, they do not persist long after implantation and do not cause any adverse chronic local reactions. Bioabsorbable polymers that can be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), Included are polyphosphoesters, polyphosphoesterurethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), copoly(ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinkable or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art.Biostable polymers that have a relatively low chronic tissue reaction, such as polyurethane, silicone, and polyester, can also be used, provided they can be dissolved and cured or polymerized on the medical device, such as polyolefins, polyisobutylene, and ethylene-alpha-olefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatic compounds such as polystyrene, polyvinyl esters such as polyvinyl acetate; ethylene-methyl methacrylate copolymer, acrylonitrile-styrene copolymer, Other polymers such as ABS resins and copolymers with vinyl monomers and olefins, such as ethylene-vinyl acetate copolymers; pyran copolymers; polyhydroxypropylmethacrylamidephenol; polyhydroxyethylaspartamidephenol; polyethyleneoxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose may also be used.

[0179] The polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubing, prostheses, and the like.

[0180] In certain embodiments of the invention, the compounds of the invention are bound to a polymer or semipermeable polymer matrix formed into a stent or stent-graft device.

[0181] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be used for this purpose. Spraying methods include conventional methods as well as microdeposition techniques using inkjet-type dispensers. Additionally, the polymer can be deposited onto the implantable device using photopatterning, which places the polymer only on specific portions of the device. This coating of the device provides a uniform layer around the device, allowing for improved diffusion of various analytes through the device coating.

[0182] In certain embodiments of the present invention, the compound is formulated to be released from the polymer coating into the environment in which the medical device is placed. Preferably, the compound is released in a controlled manner over an extended time frame (e.g., several months) using at least one of several well-known techniques for polymeric carriers or layers that control elution. Some of these techniques are described in U.S. Patent Application No. 2004 / 0243225A1, the entire disclosure of which is incorporated herein by reference in its entirety.

[0183] Additionally, the reagents and reaction conditions of the polymer composition can be manipulated to thereby control the release of a compound from a polymer coating, as described, for example, in U.S. Pat. No. 6,770,729 (incorporated herein in its entirety). For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of a compound from a polymer coating. In a variation on this theme, the diffusion coefficient of one or more polymer coatings can be controlled to adjust the ability of an analyte present in the environment in which the medical device is placed (e.g., an analyte that promotes the breakdown or hydrolysis of a portion of the polymer) to access one or more components within the polymer composition (and thereby, for example, adjust the release of a compound from the polymer coating). Yet another embodiment of the present invention includes a device having multiple polymer coatings, each with multiple diffusion coefficients. In such an embodiment of the present invention, the release of a compound from the polymer coating can be adjusted by the multiple polymer coatings.

[0184] In yet another embodiment of the present invention, the release of the compound from the polymer coating is controlled by the presence of one or more endogenous or exogenous compounds, or alternatively by adjusting one or more properties of the polymer composition, such as the pH of the polymer composition. For example, certain polymer compositions can be designed to release the compound in response to a decrease in the pH of the polymer composition.

[0185] kit The invention also provides a kit comprising a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, and the other one or more therapeutic agents to a mammal to treat or prevent a disease or condition characterized by abnormal complement activity. In one embodiment, the mammal is a human.

[0186] It will be appreciated by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and can be made without departing from the scope of the invention or any embodiment thereof. [Example]

[0187] Having now described the invention in detail, the same will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0188] Scheme 1 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (1h) Step-1: Preparation of 2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b) To a solution of 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (1a) (3 g, 15.96 mmol, CAS# 918538-05-3) in DMF (50 mL) under an argon atmosphere was added 1-ethoxyvinyltri-n-butyltin (7.07 mL, 20.74 mmol, CAS# 97674-02-7) and bis(triphenylphosphine)palladium(II) chloride (0.56 g, 0.8 mmol). The mixture was heated with stirring at 100 °C for 30 min, cooled to room temperature, and diluted with EtOAc (150 mL). The reaction mixture was washed with water (50 mL), brine (30 mL), dried, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica (24 g), elution with 0 to 50% EtOAc in hexanes] to give 2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b) (2.2 g, 62% yield) as an orange oil.1 H NMR (300 MHz, DMSO-d6) δ 8.23 (dd, J = 2.6, 1.4 Hz, 1H), 7.34 (dd, J = 4.7, 1.4 Hz, 1H), 7.11 (dd, J = 4.7, 2.6 Hz, 1H), 5.64 (d, J = 2.4 Hz, 1H), 4.88 (d, J = 2.4 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H).

[0189] Step-2: Preparation of ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) Sodium periodate (1.17 g, 5.47 mmol) was suspended in water (9 mL) and sonicated until a clear solution (pH ∼4) was obtained. This solution was added to a solution of 2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b) (612 mg, 2.74 mmol) in 1,4-dioxane (40 mL). KMnO (43 mg, 0.27 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 7–8 using saturated aqueous KCO solution. The precipitate was filtered off and rinsed thoroughly with DCM (4 × 20 mL). The combined filtrate was washed with water, brine, dried, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0 to 60% EtOAc in hexanes] to give ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (yield 212 mg, 34%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.43 (dd, J = 2.5, 1.3 Hz, 1H), 7.45 (dd, J = 4.8, 1.3 Hz, 1H), 7.30 (dd, J = 4.8, 2.5 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0190] Step-3: Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (1e) To a solution of ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (150 mg, 0.67 mmol) in dioxane (6 mL) was added 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (192 mg, 0.77 mmol; CAS#199609-62-6), potassium triphosphate (282 mg, 1.33 mmol), tricyclohexylphosphine (56 mg, 0.2 mmol), and Pd(dba) (61 mg, 0.07 mmol) in water (1 mL). The mixture was degassed, backfilled with argon, and then heated at 125 °C for 30 min. The mixture was cooled to room temperature, diluted with EtOAc, washed with water, brine, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0-30% MeOH in DCM] to give 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (1e) (yield 150 mg, 61%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.21 - 8.08 (m, 3H), 7.53 (dd, J = 11.2, 5.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.14 - 7.08 (m, 1H), 7.06 - 7.00 (m, 1H), 4.22 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H).

[0191] Step-4: Preparation of methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1f) To a solution of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (1e) (95 mg, 0.26 mmol) in DMF (8 mL) was added methyl 2-(2-aminophenyl)acetate (51 mg, 0.31 mmol, CAS#35613-44-6), DIPEA (0.14 mL, 0.77 mmol), and HATU (118 mg, 0.31 mmol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (60 mL), washed with water (3×s), brine, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes from 0-100%] to give methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1f) (98 mg, 74% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.41 - 8.31 (m, 2H), 7.82 - 7.75 (m, 1H), 7.58 - 7.48 (m, 3H), 7.46 - 7.37 (m, 3H), 7.31 - 7.23 (m, 2H), 4.27 (d, J = 6.1 Hz, 2H), 3.89 (s, 2H), 3.56 (s, 3H), 1.41 (s, 9H).

[0192] Step-5: Preparation of methyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1g) To a solution of methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1f) (92 mg, 0.18 mmol) in DCM (8 mL) was added TFA (0.28 mL, 3.57 mmol). The resulting mixture was stirred at room temperature for 2 h and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] to give compound (1g) (73 mg, 98% yield) as a yellow solid. 23 mg was converted to the HCl salt and lyophilized to give the HCl salt of methyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1g) (25 mg) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H, D2O exchangeable), 8.69 - 8.62 (m, 1H), 8.58 (d, J = 7.5, 1.6 Hz, 1H), 8.50 - 8.39 (m, 3H, D2O exchangeable), 8.39 - MS (ES+): 416.3 (M+1);(ES-): 414.4 (M-1), 450.3 (M+Cl); HPLC, purity 92.70%.

[0193] Step-6: Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (1h) To a solution of methyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (1g) (62 mg, 0.15 mmol) in THF (10 mL) was added lithium hydroxide hydrate (63 mg, 1.49 mmol) in water (2 mL). The resulting mixture was stirred at room temperature overnight. THF was removed in vacuo, and the resulting residue was acidified to pH 4 with HCl (2 N). The resulting solid was collected by filtration, washed with water (3 × 2 mL), and dried under vacuum to give 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (1h) (36 mg, 61% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H, D2O exchangeable), 9.36 (s, 1H), 9.19 (s, 3H, D2O exchangeable), 8.43 - 8.33 (m, 1H), 8.33 - 8.21 (m, 1H), 8.00 - MS (ES+): 402.4 (M+1);(ES-): 400.4 (M-1);HPLC purity, 90.46%.

[0194] Scheme 2 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetic acid (2f) Step-1: Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate (2b) Compound 2b was prepared by the procedure reported in Step 3 of Scheme 1 using ethyl 2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate (2a) (200 mg, 0.88 mmol; CAS#1660116-32-4; Blaquiere, Nicole et al. in PCT International Application No. 2015025026 (February 26, 2015)) in DMF (20 mL). This was prepared from 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (251 mg, 0.97 mmol), potassium fluoride (169 mg, 2.91 mmol), tri-tert-butylphosphine (1.59 mL, 1.59 mmol), and Pd(dba) (162 mg, 0.18 mmol) under a nitrogen atmosphere by heating at 120 °C for 14 h. Workup and purification by flash column chromatography [silica (12 g), eluting with hexane / ethyl acetate (1:0 to 4:1)] afforded ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate (2b) (128 mg, 37% yield) as a colorless gum. 1 H NMR (300 MHz, DMSO-d6) δ 8.32 - 8.22 (m, 2H), 7.57 - 7.33 (m, 3H), 4.40 (q, J = 7.1 Hz, 2H), 4.22 (d, J = 6.2 Hz, 2H), 3.22 (t, J = 7.5 MS (ES+): 420.3 (M+Na).

[0195] Step-2: Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylic acid (2c) Compound 2c was prepared from ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate (2b) (125 mg, 0.31 mmol) in THF (10 mL) and MeOH (10 mL) using a solution of lithium hydroxide hydrate (81 mg, 1.89 mmol) in water (10 mL) according to the procedure reported in Step 6 of Scheme 1. Workup afforded 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylic acid (2c), which was used directly in the next step. MS (ES-) 368.4 (M-1).

[0196] Step-3: Preparation of methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2d) Compound 2d was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylic acid (2c) using methyl 2-(2-aminophenyl)acetate (104 mg, 0.63 mmol), DIPEA (0.22 mL, 1.26 mmol) and HATU (239 mg, 0.63 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with hexane / ethyl acetate (1:0 to 2:1)] to give methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2d) (127 mg) as a yellow solid, which was used directly in the next step. MS (ES+): 517.4 (M+1), 539.4 (M+Na); (ES-): 515.4 (M-1).

[0197] Step-4: Preparation of methyl 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2e) Compound 2e was prepared from methyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2d) (127 mg, 0.25 mmol) using TFA (0.57 mL, 7.38 mmol) in DCM (20 mL) according to the procedure reported in Step 5 of Scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), eluted with DCM / DMA-80 (1:0 to 4:1)] to give methyl 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2e) (68 mg, 66% yield over three steps) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.58 - 8.54 (m, 1H), 8.47 - 8.42 (m, 1H), 7.91 - 7.67 (m, 1H), 7.56 - 7.43 (m, 2H), 7.42 - 7.34 (m, 2H), 7.29 - 7.17 (m, 1H), 3.87 (s, 2H), 3.84 (s, 2H), 3.55 (s, 3H), 3.09 (t, J = 7.8 Hz, 2H), 2.21 - 2.07 (m, 2H);MS (ES+): 417.3 (M+1);(ES-) 415.3 (M-1).

[0198] Step-5: Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetic acid (2f) Compound 2f was prepared from methyl 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate (2e) (34 mg, 0.082 mmol) in THF (5 mL) and MeOH (5 mL) using a solution of lithium hydroxide hydrate (21 mg, 0.49 mmol) in water (5 mL) according to the procedure reported in Step 6 of Scheme 1. Workup afforded 2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetic acid (2f) (yield 24 mg, 73%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.46 (s, 1H), 9.27 (s, 3H), 8.46 - 8.23 (m, 1H), 7.87 - 7.77 (m, 1H), 7.55 - 7.47 (m, 2H), 7.30 - 7.19 (m, 2H), 7.13 - 7.05 (m, 1H), 4.11 (s, 2H), 3.42 (s, 2H), 3.08 (t, J = 7.8 Hz, 2H), 2.22 - 2.05 (m, 2H);MS (ES+): 403.3 (M+1);(ES-): 401.4 (M-1).

[0199] Scheme 3 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (3i) Step-1: Preparation of tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3c) Compound 3c was prepared by the procedure reported in Step 3 of Scheme 1 by dissolving 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3a) (5 g, 14.61 mmol; CAS#934524-10-4; Journal of Medicinal Chemistry, Vol. 1, No. 1, pp. 111-114, 2002) in dioxane (100 mL) according to the procedure reported in Step 3 of Scheme 1. tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (prepared according to the procedure reported by Su, Qibin et al. in Chemistry, 57(1), 144-158; 2014) was prepared from tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (3.25 g, 9.74 mmol; CAS#: 832114-05-3), potassium phosphate tripotassium (4.55 g, 21.43 mmol), tricyclohexylphosphine (0.82 g, 2.92 mmol), and Pd(dba) (0.89 g, 0.97 mmol) in water (1 mL) under argon atmosphere and heated at 120 °C for 1 h. This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-70% EtOAc in hexanes] to give tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3c) (yield 2.9 g, 58.0%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J = 4.1 Hz, 1H), 8.10 - 8.07 (m, 1H), 8.06 - 8.04 (m, 1H), 7.96 - 7.90 (m, 2H), 7.58 - 7.44 (m, 5H), 7.24 (d, J = 4.1 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 2.39 (s, 3H), 1.40 (s, 9H);MS (ES+): 535.3, 537.3 (M+Na);(ES-): 511.3, 513.3 (M-1).

[0200] Step-2: Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3d) Compound 3d was prepared from tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3c) (2.5 g, 4.87 mmol) in DMF (100 mL) using 1-ethoxyvinyltri-n-butyltin (2.16 mL, 6.34 mmol) and Pd(PhP) (0.28 g, 0.24 mmol) under argon atmosphere at 110 °C for 4 h according to the procedure reported in Scheme 1, Step 1. This was worked up and purified by flash column chromatography [silica (24 g), elution with 0-70% EtOAc in hexanes] to give tert-butyl 3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3d) (yield 1.7 g, 64%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 4.0 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.59 - 7.50 (m, 2H), 7.50 - 7.40 (m, 3H), 7.18 (d, J = 4.1 Hz, 1H), 5.72 (d, J = 1.7 Hz, 1H), 4.73 (d, J = 1.7 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 4.02 (q, J = 6.9 Hz, 2H), 2.38 (s, 3H), 1.52 (t, J = 6.9 Hz, 3H), 1.40 (s, 9H);MS (ES+): 571.4 (M+Na);(ES-): 547.4 (M-1).

[0201] Step-3: Preparation of ethyl 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (3e) Compound 3e was prepared from tert-butyl 3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3d) (1.5 g, 2.73 mmol) in 1,4-dioxane (50 mL) using sodium periodate solution (1.17 g, 5.47 mmol) and KMnO (2 × 86 mg, 2 × 0.55 mmol (second charge after 12 h)) in water (10 mL) according to the procedure reported in Scheme 1, Step 2. This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-60% EtOAc in hexanes] to give ethyl 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (3e) (500 mg, 33% yield) as a yellow solid. MS (ES+): 551.3 (M+1), 573.3 (M+Na); (ES-): 549.4 (M-1).

[0202] Step-4: Preparation of 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (3f) Compound 3f was prepared from ethyl 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (3e) (500 mg, 0.91 mmol) in THF (10 mL) using lithium hydroxide hydrate (76 mg, 1.82 mmol) in water (4 mL) according to the procedure reported in Step 6 of Scheme 1. Workup afforded 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (3f) (yield 145 mg, 43%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H, D2O exchangeable), 12.69 (d, J = 21.6 Hz, 1H, D2O exchangeable), 8.18 - 8.05 (m, 2H), 7.97 - 7.88 (m, 1H), 7.62 - 7.53 (m, 2H), 7.48 - 7.40 (m, 1H), 7.05 - 6.97 (m, 1H), 4.27 (d, J = 6.3 Hz, 2H), 1.41 (s, 9H);MS (ES-): 367.3 (M-1).

[0203] Step-5: Preparation of methyl 2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3g) Compound 3g was prepared from 4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (3f) (120 mg, 0.33 mmol) in DMF (5 mL) using methyl 2-(2-aminophenyl)acetate (161 mg, 0.98 mmol), DIPEA (0.11 mL, 0.65 mmol) and HATU (186 mg, 0.49 mmol) according to the procedure reported in Scheme 1, Step 4. Workup and purification by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes, 0-100% elution] afforded methyl 2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3 g) (42 mg, 25% yield) as a white solid. MS (ES+) 538.3 (M+1).

[0204] Step-6: Preparation of methyl 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3h) Compound 3h was prepared from methyl 2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3g) (40 mg, 0.078 mmol) in DCM (8 mL) using TFA (0.06 mL, 0.78 mmol). This gave methyl 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3h) (yield 13 mg, 40%), which was used directly in the next step.

[0205] Step-7: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (3i) To a solution of methyl 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (3h) (13 mg obtained in the above step) in MeOH (5 mL) was added NaOH (12 mg, 0.31 mmol) in water (1 mL) and stirred at room temperature for 2 h. MeOH was removed in vacuo, and the residue was acidified to pH 3 and purified by reverse-phase chromatography [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (3i) (2 mg, 6% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H, D2O exchangeable), 10.83 (s, 1H, D2O exchangeable), 8.49 - 8.23 (m, 5H, partially D2O exchangeable), 8.01 - 7.92 (m, 2H), 7.69 (d, J = 4.8 Hz, 2H), 7.43 - 7.32 (m, 2H), 7.27 - 7.12 (m, 2H), 4.28 - 4.14 (m, 2H), 3.77 (s, 2H);MS (ES+): 402.3 (M+1);(ES-): 436.3 (M+Cl); HPLC purity 98.03%.

[0206] Scheme 4 [ka] Preparation of (R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (4e) Step-1: Preparation of (R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (4b) Compound 4b was prepared from ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33 mmol) in dioxane (6 mL) according to the procedure reported in Scheme 1, Step 3, by conversion of (R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl tert-butyl carbamate (4a) (600 mg, 1.73 mmol; (R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (4b) (CAS#887254-66-2, prepared according to the procedure reported in PCT International Application No. 2015009977 (January 22, 2015)), a solution of tripotassium phosphate (564 mg, 2.66 mmol) in water (1 mL), tricyclohexylphosphine (112 mg, 0.4 mmol), and Pd(dba) (122 mg, 0.13 mmol) under argon atmosphere, heated at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0–30% MeOH in DCM] to give (R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (4b) (150 mg, 30% yield) as a yellow solid. MS (ES-): 381.3 (M-1).

[0207] Step-2: Preparation of (R)-2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)methyl acetate (4c) Compound 4c was prepared from (R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (4b) (150 mg, 0.39 mmol) in DMF (8 mL) using methyl 2-(2-aminophenyl)acetate (78 mg, 0.47 mmol), DIPEA (0.21 mL, 1.18 mmol) and HATU (179 mg, 0.47 mmol) according to the procedure reported in Scheme 1, Step 4. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes, 0-100% elution] to give (R)-2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)methyl acetate (4c) (60 mg, 29% yield) as a yellow solid. MS (ES+): 552.4 (M+1).

[0208] Step-3: Preparation of (R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)methyl acetate (4d) Compound 4d was prepared from (R)-2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)methyl acetate (4c) (60 mg, 0.11 mmol) in DCM (8 mL) using TFA (0.087 mL, 1.13 mmol) according to the procedure reported in Scheme 1, Step 5. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] to give (R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)methyl acetate (4d) (12 mg, 25% yield). MS (ES+): 452.3 (M+Na);(ES-): 428.3 (M-1).

[0209] Step-4: Preparation of (R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (4e) To a solution of (R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)methyl acetate (4d) (12 mg, 0.028 mmol) in MeOH (5 mL) was added a solution of NaOH (18 mg, 0.45 mmol) in water (1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo to remove MeOH. The residue was acidified to pH 3 and purified by reverse-phase chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give (R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (4e) (yield 7 mg, 15%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H, D2O exchangeable), 10.89 (s, 1H, D2O exchangeable), 8.70 - 8.46 (m, 5H, partially D2O exchangeable), 8.42 - 8.35 (m, 1H), 7.89 - 7.81 (m, 1H), 7.78 - 7.69 (m, 1H, , D2O exchangeable), 7.69 - 7.58 (m, 2H), 7.46 - 7.35 (m, 2H), 7.33 - 7.21 (m, 2H), 4.65 - 4.47 (m, 1H), 3.81 (s, 2H), 1.60 (d, J = 6.7 Hz, 3H);MS (ES+): 438.3 (M+Na);(ES-): 414.4 (M-1);HPLC purity, 98.78%.

[0210] Scheme 5 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetic acid (5h) Step-1: Preparation of tert-butyl 3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a) Compound 5a was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (1a) (1 g, 5.32 mmol) in dioxane (50 mL) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (1.48 g, 4.43 mmol), potassium phosphate tribasic (1.88 g, 8.86 mmol), tricyclohexylphosphine (373 mg, 1.33 mmol) and Pd(dba) (0.406 g, 0.44 mmol) in water (5 mL) under argon atmosphere and heated at 75 °C for 60 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-30% MeOH in DCM] to give tert-butyl 3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a) (yield 1 g, 63%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.34 - 8.27 (m, 1H), 8.08 - 7.98 (m, 2H), 7.65 - 7.50 (m, 3H), 7.40 - 7.30 (m, 1H), 7.24 - 7.14 (m, 1H), 4.27 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H).

