As alpha V Indazole derivatives as integrin antagonists

Abstract

The present application provides compounds of Formula (Ia) or (Ib): (Ia) or (Ib), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all variables are as defined herein. These compounds are antagonists of alphaV-containing integrins. The present application also relates to pharmaceutical compositions comprising these compounds, and methods of treating diseases, disorders, or conditions associated with dysregulation of alphaV-containing integrins, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

Description

[0001] This application is Chinese patent application No. 201780082125.5 (filed on November 7, 2017, invention title: As α) V Divisional application for indazole derivatives of integrin antagonists.

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application Serial No. 62 / 418,842, filed November 8, 2016, which is incorporated herein by reference. Technical Field

[0004] This invention relates to substituted azole amides and amines as αV integrin antagonists, pharmaceutical compositions comprising such compounds, and their use in therapy (particularly for the treatment or prevention of diseases, disorders, and conditions in humans exhibiting αV integrin antagonist activity). Background Technology

[0005] Integrins belong to a large family of α / β heterodimeric transmembrane proteins involved in cell adhesion to various extracellular matrix proteins, cell-cell interactions, cell migration, proliferation, survival, and maintaining tissue integrity (Barczyk et al., Cell and Tissue Research 2010, 339, 269; Srichai, MB; Zent, ​​R. in Cell-Extracellular Matrix Interactions in Cancer, 2010). In mammals, 24 α / β integrin heterodimers exist, known to arise from various combinations of 18 α and 8 β subunits. Transforming growth factor-β (TGF-β) plays a major role in driving many pathological processes that underlie fibrosis, cell growth, and autoimmune diseases. Alpha V (αV) integrins (including αVβ1, αVβ3, αVβ5, αVβ6 and αVβ8) are involved in key pathways leading to the conversion of latent TGF-β to its active form (Henderson, NC; Sheppard, D. Biochim, Biophys. Acta 2013, 1832, 891). Therefore, antagonism of this αV integrin-mediated latent TGF-β activation provides a feasible therapeutic approach for intervening in TGF-β-driven pathological states (Sheppard, D. Eur. Resp. Rev. 2008, 17, 157; Goodman, SL; Picard, M. Trends Pharmacol. Sciences 2012, 33(7), 405; Hinz, B. Nature Medicine 2013, 19(12), 1567; Pozzi, A.; Zent, ​​RJ Am. Soc. Nephrol. 2013, 24(7), 1034). All five αV integrins belong to a small subset (8 out of 24) of integrins that recognize the arginine-glycine-aspartic (RGD) motif present in their native ligands, such as fibronectin, pornectin, and latent-related peptide (LAP)).

[0006] α V The expression of integrin subtypes varies considerably. For example, α V β6 is expressed at very low levels on epithelial cells in healthy tissues, but is significantly upregulated during inflammation and wound healing. α V β3 and α V β5 is expressed on osteoclasts, endothelial cells, smooth muscle cells, and solid tumor cells, as well as on pericytes and podocytes, while α... Vβ1 is expressed on activated fibroblasts and mesangial cells.

[0007] Common fibrotic conditions representing major unmet medical needs include idiopathic pulmonary fibrosis (IPF), liver and kidney fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and systemic sclerosis. Two drugs (pirfenidone and nintedanib) that act via nonintegrin-mediated mechanisms have recently been approved for the treatment of IPF. This invention relates to inhibiting or antagonizing one or more α... V Compounds that describe the role of integrins in treating pathological conditions mediated by these integrins, such as fibrosis and cancer.

[0008] Numerous selective or non-selective small molecule, peptide, and antibody-based antagonists of αV integrin have been reported in the literature (Kapp, TG et al., Expert Opin. Ther. Patents 2013, 23(10), 1273; O'Day, S. et al., Brit. J. Cancer 2011, 105(3), 346; Pickarski, M. et al., Oncol. Rep. 2015, 33, 2737; Wirth, M. et al., Eur. Urol. 2014, 897; Henderson, NC et al., Nature Medicine 2012, 19(12), 1617; Horan, GS et al., Am. J. Resp. Crit. Care Med. 2008, 177, 56; Puthawala, K. et al., Am. J. Resp. Crit. Care Med. 2008, 177, ). 82; Reed, NI et al. Sci. Transl. Med.2015, 7(288), 288ra79; Anderson, NA et al. WO2014 / 154725 A1, WO 2016 / 046225 A1, WO 2016 / 046226 A1, WO 2016 / 046230 A1, WO 2016 / 046241 A1). Summary of the Invention

[0009] In one aspect, the present invention provides compounds of formulas (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), and (IVf), and their subgenuses and species, including their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates, which can be used as α V Integrin antagonists.

[0010] In another aspect, the present invention also provides methods and intermediates for preparing the compounds of the present invention.

[0011] In another aspect, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0012] In another aspect, the compounds of the present invention can be used alone or in combination with one or more other therapeutic agents in a therapeutic manner. By administering a therapeutically effective amount of the compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates to a patient, the compounds of the present invention can be used to treat patients requiring such treatment with α-containing... V Diseases, disorders, or conditions associated with abnormal regulation of integrin. These diseases, disorders, or conditions may be related to pathological fibrosis. The compounds of the present invention can be used alone, in combination with one or more compounds of the present invention, or in combination with one or more (e.g., one to two) other therapeutic agents.

[0013] The compounds of the present invention can be used to manufacture drugs for treating patients with α-containing... V Diseases, disorders, or conditions associated with abnormal regulation of integrin.

[0014] Other features and advantages of the invention will become clear from the following detailed description and claims. Detailed Implementation

[0015] This application provides compounds according to formula (Ia) or (Ib), including all stereoisomers, solvates, prodrugs, and pharmaceutically acceptable salts and solvates thereof. This application also provides pharmaceutical compositions comprising at least one compound according to formula (Ia) or (Ib), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, and optionally at least one additional therapeutic agent. Furthermore, this application provides a method for treating patients with diseases or disorders regulated by αV integrin (e.g., idiopathic pulmonary fibrosis (IPF), liver and kidney fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cardiac fibrosis, and systemic sclerosis) by administering a therapeutically effective amount of the compound of the invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof (and optionally in combination with at least one additional therapeutic agent) to a patient requiring such treatment.

[0016] In one embodiment, the present invention particularly provides a compound of formula (Ia) or (Ib):

[0017] (Ia) or (Ib),

[0018] Or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates, wherein:

[0019] A, E, G, and J are independently N, C, or CH; provided that at least one of A, E, G, and J is a C attached to Y.

[0020] X is determined by 0, 1, or 2 R's. 8a Replacement C 1-4 Alkylene;

[0021] Y represents a covalent bond, O, S, NH, or -O-(C). 1-3 alkylene)-, -S-(C 1-3 alkylene)- or -NH-(C 1-3 alkylene)-, wherein the C 1-3 Each alkylene group is independently bounded by 0, 1, or 2 R groups. 8b replace;

[0022] R 1 It is selected from the following arginine mimicry section

[0023]

[0024]

[0025]

[0026]

[0027]

[0028] One asterisk in each arginine analogue portion is an attachment point to X, and the other two asterisks are hydrogen atoms;

[0029] R e It is OH, amino, amide, carbamate, sulfonamide, C 1-4 Alkyl, Halogenated, C 1-4 Halogenated alkyl or C 3-6 cycloalkyl;

[0030] R f = H, CH3, CH2CH3, C(O)OCH2CH3;

[0031] R g = CH3, CH2CCl3, phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl ;

[0032] r is an integer of 0, 1, 2 or 3;

[0033] R 2 Is it hydrogen, halogenated, or C? 1-6 alkyl;

[0034] R 3 It is hydrogen, C1-6 alkyl, 3- to 10-membered carbocyclic, carbocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 3- to 14-membered heterocyclic, heterocyclic alkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, wherein the alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 6 replace;

[0035] R 3a It is hydrogen; or alternatively, R 3a and R 3 A ring that, together with one or more atoms to which it is attached, forms a 3- to 6-membered carbon ring or heterocycle, optionally substituted by one or more groups independently selected from: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, or sulfonamide;

[0036] R 4 It is hydrogen, C 1-6Alkyl, 3- to 10-membered carbocyclic, carbocyclic alkyl, 3- to 10-membered heterocyclic, heterocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, -S(O) m R 7 -C(O)NR a R b -NHC(O)OR a -NHC(O)NR a R b -NHC(O)R 7 -OC(O)NR a R b -OC(O)R 7 -NHS(O) m NR a R b Or -NHS(O) m R 7 The alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, whether individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 9 replace;

[0037] R 6 It can be halogenated, cyano, hydroxyl, amino, oxo, nitro, or -S(O). m R 12 C 1-6 Alkyl, alkoxy, haloalkyl, haloalkoxy, haloaminoalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered carbocyclic or 3- to 7-membered heterocyclic; wherein the alkyl, aryl, heteroaryl, carbocyclic or heterocyclic group, either itself or as part of another group, is independently bounded by 0, 1 or 2 R groups. 10 replace;

[0038] R 7 Each is C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Halogenated alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 11 replace;

[0039] R 8a R 8b and R 11Each time it appears, it is independently of halogen, cyano, hydroxyl, amino, oxo, or C. 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, or haloalkoxy;

[0040] R 9 Each group independently represents a halogenated, cyano, hydroxyl, amino, oxo, nitro, or C group. 1-6 Alkyl, alkoxy, haloalkyl, haloalkoxy, haloaminoalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered carbocyclic or 3- to 7-membered heterocyclic; wherein the alkyl, aryl, heteroaryl, carbocyclic or heterocyclic group, either itself or as part of another group, is independently bounded by 0, 1 or 2 R groups. 13 replace;

[0041] R 10 and R 13 Each is independently a halogenated, cyano-based, hydroxyl-based, amino-based, oxo-based, or C-based group. 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, or sulfonamide;

[0042] R 12 It is -N(R) x R y C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; and

[0043] R x and R y Each is independently hydrogen or C 1-6 alkyl;

[0044] R a and R b Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or alkoxyalkyl; or alternatively, R a and R b These rings, together with the atoms to which they are attached, form 3- or 8-membered carbon rings or heterocycles, which are optionally substituted by one or more groups independently selected from: halogenated, cyano, hydroxyl, amino, oxo, C 1-6Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, and sulfonamide;

[0045] m is an integer of 1 or 2;

[0046] R 5 It is hydrogen, R 5a Or selected from the following structural parts

[0047] ;

[0048] L 1 and L 2 Each is C independently 1-4 Alkylene;

[0049] R 5a and R 5b Each is C independently 1-6 Alkyl, phenyl, benzyl, or 5- to 7-membered heterocyclic groups; wherein each of the alkyl, phenyl, and heterocyclic groups is independently surrounded by 0 to 3 R groups. 5d replace;

[0050] R 5c It is C 1-6 Alkyl or 5- to 7-membered carbocyclic group; wherein the C 1-6 Alkyl, phenyl, and heterocyclic groups are each independently bounded by 0 to 3 R groups. 5d Replace; and

[0051] R 5d Each time it appears, it is independently halogenated, OH, alkoxy, oxo, or alkyl; or alternatively, two adjacent Rs. 5d Together with the atoms to which they are attached, they form a carbonyl group.

[0052] In one implementation of formula (Ia) or (Ib), R 9 It is halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0053] In one embodiment of formula (Ia) or (Ib), A, E, G, and J together with two carbon atoms form a ring portion selected from the following structural formulas:

[0054]

[0055] In one implementation of formula (Ia) or (Ib), R 1 It is selected from the following arginine mimicry section

[0056]

[0057] ,

[0058] R e It is OH, C 1-4 Alkyl, halogenated, haloalkyl or C 1-4 Cycloalkyl; and r is an integer of 0, 1, 2 or 3.

[0059] In one implementation of formula (Ia) or (Ib), R 1 It is selected from the following arginine mimicry section

[0060]

[0061] One asterisk in each arginine analogue portion is an attachment point to X, and the other two asterisks are hydrogen atoms;

[0062] R f = H, Me, Et, COOEt;

[0063] R g = CH3, CH2CH3, CH2CCl3, phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl ;

[0064] R e It is OH, C 1-4 Alkyl, halogenated, haloalkyl or C 1-4 cycloalkyl; and

[0065] r is an integer of 0, 1, 2 or 3.

[0066] In one implementation of formula (Ia) or (Ib), R 3a It is hydrogen; and R 3 It is hydrogen or selected from the following structural parts

[0067]

[0068] .

[0069] In one implementation of formula (Ia) or (Ib), R 3a and R 3 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl moiety.

[0070] In one implementation of formula (Ia) or (Ib), R 4 It is hydrogen or selected from the following structural parts

[0071] .

[0072] In one implementation of formula (Ia) or (Ib), R 4 It is H, and R 3 Not H; or alternatively, R 3 It is H, and R 4 Not H.

[0073] In one implementation of formula (Ia) or (Ib), R 5 Is it H or R? 5a And R 5a It is methyl, ethyl, isopropyl, n-butyl, isopentyl, or a structural moiety selected from the following:

[0074]

[0075] In one embodiment of formula (Ia) or (Ib), the compound is represented by structural formula (IIa), (IIb), (IIc), or (IId):

[0076] (IIa) (IIb)

[0077] (IIc) or (IId);

[0078] Where R 1 X, Y, R 3 R 4 and R 5 It is the same as the one defined above.

[0079] In one embodiment of formula (IIa), (IIb), (IIc) or (IId), R 1 The structural formula is selected from the following:

[0080]

[0081] .

[0082] In one embodiment of formula (IIa), (IIb), (IIc), or (IId), X is C 1-4 Alkylene; and Y is either covalent or O.

[0083] In one embodiment of formula (IIa), (IIb), (IIc) or (IId),

[0084] R 3 It is hydrogen, C 1-6 Alkyl, 3- to 6-membered carbocyclic, carbocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 3- to 6-membered heterocyclic, heterocyclic alkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, wherein the alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 6 replace;

[0085] R 3a It is hydrogen;

[0086] R 4 It is hydrogen;

[0087] R 6 It is halogenated, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, amide moiety, ester moiety, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic alkyl; wherein the alkyl, alkoxy, aminoalkyl, haloalkyl, aryl, aryloxy, heteroaryl, cycloalkyl, or heterocyclic alkyl, either individually or as part of another group, is independently marked with 0, 1, or 2 R groups. 10 Replace; and

[0088] R 10 Each time it appears, it is independently halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0089] In one embodiment of formula (IIa), (IIb), (IIc) or (IId), R 4 It is hydrogen; R 3a and R 3 Together with one or more atoms to which they are attached, they form rings of 3 to 6-membered carbon.

[0090] In one embodiment of formula (IIa), (IIb), (IIc) or (IId),

[0091] R 3 It is hydrogen;

[0092] R 3a It is hydrogen;

[0093] R 4 It is C 1-6 Alkyl, arylalkyl, -S(O)m R 7 -C(O)NR a R b -NHC(O)OR a -NHC(O)NR a R b -NHC(O)R 7 -OC(O)NR a R b -OC(O)R 7 -NHS(O) m NR a R b Or -NHS(O) m R 7 ; wherein the alkyl and arylalkyl groups are each independently marked with 0, 1, 2 or 3 R groups. 9 replace;

[0094] R 7 Each is C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Halogenated alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 11 replace;

[0095] R 9 and R 11 Each time it appears, it is independently halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0096] In one embodiment of formula (IIa), (IIb), (IIc) or (IId), R 5 It is hydrogen.

[0097] In one embodiment of formula (Ia) or (Ib), the compound is represented by structural formula (IIIa), (IIIb), (IIIc), or (IIId):

[0098] (IIIa) (IIIb)

[0099] (IIIc) or (IIId);

[0100] Where R1 X, Y, R 3 R 4 and R 5 It is the same as the one defined above.

[0101] In one embodiment of formula (IIIa), (IIIb), (IIIc), or (IIId), X is C 2-4 Alkylene; and Y is either covalent or O.

[0102] In one embodiment of formula (IIIa), (IIIb), (IIIc) or (IIId),

[0103] R 3 It is C 1-6 Alkyl, 3- to 6-membered carbocyclic, carbocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 3- to 6-membered heterocyclic, heterocyclic alkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, wherein the alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 6 replace;

[0104] R 3a It is hydrogen;

[0105] R 4 It is hydrogen;

[0106] R 6 It is halogenated, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, amide moiety, ester moiety, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic alkyl; wherein the alkyl, alkoxy, aminoalkyl, haloalkyl, aryl, aryloxy, heteroaryl, cycloalkyl, or heterocyclic alkyl, either individually or as part of another group, is independently marked with 0, 1, or 2 R groups. 10 Replace; and

[0107] R 10 Each time it appears, it is independently halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0108] In one embodiment of formula (IIIa), (IIIb), (IIIc) or (IIId),

[0109] R 3 It is hydrogen;

[0110] R 3a It is hydrogen;

[0111] R 4 It is C 1-6 Alkyl, arylalkyl, -S(O) m R 7 -C(O)NR a R b -NHC(O)OR a -NHC(O)NR a R b -NHC(O)R 7 -OC(O)NR a R b -OC(O)R 7 -NHS(O) m NR a R b Or -NHS(O) m R 7 ; wherein the alkyl and arylalkyl groups are each independently marked with 0, 1, 2 or 3 R groups. 9 replace;

[0112] R 7 Each is C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Halogenated alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 11 Replace; and

[0113] R 9 and R 11 Each time it appears, it is independently halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0114] In one embodiment of formula (IIIa), (IIIb), (IIIc), or (IIId), R 5 It is hydrogen.

[0115] In one embodiment of formula (Ia) or (Ib), the compound is represented by structural formulas (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf):

[0116] (IVa) (IVb)

[0117] (IVc) (IVd)

[0118] (IVe) or (IVf);

[0119] Where R 1 X, Y, R 3 R 4 and R 5 It is the same as the one defined above.

[0120] In one embodiment of formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf), X is C 2-4 Alkylene; and Y is either covalent or O.

[0121] In one embodiment of formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf),

[0122] R 3 It is C 1-6 Alkyl, 3- to 6-membered carbocyclic, carbocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 3- to 6-membered heterocyclic, heterocyclic alkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, wherein the alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 6 replace;

[0123] R 3a It is hydrogen;

[0124] R 4 It is hydrogen;

[0125] R 6 It is halogenated, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, amide moiety, ester moiety, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic alkyl; wherein the alkyl, alkoxy, aminoalkyl, haloalkyl, aryl, aryloxy, heteroaryl, cycloalkyl, or heterocyclic alkyl, either individually or as part of another group, is independently marked with 0, 1, or 2 R groups. 10 Replace; and

[0126] R 10 Each time it appears, it is independently halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0127] In one embodiment of formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf),

[0128] R 3 It is hydrogen;

[0129] R 3a It is hydrogen;

[0130] R 4 It is C 1-6 Alkyl, arylalkyl, -S(O) m R 7 -C(O)NR a R b -NHC(O)OR a -NHC(O)NR a R b -NHC(O)R 7 -OC(O)NR a R b -OC(O)R 7 -NHS(O) m NR a R b Or -NHS(O) m R 7 ; wherein the alkyl and arylalkyl groups are each independently marked with 0, 1, 2 or 3 R groups. 9 replace;

[0131] R 7 Each is C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Halogenated alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 11 Replace; and

[0132] R 9 and R 11 Each time it appears, it is independently halogenated, cyano, hydroxyl, amino, oxo, or C. 1-6 alkyl.

[0133] In one embodiment of formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf), R 5 It is hydrogen.

[0134] In any embodiment of formula (Ia) or (Ib), the compound is selected from any of the embodiments described in this specification, or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0135] Pharmaceutical compositions, therapeutic uses and combinations

[0136] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0137] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0138] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0139] In another embodiment, the present invention provides a method for preparing the compounds of the present invention.

[0140] In another embodiment, the present invention provides an intermediate for preparing the compounds of the present invention.

[0141] In another embodiment, the present invention provides a pharmaceutical composition as defined above, the pharmaceutical composition further comprising one or more additional therapeutic agents.

[0142] In another embodiment, the present invention provides a method for treating patients requiring such treatment, using α V Methods for treating diseases, disorders, or conditions associated with abnormal regulation of integrin, the methods comprising administering to the patient a therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0143] In another embodiment, the present invention provides a method for treating a disease, disorder, or ailment, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention (alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent).

[0144] In another embodiment, the present invention provides a method for inducing integrin receptor antagonism in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. In one embodiment, integrin receptor antagonism is against α-... V β6, α V β1, α V β3, α V β5 and α V Any of β8; or α V β6, α V β1, α V β3, α V β5 and α V Antagonistic effects of one or more of β8 receptors in combination. For example, integrin receptor antagonism can be α-receptor antagonism. V β6, α V β1, α V β3, α V β5 and α V β8 antagonistic effect.

[0145] In some implementations, the disease, disorder, or condition is associated with fibrosis (including fibrosis of the lungs, liver, kidneys, heart, skin, eyes, and pancreas).

[0146] In other embodiments, the disease, disorder, or symptom is associated with a cell proliferation disorder (such as cancer). In some embodiments, the cancer includes solid tumor growth or tumor formation. In other embodiments, the cancer includes tumor metastasis. In some embodiments, the cancer is a cancer of the bladder, blood, bones, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, reproductive organs, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid gland. In other embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. The disease, disorder, or symptom associated with α can be prevented, regulated, or treated according to the present invention. V Examples of diseases, disorders, or conditions associated with integrin activity include, but are not limited to, transplantation, fibrotic disorders (e.g., idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, kidney fibrosis, skin fibrosis, systemic sclerosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatohepatitis (NASH), psoriasis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), osteoporosis, and cell proliferation disorders (e.g., cancer, myeloma, fibroma, liver cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0147] The fibrotic disorders, inflammatory disorders, and cell proliferation disorders suitable for prevention or treatment by the compounds of this invention include, but are not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP), common interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, virus-induced fibrosis, nonalcoholic fatty liver disease (NAFLD), alcoholic or nonalcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, and biliary hepatitis. Sclerosis, portal hypertension, regenerative failure, impaired liver function, impaired hepatic blood flow, kidney disease, pneumonia, psoriasis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretion disorders, benign prostatic hyperplasia, neurogenic bladder disease, spinal cord tumors, intervertebral disc herniation, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot-and-mouth disease, cancer, myeloma, fibroma, liver cancer, leukemia, chronic lymphocytic leukemia, Kaposi's sarcoma, solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma, filtration surgery scarring, Crohn's disease or systemic lupus erythematosus, keloid formation due to abnormal wound healing, fibrosis after organ transplantation, myelofibrosis, and fibrosis. In one embodiment, the present invention provides a method for treating fibrotic disorders, inflammatory disorders, or cell proliferation disorders, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention (alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent).

[0148] In another embodiment, the present invention provides compounds for use in therapeutic applications.

[0149] In another embodiment, the present invention provides compounds of the invention for use in therapies for treating fibrotic disorders, inflammatory disorders, or cell proliferation disorders.

[0150] In another embodiment, the present invention also provides the use of the compounds of the present invention in the manufacture of medicaments for treating fibrotic disorders, inflammatory disorders, or cell proliferation disorders.

[0151] In another embodiment, the present invention provides a method for treating fibrotic disorders, inflammatory disorders, or cell proliferation disorders, the method comprising administering to a patient in need a therapeutically effective amount of a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention.

[0152] In another embodiment, the present invention provides a combination formulation of the compound of the present invention and one or more other therapeutic agents for use simultaneously, separately or sequentially in a therapy.

[0153] In another embodiment, the present invention provides a combination formulation of the compound of the present invention and one or more other therapeutic agents for simultaneous, separate or sequential use in the treatment of fibrotic disorders, inflammatory disorders or cell proliferation disorders.

[0154] The compounds of the present invention can be used in combination with one or more other therapeutic agents, such as one or more antifibrotic and / or anti-inflammatory therapeutic agents.

[0155] In one embodiment, one or more additional therapeutic agents used in combination with the pharmaceutical composition or method or use are selected from one or more of the following therapeutic agents (preferably one to three): inhibitors of TGFβ synthesis (e.g., pirfenidone), inhibitors of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptor kinases (e.g., nintedanib), humanized anti-α V β6 monoclonal antibodies (e.g., 3G9), recombinant human penetrantin-2, recombinant human serum amyloid P, recombinant human antibodies against TGFβ-1, -2, and -3, endothelin receptor antagonists (e.g., macitentan), interferon-γ, c-Jun N-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purine-2-yl]amino]-trans-cyclohexanol) 3-Pentylphenylacetic acid (PBI-4050), manganese(III)-containing tetrasubstituted porphyrin derivatives, monoclonal antibodies targeting eosinophil chemokine-2, interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., Sar... 9 Met(O2) 11-P substance), Cintredekin Besudotox, a human recombinant DNA-derived IgG1κ monoclonal antibody against connective tissue growth factor, and fully human IgG1 selective for CC-chemokine ligand 2. κ antibodies (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), agents used to treat obstructive airway diseases such as muscarinic antagonists (e.g., tiotropium bromide, ipratropium bromide), adrenergic β2 agonists (e.g., salbutamol, salmeterol), corticosteroids (e.g., triamcinolone acetonide, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus), and agents that can be used to treat NALFD, NASH, or systemic sclerosis such as FXR agonists (e.g., OCA, GS-9674, and LJN452), LOXL2 inhibitors (e.g., simtuzumab), and LPA1 antagonists (e.g., SAR). 100842), PPAR modulators (e.g., elafibrinor, pioglitazone, saroglitazar, IVA337), SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), ASK-1 inhibitors (e.g., GS-4997), ACC inhibitors (e.g., CP-640186 and NDI-010976), FGF21 agonists (e.g., LY2405319), caspase inhibitors (e.g., emricasan), NOX4 inhibitors (e.g., GKT137831), MGAT2 inhibitors, and bile acid / fatty acid conjugates (e.g., aramchol). The α-elements of various embodiments of the invention... VInhibitors can also be used in combination with one or more therapeutic agents, such as CCR2 / 5 inhibitors (e.g., cenicriviroc), galactoglobulin-3 inhibitors (e.g., TD-139, GR-MD-02), leukotriene receptor antagonists (e.g., tipelukast, montelukast), SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin), and GLP-1 agonists (e.g., liraglutide and...). Semaglutide), FAK inhibitors (e.g., GSK-2256098), CB1 inverse agonists (e.g., JD-5037), CB2 agonists (e.g., APD-371 and JBT-101), autotaxin inhibitors (e.g., GLPG1690), prolyl tRNA synthetase inhibitors (e.g., halofugenone), FPR2 agonists (e.g., ZK-994), and THR agonists (e.g., MGL:3196).

[0156] The compounds of the invention may be administered for any of the uses described herein by any of the following suitable methods: for example, orally (e.g., tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions); sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to a nasal membrane, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They may be administered alone, but are generally administered together with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0157] The term "pharmaceutical composition" means a composition comprising a compound of the present invention combined with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a bioactive agent to animals (particularly mammals), including adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the manner of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated based on a number of factors known to those skilled in the art. These include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the pharmaceutical agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers may also include many different ingredients and additives in addition to active agents, which are included in the formulation for a variety of reasons well known to those skilled in the art (e.g., stabilization of active agents, binders, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 18th edition (1990).

[0158] As used herein, the term "treating" refers to a method for obtaining a beneficial or desired outcome (including clinical outcomes) through the use of compounds or compositions of the present invention. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing the severity and / or frequency of one or more symptoms caused by a disease, disorder, or condition; reducing the degree of a disease, disorder, or condition or causing its remission; stabilizing a disease, disorder, or condition (e.g., preventing or delaying the worsening of a disease, disorder, or condition); delaying or slowing the progression of a disease, disorder, or condition; improving the state of a disease, disorder, or condition; reducing the dosage of one or more other medicines required to treat a disease, disorder, or condition; and / or improving quality of life.

[0159] Of course, the dosing regimen of the compounds of the present invention will vary according to known factors such as the pharmacodynamic characteristics of the particular agent and its administration method and route; the species, age, sex, health, medical condition and weight of the recipient; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function and the desired effect.

[0160] As a general guideline, when used for the effects shown, the daily oral dose of each active ingredient will range from about 0.01 to about 5000 mg / day, preferably from about 0.1 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. Intravenous administration, during a constant rate infusion, will preferably range from about 0.01 to about 10 mg / kg / min. The compounds of the invention can be administered as a single daily dose, or the total daily dose can be administered in divided doses twice, three, or four times daily.

[0161] The compound is typically administered in combination with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier), which is appropriately selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and is consistent with conventional pharmaceutical practice.

[0162] Each dose unit of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 2000 mg of the active ingredient. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1% to 95% by weight based on the total weight of the composition.

[0163] Typical capsules for oral administration contain at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[0164] A typical injectable formulation is produced by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically freeze-drying it, and sealing it. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce the injectable formulation.

[0165] This invention includes pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention (alone or in combination with a drug carrier) as an active ingredient. Optionally, the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more (preferably one to three) other therapeutic agents (e.g., FXR agonists or other pharmaceutically active materials).

[0166] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amounts indicated in Physicians' Desk Reference, as in the aforementioned patents, or as otherwise determined by those skilled in the art.

[0167] In particular, when provided as a single dose unit, there is a possibility of chemical interactions between the combined active ingredients. Therefore, when the compounds of the present invention and the second therapeutic agent are combined in a single dose unit, they are formulated such that physical contact between the active ingredients is minimized (i.e., reduced) despite being combined in a single dose unit. For example, one active ingredient may be enteric-coated. By enteric-coating one of the active ingredients, not only is contact between the combined active ingredients minimized, but the release of one of these components in the gastrointestinal tract can also be controlled, such that one of these components is released in the intestine rather than in the stomach. One of the active ingredients may also be coated with a material that enables sustained release throughout the gastrointestinal tract, and also serves to minimize physical contact between the combined active ingredients. Furthermore, a sustained-release component may be additionally enteric-coated so that the release of this component occurs only in the intestine. Another method involves formulating a combined product in which one component is coated with a sustained-release and / or enteric-release polymer, and another component is also coated with a polymer (such as low-viscosity hydroxypropyl methylcellulose (HPMC)) or other suitable materials known in the art to further separate the active components. Polymer coatings are used to form additional barriers against interactions with another component.

[0168] Once combined with this disclosure, these and other methods that minimize contact between the components of the combined products of the present invention, whether administered in a single dosage form or separately (but simultaneously in the same manner), will be readily apparent to those skilled in the art.

[0169] The compounds of the present invention can be administered alone or in combination with one or more (preferably one to three) additional therapeutic agents. "Administered in combination" or "combination therapy" means that the compounds of the present invention and one or more (preferably one to three) additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component can be administered at the same time or sequentially at different time points in any order. Thus, each component can be administered separately, but close enough in time to provide the desired therapeutic effect.

[0170] The compounds of the present invention relate to α V These compounds can also be used as standard or reference compounds in the testing or assay of integrins, for example, as quality standards or controls. Such compounds are available in commercial kits, for example, for use in assays involving α-integrins. VIn pharmaceutical studies of integrin activity, compounds of the present invention can be used as references in assays to compare their known activities with those of compounds with unknown activities. This ensures that the experimenter performs the assay correctly and provides a basis for comparison, especially if the test compound is a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention can be used to test their effectiveness.

[0171] This invention also includes articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packaging. Articles of manufacture of this invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a package insert indicating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent for treating fibrosis and its sequelae (as previously defined). The articles of manufacture may also comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located within or outside the second container. Being located within the first and second containers means that the respective containers hold the articles within their boundaries.

[0172] The first container is a receiving container for holding a pharmaceutical composition. This container may be used for manufacturing, storing, transporting, and / or selling individually / in bulk. The first container is intended to encompass bottles, cans, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used for manufacturing, holding, storing, or dispensing pharmaceutical products.

[0173] The second container is used to hold the first container and optionally the instruction manual. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), sachets, and pouches. The instruction manual may be physically attached to the outside of the first container by tape, glue, staples, or other attachment methods, or it may remain inside the second container without any physical attachment to the first container. Alternatively, the instruction manual may be located outside the second container. When located outside the second container, it is preferred that the instruction manual be physically attached by tape, glue, staples, or other attachment methods. Alternatively, it may be adjacent to or in contact with the outside of the second container, rather than physically attached.

[0174] The package insert, such as a label, tag, or marker, lists information relating to the pharmaceutical composition located within the first container. The listed information will typically be determined by the regulatory authority governing the sale of the product therein (e.g., the U.S. Food and Drug Administration). Preferably, the package insert specifically lists the indications for which the approved pharmaceutical composition is intended. The package insert can be made of any material on or in which the information is readable by a person. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the required information has been formed (e.g., printed or applied).

[0175] definition

[0176] Throughout the specification and appended claims, the given chemical formula or name shall include all its stereo and optical isomers and racemates, where such isomers are present. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc., may also exist in the compounds, and all such stable isomers are considered in this invention. Cis and trans (or E- and Z-) geometric isomers of the compounds of this invention are described and can be separated as mixtures of isomers or as individual isomers. The compounds of this invention can be separated in optically active or racemic forms. Optically active forms can be prepared by resolving racemic forms or by synthesis from optically active starting materials. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. When preparing enantiomers or diastereomers, they can be separated by conventional methods, such as chromatography or fractional crystallization. Depending on the method conditions, the final products of this invention are obtained in free (neutral) or salt form. The free forms and salts of these final products are within the scope of this invention. If desired, one form of the compound can be converted to another. A free base or acid can be converted to a salt; a salt can be converted to a free compound or another salt; a mixture of isomers of the present invention can be separated into individual isomers. The compounds of the present invention (in their free forms and salts) can exist in a variety of tautomer forms, wherein hydrogen atoms are transposed to other parts of the molecule, and thus the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomer forms are included within the scope of this invention as long as they can exist. As used herein, “a compound of the present invention” or “a variety of compounds of the present invention” means one or more compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, covered by any one of formulas (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf).

[0177] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1 to C2" 10 "alkyl" or "C" 1-10 Alkyl (or alkylene) is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Alkyl groups. Additionally, for example, "C1 to C6 alkyl" or "C 1-6"alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted (where at least one hydrogen atom is replaced by another chemical group). Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "CO alkyl" or "CO alkylene" is used, it is intended to indicate a direct bond.

[0178] Unless otherwise specified, the term "lower alkyl" as used alone or as part of another group herein includes straight-chain hydrocarbons and branched hydrocarbons containing 1 to 8 carbons, and the terms "alkyl" and "alk" as used alone or as part of another group herein include straight-chain hydrocarbons and branched hydrocarbons containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons in the positive chain, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and their various branched isoalkyl groups. The structure, etc., and such groups comprising one to four substituents, said substituents being such as halogen (e.g., F, Br, Cl or I or CF3), alkyl, alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, arylalkyl, arylalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, hydroxyl, hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamide, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and / or alkylthio.

[0179] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom (such as O, N, or S). For example, if the carbon atom of an alkyl group attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CH3)2, etc.), or a thioalkyl group (e.g., -SCH3). If the non-terminal carbon atom of an alkyl group not attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkylamine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g., -CH2-S-CH3). If the terminal carbon atom of the alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or an alkylthiol group (e.g., -CH2CH2-SH). The heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C1-C6 heteroalkyl groups refer to heteroalkyl groups having 1 to 6 carbon atoms.

[0180] "Alkenyl" or "alkenyl" is intended to comprise a hydrocarbon chain having a specified number of carbon atoms and one or more (preferably one to two) carbon-carbon double bonds in a straight-chain or branched configuration, wherein the carbon-carbon double bonds may be present at any stable point along the chain. For example, "C2 to C6 alkenyl" or "C 2-6 "Alkenyl" (or alkenylyl) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

[0181] "Alynyl" or "hypoynyl" is intended to include hydrocarbon chains having a straight-chain or branched configuration with one or more (preferably one to three) carbon-carbon triple bonds, which can be present at any stable point along the chain. For example, "C2 to C6 ynyl" or "C 2-6 "Alynyl" (or ynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentylyl and hexynyl.

[0182] As used herein, “arylalkyl” (also known as arylalkyl), “heteroarylalkyl”, “carbocyclic alkyl” or “heterocyclic alkyl” refers to an acyclic alkyl radical, wherein the radical is associated with a carbon atom (typically terminal or sp). 3One of the hydrogen atoms bonded to a carbon atom is replaced by an aryl, heteroaryl, carbocyclic, or heterocyclic radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, and 2-naphthophenylethyl-1-yl. Arylalkyl, heteroarylalkyl, carbocyclic, or heterocyclic alkyl groups can contain 4 to 20 carbon atoms and 0 to 5 heteroatoms; for example, the alkyl moiety can contain 1 to 6 carbon atoms.

[0183] As used herein, the term "benzyl" refers to a methyl group in which one of its hydrogen atoms is replaced by a phenyl group, wherein the phenyl group may optionally be replaced by one to five groups (preferably one to three groups) (OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3). "Benzyl" may also be represented by the formula "Bn".

[0184] The terms "lower alkoxy," "alkoxy," or "alkyloxy," "aryloxy," or "aralkyloxy" refer to any of the aforementioned alkyl, aralkyl, or aryl groups bonded to an oxygen atom. "C1 to C6 alkoxy" or "C 1-6 "Alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "lower alkathio", "alkathio", "thioalkoxy", "arylthio", or "aryl alkathio" means an alkyl, aryl, or aralkyl group as defined above, in which a specified number of carbon atoms are attached by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0185] The terms “alkanoyl” or “alkylcarbonyl” as used alone or as part of another group herein refer to an alkyl group attached to a carbonyl group. For example, an alkylcarbonyl group may be represented by alkyl-C(O)-. “C1 to C6 alkylcarbonyl” (or alkylcarbonyl) is intended to include C1, C2, C3, C4, C5, and C6 alkyl-C(O)- groups.

[0186] The terms “alkylsulfonyl” or “sulfonamide” as used alone or as part of another group herein refer to an alkyl or amino group attached to a sulfonyl group. For example, an alkylsulfonyl group can be represented by -S(O)₂R', while a sulfonamide can be represented by -S(O)₂NR. c R d R' is a C1 to C6 alkyl group; and R c and Rd Same as the definition of "amino" below.

[0187] The term "urethane ester," as used alone or as part of another group herein, refers to oxygen attached to an amide group. For example, urethane esters can be composed of N(R) c R d )-C(O)-O- represents, and R c and R d Same as the definition of "amino" below.

[0188] The term "amide group," as used alone or as part of another group herein, refers to an amino group attached to a carbonyl group. For example, an amide group can be formed from N(R) c R d )-C(O)- represents, and R c and R d Same as the definition of "amino" below.

[0189] The term "amino" is defined as -NR c R d , where R c and R d Independently hydrogen or C 1-6 Alkyl; or alternatively, R c and R d These rings, together with the atoms to which they are attached, form 3- to 8-membered carbon rings or heterocycles, which are optionally substituted by one or more groups independently selected from: halogenated, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, or sulfonamide. When R c Or R d (or both) are C 1-6 When alkyl is used, the amino group can also be called alkylamino. Examples of alkylamino groups include, but are not limited to, -NH2, methylamino, ethylamino, propylamino, isopropylamino, etc.

[0190] The term "aminoalkyl" refers to an alkyl group in which one of the hydrogen atoms is replaced by an amino group. For example, an aminoalkyl group can be formed by N(R) c R d )-alkylene- indicates. "C1 to C6" or "C 1-6 "Aminoalkyl means to include C1, C2, C3, C4, C5 and C6 aminoalkyl groups."

[0191] The term “halogen” or “halogenated” as used alone or as part of another group herein refers to chlorine, bromine, fluorine, and iodine, wherein chlorine or fluorine is preferred.

[0192] "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more halogens. "C1 to C6 haloalkyl" or "C 1-6 "Halogenated alkyl" (or halogenated alkyl) is intended to include C1, C2, C3, C4, C5, and C6 halogenated alkyl groups. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl groups also include "fluoroalkyl," which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more fluorine atoms. As used herein, the term "polyhalogenated alkyl" refers to an "alkyl" group as defined above that includes from 2 to 9 (preferably from 2 to 5) halogenated substituents (such as F or Cl, preferably F), such as polyfluoroalkyl, for example CF3CH2, CF3, or CF3CF2CH2.

[0193] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above, in which a specified number of carbon atoms are attached via an oxygen bridge. For example, "C1 to C6 haloalkoxy" or "C 1-6 The term "haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above in which a specified number of carbon atoms are attached by a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-. As used herein, the term "polyhaloalkyloxy" refers to an "alkoxy" or "alkyloxy" group as defined above that includes 2 to 9 (preferably 2 to 5) halosubstituents (such as F or Cl, preferably F), such as polyfluoroalkoxy groups, for example CF3CH2O, CF3O, or CF3CF2CH2O.

[0194] "Hydroxyalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, each substituted with one or more hydroxyl (OH) or amino groups. "C1 to C6 hydroxyalkyl" (or hydroxyalkyl) is intended to include C1, C2, C3, C4, C5 and C6 hydroxyalkyl groups.

[0195] The term "cycloalkyl" refers to a cyclic alkyl group, including monocyclic, bicyclic, or polycyclic cyclic systems. "C3 to C7 cycloalkyl" or "C 3-7"Cycloalkyl" is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups (such as 1-methylcyclopropyl and 2-methylcyclopropyl) are included in the definition of "cycloalkyl".

[0196] The term "cyclohexaalkyl" refers to a cyclic heteroalkyl group, including monocyclic, bicyclic, or polycyclic cyclic systems. "C3 to C7 cyclohexaalkyl" or "C 3-7 "Cyclohexaalkyl" is intended to include C3, C4, C5, C6, and C7 cyclohexaalkyl groups. Exemplary cyclohexaalkyl groups include, but are not limited to, oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirane, pyrroliyl, piperidinyl, morpholinyl, and piperazinyl. Branched cyclohexaalkyl groups (such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidinylmethyl, and pyrazinylmethyl) are included in the definition of "cyclohexaalkyl".

[0197] As used herein, the term "aza-heterocyclic" refers to a cyclic heteroalkyl group containing one or more nitrogen atoms in a ring. Exemplary aza-heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, and piperazineyl.

[0198] As used herein, “carbocyclic,” “carbocyclic group,” or “carbocyclic” is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered polycyclic (including bicyclic or tricyclic) hydrocarbon ring, any of which may be saturated or partially unsaturated. That is, the terms “carbocyclic,” “carbocyclic group,” or “carbocyclic” include, but are not limited to, cycloalkyl and cycloalkenyl groups. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decahydronaphthalene), [2.2.2]bicyclooctane, fluorenyl, indanyl, adamantyl, and tetrahydronaphthalene (tetrahydronaphthalene). As shown above, bridged rings are also included in the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). Unless otherwise stated, preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and tetrahydronaphthalene. A bridged ring occurs when one or more (preferably one to three) carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It should be noted that bridging always transforms a single-ring ring into a three-ring ring. When rings are bridged, the substituents described for the rings can also be present on the bridge.

[0199] Furthermore, the term "carbocyclic" (including "cycloalkyl" and "cycloalkenyl") as used alone or as part of another group herein includes saturated or partially unsaturated cyclic hydrocarbon groups (containing one or two double bonds) containing one to three rings, including monocycloalkyl, dicycloalkyl, and tricycloalkyl groups, which contain a total of three to 20 carbon-forming rings (preferably three to ten carbon-forming rings) and which may be fused with one or two aromatic rings as described for aryl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloundecyl, cyclododecyl, and cyclohexenyl.

[0200]

[0201] Any of the groups may optionally be replaced by one to four substituents (such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamide, alkylacylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or any alkyl substituent).

[0202] As used herein, the term "bicyclic carbocyclic" or "bicyclic carbocyclic group" is intended to refer to a stable 9- or 10-membered carbon ring system containing two fused rings composed of carbon atoms. Of the two fused rings, one is a benzo[a] ring fused to the second ring; and the second ring is a saturated or partially unsaturated 5- or 6-membered carbon ring. A bicyclic carbocyclic group can be attached to its side groups at any carbon atom, resulting in a stable structure. If the resulting compound is stable, the bicyclic carbocyclic group described herein can be substituted at any carbon atom. Examples of bicyclic carbocyclic groups are, but are not limited to, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0203] As used herein, the term "aryl" (as used alone or as part of another group) refers to a monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbon, including, for example, phenyl, naphthyl, anthracene, and phenanthrene. The aryl moiety is well known and described, for example, in Lewis, RJ, Hawley's Condensed Chemical Dictionary, 13th edition, John Wiley & Sons, Inc., New York (1997). In one embodiment, the term "aryl" means a monocyclic or bicyclic aromatic group (such as phenyl or naphthyl (including 1-naphthyl and 2-naphthyl)) containing 6 to 10 carbons in the ring moiety. For example, "C6 or C..." 10 "Aryl" or "C" 6-10 "Aryl" refers to phenyl and naphthyl groups. Unless otherwise stated, "aryl" means "C6 or C6". 10 Aryl", C 6-10The "aryl" or "aromatic residue" may be unsubstituted or substituted with one to five groups (preferably one to three groups), said groups being selected from -OH, -OCH3, -Cl, -F, -Br, -I, -CN, -NO2, -NH2, -N(CH3)H, -N(CH3)2, -CF3, -OCF3, -C(O)CH3, -SCH3, -S(O)CH3, -S(O)2CH3, -CH3, -CH2CH3, -CO2H, and -CO2CH3.

[0204] As used herein, the terms “heterocyclic,” “heterocyclic group,” or “heterocyclic group” are intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic (including bicyclic or tricyclic) heterocyclic ring that is saturated or partially unsaturated and contains a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S; and include any polycyclic group in which any of the heterocyclic rings defined above are fused to a carbon ring or an aryl (e.g., benzene) ring. That is, the terms “heterocyclic,” “heterocyclic group,” or “heterocyclic group” include non-aromatic ring systems such as heterocyclic alkyl and heterocyclic alkenyl groups. Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, where p is 0, 1, or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The ring of the heterocycle can be attached to its side groups at any heteroatom or carbon atom, resulting in a stable structure. If the resulting compound is stable, the ring of the heterocycle described herein can be substituted on a carbon atom or on a nitrogen atom. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. Examples of heterocyclic groups include, but are not limited to, nitrogen-containing heterocyclic butyl, piperazine, piperidinyl, piperidinone, piperinyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, dihydrofurano[2,3-b]tetrahydrofuran.

[0205] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to refer to a stable 9- or 10-membered heterocyclic ring system containing two fused rings and consisting of a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring containing a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo[a] ring, each fused to the second ring. The second ring is a saturated, partially unsaturated, or unsaturated 5- or 6-membered monocyclic ring and contains a 5-membered heterocycle, a 6-membered heterocycle, or a carbocyclic ring (provided that the first ring is not benzo[a] when the second ring is a carbocyclic ring).

[0206] Bicyclic heterocyclic groups can be attached to their side groups at any heteroatom or carbon atom, resulting in a stable structure. If the resulting compound is stable, the bicyclic heterocyclic groups described herein can be substituted on a carbon atom or a nitrogen atom. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. Examples of bicyclic heterocyclic groups include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromiumyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.

[0207] Bridged rings are also included in the definition of heterocycles. A bridged ring occurs when one or more (preferably one to three) atoms (i.e., C, O, N, or S) are connected to two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and carbon-nitrogen groups. It should be noted that a bridge always transforms a monocyclic ring into a tricyclic ring. When rings are bridged, the substituents described for the ring may also be present on the bridge.

[0208] As used herein, the term "heteroaryl" is intended to refer to stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom ring member (such as sulfur, oxygen, or nitrogen). Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiophene, imidazolyl, thiazolyl, indoleyl, pyrroleyl, etc. Azolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, iso Azolyl, pyrazolyl, triazolyl, tetrazolyl, indazole, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazole, benzimidazole, indololinyl, benzodioxolane, and benzodioxane Alkane. The heteroaryl group may be substituted or unsubstituted. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, where p is 0, 1 or 2).

[0209] Examples of heteroaryl groups include, but are not limited to, acridinel, acridinel, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzophenylthiol, and benzo[] azole, benzo[ Azoline, benzothiazolyl, benzotriazolyl, benzotetrazole, benzoisocyanate Azolyl, benzoisothiazolyl, benzoimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, imidazopyridyl, indolenyl, indolinyl, indazinyl, indoleyl, 3H-indoleyl, isatinoyl, isobenzofuranyl, isochromyl, isoindazole, isoindolinyl, isoindoleyl, isoquinolinyl, isothiazolyl, isothiazolpyridyl, iso... azole group, iso Azopyridyl, methylenedioxyphenyl, naphthidyl, octahydroisoquinolinyl, Diazole group, 1,2,3- Diazolyl, 1,2,4- Diazolyl, 1,2,5- Diazolyl, 1,3,4- diazole group, azolealkyl, azole group, zopyridyl, azolealkyl-vinidinyl, hydroxyindolyl, pyrimidinyl, phenanthridine, phenanthrololinyl, phenazinyl, phenothiazinyl, phenanthridine phenoxathianyl, phen Azinyl, phthalazinyl, pteridinyl, purine, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyrido Azolyl, pyridinium imidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolylalkyl, pyrrololinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quininecycloyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianyl, thiazolyl, thiazolyl, thiazopyridyl, thiazolyl-pyridyl, thiazolyl-pyridyl, thiazolyl-pyridyl Azolyl, thiophene-imidazolyl, phenylthio, triazine, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl.