[0211] Step-2: Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5b) Compound 5b was prepared from tert-butyl 3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a) (3.2 g, 8.92 mmol) in DMF (60 mL) using 1-ethoxyvinyltri-n-butyltin (3.65 mL, 10.70 mmol) and Pd(PPh3)4 (0.515 g, 0.45 mmol) under argon atmosphere at 110 °C for 10 h according to the procedure reported in Scheme 1, Step 1. This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-70% EtOAc in hexanes] to give tert-butyl 3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5b) (3.1 g, 88% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.28 - 8.21 (m, 1H), 8.11 - 8.00 (m, 2H), 7.64 - 7.47 (m, 3H), 7.22 (dd, J = 4.6, 1.4 Hz, 1H), 7.12 - 7.04 (m, 1H), 5.74 (d, J = 1.8 Hz, 1H), 4.79 (d, J = 1.8 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.99 (q, J = 6.9 Hz, 2H), 1.46 - 1.31 (m, 12H).

[0212] Step-3: Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylate (5c) Compound 5c was prepared from tert-butyl 3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5b) (500 mg, 1.27 mmol) in 1,4-dioxane (50 mL) using sodium periodate solution (542 mg, 2.54 mmol) and KMnO (120 mg, 0.76 mmol, first charge and second charge after 12 h of 40 mg, 0.25 mmol) in water (20 mL) according to the procedure reported in Scheme 1, Step 2. This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-60% EtOAc in hexanes] to give ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylate (5c) (yield 255 mg, 51%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.45 - 8.39 (m, 1H), 8.10 - 8.01 (m, 2H), 7.64 - 7.49 (m, 3H), 7.38 - 7.33 (m, 1H), 7.33 - 7.26 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 1.47 - 1.31 (m, 12H);MS (ES+): 397.3 (M+1);(ES-): 395.4 (M-1)

[0213] Step-4: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid (5d) Compound 5d was prepared from ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylate (5c) (1.6 g, 4.04 mmol) in MeOH / THF (20 mL, 1:1) using sodium hydroxide (258 mg, 6.46 mmol) in water (3 mL) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by flash column chromatography [silica (24 g), elution with 0-10% MeOH in DCM] to give 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid (5d) (960 mg, 65% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.43 - 8.33 (m, 1H), 8.11 - 8.02 (m, 2H), 7.64 - 7.47 (m, 3H), 7.34 (dd, J = 4.6, 1.4 Hz, 1H), 7.32 - 7.25 (m, 1H), 4.27 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H);MS (ES+): 369.3 (M+1);(ES-): 367.3 (M-1).

[0214] Step-5: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate (5f) Compound 5f was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid (5d) (200 mg, 0.54 mmol) in DMF (10 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (117 mg, 0.65 mmol), DIPEA (0.142 mL, 0.81 mmol) and HATU (248 mg, 0.65 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate (5f) (yield 212 mg, 74%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.44 (dd, J = 2.7, 1.3 Hz, 1H), 8.29 - 8.18 (m, 2H), 7.85 - 7.75 (m, 1H), 7.66 - 7.53 (m, 3H), 7.47 - 7.41 (m, 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.34 - 7.29 (m, 1H), 7.28 - 7.19 (m, 1H), 4.30 (d, J = 6.2 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 1.40 (s, 9H), 0.99 (t, J = 7.1 Hz, 3H);MS (ES+): 530.4 (M+1);(ES-): 528.5 (M-1).

[0215] Step-6: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate (5 g) Compound 5g was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate (5f) (210 mg, 0.4 mmol) in DCM (10 mL) using TFA (0.31 mL, 3.97 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate (5 g) (yield 152 mg, 89%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H, D2O exchangeable), 8.62 (s, 3H, D2O exchangeable), 8.51 - 8.44 (m, 2H), 8.42 - 8.35 (m, 1H), 7.86 - 7.80 (m, 1H), 7.80 - 7.64 (m, 3H), 7.43 - 7.31 (m, 3H), 7.28 - 7.20 (m, 1H), 4.23 - 4.17 (m, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 430.3 (M+1), 452.3 (M+Na); HPLC purity, 99.46%.

[0216] Step-7: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetic acid (5h) Compound 5h was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate (5g) (70 mg, 0.16 mmol) in MeOH (10 mL) using sodium hydroxide (33 mg, 0.82 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetic acid (5h) (yield 39 mg, 60%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H, D2O exchangeable), 10.78 (s, 1H, D2O exchangeable), 8.59 - 8.32 (m, 6H), 7.90 - 7.83 (m, 1H), 7.84 - 7.77 (m, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.64 (dd, J = 4.7, 1.3 Hz, 1H), 7.42 - 7.31 (m, 3H), 7.27 - 7.18 (m, 1H), 4.22 (s, 2H), 3.75 (s, 2H); (ES+): 402.3 (M+1);(ES-): 400.4 (M-1), 436.3 (M+Cl); HPLC purity, 99.40%.

[0217] Scheme-6 [ka] Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetic acid (6e) Step-1: Preparation of ethyl 2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b) To a solution of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (6a) (650 mg, 3.31 mmol; CAS# 155735-02-7) in MeOH (10 mL) was added ethyl 2-(2-aminophenyl)acetate (5e) (593 mg, 3.31 mmol; CAS# 87-25-2) and N-((ethylimino)methylene)-N,N-dimethylpropane-1,3-diamine hydrochloride (EDCI, 697 mg, 3.64 mmol). The resulting mixture was stirred at room temperature overnight and diluted with EtOAc (60 mL). The organic layer was separated, washed with water (3×s), brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b) (yield 770 mg, 65%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.15 (d, J = 2.1 Hz, 1H), 8.22 - 8.08 (m, 2H), 8.03 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 1.3 Hz, MS (ES+): 358.2 (M+1), 380.2 (M+Na).

[0218] Step-2: Preparation of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6d) Compound 6d was prepared from ethyl 2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b) (250 mg, 0.70 mmol) in dioxane (3 mL) according to the procedure reported in Step 3 of Scheme 1, using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (196 mg, 1.05 mmol; CAS#146285-80-5), potassium phosphate tripotassium (1.3 M solution) (1.61 mL, 2.10 mmol), tricyclohexylphosphine (58.8 mg, 0.210 mmol) and Pd(dba) (64.0 mg, 0.07 mmol) under argon atmosphere and microwave heating at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6d) (yield 195 mg, 65%) as a white solid. 1 H NMR (300 MHz, DMSO-d6 (with D2O)) δ 9.29 (s, 1H), 8.73 (s, 1H), 8.33 - 8.26 (m, 1H), 7.99 - 7.89 (m, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.60 - 7.52 (m, 1H), 7.43 - 7.33 (m, 2H), 7.33 - 7.22 (m, 1H), 4.16 - 4.09 (m, 2H), 3.93 - 3.92 (m, 2H), 3.83 (s, 2H), 0.99 - 0.89 (m, 3H);MS (ES+): 429.3 (M+1);451.3 (M+Na);(ES-): 463.4 (M+Cl);HPLC purity 99.56%.

[0219] Step-3: Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetic acid (6e) Compound 6e was prepared from ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6d) (108 mg, 0.25 mmol) in MeOH (10 mL) using sodium hydroxide (50.4 mg, 1.26 mmol) in water (2.0 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetic acid (6e) (yield 90 mg, 89%) as a white solid. 1 H NMR (300 MHz, DMSO-d6 (with D2O)) δ 9.29 (d, J = 1.7 Hz, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.42 - 7.31 (m, 2H), 7.31 - 7.21 (m, 1H), 4.12 (s, 2H), 3.77 (s, 2H);MS (ES+): 401.3 (M+1);(ES-): 399.4 (M-1), 435.4 (M+Cl);HPLC purity, 100%.

[0220] Scheme-7 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetic acid (7d) Step-1: Preparation of ethyl 2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) To a solution of 4-bromo-1H-indazole-6-carboxylic acid 7a (500 mg, 2.07 mmol; CAS# 885523-43-3) in MeOH (10 mL), ethyl 2-(2-aminophenyl)acetate 5e (372 mg, 2.07 mmol) and N-((ethylimino)methylene)-N,N-dimethylpropane-1,3-diamine hydrochloride (EDCI, 437 mg, 2.28 mmol) were added, stirred at room temperature overnight, and concentrated in vacuo to remove MeOH. The resulting residue was taken up in water (5 mL) and TBME (3 mL), stirred at room temperature for 30 minutes, and the solid was collected by filtration to give ethyl 2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate 7b (650 mg, 78% yield) as a tan solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.87 (s, 1H), 10.22 (s, 1H), 8.17 (s, 2H), 7.86 (s, 1H), 7.44 - 7.20 (m, 4H), 3.96 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H).

[0221] Step-2: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate (7c) Compound 7c was prepared from ethyl 2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) (300 mg, 0.75 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (210 mg, 1.12 mmol), potassium phosphate tripotassium (1.3 M solution) (1.72 mL, 2.24 mmol), tricyclohexylphosphine (63 mg, 0.22 mmol) and Pd(dba) (68 mg, 0.075 mmol) under argon atmosphere and microwave heating at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate (7c) (210 mg, 66%) as a white solid. 110 mg of the product was further purified by reverse-phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate (7c) (57 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6 (with D2O)) δ 10.28 (s, 1H, D2O exchangeable), 8.56 (s, 3H, D2O exchangeable), 8.47 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.91 - 7.81 (m, 2H), 7.68 - 7.54 (m, 2H), 7.46 - 7.39 (m, 1H), 7.39 - 7.31 (m, 2H), 7.31 - 7.22 (m, 1H), 4.15 (t, J = 5.9 Hz, 3H), 3.95 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 0.97 (t, J = 7.1 Hz, 3H);MS (ES+): 429.3 (M+1);451.3 (M+Na);(ES-): 463.4 (M+Cl);HPLC, purity 99.41%.

[0222] Step-3: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetic acid (7d) Compound 7d was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate (7c) (95 mg, 0.22 mmol) in MeOH (10 mL) using sodium hydroxide (44 mg, 1.11 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetic acid (7d) (40 mg, 45% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.75 (brs, 1H, D2O exchangeable), 10.28 (s, 1H, D2O exchangeable), 8.59 - 8.43 (m, 4H, partially D2O exchangeable), 8.19 (s, 1H), 8.00 (s, 1H), 7.91 - 7.82 (m, 2H), 7.67 - 7.54 (m, 2H), 7.51 - 7.44 (m, 1H), 7.40 - 7.30 (m, 2H), 7.30 - 7.19 (m, 1H), 4.20 - 4.15 (m, 2H), 3.72 (s, 2H);MS (ES+): 401.3 (M+1);423.3 (M+Na);(ES-): 399.3 (M-1), 435.3 (M+Cl);HPLC, purity, 100%.

[0223] Scheme-8 [ka] Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetic acid (8e) Step-1: Preparation of tert-butyl 3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (8a) To a stirred solution of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid (5d) (390 mg, 1.06 mmol) and N-methylmorpholine (0.13 mL, 1.17 mmol) in THF (5 mL) was added isobutyl chloroformate (0.15 mL, 1.17 mmol) at −5° C. After 10 min, the mixture was filtered through Celite, and the precipitate was washed with THF (3×5 mL). The filtrate was cooled to 0° C., and a solution of NaBH (60 mg, 1.59 mmol) in water (0.5 mL) was carefully added dropwise. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×). The combined organic layers were dried, filtered, and concentrated in vacuo to give tert-butyl 3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (8a) (300 mg, 80% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.19 - 8.11 (m, 1H), 8.07 - 7.95 (m, 2H), 7.63 - 7.45 (m, 3H), 7.21 - 7.13 (m, 1H), 7.11 - 7.03 (m, 1H), 5.51 (t, J = 6.3 Hz, 1H), 4.60 (d, J = 5.7 Hz, 2H), 4.26 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H);MS (ES+): 355.3 (M+1);(ES-): 353.3 (M-1).

[0224] Step-2: Preparation of ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8c) To a solution of tert-butyl 3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (8a) (250 mg, 0.71 mmol) in THF (5 mL) at 0 °C was added DIAD (0.18 mL, 0.92 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (165 mg, 0.917 mmol; CAS#41873-65-8), and triphenylphosphine (241 mg, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc (3x). The organic layers were combined, washed with saturated aqueous NH4Cl, water, brine, dried, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc in hexanes] to give ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8c) (yield 300 mg, 82%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.23 - 8.17 (m, 1H), 8.08 - 7.94 (m, 2H), 7.63 - 7.48 (m, 3H), 7.31 - 7.16 (m, 4H), 7.15 - 7.09 (m, 1H), 6.93 (td, J = 7.3, 1.3 Hz, 1H), 5.22 (s, 2H), 4.26 (d, J = 6.2 Hz, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.34 (s, 2H), 1.39 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H);MS (ES+): 517.4 (M+1);(ES-): 515.4 (M-1).

[0225] Step-3: Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8d) Compound 8d was prepared from ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8c) (300 mg, 0.58 mmol) in DCM (10 mL) using TFA (0.45 mL, 5.81 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8d) (yield 200 mg, 83%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.75 (brs, 1H, D2O exchangeable), 10.28 (s, 1H, D2O exchangeable), 8.59 - 8.43 (m, 4H, partially D2O exchangeable), 8.19 (s, 1H), 8.00 (s, 1H), 7.91 - 7.82 (m, 2H), 7.67 - 7.54 (m, 2H), 7.51 - 7.44 (m, 1H), 7.40 - 7.30 (m, 2H), 7.30 - 7.19 (m, 1H), 4.20 - 4.15 (m, 2H), 3.72 (s, 2H);MS (ES+): 417.3 (M+1);439.3 (M+Na);HPLC purity, 99.88%.

[0226] Step-4: Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetic acid (8e) Compound 8e was prepared from ethyl 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate (8d) (100 mg, 0.24 mmol) in MeOH / THF (10 mL, 1:1) using sodium hydroxide (48 mg, 1.2 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetic acid (8e) (71 mg, 76% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 3H, D2O exchangeable), 8.30 - 8.20 (m, 2H), 8.19 - 8.11 (m, 1H), 7.84 - 7.74 (m, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 4.7, 1.3 Hz, 1H), 7.28 - 7.11 (m, 4H), 6.92 (t, J = 7.2, 1.4 Hz, 1H), 5.26 (s, 2H), 4.22 - 4.14 (m, 2H), 3.61 (s, 2H);MS (ES+): 389.4 (M+1);(ES-): 387.4 (M-1);423.4 (M+Cl);HPLC purity, 100%.

[0227] Scheme-9 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (9d) Step-1: Preparation of ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) Compound 9b was prepared from 4-bromo-1H-indole-6-carboxylic acid 9a (500 mg, 2.08 mmol; CAS#374633-27-9) in MeOH (10 mL) using ethyl 2-(2-aminophenyl)acetate 5e (411 mg, 2.29 mmol) and EDCI (479 mg, 2.5 mmol) according to the procedure reported in Scheme 7, Step 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] to give ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate 9b (320 mg, 38% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.02 (s, 1H), 8.10 - 8.02 (m, 1H), 7.83 (d, J = 1.3 Hz, 1H), 7.68 (t, J = 2.8 Hz, 1H), 7.42 - 7.28 (m, 3H), 7.28 - 7.19 (m, 1H), 6.54 - 6.44 (m, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H).

[0228] Step-2: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate (9c) Compound 9c was prepared from ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (300 mg, 0.75 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (210 mg, 1.12 mmol), potassium phosphate tripotassium (1.3 M solution) (1.72 mL, 2.24 mmol), tricyclohexylphosphine (63 mg, 0.22 mmol) and Pd(dba) (69 mg, 0.075 mmol) under argon atmosphere and microwave heating at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate (9c) (yield 133 mg, 42%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.03 (s, 1H), 8.38 (s, 3H, D2O exchangeable), 8.08 (s, 1H), 7.90 (s, 1H), 7.82 - 7.72 (m, 2H), 7.65 (t, J = 2.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.46 - 7.39 (m, 1H), 7.37 - 7.29 (m, 2H), 7.27 - 7.20 (m, 1H), 6.76 (t, J = 2.4 Hz, 1H), 4.23 - 4.08 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H);MS (ES+): 428.3 (M+1);450.3 (M+Na);(ES-): 426.4 (M-1);HPLC purity, 97.82%.

[0229] Step-3: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (9d) Compound 9d was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate (9c) (70 mg, 0.16 mmol) in MeOH (10 mL) using sodium hydroxide (66 mg, 1.61 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. It was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (9d) (yield 23 mg, 35%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H, D2O exchangeable), 11.76 (t, 1H), 10.08 (s, 1H, D2O exchangeable), 8.48 (s, 3H, D2O exchangeable), 8.10 (s, 1H), 7.91 (s, 1H), 7.83 - 7.74 (m, 2H), 7.65 (t, J = 2.8 Hz, 1H), 7.61 - 7.46 (m, 3H), 7.37 - 7.27 (m, 2H), 7.25 - 7.17 (m, 1H), 6.79 - 6.72 (m, 1H), 4.20 - 4.08 (m, 2H), 3.70 (s, 2H); MS (ES + ) 400.3 (M+1);422.3 (M+Na);(ES - ) 398.4 (M-1);434.4 (M+Cl);HPLC purity, 99.02%.

[0230] Scheme-10 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetic acid (10d) Step-1: Preparation of ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate (10a) and ethyl 2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate (10b) To a solution of ethyl 2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) (300 mg, 0.75 mmol) in DMF was added (bromomethyl)cyclopropane (151 mg, 1.12 mmol) and potassium carbonate (206 mg, 1.49 mmol). The resulting mixture was stirred at 60° C. overnight, cooled to room temperature, diluted with EtOAc (100 mL), washed with water (3×), brine, dried, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc in hexanes] to give ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate (10a) (yield 106 mg, 31%). 1 H NMR (300 MHz, DMSO-d) δ 8.28 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.44–7.15 (m, 4H), 4.34 (d, J = 7.0 Hz, 2H), 3.96–3.89 (m, 2H), 3.71 (s, 2H), 1.37–1.23 (m, 1H), 0.94 (t, J = 7.1 Hz, 3H), 0.53–0.32 (m, 4H); further elution gave ethyl 2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate (10b) (86 mg, 25% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 7.79 - 7.73 (m, 1H), 7.41 (d, J = 6.9 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.28 - 7.21 (m, 1H), 4.37 (d, J = 7.3 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 1.53 - 1.31 (m, 1H), 1.02 (t, J = 7.1, 2.1 Hz, 3H), 0.68 - 0.41 (m, 4H).

[0231] Step-2: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetic acid (10d) Compound 10d was prepared from ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate (10a) (95 mg, 0.21 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (59 mg, 0.31 mmol), potassium phosphate tripotassium (1.3 M solution) (0.48 mL, 0.63 mmol), tricyclohexylphosphine (18 mg, 0.06 mmol) and Pd(dba) (19 mg, 0.021 mmol) under argon atmosphere and microwave heating at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse-phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate (10c) (yield 26 mg, 0.054 mmol, 25.9%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H, D2O exchangeable), 8.52 (s, 3H, D2O exchangeable), 8.46 - 8.36 (m, 2H), 8.00 (s, 1H), 7.93 - 7.78 (m, 2H), 7.67 - 7.53 (m, 2H), 7.50 - 7.41 (m, 1H), 7.41 - 7.32 (m, 2H), 7.32 - 7.22 (m, 1H), 4.44 (d, J = 7.0 Hz, 2H), 4.21 - 4.11 (m, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 1.45 - 1.32 (m, 1H), 0.96 (t, J = 7.1 Hz, 3H), 0.59 - 0.38 (m, 4H); MS (ES+): 483.4 (M+1); (ES-): 517.5 (M+Cl); HPLC purity, 97.36%, and び2-(2-(4-(3-(アミノメチル)フェニル))-1-(シクロプロピルメチル)-1H-インダゾール-6-Kanthionic acid (10 days) (yield 7 mg, 0.015 mmol, yield 7.40%) was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H, D2O exchangeable), 8.55 - 8.33 (m, 5H), 7.98 (d, J = 1.7 Hz, 1H, partially D2O exchangeable), 7.91 - 7.80 (m, 2H), 7.67 - 7.54 (m, 2H), 7.54 - 7.45 (m, 1H), 7.41 - 7.30 (m, 2H), 7.30 - 7.18 (m, 1H), 4.44 (d, J = 7.0 Hz, 2H), 4.22 - 4.09 (m, 2H), 3.72 (s, 2H), 1.50 - 1.33 (m, 1H), 0.64 - 0.38 (m, 4H); MS (ES+): 455.4 (M+1); (ES-): 453.4 (M-1), 489.4 (M+Cl); HPLC purity, 99.31%.

[0232] スキーム-11 [ka] Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate (11a) and 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetic acid (11b) Compounds 11a and 11b were prepared from ethyl 2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate (10b) (86 mg, 0.19 mmol) in dioxane (3 mL) according to the procedure reported in Step 3 of Scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (53 mg, 0.28 mmol), potassium phosphate tripotassium (1.3 M solution) (0.44 mL, 0.57 mmol), tricyclohexylphosphine (16 mg, 0.06 mmol) and Pd(dba) (17 mg, 0.02 mmol) under argon atmosphere and microwave heating at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse-phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate (11a) (yield 10 mg, 11%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H, D2O exchangeable), 8.94 (s, 1H), 8.55 (s, 3H, D2O exchangeable), 8.33 (s, 1H), 7.96 (s, 1H), 7.87 - 7.72 (m, 2H), 7.68 - 7.52 (m, 2H), 7.48 - 7.41 (m, 1H), 7.39 - 7.30 (m, 2H), 7.30 - 7.21 (m, 1H), 4.39 (d, J = 7.2 Hz, 2H), 4.16 (q, J = 6.0 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 1.53 - 1.39 (m, 1H), 1.01 (t, J = 7.1 Hz, 3H), 0.62 - 0.44 (m, 4H); MS (ES+): 483.4 (M+1); 505.4 (M+Na); (ES-): 481.4 (M-1); HPLC purity, 95.20% and 2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetic acid (11b) (yield 13 mg, 15%) was obtained as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H, D2O exchangeable), 8.96 (s, 1H), 8.59 (s, 3H, D2O exchangeable), 8.33 (s, 1H), 7.97 (s, 1H), 7.86 - 7.80 (m, 1H), 7.80 - 7.74 (m, 1H), 7.66 - 7.48 (m, 3H), 7.39 - 7.29 (m, 2H), 7.28 - 7.19 (m, 1H), 4.38 (d, J = 7.3 Hz, 2H), 4.21 - 4.09 (m, 2H), 3.73 (s, 2H), 1.57 - 1.38 (m, 1H), 0.61 - 0.45 (m, 4H);MS (ES+): 455.4 (M+1);477.4 (M+Na);(ES-): 453.4 (M-1);HPLC purity, 98.50%.