[0210] Examples of 5- to 10-membered heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophene, pyrazolyl, imidazolyl, imidazoalkyl, indoleyl, tetrazolyl, and isoaryl. azole group, azole group, diazole group, Alzolyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benzotetrazoleyl, benzotriazolyl, benzisiso azole, benzo[ azole, hydroxyindole, benzo[] Azolinyl, benzothiazolyl, benzoisothiazolyl, indigo yl, isoquinolinyl, octahydroisoquinolinyl, iso Azopyridyl, quinazolinyl, quinolinyl, isothiazolopyridyl, thiazopyridyl Zolopyridyl, imidazopyridyl, and pyrazolopyridyl. Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridyl, furanyl, thiophene, pyrrole, pyrazolyl, pyrazinyl, imidazolyl, imidazoalkyl, indoleyl, tetrazolyl, and iso... azole group, azole group, diazole group, Alzolyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0211] Unless otherwise specified, "carbocyclic" or "heterocyclic" includes one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as an aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl ring), for example,

[0212]

[0213]

[0214]

[0215] And optionally, the available carbon atom can be substituted by one, two, or three groups selected from the following: hydrogen, halogen, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cyclohexaalkyl, cyclohexaalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroaryl. Alkyl, heteroarylalyl, heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, aminoalkylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino and arylsulfonylaminocarbonyl and / or any alkyl substituents described herein.

[0216] According to conventions used in this field, keys pointing to thick lines (such as those used in the structural formulas herein) It describes the bond between a portion or substituent and the attachment point of the core or skeletal structure.

[0217] According to conventions used in this art, wavy bonds in structural formulas (such as...) This is used to depict the stereocenter of carbon atoms attached to X', Y', and Z' and is intended to represent two enantiomers in a single diagram. That is, structural formulas with wavy bonds represent each enantiomer (e.g., ...). or ) and its racemic mixture.

[0218] It should be understood in this document that if the carbocyclic, aryl, heterocyclic, or heteroaryl moiety can be attached to a specified substrate by different ring atoms or otherwise without indicating a specific attachment site, then all possible sites are expected, whether by a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" refers to 2-, 3-, or 4-pyridinyl, and the term "thiophenyl" refers to 2-, or 3-thiophenyl, and so on.

[0219] When a dashed ring is used within a ring structure, it indicates that the ring structure may be saturated, partially saturated, or unsaturated.

[0220] When a substituent is shown to cross a bond between two atoms in the linking ring, such a substituent may bond with any atom in the ring. When a substituent is listed without indicating the atoms to which such a substituent bonds with the remainder of the compound in the given formula, such a substituent may bond via any atom in such a substituent. Such combinations are only permitted if the combination of substituents and / or variables produces a stable compound.

[0221] Those skilled in the art will recognize that the substituents and other portions of the compounds of the present invention should be selected in order to provide sufficiently stable compounds to provide pharmaceutically useful compounds that can be formulated into acceptable and stable pharmaceutical compositions. Compounds of the present invention having such stability are considered to fall within the scope of the present invention.

[0222] The term "counter ion" is used to refer to negatively charged substances, such as chloride ions, bromide ions, hydroxide ions, acetate ions, and sulfate ions. The term "metal ion" refers to alkali metal ions (such as sodium, potassium, or lithium) and alkaline earth metal ions (such as magnesium and calcium), as well as zinc and aluminum.

[0223] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution produces a stable compound. When the substituent is a ketone group (i.e., =O), two hydrogen atoms on the atom are replaced. Ketone substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is allegedly substituted with a carbonyl group or double bond, the carbonyl group or double bond is expected to be part of the ring (i.e., within the ring). As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0224] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass the nitrogen shown and its N oxides (N... O) derivatives.

[0225] When any variable appears more than once in any component or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence. Thus, for example, if a group is shown to be substituted by 0, 1, 2, or 3 R groups, then when said group is substituted by 0 R groups it is unsubstituted, or when said group is substituted by at most three R groups it is substituted, and R is independently selected from the definition of R at each occurrence.

[0226] Furthermore, such combinations are only permissible if the combination of substituents and / or variables produces a stable compound.

[0227] As used herein, the term "tautomer" refers to each of two or more isomers of a compound, which exist together in equilibrium and are readily interchangeable by the migration of atoms or groups within the molecule. For example, those skilled in the art will readily understand that 1,2,3-triazole exists in two tautomer forms as defined above:

[0228] .

[0229] Therefore, even when only one of the structures is described, this disclosure is intended to cover all possible tautomers.

[0230] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues within the bounds of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0231] The compounds of the present invention can exist as salts, and said salts are also within the scope of the present invention. Pharmaceutically acceptable salts are preferred. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing its acid salt or base salt. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts can be prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both (generally preferably a non-aqueous medium, such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile). A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

[0232] If the compounds of the present invention have, for example, at least one basic center, they can form acid addition salts. These form, for example, with the following acids: strong inorganic acids, such as inorganic acids (e.g., sulfuric acid, phosphoric acid, or hydrohalic acid); organic carboxylic acids, such as alkyl carboxylic acids with one to four carbon atoms, such as acetic acid (which is unsubstituted or substituted with, for example, halogenated chloroacetic acid), such as saturated or unsaturated dicarboxylic acids (e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid), such as hydroxycarboxylic acids (e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid), such as amino acids (e.g., aspartic acid, glutamic acid, lysine, or arginine) or benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted with, for example, halogenated (C1-C4) alkyl or aryl sulfonic acids, such as methyl- or p-toluene-sulfonic acid. If desired, corresponding acid addition salts having additionally present basic centers can also be formed. Compounds of the present invention having at least one acid group (e.g., COOH) can also form salts with bases. Suitable salts that form with a base are, for example, metal salts, such as alkali metal or alkaline earth metal salts (e.g., sodium, potassium, or magnesium salts); or salts that form with ammonia or organic amines (e.g., morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines (e.g., ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine), or mono-, di-, or tri-hydroxylower alkylamines (e.g., mono-, di-, or triethanolamine)). Additionally, corresponding internal salts can be formed. Salts that are unsuitable for pharmaceutical use but can be used, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts are also included.

[0233] Preferred salts of compounds of formula I containing a basic group include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, nitrate, or acetate.

[0234] Preferred salts of compounds of formula I containing acid groups include sodium, potassium, and magnesium salts, as well as pharmaceutically acceptable organic amines.

[0235] Furthermore, the compounds of the present invention may be in prodrug form. Any compound that will be converted in vivo to provide a bioactive agent is a prodrug within the scope and spirit of the present invention. As used herein, the term "prodrug" includes prodrugs based on carboxylic acid residues, i.e., "prodrug esters"; and prodrugs based on arginine mimic moieties, i.e., "arginine mimic prodrugs". Such prodrugs are preferably administered orally because, in many cases, hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration may be used where the ester itself is active, or in those cases where hydrolysis occurs in the bloodstream.

[0236] The compounds of the present invention contain a carboxyl group, which can form a physiologically hydrolyzable ester, i.e., a "prodrug ester," used as a prodrug, by hydrolysis in vivo to produce the compounds of the present invention themselves. Examples of physiologically hydrolyzable esters of the compounds of the present invention include C1 to C6 alkyl, C1 to C6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C... 1-6 Alkyloxy-C 1-6 Alkyl groups (e.g., acetoxymethyl, neopentyloxymethyl, or propionyloxymethyl), C1 to C6 alkoxycarbonyloxy-C1 to C6 alkyl groups (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)-methyl), and other well-known physiologically hydrolyzable esters, such as those used in the fields of penicillins and cephalosporins. Such esters can be prepared using conventional techniques known in the art. “Prodrug esters” can be formed by reacting the carboxylic acid moiety of the compounds of the present invention with an alkyl or aryl alcohol, a halide, or a sulfonate using procedures known to those skilled in the art. Examples of such prodrug esters include:

[0237]

[0238] The compounds of the present invention contain an arginine mimic moiety that can form a physiologically hydrolyzable ester, i.e., an "arginine mimic prodrug," which is hydrolyzed in vivo to produce the compounds of the present invention themselves. Representative examples of arginine mimic prodrugs include:

[0239]

[0240] In each arginine analogue portion, one asterisk represents the attachment site to the parent molecule, and the other two asterisks represent hydrogen atoms; R f = H, Me, Et, COOEt; Rg = CH3, CH2CCl3, phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl ;R e It is OH, C 1-4 Alkyl, halogenated, haloalkyl or C 1-4 Cycloalkyl; and r is an integer of 0, 1, 2 or 3.

[0241] Furthermore, various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, please see:

[0242] Bundgaard, H. (ed.), Design of Prodrugs, Elsevier (1985), and Widder, K. et al. (eds.), Methods in Enzymology, 112:309-396, Academic Press (1985);

[0243] Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, edited by Krosgaard-Larsen, P. et al., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991);

[0244] Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

[0245] Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

[0246] Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

[0247] The preparation of prodrugs is well known in the art and described, for example, in King, FD, ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).

[0248] This invention aims to include all isotopes of the atoms appearing in the compounds of this invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of the originally used unlabeled reagents. Such compounds have a variety of potential uses, such as serving as standards and reagents in determining the ability of potential pharmaceutical compositions to bind to target proteins or receptors, or for imaging the compounds of the present invention that bind to biological receptors in vivo or in vitro.

[0249] The terms "stable compound" and "stable structure" are intended to indicate that the compound is robust enough to withstand separation from the reaction mixture to a useful level of purity and to be formulated into an effective therapeutic agent. Preferably, the compounds of the present invention do not contain N-halogenated, S(O)₂H, or S(O)H groups.

[0250] The term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. Solvent molecules in a solvate can exist in a regular and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvent" includes solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0251] The abbreviations used in this document are defined as follows: "1 x" means once, "2 x" means twice, "3 x" means three times, "ºC" means degrees Celsius, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means equivalent concentration, "M" means mole, "nM" means nanomolar, "mol" means mole, "mmol" means millimole, "min" means minute, "h" means hour, "rt" means room temperature, "RT" means retention time, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentrated, "sat" or "sat'd" means saturated, "MW" means molecular weight, "mp" means melting point, "MS" or "Mass Spec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "HR" means high resolution, "HRMS" means high resolution mass spectrometry, "LCMS" means liquid chromatography-mass spectrometry, "HPLC" means high performance liquid chromatography, "RP" means high resolution liquid chromatography, "RP ... "HPLC" indicates reversed-phase HPLC, "TLC" or "tlc" indicates thin-layer chromatography, "NMR" indicates nuclear magnetic resonance spectroscopy, "nOe" indicates nuclear Overhauser effect spectroscopy, "1H" indicates proton, "δ" indicates delta, "s" represents singlet, "d" represents doublet, "t" represents triplet, "q" represents quartet, "m" represents multiplet, "br" represents broad peak, "Hz" indicates Hertz, and "α", "β", "R", "S", "E" and "Z" are stereochemical names familiar to those skilled in the art.

[0252] The compounds of the present invention can be prepared as shown in the reaction schemes below and their descriptions, as well as in relevant published procedures that may be used by those skilled in the art. Exemplary reagents and procedures for these reactions are described below and in the working examples.

[0253] abbreviation

[0254] The following abbreviations are used in this article:

[0255] Bn = benzyl

[0256] t-Bu = tert-butyl

[0257] Boc = tert-butyloxycarbonyl

[0258] Boc2O = ditert-butyl dicarbonate

[0259] Cs₂CO₃ = Cesium carbonate

[0260] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

[0261] DCM or CH2Cl2 = dichloromethane

[0262] DIAD = Diisopropyl azodicarbonate

[0263] Dys-Martin oxidant or DMP = 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl-3(1H)-one

[0264] DIPEA or i-Pr2NEt = diisopropylethylamine

[0265] DMAP = 4-Dimethylaminopyridine

[0266] DMF = dimethylformamide

[0267] Et = Ethyl

[0268] Et3N = Triethylamine

[0269] EtOH = ethanol

[0270] Et2O = Diethyl ether

[0271] EtOAc = Ethyl acetate

[0272] HOAc or AcOH = Acetic acid

[0273] K2CO3 = Potassium carbonate

[0274] LiCl = Lithium chloride

[0275] LiOAc = Lithium acetate

[0276] LiOH = Lithium hydroxide

[0277] Me = methyl

[0278] MeCN or ACN = Acetonitrile

[0279] MeOH = Methanol

[0280] MgSO4 = Magnesium sulfate

[0281] NaBH4 = Sodium borohydride

[0282] NaOH = Sodium hydroxide

[0283] NaHCO3 = Sodium bicarbonate

[0284] PBu3 = Tributylphosphine

[0285] Ph = phenyl

[0286] Pd / C = Palladium on carbon

[0287] Pd(OAc)₂ = Palladium(II) acetate

[0288] Ph3P = Triphenylphosphine

[0289] PtO2 = Platinum dioxide

[0290] TBAF = Tetra-n-Butylammonium Fluoride

[0291] TBDMS = tert-butyldimethylsilyl

[0292] TMS = Trimethylsilyl

[0293] THF = Tetrahydrofuran

[0294] TFA = Trifluoroacetic acid

[0295] min = minutes

[0296] hr or hrs = hours

[0297] L = Lift

[0298] mL = milliliters

[0299] µL = microliter

[0300] g = grams

[0301] mg = milligram

[0302] mol = mole

[0303] mmol = millimole

[0304] meq = milliequivalence

[0305] sat or sat'd = saturated

[0306] aq. = water-based

[0307] TLC = Thin Layer Chromatography

[0308] HPLC = High Performance Liquid Chromatography

[0309] LC / MS = High Performance Liquid Chromatography / Mass Spectrometry

[0310] MS or Mass Spec = Mass Spectrometry

[0311] NMR = Nuclear Magnetic Resonance

[0312] mp = melting point

[0313] IV. Preparation Method

[0314] Compounds of formula (I) can be prepared by the exemplary methods described in the following schemes and working examples, as well as by procedures published in relevant literature that are used by those skilled in the art. Exemplary reagents and procedures for these reactions are described below and in the working examples. Protection and deprotection in the methods below can be performed by procedures commonly known in the art (see, for example, Wuts, PGM et al., Protecting Groups in Organic Synthesis, 4th edition, Wiley (2007)). General methods for organic synthesis and functional group transformations can be found in: Trost, BM et al. (eds.), Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, MB et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed., Wiley & Sons, New York, NY (2007); Katritzky, AR et al. (eds.), Comprehensive Organic Functional Groups Transformations II, 2nd ed., Elsevier Science Inc., Tarrytown, NY (2004); Larock, RC, Comprehensive Organic Transformations, VCHPublishers, Inc., New York, NY (1999), and the references therein.

[0315] Novel compounds of formula I can be prepared using the reactions and techniques described in this section. Reactions are carried out in solvents suitable for the reagents and materials used and for the achieved transformations. Furthermore, in the description of the synthetic methods below, it should be understood that all proposed reaction conditions (including solvents, reaction atmospheres, reaction temperatures, experimental durations, and post-treatment procedures) have been selected as standard conditions for the reaction, and this should be readily apparent to those skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule must be compatible with the proposed reagents and reactions. Not all compounds of formula I falling into a given category are compatible with some of the reaction conditions required in some of the described methods. Such limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods must be used.

[0316] Option 1

[0317]

[0318] Scheme 1 describes the preparation of formulas Ia and Ib (a subset of formula (I)). Starting material indazole A with leaving groups L in multiple positions is commercially available or can be synthesized using existing techniques according to literature procedures. For a review of indazole synthesis, see: a) Science of Synthesis: Houben-Weyl Methods of Molecular Transformations, Vol. 12, 2002; b) Naděžda Cankařová, Jan Hlaváč and Viktor KrchňákOrg. Prep. and Proc. Int., 2010, 42, 433-465. A suitable protecting group P* (such as Boc-, Ar-SO2-, MeOCH2CH2-, -SEM (2-trimethylsilylethoxymethyl) etc.) can be attached to an indazole nitrogen to provide intermediate B. In Scheme 1, as an example, the P* group is shown at the 1H- position. Those skilled in the art will recognize that during the N-protection step, the P* group can be selectively or non-selectively mounted at N1 or N2 of the 5-membered ring, and this is irrelevant because the protecting group is removed in a later step. The Heck reaction between B and methyl vinyl ketone (MVK) under Pd(OAc)2 catalysis at elevated temperatures provides intermediate C, which can be hydrogenated to intermediate D in the presence of Pd-C. The Friedländer reaction between intermediate D and 2-aminonicotinaldehyde can be catalyzed by pyrrolidine or proline to provide intermediate E-1 as the major product and E-2 as the minor product. Hydrogenation of E-1 and E-2 in the presence of Adams' catalyst (PtO2) can provide the corresponding tetrahydronaphthidines F-1 and F-2, where the protecting group P* can be removed to provide G-1 and G-2. Indazoles have been reported to undergo aza-Michael addition to 2-acrylamides, α,β-unsaturated ketones, or alkyl acrylates (see, for references: a) Han, X. Tetrahedron Lett. 2007, 48, 2845-2849; b) Yang, J. et al. Synthesis 2016, 48, 1139-1146; c) An, Y.-L. et al. Synthesis, 2015, 47, 1581-1592). However, no reports have been documented regarding β-substituted α,β-unsaturated esters. Here we report that fully purified indazole intermediates such as G-1 and G-2 can undergo aza-Michael addition with various Michael addition acceptors such as intermediate H (where R...). 3 and R 3a It can be H, aryl, or alkyl, R 4The reaction can be alkyl or N(Boc)2. Typical reaction conditions for such aza-Michael additions are mediated by bases (such as DBU, K2CO3, Cs2CO3, etc.) or Lewis acids (such as BF3 ethers). After ester hydrolysis, formulas Ia and Ib can be obtained after preparative HPLC purification or reversed-phase chromatography purification.

[0319] Option 2

[0320]

[0321] Scheme 2 details the preparation of formulas Ic and Id (a subset of formula I). ​​Under Heck reaction conditions, intermediate B can react with a suitable terminal alkene or alkyne to form intermediates I-1 and I-2. Following hydrogenation, the secondary alcohol J can be oxidized to the methyl ketone K. By following the reaction sequence in Scheme 1, the conversion of K to formulas Ic and Id can be achieved.

[0322] Option 3

[0323]

[0324] Scheme 3 describes the preparation of formula Ie (a subset of formula I). ​​The indazole L with the starting hydroxyl group is commercially available or can be synthesized via indazole following a literature procedure. L can be converted to M via protecting group manipulation (to install a suitable protecting group such as Boc- or ArSO2-). 3,4-Dihydro-1,8-naphthidium N is commercially available or can be synthesized by following a literature procedure. The Mitsunobu reaction between M and N provides O, which can be further converted to P via the cleavage of the protecting group. The key intermediate P can then be converted to formula Ie via the reaction sequence described in Scheme 1.

[0325] Option 4

[0326]

[0327] Scheme 4 describes an alternative route for the synthesis of intermediate O. The reaction between B and N can be catalyzed at elevated temperatures using Pd, Cu, or Ni catalysts and suitable ligands. For a review of O-arylation, see: Muci, AR; Buchwald, SL Topics in Current Chemistry 2002, 219 (Cross-coupling reactions), 131-209.

[0328] Option 5

[0329]

[0330] Scheme 5 describes the preparation of formula If (a subset of formula I). ​​The substitution reaction of M with intermediate N-1 to provide Q can be carried out in a suitable solvent in the presence of a base such as K₂CO₃ or Cs₂CO₃ at room temperature or elevated temperatures. After selective deprotection of P*, intermediate R can undergo an aza-Michael reaction with various acceptors (see Scheme 1) to form S. This can be carried out under acidic conditions (e.g., TFA or in a dihydropyridine system). The Boc- protecting group of S is removed by HCl in an alkane to provide T, which reacts with various monocyclic or bicyclic aromatic or partially aromatic ring systems with leaving groups L to form intermediate U. Ester hydrolysis under aqueous alkaline conditions yields If.

[0331] Option 6

[0332]

[0333] Scheme 6 describes the preparation of formula Ig (a subset of formula I). ​​The key intermediate G-3 can be intermediate G-1 (from Scheme 1) or any similar intermediate from Schemes 2 through 4. The aziridine ring-opening reaction between G-3 and V can be selectively carried out at elevated temperatures in the presence of a Lewis acid such as TFA to provide 2H-indazole W as the major product. W can then be converted into intermediate X (R... 100 = H), which can be further transformed into having other R. 100 The X of the group (such as R) 100 =R 101 SO2-, R 101 C(O)- etc.; where R 101 It may optionally be a substituted alkyl, aryl, or arylalkyl group. Hydrolysis in the presence of a base yields formula Ig.

[0334] Option 7

[0335]

[0336] Scheme 7 describes the preparation of formula Ij (a subset of formula I). ​​The 2-nitrobenzaldehyde analog AA is commercially available or can be synthesized using a literature procedure. The intermediate AB (chiral or racemic) is available from a commercial source or synthesized by following a literature procedure. AA can react with AB under thermal conditions to form an imine, which can be reduced in one pot by Bu3P to provide the cyclically closed product 2H-indazole AC. AC can be converted to formula Ij following a similar sequence as described in Scheme 1.

[0337] Option 8

[0338]

[0339] Scheme 8 describes the preparation of formula Ik (a subset of formula I). ​​Three different methods exist to obtain the intermediate AG. Method 1 is the Mitsunobu reaction between AF and N; Method 2 involves a base-mediated SNA2 substitution reaction between the hydroxyl group of N and the leaving group L in AA; Method 3 is a typical O-arylation, in which the hydroxyl group of N reacts with AA in the presence of a Pd-based catalyst and a suitable ligand. The ring-closing reaction between AB and AG can occur as described in Scheme 7 to provide AH. Formula Ik can be obtained after Boc deprotection and ester hydrolysis.

[0340] Option 9

[0341]

[0342] Scheme 9 describes the preparation of Formula Il (a subset of Formula I). ​​The intermediate AF can react with N-1 under basic conditions to form AI, which can then be cyclized with AB to form AJ, as described in Scheme 7. This can be done under acidic conditions (TFA or in a di-1 mixture). The Boc protecting group is removed by HCl in the alkane to provide AK. The conversion of AK to formula II can occur in a sequence similar to that shown in scheme 5.

[0343] Option 10

[0344]

[0345] Scheme 10 describes the synthesis of intermediate H, which is used in the above-described synthetic scheme. For example, a suitable aldehyde AM can react with a suitable Wittig reagent to form intermediate H (Method 1). Alternatively, AN can react with a suitable alkene under Heck reaction conditions (Method 2) or under Suzuki coupling reaction conditions (Method 3) to provide intermediate H. For methods 2 and 3, R 3 Typically, it is aryl or heteroaryl, rather than alkyl (which is less common). However, when R 3 Or R 3a When the substance is alkyl, aryl, or heteroaryl, method 1 can be used.

[0346] Option 11

[0347]

[0348] Scheme 11 describes the preparation of formulas Im, In, Io, and Ip (a subset of formula I). ​​Intermediate G-1 (from Scheme 5) can be reacted with an alkynyl ester AO (commercially available or synthesized by following a literature procedure) to form a Michael addition adduct AP. Hydrogenation of AP under Pd catalysis (with or without a chiral ligand) yields intermediate AQ in its chiral or racemic form. Ester hydrolysis of AQ provides formula Im. Similarly, intermediates P, R, and G-3 can undergo the above sequence to provide formulas In, Io, and Ip, respectively.

[0349] Option 12

[0350]

[0351] Alternatively, the intermediate AP can be prepared using the N-arylation method detailed in Scheme 12. Thus, the alkynyl ester AO can be converted to AR via treatment with NaI in acetic acid. The reaction between G-1 and AR can be achieved using standard Buckwald N-arylation reaction conditions (see: PNAS, 2004, 101, 5821-5823).

[0352] Option 13

[0353]

[0354] Scheme 13 describes the preparation of formula Ia using an alternative route. Intermediate G-4 (see above scheme for preparation) can undergo an aza-Michael addition with alkyl propynate AO to form an anti-adduct S-1 (mainly) and a cis-adduct S-2. S-1 or S-2, or with R... 3 B(OR 102 The Rh(I)-mediated Hayashi reaction of the mixture of )2 can provide S-3, which can be further converted into formula Ia after ester hydrolysis.

[0355] V. Example

[0356] The following examples are provided as illustrations, representing part of the scope and specific embodiments of the invention, and are not intended to limit the scope of the invention. Unless otherwise specified, abbreviations and chemical symbols have their usual and conventional meanings. Unless otherwise specified, the compounds described herein have been prepared, isolated, and characterized using the schemes and other methods disclosed herein, or may be prepared using them.

[0357] Depending on the circumstances, conduct the reaction under a dry nitrogen (or argon) atmosphere. For anhydrous reactions, use DRISOLV® solvent from EM. For other reactions, use reagent-grade or HPLC-grade solvents. Unless otherwise specified, all commercially available reagents should be used as is.

[0358] HPLC / MS and preparative / analytical HPLC methods used in characterization or purification in the examples

[0359] NMR (nuclear magnetic resonance) spectra are typically obtained in specified solvents on Bruker or JEOL 400 MHz and 500 MHz instruments. Solvent resonance is used as an internal standard to report all chemical shifts from tetramethylsilane in ppm. 1 The 1H NMR spectral data are reported as follows: chemical shifts, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = twin doublet, t = triplet, q = quartet, sep = septet, m = multiplet, app = distinct), coupling constant (Hz), and integral.

[0360] The term HPLC refers to Shimadzu high-performance liquid chromatography instruments that use one of the following methods:

[0361] HPLC-1: Sunfire C18 column (4.6 × 150 mm) 3.5 μm, gradient from 10% to 100% B:A for 12 min, then held at 100% B for 3 min.

[0362] Mobile phase A: 0.05% TFA in water: CH3CN (95:5)

[0363] Mobile phase B: 0.05% TFA in CH3CN: water (9:5:5)

[0364] TFA buffer pH = 2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0365] HPLC-2: XBridge Phenyl (4.6 × 150 mm) 3.5 μm, gradient from 10% to 100% B: A for 12 min, then held at 100% B for 3 min.

[0366] Mobile phase A: 0.05% TFA in water: CH3CN (95:5)

[0367] Mobile phase B: 0.05% TFA in CH3CN: water (95:5)

[0368] TFA buffer pH = 2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0369] HPLC-3: Chiralpak AD-H, 4.6 × 250 mm, 5 μm.

[0370] Mobile phase: 30% EtOH-heptane (1:1) / 70% CO2

[0371] Flow rate = 40 mL / min, 100 bar, 35ºC; Wavelength: 220 nm

[0372] HPLC-4: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm particles;

[0373] Mobile phase A: 5:95 CH3CN: water containing 10 mM NH4OAc;

[0374] Mobile phase B: 95:5 CH3CN: water containing 10 mM NH4OAc;

[0375] Temperature: 50ºC; Gradient: 3 min 0-100% B, then 0.75 min 100% B; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0376] HPLC-5: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm particles;

[0377] Mobile phase A: 5:95 CH3CN: water containing 0.1% TFA;

[0378] Mobile phase B: 95:5 CH3CN: water containing 0.1% TFA;

[0379] Temperature: 50ºC; Gradient: 3 min 0-100% B, then 0.75 min 100% B; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0380]

[0381] Intermediate 1A can be synthesized using three different methods: the Heck reaction, the Wittig reaction, or the Suzuki coupling reaction. The following procedures serve as examples of all acrylates synthesized and used in this application.

[0382] Method 1. 15 g of molecular sieve 4Å was added to a solution of 6-methoxynicotinaldehyde (3 g, 21.88 mmol) in THF (45 mL), followed by the addition of ethyl 2-(diethoxyphosphoryl)ethyl acetate (5.25 mL, 26.3 mmol) and LiOH (0.629 g, 26.3 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth pad, and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with 10% NaHCO3 (aqueous, 12 mL), followed by washing with brine (12 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (220 g silica gel, 0 to 20% hexane / ethyl acetate) to provide intermediate 1A (4.5 g, 21.72 mmol, 99% yield) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ 8.28 (d, J = 2.5 Hz, 1H), 7.77 (dd, J =8.8, 2.5 Hz, 1H), 7.64 (d, J = 16.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.34(d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.34 (t, J =7.2 Hz, 3H). LCMS (ES): m / z 208.1 [M+H] + .

[0383] Method 2. A solution of 5-bromo-2-methoxypyridine (1.03 mL, 7.98 mmol), ethyl acrylate (3.0 mL, 27.9 mmol), Et3N (3.0 mL, 21.54 mmol), Pd(OAc)2 (0.202 g, 0.899 mmol), and tri-o-tolylphosphine (0.404 g, 1.327 mmol) in ACN (2.0 mL) was degassed with argon for 10 min. The mixture was heated at 90ºC for 12 h. The solvent was removed under reduced pressure. Toluene (1.5 mL) was added, and the mixture was concentrated again under reduced pressure. Ether (10 mL) was added, and the mixture was filtered through a silica gel pad and eluted with ether. The solvent was removed, and the residue was purified by rapid chromatography (80 g silica gel, 0 to 100% hexane / ethyl acetate) to provide intermediate 1A (1.59 g, 7.67 mmol, 96% yield) as a yellow solid.

[0384] Method 3. 5-Bromo-2-methoxypyridine (2 g, 10.64 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)acrylate (2.405 g, 10.64 mmol) and K₂CO₃ (4.41 g, 31.9 mmol) were reacted in a 1,4-dioxane-2-dioxane-2-yl acrylate solution. Pd(PPh3)4 (0.492 g, 0.425 mmol) was added to a degassed solution of alkane (30 mL) and water (10 mL). The reaction mixture was stirred overnight at 100ºC in a sealed vial. After cooling to room temperature, the mixture was diluted with water (15 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic matter was dried (Na2SO4), filtered, and concentrated. The residue was purified by rapid chromatography (80 g silica gel, 0 to 100% hexane / ethyl acetate) to provide intermediate 1A (662 mg, 3.19 mmol, 30% yield) as a yellow solid.

[0385] The following intermediates can be synthesized using one of the methods described above or procedures known to those skilled in the art in the literature.

[0386]

[0387] Intermediate 1B: 1 ¹H NMR (400 MHz, chloroform-d) δ 7.70 (dt, J = 16.0, 0.5 Hz, 1H), 7.62 – 7.54 (m, 2H), 7.50 – 7.38 (m, 2H), 6.48 (d, J = 16.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.15 (s, 3H), 3.01 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS(ES): m / z 248.2 [M+H] + .

[0388]

[0389] Intermediate 1C: 1H NMR (500 MHz, chloroform-d) δ 8.94 (s, 1H), 8.08 – 7.99 (m,2H), 7.83 (d, J = 15.9 Hz, 1H), 7.73 (td, J = 6.3, 5.8, 3.3 Hz, 2H), 7.08 (d,J = 15.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). LCMS(ES): m / z 229.1 [M+H] + .

[0390]

[0391] Intermediate 1D: 1 ¹H NMR (400 MHz, chloroform-d) δ 7.64 – 7.51 (d, J = 16.0 Hz, 1H), 7.43 – 7.33 (m, 3H), 6.46 (d, J = 16.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 245.1 [M+H] + .

[0392]

[0393] Intermediate 1E: 1 ¹H NMR (500 MHz, chloroform-d) δ 8.10 (d, J = 1.7 Hz, 1H), 7.89–7.80 (m, 2H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.88 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 248.0 [M+H] + .

[0394]

[0395] Intermediate 1F: 1H NMR (400 MHz, chloroform-d) δ 8.61 (dd, J = 19.0, 2.0 Hz, 2H), 7.84 (t, J = 2.1 Hz, 1H), 7.64 (d, J = 16.1 Hz, 1H), 6.54 (d, J = 16.1 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 211.9[M+H] + .

[0396]

[0397] Intermediate 1G: 1 H NMR (400 MHz, chloroform-d) δ 7.66 (d, J = 16.0 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.6, 1.8 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 16.0 Hz, 1H), 4.65 (t, J = 8.7 Hz, 2H), 4.28 (q, J = 7.1Hz, 2H), 3.25 (t, J = 8.7 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z219.1 [M+H] + .

[0398]

[0399] Intermediate 1H: 1H NMR (500 MHz, chloroform-d) δ 7.68 (d, J = 16.1 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.08 (dt, J = 7.6, 1.1 Hz, 1H), 7.06 (t, J = 2.1 Hz, 1H), 6.97 (dd, J = 8.1, 2.5 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.29 (q, J =7.1 Hz, 2H), 3.93 – 3.82 (m, 4H), 3.25 – 3.13 (m, 4H), 1.36 (t, J = 7.1 Hz,3H). LCMS (ES): m / z 262.0 [M+H] + .

[0400]

[0401] Intermediate 1I: 1 H NMR (500 MHz, chloroform-d) δ 7.73 (d, J = 16.0 Hz, 1H), 7.56 (t, J = 1.8 Hz, 1H), 7.51 – 7.39 (m, 3H), 7.13 (t, J = 2.2 Hz, 2H), 6.51 (d,J = 16.0 Hz, 1H), 6.40 (t, J = 2.1 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 242.1 [M+H] + .

[0402]

[0403] Intermediate 1J: 1H NMR (500 MHz, chloroform-d) δ 7.82 (t, J = 2.0 Hz, 1H), 7.74 –7.66 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.34 (dt, J = 7.7, 1.3 Hz, 1H), 6.48(d, J = 16.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.91 (t, J = 7.1 Hz, 2H), 2.66 (t, J = 8.1 Hz, 2H), 2.28 – 2.14 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H). LCMS(ES): m / z 260.1 [M+H] + .

[0404]

[0405] Intermediate 1K: 1 H NMR (500 MHz, chloroform-d) δ 7.72 (s, 1H), 7.62 – 7.54 (m,2H), 6.18 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.10 (t, J = 7.0Hz, 2H), 1.92 (h, J = 7.3 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4Hz, 3H). LCMS (ES): m / z 209.2 [M+H] + .

[0406]

[0407] Intermediate 1L: 1 H NMR (500 MHz, chloroform-d) δ 7.61 (dd, J = 9.6, 2.5 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 15.9 Hz, 1H), 6.64 (d, J = 9.5 Hz, 1H), 6.17 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.60 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 208.1 [M+H] + .

[0408]

[0409] Intermediate 1M: 1 H NMR (500 MHz, chloroform-d) δ 7.44 (d, J = 15.9 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 15.9 Hz, 1H), 6.31 (dd, J = 7.1, 2.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.57 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 208.1 [M+H] + .

[0410]

[0411] Intermediate 1N: 1 H NMR (500 MHz, chloroform-d) δ 7.72 (d, J = 16.0 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.54 – 7.44 (m, 3H), 6.50 (d, J = 16.0 Hz, 1H), 6.04 (s,1H), 4.29 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 1.36 (t, J = 7.1Hz, 3H). LCMS (ES): m / z 271.1 [M+H] + .

[0412]

[0413] Intermediate 1O: 1 ¹H NMR (500 MHz, chloroform-d) δ 8.71 – 8.65 (m, 2H), 7.62 (d, J = 16.0 Hz, 1H), 7.41 – 7.35 (m, 2H), 6.62 (d, J = 16.0 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 178.2 [M+H] + .

[0414]

[0415] Intermediate 1P: 1 H NMR (500 MHz, chloroform-d) δ 8.68 (s, 2H), 7.59 (d, J = 16.1Hz, 1H), 6.46 (d, J = 16.2 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.30 (q, J =7.1 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 223.2 [M+H] + .

[0416]

[0417] Intermediate 1Q: 1 H NMR (500 MHz, chloroform-d) δ 8.90 (s, 2H), 8.63 (d, J = 2.6Hz, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 16.2 Hz, 1H), 6.60 (d, J =16.1 Hz, 1H), 6.56 (dd, J = 2.7, 1.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 245.1 [M+H] + .

[0418]

[0419] Intermediate 1R: 1 H NMR (500 MHz, chloroform-d) δ 8.26 (d, J = 1.3 Hz, 1H), 8.18 (d, J = 1.3 Hz, 1H), 7.67 (d, J = 15.7 Hz, 1H), 6.86 (d, J = 15.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 209.1 [M+H] + .

[0420]

[0421] Intermediate 1S: 1 H NMR (500 MHz, chloroform-d) δ 8.90 (d, J = 1.9 Hz, 1H), 8.88(d, J = 1.8 Hz, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.99(dd, J = 8.7, 2.0 Hz, 1H), 7.91 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 16.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 229.2[M+H] + .

[0422]

[0423] Intermediate 1T: 1 H NMR (500 MHz, chloroform-d) δ 7.53 (dd, J = 2.6, 1.3 Hz, 1H),7.47 – 7.37 (m, 2H), 6.19 (d, J = 15.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.07 (s, 2H), 3.59 (s, 1H), 2.22 (d, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.30 (s, 6H). LCMS (ES): m / z 280.2 [M+H] + .

[0424]

[0425] Intermediate 1U: 1H NMR (500 MHz, chloroform-d) δ 8.07 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 16.0, 1.6 Hz, 1H), 7.53 (dd, J = 10.8, 2.1 Hz, 1H), 6.34 (d, J =16.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.09 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 226.2 [M+H] + .

[0426]

[0427] Intermediate 1V: 1 H NMR (500 MHz, chloroform-d) δ 7.49 (d, J = 15.5 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 4.33 – 4.20 (m, 5H), 3.59 (td, J = 4.5, 2.3 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 235.2 [M+H] + .

[0428]

[0429] Intermediate 1W: 1 H NMR (500 MHz, chloroform-d) δ 9.28 (s, 1H), 8.60 (d, J = 5.7Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.86 (d, J =16.1 Hz, 1H), 7.81 (dd, J = 8.6, 1.7 Hz, 1H), 7.69 (d, J = 5.6 Hz, 1H), 6.64(d, J = 16.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). LCMS(ES): m / z 228.1 [M+H] + .

[0430]

[0431] Intermediate 1X: 1 ¹H NMR (500 MHz, chloroform-d) δ 8.69 (s, 2H), 7.60 (d, J = 16.2 Hz, 1H), 6.47 (d, J = 16.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 209.2 [M+H] + .

[0432]

[0433] Intermediate 1Y: 1 H NMR (500 MHz, chloroform-d) δ 7.86 (d, J = 16.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 16.2 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.21 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 209.3 [M+H] + .

[0434]

[0435] Intermediate 1Z: 1 H NMR (500 MHz, chloroform-d) δ 9.19 (dd, J = 4.2, 2.1 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.22 (dd, J = 8.1, 2.0 Hz, 1H), 7.93 (d, J = 15.8Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 8.1, 4.2 Hz, 1H), 7.22 (d, J = 15.9 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 229.2 [M+H] + .

[0436]

[0437] Intermediate 1AA: 1 H NMR (500 MHz, chloroform-d) δ 8.60 – 8.56 (m, 1H), 8.39 (d, J= 5.2 Hz, 1H), 7.65 (d, J = 16.1 Hz, 1H), 7.14 (dd, J = 5.3, 1.5 Hz, 1H), 6.64 (d, J = 16.1 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.18 – 4.08 (m, 2H), 2.71 (t, J = 8.1 Hz, 2H), 2.23 – 2.10 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H). LCMS(ES): m / z 261.2 [M+H] + .

[0438]

[0439] Intermediate 1AB: 1 H NMR (500 MHz, chloroform-d) δ 9.38 (d, J = 2.4 Hz, 1H), 9.10(d, J = 1.7 Hz, 1H), 9.01 (d, J = 1.7 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 7.92(d, J = 16.2 Hz, 1H), 6.80 (d, J = 16.1 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 230.2 [M+H] + .

[0440]

[0441] Intermediate 1AC: 1H NMR (500 MHz, chloroform-d) δ 7.82 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 16.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 5.34 (s, 1H), 4.31 – 4.20 (m, 4H), 3.63 (td, J = 4.6, 2.2 Hz, 2H), 1.35 (t, J= 7.1 Hz, 3H). LCMS (ES): m / z 235.2 [M+H] + .

[0442]

[0443] Intermediate 1AD: 1 H NMR (500 MHz, chloroform-d) δ 8.75 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 7.82 (d, J = 16.0 Hz, 1H), 6.53 (d, J =16.0 Hz, 1H), 6.14 (dd, J = 10.5, 2.6 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.18– 4.10 (m, 1H), 3.85 (tt, J = 11.5, 2.5 Hz, 1H), 2.25 – 2.11 (m, 1H), 2.05 –1.97 (m, 1H), 1.89 – 1.75 (m, 2H), 1.73 – 1.61 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 302.1 [M+H] + .

[0444]

[0445] Intermediate 1AE: 1H NMR (500 MHz, chloroform-d) δ 8.72 (d, J = 2.5 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.48 (t, J = 2.3 Hz, 1H), 7.71 (d, J = 16.2 Hz, 1H), 6.57 (d, J = 16.1 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.95 (t, J = 7.1 Hz,2H), 2.68 (t, J = 8.1 Hz, 2H), 2.32 – 2.21 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 261.2 [M+H] + .

[0446]

[0447] Intermediate 1AF: 1 H NMR (500 MHz, chloroform-d) δ 7.98 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 16.0 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 4.53 – 4.47 (m, 2H), 4.34 – 4.23 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 236.0 [M+H] + .

[0448]

[0449] Intermediate 1AG: 1 H NMR (500 MHz, chloroform-d) δ 9.13 (d, J = 1.7 Hz, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 7.99 – 7.90 (m, 2H), 7.23 (d,J = 15.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). LCMS(ES): m / z 230.2 [M+H] + .

[0450]

[0451] Intermediate 1AH: 1 H NMR (500 MHz, chloroform-d) δ 9.07 (s, 1H), 8.16 (d, J = 8.5Hz, 1H), 8.13 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 16.0 Hz, 1H), 7.74 (dd, J =8.5, 1.8 Hz, 1H), 6.55 (d, J = 16.1 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.38 (td, J = 7.2, 1.4 Hz, 3H). LCMS (ES): m / z 234.1 [M+H] + .

[0452]

[0453] Intermediate 1AI: 1 H NMR (500 MHz, chloroform-d) δ 8.49 (s, 2H), 7.52 (d, J = 16.2Hz, 1H), 6.33 (d, J = 16.1 Hz, 1H), 5.40 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.08 (d, J = 5.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 208.3 [M+H] + .

[0454]

[0455] Intermediate 1AJ: 1 H NMR (500 MHz, chloroform-d) δ 8.50 (s, 2H), 7.52 (d, J = 16.0Hz, 1H), 6.33 (d, J = 16.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.90 (dd, J =5.7, 4.0 Hz, 4H), 3.79 (dd, J = 5.7, 4.1 Hz, 4H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 264.2 [M+H] + .

[0456]

[0457] Intermediate 1AK: 1 ¹H NMR (500 MHz, chloroform-d) δ 8.98 (s, 2H), 7.64 (d, J = 16.2 Hz, 1H), 6.70 (d, J = 16.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 204.4 [M+H] + .

[0458]

[0459] Intermediate 1AL: 1 H NMR (500 MHz, chloroform-d) δ 8.75 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.07 (s, 1H), 7.84 (d, J = 16.1 Hz, 1H), 6.54 (d, J =16.1 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.20 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 232.4 [M+H] + .

[0460]

[0461] Intermediate 1AM: 1 H NMR (500 MHz, chloroform-d) δ 8.93 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.79 (d, J = 16.0 Hz, 1H), 6.55 (d, J =16.0 Hz, 1H), 4.35 – 4.30 (m, 2H), 4.30 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 232.4 [M+H] + .

[0462]

[0463] Intermediate 1AN: 1H NMR (500 MHz, chloroform-d) δ 8.48 (s, 2H), 7.51 (d, J = 16.0Hz, 1H), 6.31 (d, J = 16.0 Hz, 1H), 4.27 (dt, J = 15.1, 7.3 Hz, 6H), 2.45 (p,J = 7.6 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 234.4 [M+H] + .

[0464]

[0465] Intermediate 1AO: 1 H NMR (500 MHz, chloroform-d) δ 8.81 (d, J = 1.9 Hz, 1H), 8.41 (s, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 16.2 Hz, 1H), 6.59 (d, J =16.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 219.2 [M+H] + .

[0466]

[0467] Intermediate 1AP: 1 H NMR (500 MHz, chloroform-d) δ 8.32 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H), 7.27 (t, J = 2.3 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.98 – 3.84 (m, 4H), 3.28 – 3.20 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 263.2 [M+H] + .

[0468]

[0469] Intermediate 1AR: 1H NMR (500 MHz, chloroform-d) δ 8.67 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 7.78 (t, J = 2.2 Hz, 1H), 7.69 (d, J = 16.1 Hz, 1H), 6.53 (d, J = 16.0 Hz, 1H), 4.96 (s, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.31 (q, J= 7.1 Hz, 2H), 1.49 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 307.1 [M+H] + .

[0470]

[0471] Intermediate 1AS: 1 H NMR (500 MHz, chloroform-d) δ 8.87 (s, 1H), 8.26 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.63 (d, J = 15.9 Hz, 1H), 7.52 (dd, J = 9.6, 1.6Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.38 (t, J =7.1 Hz, 3H). LCMS (ES): m / z 218.4 [M+H] + .

[0472]

[0473] Intermediate 1AT: LCMS (ES): m / z 219.2 [M+H] + .

[0474]

[0475] Intermediate 1AU: 1H NMR (500 MHz, chloroform-d) δ 8.94 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.09 (t, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J =16.2 Hz, 1H), 7.54 (s, 1H), 6.62 (d, J = 16.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 245.4 [M+H] + .

[0476]

[0477] Intermediate 1AV: 1 H NMR (500 MHz, MeOH-d4) δ 8.74 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 16.1 Hz, 1H), 6.68 (d, J = 16.4 Hz, 1H), 5.87 (s, 1H), 4.31 – 4.22 (m, 2H), 4.19 – 4.00 (m,4H), 1.34 (t, J = 7.2 Hz, 3H). LCMS (ES): m / z 250.2 [M+H] + .

[0478]

[0479] Intermediate 1AW: 1H NMR (400 MHz, chloroform-d) δ 8.64 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.67 (d, J = 16.1 Hz, 1H), 7.54 –7.45 (m, 6H), 7.36 – 7.30 (m, 6H), 7.28 (t, J = 1.4 Hz, 1H), 7.26 (m, 2H), 6.49 (d, J = 16.2 Hz, 1H), 4.29 (m, 4H), 1.35 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 450.4 [M+H] + .

[0480]

[0481] Intermediate 1AX: 1 H NMR (500 MHz, chloroform-d) δ 8.86 (s, 1H), 8.15 (d, J = 7.2Hz, 1H), 7.89 (s, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.07 (dd, J = 7.2, 1.4 Hz,1H), 6.54 (d, J = 16.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1Hz, 3H). LCMS (ES): m / z 218.4 [M+H] + .

[0482]

[0483] Intermediate 1AY: 1 H NMR (400 MHz, MeOH-d4) δ 7.76 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 6.16 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 222.2 [M+H] + .

[0484]

[0485] Intermediate 1AZ: 1 H NMR (500 MHz, chloroform-d) δ 8.57 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.07 (s, 1H), 7.84 (d, J = 16.0 Hz, 1H), 6.53 (d, J =16.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). LCMS (ES): m / z 232.2 [M+H] + .

[0486]

[0487] Intermediate 1BA: 1 H NMR (500 MHz, chloroform-d) δ 8.06 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 16.0 Hz, 1H), 6.88 (t, J = 2.3 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.37 – 3.26 (m, 4H), 2.09 – 2.00 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 247.2 [M+H] + .

[0488]

[0489] Intermediate 1BB: 1H NMR (500 MHz, chloroform-d) δ 9.12 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 2.1 Hz, 1H), 8.34 (t, J = 2.2 Hz, 1H), 7.71 (d, J = 16.1 Hz, 1H), 6.63 (d, J = 16.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.14 (s, 3H), 1.36 (t, J= 7.1 Hz, 3H). LCMS (ES): m / z 256.1 [M+H] + .

[0490]

[0491] Intermediate 1BC: 1 H NMR (500 MHz, chloroform-d) δ 8.75 (d, J = 2.2 Hz, 1H), 8.13(s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 16.0 Hz, 1H), 6.55 (d, J =16.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 232.2 [M+H] + .