[0233] Scheme-12 [ka] Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (12c) Step-1: Preparation of (S)-2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)ethyl acetate (12a) Compound 12a was prepared from ethyl 2-(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate (211a) (0.6 g, 1.17 mmol) in dioxane (5 mL) using a solution of (S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (220c) (0.46 g, 1.75 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.18 mmol) and KCO (0.40 g, 2.92 mmol) in water (0.5 mL) under argon atmosphere and heated in an oil bath at 90 °C for 4 h. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% EtOAc / MeOH 9:1 in DCM] to give ethyl (S)-2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12a) (yield 0.33 g, 46%) as a yellow solid. MS (ES+): 616.0 (M+1).

[0234] Step-2: Preparation of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12b) Compound 12b was prepared from ethyl (S)-2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12a) (0.33 g, 0.54 mmol) in methanol (10 mL) using hydrochloric acid (4 M in 1,4-dioxane, 0.40 mL, 1.61 mmol) according to the procedure reported in Step 5 of Scheme 220. Workup afforded compound 12b (0.26 g, 95% yield) as a yellow solid. This was purified using reverse phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12b) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 3H), 8.61 (d, J = 4.9 Hz, 1H), 8.10 (t, J = 1.0 Hz, 1H), 7.75 (d, J = 3.8 Hz, 1H), 7.67 (t, J = 5.3 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.31 - 7.19 (m, 2H), 7.14 (dd, J = 8.3, 1.1 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 6.81 - 6.76 (m, 1H), 5.32 (s, 2H), 4.34 (d, J = 6.0 Hz, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.63 (s, 2H), 3.55 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H); 19F NMR (282 MHz, DMSO-d6) δ -128.70;MS (ES+): 512.9 (M+1).

[0235] Step-3: Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (12c) Compound 12c was prepared from ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12b) (0.15 g, 0.29 mmol) in MeOH / THF (4 mL each) using lithium hydroxide hydrate (123 mg, 2.93 mmol) in water (1 mL) according to the procedure reported in step 6 of scheme 1. This was worked up and purified by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (12c) (yield 0.06 g, 52%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.57 (s, 3H), 8.56 - 8.54 (m, 1H), 7.69 (t, J = 5.4 Hz, 1H), 7.65 (d, J = 1.1 Hz, 1H), 7.49 (t, J = 2.8 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.14 - 7.08 (m, 1H), 6.89 (td, J = 7.4, 1.1 Hz, 1H), 6.39 (t, J = 2.7 Hz, 1H), 5.26 (s, 2H), 4.44 - 4.30 (m, 2H), 3.57 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -128.77;MS (ES+): 406.0 (M+1). HPLC purity: 98.02%.

[0236] Scheme-13 [ka] Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)acetic acid (13c) Step-1: Preparation of ethyl 2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate (13b) Compound 13b was prepared from 8-bromoquinoline-6-carboxylic acid 13a (250 mg, 0.992 mmol, CAS#791632-21-8) using ethyl 2-(2-aminophenyl)acetate 5e (213 mg, 1.19 mmol), DIPEA (0.52 mL, 2.98 mmol), and HATU (453 mg, 1.19 mmol) according to the procedure reported in Step 4 of Scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with MeOH:EtOAc (9:1) in hexanes (0-60%)] to give ethyl 2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate 13b (315 mg, 77%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.13 (dd, J = 4.2, 1.6 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.62 (td, J = 4.1, 1.7 Hz, 2H), 7.75 (dd, J = 8.3, 4.2 Hz, 1H), 7.45 - 7.23 (m, 4H), 3.96 (q, J = 7.1 Hz, 2H), 3.78 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H).

[0237] Step-2: Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)acetic acid (13c) Compound 13c was prepared from ethyl 2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate (13b) (150 mg, 0.36 mmol) in dioxane (2 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (68 mg, 0.363 mmol), potassium phosphate tripotassium (1.3 M solution) (0.84 mL, 1.09 mmol), tricyclohexylphosphine (31 mg, 0.11 mmol) and Pd(dba) (33 mg, 0.036 mmol) under argon atmosphere and microwave heating at 125 °C for 1 h. This was worked up and purified by flash column chromatography [silica (40 g), elution with ethyl acetate (0-40%) in hexane] followed by reverse-phase column [C18 (50 g), elution with ACN (0-100%) in water (containing 0.1% HCl)] to give 2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)acetic acid (13c) (yield 18 mg, 12%) as a white powder. 1 H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H, D2O exchangeable), 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.70 (s, 1H), 8.65 (dt, J = 8.5, 1.8 Hz, 1H), 8.50 (s, 3H, D2O exchangeable), 8.35 (t, J = 1.6 Hz, 1H), 7.87 (s, 1H), 7.82 - 7.76 (m, 1H), 7.76 - 7.69 (m, 1H), 7.60 - 7.55 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.40 - 7.30 (m, MS (ES+): 412.3 (M+1); MS (ES-): 410.4 (M-1); HPLC purity: 93.59 %.

[0238] Scheme-14 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetic acid (14d) Step-1: Preparation of ethyl 2-(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate (14b) Compound 14b was prepared from 4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (14a) (300 mg, 1.25 mmol; CAS# 1190321-81-3) in MeOH (10 mL) using 2-(2-aminophenyl)ethyl acetate (5e) (268 mg, 1.49 mmol) and EDCI (286 mg, 1.49 mmol) according to the procedure reported in Scheme 7, Step 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] to give 2-(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)ethyl acetate (14b) (yield 356 mg, 71%) as an off-white solid. MS (ES+): 424.2, 426.2 (M+Na), (ES-): 400.2, 402.3 (M-1).

[0239] Step-2: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate (14c) Compound 14c was prepared from ethyl 2-(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate (14b) (200 mg, 0.55 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (154 mg, 0.82 mmol), potassium phosphate tripotassium (1.3 M solution) (0.72 mL, 0.93 mmol), tricyclohexylphosphine (46 mg, 0.16 mmol) and Pd(dba) (50 mg, 0.055 mmol) under argon atmosphere by microwave heating at 125 °C for 1 h. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate (14c) (yield 108 mg, 46%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H, D2O exchangeable), 10.31 (s, 1H, D2O exchangeable), 8.55 (s, 3H, D2O exchangeable), 8.06 (s, 1H), 7.98 (s, 1H), 7.89 - 7.76 (m, 3H), 7.64 (d, J = 4.5 Hz, 2H), 7.42 - 7.29 (m, 2H), 7.27 - 7.14 (m, 1H), 6.93 - 6.82 (m, 1H), 4.23 - 4.12 (m, 2H), 4.08 (q, J = 7.1Hz, 2H), 3.81 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H);MS (ES+): 429.4 (M+1);(ES-): 427.4 (M-1), 463.4 (M+Cl);HPLC purity, 99.45%.

[0240] Step-3: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetic acid (14d) Compound 14d was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate (14c) (16 mg, 0.038 mmol) in MeOH / THF (3 mL) using lithium hydroxide hydrate (7.98 mg, 0.19 mmol) in water (1 mL) according to the procedure reported in Step 6 of Scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetic acid (14d) (12 mg, 79% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H, D2O exchangeable), 10.35 (s, 1H, D2O exchangeable), 8.39 (s, 3H, D2O exchangeable), 8.07 (s, 1H), 7.98 (s, 1H), 7.90 - 7.78 (m, 3H), 7.70 - 7.57 (m, 2H), 7.43 - 7.30 (m, 2H), 7.26 - 7.13 (m, 1H), 6.90 - 6.80 (m, 1H), 4.18 (q, J = 5.9 Hz, 2H), 3.73 (s, 2H);MS (ES+): 401.3 (M+1);(ES-): 399.3 (M-1), 435.4 (M+Cl); HPLC purity, 96.09%.

[0241] Scheme-15 [ka] Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetic acid (15d) Step-1: Preparation of ethyl 2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b) Compound 15b was prepared from 7-bromobenzofuran-5-carboxylic acid 15a (100 mg, 0.42 mmol; CAS# 286836-25-7) in MeOH (10 mL) using 2-(2-aminophenyl)ethyl acetate 5e (89 mg, 0.5 mmol) and EDCI (95 mg, 0.5 mmol) according to the procedure reported in Scheme 7, Step 1. Purification by flash column chromatography (silica (12 g), eluting with 0-60% EtOAc in hexane) afforded 2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)ethyl acetate 15b (80 mg, 48%) as a pink semi-solid. MS (ES+): 424.2, 426.2 (M+Na), (ES-): 400.2, 402.2 (M-1).

[0242] Step-2: Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetic acid (15d) Compound 15d was prepared from ethyl 2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b) (80 mg, 0.2 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (56 mg, 0.3 mmol), potassium phosphate tripotassium (1.3 M solution) (0.26 mL, 0.34 mmol), tricyclohexylphosphine (17 mg, 0.06 mmol) and Pd(dba) (18 mg, 0.02 mmol) under argon atmosphere and microwave heating at 125 °C for 1 h. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% DMA80 in DCM] followed by reverse-phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetate (15c) (yield 21 mg, 25%) as a white solid; 1 H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H, D2O exchangeable), 8.43 (s, 3H, D2O exchangeable), 8.33 - 8.27 (m, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.21 - 8.18 (m, 1H), 8.08 (s, 1H), 8.03 - 7.94 (m, 1H), 7.67 - 7.54 (m, 2H), 7.45 - 7.39 (m, 1H), 7.38 - 7.30 (m, 2H), 7.30 - 7.18 (m, 2H), 4.16 (s, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 0.98 (t, J = 7.1 Hz, 3H); MS (ES+): 429.3 (M+1); 451.3 (M+Na); (ES-): 463.3 (M+Cl); HPLC purity, 99.50% and 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetic acid (15d) (yield 25 mg, 31%) was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H, D2O exchangeable), 10.20 (s, 1H, D2O exchangeable), 8.41 (s, 3H, D2O exchangeable), 8.34 - 8.29 (m, 1H), 8.24 - 8.20 (m, 1H), 8.20 - 8.16 (m, 1H), 8.09 - 8.04 (m, 1H), 8.02 - 7.96 (m, 1H), 7.66 - 7.55 (m, 2H), 7.51 - 7.44 (m, 1H), 7.38 - 7.28 (m, 2H), 7.27 - 7.19 (m, 2H), 4.21 - 4.09 (m, 2H), 3.71 (s, 2H);MS (ES+): 401.3 (M+1);423.3 (M+Na);(ES-): 399.3 (M-1), 435.3 (M+Cl);HPLC purity, 92.60%.

[0243] Scheme-16 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (16i) Step-1: Preparation of 2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b) To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (16a) (1 g, 5.32 mmol; CAS#90213-66-4) in acetonitrile (35 mL) at 0 °C was added sodium hydride (319 mg, 7.98 mmol) in portions. The reaction mixture was stirred at room temperature for 30 minutes until gas evolution ceased. (Bromomethyl)cyclopropane (1.62 g, 11.97 mmol) was then added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc (3x). The organic layers were combined, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (24 g), elution with 0-60% EtOAc in hexanes] to give 2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b) (998 mg, 78% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.88 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 1.34 - 1.17 (m, 1H), 0.58 - 0.48 (m, 2H), 0.48 - 0.37 (m, 2H);MS (ES+): 265.3 (M+Na).

[0244] Step-2: Preparation of tert-butyl 3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16c) Compound 16c was prepared from 2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b) (4.5 g, 18.59 mmol) in dioxane (100 mL) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (4.42 g, 13.28 mmol), potassium phosphate tripotassium (22.47 mL, 29.2 mmol, 1.3 M solution in water), tricyclohexylphosphine (1.12 g, 3.98 mmol) and Pd(dba) (1.22 g, 1.33 mmol) under argon atmosphere and heated in an oil bath at 120 °C for 60 min. This was worked up and purified by flash column chromatography [silica (80 g), elution with 0-70% EtOAc in hexanes] to give tert-butyl 3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16c) (yield 3.2 g, 58%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.10 - 7.97 (m, 2H), 7.87 (d, J = 3.7 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.49 - 7.41 (m, 1H), 6.99 (d, J = 3.7 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 4.11 (d, J = 7.2 Hz, 2H), 1.41 (s, 9H), 1.35 - 1.31 (m, 1H), 0.58 - 0.49 (m, 2H), 0.49 - 0.40 (m, 2H);MS (ES+): 413.4 (M+1);435.3 (M+Na);(ES-): 411.4 (M-1)

[0245] Step-3: Preparation of tert-butyl 3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16d) Compound 16d was prepared according to the procedure reported in Scheme 1, Step 1, from tert-butyl 3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16c) (3.2 g, 7.75 mmol) in DMF (35 mL) using 1-ethoxyvinyltri-n-butyltin (3.17 mL, 9.30 mmol) and Pd(PPh3)4 (0.448 g, 0.39 mmol) under argon atmosphere and heating at 110 °C for 12 h. This was worked up and purified by flash column chromatography [silica (24 g), elution with 0-60% EtOAc in hexanes] to give tert-butyl 3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16d) (yield 2.5 g, 72%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.14 - 8.02 (m, 2H), 7.83 (d, J = 3.6 Hz, 1H), 7.55 (q, J = 7.8, 7.0 Hz, 2H), 7.45 - 7.36 (m, 1H), 6.92 (d, J = 3.6 Hz, 1H), 5.63 (d, J = 1.4 Hz, 1H), 4.61 (d, J = 1.5 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 4.16 (d, J = 7.2 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 1.45 - 1.25 (m, 13H), 0.57 - 0.46 (m, 4H);MS (ES+) 449.4 (M+1);(ES-) 447.4 (M-1).

[0246] Step-4: Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (16e) Compound 16e was prepared from tert-butyl 3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (16d) (2.5 g, 5.57 mmol) in 1,4-dioxane (50 mL) using sodium periodate solution (2.384 g, 11.15 mmol) in water (20 mL) and KMnO (0.881 g, 5.57 mmol in 4 mL of water as a first charge and 528 mg, 3.34 mmol after 12 h). This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-60% EtOAc in hexanes] to give ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (16e) (yield 1.06 g, 42%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.12 - 8.03 (m, 3H), 7.62 - 7.52 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 3.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 4.22 (d, J = 7.2 Hz, 2H), 1.45 - 1.30 (m, 13H), 0.57 - 0.45 (m, 4H).

[0247] Step-5: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (16f) Compound 16f was prepared from ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate (16e) (1.06 g, 2.353 mmol) in MeOH / THF (15 mL, 1:1) using sodium hydroxide (235 mg, 5.88 mmol) in water (3 mL) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by flash column chromatography [silica (24 g), elution with 0-20% MeOH in DCM] to give 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (16f) (650 mg, 65% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.11 - 8.00 (m, 2H), 7.89 (d, J = 3.6 Hz, 1H), 7.60 - 7.48 (m, 2H), 7.46 - 7.38 (m, 1H), 6.94 (d, J = 3.5 Hz, MS (ES+) 423.3 (M+1);445.3 (M+Na);(ES-), 421.4 (M-1), 457.4 (M+Cl).

[0248] Step-6: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (16g) Compound 16g was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (16f) (150 mg, 0.536 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (95 mg, 0.533 mmol), DIPEA (0.12 mL, 0.71 mmol) and HATU (203 mg, 0.533 mmol) according to the procedure reported in step 4 of scheme 1. Workup and purification by flash column chromatography [silica (12 g), elution with 0-100% EtOAc / MeOH in hexanes] afforded ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (16 g) (152 mg, 73% yield) as a white solid. MS (ES+) 584.5 (M+1).

[0249] Step-7: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (16h) Compound 16h was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (16g) (150 mg, 0.26 mmol) in DCM (10 mL) using TFA (0.4 mL, 5.14 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse-phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (16h) (yield 88 mg, 71%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H, D2O exchangeable), 8.68 (s, 3H, D2O exchangeable), 8.46 (d, J = 1.7 Hz, 1H), 8.43 - 8.35 (m, 1H), 8.11 (d, J = 3.6 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.79 - 7.73 (m, 1H), 7.73 - 7.61 (m, 1H), 7.44 - 7.36 (m, 2H), 7.34 (d, J = 3.6 Hz, 1H), 7.27 - 7.15 (m, 1H), 4.37 - 4.25 (m, 2H), 4.17 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.88 (s, 2H), 1.46 - 1.32 (m, 1H), 1.00 (t, J = 7.1 Hz, 3H), 0.60 - 0.45 (m, 4H);MS (ES+): 484.5 (M+1);(ES-): 482.5 (M-1);518.5 (M+Cl);HPLC purity, 99.46%.

[0250] Step-8: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (16i) Compound 16i was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (16h) (50 mg, 0.10 mmol) in MeOH (10 mL) using sodium hydroxide (21 mg, 0.52 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (16i) (24 mg, 51% yield) was obtained as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H, D2O exchangeable), 8.56 (s, 3H, D2O exchangeable), 8.46 - 8.40 (m, 1H), 8.40 - 8.32 (m, 1H), 8.11 (d, J = 3.6 Hz, 1H), 7.98 (dd, J = 8.4, 1.3 Hz, 1H), 7.78 - 7.63 (m, 2H), 7.44 - 7.33 (m, 2H), 7.31 (d, J = 3.6 Hz, 1H), 7.27 - 7.13 (m, 1H), 4.29 (d, J = 7.2 Hz, 2H), 4.23 - 4.18 (m, 2H), 3.78 (s, 2H), 1.44 - 1.31 (m, 1H), 0.59 - 0.47 (m, 4H);MS (ES+): 456.3 (M+1);478.3 (M+Na);(ES-): 454.3 (M-1);490.3 (M+Cl); HPLC, purity, 99.60%.

[0251] Scheme-17 [ka] Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetic acid (17c) Step-1: Preparation of ethyl 2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate (17b) Compound 17b was prepared from 8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (17a) (500 mg, 2.07 mmol, CAS#1216475-30-7) using ethyl 2-(2-aminophenyl)acetate (5e) (648 mg, 3.62 mmol), DIPEA (1.08 mL, 6.2 mmol) and HATU (1375 mg, 3.62 mmol) according to the procedure reported in Step 4 of Scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with MeOH:EtOAc (9:1) in hexanes from 0 to 100%] to give ethyl 2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate (17b) (yield 200 mg, 24%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.56 (s, 1H), 9.25 (s, 1H), 8.20 (s, 1H), 7.41 - 7.23 (m, 4H), 3.98 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 1.05 (t, J = 7.1 Hz, 3H).

[0252] Step-2: Preparation of 2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetic acid (17c) Compound 17c was prepared from ethyl 2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate (17b) (200 mg, 0.5 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (139 mg, 0.74 mmol), potassium phosphate tripotassium (1.3 M solution) (1.145 mL, 1.49 mmol), tricyclohexylphosphine (42 mg, 0.15 mmol) and Pd(dba) (45 mg, 0.05 mmol) under argon atmosphere and microwave heating at 120 °C for 1 h. This was worked up and purified by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetic acid (17c) (yield 41 mg, 21%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H, D2O exchangeable), 9.66 - 9.54 (m, 1H), 9.39 - 9.28 (m, 1H), 8.56 (s, 3H, D2O exchangeable), 8.41 (s, 1H), 8.39 - 8.30 (m, 2H), 7.64 (d, J = 4.4 Hz, 2H), 7.48 - 7.38 (m, 1H), 7.42 - 7.31 (m, 2H), 7.33 - 7.23 (m, 1H), 4.32 - 4.02 (m, 2H), 3.72 (d, J = 2.3 Hz, 2H);MS (ES+): 402.3 (M+1);MS (ES-): 400.4 (M-1);HPLC purity: 93.65 %.

[0253] Scheme-18 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetic acid (18f) Step-1: Preparation of methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoate (18b) Compound 18b was prepared from methyl 4-bromo-2-naphthoate (18a) (250 mg, 0.94 mmol; CAS#1013-80-5) in DMF (3 mL) using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (355 mg, 1.42 mmol), potassium phosphate tripotassium (1.3 M solution, 1.45 mL, 1.89 mmol), tricyclohexylphosphine (79 mg, 0.28 mmol) and Pd(dba) (86 mg, 0.09 mmol) under nitrogen atmosphere at 120 °C for 14 h according to the procedure reported in Scheme 1, Step 3. This was worked up and purified by flash column chromatography [silica (40 g), elution with hexane / ethyl acetate from 0% to 100%] to give methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoate (18b) (yield 257 mg, 70%) as an oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.32 - 8.19 (m, 1H), 7.95 - 7.81 (m, 2H), 7.72 - 7.61 (m, 2H), 7.57 - 7.47 (m, 2H), 7.44 - 7.27 (m, 3H), 4.27 - 4.16 (m, 2H), 3.93 (s, 3H), 1.38 (s, 9H).

[0254] Step-2: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c) Compound 18c was prepared from methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoate (18b) (240 mg, 0.613 mmol) in THF (10 mL) using a solution of lithium hydroxide hydrate (29 mg, 1.23 mmol) in water (2 mL) according to the procedure reported in step 6 of scheme 1. Workup gave 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c) (150 mg, 65%), which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.24 - 8.11 (m, 1H), 7.89 - 7.77 (m, 2H), 7.67 - 7.56 (m, 2H), 7.48 (m, 2H), 7.35 (m, 3H), 4.22 (d, J = 6.1 Hz, 2H), 1.35 (s, 9H).

[0255] Step-3: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthamido)phenyl)acetate (18d) Compound 18d was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c) (150 mg, 0.397 mmol) in DMF (8 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (125 mg, 0.695 mmol), DIPEA (0.21 mL, 1.2 mmol) and HATU (264 mg, 0.695 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes from 0-100%] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthamido)phenyl)acetate (18d) (yield 169 mg, 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.59 (s, 1H), 8.13 (dd, J = 20.3, 7.9 Hz, 1H), 7.97 - 7.83 (m, 2H), 7.64 (p, J = 7.0 Hz, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.46 - 7.29 (m, 7H), 7.30 - 7.08 (m, 1H), 4.25 (d, J = 6.2 Hz, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 1.38 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H).

[0256] Step-4: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetate (18e) Compound 18e was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthamido)phenyl)acetate (18d) (150 mg, 0.28 mmol) using TFA (0.22 mL, 2.78 mmol) in DCM (10 mL) according to the procedure reported in Step 5 of Scheme 1. Workup afforded ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetate (18e) (84 mg, 69%), which was used directly in the next step. MS (ES+): 439.4 (M+1).

[0257] Step-5: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetic acid (18f) Compound 18f was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetate (18e) (70 mg, 0.16 mmol) in THF (5 mL) using a solution of lithium hydroxide hydrate (19 mg, 0.8 mmol) in water (2 mL) according to the procedure reported in step 6 of scheme 1. It was worked up and purified by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetic acid (18f) (yield 43 mg, 66%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1H, D2O exchangeable), 10.41 (s, 1H, D2O exchangeable), 8.64 (s, 1H), 8.34 (s, 3H, D2O exchangeable), 8.17 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.74 - 7.56 (m, 6H), 7.50 (d, J = 7.7 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.28 - 7.20 (m, 1H), 4.16 (s, 2H), 3.70 (s, 2H);MS (ES+): 411.3 (M+1), 433.3 (M+Na), (ES-): 409.4 (M-1, 445.4 (M+Cl);HPLC purity: 93.35 %.

[0258] Scheme-19 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19c) Step-1: Preparation of 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19b) Compound 19b was prepared from ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (320 mg, 0.80 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1, using tert-butyl 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (19a) (420 mg, 1.2 mmol; CAS#1421773-36-5), potassium phosphate tripotassium (1.3 M solution) (1.23 mL, 1.60 mmol), tricyclohexylphosphine (67 mg, 0.24 mmol) and Pd(dba) (73 mg, 0.08 mmol) under argon atmosphere and microwave heating at 120 °C for 60 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-90% DMA80 in DCM] to give 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19b) (175 mg, 42% yield) as a yellow solid. MS (ES+): 518.4 (M+1); (ES-): 516.4 (M-1).

[0259] Step-2: Preparation of 2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19c) Compound 19c was prepared from 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19b) (170 mg, 0.33 mmol) in DCM (10 mL) using TFA (0.25 mL, 3.28 mmol) according to the procedure reported in Scheme 1, Step 5. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (19c) (69 mg, 50% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H, D2O exchangeable), 11.80 (t, J = 2.2 Hz, 1H), 10.08 (s, 1H, D2O exchangeable), 8.52 (s, 3H, D2O exchangeable), 8.12 (s, 1H), 7.86 - 7.81 (m, 1H), 7.80 - 7.75 (m, 1H), 7.68 (t, J = 2.8 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.53 - 7.39 (m, 2H), 7.38 - 7.28 (m, 2H), 7.27 - 7.18 (m, 1H), 6.84 - 6.76 (m, 1H), 4.17 (s, 2H), 3.70 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -112.22;MS (ES+): 418.4 (M+1);(ES-): 416.4 (M-1);452.4 (M+Cl);HPLC purity;98.96%.

[0260] Scheme-20 [ka] Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetic acid (20e) Step-1: Preparation of 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (20b) Compound 20b was prepared from methyl 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (20a) (500 mg, 1.953 mmol; CAS#1801262-20-3) in dioxane (3 mL) using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (735 mg, 2.93 mmol), potassium phosphate tripotassium (1.3 M solution, 3.0 mL, 3.91 mmol), tricyclohexylphosphine (164 mg, 0.59 mmol), and Pd(dba) (179 mg, 0.2 mmol) under nitrogen atmosphere by microwave heating at 120 °C for 1 h according to the procedure reported in Scheme 1, Step 3. This was worked up and purified by flash column chromatography [silica (40 g), elution with ethyl acetate in hexanes from 0% to 100%] to give 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (20b) (200 mg, 28%) as an oil. MS (ES-) 367.3 (M-1).

[0261] Step-2: Preparation of ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20c) Compound 20c was prepared from 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (20b) (200 mg, 0.54 mmol) in DMF (8 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (170 mg, 0.95 mmol), DIPEA (0.28 mL, 1.63 mmol) and HATU (361 mg, 0.95 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes from 0-100%] to give ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20c) (yield 153 mg, 53%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.63 (d, J = 1.8 Hz, 1H), 8.78 (s, 1H), 8.70 (d, J = 1.8 Hz, 1H), 8.19 - 8.09 (m, 1H), 7.77 (m, 2H), 7.51 (m, 2H), 7.38 (m, 3H), 7.23 (m, 1H), 4.26 (d, J = 6.1 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.96 (s, 2H), 1.40 (s, 9H), 1.09 (t, J = 7.1 Hz, 3H).

[0262] Step-3: Preparation of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20d) Compound 20d was prepared from ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20c) (140 mg, 0.264 mmol) using TFA (0.41 mL, 5.29 mmol) in DCM (2 mL) according to the procedure reported in step 5 of scheme 1. Workup gave ethyl 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20d) (65 mg, 57%), which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.64 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.13 (dd, J = 7.3, 2.0 Hz, 1H), 7.87 (s, 1H), 7.76 - 7.68 (m, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.40 - 7.35 (m, 2H), 7.26 - 7.16 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 3.82 (s, 2H), 2.11 (s, 2H), 1.09 (t, J = 7.1 Hz, 3H);MS (ES+): 430.4 (M+1).

[0263] Step-4: Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetic acid (20e) Compound 20e was prepared from ethyl 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate (20d) (60 mg, 0.14 mmol) in THF (5 mL) using a solution of lithium hydroxide hydrate (17 mg, 0.7 mmol) in water (1 mL) according to the procedure reported in Step 6 of Scheme 1. This was worked up and purified by reverse-phase column [C18 (50 g), eluting with ACN in water (0.1% HCl) from 0 to 100%] to give 2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetic acid (20e) (yield 53 mg, 95%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.69 (d, J = 1.8 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.76 (s, 1H), 8.48 (s, 3H, D2O exchangeable), 8.21 - 8.13 (m, 1H), 8.09 (s, 1H), 7.95 (dt, J = 6.5, 2.3 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.43 - 7.31 (m, 2H), 7.25 - 7.16 (m, 1H), 4.16 (d, J = 5.8 Hz, 2H), 3.89 (s, 2H);MS (ES+) 402.3 (M+1), (ES-) 400.4 (M-1), 436.4 (M+Cl);HPLC purity: 98.75 %.

[0264] Scheme-21 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (21d) Step-1: Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (21a) Compound 21a was prepared from ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (200 mg, 0.89 mmol) in dioxane (3 mL) using tert-butyl 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (19a) (467 mg, 1.33 mmol), potassium phosphate tripotassium (1.3 M solution, 1.36 mL, 0.089 mmol), tricyclohexylphosphine (75 mg, 0.27 mmol), and Pd(dba) (81 mg, 0.089 mmol) under nitrogen atmosphere by microwave heating at 120 °C for 1 h according to the procedure reported in Scheme 1, Step 3. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-90% DMA80 in DCM] to give 2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (21a) (yield 118 mg, 35%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 8.01 (t, J = 2.0 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.58 (t, J = 6.2 Hz, 1H), 7.17 (dt, J = 9.8, 2.0 Hz, 1H), 6.99 - 6.93 (m, 2H), 4.23 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H).

[0265] Step-2: Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21b) Compound 21b was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (21a) (110 mg, 0.29 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (77 mg, 0.43 mmol), DIPEA (0.1 mL, 0.57 mmol) and HATU (162 mg, 0.43 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes, 0-100% elution] to give ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21b) (125 mg, 80% yield) as a yellow solid. MS (ES-): 546.5 (M-1).

[0266] Step-3: Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21c) Compound 21c was prepared from ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21b) (42 mg, 0.08 mmol) using TFA (0.06 mL, 0.77 mmol) in DCM (10 mL) according to the procedure reported in step 5 of scheme 1. Workup followed by purification by flash chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] and then by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] gave ethyl 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21c) (yield 33 mg, 96%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.58 - 8.49 (m, 1H), 8.45 - 8.36 (m, 2H), 8.26 (s, 3H), 7.71 (d, J = 7.9 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.60 - 7.53 (m, 1H), 7.46 - 7.38 (m, 2H), 7.35 - 7.25 (m, 2H), 4.20 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.86 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H).

[0267] Step-4: Preparation of 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (21d) Compound 21d was prepared from ethyl 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (21c) (19 mg, 0.042 mmol) in MeOH (10 mL) using sodium hydroxide (17 mg, 0.43 mmol) in water (2 mL) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (21d) (yield 15 mg, 84%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H, D2O exchangeable), 10.94 (s, 1H, D2O exchangeable), 8.52 (s, 3H, D2O exchangeable), 8.48 - 8.45 (m, 1H), 8.45 - 8.35 (m, 2H), 7.81 - 7.74 (m, 1H), 7.65 - 7.57 (m, 2H), 7.45 - 7.35 (m, 2H), 7.34 - 7.24 (m, 2H), 4.27 - 4.13 (m, 2H), 3.78 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -112.09;MS (ES + ) 420.3 (M+1);(ES - ) 418.4 (M-1); HPLC purity, 98.34%.

[0268] Scheme-22 [ka] Preparation of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (22a) Compound 22a was prepared from ethyl 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (12b) (0.1 g, 0.20 mmol) in MeOH / THF (4 mL each) using lithium hydroxide hydrate (8 mg, 0.2 mmol) in water (1 mL) according to the procedure reported in step 6 of scheme 1. This was worked up and purified by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of 2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetic acid (22a) (yield 0.03 g, 36%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 4.9 Hz, 1H), 8.53 (s, 3H), 8.12 (s, 1H), 7.75 (d, J = 3.8 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.29 - 7.18 (m, 2H), 7.16 - 7.07 (m, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 6.76 (t, J = 3.3 Hz, 1H), 5.34 (s, 2H), 4.37 (d, J = 6.0 Hz, 2H), 3.59 (s, 2H), 3.55 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -128.61;MS (ES+): 484.9 (M+1);MS (ES-): 482.9 (M-1). HPLC purity: 93.84%.

[0269] Scheme-23 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23e) Step-1: Preparation of (7-bromobenzofuran-5-yl)methanol (23a) To a stirred solution of 7-bromobenzofuran-5-carboxylic acid (15a) (10 g, 41.5 mmol) and N-methylmorpholine (5.47 mL, 49.8 mmol) in THF (200 mL) at −5° C. was added isobutyl chloroformate (6.54 mL, 49.8 mmol). The reaction mixture was stirred for 15 min, filtered through a pad of Celite, and the precipitate was washed with THF (3×20 mL). The filtrate was cooled to 0° C., and a solution of NaBH (4.71 g, 124 mmol) in water (10 mL) was carefully added (rapid gas evolution occurred). The reaction mixture was stirred for 30 min, diluted with water (20 mL), and washed with ethyl acetate (3×). The organic layers were combined, dried, filtered, and concentrated in vacuo to give (7-bromobenzofuran-5-yl)methanol (23a) (9 g, 96% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 5.34 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H).

[0270] Step-2: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) To a solution of (7-bromobenzofuran-5-yl)methanol (23a) (9 g, 39.6 mmol), triphenylphosphine (11.44 g, 43.6 mmol), and ethyl 2-(2-hydroxyphenyl)acetate (23b) (7.86 g, 43.6 mmol; CAS# 41873-65-8) in DCM (180 mL) at 0° C. was added a solution of bis(4-chlorobenzyl)azodicarboxylic acid (DCAD, 16.01 g, 43.6 mmol; CAS#: 916320-82-6) in DCM (40 mL) dropwise. The resulting mixture was stirred at room temperature for 30 minutes and filtered to remove solids. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography [silica (80 g), elution with 0 to 50% EtOAc in hexanes] to give ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (yield 11.5 g, 75%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.30 - 7.19 (m, 2H), 7.11 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H).

[0271] Step-3: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23d) Compound 23d was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (300 mg, 0.77 mmol) in dioxane (6 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (217 mg, 1.16 mmol), potassium phosphate tripotassium (1.3 M solution) (0.77 mL, 2.31 mmol), tricyclohexylphosphine (65 mg, 0.23 mmol) and Pd(dba) (71 mg, 0.077 mmol) under argon atmosphere and microwave heating at 125 °C for 45 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse phase column chromatography [C18 (30 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23d) (yield 107 mg, 33%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3H, D2O exchangeable), 8.14 - 8.09 (m, 1H), 7.98 (s, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.81 - 7.71 (m, 1H), 7.67 - 7.47 (m, 3H), 7.34 - 7.19 (m, 2H), 7.17 - 7.06 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 4.01 - 3.86 (m, 2H), 3.63 (s, 2H), 1.04 - 0.93 (m, 3H);MS (ES+): 416.3 (M+1);831.5 (2M+1);MS (ES-): 450.4 (M+Cl);HPLC purity: 96.49%

[0272] Step-4: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23e) Compound 23e was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23d) (2.25 g, 5.42 mmol) in MeOH / THF (30 mL) using a solution of lithium hydroxide hydrate (682 mg, 16.25 mmol) in water (5 mL) according to the procedure reported in step 6 of scheme 1. It was worked up and purified by reverse phase column [C18 (50 g), elution with ACN in water (containing 0.1% HCl) from 0 to 100%] to give 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23e) (yield 1.5 g, 72%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H, D2O exchangeable), 8.53 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.04 - 7.99 (m, 1H), 7.97 - 7.89 (m, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.23 (d, J = 7.4 Hz, 2H), 7.13 - 7.04 (m, 2H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H);MS (ES+): 388.3 (M+1);(ES-): 386.3 (M-1);422.3 (M+Cl);HPLC purity: 99.44%.

[0273] Scheme-24 [ka] Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetic acid (24b) Step-1: Preparation of ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate (24a) Compound 24a was prepared from ethyl 2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate (225f) (191 mg, 0.388 mmol) in dioxane (5 mL) using (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117 mg, 0.692 mmol), a solution of KCO (186 mg, 1.346 mmol) in water (0.5 mL), Pd(PPh)Cl (55 mg, 0.078 mmol) and heating at 100 °C for 3 h under argon atmosphere. This was worked up and purified by flash column chromatography (12 g silica gel, elution with 0-50% DMA80 in DCM) to give ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate (24a) (181 mg, 100% yield) as a pale yellow oil. MS (ES+): 467.9 (M+1).

[0274] Step-2: Preparation of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetic acid (24b) Compound 24b was prepared from ethyl 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate (24a) (205 mg, 0.438 mmol) in MeOH / THF (6 mL) using a solution of lithium hydroxide (132 mg, 3.15 mmol) in water (2 mL) according to the procedure reported in step 6 of scheme 1. It was worked up and purified by reverse phase column (C18, 100 g, 0-60% MeCN in HO containing 0.1% HCl) to give the HCl salt of 2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetic acid (24b) (yield 60 mg, 31%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 2H), 7.70 (s, 1H), 7.62 (t, J = 7.1 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.4 Hz, 2H), 7.02 (dd, J = 13.9, 5.9 Hz, 2H), 6.84 (t, J = 7.3 Hz, 1H), 5.23 (s, 2H), 4.09 (s, 2H), 3.53 (s, 2H). MS (ES+): 439.9 (M+1);MS(ES-): 437.9 (M-1).

[0275] Scheme-25 [ka] Preparation of 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetic acid (25d) Step-1: Preparation of tert-butyl 3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate (25a) Compound 25a was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (1e) (570 mg, 1.55 mmol) in THF (30 mL) using N-methylmorpholine (0.2 mL, 1.86 mmol), isobutyl chloroformate (0.24 mL, 1.86 mmol), and NaBH (176 mg, 4.64 mmol) in water (0.8 mL) according to the procedure reported in Scheme 23, Step 1. Workup afforded tert-butyl 3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate (25a) (yield 100 mg, 18%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.23 - 8.17 (m, 2H), 8.12 (s, 1H), 7.57 - 7.43 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 4.5 Hz, 1H), 7.02 (dd, J = 4.5, 2.5 Hz, 1H), 5.77 (d, J = 5.7 Hz, 1H), 4.87 (d, J = 6.1 Hz, 2H), 4.22 (d, J = 6.2 Hz, 2H), 1.42 (s, 9H);MS (ES+): 355.3 (M+1), 377.3 (M+Na), (ES-): 353.4 (M-1).

[0276] Step-2: Preparation of ethyl 2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25b) Compound 25b was prepared from tert-butyl 3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate (25a) (95 mg, 0.27 mmol) in THF (5 mL) using triphenylphosphine (91 mg, 0.35 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (63 mg, 0.35 mmol) and diisopropyl azodicarboxylate (DIAD, 71 mg, 0.35 mmol) according to the procedure reported in Scheme 23, Step 2. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-40% EtOAc in hexanes] to give ethyl 2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25b) (42 mg, 30% yield) as a solid. MS (ES+): 539.4, 540.5 (M+Na), (ES-): 515.4, 516.5 (M-1).

[0277] Step-3: Preparation of ethyl 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25c) Compound 25c was prepared from ethyl 2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25b) (140 mg, 0.27 mmol) using TFA (0.21 mL, 2.71 mmol) in DCM (5 mL) according to the procedure reported in Step 5 of Scheme 1. Workup and subsequent purification by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] gave ethyl 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25c) (yield 26 mg, 23%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.45 - 8.40 (m, 1H), 8.40 - 8.27 (m, 4H, partially exchangeable with D2O), 8.22 - 8.16 (m, 1H), 7.68 - 7.54 (m, 2H), 7.30 - 7.20 (m, 2H), 7.20 - 7.14 (m, 2H), 7.12 - 7.07 (m, 1H), 7.00 - 6.91 (m, 1H), 5.54 (s, 2H), 4.21 - 4.08 (m, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 1.04 (t, J = 7.1 Hz, 3H);MS (ES+): 417.3 (M+1);439.3 (M+Na);HPLC purity: 97.50%.

[0278] Step-4: Preparation of 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetic acid (25d) Compound 25d was prepared from ethyl 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate (25c) (38 mg, 0.09 mmol) in MeOH (5 mL) using sodium hydroxide (15.49 mg, 0.39 mmol) in water (0.5 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (30 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetic acid (25d) (yield 3.6 mg, 12%) as a yellow solid. 1H NMR (300 MHz, methanol-d4) δ 8.50 (s, 1H), 8.44 - 8.36 (m, 1H), 8.08 - 8.03 (m, 1H), 7.63 - 7.56 (m, 2H), 7.31 - 7.19 (m, 3H), 7.11 - 7.02 (m, 2H), 7.01 - 6.92 (m, 1H), 5.58 (s, 2H), 4.23 (s, 2H), 3.75 (s, 2H);MS (ES+): 389.3 (M+1);411.3 (M+Na);(ES-): 387.2 (M-1);423.4 (M+Cl);HPLC, purity, 87.71%.

[0279] Scheme-26 [ka] Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetic acid (26d) Step-1: Preparation of tert-butyl 3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (26a) Compound 26a was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (16f) (500 mg, 1.18 mmol) in THF (30 mL) using N-methylmorpholine (0.14 mL, 1.3 mmol), isobutyl chloroformate (0.17 mL, 1.3 mmol) and NaBH (90 mg, 2.37 mmol) in water (0.8 mL) according to the procedure reported in Scheme 23, Step 1. This was worked up to give tert-butyl 3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (26a) (yield 330 mg, 68%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.10 - 8.03 (m, 2H), 7.78 (d, J = 3.6 Hz, 1H), 7.61 - 7.48 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 3.6 Hz, 1H), 5.17 (t, J = 6.1 Hz, 1H), 4.71 (d, J = 6.1 Hz, 2H), 4.25 (d, J = 6.3 Hz, 2H), 4.16 (d, J = 7.2 Hz, 2H), 1.41 (s, 9H), 1.34 - 1.21 (m, 1H), 0.58 - 0.40 (m, 4H); 1 H NMR (300 MHz, DMSO-d6 / D2O) δ 8.05 - 7.96 (m, 2H), 7.70 (d, J = 3.6 Hz, 1H), 7.57 - 7.43 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 3.6 Hz, 1H), 4.69 (s, 2H), 4.23 (d, J = 4.8 Hz, 2H), 4.13 (d, J = 7.2 Hz, 2H), 1.37 (s, 9H), 1.31 - 1.17 (m, 1H), 0.54 - 0.36 (m, 4H).

[0280] Step-2: Preparation of ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate (26b) Compound 26b was prepared from tert-butyl 3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (26a) (327 mg, 0.8 mmol) in THF (8 mL) using triphenylphosphine (273 mg, 1.04 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (188 mg, 1.04 mmol) and diisopropyl (E)-diazene-1,2-dicarboxylate (DIAD, 210 mg, 1.04 mmol). This was worked up by flash column chromatography [silica (12 g), elution with 0-60% EtOAc in hexanes] to give ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate (26b) (yield 352 mg, 77%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 2H), 8.08 - 7.98 (m, 2H), 7.82 (d, J = 3.6 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.24 - 7.13 (m, 3H), 6.96 - 6.83 (m, 2H), 5.35 (s, 2H), 4.25 (d, J = 6.2 Hz, 2H), 4.13 (d, J = 7.2 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 1.40 (s, 9H), 1.34 - 1.19 (m, 1H), 1.01 (t, J = 7.1 Hz, 3H), 0.51 - 0.34 (m, 4H).