[0492]

[0493] Intermediate 1BD: 1H NMR (400 MHz, chloroform-d) δ 8.65 (dd, J = 2.6, 0.7 Hz, 1H), 7.99 (dd, J = 8.3, 0.9 Hz, 1H), 7.83 (dd, J = 8.3, 7.5 Hz, 1H), 7.75 (dd, J =1.7, 0.8 Hz, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.28 (dd, J = 7.6, 0.9 Hz, 1H), 7.01 (d, J = 15.6 Hz, 1H), 6.48 (dd, J = 2.6, 1.7 Hz, 1H), 4.30 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 244.1 [M+H] + .

[0494]

[0495] Intermediate 1BE: 1 H NMR (400 MHz, chloroform-d) δ 8.74 – 8.67 (m, 2H), 8.17 (s,1H), 7.97 (s, 1H), 7.65 – 7.62 (m, 2H), 7.59 (d, J = 16.0 Hz, 1H), 6.32 (d, J= 16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 244.1 [M+H] + .

[0496]

[0497] Intermediate 1BF: LCMS (ES): m / z 232.1 [M+H] + .

[0498]

[0499] Intermediate 1BG: 1H NMR (500 MHz, chloroform-d) δ 8.79 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 1.0 Hz, 1H), 7.91 – 7.81 (m, 2H), 6.66 (d, J = 16.2 Hz, 1H), 4.33 (q,J = 7.1 Hz, 2H), 4.15 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 232.1[M+H] + .

[0500]

[0501] Intermediate 1BH: 1 H NMR (500 MHz, chloroform-d) δ 8.79 (d, J = 1.9 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 16.0 Hz, 1H), 6.62 (d, J =16.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.31 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 232.1 [M+H] + .

[0502]

[0503] Intermediate 1BI: 1 ¹H NMR (500 MHz, chloroform-d) δ 8.80 - 8.74 (m, 1H), 8.19 - 8.14 (m, 1H), 7.93 - 7.82 (m, 2H), 6.61 - 6.52 (m, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.93 (s, 3H), 1.38 (t, J=7.0 Hz, 3H). LCMS (ES): m / z 232.2 [M+H] + .

[0504]

[0505] Intermediate 1BJ: LCMS (ES): m / z 328.1 [M+H] + .

[0506]

[0507] Intermediate 1BK: 1 H NMR (500 MHz, chloroform-d) δ 8.16 - 8.11 (m, 1H), 8.00 - 7.92(m, 1H), 7.60 - 7.50 (m, 1H), 7.00 - 6.87 (m, 1H), 4.28 (q, J=7.3 Hz, 2H), 3.89 - 3.80 (m, 4H), 3.70 - 3.59 (m, 4H), 1.35 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 264.1 [M+H] + .

[0508]

[0509] Intermediate 1BL: 1 H NMR (400 MHz, chloroform-d) δ 8.72 (d, J = 2.1 Hz, 1H), 8.58(d, J = 2.0 Hz, 1H), 7.86 (t, J = 2.2 Hz, 1H), 7.81 (d, J = 0.9 Hz, 1H), 7.69(m, 1H), 7.69 (d, J = 16.2 Hz, 1H), 6.55 (d, J = 16.1 Hz, 1H), 4.29 (q, J =7.1 Hz, 2H), 3.98 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ES): m / z 258.1 [M+H] + .

[0510]

[0511] Intermediate 1BM: 1 H NMR (400 MHz, chloroform-d) δ 8.73 - 8.66 (m, 1H), 8.62 - 8.55(m, 1H), 8.05 - 7.98 (m, 1H), 7.67 (d, J=16.1 Hz, 1H), 6.60 - 6.45 (m, 1H), 4.33 - 4.20 (m, 2H), 1.63 (s, 6H), 1.34 (t, J=7.2 Hz, 3H). LCMS (ES): m / z236.1 [M+H] + .

[0512]

[0513] Intermediate 1BN: 1 ¹H NMR (400 MHz, chloroform-d) δ 8.25–8.17 (m, 2H), 7.67–7.60 (m, 1H), 7.04 (d, J=15.4 Hz, 1H), 4.37–4.27 (m, 2H), 4.07–3.98 (m, 3H), 1.38 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 209.0 [M+H] + .

[0514]

[0515] Intermediate 1BO: 1 H NMR (500 MHz, chloroform-d) δ 8.86 - 8.74 (m, 1H), 8.70 - 8.58(m, 1H), 7.96 - 7.84 (m, 1H), 7.75 - 7.62 (m, 1H), 6.62 - 6.49 (m, 1H), 4.36- 4.24 (m, 2H), 3.97 - 3.40 (m, 8H), 1.42 - 1.31 (m, 3H). LCMS (ES): m / z 291.1[M+H] + .

[0516]

[0517] Intermediate 1BP: 1 H NMR (500 MHz, chloroform-d) δ 8.79 (d, J=1.9 Hz, 1H), 8.67 (d,J=1.9 Hz, 1H), 7.93 (t, J=1.9 Hz, 1H), 7.69 (d, J=16.2 Hz, 1H), 6.56 (d, J=16.2 Hz, 1H), 4.35 - 4.25 (m, 2H), 3.25 - 3.10 (m, 3H), 3.10 - 3.00 (m, 3H), 2.99 - 2.87 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 249.1 [M+H] + .

[0518]

[0519] Intermediate 1BQ: 1 H NMR (500 MHz, chloroform-d) δ 8.84 - 8.76 (m, 1H), 8.68 - 8.62(m, 1H), 7.91 (t, J=2.1 Hz, 1H), 7.75 - 7.65 (m, 1H), 6.61 - 6.51 (m, 1H), 4.35 - 4.27 (m, 2H), 3.95 - 3.78 (m, 2H), 3.55 - 3.38 (m, 2H), 2.61 - 2.38 (m, 4H), 2.36 (s, 3H), 1.37 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 304.1 [M+H] + .

[0520]

[0521] Intermediate 1BR: 1 H NMR (500 MHz, chloroform-d) δ 8.59 - 8.47 (m, 1H), 8.47 - 8.37(m, 1H), 7.70 - 7.61 (m, 1H), 7.49 - 7.42 (m, 1H), 6.57 - 6.43 (m, 1H), 4.30(q, J=7.2 Hz, 2H), 2.01 - 1.89 (m, 1H), 1.42 - 1.32 (m, 3H), 1.13 - 1.07 (m,2H), 0.81 - 0.75 (m, 2H). LCMS (ES): m / z 218.2 [M+H] + .

[0522]

[0523] Intermediate 1BS: 1H NMR (500 MHz, chloroform-d) δ 8.39 - 8.30 (m, 1H), 8.30 - 8.21(m, 1H), 7.72 - 7.61 (m, 1H), 7.35 - 7.24 (m, 1H), 6.49 (d, J=16.0 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.35 - 3.23 (m, 4H), 2.70 - 2.55 (m, 4H), 2.39 (s, 3H), 1.36 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 276.1 [M+H] + .

[0524]

[0525] Intermediate 1BT: 1 H NMR (500 MHz, chloroform-d) δ 8.88 - 8.74 (m, 2H), 8.23 ​​- 8.10(m, 1H), 7.77 - 7.61 (m, 1H), 6.73 - 6.49 (m, 1H), 4.50 - 4.21 (m, 6H), 2.41 (quin, J=7.8 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 261.1 [M+H] + .

[0526]

[0527] Intermediate 1BUP: 1 H NMR (500 MHz, chloroform-d) δ 9.04 - 8.95 (m, 1H), 8.90 -8.82 (m, 1H), 8.36 - 8.25 (m, 1H), 7.78 - 7.67 (m, 1H), 7.09 - 6.97 (m, 1H),6.69 - 6.54 (m, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.57 (q, J=5.4 Hz, 2H), 2.58 (t,J=5.9 Hz, 2H), 2.37 - 2.29 (m, 6H), 1.38 (t, J=7.0 Hz, 3H). LCMS (ES): m / z292.1 [M+H] + .

[0528]

[0529] Intermediate 1BV: 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 7.63 (d, J = 16.1Hz, 1H), 6.87 (d, J = 16.3 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). LCMS (ES): m / z 193.1 [M+H] + .

[0530]

[0531] Intermediate 1BW: 1 H NMR (500 MHz, chloroform-d) δ 9.40 - 9.31 (m, 1H), 9.24 - 9.15(m, 1H), 8.32 - 8.28 (m, 1H), 8.28 - 8.23 ​​(m, 1H), 7.88 (d, J=16.2 Hz, 1H), 7.57 (dd, J=8.1, 4.3 Hz, 1H), 6.73 (d, J=16.0 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 229.2 [M+H] + .

[0532]

[0533] Intermediate 1BX: LCMS (ES): m / z 244.0 [M+H] + .

[0534]

[0535] Intermediate 1BY: LCMS (ES): m / z 262.1 [M+H] + .

[0536]

[0537] Intermediate 1BZ: LCMS (ES): m / z 249.1 [M+H] + .

[0538]

[0539] Intermediate 1CA: 1 ¹H NMR (500 MHz, chloroform-d) δ 6.96 - 6.72 (m, 1H), 5.84 - 5.71 (m, 1H), 4.19 - 3.99 (m, 2H), 2.24 - 2.05 (m, 1H), 1.82 - 1.54 (m, 5H), 1.35 - 1.00 (m, 8H).

[0540]

[0541] Intermediate 1CB: 1 H NMR (500 MHz, chloroform-d) δ 9.18 - 9.12 (m, 1H), 9.04 - 8.97(m, 1H), 8.41 - 8.33 (m, 1H), 7.79 - 7.69 (m, 1H), 6.71 - 6.61 (m, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.17 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LCMS (ES): m / z 256.1[M+H] + .

[0542]

[0543] Intermediate 1CC: 1 ¹H NMR (500 MHz, chloroform-d) δ 8.77 (s, 2H), 7.55 - 7.44 (m, 1H), 6.57 - 6.39 (m, 1H), 2.85 - 2.72 (m, 3H), 1.61 - 1.47 (m, 9H)).

[0544] Intermediate 2A. Ethyl (S)-3-amino-3-(3-fluoro-4-methoxyphenyl)propionate

[0545]

[0546] Intermediate 2A was prepared according to the procedure described in the following literature: Hutchinson, JH et al., J. Med. Chem. 2003, 46, 4790. 1H NMR (500MHz, chloroform-d) δ 8.16 (d, J =2.2 Hz, 1H), 7.67 (dd, J =8.5, 2.5 Hz, 1H), 6.76 (d, J =8.5 Hz, 1H), 4.47 (dd, J =8.8, 5.0Hz, 1H), 4.00 - 3.92 (m, 3H), 2.92 - 2.64 (m, 2H). LCMS (ES): m / z 225.0 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 2.5 Hz, 1H), 7.77 (dd, J = 8.8, 2.5Hz, 1H), 7.64 (d, J = 16.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.34 (d, J =16.0 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0547] Intermediate 2B.(S)-3-amino-3-(2-methoxypyrimidin-5-yl)propionate ethyl ester

[0548]

[0549] NH3 gas was bubbled into cooled t-BuOH (300 mL) for 1 hr. It was then added together with (E)-ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (20 g, 96 mmol) to a 1 L autoclave. The mixture was heated at 80ºC for 30 hr. The mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (5% methanol in chloroform) to provide racemic ethyl-3-amino-3-(2-methoxypyrimidin-5-yl)propionate. It was further purified in a chiral SFC (Chiralpak IA, 0.4% DEA in EtOH) to provide intermediate 2B (2.3 g, 9.80 mmol, 10.2% yield). LCMS (ES): m / z 226.8 [M+H] + .

[0550] Other β-amino acids were prepared similarly using the procedures described above for intermediates 2A and 2B.

[0551] Example 1

[0552] 3-(6-methoxypyridin-3-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid

[0553]

[0554] Intermediate E1A: Pentyl-4-en-2-ol (0.28 mL, 2.66 mmol), Pd(OAc)₂ (0.199 g, 0.888 mmol), LiCl (75 mg, 1.776 mmol), tetrabutylammonium chloride (0.99 g, 3.55 mmol), and LiOAc (0.294 g, 4.46 mmol) were added to a solution of 4-bromoindazole (0.35 g, 1.776 mmol) in DMF (5.59 mL). The mixture was heated at 100ºC for 72 hr. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with H₂O (3 mL) and brine (5 mL). The mixture was concentrated and purified by rapid chromatography (SiO₂) to give intermediate E1A (82 mg, 23%). 1 ¹H NMR (500 MHz, chloroform-d) δ 8.17 (s, 1H), 7.40–7.25 (m, 2H), 6.94 (d, J = 6.9 Hz, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.48 (t, J = 7.3 Hz, 2H), 2.12 (s, 3H), 2.11–2.01 (m, 2H).

[0555] Intermediate E1B: Pyrrolidine (8.4 µL, 0.102 mmol) was added to a solution of intermediate E1A (82 mg, 0.406 mmol) in CH2Cl2 (203 µL) and MeOH (610 µL), followed by the addition of 2-aminonicotinic acid (49.6 mg, 0.406 mmol). The mixture was stirred overnight at room temperature. The reaction was evaporated under reduced pressure. The residue was purified by rapid chromatography (SiO2) to give intermediate E1B (93 mg, 80%). 1H NMR (500 MHz, chloroform-d) δ 9.09 (dd, J = 4.3, 2.1 Hz, 1H), 8.15 (dd, J = 8.1, 2.0 Hz, 1H), 8.12 - 8.06 (m, 2H), 7.44 (dd, J= 8.1, 4.2 Hz, 1H), 7.36 (dd, J = 8.3, 6.6 Hz, 2H), 7.30 - 7.23 (m, 1H), 6.98 (d, J = 6.9 Hz, 1H), 3.18 - 3.11 (m, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.48 -2.33 (m, 2H).

[0556] Intermediate E1C: A mixture of E1B (31 mg, 0.108 mmol), intermediate 1A (44.6 mg, 0.215 mmol), and DBU (16.20 µL, 0.108 mmol) in acetonitrile (717 µL) was heated overnight at 100ºC. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 30% A:70% B to 0% A:100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to yield intermediate E1C (17 mg, 32%). LCMS(ES): m / z 492.2 [M+H] + .

[0557] Intermediate E1D: PtO2 (1.74 mg, 7.67 µmol) was added to a solution of E1C (19 mg, 0.038 mmol) in ethanol (1.0 mL). The mixture was purged with N2 and then bubbled through an H2 balloon. The mixture was stirred overnight at room temperature. It was then filtered through a diatomaceous earth filter. The solvent was removed, and the residue was used in the next step without further purification. LCMS (ES): m / z 500.5 [M+H] + .

[0558] Example 1: NaOH (aqueous, 1 N, 96 µL, 0.096 mmol) was added to a solution of intermediate E1D (16 mg, 0.032 mmol) in ethanol (582 µL), and the mixture was stirred at room temperature for two hours. It was then neutralized with AcOH (0.1 mL). The solvent was removed under reduced pressure, and the residue was purified by preparative LC / MS (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 0.1% TFA; mobile phase B: 95:5 acetonitrile: water containing 0.1% TFA; gradient: 10%–50% B for 20 min, then held at 100% B for 5 min; flow rate: 20 mL / min) to give Example 1 (4.8 mg, 30%). 1 H NMR (500 MHz, DMSO-d6) δ 8.20 (d, J = 2.5 Hz, 1H),8.12 (s, 1H), 7.67 (dd, J = 8.8, 2.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.25(t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.71(d, J = 8.6 Hz, 1H), 6.26 (d, J = 7.3 Hz, 1H), 6.15 (dd, J = 9.4, 5.3 Hz,1H), 3.74 (dt, J = 14.7, 7.1 Hz, 2H), 3.54 (dd, J = 16.5, 9.4 Hz, 1H), 3.27 –3.07 (m, 3H), 2.84 (t, J = 7.7 Hz, 2H), 2.56 (q, J = 7.8, 7.0 Hz, 2H), 2.45(t, J = 7.7 Hz, 2H), 1.91 (dd, J = 14.3, 6.5 Hz, 2H), 1.77 – 1.62 (m, 2H). LC / MS (m / z) = 472.0 (M+H) + Human αVβ6 IC 50 (nM) = 1600.

[0559] Example 2

[0560] 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid

[0561]

[0562] Intermediate E2A: A mixture of 2-methyl-1,8-naphthidine (250 mg, 1.734 mmol), 1H-indazole-5-carboxaldehyde (253 mg, 1.734 mmol), and 4-methylbenzenesulfonamide (297 mg, 1.734 mmol) in toluene (4 mL) was heated overnight at 110ºC. The reaction was cooled to room temperature and diluted with EtOAc (15 mL). The solid was collected by filtration, washed with EtOAc (2 x 2 mL), and dried under vacuum to provide intermediate E2A (415 mg, 1.524 mmol, 88% yield). The crude product was used in the next reaction without further purification. LCMS (ES): m / z 273.2 [M+H] + .

[0563] Intermediate E2B: PtO2 (33.4 mg, 0.147 mmol) was added to a degassed solution of intermediate E2A (200 mg, 0.734 mmol) in EtOH (5 mL). The mixture was bubbled through an H2 balloon and stirred overnight at room temperature. The reaction was filtered and concentrated to obtain intermediate E2B (203 mg, 0.729 mmol, 99% yield), and the product was used in the next reaction. LCMS(ES): m / z 279.2 [M+H] + .

[0564] Intermediate E2C: Cesium carbonate (29.3 mg, 0.09 mmol) was added to a solution of intermediate E2B (25 mg, 0.09 mmol) in acetonitrile (0.5 mL). After stirring for 5 min at room temperature, intermediate 1A (18.61 mg, 0.09 mmol) was added. The resulting mixture was stirred overnight at 80ºC. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μC18 30 x 100 mm; 10 min gradient from 75% A : 25% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E2C (19 mg, 0.039 mmol, 43.6% yield). LCMS (ES): m / z 486.4 [M+H] + .

[0565] Example 2: A solution of LiOH (aqueous, 1 N, 0.12 mL, 0.12 mmol) was added to a solution of intermediate E2C (19 mg, 0.039 mmol) in THF (0.5 mL). After stirring at room temperature for 5 hr, the mixture was neutralized with TFA (50 μL), filtered, and concentrated. The residue was purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 10%-50% B for 30 min, then held at 100% B for 5 min; flow rate: 20 mL / min) to produce Example 2 (5.5 mg, 30% yield). LCMS (ES): m / z 458.2 [M+H] + . 1H NMR(500MHz, DMSO-d6) δ 8.23 ​​(br. s., 1H), 8.00 (s, 1H), 7.67 (t, J =8.5 Hz, 2H), 7.51 (s, 1H), 7.24 (d, J =8.6 Hz, 1H), 7.01 (d, J =7.3 Hz, 1H), 6.72 (d, J =8.6 Hz, 1H), 6.28 (d, J =7.2 Hz, 1H), 6.17 (br. s., 1H), 3.76 (s, 3H), 3.23(br. s., 2H), 3.16 (br. s., 2H), 2.98 - 2.88 (m, 2H), 2.72 (t, J =7.8 Hz, 2H), 2.58 (t, J =5.8 Hz, 2H), 1.73 (br. s., 2H). Human αVβ6 IC 50 (nM) = 110.

[0566] Example 3

[0567] 3-(6-methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid

[0568]

[0569] Intermediate E3A: A solution of lithium borohydride (2 M, 2.12 mL, 4.24 mmol) in THF was added to a solution of tert-butyl 7-(2-methoxy-2-oxoethyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (1 g, 3.26 mmol) in THF (20 mL). The reaction was stirred overnight at room temperature. Water (15 mL) was slowly added to the reaction mixture. After stirring at room temperature for 10 min, the mixture was diluted with EtOAc (12 mL) and extracted with EtOAc (3 x 8 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by rapid chromatography (SiO2) to give intermediate E3A (782 mg, 86%). LCMS (ES): m / z 279.1 [M+H] + .

[0570] Intermediate E3B: DIAD (0.249 mL, 1.283 mmol) was slowly added to a solution of intermediate E3A (340 mg, 1.221 mmol), 1H-indazole-4-ol (164 mg, 1.22 mmol), and Ph3P (336 mg, 1.283 mmol) in THF (10 mL). The reaction was stirred at room temperature for 3 hr. The mixture was washed with NaHCO3 solution (aqueous, saturated, 10 mL), and the aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (10 mL) and then dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography to give intermediate E3B (178 mg, 37%). LCMS (ES): m / z 395.3 [M+H] + .

[0571] Intermediate E3C: TFA (0.174 mL, 2.256 mmol) was added to a solution of intermediate E3B (178 mg, 0.451 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 5 hr. The mixture was concentrated, and the crude product was used in the next step without further purification. LCMS (ES): m / z 295.2 [M+H] + .

[0572] Intermediate E3D: Cesium carbonate (37.4 mg, 0.115 mmol) was added to a solution of intermediate E3C (20 mg, 0.038 mmol) in acetonitrile (0.5 mL). After stirring at room temperature for 5 min, intermediate 1A (7.93 mg, 0.038 mmol) was added, and the resulting mixture was stirred at 80ºC for 4 hr. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 75% A: 25% B to 0% A: 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E3D (6 mg, 0.012 mmol, 31.2% yield). LCMS(ES): m / z 502.1 [M+H] + .

[0573] Example 3: A solution of LiOH (aqueous, 1 M, 0.036 mL, 0.036 mmol) was added to a solution of intermediate E3D (6 mg, 0.012 mmol) in THF (0.5 mL). The reaction mixture was stirred at room temperature for 6 hr. The reaction mixture was neutralized with TFA (25 μL), filtered, and concentrated under reduced pressure. The residue was purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 10%-50% B for 30 min, then held at 100% B for 5 min; flow rate: 20 mL / min) to produce Example 3 (5.8 mg, 102% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.22 (br. s., 1H), 8.04 (s, 1H), 7.68 - 7.62 (m, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.74 (dd, J =13.7, 8.0 Hz, 2H), 6.58 (d, J =7.7 Hz, 1H), 6.15 (dd, J =9.8, 5.1 Hz, 1H), 4.42 - 4.32 (m, 2H), 3.76 (s, 2H), 3.39 (br. s., 1H), 3.16 (s, 5H), 2.71 (br.s., 2H), 1.80 (br.s., 2H). LCMS (ES): m / z 473.9 [M+H] + Human αVβ6 IC 50 (nM) = 2300.

[0574] Example 4

[0575] (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-2H-indazol-2-yl)propionic acid

[0576]

[0577] Intermediate E4A: A solution of 1H-indazole-5-ol (5.1 g, 38.0 mmol), tert-butylchlorodimethylsilane (16.8 g, 111 mmol), and imidazole (12.7 g, 187 mmol) in DCM (200 mL) was stirred overnight at room temperature. The mixture was diluted with brine (60 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (50 mL) and then with brine (50 mL). It was dried (Na2SO4), filtered, and concentrated. The residue was purified by rapid column chromatography (SiO2) to provide E4A (7.48 g, 30.1 mmol, 79% yield) as a pale yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 10.27 (s, 1H), 7.99 (d, J = 1.1 Hz, 1H), 7.38 (dt, J = 8.9, 0.9 Hz, 1H), 7.17–7.14 (m, 1H), 7.01 (dd, J = 8.9, 2.2 Hz, 1H), 1.04 (s, 9H), 0.24 (s, 6H).

[0578] Intermediate E4B: Boc2O (5.72 mL, 24.62 mmol) was added to a solution of E4A (5-((tert-butyldimethylsilyl)oxy)indazole) (5.56 g, 22.38 mmol) in DCM (100 mL), followed by the addition of DMAP (0.547 g, 4.48 mmol) and Et3N (3.43 mL, 24.62 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by rapid column chromatography (silica gel, hexane / EtOAc gradient 0 to 25% EtOAc) to give E4B (7.74 g, 22.21 mmol, 99% yield) as a mixture of the following isomers: tert-butyl 5-((tert-butyldimethylsilyl)oxy)indazole-1-carboxylate and tert-butyl 5-((tert-butyldimethylsilyl)oxy)-2H-indazole-2-carboxylate.

[0579] Intermediate E4C: A solution of TBAF (44.4 mL, 44.4 mmol) was added to a solution of intermediate E4B (5-((tert-butyldimethylsilyl)oxy)indazole-1-carboxylate) (7.74 g, 22.21 mmol) in THF (100 mL). The mixture was stirred at room temperature for 2 hr. The mixture was diluted with NH4Cl (aqueous, saturated, 30 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (30 mL) and dried (Na2SO4), filtered, and concentrated. The residue was purified by rapid column chromatography to provide intermediate E4C (3.42 g, 14.60 mmol, 65.7% yield) as a mixture of two positional isomers: tert-butyl 5-hydroxyindazole-1-carboxylate and tert-butyl 5-hydroxy-2H-indazole-2-carboxylate.