[0281] Step-3: Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate (26c) Compound 26c was prepared from ethyl 2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate (26b) (350 mg, 0.61 mmol) using TFA (0.47 mL, 6.13 mmol) in DCM (25 mL) according to the procedure reported in step 5 of scheme 1. Workup followed by purification by flash column chromatography [silica (12 g), elution with 0-100% DMA-80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] afforded ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate (26c) (yield 256 mg, 89%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 3H, D2O exchangeable), 8.27 (s, 1H), 8.18 (dt, J = 7.4, 1.6 Hz, 1H), 7.88 (d, J = 3.6 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.27 - 7.10 (m, 4H), 6.90 (td, J = 7.2, 1.3 Hz, 1H), 5.38 (s, 2H), 4.16 (t, J = 7.1 Hz, 4H), 3.97 (q, J = 7.1 Hz, 2H), 3.70 (s, 2H), 1.36 - 1.19 (m, 1H), 1.02 (t, J = 7.1 Hz, 3H), 0.55 - 0.34 (m, 4H);MS (ES+): 471.4 (M+1);493.4 (M+Na);(ES-): 505.4 (M+Cl);HPLC purity: 99.60%.

[0282] Step-4: Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetic acid (26d) Compound 26d was prepared from ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate (26c) (105 mg, 0.22 mmol) in MeOH (10 mL) using sodium hydroxide (44.6 mg, 1.12 mmol) in water (2 mL) according to the procedure reported in step 4 of scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetic acid (26d) (yield 23 mg, 23%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 3H, D2O exchangeable), 8.26 (d, J = 2.1 Hz, 1H), 8.18 (dd, J = 7.6, 1.6 Hz, 1H), 7.87 (d, J = 3.6 Hz, 1H), 7.73 - 7.58 (m, 2H), 7.25 - 7.09 (m, 4H), 6.92 - 6.84 (m, 1H), 5.40 (s, 2H), 4.22 - 4.09 (m, 4H), 3.67 (s, 2H), 1.32 - 1.21 (m, 1H), 0.52 - 0.31 (m, 4H);MS (ES+): 443.4 (M+1);465.4 (M+Na);(ES-): 441.5 (M-1);477.4 (M+Cl);HPLC purity: 99.44%

[0283] Scheme-27 [ka] Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetic acid (27f) Step-1: Preparation of 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid (27c) Compound 27c was prepared from ethyl 6-chloroimidazo[1,2-b]pyridazine-8-carboxylate (27a) (500 mg, 2.22 mmol; CAS# 1161847-33-1) in dioxane (6 mL) using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (835 mg, 3.32 mmol), potassium phosphate tripotassium (1.5 mL, 4.43 mmol, 1.3 M aqueous solution), tricyclohexylphosphine (186 mg, 0.67 mmol) and Pd(dba) (203 mg, 0.22 mmol) under nitrogen atmosphere by microwave heating at 120 °C for 1 h according to the procedure reported in Scheme 1, Step 3. This was worked up and purified by flash column chromatography [silica (40 g), elution with hexane in ethyl acetate from 0 to 100%] to give ethyl 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylate (27b) (123 mg, 14% yield) as a colorless gum; 1 H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 1.2 Hz, 1H), 8.09 (s, 1H), 7.99 - 7.94 (m, 2H), 7.92 (d, J = 1.2 Hz, 1H), 7.58 - 7.39 (m, 3H), 4.47 (q, J = 7.1 Hz, 2H), 4.24 (d, J = 6.2 Hz, 2H), 1.43 - 1.30 (m, 12H);MS (ES+): 397.3 (M+1), which further eluted gave 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid (27c) (60 mg, 7% yield) as an oil. 1H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.05 (s, 1H), 8.00 - 7.94 (m, 2H), 7.91 (d, J = 1.3 Hz, 1H), 7.59 - 7.38 (m, 3H), 4.24 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H).

[0284] Step-2: Preparation of ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate (27d) Compound 27d was prepared from 6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid (27c) (180 mg, 0.489 mmol) using ethyl 2-(2-aminophenyl)acetate (5e) (153 mg, 0.86 mmol), DIPEA (0.26 mL, 1.47 mmol) and HATU (325 mg, 0.87 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% EtOAc / MeOH in hexanes (9:1)] to give ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate (27d) (yield 140 mg, 54%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.20 - 8.13 (m, 1H), 8.05 - 7.97 (m, 2H), 7.93 (s, 1H), 7.62 - 7.52 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.22 (t, J = 7.5 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.98 (s, 2H), 1.41 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H);MS (ES+): 530.4 (M+1).

[0285] Step-3: Preparation of ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate (27e) Compound 27e was prepared from ethyl 2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate (27d) (125 mg, 0.24 mmol) using TFA (0.18 mL, 2.36 mmol) in DCM (5 mL) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate (27e) (yield 100 mg, 99%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.78 (s, 1H, D2O exchangeable), 8.61 (d, J = 1.4 Hz, 1H), 8.51 - 8.35 (m, 4H, 3H D2O exchangeable), 8.31 (s, 1H), 8.18 (dd, J = 7.9, 4.2 Hz, 2H), 7.97 (d, J = 1.4 Hz, 1H), 7.75 - 7.61 (m, 2H), 7.47 - 7.37 (m, 2H), 7.24 (t, J = 7.4 Hz, 1H), 4.20 (q, J = 5.9 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.99 (s, 2H), 1.10 (t, J = 7.1 Hz, 3H);MS (ES+:) 430.5 (M+1), 452.4 (M+Na), (ES-): 464.5 (M+Cl);HPLC purity: 97.66 %.

[0286] Step-4: Preparation of 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetic acid (27f) Compound 27f was prepared from ethyl 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate (27e) (61 mg, 0.142 mmol) in THF (5 mL) using a solution of lithium hydroxide hydrate (10 mg, 0.43 mmol) in water (1 mL) according to the procedure reported in step 6 of scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetic acid (27f) (yield 65 mg, 100%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H, D2O exchangeable), 8.61 (d, J = 1.4 Hz, 1H), 8.58 - 8.43 (m, 4H, 3H D2O exchangeable), 8.32 (d, J = 1.9 Hz, 1H), 8.22 - 8.10 (m, 2H), 8.00 (d, J = 1.4 Hz, 1H), 7.75 - 7.62 (m, 2H), 7.39 (m, 2H), 7.22 (td, J = 7.5, 1.3 Hz, 1H), 4.18 (q, J = 5.5 Hz, 2H), 3.90 (s, 2H);MS (ES+): 402.4 (M+1), 424.4 (M+Na);(ES-): 400.5 (M-1);HPLC purity: 97.80 %.

[0287] Scheme-28 [ka] Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetic acid (28d) Step-1: Preparation of ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b) Compound 28b was prepared from 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid 28a (500 mg, 2.53 mmol; CAS# 478148-53-7) in DMF (4 mL) using ethyl 2-(2-aminophenyl)acetate 5e (794 mg, 4.43 mmol), DIPEA (1.33 mL, 7.59 mmol), and HATU (1684 mg, 4.43 mmol) according to the procedure reported in Step 4 of Scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc / MeOH in hexanes] to give ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate 28b (500 mg, 55% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.53 (s, 1H), 8.49 (d, J = 2.1 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.39 - 7.32 (m, 3H), 7.25 - 7.15 (m, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 1.11 (t, J = 7.1 Hz, 3H);MS (ES+): 359.2 (M+1);(ES-) 357.3 (M-1).

[0288] Step-2: Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28c) Compound 28c was prepared from ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b) (500 mg, 1.394 mmol) in dioxane (11 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (261 mg, 1.394 mmol), potassium phosphate tripotassium (1.3 M solution) (1.394 mL, 4.18 mmol), tricyclohexylphosphine (117 mg, 0.418 mmol) and Pd(dba) (128 mg, 0.139 mmol) under argon atmosphere and microwave heating at 125 °C for 1 h. This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-100% ethyl acetate in hexanes] to give ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28c) (yield 0.304 g, 51%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.69 (s, 1H), 8.61 - 8.56 (m, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 4.6 Hz, 2H), 7.44 - 7.33 (m, 3H), 7.27 - 7.18 (m, 1H), 4.20 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.86 (s, 2H), 0.93 (t, J = 7.1 Hz, 3H);MS (ES+): 430.3 (M+1);MS (ES-): 428.3 (M-1), 474.4 (M+Cl);HPLC purity: 96.63 %.

[0289] Step-3: Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetic acid (28d) Compound 28d was prepared from ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28c) (61 mg, 0.142 mmol) in THF (8 mL) using a solution of lithium hydroxide hydrate (41 mg, 1.71 mmol) in water (2 mL) according to the procedure reported in Step 6 of Scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetic acid (28d) (yield 140 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.75 (s, 1H), 8.69 (s, 1H), 8.59 - 8.56 (m, 1H), 8.55 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.43 (s, 3H), 7.96 (d, J = 7.6 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.41 - 7.34 (m, 3H), 7.24 - 7.17 (m, 1H), 4.21 (d, J = 5.7 Hz, 2H), 3.78 (s, 2H);MS (ES+): 402.3 (M+1);424.3 (M+Na), (ES-): 400.3 (M-1);HPLC purity 98.75.

[0290] Scheme-29 [ka] Preparation of (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (29d) Step-1: Preparation of (S)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (29a) Compound 29a was prepared from ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33 mmol) in dioxane (6 mL) according to the procedure reported in step 3 of scheme 1, into tert-butyl (S)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (29e) (693 mg, 1.99 mmol; 29a was prepared using CAS#887254-65-1 (prepared according to the procedure reported in PCT International Application No. 2015009977 (January 22, 2015)), tripotassium phosphate (0.753 mL, 2.26 mmol, 3 M aqueous solution), tricyclohexylphosphine (112 mg, 0.4 mmol), and Pd(dba) (122 mg, 0.13 mmol) under an argon atmosphere and heated in a microwave at 125 °C for 1 h. Workup and purification by flash column chromatography [silica (12 g), elution with 0–30% MeOH in DCM] gave (S)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (29a) (110 mg, 15% yield) as a solid. MS (ES-): 381.4, 382.4 (M-1).

[0291] Step-2: Preparation of (S)-2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid ethyl ester (29b) Compound 29b was prepared from (S)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (29a) (110 mg, 0.29 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (77 mg, 0.43 mmol), DIPEA (0.1 mL, 0.575 mmol) and HATU (164 mg, 0.431 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes, 0-100% elution] to give ethyl (S)-2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (29b) (103 mg, 66% yield) as a white solid. MS (ES+): 566.4 (M+Na); (ES-) 542.5, 543.5 (M-1).

[0292] Step-3: Preparation of (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid ethyl ester (29c) Compound 29c was prepared from ethyl (S)-2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (29b) (103 mg, 0.19 mmol) in DCM (5 mL) using TFA (0.15 mL, 1.90 mmol) according to the procedure reported in Step 5 of Scheme 1. Workup afforded ethyl (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (29c) (yield 29 mg, 35%) as a yellow solid. MS (ES+): 444.4 (M+1).

[0293] Step-4: Preparation of (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (29d) Compound 29d was prepared from ethyl (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (29c) (29 mg, 0.065 mmol) in MeOH (5 mL) using a solution of NaOH (38 mg, 0.95 mmol) in water (0.5 mL) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give (S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (29d) (yield 28 mg, 35%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H, D2O exchangeable), 10.91 (s, 1H), 8.66 (s, 1H), 8.60 (s, 3H, D2O exchangeable), 8.55 - 8.50 (m, 1H), 8.39 (dd, J = 2.5, 1.4 Hz, 1H), 7.90 - 7.80 (m, 1H), 7.77 - 7.71 (m, 1H), 7.70 - 7.57 (m, 2H), 7.48 - 7.35 (m, 2H), 7.34 - 7.21 (m, 2H), 4.67 - 4.45 (m, 1H), 3.81 (s, 2H), 1.61 (d, J = 6.7 Hz, 3H); MS (ES+): 416.3 (M+1); (ES-): 414.4 (M-1); 450.4 (M+Cl); HPLC purity; 99.56%.

[0294] Scheme-30 [ka] Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetic acid (30d) Step-1: Preparation of ethyl 2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate (30b) Compound 30b was prepared from 7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid 30a (500 mg, 2.53 mmol; CAS# 1420800-25-4) in MeOH (10 mL) using 2-(2-aminophenyl)ethyl acetate 5e (549 mg, 3.07 mmol) and EDCI (641 mg, 3.34 mmol) according to the procedure reported in Scheme 7, Step 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] to give 2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)ethyl acetate 30b (300 mg, 28%) as an off-white solid. MS (ES+): 432.3 (M+1);(ES-) 464.3, 466.3 (M+Cl).

[0295] Step-2: Preparation of ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate (30c) Compound 30c was prepared from ethyl 2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate (30b) (300 mg, 0.697 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (196 mg, 1.046 mmol), potassium phosphate tripotassium (1.3 M solution) (0.697 mL, 2.092 mmol), tricyclohexylphosphine (59 mg, 0.209 mmol) and Pd(dba) (64 mg, 0.07 mmol) under argon atmosphere by microwave heating at 125 °C for 45 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate (30c) (yield 220 mg, 69%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.70 (s, 3H), 8.43 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.72 - 7.51 (m, 3H), 7.41 - 7.21 (m, 4H), 4.13 (d, J = 5.8 Hz, 3H), 3.93 (q, J = 7.1 Hz, 2H), 2.84 (s, 3H), 3.45 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H).

[0296] Step-3: Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetic acid (30d) Compound 30d was prepared from ethyl 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate (30c) (125 mg, 0.27 mmol) in MeOH (10 mL) using a solution of sodium hydroxide (110 mg, 2.74 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetic acid (30d) (yield 81 mg, 69%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H, D2O exchangeable), 8.71 (s, 3H, D2O exchangeable), 8.45 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.67 - 7.54 (m, 2H), 7.43 - 7.20 (m, 4H), 4.13 (q, J = 5.9 Hz, 2H), 3.68 (s, 2H), 3.46 (s, 3H), 2.85 (s, 3H);MS (ES+): 429.4 (M+1);(ES-): 427.4 (M-1);463.4 (M+Cl);HPLC purity: 100%.

[0297] Scheme-31 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (31f) Step-1: Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate (31b) Compound 31b was prepared from ethyl 4-chlorothieno[3,2-d]pyrimidine-2-carboxylate (31a) (350 mg, 1.44 mmol; CAS#319442-18-7) in dioxane (3 mL) according to the procedure reported in Scheme 1, Step 3, using (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1d) (543 mg, 2.16 mmol), potassium phosphate tripotassium (0.82 mL, 2.452 mmol, 3 M aqueous solution), tricyclohexylphosphine (81 mg, 0.288 mmol) and Pd(dba) (73 mg, 0.079 mmol) under argon atmosphere and microwave heating at 125 °C for 30 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% EtOAc in hexanes] to give ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate (31b) (400 mg, 67% yield) as a yellow solid.

[0298] Step-2: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylic acid (31c) Compound 31c was prepared from ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate (31b) (400 mg, 0.97 mmol) in MeOH (10 mL) using a solution of NaOH (193 mg, 4.84 mmol) in water (2 mL) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylic acid (31c) (365 mg, 98% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.72 (d, J = 5.6 Hz, 1H), 8.19 - 7.99 (m, 2H), 7.86 (d, J = 5.6 Hz, 1H), 7.69 - 7.47 (m, 3H), 4.28 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H).

[0299] Step-3: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31d) Compound 31d was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylic acid (31c) (365 mg, 0.95 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (204 mg, 1.14 mmol), DIPEA (0.331 mL, 1.894 mmol) and HATU (432 mg, 1.14 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes from 0-100%] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31d) (yield 425 mg, 82%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.77 (d, J = 5.5 Hz, 1H), 8.27 - 8.19 (m, 2H), 7.90 (d, J = 5.5 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.70 - 7.61 (m, 1H), 7.60 - 7.51 (m, 2H), 7.44 - 7.34 (m, 2H), 7.28 - 7.19 (m, 1H), 4.30 (d, J = 6.2 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.86 (s, 2H), 1.40 (s, 9H), 0.98 (t, J = 7.1 Hz, 3H).

[0300] Step-4: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31e) Compound 31e was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31d) (400 mg, 0.73 mmol) in DCM (5 mL) using TFA (0.56 mL, 7.32 mmol) according to the procedure reported in Step 5 of Scheme 1. This was worked up and purified by reverse-phase column purification [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31e) (yield 308 mg, 94%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H, D2O exchangeable), 8.80 (d, J = 5.4 Hz, 1H), 8.60 (s, 3H, D2O exchangeable), 8.51 (s, 1H), 8.39 - 8.31 (m, 1H), 7.93 (d, J = 5.5 Hz, 1H), 7.89 - 7.72 (m, 3H), 7.45 - 7.35 (m, 2H), 7.32 - 7.21 (m, 1H), 4.22 (s, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 447.3 (M+1);(ES-): 481.3 (M+Cl);HPLC purity, 99.72%.

[0301] Step-5: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (31f) Compound 31f was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (31e) (256 mg, 0.57 mmol) in MeOH / THF (10 mL, 1:1) using a solution of NaOH (92 mg, 2.29 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (31f) (yield 112 mg, 47%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H, D2O exchangeable), 8.80 (d, J = 5.5 Hz, 1H), 8.60 - 8.42 (m, 4H, partially D2O exchangeable), 8.39 - 8.30 (m, 1H), 7.95 - 7.70 (m, 4H), 7.45 - 7.33 (m, 2H), 7.23 (t, J = 7.4 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.79 (s, 2H);MS (ES + ) 419.3 (M+1);441.3 (M+Na);(ES - ) 417.3 (M-1), 453.3 (M+Cl);HPLC, 0.395 min, 98.46%.

[0302] Scheme-32 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (32h) Step-1: Preparation of tert-butyl 3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b) Compound 32b was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (32a) (4.5 g, 21.94 mmol; CAS#18740-39-1) in dioxane (100 mL) according to the procedure reported in Scheme 1, Step 3, using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (5.63 g, 16.88 mmol), potassium phosphate tripotassium (22.07 mL, 28.7 mmol), tricyclohexylphosphine (0.95 g, 3.38 mmol), and Pd(dba) (0.85 g, 0.93 mmol) in water (1 mL) under argon atmosphere, heated in an oil bath at 120 °C for 1 h. This was worked up and purified by flash column chromatography [silica (80 g), elution with 0-70% EtOAc in hexanes] to give tert-butyl 3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b) (4.5 g, 71% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J = 6.0 Hz, 1H), 7.89 - 7.83 (m, 2H), 7.74 (d, J = 6.1 Hz, 1H), 7.62 - 7.47 (m, 3H), 4.25 (d, J = 6.2 Hz, 2H), 1.40 (s, 9H).

[0303] Step-2: Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c) Compound 32c was prepared according to the procedure reported in Scheme 1, Step 1 from tert-butyl 3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b) (4.5 g, 11.97 mmol) in DMF (60 mL) using 1-ethoxyvinyltri-n-butyltin (4.89 mL, 14.37 mmol) and Pd(PPh3)4 (0.692 g, 0.599 mmol) under argon atmosphere and heated at 110 °C for 10 h. Workup and purification by flash column chromatography [silica (80 g), elution with 0-70% EtOAc in hexanes] afforded tert-butyl 3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c) (4.4 g, 89% yield) as a yellow solid. MS (ES+): 412.2 (M+1).

[0304] Step-3: Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate (32d) Compound 32d was prepared from tert-butyl 3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c) (4.4 g, 10.69 mmol) in 1,4-dioxane (50 mL) using a solution of sodium periodate (4.57 g, 21.38 mmol) and KMnO (0.676 g, 4.28 mmol, and a second charge of 0.338 g, 2.138 mmol after 12 h) in water (20 mL) according to the procedure reported in Scheme 1, Step 2. Workup and purification by flash column chromatography [silica (40 g), elution with 0-60% EtOAc in hexanes] gave ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate (32d) (1.6 g, 36% yield) as a yellow solid. MS (ES+): 414.2 (M+1), 436.1 (M+Na).

[0305] Step-4: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylic acid (32e) Compound 32e was prepared from ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate (32d) (1.6 g, 3.87 mmol) in THF / MeOH (30 mL, 1:1) using lithium hydroxide hydrate (0.812 g, 19.35 mmol) in water (5 mL) according to the procedure reported in Step 6 of Scheme 1. This was worked up and purified by reverse-phase column [C18 (50 g), elution with ACN in water (0.1% HCl) from 0 to 100%] to give 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylic acid (32e) (0.55 g, 37% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.82 (d, J = 6.1 Hz, 1H), 7.64 - 7.44 (m, 3H), 4.26 (d, J = 6.2 Hz, 2H), 1.40 (s, 9H).

[0306] Step-5: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32f) Compound 32f was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylic acid (32e) (547 mg, 1.42 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (305 mg, 1.703 mmol), DIPEA (0.5 mL, 2.84 mmol) and HATU (648 mg, 1.703 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes from 0-100%] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32f) (yield 620 mg, 1.134 mmol, 80%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.29 (d, J = 6.1 Hz, 1H), 8.12 - 7.99 (m, 2H), 7.89 (d, J = 6.1 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.65 - 7.48 (m, 3H), 7.38 (d, J = 7.5 Hz, 2H), 7.29 - 7.18 (m, 1H), 4.29 (d, J = 6.1 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 1.40 (s, 9H), 0.98 (t, J = 7.1 Hz, 3H);MS (ES+): 569.4 (M+Na);(ES-): 545.5 (M-1).

[0307] Step-6: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32 g) Compound 32g was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32f) (600 mg, 1.10 mmol) in DCM (10 mL) using TFA (0.85 mL, 10.98 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32 g) (yield 385 mg, 79%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H, D2O exchangeable), 8.58 (s, 3H, D2O exchangeable), 8.35 - 8.27 (m, 2H), 8.24 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 6.1 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.75 - 7.68 (m, 1H), 7.42 - 7.34 (m, 2H), 7.29 - 7.20 (m, 1H), 4.30 - 4.14 (m, 2H), 3.98 (q, J = 7.2 Hz, 2H), 3.85 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H);MS (ES+): 447.3 (M+1);(ES-): 481.3 (M+Cl);HPLC purity, 99.41%.

[0308] Step-7: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (32h) Compound 32h was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate (32g) (200 mg, 0.448 mmol) in MeOH / THF (10 mL, 1:1) using a solution of NaOH (72 mg, 1.79 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetic acid (32h) (yield 150 mg, 80%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H, D2O exchangeable), 10.81 (s, 1H, D2O exchangeable), 8.60 (s, 3H, D2O exchangeable), 8.35 - 8.27 (m, 2H), 8.27 - 8.20 (m, 1H), 8.17 - 8.07 (m, 1H), 7.95 - 7.84 (m, 1H), 7.83 - 7.77 (m, 1H), 7.77 - 7.67 (m, 1H), 7.44 - 7.33 (m, 2H), 7.29 - 7.17 (m, 1H), 4.26 - 4.17 (m, 2H), 3.78 (s, 2H);MS (ES+): 419.3 (M+1);441.3 (M+Na);(ES-): 417.3 (M-1), 453.3 (M+Cl);HPLC, 0.406 min, 100%.

[0309] Scheme-33 [ka] Preparation of (R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (33f) Step-1: Preparation of (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (33b) Compound 33b was prepared from ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (450 mg, 1.99 mmol) in dioxane (15 mL) by the procedure reported in step 3 of scheme 1, yielding tert-butyl (R)-(1-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (33a) (1.093 g, 2.99 mmol). (prepared according to the procedure reported in PCT International Application No. 2015009977 (January 22, 2015)), potassium phosphate tripotassium (3M in water) (1.33 mL, 3.99 mmol), tricyclohexylphosphine (112 mg, 0.4 mmol), and Pd(dba) (183 mg, 0.2 mmol) under an argon atmosphere, heated in a microwave at 125 °C for 45 minutes. This was worked up and purified by flash column chromatography [silica (24 g), elution with 0-50% EtOAc in DCM] to give ethyl (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (33b) (0.73 g, 85% yield) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.44 - 8.37 (m, 1H), 7.88 - 7.79 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.41 - 7.32 (m, 2H), 7.29 (dd, J = 4.6, 2.6 Hz, 1H), 5.07 - 4.91 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.45 - 1.27 (m, 15H);MS (ES+): 429.3 (M+1);(ES-): 427.3 (M-1).

[0310] Step-2: Preparation of (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (33c) Compound 33c was prepared from (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (33b) (0.73 g, 1.704 mmol) in THF (15 mL) using lithium hydroxide hydrate (0.107 g, 2.56 mmol) in water (3 mL) according to the procedure reported in step 6 of scheme 1. Workup afforded (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (33c) (yield 0.67 g, 98%) as a pale orange foam. 1 H NMR (300 MHz, DMSO-d6) δ 14.37 (s, 1H), 8.39 - 8.34 (m, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.40 - 7.31 (m, 2H), 7.25 (dd, J = 4.6, 2.6 Hz, 1H), 4.99 (t, J = 7.4 Hz, 1H), 1.46 - 1.24 (m, 12H);MS (ES+): 423.3 (M+Na);(ES-): 399.4 (M-1).

[0311] Step-3: Preparation of ethyl (R)-2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33d) Compound 33d was prepared from (R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (33c) (200 mg, 0.499 mmol) in DMF (3 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (134 mg, 0.75 mmol), DIPEA (0.174 mL, 1.00 mmol) and HATU (228 mg, 0.6 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% EtOAc in hexanes] to give ethyl (R)-2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33d) (yield 0.22 g, 78%) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.16 (t, J = 7.4 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.61 - 7.51 (m, 2H), 7.44 - 7.32 (m, 3H), 7.32 - 7.20 (m, 2H), 5.09 - 4.93 (m, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 1.43 - 1.19 (m, 12H), 1.02 - 0.90 (m, 3H);MS (ES+): 584.4 (M+Na);(ES-): 560.5 (M-1).

[0312] Step-4: Preparation of ethyl (R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33e) Compound 33e was prepared from ethyl (R)-2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33d) (200 mg, 0.356 mmol) in DCM (2 mL) using TFA (0.274 mL, 3.56 mmol) according to the procedure reported in Scheme 1, Step 5. This was worked up and purified by reverse column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of ethyl (R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33e) (yield 0.164 g, 100%) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.48 - 8.35 (m, 5H), 7.83 - 7.72 (m, 2H), 7.64 - 7.57 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.36 - 7.23 (m, 2H), 4.85 - 4.69 (m, 1H), 3.97 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 1.58 (d, J = 6.7 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -118.34;MS (ES+): 462.3 (M+1), 484.3 (M+Na);HPLC purity 99.38 %

[0313] Step-5: Preparation of (R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (33f) Compound 33f was prepared from ethyl (R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (33e) (120 mg, 0.26 mmol) in THF (4 mL) using a 2 M aqueous solution of NaOH (0.52 mL, 1.04 mmol) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of (R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (33f) (yield 0.06 g, 53%) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.74 (s, 1H), 8.62 (s, 3H), 8.46 - 8.32 (m, 2H), 7.92 - 7.78 (m, 2H), 7.66 - 7.58 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.32 (dd, J = 4.6, 2.6 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 4.84 - 4.70 (m, 1H), 3.76 (s, 2H), 1.60 (d, J = 6.7 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -118.36;MS (ES+): 434.3 (M+1), MS (ES-): 432.4 (M-1);HPLC purity 99.62%.

[0314] Scheme-34 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (34f) Step-1: Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (34b) Compound 34b was prepared from ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (400 mg, 1.77 mmol) in dioxane (15 mL) according to the procedure reported in Scheme 1, Step 3, using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (1.093 g, 2.99 mmol; CAS#1360819-53-9), 3 M aqueous potassium phosphate (1.18 mL, 3.55 mmol), tricyclohexylphosphine (99 mg, 0.36 mmol), and Pd(dba) (162 mg, 0.18 mmol) under argon atmosphere, heated in a microwave at 125 °C for 45 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% EtOAc in hexanes] to give ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (34b) (0.61 g, 83% yield) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.40 (dd, J = 2.6, 1.4 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.57 - 7.42 (m, 2H), 7.41 - 7.31 (m, 2H), 7.29 (dd, J = 4.6, 2.5 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.26 (d, J = 6.0 Hz, 2H), 1.47 - 1.30 (m, 12H);MS (ES+): 415.3 (M+1);(ES-): 413.4 (M-1).

[0315] Step-2: Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (34c) Compound 34c was prepared from ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (34b) (0.6 g, 1.448 mmol) in THF (15 mL) using lithium hydroxide hydrate (0.122 g, 2.90 mmol) in water (1 mL) according to the procedure reported in step 6 of scheme 1. Workup afforded 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (34c) (yield 0.54 g, 97%) as a pale orange foam. 1 H NMR (300 MHz, DMSO-d6) δ 14.37 (s, 1H), 8.36 (dd, J = 2.6, 1.4 Hz, 1H), 7.95 - 7.87 (m, 1H), 7.57 - 7.42 (m, 2H), 7.39 - 7.31 (m, 2H), 7.25 (dd, J = 4.6, 2.5 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 1.40 (s, 9H);MS (ES-): 385.3 (M-1).

[0316] Step-3: Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34d) Compound 34d was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (34c) (250 mg, 0.647 mmol) in DMF (4 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (125 mg, 0.7 mmol), DIPEA (0.23 mL, 1.29 mmol) and HATU (295 mg, 0.776 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-100% EtOAc in hexanes] to give ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34d) (yield 0.31 g, 87%) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.40 (dd, J = 2.7, 1.4 Hz, 1H), 8.22 (t, J = 7.5 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.61 - 7.55 (m, 2H), 7.50 (dt, J = 13.5, 6.3 Hz, 1H), 7.44 - 7.32 (m, 3H), 7.32 - 7.21 (m, 2H), 4.28 (d, J = 6.1 Hz, 2H), 3.96 (q, J = 7.0 Hz, 2H), 3.83 (s, 2H), 1.41 (s, 9H), 0.97 (t, J = 7.1 Hz, 3H);MS (ES+): 570.4 (M+Na);(ES-): 546.5 (M-1).

[0317] Step-4: Preparation of ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34e) Compound 34e was prepared from ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34d) (200 mg, 0.365 mmol) in DCM (5 mL) using TFA (0.281 mL, 3.65 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34e) (yield 0.16 g, 98%) as the HCl salt. 1 H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.53 - 8.36 (m, 5H), 7.81 - 7.71 (m, 2H), 7.60 (dd, J = 4.6, 1.4 Hz, 1H), 7.52 - 7.36 (m, 3H), 7.34 - 7.23 (m, 2H), 4.20 (s, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -116.67;MS (ES+): 448.3 (M+1), MS (ES-): 482.4 (M+Cl);HPLC purity 98.75%

[0318] Step-5: Preparation of 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (34f) Compound 34f was prepared from ethyl 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (34e) (110 mg, 0.246 mmol) in THF (4 mL) using a 2 M aqueous solution of NaOH (0.62 mL, 1.23 mmol) according to the procedure reported in step 4 of scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-40% ACN in water (containing 0.1% HCl)] to give 2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (34f) (yield 0.072 g, 70%) as the HCl salt. 1 H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.76 (s, 1H), 8.57 - 8.34 (m, 5H), 7.86 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 7.1 Hz, 1H), 7.62 (d, J = 4.5 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.32 (dd, J = 4.6, 2.6 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 4.20 (s, 2H), 3.76 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -116.66;MS (ES+): 420.3 (M+1), MS (ES-): 418.3 (M-1);HPLC purity 99.49%.

[0319] Scheme-35 [ka] Preparation of 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetic acid (35f) Step-1: Preparation of ethyl 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate (35b) Compound 35b was prepared from ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (35a) (1000 mg, 4.23 mmol; CAS#263881-19-2) in DMF (11 mL) using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (1.59 g, 6.34 mmol), potassium phosphate tripotassium (1.3 M solution, 2.82 mL, 8.45 mmol), tricyclohexylphosphine (355 mg, 1.27 mmol) and Pd(dba) (387 mg, 0.42 mmol) under nitrogen atmosphere by microwave heating at 120 °C for 1 h according to the procedure reported in Scheme 1, Step 3. This was worked up and purified by flash column chromatography [silica (40 g), elution with hexane / ethyl acetate from 0% to 100%] to give ethyl 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate (35b) (yield 1.32 g, 77%) as an oil. 1 H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.88 (d, J = 5.7 Hz, 1H), 8.67 (s, 1H), 8.21 (dd, J = 5.7, 1.0 Hz, 1H), 7.68 - 7.45 (m, 5H), 4.43 (q, J = 7.1 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 1.40 - 1.28 (m, 12H).

[0320] Step-2: Preparation of 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylic acid (35c) Compound 35c was prepared from ethyl 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate (35b) (1250 mg, 3.07 mmol) in THF (20 mL) using a solution of lithium hydroxide hydrate (220 mg, 9.2 mmol) in water (4 mL) according to the procedure reported in step 6 of scheme 1. Workup gave 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylic acid (35c) (300 mg, 26%), which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.86 (d, J = 5.7 Hz, 1H), 8.62 (s, 1H), 8.17 (d, J = 5.8 Hz, 1H), 7.72 - 7.41 (m, 5H), 4.27 (d, J = 6.2 Hz, 2H), 1.38 (s, 9H).

[0321] Step-3: Preparation of ethyl 2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35d) Compound 35d was prepared from 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylic acid (35c) (300 mg, 0.79 mmol) in DMF (4 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (248 mg, 1.38 mmol), DIPEA (0.41 mL, 2.37 mmol) and HATU (526 mg, 1.38 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes from 0-100%] to give ethyl 2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35d) (yield 300 mg, 70%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.55 (s, 1H), 8.90 (d, J = 5.7 Hz, 1H), 8.74 (s, 1H), 8.26 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.44 - 7.32 (m, 2H), 7.21 (t, J = 7.4 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.87 - 3.73 (m, 4H), 1.37 (s, 9H), 0.88 (t, J = 7.1 Hz, 3H).

[0322] Step-4: Preparation of ethyl 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35e) Compound 35e was prepared from ethyl 2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35d) (300 mg, 0.56 mmol) using TFA (0.43 mL, 5.55 mmol) in DCM (5 mL) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35e) (yield 0.21 g, 86%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.74 (s, 1H), 8.94 (d, J = 5.6 Hz, 1H), 8.81 (s, 1H), 8.64 (s, 2H), 8.39 (d, J = 5.7 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 8.3 Hz, 2H), 7.23 (td, J = 7.3, MS (ES+): 441.3 (M+1), 463.3 (M+Na);(ES-): 475.3 (M+Cl);HPLC purity: 98.24%.

[0323] Step-5: Preparation of 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetic acid (35f) Compound 35f was prepared from ethyl 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate (35e) (150 mg, 0.34 mmol) in MeOH / THF (10 mL, 1:1) using a solution of sodium hydroxide (54 mg, 1.36 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. It was worked up and purified by reverse-phase column [C18 (50 g), eluted with ACN in water (containing 0.1% HCl) from 0 to 100%] to give 2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetic acid (35f) (yield 0.12 g, 85%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.81 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.71 (d, J = 6.4 Hz, 3H), 8.47 (d, J = 5.5 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 8.02 - 7.92 (m, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.28 - 7.13 (m, 1H), 4.20 (q, J = 5.9 Hz, 2H), 3.74 (s, 2H);MS (ES+): 413.3 (M+1), 435.3 (M+Na);(ES-): 411.4 (M-1), 447.3 (M+Cl);HPLC purity: 94.81%.

[0324] Scheme-36 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (36h) Step-1: Preparation of tert-butyl 3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) Compound 36b was prepared from 2,4-dichlorofuro[3,2-d]pyrimidine (36a) (3 g, 15.87 mmol; CAS#956034-07-4) in dioxane (100 mL) by the procedure reported in Scheme 1, Step 3, with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (3.78 g, 11.34 mmol), potassium phosphate tribasic (8.31 mL, 24.94 mmol, 3M aqueous solution, tricyclohexyl methyl phosphate) in water (1 mL). This was prepared using phosphine (0.95 g, 3.38 mmol) and Pd(dba) (1.04 g, 1.13 mmol) under argon atmosphere and heated in an oil bath at 120 °C for 1.5 h. Workup and purification by flash column chromatography [silica (40 g), elution with 0–70% EtOAc in hexanes] afforded tert-butyl 3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) (2.65 g, 65% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 7.5 Hz, 2H), 7.66 - 7.47 (m, 3H), 7.33 (d, J = 2.3 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 1.42 (s, 9H);MS (ES-): 358.3 & 360.3 (M-1).

[0325] Step-2: Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c) Compound 36c was prepared from tert-butyl 3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) (2 g, 5.56 mmol) in DMF (30 mL) using 1-ethoxyvinyltri-n-butyltin (2.46 mL, 7.23 mmol) and Pd(PPh) (0.64 g, 0.56 mmol) under argon atmosphere and heated at 110 °C for 4 h according to the procedure reported in Scheme 1, Step 1. This was worked up and purified by flash column chromatography [silica (40 g), eluting with 0-50% EtOAc in hexane] to give tert-butyl 3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c) (yield 1.80 g, 82%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 7.4 Hz, 2H), 7.66 - 7.46 (m, 3H), 7.35 (d, J = 2.2 Hz, 1H), 5.68 (d, J = MS (ES+): 396.3 (M+1);MS (ES-): 430.4 (M+Cl).

[0326] Step-3: Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate (36d) Compound 36d was prepared from tert-butyl 3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c) (1.7 g, 4.30 mmol) in 1,4-dioxane (100 mL) using a solution of sodium periodate (1.839 g, 8.60 mmol) and KMnO (0.41 g, 2.58 mmol, and a second charge of 0.41 g, 2.58 mmol after 12 h) in water (10 mL) according to the procedure reported in Scheme 1, Step 2. This was worked up and purified by flash column chromatography [silica (24 g), elution with 0-60% EtOAc in hexanes] to give ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate (36d) (0.55 g, 32% yield) as a yellow solid. MS (ES) - ) 396.4 (M-1).

[0327] Step-4: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylic acid (36e) Compound 36e was prepared from ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate (36d) (0.35 g, 0.88 mmol) in THF / MeOH (10 mL, 1:1) using sodium hydroxide (0.14 g, 3.52 mmol) in water (2 mL) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse-phase column [C18 (50 g), elution with ACN in water (containing 0.1% HCl) from 0 to 100%] to give 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylic acid (36e) (yield 0.22 g, 68%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J = 2.3 Hz, 1H), 8.36 - 8.24 (m, 2H), 7.57 (dd, J = 9.4, 6.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 1.40 (s, 9H);MS (ES-): 368.3 (M-1).

[0328] Step-5: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36f) Compound 36f was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylic acid (36e) (0.2 g, 0.54 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (120 mg, 0.65 mmol), DIPEA (0.19 mL, 1.08 mmol) and HATU (250 mg, 0.65 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc / MeOH (9:1) in hexanes, 0-100% elution] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36f) (0.17 g, 59% yield) as a white solid. MS (ES+): 553.5 (M+Na).

[0329] Step-6: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36 g) Compound 36g was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36f) (170 mg, 0.32 mmol) in DCM (5 mL) using TFA (0.25 mL, 3.2 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36 g) (yield 0.12 g, 87%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.88 - 8.77 (m, 2H), 8.69 (s, 2H), 8.66 - 8.61 (m, 1H), 7.85 (m, 1H), 7.80 - 7.69 (m, 2H), 7.53 - 7.46 (m, 1H), 7.43 - 7.35 (m, 2H), 7.30 - 7.21 (m, 1H), 4.20 (q, J = 5.8 Hz, 2H), 3.99 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 431.3 (M+1); HPLC purity: 97.05%.

[0330] Step-7: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (36h) Compound 36h was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate (36g) (600 mg, 0.14 mmol) in MeOH / THF (10 mL, 1:1) using a solution of NaOH (20 mg, 0.56 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetic acid (36h) (0.03 g, 57% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.84 (d, J = 2.2 Hz, 1H), 8.75 (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 8.52 (s, 2H), 7.94 - 7.70 (m, MS (ES+): 403.3 (M+1), 425.3 (M+Na);MS (ES-): 401.3 (M-1), 437.3 (M+Cl).

[0331] Scheme-37 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (37c) Step-1: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37a) Compound 37a was prepared from ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (0.23 g, 0.57 mmol) in dioxane (30 mL) using tert-butyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (34a) (200 mg, 0.57 mmol), potassium phosphate tripotassium (0.42 mL, 1.25 mmol, 3 M aqueous solution) in water (1 mL), tricyclohexylphosphine (0.05 g, 0.06 mmol) and Pd(dba) (0.05 g, 0.06 mmol) under argon atmosphere in an oil bath at 120 °C for 1 h. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% EtOAc in hexanes] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37a) (yield 0.21 g, 68%) as a white solid. MS (ES-): 544.5 (M-1).

[0332] Step-2: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37b) Compound 37b was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37a) (150 mg, 0.28 mmol) in DCM (5 mL) using TFA (0.21 mL, 2.75 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37b) (yield 0.09 g, 74%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.01 (s, 1H), 8.50 (s, 3H), 8.17 - 8.07 (m, 1H), 7.74 - 7.58 (m, 4H), 7.49 - 7.38 (m, 1H), 7.32 (m, 2H), 7.29 - 7.18 (m, 1H), 6.50 - 6.36 (m, 1H), 4.18 (d, J = 6.0 Hz, 2H), 4.02 - 3.90 (m, 2H), 3.75 (s, 2H), 1.14 - 0.86 (m, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -118.67;MS (ES+): 446.3 (M+1), 448.3 (M+Na);MS (ES-): 480.4 (M+Cl). HPLC purity: 93.30%.

[0333] Step-3: Preparation of 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (37c) Compound 37c was prepared from ethyl 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate (37b) (80 mg, 0.17 mmol) in MeOH / THF (5 mL, 1:1) using a solution of NaOH (30 mg, 0.67 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetic acid (37c) (yield 0.04 g, 54%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.74 (s, 1H), 10.05 (s, 1H), 8.50 (s, 3H), 8.15 (s, 1H), 7.71 (s, 1H), 7.69 - 7.59 (m, 2H), 7.54 - 7.38 (m, 2H), 7.32 (m, 2H), 7.26 - 7.17 (m, 1H), 6.45 (d, J = 2.8 Hz, 1H), 4.18 (d, J = 5.9 Hz, 2H), 3.68 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -118.51;MS (ES+): 418.3 (M+1);MS (ES-): 416.4 (M-1), 452.3 (M+Cl). HPLC purity: 97.67%.

[0334] Scheme-38 [ka] Preparation of 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (38f) Step-1: Preparation of (S)-N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2-sulfinamide (38b) Compound 38b was prepared from 7-bromobenzofuran-3-carbaldehyde (38a) (110 mg, 0.489 mmol; CAS# 1368142-94-2) in DCM (20 mL) using CsCO (381 mg, 1.169 mmol) and (S)-2-methylpropane-2-sulfinamide (119 mg, 0.982 mmol) according to the procedure reported in Scheme 220, Step 1. Workup afforded (S)-N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2-sulfinamide (38b) (yield 160 mg, 100%), which was used directly in the next step without further purification. MS (ES+): 328.0 (M+1).