[0580] Intermediate E4D: E3A (tert-butyl 5-hydroxyindazole-1-carboxylate) (2.7 g, 11.53 mmol) was added to a solution of E4C (3.53 g, 12.68 mmol) and Ph3P (3.78 g, 14.41 mmol) in THF (70 mL) at 0ºC, followed by (E)-diazepine-1,2-dimethylbis(piperidin-1-ylmethyl ketone) (3.64 g, 14.41 mmol). The reaction was stirred and gradually warmed to room temperature overnight. A solution of NaHCO3 (aqueous, saturated, 25 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (20 mL) and then with brine (20 mL). The mixture was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography to provide intermediate E4D as a pale yellow solid (3.94 g, 7.97 mmol, 69.1% yield). LCMS (ES): m / z 495.1 [M+H] + .

[0581] Intermediate E4E: TFA (8 mL, 104 mmol) was added to a solution of E4D (3.94 g, 7.97 mmol) in DCM (40 mL) at 0ºC. The mixture was gradually warmed to room temperature and stirred overnight at room temperature. The reaction was monitored by LCMS. Additional TFA was added as needed. After completion, the mixture was concentrated under reduced pressure and the residue was purified by rapid column chromatography (C18 column, 10% ACN in water containing 0.1% TFA to 80% ACN in water, 12 min gradient) to give E4E (7-(2-((1H-indazol-5-yl)oxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine TFA salt) (2.63 g, 6.44 mmol, 81% yield) as a pale yellow solid. 1 H NMR (500 MHz, chloroform-d) δ 15.60 (s, 1H), 10.31(s, 1H), 8.01 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H),7.15 (d, J = 2.3 Hz, 1H), 7.11 – 6.99 (m, 1H), 6.53 (d, J = 7.2 Hz, 1H), 4.34(t, J = 5.8 Hz, 2H), 3.51 (d, J = 6.0 Hz, 2H), 3.22 (t, J = 5.9 Hz, 2H), 2.77(t, J = 6.3 Hz, 2H), 1.94 (q, J = 5.9 Hz, 2H). LCMS (ES): m / z 295.2 [M+H] + .

[0582] Intermediate E4F: A mixture of intermediate E4E (37 mg, 0.091 mmol) and (S)-1-benzyl-2-methylazacyclopropane-1,2-dicarboxylate (27.7 mg, 0.118 mmol) in toluene (1 mL) was heated overnight at 110ºC. The solution was concentrated and the crude product was purified by preparative HPLC (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10 mM ammonium acetate; gradient: 25 min 12%–42% B, then 2 min at 42% B; flow rate: 20 mL / min) to give intermediate E4F (16 mg, 0.030 mmol, 33.3% yield). LCMS (ES): m / z 530.0 [M+H] + .

[0583] Example 4: A solution of LiOH (aqueous, 1 M, 0.091 mL, 0.091 mmol) was added to a solution of intermediate E4F (16 mg, 0.030 mmol) in THF (0.5 mL). The mixture was stirred at room temperature for 2 hr. The mixture was neutralized with TFA (20 μL) and concentrated under reduced pressure. The residue was purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 10%-60% B for 20 min, then hold at 100% B for 5 min; flow rate: 20 mL / min) to give Example 4 (11.3 mg, 73%). 1H NMR (400 MHz, MeOH-d4) δ 7.87 (s,1H), 7.44 – 7.33 (m, 2H), 7.22 (d, J = 9.2 Hz, 5H), 6.85 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 7.3 Hz, 1H), 5.07 – 4.89 (m, 2H), 4.88 – 4.65 (m, 2H), 4.58 (s,1H), 4.16 (t, J = 6.3 Hz, 2H), 3.41 (t, J = 5.7 Hz, 2H), 3.02 (t, J = 6.3 Hz,2H), 2.73 (t, J = 6.3 Hz, 2H), 1.92 – 1.82 (m, 2H). LCMS (ES): m / z 516.3 [M+H] + Human αVβ6 IC 50 (nM) = 21.

[0584] Example 5

[0585] 3-Phenylacetic-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propoxy)-1H-indazol-1-yl)propionic acid

[0586]

[0587] Intermediate E5A: DABCO (0.034 g, 0.300 mmol) was added to a solution of E4A (0.745 g, 3.00 mmol) in DCM (6 mL) at 0ºC under argon atmosphere, followed by the slow addition of tert-butyl propynate (0.51 mL, 3.6 mmol). The mixture was stirred at this temperature for another 20 min, then gradually warmed to room temperature overnight. The mixture was acidified with HOAc (34 μL). The solvent was removed under reduced pressure and the residue was purified by rapid column chromatography (SiO2, hexane / EtOAc gradient 0 to 40% EtOAc) to give E5B (0.19 g, 17% yield). 1H NMR (500 MHz, chloroform-d) δ 8.03 (d, J =0.9 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 9.6 Hz, 1H), 7.12 (d, J =2.2 Hz, 1H), 7.03 (dd, J = 8.9, 2.2 Hz, 1H), 5.62 (d, J = 9.5 Hz, 1H), 1.47 (s, 9H), 1.03 (s, 9H), 0.23 (s, 6H).

[0588] Intermediate E5B: A chloro(1,5-cyclooctadiene)rhodium(I) dimer (3.04 mg, 6.17 µmol) was added to a solution of E5A (46.2 mg, 0.123 mmol), Et3N (103 µL, 0.740 mmol), and phenylboronic acid (30.1 mg, 0.247 mmol) in MeOH (617 µL). The mixture was degassed for 10 min and heated overnight at 60ºC. The solvent was removed, and the residue was purified by rapid column chromatography (SiO2) to give E5B (39 mg, 70% yield). 1 H NMR (500 MHz, chloroform-d) δ7.93 (d, J = 0.9 Hz, 1H), 7.40 - 7.22 (m, 6H), 7.08 (d, J = 2.2 Hz, 1H), 6.92(dd, J = 8.9, 2.3 Hz, 1H), 6.40 (d, J = 13.7 Hz, 0H), 6.03 (dd, J = 9.6, 5.6Hz, 1H), 3.65 (dd, J = 15.9, 9.6 Hz, 1H), 3.18 (dd, J = 15.9, 5.7 Hz, 1H), 1.26 (s, 9H), 1.01 (s, 9H), 0.20 (d, J = 1.7 Hz, 6H).

[0589] Intermediate E5C: TBAF (265 µL, 0.265 mmol) was added to a solution of intermediate E5B (80 mg, 0.177 mmol) in CH2Cl2 (353 µL). The mixture was stirred at room temperature for 3 hr. It was then neutralized with HOAc (150 μL). The solvent was removed and the residue was purified by rapid column chromatography (SiO2) to give intermediate E5C (51 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 0.9 Hz, 1H), 7.36 - 7.18 (m, 7H), 7.10 -6.94 (m, 1H), 6.89 (dd, J = 9.0, 2.3 Hz, 1H), 6.02 (dd, J = 9.7, 5.6 Hz, 1H), 3.65 (dd, J = 15.9, 9.8 Hz, 1H), 3.16 (dd, J = 16.0, 5.6 Hz, 1H), 1.26 (s, 9H).

[0590] Intermediate E5D: Cs₂CO₃ (92 mg, 0.284 mmol) was added to a solution of intermediate E5C (32 mg, 0.095 mmol) and 2-(3-iodopropyl)-2-methyl-1,3-dioxolane (36.3 mg, 0.142 mmol) in acetonitrile (946 µL). The mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by rapid column chromatography (SiO₂) to give E5D (37 mg, 84% yield). LCMS (ES): m / z 467.3 [M+H] + .

[0591] Intermediate E5E: TFA (566 µL) was added to a solution of intermediate E5D (37 mg, 0.079 mmol) in DCM (227 µL). The mixture was stirred at room temperature for 4 hr. The solvent was removed under reduced pressure, and the residue was used in the next reaction without further purification. LCMS (ES): m / z 367.1 [M+H] + .

[0592] Intermediate E5F: Pyrrolidine (13.1 µL, 0.158 mmol) was added to a solution of intermediate E5E (29 mg, 0.079 mmol) in DCM (198 µL) and MeOH (594 µL). The mixture was stirred at room temperature for 15 min. Then 2-aminonicotinic acid (11.60 mg, 0.095 mmol) was added. The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 85% A: 15% B to 0% A: 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm) to yield intermediate E5F (11.3 mg, 36% yield). 1 H NMR (500 MHz,MeOH-d4) δ 9.11 (s, 1H), 8.90 (dd, J = 8.2, 1.7 Hz, 1H), 8.80 (d, J = 8.5 Hz,1H), 8.00 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 8.2, 4.8 Hz, 1H), 7.91 (d, J =0.7 Hz, 1H), 7.36 - 7.22 (m, 6H), 7.06 (d, J = 2.2 Hz, 1H), 6.67 (dd, J =9.1, 2.3 Hz, 1H), 6.12 (dd, J = 9.9, 5.1 Hz, 1H), 4.18 (t, J = 5.7 Hz, 2H), 3.71 (dd, J = 16.7, 9.9 Hz, 1H), 3.44 (t, J = 7.2 Hz, 2H), 3.24 (dd, J =16.6, 5.1 Hz, 1H), 2.54 - 2.43 (m, 2H).

[0593] Example 5: Sodium bicarbonate (4.20 mg, 0.050 mmol) was added to a solution of intermediate E5F (11.3 mg, 0.025 mmol) in MeOH (675 µL), followed by the addition of PtO2 (1.134 mg, 4.99 µmol). The mixture was bubbled through an H2 balloon. It was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth pad. The filtrate was purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 15%-55% B for 15 min, then held at 100% B for 3 min; flow rate: 20 mL / min) to give Example 5 (3.9 mg, 33%). LCMS (ES): m / z 457.1 [M+H] + . 1 H NMR (500 MHz, MeOH-d4) δ 7.95 (d, J = 0.8 Hz, 1H), 7.55 (d,J = 7.4 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.30 (d, J = 4.3 Hz, 4H), 7.28 -7.23 (m, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 9.1, 2.3 Hz, 1H), 6.64(d, J = 7.3 Hz, 1H), 6.18 (dd, J = 9.9, 5.1 Hz, 1H), 4.07 (t, J = 5.7 Hz,2H), 3.72 (dd, J = 16.6, 9.9 Hz, 1H), 3.46 (td, J = 5.3, 2.3 Hz, 2H), 3.25(dd, J = 16.6, 5.0 Hz, 1H), 2.92 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 6.3 Hz, 2H), 2.20 (dq, J = 13.2, 6.2 Hz, 2H), 1.94 (p, J = 6.1 Hz, 2H). Human αVβ6 IC 50 (nM) = 440.

[0594] Example 6

[0595] (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-2H-indazol-2-yl)propionic acid

[0596]

[0597] Intermediate E6A: 5-hydroxy-2-nitrobenzaldehyde (53 mg, 0.317 mmol) was added to a solution of Ph3P (104 mg, 0.396 mmol) and intermediate E3A (97 mg, 0.349 mmol) in THF (1.86 mL) at 0ºC, followed by the addition of DIAD (77 µL, 0.396 mmol). The mixture was stirred under argon and gradually warmed to room temperature overnight. The reaction mixture was diluted with EtOAc (10 mL) and washed with NaHCO3 (aqueous, saturated, 8 mL). The aqueous layer was extracted with EtOAc (3 x 6 mL). The combined organic layers were washed with water (8 mL) and then with brine (8 mL). The mixture was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, hexane / EtOAc gradient 0 to 100% EtOAc) to give intermediate E6A (73.8 mg, 0.173 mmol, 54.4% yield). 1 H NMR (500 MHz, chloroform-d) δ 10.49 (s, 1H),8.16 (d, J = 9.1 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.19 (dd, J = 9.1, 2.9 Hz,1H), 6.92 (d, J = 7.5 Hz, 1H), 4.55 (t, J = 6.7 Hz, 2H), 3.84 - 3.73 (m, 2H), 3.25 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H), 1.95 (p, J = 6.5 Hz, 2H), 1.53 (s, 9H).

[0598] Intermediate E6B: E6A (43 mg, 0.101 mmol) was added to a solution of intermediate 2A (24.82 mg, 0.111 mmol) in 2-propanol (234 µL). The mixture was heated at 80 ºC for 4 hours. It was then cooled to room temperature. PBu3 (74.5 µl, 0.302 mmol) was added in a single addition. The mixture was heated at 80 ºC for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (5 mL), and then washed with ammonium chloride (5 mL), followed by brine (5 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0-100% EtOAc / heptane) to provide intermediate E6B (16 mg, 27%). LCMS (ES): m / z 602.8 [M+H] + .

[0599] Example 6: TFA (68.4 µL) was added to a solution of intermediate E6B (16.3 mg, 0.027 mmol) in CH2Cl2 (342 µL). The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in THF (342 µL), and LiOH (aqueous, 1N, 81 µL, 0.081 mmol) was added. The mixture was stirred overnight at room temperature. It was neutralized with HCl (aqueous, 1 N, 100 μL) and purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5 : 95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95 : 5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 3%-40% B for 25 min, then hold at 100% B for 5 min; flow rate: 20 mL / min) to give Example 6 (5 mg, 37%). 1H NMR (500 MHz, MeOH-d4) δ 8.18 (d, J = 0.9Hz, 1H), 8.15 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.7, 2.6 Hz, 1H), 7.44 (dt,J = 9.0, 1.0 Hz, 1H), 7.30 (dt, J = 7.4, 1.1 Hz, 1H), 6.89 - 6.85 (m, 2H), 6.73 (dd, J = 8.7, 0.7 Hz, 1H), 6.53 (d, J = 7.3 Hz, 1H), 6.10 (dd, J = 9.1,6.1 Hz, 1H), 4.13 (td, J = 6.5, 4.2 Hz, 2H), 3.86 (s, 3H), 3.49 (dd, J =16.0, 9.2 Hz, 1H), 3.38 (dd, J = 6.5, 4.7 Hz, 2H), 3.18 (dd, J = 16.0, 6.1Hz, 1H), 2.98 (t, J = 6.3 Hz, 2H), 2.71 (t, J = 6.3 Hz, 2H), 1.91 - 1.81 (m,2H). LCMS (ES): m / z 474.0 [M+H] + Human αVβ6 IC 50 (nM) = 600.

[0600] Example 7

[0601] (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid

[0602] as well as

[0603] Example 8

[0604] (S)-3-(6-methoxypyridin-3-yl)-3-(6-((2-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)methyl)-2H-indazol-2-yl)propionic acid

[0605]

[0606] Intermediate E7A: 4-Bromo-2-nitrobenzaldehyde (326 mg, 1.417 mmol) was added to a solution of intermediate 2A (350 mg, 1.559 mmol) in 2-propanol (3.3 mL). The mixture was heated at 80ºC for 4 hr under argon. It was then cooled to room temperature. PBu3 (1.1 mL, 4.25 mmol) was added. The mixture was heated at 80ºC for 16 hr. The mixture was cooled to room temperature and diluted with EtOAc (5 mL) and washed with ammonium chloride (5 mL), followed by brine (5 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0-100% EtOAc / heptane) to provide intermediate E7A (501 mg, 70%). 1 H NMR (400 MHz, chloroform-d) δ 8.21 (d, J = 2.5 Hz, 1H), 7.95 (d, J = 1.0 Hz, 1H), 7.88 (dt, J = 1.7, 0.9 Hz, 1H), 7.67 (dd, J =8.7, 2.5 Hz, 1H), 7.47 (dd, J = 9.0, 0.8 Hz, 1H), 7.13 (dd, J = 8.8, 1.6 Hz,1H), 6.71 (dd, J = 8.6, 0.7 Hz, 1H), 6.01 (dd, J = 8.8, 6.0 Hz, 1H), 4.07(qd, J = 7.2, 1.0 Hz, 2H), 3.91 (s, 3H), 3.75 (dd, J = 16.6, 8.8 Hz, 1H), 3.19 (dd, J = 16.5, 6.0 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H).

[0607] Intermediate E7B: A solution of intermediate E7A (0.199 g, 0.492 mmol), but-3-en-2-one (0.142 mL, 1.723 mmol), Et3N (0.185 mL, 1.329 mmol), Pd(OAc)2 (12 mg, 0.055 mmol), and tri-o-tolylphosphine (0.025 g, 0.082 mmol) in ACN (4 mL) was degassed with argon for 10 min. The mixture was then sealed and heated at 120ºC for 12 hr. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (SiO2) to provide intermediate E7B (0.156 g, 0.397 mmol, 81% yield). 1H NMR (400 MHz, chloroform-d) δ 8.23 ​​(d, J = 2.4Hz, 1H), 7.96 (d, J = 1.0 Hz, 1H), 7.84 (s, 1H), 7.68 (dd, J = 8.7, 2.6 Hz,1H), 7.62 (d, J = 5.2 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.8,1.4 Hz, 1H), 6.79 - 6.70 (m, 2H), 6.04 (dd, J = 8.7, 6.1 Hz, 1H), 4.08 (qd, J= 7.2, 0.8 Hz, 2H), 3.91 (s, 3H), 3.77 (dd, J = 16.6, 8.8 Hz, 1H), 3.22 (dd,J = 16.5, 6.1 Hz, 1H), 2.40 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0608] Intermediate E7C: Pd / C (10%, 0.021 g, 0.020 mmol) was added to a solution of intermediate E7B (0.156 g, 0.397 mmol) in EtOAc (3.97 ml). The mixture was purged with H2 gas and then passed through an H2 balloon. It was stirred overnight at room temperature. It was filtered through a diatomaceous earth pad and washed with MeOH. The filtrate was concentrated under reduced pressure to provide E7C, which was used in the next reaction without further purification. LCMS (ES): m / z 396.1 [M+H] + .

[0609] Intermediates E7D and E7E: Pyrrolidine (16.19 µL, 0.196 mmol) was added to a solution of intermediate E7C (38.7 mg, 0.098 mmol) in CH2Cl2 (245 µL) and MeOH (734 µL). After stirring at room temperature for 15 min, 2-aminonicotinic acid (14.34 mg, 0.117 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by chromatography to provide intermediates E7D and E7E as a mixture. Intermediate E7D: LCMS (ES): m / z 482.0 [M+H] + Intermediate E7E: LCMS (ES): m / z 482.0 [M+H] + .

[0610] Examples 7 and 8 were prepared from a mixture of intermediates E7D and E7E according to the method described in Example 6.

[0611] Example 7: 1 H NMR (500 MHz, MeOH-d4) δ 8.28 (s, 1H), 8.15 (d, J = 2.5 Hz,1H), 7.72 (dd, J = 8.7, 2.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.30 (d, J =7.3 Hz, 1H), 7.17 (s, 1H), 6.87 (dd, J = 8.7, 1.4 Hz, 1H), 6.73 (d, J = 8.6Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.13 (dd, J = 9.4, 5.9 Hz, 1H), 3.86 (s,3H), 3.49 (dd, J = 15.8, 9.4 Hz, 1H), 3.39 (t, J = 5.7 Hz, 2H), 3.18 (dd, J =15.8, 5.9 Hz, 1H), 2.88 (h, J = 6.1, 5.0 Hz, 4H), 2.70 (t, J = 6.3 Hz, 2H),1.86 (p, J = 6.1 Hz, 2H). LCMS (ES): m / z 458.3 [M+H] + Human αVβ6 IC 50 (nM) = 6.6. Example 8: 1H NMR (500 MHz, MeOH-d4) δ 8.32 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.7, 2.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.29 (s, 1H), 7.22 (s,1H), 6.87 (dd, J = 8.6, 1.4 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.12 (dd, J =8.9, 6.4 Hz, 1H), 3.90 (s, 2H), 3.85 (s, 3H), 3.48 - 3.35 (m, 3H), 3.16 (dd,J = 15.6, 6.4 Hz, 1H), 2.70 (t, J = 6.3 Hz, 2H), 2.28 (s, 3H), 1.92 - 1.82(m, 2H). LCMS (ES): m / z 458.3 [M+H] + Human αVβ6 IC 50 (nM) = 390.

[0612] Example 9

[0613] (S)-3-(6-methoxypyridin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2H-indazol-2-yl)propionic acid

[0614] as well as

[0615] Example 10

[0616] (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)ethyl)-2H-indazol-2-yl)propionic acid

[0617]

[0618] Intermediate E9A: A solution of intermediate E7A (0.1295 g, 0.320 mmol), pent-4-en-2-ol (0.117 mL, 1.121 mmol), Et3N (0.12 mL, 0.865 mmol), Pd(OAc)2 (8.11 mg, 0.036 mmol), and tri-o-tolylphosphine (0.016 g, 0.053 mmol) in ACN (4 mL) was degassed with argon for 10 min. The mixture was sealed and heated at 120ºC for 12 hr. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by chromatography to provide intermediate E9A (85 mg, 65%). 1 H NMR (400 MHz, chloroform-d) δ 8.21 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.67 (dd, J = 8.7, 2.7 Hz, 1H), 7.59 - 7.48 (m,2H), 7.21 (dd, J = 8.8, 1.5 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.57 (d, J =15.8 Hz, 1H), 6.25 (ddd, J = 15.8, 7.8, 6.9 Hz, 1H), 6.01 (dd, J = 8.6, 6.3Hz, 1H), 4.18 - 4.01 (m, 3H), 3.99 - 3.92 (m, 1H), 3.90 (s, 3H), 3.75 (dd, J= 16.4, 8.6 Hz, 1H), 3.21 (dd, J = 16.5, 6.4 Hz, 1H), 2.53 - 2.28 (m, 2H),1.32 - 1.20 (m, 3H), 1.20 - 1.08 (m, 3H).

[0619] Intermediate E9B: Pd / C (10%, 11.08 mg, 10.42 µmol) was added to a solution of intermediate E9A (85.3 mg, 0.208 mmol) in EtOAc (2.1 mL). The mixture was purged with H2 gas and then passed through an H2 balloon. The mixture was stirred overnight at room temperature. It was filtered through a diatomaceous earth pad and washed with MeOH. The filtrate was concentrated and the residue was used in the next reaction without further purification. LCMS (ES): m / z 412.1 [M+H] + .

[0620] Intermediate E9C: Add Dysmart oxidant (103 mg, 0.242 mmol) to a solution of intermediate E9B (83 mg, 0.202 mmol) in CH2Cl2 (2.1 mL). After stirring at room temperature for 1 hr, dilute the mixture with Et2O (10 mL), filter off the precipitate, and wash with Et2O (10 mL). Concentrate the filtrate under reduced pressure and purify the residue by rapid column chromatography to give intermediate E9C (74 mg, 90%). 1 H NMR (500 MHz, chloroform-d) δ 8.23 ​​(d, J =2.5 Hz, 1H), 7.93 (s, 1H), 7.70 (dd, J = 8.7, 2.5 Hz, 1H), 7.58 - 7.50 (m,1H), 7.47 (s, 1H), 6.93 (dd, J = 8.5, 1.4 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.04 (dd, J = 8.5, 6.3 Hz, 1H), 4.10 (qd, J = 7.1, 1.5 Hz, 2H), 3.92 (d, J =2.2 Hz, 3H), 3.76 (dd, J = 16.5, 8.5 Hz, 1H), 3.25 (dd, J = 16.5, 6.4 Hz,1H), 2.72 (t, J = 7.4 Hz, 2H), 2.47 (t, J = 7.4 Hz, 2H), 2.13 (d, J = 1.9 Hz,3H), 1.97 (p, J = 7.4 Hz, 2H), 1.17 (td, J = 7.2, 1.8 Hz, 3H).

[0621] Examples 9 and 10 were prepared from intermediate E9C according to the method described in Example 7. Example 9: 1¹HNMR (500 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.79 (dd, J = 8.6, 2.4 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 6.09 (s, 1H), 3.79 (s, 2H), 3.23 (d, J = 23.7 Hz, 3H), 2.88 (m, 1H), 2.72 (m, 1H), 2.62 (t, J = 7.4 Hz, 2H), 2.57 (d, J = 6.3 Hz, 1H), 2.43 (t, J = 7.7 Hz, 2H), 1.78 – 1.67 (m, 3H), 1.22 (m, 2H). LC / MS (m / z) = 472.0 (M+H) + . Human αVβ6 IC 50 (nM) = 2.6. Example 10: 1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.94 (s, 1H), 7.77 (dd, J = 8.6, 2.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 6.99 – 6.88 (m, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.09 (t, J = 7.8 Hz, 1H), 3.80 (s, 2H), 3.60 (s, 3H), 3.25 – 3.12 (m, 2H), 2.89 (s, 1H), 2.82 – 2.70 (m, 2H), 2.65 (dd, J = 10.2, 6.0 Hz, 1H), 2.55 (d, J = 5.8 Hz, 2H), 1.90 (s, 3H), 1.76 (s, 1H), 1.73 (d, J = 6.3 Hz, 2H). LC / MS (m / z) = 472.0 (M+H) + . Human αVβ6 IC 50(nM) = 160.

[0622] Example 11

[0623] 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)pyrazolo[4,3-b]pyridin-1-yl)propionic acid

[0624]

[0625] Intermediate E11A: 4-Methylbenzenesulfonic acid (38 mg, 0.222 mmol) was added to a solution of 5-bromopyrazolo[4,3-b]pyridine (0.4395 g, 2.22 mmol) and 3,4-dihydro-2H-pyran (0.25 mL, 2.66 mmol) in CH2Cl2 (4.1 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with DCM (20 mL) and washed with water (3 x 8 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give E11A (527 mg, 84%). 1 H NMR (500 MHz, chloroform-d) δ 8.19 (d, J = 1.0 Hz, 1H), 7.89 (dd, J= 8.8, 0.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 5.75 (dd, J = 8.7, 2.6 Hz, 1H), 3.99 (dtd, J = 11.7, 4.0, 1.4 Hz, 1H), 3.81 - 3.71 (m, 1H), 2.56 - 2.42 (m,1H), 2.20 - 2.10 (m, 2H), 1.87 - 1.67 (m, 3H).

[0626] Intermediate E11B: A mixture of intermediate E11A (284 mg, 1.021 mmol), 1,10-o-phenanthroline (30.7 mg, 0.170 mmol), copper iodide(I) (16.2 mg, 0.085 mmol), and Cs₂CO₃ (416 mg, 1.276 mmol) in toluene (1.1 mL) was degassed with argon for 10 min. The mixture was then sealed and heated overnight at 120ºC. The mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (using 10% EtOAc in hexane) to give E11B (90 mg, 22%). LCMS (ES): m / z 480.5 [M+H] + .

[0627] Intermediate E11C: Add to a solution of E11B (90 mg, 0.19 mmol) in MeOH (164 µL) in dimethyl methacrylate (DMSO). HCl solution in alkane (4 M, 1 mL, 4 mmol). After stirring at room temperature for 48 hr, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Luna Axia 5 μC18 30 x 100 mm; 10 min gradient from 85% A: 15% B to 0% A: 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm) to give E11C (10 mg, 18%). LCMS (ES): m / z 296.3 [M+H) + .

[0628] Example 11 was prepared from intermediate E11C according to the method described in Example 3. 1 H NMR (500 MHz, MeOH-d4) δ 8.23 ​​– 8.19 (m, 0H), 8.15 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 9.1Hz, 1H), 7.92 (s, 1H), 7.72 (dd, J = 8.7, 2.6 Hz, 1H), 7.44 (d, J = 7.4 Hz,1H), 6.79 (d, J = 9.1 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 7.4 Hz,1H), 6.17 (dd, J = 9.8, 5.1 Hz, 1H), 4.65 (ddt, J = 14.6, 11.5, 5.7 Hz, 2H), 3.85 (s, 3H), 3.67 (dd, J = 16.5, 9.8 Hz, 1H), 3.47 – 3.40 (m, 2H), 3.20 (dd,J = 16.6, 5.1 Hz, 1H), 3.13 (t, J = 6.1 Hz, 2H), 2.67 (d, J = 11.3 Hz, 2H), 1.85 (p, J = 6.0 Hz, 2H). LC / MS (m / z) = 475.2 (M+H) + Human αVβ6 IC 50(nM) = 120.

[0629] Example 12

[0630] 3-(5-(2-((4,5-dihydroimidazol-2-yl)amino)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3-yl)propionic acid

[0631]

[0632] Intermediate E12A: K₂CO₃ (2.06 g, 14.91 mmol) was added to a solution of 1H-indazole-5-ol (1 g, 7.46 mmol) in DMF (5 mL), followed by the addition of tert-butyl (2-bromoethyl)carbamate (2.01 g, 8.95 mmol). The reaction mixture was stirred at room temperature for 1 day. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (10 mL), followed by brine (10 mL). It was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 85% A : 15% B to 0% A : 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm) to give E12A (526 mg, 1.897 mmol, 25.4% yield). LCMS (ES): m / z 278.2 [M+H] + .

[0633] Intermediate E12B: Cesium carbonate (264 mg, 0.811 mmol) was added to a solution of E12A (75 mg, 0.270 mmol) in acetonitrile (1.5 mL) and stirred at room temperature for 5 min. Then intermediate E1A (56.0 mg, 0.270 mmol) was added and stirred at 80ºC for 5 hr. The reaction was cooled to room temperature, filtered, and concentrated. The crude product was diluted with MeCN, filtered, and purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 85% A: 15% B to 0% A: 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm) to give E12B (53 mg, 0.089 mmol, 32.7% yield). LCMS (ES): m / z 485.1 [M+H] + .

[0634] Intermediate E12C: TFA (0.05 mL, 0.649 mmol) was added to a solution of intermediate E12B (53 mg, 0.089 mmol) in DCM (0.7 mL), and the mixture was stirred at room temperature for 5 hr. The reaction was concentrated. The crude product was diluted with MeCN, filtered, and purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 85% A : 15% B to 0% A : 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E12C (57 mg, 0.093 mmol, 105% yield). LCMS (ES): m / z 385.1 [M+H] + .

[0635] Intermediate E12D: A solution of E12C (57 mg, 0.093 mmol), 2-(methylthio)-4,5-dihydroimidazolium HCl salt (21.31 mg, 0.140 mmol), and DIPEA (0.081 mL, 0.465 mmol) in EtOH (2 mL) was heated to 150ºC for 15 min in a microwave reactor. The crude product was purified to E12D (46 mg, 0.081 mmol, 87% yield) by preparative HPLC (Phenomenex Luna Axia 5μC18 30 x 100 mm; 10 min gradient from 85% A : 15% B to 0% A : 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm). LCMS (ES): m / z 453.4 [M+H] + .

[0636] Example 12: A solution of LiOH (aqueous, 1 N, 0.244 mL, 0.244 mmol) was added to a solution of intermediate E12D (46 mg, 0.081 mmol) in THF (1 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated and purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 12%-52% B for 25 min, then held at 100% B for 3 min; flow rate: 20 mL / min) to give Example 12 (2.5 mg, 7.4%). 1H NMR (500MHz, chloroform-d) δ 7.94 (s, 1H), 7.66 (d, J =9.1 Hz, 1H), 7.34 (d, J =7.2 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.99 (d, J =9.1 Hz, 1H), 6.57 (d, J =8.0 Hz, 1H), 6.50 (d, J =7.2 Hz, 1H), 6.21 (t, J =6.7 Hz, 1H), 4.28 (t, J =5.6 Hz, 2H), 4.19 (dt, J =8.5, 4.4 Hz, 2H), 3.69 - 3.52 (m, 3H),3.51 - 3.39 (m, 3H), 3.16 (t, J =5.6 Hz, 2H), 2.74 (t, J =6.1 Hz, 2H), 1.97 -1.85 (m, 2H). LC / MS (m / z) = 501.4 (M+H) + Human αVβ6 IC 50 (nM) = 2,000.

[0637] Example 13

[0638] 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-2-((2,4,6-trimethylphenyl)sulfonamide)propionic acid

[0639]

[0640] Intermediate E13B: K₂CO₃ (112 mg, 0.811 mmol) was added to a solution of E4A (55.2 mg, 0.135 mmol) and E13A (51.0 mg, 0.135 mmol) in acetonitrile (1.35 mL). The mixture was stirred overnight at room temperature. The mixture was filtered and washed with acetonitrile. The filtrate was concentrated and the residue was purified by rapid column chromatography to provide E13B (55 mg, 60%). LCMS (ES): m / z 672.8 [M+H] + .

[0641] Intermediate E13C: TFA (82 µL, 1.062 mmol) was added to a solution of E13B (54.9 mg, 0.082 mmol) in CH2Cl2 (545 µL). The mixture was stirred overnight at room temperature. The solvent was removed, and the residue was used in the next reaction without further purification. LCMS (ES): m / z 472.5 [M+H] + .

[0642] Intermediate E13D: Et3N (22.46 µL, 0.161 mmol) was added to a solution of intermediate E13C (19 mg, 0.040 mmol) in THF (403 µL), followed by 2,4,6-trimethylbenzene-1-sulfonyl chloride (9.1 mg, 0.04 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated and purified to E13D (4.4 mg, 17% yield) by preparative HPLC (Sunfire 5μC18 30 x 100 mm; 10 min gradient from 95% A: 5% B to 0% A: 100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm). LCMS (ES): m / z 654.6 [M+H] + .

[0643] Example 13: NaOH (aqueous, 1 N, 20.2 µL, 0.020 mmol) was added to a solution of intermediate E13D (4.4 mg, 6.73 µmol) in MeOH (122 µL). The mixture was stirred overnight at room temperature. The mixture was neutralized and concentrated with 1 N HCl. The crude product was dissolved in 2 mL of MeOH, filtered, and purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 10%-50% B for 19 min, then held at 100% B for 5 min; flow rate: 20 mL / min) to give Example 13 (1.5 mg, 32%). 1H NMR (500 MHz, MeOH-d4) δ7.63 (s, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.99 (d, J= 2.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.68 (s,2H), 4.61 (dd, J = 14.3, 4.4 Hz, 1H), 4.47 (dd, J = 14.3, 8.1 Hz, 1H), 4.27(t, J = 6.0 Hz, 2H), 4.15 (s, 1H), 3.49 (t, J = 5.6 Hz, 1H), 3.15 (t, J = 6.1Hz, 2H), 2.81 (t, J = 6.3 Hz, 2H), 2.66 (s, 2H), 2.36 (s, 5H), 2.16 (s, 3H), 1.93 (t, J = 6.0 Hz, 2H). LC / MS (m / z) = 564.4 (M+H) + Human αVβ6 IC 50 (nM) = 320.

[0644] Example 14

[0645] 2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid

[0646]

[0647] Intermediate E14A: Sodium bicarbonate (aqueous, 1N, 201 µL, 0.201 mmol) was added to a solution of 2-amino-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)propionate (19 mg, 0.04 mmol) in THF (403 µL), followed by benzyl chloroformate (6.87 µL, 0.048 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The crude product was dissolved in 2 mL of MeOH, filtered, and purified by preparative HPLC under the following conditions (column: Phenomenex Luna AXIA 5u C18 21.2 x 100 mm; mobile phase A: 10 : 90 MeOH : water containing 0.1% TFA; mobile phase B: 90 : 10 MeOH : water containing 0.1% TFA; gradient: 20%-100% B for 10 min, then hold at 100% B for 2 min; flow rate: 20 mL / min) to give intermediate E14A (17.6 mg, 72%). 1 H NMR (400 MHz, MeOH-d4) δ 7.88 (s, 1H), 7.59 (dt, J = 7.3, 1.3 Hz, 1H), 7.36 (d, J = 9.1 Hz, 1H), 7.31 – 7.12 (m, 11H), 6.98 (dd, J = 9.1, 2.3 Hz,1H), 6.74 (d, J = 7.3 Hz, 1H), 5.16 – 5.00 (m, 2H), 4.96 (s, 2H), 4.81 – 4.66(m, 3H), 4.31 (t, J = 5.9 Hz, 2H), 3.48 (dd, J = 6.5, 4.8 Hz, 2H), 3.19 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 6.3 Hz, 2H), 1.98 – 1.87 (m, 2H). LC / MS (m / z) =606.7 (M+H) + .

[0648] Example 14: Benzyl propionate (2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionate (17.6 mg, 0.029 mmol) in MeOH (528 µL) was mixed with NaOH (aqueous, 87 µL, 1 N, 0.087 mmol). The mixture was stirred overnight at room temperature. The mixture was neutralized with HCl (aqueous, 1 N, 87 μL) and concentrated under reduced pressure. The crude product was purified by preparative LC / MS under the following conditions (column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 10%-50% B for 20 min, then hold at 100% B for 4 min; flow rate: 20 mL / min) to give Example 14 (9.3 mg, 62%). 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.48 (s, 2H), 7.28 (d, J = 7.0 Hz, 4H), 7.17 (d, J = 6.7Hz, 2H), 7.07 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.38 (d, J = 7.3Hz, 1H), 6.30 (s, 1H), 4.92 (s, 2H), 4.68 (s, 3H), 4.23 (s, 2H), 3.24 (s,2H), 3.17 (s, 1H), 2.90 (s, 2H), 2.61 (t, J = 6.3 Hz, 2H), 1.75 (t, J = 6.1Hz, 2H). LC / MS (m / z) = 516.3 (M+H) + Human αVβ6 IC 50 (nM) = 300.

[0649] Example 15

[0650] (±)-3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid

[0651]

[0652] (±)-3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid was synthesized using intermediate E4A and (E)-3-(quinoxalo-2-yl)ethyl acrylate according to the procedure described in Example 3. 1 H NMR (500MHz, MeOH-d4) δ 8.39 (s, 1H), 8.14 (d, J =8.2 Hz, 1H), 8.02 (dd, J =9.5, 7.9 Hz, 2H), 7.91 - 7.78 (m, 2H), 7.67 (d, J =9.2 Hz, 1H),7.57 (d, J =7.5 Hz, 1H), 7.22 (d, J =2.0 Hz, 1H), 7.10 (dd, J =9.2, 2.1 Hz,1H), 6.73 (d, J =7.3 Hz, 1H), 6.62 (d, J =5.5 Hz, 1H), 4.33 (t, J =6.0 Hz,2H), 3.85 (d, J =17.5 Hz, 1H), 3.52 - 3.44 (m, 2H), 3.17 (t, J =6.0 Hz, 2H), 2.79 (t, J =6.3 Hz, 2H), 1.97 - 1.85 (m, 2H). LC / MS (m / z) = 495.1 (M+H) + Human αVβ6 IC 50 (nM) = 6.0; human αVβ1 IC 50 (nM) = 270; human αVβ3 IC 50 (nM) = 2.7; human αVβ5 IC 50 (nM) = 0.31; and human αVβ8 IC 50 (nM) = 1,500.

[0653] Examples 16 and 17

[0654] (R)-3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid and (S)-3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid

[0655]

[0656] Example 15 (60 mg) was purified using a preparative chiral SFC (column: Chiralpak IA, 21 x 250 mm, 5 μm, BPR pressure: 120 bar, temperature: 40ºC, flow rate: 45 mL / min, mobile phase: CO2 / MeOH (60 / 40), detector wavelength: 220 nm) to provide Example 16 (15 mg) and Example 17 (19 mg) as yellow solids. The enantiomeric excess of both Example 16 and Example 17 was ≥ 99.0%. Example 16: Human αVβ6 IC 50 (nM) = 136.76. Example 17: Human αVβ6 IC 50 (nM) = 4.2; human αVβ1 IC 50 (nM) = 190; human αVβ3 IC 50 (nM) = 2.1; human αVβ5 IC 50 (nM) = 0.25; and human αVβ8 IC 50 (nM) = 1,900.

[0657] The following examples were prepared using methods similar to those shown in the table below.

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808] Example 167

[0809] 3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid, 2 TFA

[0810]

[0811] Intermediate E167A: (E)-diazepine-1,2-dimethylbis(piperidin-1-methylmethyl ketone) (3.64 g, 14.41 mmol) was added dropwise to a solution of intermediate E3A (3.53 g, 12.7 mmol), tert-butyl 5-hydroxy-1H-indazole-1-carboxylate [(WO 2016 / 21043), 2.7 g, 11.5 mmol] and Ph3P (3.78 g, 14.4 mmol) in THF (70 mL) maintained in an ice-water bath for 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with NaHCO3 solution (aqueous, saturated, 30 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (10 mL) and then dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography (hexane / ethyl acetate, 0-100% gradient) to give intermediate E167A (3.94 g, 69%). 1H NMR (500MHz, chloroform-d) δ 8.09 - 8.01 (m, 2H), 7.37 - 7.32 (m, 1H), 7.20 - 7.15 (m, 2H), 6.98 - 6.93 (m, 1H), 4.44 (t, J=6.9 Hz, 2H), 3.81 - 3.76 (m, 2H), 3.29 - 3.20(m, 2H), 2.80 - 2.74 (m, 2H), 1.98 - 1.92 (m, 2H), 1.76 - 1.75 (m, 1H), 1.75- 1.73 (m, 9H), 1.53 (s, 9H). LCMS (ES): m / z 495.1 [M+H] + .

[0812] Intermediate E167B: TFA (8 mL, 104 mmol) was added to a solution of intermediate E167A (3.94 g, 7.97 mmol) in DCM (40 mL), and the mixture was stirred at room temperature for 16 hr. The mixture was concentrated, and the crude product was purified by medium-pressure reversed-phase chromatography (10%–90% water, 0.1% TFA / acetonitrile gradient) to provide intermediate E167B, TFA salt (2.63 g, 6.44 mmol, 81% yield). 1 ¹H NMR (500 MHz, chloroform-d) δ 10.39 - 10.23 (m, 1H), 8.17 - 7.88 (m, 1H), 7.45 - 7.38 (m, 1H), 7.37 - 7.31 (m, 1H), 7.19 - 7.12 (m, 1H), 7.11 - 6.96 (m, 1H), 6.59 - 6.48 (m, 1H), 4.48 - 4.23 (m, 2H), 3.63 - 3.41 (m, 2H), 3.31 - 3.09 (m, 2H), 2.84 - 2.61 (m, 2H), 2.04 - 1.83 (m, 2H). LCMS(ES): m / z 295.2 [M+H] + .

[0813] Intermediate E167C: Cesium carbonate (239 mg, 0.735 mmol) was added to a solution of intermediate E167B, TFA salt (100 mg, 0.245 mmol), in acetonitrile (2 mL). After stirring at room temperature for 5 min, intermediate 1AR (75 mg, 0.245 mmol) was added, and the resulting mixture was stirred at 80ºC for 8 hr. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 75% A : 25% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E167C, a bis-TFA salt (95 mg, 0.115 mmol, 47% yield). LCMS (ES): m / z 601.3 [M+H] + .

[0814] Intermediate E167D: Add intermediate E167C, bis-TFA salt (95 mg, 0.115 mmol) to a solution of methanol (1 mL) in a di-... The mixture was prepared in 4 M HCl solution (0.115 mL, 0.459 mmol) in alkane. The reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with acetonitrile and purified by reversed-phase preparative HPLC (Phenomenex Luna Axia 5 μC18 30 x 100 mm; 10 min gradient from 75% A : 25% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E167D,3 TFA salt (50 mg, 0.060 mmol, 53% yield). LCMS (ES): m / z 487.1 [M+H] + .

[0815] Intermediate E167E: Triethylamine (0.013 mL, 0.097 mmol) was added to a solution of E167D, 3 TFA (16 mg, 0.019 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 10 min, and then methyl chloroformate (2.74 mg, 0.029 mmol) was added and stirred at room temperature for 4 hr. After 4 hr, the reaction mixture was diluted with a saturated aqueous NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The mixture was diluted with acetonitrile and purified by reversed-phase preparative HPLC (Phenomenex LunaAxia 5μ C18 30 x 100 mm; 10 min gradient from 20% A: 80% B to 0% A: 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E167E, a bis-TFA salt (13 mg, 0.017 mmol, 87% yield). LCMS (ES): m / z 545.1 [M+H] + .

[0816] Example 167: An aqueous 1 M LiOH solution (0.067 mL, 0.067 mmol) was added to a solution of intermediate E167E, a bis-TFA salt (13 mg, 0.017 mmol), in THF (0.5 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with TFA, filtered, and concentrated under reduced pressure. The residue was diluted and purified using reversed-phase preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 20% A : 80% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E167, a bis-TFA salt (12 mg, 0.016 mmol, 94% yield). 1H NMR (500 MHz, methanol-d4) δ 8.55 (br s, 1H), 8.47 (br s, 1H), 8.10 - 7.91 (m, 2H), 7.59 (br t, J=9.4 Hz, 2H), 7.20 (d, J=2.2 Hz, 1H), 7.07 (dd, J=9.1, 2.2 Hz,1H), 6.77 - 6.72 (m, 1H), 6.34 (br dd, J=9.2, 5.4 Hz, 1H), 4.37 - 4.28 (m,4H), 3.72 (br dd, J=16.8, 9.4 Hz, 1H), 3.65 (s, 3H), 3.54 - 3.46 (m, 2H), 3.43 - 3.35 (m, 1H), 3.19 (br t, J=5.9 Hz, 2H), 2.82 (br t, J=6.1 Hz, 2H), 1.99 - 1.91 (m, 2H). LC / MS (m / z) = 531.1 (M+H) + Human αVβ6 IC 50 (nM) = 15.

[0817] The following examples were prepared using methods similar to those shown in the table below.

[0818]

[0819]

[0820]

[0821]

[0822]

[0823] Example 172

[0824] 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)propionic acid, 2 TFA

[0825]

[0826] Intermediate E172A: Cesium carbonate (132 mg, 0.404 mmol) was added to a solution of intermediate E167B, TFA salt (55 mg, 0.135 mmol), in acetonitrile (1.2 mL). After stirring at room temperature for 5 min, intermediate 1BW (30.7 mg, 0.135 mmol) was added, and the resulting mixture was stirred at 80ºC for 6 hr. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 20% A : 80% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E172A, a bis-TFA salt (62 mg, 0.083 mmol, 61.3% yield). LCMS (ES): m / z 523.1 [M+H] + .

[0827] Intermediate E172B: Platinum oxide (IV) (3 mg, 0.013 mmol) was added to a degassed solution of E172A in EtOH (0.7 mL). The reaction mixture was stirred at room temperature for 4 hours under a hydrogen (balloon) atmosphere. The reaction was purged with nitrogen, filtered, and concentrated under vacuum. The crude product was diluted with MeCN, filtered, and purified by reversed-phase preparative HPLC (Phenomenex LunaAxia 5μ C18 30 x 100 mm; 10 min gradient from 75% A : 25% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E172B, a bis-TFA salt (22 mg, 0.029 mmol, 35.3% yield). LCMS (ES): m / z 527.1 [M+H] + .

[0828] Example 172: An aqueous 1 M LiOH solution (0.117 mL, 0.117 mmol) was added to a solution of intermediate E172B, a bis-TFA salt (22 mg, 0.029 mmol), in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with TFA, filtered, and concentrated under reduced pressure. The residue was diluted and purified using reversed-phase preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 20% A : 80% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E172, a bis-TFA salt (11 mg, 0.014 mmol, 46.7% yield). 1 HNMR (500 MHz, methanol-d4) δ 7.96 (s, 1H), 7.72 (s, 1H), 7.70 (br s, 1H), 7.65 -7.52 (m, 2H), 7.18 (s, 1H), 7.06 (br d, J=9.1 Hz, 1H), 6.73 (d, J=7.4 Hz,1H), 6.10 (br dd, J=8.8, 6.1 Hz, 1H), 4.31 (br t, J=5.6 Hz, 2H), 3.59 (br dd,J=16.5, 9.1 Hz, 1H), 3.53 - 3.39 (m, 4H), 3.30 - 3.22 (m, 1H), 3.18 (br t, J=5.5 Hz, 2H), 2.87 - 2.72 (m, 4H), 2.01 - 1.85 (m, 4H). LC / MS (m / z) = 499.1 (M+H) + Human αVβ6 IC 50 (nM) = 12.

[0829] Example 173

[0830] 4-((6-(2-carboxy-1-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)ethyl)pyrazin-2-yl)amino)butyric acid, TFA

[0831]

[0832] Intermediate E173A: Cesium carbonate (453 mg, 1.389 mmol) was added to a solution of intermediate E167B, TFA salt (136 mg, 0.463 mmol), in acetonitrile (2.5 mL). After stirring at room temperature for 5 min, intermediate 1BY (121 mg, 0.463 mmol) was added, and the resulting mixture was stirred at 80ºC for 16 hr. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Axia 5μ C18 30 x 100 mm; 10 min gradient from 20% A:80% B to 0% A:100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give intermediate E173A, a bis-TFA salt (19.6 mg, 0.035 mmol, 7% yield). LCMS (ES): m / z 556.3 [M+H] + .