[0335] Step-2: Preparation of (S)-N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropane-2-sulfinamide (38c) Compound 38c was prepared from (S)—N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2-sulfinamide (38b) (160 mg, 0.487 mmol) in DCM (12 mL) and methanol (4 mL) using NaBH (83 mg, 2.194 mmol) according to the procedure reported in Scheme 220, Step 2. Workup and purification by flash column chromatography (silica gel, 12 g, elution with 30-100% ethyl acetate in hexane) gave (S)—N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropane-2-sulfinamide (38c) (yield 120 mg, 75%) as a colorless oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J = 1.1 Hz, 1H), 7.72 (dd, J = 7.8, 1.1 Hz, 1H), 7.56 (dd, J = 7.8, 1.0 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 5.77 (t, J = 5.5 Hz, 1H), 4.28 (dt, J = 5.6, 1.1 Hz, 2H), 1.11 (s, 9H).

[0336] Step-3: Preparation of (S)-2-(2-((3'-((1,1-dimethylethylsulfinamido)methyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid ethyl ester (38d) Compound 38d was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (59a) (178 mg, 0.408 mmol) in dioxane (5 mL) using a solution of (S)—N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropane-2-sulfinamide (38c) (120 mg, 0.363 mmol), bis(triphenylphosphine)palladium(II) chloride (45 mg, 0.064 mmol) and KCO (158 mg, 1.143 mmol) in water (0.5 mL) under argon atmosphere and heated in an oil bath at 100° C. for 3 h. This was worked up and purified by flash column chromatography (12 g silica gel, eluting with 30–100% hexane in ethyl acetate) to give ethyl (S)-2-(2-((3'-((1,1-dimethylethylsulfinamido)methyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (38d) (189 mg, 83%) as a pale yellow oil. MS (ES+): 560.0 (M+1).

[0337] Step-4: Preparation of ethyl 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (38e) Compound 38e was prepared from ethyl (S)-2-(2-((3'-((1,1-dimethylethylsulfinamido)methyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (38d) (182 mg, 0.325 mmol) in methanol (8 mL) using hydrochloric acid (4 M in 1,4-dioxane, 0.35 mL, 1.400 mmol). This was worked up and purified by flash column chromatography (12 g silica gel, elution with DMA80 / DCM 0-80%) to give ethyl 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (38e) (96 mg, 45%) as a yellow foam. (ES+): 456.0 (M+1).

[0338] Step-5: Preparation of 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (38f) Compound 38f was prepared from ethyl 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetate (38e) (94 mg, 0.206 mmol) in THF / methanol (6 mL each) using lithium hydroxide hydrate (84 mg, 2.0 mmol) in water (2 mL) according to the procedure reported in step 6 of scheme 1. This was worked up and purified by reverse phase column [C18 (50 g), elution with ACN in water (0.1% HCl) from 0 to 100%] to give the HCl salt of 2-(2-((3'-(aminomethyl)-[7,7'-bibenzofuran]-5-yl)methoxy)phenyl)acetic acid (38f) (yield 61 mg, 69%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 2H), 8.12 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 7.9, 1.2 Hz, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 4.7, 3.0 Hz, 2H), 7.42 (t, J = 7.7 Hz, 1H), 7.17 (dd, J = 9.4, 6.7 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.83 (t, J = 7.3 Hz, 1H), 5.22 (s, 2H), 4.18 (s, 2H), 3.53 (s, 2H). MS (ES+): 427.9 (M+1);MS(ES-): 425.9 (M-1). HPLC purity 99.10%.

[0339] Scheme-39 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetic acid (39d) Step-1: Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39b) Compound 39b was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (1e) (0.15 g, 0.41 mmol) in DMF (3 mL) using ethyl 2-(2-amino-4-methylphenyl)acetate (39a) (118 mg, 0.611 mmol, CAS#1261742-93-1), DIPEA (0.213 mL, 1.22 mmol) and HATU (186 mg, 0.489 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0–60% EtOAc in hexanes] to give ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39b) (0.18 g, 81% yield) as an orange foam. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.40 - 8.32 (m, 2H), 7.63 (d, J = 1.6 Hz, 1H), 7.60 - 7.47 (m, 3H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 - 7.22 (m, 2H), 7.12 - 7.03 (m, 1H), 4.26 (d, J = 6.1 Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 2.36 (s, 3H), 1.41 (s, 9H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 544.5 (M+1).

[0340] Step-2: Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39c) Compound 39c was prepared from ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39b) (180 mg, 0.33 mmol) in DCM (5 mL) using TFA (0.255 mL, 3.31 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39c) (yield 0.055 g, 38%) as a solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.66 - 8.55 (m, 2H), 8.43 - 8.27 (m, 4H), 7.74 - 7.54 (m, 4H), 7.33 - 7.25 (m, 2H), 7.15 - 7.06 (m, 1H), 4.18 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 2.36 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+) 444.4 (M+1), MS (ES-) 478.4 (M+Cl);HPLC purity: 94.27%

[0341] Step-3: Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetic acid (39d) Compound 39d was prepared from ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate (39c) (0.11 g, 0.248 mmol) in THF (30 mL) using sodium hydroxide (0.62 mL, 1.24 mmol, 2 M aqueous solution) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetic acid (39d) (yield 0.05 g, 48.5%) as a solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.85 (s, 1H), 8.61 (s, 1H), 8.54 (dt, J = 7.1, 1.8 Hz, 1H), 8.44 - 8.30 (m, 4H), 7.73 - 7.59 (m, 4H), 7.32 - 7.25 (m, 2H), 7.08 (dd, J = 7.6, 1.7 Hz, 1H), 4.24 - 4.12 (m, 2H), 3.74 (s, 2H), 2.36 (s, 3H). MS (ES+) 416.3 (M+1), MS (ES-) 414.4 (M-1), 829.7 (2M-1);HPLC purity: 97.48 %.

[0342] Scheme-40 [ka] Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (40e) Step-1: Preparation of 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) To a solution of 4-bromo-1H-indole-6-carboxylic acid (9a) (1.5 g, 6.25 mmol) in DMF (9.5 mL) at 0 °C was added NaH (60% in mineral oil, 0.625 g, 15.62 mmol). After stirring at 0 °C for 15 min, tosyl-Cl (1.43 g, 7.50 mmol) was added in 1 g portions every 15 min at 0 °C, and the reaction was allowed to warm slowly to 10 °C in an ice bath. After stirring for 2 h, the mixture was poured into HO and acidified with 5 M HCl. The precipitate was collected by filtration, washed with water, and dried to give 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) (1.85 g, 4.69 mmol, 75% yield) as a tan solid, which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.54 - 8.48 (m, 1H), 8.19 (d, J = 3.8 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.93 - 7.84 (m, 2H), 7.44 (d, J = 8.1 Hz, 2H), 6.92 - 6.84 (m, 1H), 2.33 (s, 3H).

[0343] Step-2: Preparation of (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b) Compound 40b was prepared from 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) (1.5 g, 3.8 mmol) according to the procedure reported in Scheme 23, Step 1, using N-methylmorpholine (0.5 mL, 4.57 mmol), isobutyl chloroformate (0.6 mL, 4.57 mmol), and NaBH (0.43 g, 11.41 mmol) in water (0.8 mL) in THF (30 mL). Workup afforded (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b) (1.2 g, 82%) as a clear oil, which was used directly in the next step without further purification. MS (ES+) 402.1, 404.1 (M+Na), (ES-) 378.2, 380.2 (M-1).

[0344] Step-3: Preparation of ethyl 2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) Compound 40c was prepared from (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b) (1.2 g, 3.16 mmol) in THF (15 mL) using triphenylphosphine (1.07 g, 4.1 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (0.739 g, 4.1 mmol), and DIAD (0.83 g, 4.1 mmol) according to the procedure reported in Scheme 23, Step 2. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] to give ethyl 2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) (0.4 g, 23% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.94 (d, J = 3.7 Hz, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.81 - 6.69 (m, 4H), 5.26 (s, 2H), 4.07 - 4.01 (m, 2H), 3.66 (s, 2H), 2.31 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H).

[0345] Step-4: Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40d) Compound 40d was prepared from ethyl 2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) (400 mg, 0.74 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (207 mg, 1.11 mmol), potassium phosphate tripotassium (1.3 M solution, 0.42 mL, 1.25 mmol), tricyclohexylphosphine (62 mg, 0.22 mmol) and Pd(dba) (68 mg, 0.074 mmol) under argon atmosphere and microwave heating at 125 °C for 20 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (30 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40d) (yield 48 mg, 11%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 3H, D2O exchangeable), 8.07 (s, 1H), 7.94 - 7.85 (m, 3H), 7.70 (s, 1H), 7.61 - 7.48 (m, 3H), 7.41 (s, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.28 - 7.19 (m, 2H), 7.12 - 7.04 (m, 1H), 7.00 (d, J = 3.8 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 5.32 (s, 2H), 4.15 - 4.04 (m, 2H), 3.90 (q, MS (ES+): 569.4 (M+1);591.4 (M+Na);(ES-): 603.4 (M+Cl);HPLC purity: 95.30%.

[0346] Step-5: Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (40e) Compound 40e was prepared from ethyl 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40d) (150 mg, 0.26 mmol) in MeOH / THF (10 mL, 1:1) using a solution of lithium hydroxide hydrate (11 mg, 0.26 mmol) in water (1 mL) according to the procedure reported in step 6 of scheme 1. It was worked up and purified by reverse phase column [C18 (50 g), elution with ACN in water (0.1% HCl) from 0 to 100%] to give the HCl salt of 2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetic acid (40e) (yield 50 mg, 35%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H, D2O exchangeable), 8.35 (s, 3H, D2O exchangeable), 8.08 (s, 1H), 7.94 - 7.89 (m, 2H), 7.88 (s, 1H), 7.70 (s, 1H), 7.61 - 7.48 (m, 3H), 7.45 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.29 - 7.18 (m, 2H), 7.09 - 7.02 (m, 1H), 6.99 (d, J = 3.8 Hz, 1H), 6.96 - 6.90 (m, 1H), 5.34 (s, 2H), 4.10 (s, 2H), 3.64 (s, 2H), 2.32 (s, 3H);MS (ES+): 541.4 (M+1);563.3 (M+Na);(ES-): 539.4 (M-1), 575.4 (M+Cl).

[0347] Scheme-41 [ka] Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetic acid (41d) Step-1: Preparation of ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (41b) Compound 41b was prepared from 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a) (200 mg, 1.01 mmol) in MeOH (10 mL) using ethyl 2-(2-aminothiophen-3-yl)acetate (41a) (225 mg, 1.22 mmol, CAS#387390-67-2, prepared according to the procedure reported by Adrian Liam and Harris, William in PCT International Application No. 2002002567 (January 10, 2002)) and EDCI (233 mg, 1.22 mmol) according to the procedure reported in Step 1 of Scheme 6. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc in hexanes] to give ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (41b) (yield 320 mg, 0.877 mmol, 87%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.58 - 8.45 (m, 2H), 7.42 - 7.33 (m, 1H), 7.16 (d, J = 5.5 Hz, 1H), 6.91 (d, J = 5.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0348] Step-2: Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetic acid (41d) Compound 41d was prepared from ethyl 2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (41b) (140 mg, 0.38 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (108 mg, 0.58 mmol), potassium phosphate tripotassium (1.3 M solution, 0.22 mL, 0.65 mmol), tricyclohexylphosphine (32 mg, 0.12 mmol) and Pd(dba) (35 mg, 0.038 mmol) under argon atmosphere and microwave heating at 125 °C for 1 h. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-70% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate (41c) (yield 37 mg, 22%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.18 (s, 1H, D2O exchangeable), 8.73 (s, 1H), 8.64 - 8.57 (m, 1H), 8.57 - 8.43 (m, 5H, partially D2O exchangeable), 7.75 - 7.66 (m, 2H), 7.38 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 5.5 Hz, 1H), 6.94 (d, J = 5.5 Hz, 1H), 6.55 (s, 1H), 4.19 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.86 (s, 2H), 1.10 (t, J = 7.1 Hz, 3H); MS (ES+): 436.3 (M+1); (ES-): 470.3 (M+Cl); HPLC purity: 98.86%. Subsequently, 2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetic acid (41d) (yield 19 mg, 12%) was obtained as a white solid.1 H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H, D2O exchangeable), 11.28 (s, 1H, D2O exchangeable), 8.73 (s, 1H), 8.65 - 8.57 (m, 1H), 8.56 - 8.37 (m, 5H, partially D2O exchangeable), 7.75 - 7.65 (m, 2H), 7.38 (d, J = 2.2 Hz, 1H), 7.15 (d, J = 5.5 Hz, 1H), 6.93 (d, J = 5.5 Hz, 1H), 4.20 (q, J = 5.7 Hz, 2H), 3.79 (s, 2H);MS (ES + ) 408.3 (M+1);(ES - ) 406.3 (M-1), 442.3 (M+Cl); HPLC purity: 99.41%.

[0349] Scheme-42 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetic acid (42d) Step-1: Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42b) Compound 42b was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (1e) (0.18 g, 0.49 mmol) in DMF (4 mL) using ethyl 2-(2-amino-4-methoxyphenyl)acetate (42a) (123 mg, 0.586 mmol, CAS#138344-20-4), DIPEA (0.26 mL, 1.47 mmol) and HATU (223 mg, 0.59 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0–100% EtOAc in hexanes] to give ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42b) (0.19 g, 70% yield) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 2.3 Hz, 2H), 7.61 - 7.39 (m, 5H), 7.32 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 4.6, 2.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.87 - 3.71 (m, 5H), 1.41 (s, 9H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 560.4 (M+1), 582.4 (M+Na);(ES-): 558.5 (M-1).

[0350] Step-2: Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42c) Compound 42c was prepared from ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42b) (190 mg, 0.34 mmol) in DCM (5 mL) using TFA (0.26 mL, 3.4 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (30 g), elution with 0-60% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42c) (yield 0.05 g, 32.0%) as the HCl salt. 1 H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.66 - 8.55 (m, 2H), 8.45 - 8.32 (m, 4H), 7.73 - 7.56 (m, 3H), 7.41 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 4.6, 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 4.18 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.86 - 3.75 (m, 5H), 1.01 (t, J = 7.1 Hz, 3H);MS (ES+): 460.3 (M+1), MS (ES-): 494.3 (M+Cl);HPLC purity: 96.26 %

[0351] Step-3: Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetic acid (42d) Compound 42d was prepared from ethyl 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate (42c) (0.11 g, 0.239 mmol) in THF (2 mL) using sodium hydroxide (0.24 mL, 0.48 mmol, 2 M aqueous solution) according to the procedure reported in Scheme 4, Step 4. This was worked up and purified by reverse phase column [C18 (30 g), elution with 0-40% ACN in water (containing 0.1% HCl)] to give 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetic acid (42d) (yield 0.045 g, 44%) as the HCl salt. 1 H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.88 (s, 1H), 8.62 (s, 1H), 8.57 - 8.34 (m, 5H), 7.74 - 7.59 (m, 3H), 7.52 (d, J = 2.7 Hz, MS (ES+): 432.3 (M+1);MS (ES-): 430.4 (M-1); HPLC purity: 98.05 %.

[0352] Scheme-43 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (43d) Step-1: Preparation of ethyl 2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b) Compound 43b was prepared from (7-bromo-2,3-dihydrobenzofuran-5-yl)methanol (43a) (200 mg, 0.87 mmol; CAS#501430-83-7) in THF (15 mL) using triphenylphosphine (0.30 g, 1.135 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (205 mg, 1.14 mmol), and DIAD (0.23 g, 1.14 mmol) according to the procedure reported in Scheme 23, Step 2. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] to give ethyl 2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b) (0.27 g, 78% yield) as a colorless oil. MS (ES-): 389.3, 391.3 (M-1).

[0353] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43c) Compound 43c was prepared from ethyl 2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b) (0.52 g, 1.33 mmol) in dioxane (6 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.37 g, 2.0 mmol), a solution of potassium carbonate (0.55 g, 4.0 mmol) in water (2 mL), and PdCl(PPh) (0.140 g, 0.2 mmol) under argon atmosphere and heated in an oil bath at 100 °C for 2 h. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-20% MeOH in DCM] followed by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give the HCl salt of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43c) (yield 0.23 g, 42%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 3H), 7.79 (s, 1H), 7.75 - 7.70 (m, 1H), 7.54 - 7.40 (m, 2H), 7.38 (s, 1H), 7.31 - 7.18 (m, 3H), 7.08 (d, J = 8.1 Hz, 1H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 5.05 (s, 2H), 4.60 (t, J = 8.7 Hz, 2H), 4.08 (s, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 3.25 (t, J = 8.7 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H);MS (ES+) 418.4 (M+1);(ES-) 416.4 (M-1).

[0354] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (43d) Compound 43d was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43c) (0.12 g, 0.29 mmol) in THF / MeOH (4 mL) using lithium hydroxide hydrate (60 mg, 1.44 mmol) in water (0.8 mL) according to the procedure reported in step 6 of scheme 1. This was worked up and purified by reverse phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (43d) (yield 40 mg, 31%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.38 (s, 3H), 7.80 (s, 1H), 7.74 (dt, J = 7.2, 1.8 Hz, 1H), 7.52 - 7.41 (m, 3H), 7.32 (d, J = 1.6 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.06 (dd, J = 8.2, 1.1 Hz, 1H), 6.89 (td, J = 7.4, 1.1 Hz, 1H), 5.07 (s, 2H), 4.60 (t, J = 8.7 Hz, 2H), 4.07 (d, J = 5.3 Hz, 2H), 3.56 (s, 2H), 3.25 (t, J = 8.7 Hz, 2H); MS (ES+): 390.4 (M+1); MS (ES-): 388.5 (M-1), 424.4 (M+Cl). HPLC purity: 91.28%.

[0355] Scheme-44 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetic acid (44c) Step-1: Preparation of ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate (44a) To a solution of ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (0.2 g, 0.50 mmol) in DMF was added (bromomethyl)cyclopropane (0.07 mL, 0.75 mmol) and potassium carbonate (0.14 g, 1.0 mmol) and stirred at 60 °C overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3 ×), brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0 to 60% EtOAc in hexanes] to give ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate (44a) (0.15 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 3.1 Hz, 1H), 7.47 - 7.19 (m, 4H), 6.50 (d, J = 3.1 MS (ES+): 455.3 & 457.3 (M+1).

[0356] Step-2: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetic acid (44c) Compound 44c was prepared from ethyl 2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate (44a) (140 mg, 0.31 mmol) in dioxane (3 mL) according to the procedure reported in step 3 of scheme 1 using 3-(aminomethyl)phenylboronic acid hydrochloride (6c) (90 mg, 0.46 mmol), potassium phosphate tripotassium (1.3 M solution) (0.71 mL, 0.92 mmol), tricyclohexylphosphine (30 mg, 0.09 mmol) and Pd(dba) (30 mg, 0.03 mmol) under argon atmosphere and microwave heating at 125 °C for 45 min. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% DMA80 in DCM] followed by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate (44b) (yield 0.06 g, 37%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.32 (s, 2H), 8.25 (s, 1H), 7.88 (s, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.77 (s, 1H), 7.75 (d, J = 3.0 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.55 - 7.40 (m, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.25 (td, J = 7.2, 1.5 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H), 4.18 (m, 2H), 4.15 (s, 2H), 3.95 (m, 2H), 3.78 (s, 2H), 1.37 (m, 1H), 0.98 (t, J = 7.1 Hz, 3H), 0.62 - 0.39 (m, 4H); MS (ES+): 482.4 (M+1); MS (ES-): 516.5 (M+Cl). HPLC purity: 96.64%. Subsequently, 2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetic acid (44c) (yield 0.01 g, 7%) was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6): δ 8.37 (s, 2H), 8.24 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.58 (t, J = 7.7 Hz, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H), 6.56 (s, 1H), 4.25 - 4.09 (m, 4H), 3.69 (s, 2H), 1.48 - 1.29 (m, 1H), 0.60 - 0.37 (m, 4H);MS (ES+): 454.4 (M+1);MS (ES-): 452.4 (M-1), 488.4 (M+Cl). HPLC purity: 97.36%.

[0357] Scheme-45 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (45e) Step-1: Preparation of methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate (45a) Compound 45a was prepared from methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (45f) (500 mg, 1.87 mmol; CAS#: 1246867-53-7) in dioxane (11 mL) using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (702 mg, 2.80 mmol), potassium phosphate tripotassium (1.3 M solution, 1.1 mL, 3.17 mmol), tricyclohexylphosphine (157 mg, 0.56 mmol) and Pd(dba) (171 mg, 0.19 mmol) under nitrogen atmosphere by microwave heating at 120 °C for 45 min according to the procedure reported in step 3 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with hexane / ethyl acetate from 0% to 100%] to give methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate (45a) (620 mg, 84% yield) as a yellow solid. MS (ES+): 417.3 (M+Na).

[0358] Step-2: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylic acid (45b) Compound 45b was prepared from methyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate (45a) (600 mg, 1.52 mmol) in THF / MeOH (15 mL) using a solution of lithium hydroxide hydrate (383 mg, 9.13 mmol) in water (1 mL) according to the procedure reported in step 6 of scheme 1. Workup afforded 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylic acid (45b) (yield 500 mg, 86%) as an off-white solid, which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H, D2O exchangeable), 8.09 (s, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.60 - 7.42 (m, 4H), 7.27 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 3.2 Hz, 1H), 4.22 (d, J = 6.2 Hz, 2H), 3.91 (s, 3H), 1.40 (s, 9H).

[0359] Step-3: Preparation of ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45c) Compound 45c was prepared from 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylic acid (45b) (300 mg, 0.79 mmol) in DMF (10 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (184 mg, 1.03 mmol), DIPEA (0.28 mL, 1.58 mmol) and HATU (360 mg, 0.79 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), eluting with 0–60% EtOAc in hexanes] to give ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45c) (yield 211 mg, 49%) as a pink semi-solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H, D2O exchangeable), 8.11 (s, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.65 (s, 1H), 7.63 - 7.57 (m, 2H), 7.54 - 7.40 (m, 3H), 7.37 - 7.31 (m, 2H), 7.30 - 7.22 (m, 2H), 6.64 (d, J = 3.1 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 3.98 - 3.88 (m, 5H), 3.77 (s, 2H), 1.40 (s, 9H), 0.98 (t, J = 7.1 Hz, 3H);MS (ES+): 564.5 (M+Na);(ES-): 540.5 (M-1).

[0360] Step-4: Preparation of ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45d) Compound 45d was prepared from ethyl 2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45c) (210 mg, 0.39 mmol) using TFA (0.3 mL, 3.88 mmol) in DCM (5 mL) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% DMA80 in DCM] followed by reverse-phase column chromatography [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45d) (yield 114 mg, 67%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H, D2O exchangeable), 8.45 (s, 3H, D2O exchangeable), 8.18 (s, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 7.80 - 7.72 (m, 1H), 7.65 (d, J = 3.1 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.44 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.25 (td, J = 7.1, 1.5 Hz, 1H), 6.75 (d, J = 3.1 Hz, 1H), 4.14 (s, 2H), 4.04 - 3.89 (m, 5H), 3.79 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H).

[0361] Step-5: Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (45e) Compound 45e was prepared from ethyl 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate (45d) (65 mg, 0.15 mmol) in MeOH / THF (10 mL, 1:1) using a solution of sodium hydroxide (35 mg, 0.88 mmol) in water (2 mL) according to the procedure reported in Step 4 of Scheme 4. It was worked up and purified by reverse phase column [C18 (50 g), elution with ACN in water (containing 0.1% HCl) from 0 to 100%] to give 2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetic acid (45e) (yield 29 mg, 48%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H, D2O exchangeable), 10.10 (s, 1H, D2O exchangeable), 8.43 (s, 3H, D2O exchangeable), 8.18 (s, 1H), 7.92 - 7.87 (m, 1H), 7.86 - 7.80 (m, 1H), 7.80 - 7.73 (m, 1H), 7.65 (d, J = 3.1 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.39 - 7.29 (m, 2H), 7.22 (td, J = 7.4, 1.4 Hz, 1H), 6.74 (d, J = 3.1 Hz, 1H), 4.14 (s, 2H), 3.93 (s, 3H), 3.71 (s, 2H);MS (ES+): 414.3 (M+1);436.3 (M+Na);(ES-): 412.4 (M-1), 448.4 (M+Cl).

[0362] Scheme-46 [ka] Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (46 g) Step-1: Preparation of ethyl 2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46a) To POCl3 (1.239 mL, 13.30 mmol) in a sealed tube cooled with ice water, DMF (0.515 mL, 6.65 mmol) was added and stirred until the reaction mixture became homogeneous. The reaction mixture was warmed to room temperature, and ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33 mmol) was added and heated in a sealed tube at 95 °C for 5 h. The reaction mixture was cooled to room temperature, poured into ice-cold saturated aqueous NaHCO3 (60 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel eluted with hexane / ethyl acetate (1:0 to 9:1)] to give ethyl 2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46a) (yield 224 mg, 66%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.78 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0363] Step-2: Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46b) Compound 46b was prepared from ethyl 2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46a) (250 mg, 0.99 mmol) in DMF (10 mL) using 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (371 mg, 1.48 mmol), potassium fluoride (189 mg, 3.25 mmol), tri-tert-butylphosphine (1.281 mL, 1.28 mmol) and Pd(dba) (90 mg, 0.099 mmol) under argon atmosphere by heating at 120 °C overnight according to the procedure reported in step 3 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with hexane / ethyl acetate from 0% to 50%] to give ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46b) (yield 339 mg, 81%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.34 - 8.27 (m, 2H), 7.73 (d, J = 5.0 Hz, 1H), 7.61 - 7.51 (m, 2H), 7.51 - 7.44 (m, 1H), 7.41 (d, J = 5.0 Hz, 1H), 4.54 (q, J = 7.1 Hz, 2H), 4.26 (d, J = 6.2 Hz, 2H), 1.49 - 1.39 (m, 12H);MS (ES+): 447.3 (M+1).

[0364] Step-3: Preparation of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46c) To a solution of ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46b) (150 mg, 0.35 mmol) in DCE (10 mL) was added pyrrolidine (27.6 mg, 0.39 mmol) and acetic acid (0.020 mL, 0.35 mmol). The resulting mixture was stirred at room temperature for 2 h, followed by the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The resulting mixture was stirred at room temperature for 2 h, diluted with EtOAc, washed with water, dried, filtered, and concentrated in vacuo. The resulting residue was purified by chromatography [silica (12 g), elution with 0-60% EtOAc in hexanes] to give ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46c) (yield 140 mg, 83%) as a yellow semi-solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.23 (d, J = 6.2 Hz, 2H), 7.59 - 7.47 (m, 2H), 7.41 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 4.6 Hz, 1H), 7.20 (d, J = 4.6 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 4.25 (d, J = 6.2 Hz, 2H), 4.18 (s, 2H), 2.64 - 2.55 (m, 4H), 1.75 - 1.63 (m, 4H), 1.50 - 1.29 (m, 12H);MS (ES+): 480.4 (M+1);502.4 (M+Na);(ES-): 478.5 (M-1).

[0365] Step-4: Preparation of 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (46d) Compound 46d was prepared from ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46c) (140 mg, 1.52 mmol) in THF / MeOH (10 mL) using a solution of sodium hydroxide (70 mg, 1.75 mmol) in water (2 mL) according to the procedure reported in Scheme 4, Step 4. Workup followed by purification by flash column chromatography [silica (4 g), elution with 0-100% MeOH in DCM] gave 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (46d) (yield 60 mg, 46%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.40 - 8.27 (m, 2H), 7.60 - 7.49 (m, 2H), 7.46 - 7.30 (m, 3H), 4.95 (s, 2H), 4.26 (d, J = 6.1 Hz, 2H), 3.57 - 3.36 (m, 4H), 2.08 - 1.83 (m, 4H), 1.41 (s, 9H);MS (ES+): 452.4 (M+1);474.4 (M+Na);(ES-): 450.4 (M-1);486.4 (M+Cl).

[0366] Step-5: Preparation of ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46e) Compound 46e was prepared from 2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (46d) (56 mg, 0.12 mmol) in DMF (10 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (29 mg, 0.16 mmol), DIPEA (0.043 mL, 0.25 mmol) and HATU (57 mg, 0.15 mmol) according to the procedure reported in step 4 of scheme 1. Workup and purification by flash column chromatography [silica (12 g), elution with 0–60% EtOAc in hexanes] afforded ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46e) (53 mg, 70% yield) as a pink semi-solid. MS (ES+): 613.4 (M+1); 635.4 (M+Na); (ES−): 611.5 (M−1).

[0367] Step-6: Preparation of ethyl 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46f) Compound 46f was prepared from ethyl 2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46e) (53 mg, 0.086 mmol) using TFA (0.067 mL, 0.87 mmol) in DCM (5 mL) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-50% DMA80 in DCM] to give ethyl 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46f) (yield 27 mg, 61%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H, D2O exchangeable), 9.00 (s, 1H, D2O exchangeable), 8.71 (d, J = 7.6 Hz, 3H), 7.72 (t, J = 7.9 Hz, 2H), 7.68 - 7.61 (m, 2H), 7.53 (d, J = 4.7 Hz, 1H), 7.42 (t, J = 7.3 Hz, 2H), 7.31 (td, J = 7.5, 7.1, 1.4 Hz, 1H), 5.07 (s, 2H), 4.19 (d, J = 5.1 Hz, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.88 (s, 2H), 3.58 - 3.43 (m, 2H), 3.33 - 3.25 (m, 2H), 2.14 - 1.97 (m, 2H), 1.95 - 1.80 (m, 2H), 1.02 (t, J = 7.1 Hz, 3H);MS (ES+): 513.4 (M+1);535.4 (M+Na).

[0368] Step-7: Preparation of 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (46 g) Compound 46g was prepared according to the procedure reported in Scheme 4, Step 4 from ethyl 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (46f) (25 mg, 0.049 mmol) in MeOH / THF (10 mL, 1:1) using a solution of sodium hydroxide (12 mg, 0.29 mmol) in water (2 mL). This was worked up and purified by reverse phase column [C18 (50 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give 2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (46 g) (yield 11 mg, 47%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H, D2O exchangeable), 11.09 (s, 1H, D2O exchangeable), 10.94 (s, 1H), 8.97 (d, J = 1.7 Hz, 1H), 8.80 - 8.60 (m, 4H, partially D2O exchangeable), 7.83 (d, J = 8.1 Hz, 1H), 7.73 - 7.60 (m, 3H), 7.55 (d, J = 4.7 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.28 (td, J = 7.4, 1.3 Hz, 1H), 5.08 (d, J = 4.5 Hz, 2H), 4.26 - 4.12 (m, 2H), 3.81 (s, 2H), 3.59 - 3.41 (m, 4H), 2.16 - 1.97 (m, 2H), 1.95 - 1.78 (m, 2H);MS (ES + ) 485.4 (M+1);(ES - ) 483.4 (M-1);HPLC purity, 93.69%.

[0369] Scheme-47 [ka] Preparation of 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (47f) Step-1: Preparation of ethyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (47b) To a solution of ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (400 mg, 1.77 mmol) in dioxane (12 mL) was added (5-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (47a) (546 mg, 2.66 mmol; CAS# 1072946-46-3), 3 M aqueous potassium triphosphate (1.182 mL, 3.55 mmol), tricyclohexylphosphine (99 mg, 0.355 mmol), and Pd(dba) (162 mg, 0.177 mmol). The mixture was degassed, backfilled with argon, and then heated in a microwave oven at 125 °C for 30 min. The mixture was cooled to room temperature and diluted with water (60 mL) and EtOAc (60 mL). To the biphasic layer was added BOC-anhydride (580 mg, 2.66 mmol) and stirred at room temperature for 3 h. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water and brine, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica (12 g), elution with 0–60% EtOAc in hexanes] to afford ethyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (47b) (yield 0.32 g, 0.772 mmol, 43.6%) as an orange foam. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 6.1 Hz, 1H), 7.49 - 7.24 (m, 4H), 4.50 (q, J = 7.1 Hz, 2H), 4.19 (d, J = 6.2 Hz, 2H), 1.44 - 1.33 (m, 12H);MS (ES+): 437.3 (M+Na)

[0370] Step-2: Preparation of 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (47c) Compound 47c was prepared from ethyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (47b) (0.32 g, 0.772 mmol) in THF (10 mL) using sodium hydroxide (0.772 mL, 1.544 mmol, 2 M aqueous solution) according to the procedure reported in Scheme 4, Step 4. Workup afforded 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (47c) (0.29 g, 97% yield) as a pale orange foam. 1 H NMR (300 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.36 (dd, J = 2.6, 1.4 Hz, 1H), 7.92 (dd, J = 7.5, 2.2 Hz, 1H), 7.53 (t, J = 6.1 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.39 - 7.32 (m, 2H), 7.24 (dd, J = 4.6, 2.5 Hz, 1H), 4.19 (d, J = 6.2 Hz, 2H), 1.39 (s, 9H);MS (ES-): 385.3 (M-1).

[0371] Step-3: Preparation of ethyl 2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47d) Compound 47d was prepared from 2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (47c) (180 mg, 0.47 mmol) in DMF (3 mL) using ethyl 2-(2-aminophenyl)acetate (5e) (125 mg, 0.7 mmol), DIPEA (0.24 mL, 1.4 mmol) and HATU (213 mg, 0.56 mmol) according to the procedure reported in step 4 of scheme 1. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc in hexanes] to give ethyl 2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47d) (yield 0.19 g, 75%) as an orange foam. 1 H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.41 (dd, J = 2.6, 1.4 Hz, 1H), 8.18 (dd, J = 7.6, 2.2 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.59 (dd, J = 4.6, 1.4 Hz, 1H), 7.55 - 7.33 (m, 5H), 7.37 - 7.20 (m, 2H), 4.23 (d, J = 6.1 Hz, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 1.38 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H);MS (ES+): 548.3 (M+1), 570.3 (M+Na);(ES-): 582.4 (M+Cl).

[0372] Step-4: Preparation of ethyl 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47e) Compound 47e was prepared from ethyl 2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47d) (180 mg, 0.329 mmol) in DCM (5 mL) using TFA (0.025 mL, 0.329 mmol) according to the procedure reported in step 5 of scheme 1. This was worked up and purified by reverse-phase column chromatography [C18 (30 g), elution with 0-100% ACN in water (containing 0.1% HCl)] to give ethyl 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47e) (yield 0.045 g, 31%) as the HCl salt. 1 H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.53 (d, J = 7.1 Hz, 1H), 8.49 - 8.32 (m, 4H), 7.81 - 7.70 (m, 2H), 7.61 (dd, J = 4.6, 1.3 Hz, 1H), 7.51 (dd, J = 11.1, 8.5 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.35 - 7.24 (m, 2H), 4.21 - 4.10 (m, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 0.97 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -113.01;MS (ES+): 448.3 (M+1), MS (ES-): 482.3 (M+Cl);HPLC purity 94.88 %.

[0373] Step-5: Preparation of 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (47f) Compound 47f was prepared from ethyl 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate (47e) (110 mg, 0.246 mmol) in THF (4 mL) using a 2 M aqueous solution of NaOH (0.246 mL, 0.492 mmol) according to the procedure reported in step 4 of scheme 4. This was worked up and purified by reverse-phase column chromatography [C18 (30 g), elution with 0-40% ACN in water (containing 0.1% HCl)] to give 2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (47f) (yield 0.045 g, 44%) as the HCl salt. 1 H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.12 - 10.76 (m, 1H), 8.66-8.55 (m, 1H), 8.51 - 8.33 (m, 4H), 7.90 - 7.82 (m, 1H), 7.75--7.65 (m, 1H), 7.63 (dd, J = 4.6, 1.3 Hz, 1H), 7.49 (dd, J = 11.1, 8.5 Hz, 1H), 7.43-7.34 (m, 2H), 7.31 (dd, J = 4.6, 2.6 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 4.23-4.08 (m, 2H), 3.74 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -112.49;MS (ES+) 42.3 (M+1), MS (ES-) 418.3 (M-1);HPLC purity: 97.95 %.

[0374] Scheme-48 [ka] Preparation of 2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetic acid (48h) Step-1: Preparation of tert-butyl 3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b) Compound 48b was prepared from 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (48a) (2 g, 10.47 mmol; CAS# 848398-41-4) in dioxane (100 mL) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (2.49 g, 7.48 mmol), potassium phosphate tripotassium (5.48 mL, 16.45 mmol, 3 M aqueous solution), tricyclohexylphosphine (0.63 g, 2.24 mmol), and Pd(dba) (0.69 g, 0.75 mmol) under argon atmosphere in an oil bath at 120 °C for 1.5 h. This was worked up and purified by flash column chromatography [silica (40 g), elution with 0-70% EtOAc in hexanes] to give tert-butyl 3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b) (0.72 g, 27% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J = 2.0 Hz, 1H), 7.74 -7.68 (m, 1H), 7.59 - 7.44 (m, 3H), 5.40 (t, J = 1.8 Hz, 2H), 5.02 (d, J = 1.8 Hz, 2H), 4.22 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H). MS (ES-): 360.4 & 362.3 (M-1).

[0375] Step-2: Preparation of tert-butyl 3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48c) Compound 48c was prepared according to the procedure reported in Scheme 1, Step 1 from tert-butyl 3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b) (0.7 g, 1.94 mmol) in DMF (20 mL) using 1-ethoxyvinyltri-n-butyltin (0.86 mL, 2.52 mmol) and Pd(PPh3)4 (0.22 g, 0.19 mmol) under argon atmosphere and heating at 110 °C for 4 h. Workup and purification by flash column chromatography [silica (40 g), elution with 0-50% EtOAc in hexanes] gave tert-butyl 3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48c) (0.51 g, 66%) as a white solid. MS (ES+): 398.4 (M+1), 420.3 (M+Na); MS (ES-): 396.4 (M-1), 432.4 (M+Cl).

[0376] Step-3: Preparation of ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (48d) Compound 48d was prepared from tert-butyl 3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48c) (0.5 g, 1.258 mmol) in 1,4-dioxane (100 mL) using a solution of sodium periodate (0.54 g, 2.52 mmol) and KMnO (0.12 g, 0.76 mmol, and a second charge of 0.12 g, 0.76 mmol after 12 h) in water (10 mL) according to the procedure reported in Scheme 1, Step 2. This was worked up and purified by flash column chromatography [silica (12 g), elution with 0-60% EtOAc in hexanes] to give ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (48d) (0.28 g, 56% yield) as a yellow solid. MS (ES+): 400.3 (M+1), 422.3 (M+Na); MS (ES-): 398.4 (M-1).

[0377] Step-4: Preparation of 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (48e) Compound 48e was prepared from ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (48d) (0.28 g, 0.70 mmol) in THF / MeOH (5 mL, 1:1) using sodium hydroxide (0.11 g, 2.80 mmol) in water (2 mL) according to the procedure reported in Scheme 4, Step 4. Workup afforded 4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (48e) (0.16 g, 62% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.45 (d, J = 7.7 Hz, 1H), 5.47 (s, 2H), 5.08 (d, J = 1.8 Hz, 2H), 4.23 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H);MS (ES-): 370.3 (M-...

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt thereof: 【Chemical 1】 [In the formula, 【change】 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R ａ is independently, for each occurrence, halogen, cyano, hydroxy, -NH ２ , —NH(Ac), —NH(alkyl), —N(alkyl) ２ , —NHC(O)(alkyl), —CH ２ NHC(O)(alkyl), —C(O)NH ２ , —C(O)(alkyl), optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; T １ is N, CH, NR Ｔ１ , or CR Ｔ１ and T ２ is NR Ｔ２ or CR Ｔ２ and T ３ is N, CH, NR Ｔ３ , or CR Ｔ３ and where: (a) T １ is CR Ｔ１ Or NR Ｔ１ and R Ｔ１ and R Ｔ２ together with the intervening atoms form an optionally substituted heteroaryl ring; T ３ is N or CH, or (b) T ３ is CR Ｔ３ Or NR Ｔ３ and R Ｔ３ and R Ｔ２ together with the intervening atoms form an optionally substituted heteroaryl ring; T １ is N or CH, (i) T ２ NR Ｔ２ (ii) T ３ is NR T3, or (iii) T １ NR Ｔ１ and R １ is -NH ２ , -CH ２ COOH, -CH(NH(CO)(alkyl))COOH, -CH(NH(CO)(cycloalkyl))COOH, -CO(NH)CH ２ Aryl, —CO(NH)CH ２ selected from the group consisting of heteroaryl, —CO(NH)aryl, and —CO(NH)heteroaryl; p is 0, 1, or 2; J is -C(O)-, -NH-, -CH ２ -, -O-, -S-, -S(O)-, -SO ２ -, -N(alkyl)-, or -CH(alkyl)-; K is -C(O)-, -NH-, -O-, -CH ２ -, -S-, -S(O)-, -SO ２ -, -N(alkyl)-, or -CH(alkyl)-; wherein at least one of J and K is —C(O)—, —CH ２ - or -CH(alkyl)-, W is N, CH, or CR ｃ and X is N, CH, or CR ｃ and Y is N, CH, or CR ｃ and Z is N, CH, or CR ｃ and R ｃ is independently, for each occurrence, a halogen, —OH, —NR ｊ R ｋ , alkoxy, and alkyl; L is a bond, —CH ２ -, -CH ２ CH ２ --, --CHR ２ -, -CF ２ --, --CFR ２ -, -C(O)-, -C(=NR Ｌ ) - and -C(=CHR Ｌ )- is selected from the group consisting of R Ｌ is H or alkyl, or R Ｌ and R ｃ together with the intervening atoms form a substituted or unsubstituted heteroaryl ring; R ２ is alkyl, hydroxyalkyl, or haloalkyl; V is N or CH.

2. The compound of claim 1, wherein is phenyl, thiophenyl, furyl, pyrazole, or pyridinyl.

3. Structure of Formula (IIa): 【Chemistry 2】 2. The compound of claim 1 having the formula:

4. The compound according to any one of claims 1 to 3, wherein p is 0.

5. R １ But -CH ２ The compound according to any one of claims 1 to 4, which is COOH.

6. -J-K- is -C(O)-NH-, -NH-C(O)-, or -CH ２ The compound of any one of claims 1 to 5, wherein the compound is selected from the group consisting of: O-.

7. The compound of any one of claims 1 to 6, wherein each of W, X, Y, and Z is CH.

8. At least one of W, X, Y, and Z is CR ｃ The compound according to any one of claims 1 to 6,

9. R ｃ The compound of claim 8 , wherein is a halogen.

10. R ｃ The compound of claim 9, wherein is fluoride.

11. L is -CH ２ The compound according to any one of claims 1 to 10, wherein

12. T １ is CR Ｔ１ and R Ｔ１ and R Ｔ２ The compound of any one of claims 1 to 11, wherein, together with the intervening atoms, forms an optionally substituted heteroaryl ring.

13. The compound of claim 12, wherein R T1 and R T2 together with the intervening atoms form an optionally substituted pyrrole, imidazole, or 1,2,4-triazole.

14. T ３ is CR Ｔ３ and R Ｔ３ and R Ｔ２ The compound of any one of claims 1 to 11, wherein, together with the intervening atoms, forms an optionally substituted heteroaryl ring.

15. The compound of claim 14, wherein R T3 and R T2 together with the intervening atoms form an optionally substituted pyrrole, imidazole, 1,2,4-triazole, or pyridine.

16. 2. The compound of claim 1 selected from the following compounds: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 【Chemistry 3-4】

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition characterized by abnormal complement system activity.

19. 19. The use according to claim 18, wherein the disease or condition characterized by abnormal complement system activity is an immunological disorder.

20. 19. The use according to claim 18, wherein the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

21. 19. The use according to claim 18, wherein the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

22. 19. The use according to claim 18, wherein the disease or condition characterized by abnormal complement system activity is a kidney disease.

23. 19. The use according to claim 18, wherein the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

24. 19. The use of claim 18, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

25. 19. The use according to claim 18, wherein the disease or condition characterized by abnormal complement system activity is paroxysmal nocturnal hemoglobinuria.

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