[0833] Example 173: An aqueous 1 M LiOH solution (0.106 mL, 0.106 mmol) was added to a solution of intermediate E173A, bis-TFA salt (19.6 mg, 0.035 mmol) in THF (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with acetonitrile, and filtered. The product was purified using reversed-phase preparative HPLC (Phenomenex Luna Axia 5 μC18 30 x 100 mm; 10 min gradient from 20% A : 80% B to 0% A : 100% B (A = 90% H2O / 10% MeOH + 0.1% TFA); (B = 90% MeOH / 10% H2O + 0.1% TFA); detection at 220 nm) to give Example 173, TFA salt (8.1 mg, 0.011 mmol, 32% yield). 1H NMR (500 MHz, methanol-d4) δ 8.00 - 7.97 (m, 1H), 7.64 - 7.61 (m, 2H), 7.59 - 7.55 (m, 1H), 7.24 -7.21 (m, 1H), 7.10 - 7.09 (m, 1H), 7.09 - 7.07 (m, 1H), 6.80 - 6.77 (m, 1H), 6.21 - 6.16 (m, 1H), 4.37 - 4.31 (m, 3H), 3.54 - 3.50 (m, 4H), 3.42 - 3.39(m, 2H), 3.23 - 3.19 (m, 3H), 2.85 - 2.81 (m, 3H), 2.36 (t, J=7.4 Hz, 2H), 1.98 - 1.94 (m, 3H), 1.86 (t, J=7.2 Hz, 2H). LC / MS (m / z) = 546.3 (M+H) + Human αVβ6IC 50 (nM) = 370.

[0834] Example 174

[0835] 3-(6-methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid, TFA

[0836]

[0837] Intermediate E174A: DBU (0.383 mL, 2.54 mmol) was added to a mixture of (E)-3-(6-methoxypyridin-3-yl) tert-butyl acrylate [(J.Org. Chem.2004, 69, 1959) 0.746 g, 3.17 mmol] and 4-bromo-1H-indazole (0.500 g, 2.54 mmol) in acetonitrile (20 mL) at room temperature. The reaction mixture was heated at 50ºC for 48 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (2% MeOH / dichloromethane) to provide E174A (447 mg, 1.034 mmol, 41% yield). 1H NMR (400 MHz, chloroform-d) δ 8.18 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.58 (dd, J=8.8, 2.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.25 - 7.16 (m, 1H), 6.67 (d, J=8.5 Hz, 1H), 6.00(dd, J=9.2, 5.9 Hz, 1H), 3.89 (s, 3H), 3.64 (dd, J=16.1, 9.3 Hz, 1H), 3.16(dd, J=16.1, 6.0Hz, 1H), 1.28 (s, 9H). LCMS (ES): m / z 432.2, 434.2 [M+H] + .

[0838] Intermediate E174B: Palladium(II) acetate (8.62 mg, 0.038 mmol) was added to a vial containing a degassed mixture of tert-butyl 7-vinyl-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate [(Eur. J. Med. Chem. 2007, 42, 334), 0.100 g, 0.384 mmol], intermediate E174A (0.166 g, 0.384 mmol), tri-o-tolylphosphine (0.023 g, 0.077 mmol), and triethylamine (0.107 mL, 0.768 mmol) in DMF (3 mL). The top space of the container was purged with nitrogen and the vial was sealed. The mixture was heated at 100ºC for 20 h. After cooling to room temperature, the container was opened and its contents were diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to provide E174B (238 mg, 0.389 mmol, 101% yield). The product was a mixture of cis / trans isomers and contaminated with minor impurities. This material was used in subsequent chemical processes without further purification. LC / MS (m / z) = 612.43 (M+H) + .

[0839] Intermediate E174C: 10% palladium on carbon (41.4 mg, 0.389 mmol) was added to a flask containing a solution of E174B (238 mg, 0.389 mmol) in methanol under a nitrogen atmosphere. The container was partially evacuated and repeatedly rinsed with hydrogen gas. The reaction was left to proceed under a hydrogen atmosphere (double-balloon) with stirring. After 24 h, the reaction mixture was purged with nitrogen and filtered through diatomaceous earth. The concentrated filtrate was purified by silica gel column chromatography (5%–10% MeOH / dichloromethane) to provide E174C (25 mg, 0.040 mmol, 10% yield). LC / MS (m / z) = 614.4 (M+H) + .

[0840] Example 174. Trifluoroacetic acid (0.5 mL) was added to a solution containing E174C (41.8 mg, 0.068 mmol) in dichloromethane (2.5 mL). The resulting mixture was heated at 40ºC for 2 h. The mixture was concentrated under a stream of dry nitrogen. The residue was dissolved in methanol and purified by preparative LC / MS under the following conditions: column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 0-40% B for 20 min, then hold at 100% B for 5 min; flow rate: 20 mL / min. Fractions containing the desired product were combined and dried by centrifugation and evaporation to provide Example 172 (29.4 mg, 0.062 mmol, 91% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.30 - 8.22 (m, 1H), 8.22 -8.15 (m, 1H), 7.74 - 7.65 (m, 1H), 7.65 - 7.56 (m, 1H), 7.31 - 7.22 (m, 1H),7.07 - 6.99 (m, 1H), 6.97 - 6.90 (m, 1H), 6.77 - 6.69 (m, 1H), 6.38 - 6.27(m, 2H), 6.25 - 6.13 (m, 1H), 3.82 - 3.73 (m, 3H), 3.63 (br s, 1H), 3.31 -3.12 (m, 5H), 2.88 - 2.77 (m, 2H), 2.64 - 2.56 (m, 2H), 1.80 - 1.70 (m, 2H). LC / MS (m / z) = 458.2 (M+H) + Human αVβ6 IC 50 (nM) = 540.

[0841] Examples 175-178

[0842] (R)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid;

[0843] (S)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid;

[0844] (R)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid;

[0845] (S)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid

[0846]

[0847]

[0848] Intermediate E175A: Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 7-(2-hydroxyethyl)-2-methyl-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate [(WO 2007 / 141473), 2.509 g, 8.58 mmol] in DCM (20 mL). The resulting mixture was allowed to be stirred at room temperature for 24 h. The reactants were concentrated under vacuum and diluted with an aqueous saturated sodium bicarbonate solution. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ISCO system, pre-loaded with ISCO silica cartridges, 90:10 dichloromethane / methanol) to provide E175A (2.509 g, 8.58 mmol). 1 H NMR (500 MHz, chloroform-d) δ 7.38 - 7.31 (m, 1H), 6.45 - 6.37 (m, 1H), 3.93 (s, 2H), 3.74 - 3.61 (m,1H), 2.93 (t, J=5.9 Hz, 2H), 2.84 - 2.69 (m, 2H), 2.06 - 1.97 (m, 1H), 1.65 -1.55 (m, 1H), 1.37 (d, J=6.6 Hz, 3H). LCMS (ES): m / z 193.1 [M+H] + .

[0849] Intermediates E175B-enantiomers A and B. A sample of E175A (1.3 g) was purified by a preparative chiral SFC (column: Chiralpak AD-H, 30 x 250 mm, 5 μm, BPR pressure: 120 bar, temperature: 35ºC, flow rate: 70.0 mL / min, mobile phase: 50% MeCN w / 0.1% DEA in CO2, detector wavelength: 314 nm, stack injection: 0.5 mL of 110 mg / mL solution) to provide E175A-enantiomer A (374 mg) and E175A-enantiomer B (391 mg). LCMS data for each enantiomer were identical to those for the racemic mixture. The absolute configuration of the separated enantiomers was not determined.

[0850] Intermediate E175B – diastereomers A and B. A sample of E175A – enantiomer A was subjected to Mitsunobu coupling (with tert-butyl 5-hydroxy-1H-indazole-1-carboxylate, WO 2016 / 21043), BOC deprotection, and Michael addition (with intermediate CC) using the method outlined in Example 152 to provide a mixture of E175B – diastereomers A and B (106 mg, 11% yield, after 3 steps). LCMS (ES): m / z 529.4 [M+H] + Samples of E175B-diastereomers A and B (106 mg each) were purified by preparative chiral HPLC (column: Chiralpak OD, 21 x 250 mm, 10 μm, flow rate: 15 mL / min, mobile phase: 20% ethanol / 80% heptane, detector wavelength: 220 nm, A and B: 1 mL of 40 mg / mL solution) to provide E175B-diastereomer A (44.6 mg) and E175B-diastereomer B (47.5 mg). LCMS data for the separated diastereomers were consistent with those for the diastereomer mixture. The relative and absolute stereochemistry of the various diastereomers was not determined.

[0851] Intermediates E175B – diastereomers C and D. A sample of E175A – enantiomer B was subjected to Mitsunobu coupling (with tert-butyl 5-hydroxy-1H-indazole-1-carboxylate, WO 2016 / 21043), BOC deprotection, and Michael addition (with intermediate CC) using the method outlined in Example 152 to provide a mixture of E175B – diastereomers C and D (121 mg, 12% yield, after 3 steps). LCMS (ES): m / z 529.4 [M+H] +Samples of E175B-diastereomers C and D (121 mg) were purified by preparative chiral HPLC (column: Chiralpak OD, 21 x 250 mm, 10 μm, flow rate: 15 mL / min, mobile phase: 20% ethanol / 80% heptane, detector wavelength: 220 nm, A and B: 1 mL of 40 mg / mL solution) to provide E175B-diastereomer C (49 mg) and E175B-diastereomer D (47 mg). LCMS data for the separated diastereomers were consistent with those for the diastereomer mixture. The relative and absolute stereochemistry of the various diastereomers was not determined.

[0852] Example 175. Trifluoroacetic acid (0.5 mL) was added to a flask containing a stirred solution of E175B-diastere A (34.6 mg, 0.065 mmol) in dichloromethane (2.0 mL). The reaction vessel was placed in a 50ºC oil bath for 2 h. The reaction contents were concentrated under a stream of dry nitrogen. The residue was dissolved in a mixture of 1 mL of 28%–30% aqueous ammonium hydroxide solution / 1 mL of DMSO / 1 mL of 95:5 water (containing 0.5% of 30% aqueous ammonium hydroxide solution) : acetonitrile. The clarified solution was loaded onto Waters Sep-Pak C18 Plus short cartridges (360 mg adsorbent per cartridge, 55-105 μM particle size (WAT020515)), which had been pretreated with 10 mL of 2 M ammonia in methanol and then equilibrated with 20 mL of 95:5 water (containing 0.5% of a 30% aqueous ammonium hydroxide solution): acetonitrile. After loading, the cartridge was rinsed with 40 mL of 95:5 water (containing 0.5% of a 30% aqueous ammonium hydroxide solution): acetonitrile at a flow rate equivalent to rapid dropping. Next, the cartridge was eluted with 5 mL of 2 M ammonia in methanol at the same rate. The salt-free product was eluted in the first 2.5 mL of methanol-ammonia. The desired fraction was concentrated under vacuum to provide Example 175 (30.9 mg, 92% yield). 1H NMR (500 MHz, methanol-d4) δ 8.76 - 8.65 (m, 2H), 8.02 - 7.95 (m, 1H), 7.57 - 7.48 (m, 1H), 7.35 -7.29 (m, 1H), 6.96 - 6.88 (m, 2H), 6.53- 6.47 (m, 1H), 6.32 - 6.23 (m, 1H), 4.09 - 3.99 (m, 1H), 3.96 - 3.88 (m, 1H), 3.63 - 3.48 (m, 2H), 3.25 - 3.15(m, 1H), 2.95 - 2.87 (m, 2H), 2.76 - 2.64 (m, 2H), 2.64 - 2.58 (m, 3H), 1.98 - 1.86 (m, 1H), 1.49 - 1.37 (m, 1H), 1.26 - 1.19 (m, 1H). LC / MS (m / z) = 473.2(M+H) + Human αVβ6 IC 50 (nM) = 6,000.

[0853] Example 176. A sample of E175B-diastere B (37.5 mg, 0.071 mmol) was subjected to the deprotection and desalting methods outlined in Example 175 to provide Example 176 (33.5 mg, 92% yield). 1 H NMR (500 MHz, methanol-d4) δ 8.80 - 8.63 (m, 2H), 8.04 - 7.95 (m, 1H), 7.61 - 7.51 (m, 1H), 7.38 - 7.29 (m, 1H), 7.00 - 6.88 (m, 2H), 6.57 - 6.47 (m, 1H), 6.34 - 6.23(m, 1H), 4.12 - 4.01 (m, 1H), 4.00 - 3.90 (m, 1H), 3.65 - 3.51 (m, 2H), 3.27- 3.18 (m, 1H), 2.97 - 2.89 (m, 2H), 2.80 - 2.67 (m, 2H), 2.66 - 2.60 (m,3H), 1.98 - 1.89 (m, 1H), 1.54 - 1.41 (m, 1H), 1.29 - 1.23 (m, 3H). LC / MS (m / z) = 473.2 (M+H) + Human αVβ6 IC50 (nM) = 33.

[0854] Example 177. A sample of E175B-diastere C (39 mg, 0.074 mmol) was subjected to the deprotection and desalting methods outlined in Example 175 to provide Example 177 (32.9 mg, 93% yield). 1 H NMR (500 MHz, methanol-d4) δ 8.75 - 8.64 (m, 2H), 8.02 - 7.92 (m, 1H), 7.58 - 7.51 (m, 1H), 7.33- 7.27 (m, 1H), 6.98 - 6.91 (m, 2H), 6.54 - 6.47 (m, 1H), 6.32 - 6.22 (m,1H), 4.13 - 4.02 (m, 1H), 4.02 - 3.92 (m, 1H), 3.58 - 3.47 (m, 2H), 3.26 -3.15 (m, 1H), 2.97 - 2.87 (m, 2H), 2.74 - 2.65 (m, 2H), 2.62 (s, 3H), 1.97 -1.88 (m, 1H), 1.45 (dtd, J=13.1, 9.4, 6.0 Hz, 1H), 1.27 - 1.21 (m, 3H). LC / MS(m / z) = 473.2 (M+H) + Human αVβ6 IC 50 (nM) = 5,000.

[0855] Example 178. A sample of E175B-diastere D (37 mg, 0.070 mmol) was subjected to the deprotection and desalting methods outlined in Example 175 to provide Example 178 (31.9 mg, 95% yield). 1H NMR (500 MHz, methanol-d4) δ 8.77 - 8.66 (m, 2H), 8.02 - 7.95 (m, 1H), 7.58 - 7.49 (m, 1H), 7.36- 7.28 (m, 1H), 6.99 - 6.91 (m, 2H), 6.54 - 6.48 (m, 1H), 6.31 - 6.23 (m,1H), 4.11 - 4.01 (m, 1H), 4.00 - 3.92 (m, 1H), 3.62 - 3.50 (m, 2H), 3.25 -3.18 (m, 1H), 2.97 - 2.87 (m, 2H), 2.76 - 2.66 (m, 2H), 1.97 - 1.87 (m, 1H), 1.51 - 1.38 (m, 1H), 1.27 - 1.20 (m, 3H). LC / MS (m / z) = 473.2 (M+H) + Human αVβ6IC 50 (nM) = 110.

[0856] Example 179

[0857] 3-(6-methoxypyridin-3-yl)-3-(5-(2-(1-methyl-1,2,3,4-tetrahydropyridino[2,3-b]pyrazin-6-yl)ethoxy)-1H-indazol-1-yl)propionic acid

[0858]

[0859] Intermediate E179A: DIAD (52.8 µl, 0.272 mmol) was added to a solution of 2-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)ethanol-1-ol [(US 2004 / 0092538) 50 mg, 0.259 mmol], tert-butyl 5-hydroxy-1H-indazole-1-carboxylate [(WO 2016 / 21043), 60.6 mg, 0.259 mmol] and Ph3P (71.3 mg, 0.272 mmol) in THF (2270 µl); the reaction was stirred overnight at room temperature. The reaction mixture was diluted with an aqueous saturated solution of NaHCO3. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with water and then with brine, and dried over sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 20%–100% EtOAc / hexane. Fractions containing the desired product were collected, and the solvent was removed under vacuum to provide E179A (52 mg, 49% yield), which was contaminated with a small amount of triphenylphosphine oxide. This material was not further purified and continued. LCMS (ES): m / z 410.0 [M+H] + .

[0860] Intermediate E179B: TFA (0.5 mL, 6.5 mmol) was added to a solution of intermediate E179A (52 mg, 0.127 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under vacuum to provide E179B, a TFA salt (30 mg, 52% yield). LCMS (ES): m / z 310.0 [M+H] + .

[0861] Intermediate E179C: Cesium carbonate (69.3 mg, 0.213 mmol) was added to a solution of intermediate E179B, TFA salt (30 mg, 0.071 mmol), in acetonitrile (0.6 mL). After stirring at room temperature for 5 min, tert-butyl (E)-3-(6-methoxypyridin-3-yl)acrylate [(J. Org. Chem. 2004, 69, 1959), 25.1 mg, 0.106 mmol] was added, and the resulting mixture was stirred at 80ºC for 16 hr. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel column chromatography (ISCO column, 40 g, 30%–100% EtOAc / hexane). The pure fraction was concentrated under vacuum to provide E179C (30 mg, 0.055 mmol, 78% yield). LCMS (ES): m / z 545.2 [M+H] + .

[0862] Example 179. Trifluoroacetic acid (1 mL) was added to a solution containing E179C (40 mg, 0.073 mmol) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum. The residue was dissolved in methanol and purified by preparative LC / MS under the following conditions: column: XBridge C18, 19 x 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water containing 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water containing 10-mM ammonium acetate; gradient: 10-100% B for 17 min, then held at 100% B for 5 min; flow rate: 20 mL / min. Fractions containing the desired product were combined and dried by centrifugation to provide Example 179 (29.4 mg, 0.062 mmol, 91% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.28 - 8.22 (m, 1H), 8.00 - 7.92 (m,1H), 7.74 - 7.68 (m, 1H), 7.68 - 7.63 (m, 1H), 7.20 - 7.13 (m, 1H), 7.01 -6.96 (m, 1H), 6.75 - 6.70 (m, 1H), 6.58 - 6.52 (m, 1H), 6.40 - 6.31 (m, 2H), 6.22 - 6.12 (m, 1H), 4.23 - 4.14 (m, 2H), 3.79 - 3.74 (m, 3H), 3.66 - 3.53(m, 1H), 3.46 - 3.37 (m, 3H), 3.23 - 3.13 (m, 1H), 3.09 - 3.02 (m, 2H), 2.87- 2.80 (m, 2H), 2.75 - 2.68 (m, 3H). LC / MS (m / z) = 489.1 (M+H) + Human αVβ6 IC 50 (nM) = 47.

[0863] Example 180

[0864] (S)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]) (6-azinyl)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3-yl)propionic acid;

[0865] as well as

[0866] Example 181

[0867] (R)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]) (azine-6-yl)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3-yl)propionic acid

[0868]

[0869]

[0870] Intermediate E180A: 6-(2-hydroxyethyl)-2,3-dihydro-4H-pyrido[3,2-b][1,4] The sample of tert-butyl 4-azine carboxylate (Bioorg. Med. Chem. Lett. 2005, 15, 2679) was converted to E173A in four steps using the method outlined in Example 3. LCMS (ES): m / z 476.0 [M+H] + .

[0871] Examples 180 and 181. A sample of E180A (143 mg) was purified by a chiral SFC (column: Chiralpak OJ-H, 30 x 250 mm, 5 μm, BPR pressure: 150 bar, temperature 35ºC, flow rate: 70.0 mL / min, mobile phase: 20% MeOH w / 0.1% NH4OH in CO2, detector wavelength: 254 nm, stack injection: 0.5 mL of 24 mg / mL solution) to provide Example 180 (29 mg) and E181 (32 mg).

[0872] Data from Example 180: 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J=2.3 Hz, 1H),7.96 (s, 1H), 7.72 - 7.67 (m, 1H), 7.67 - 7.62 (m, 1H), 7.17 - 7.15 (m, 1H),7.00 - 6.95 (m, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.67 -6.60 (m, 1H), 6.41 (d, J=7.8 Hz, 1H), 6.16 (dd, J=9.7, 5.4 Hz, 1H), 4.21 (brt, J=6.7 Hz, 2H), 4.13 - 3.95 (m, 2H), 3.77 (s, 3H), 3.56 (br dd, J=16.2, 9.7Hz, 1H), 3.35 (br s, 1H), 3.16 (br dd, J=16.6, 5.3 Hz, 1H), 2.90 (t, J=6.8Hz, 2H). LC / MS (m / z) = 476.1 (M+H) + Human αVβ6 IC 50 (nM) = 15.

[0873] Data from Example 181: 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=2.3 Hz, 1H), 7.96 (s, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.65 (dd, J=8.5, 2.5 Hz, 1H), 7.16 (d,J=2.3 Hz, 1H), 6.98 (dd, J=9.0, 2.3 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.71 (d,J=8.5 Hz, 1H), 6.67 - 6.61 (m, 1H), 6.41 (d, J=7.8 Hz, 1H), 6.16 (dd, J=9.5,5.3 Hz, 1H), 4.21 (br t, J=6.8 Hz, 2H), 4.09 - 4.02 (m, 2H), 3.77 (s, 3H), 3.57 (br dd, J=16.6, 9.8 Hz, 1H), 3.35 (br d, J=2.8 Hz, 2H), 3.18 (br dd, J=16.4, 5.1 Hz, 1H), 2.90 (br t, J=6.9 Hz, 2H). LC / MS (m / z) = 476.1 (M+H) + Human αVβ6 IC 50 (nM) = 5,000.

[0874] Biological evaluation

[0875] All binding assays were performed using HTRF (homogeneous time-resolved fluorescence) technology from Cisbio International; therefore, all assays are described as HTRF binding assays. The assay results along with characterization data from the examples are listed above. HTRF binding assays were established for the following integrins: human αVβ6, human αVβ1, human αVβ3, human αVβ5, and human αVβ8. All assays were performed using the following assay buffers: 20 mM Tris (pH 7.4), 1 mM MgCl2, 1 mM MnCl2, 0.01% Tween 20, and 0.01% BSA. Alternatively, SPA-based assays were used to evaluate receptor binding.

[0876] The following describes the components and representative procedure for the human αVβ6 HTRF binding assay: Recombinant human αVβ6 integrin (R&D systems, 3817-AV) was biotinylated. The biotinylated human αVβ6 integrin was added to the assay vessel at a final concentration of 1.25 nM. Then, FITC-conjugated fibronectin (Cytoskeleton, FNR02) was added at a final concentration of 5 nM. The mixture was centrifuged at 600 rpm for 3 minutes using a Thermo Fisher Heraeus Multifuge X3 centrifuge and then incubated at room temperature for 1 hour. Then, streptavidin terbium (Cisbiointernational 610STLB) was added at a final concentration of 0.625 nM. The resulting mixture was centrifuged at 600 rpm for 3 minutes using a Thermo Fisher Heraeus Multifuge X3 centrifuge and then incubated overnight in the dark at room temperature before reading the HTRF signal.

[0877] The SPA-based assay was performed according to a similar protocol and procedure to those described in the following references, with appropriate modifications to the reagents and ligands, which are readily understood by those skilled in the art: Pachter JA, Zhang R, Mayer-Ezell R., “Scintillation proximity assay to measure binding of soluble fibronectin to antibody-captured αVβ1 integrin” Anal Biochem. Sep 1, 1995;230(1):101-7.

[0878] In the course of the above description of exemplary embodiments, other features of the invention should become clear. These exemplary embodiments are given for illustrative purposes and are not intended to limit the invention. The invention can be practiced in other specific forms without departing from its spirit or essential attributes. The invention includes all combinations of the preferred aspects of the invention described herein. It should be understood that any and all embodiments of the invention can be combined with any one or more other embodiments to describe further embodiments. It should also be understood that each individual element of the embodiments is an independent embodiment in itself. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe further embodiments.

Claims

1. A compound of formula (Ia) or (Ib): (him) (Ib), in: A, E, G, and J are independently N, C, or CH, provided that at least one of A, E, G, and J is a C attached to Y; L 1 and L 2 Each is C independently 1-4 Alkylene; X is determined by 0, 1, or 2 R's. 8a Replacement C 1-4 Alkylene; Y represents a covalent bond, O, S, NH, or -O-(C). 1-3 alkylene)-, -S-(C 1-3 alkylene)- or -NH-(C 1-3 alkylene)-, wherein the C 1-3 Each alkylene group is independently bounded by 0, 1, or 2 R groups. 8b replace; m is an integer of 1 or 2; r is an integer of 0, 1, 2 or 3; R 1 It is selected from the following arginine mimicry section In each arginine analogue portion, one asterisk represents the attachment point to X, and the other two asterisks represent hydrogen. R 2 Is it hydrogen, halogenated, or C? 1-6 alkyl; R 3 It is hydrogen, C 1-6 Alkyl, 3- to 10-membered carbocyclic, carbocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 3- to 14-membered heterocyclic, heterocyclic alkyl, 5- to 14-membered heteroaryl or heteroarylalkyl, wherein said alkyl, carbocyclic, heterocyclic, aryl and heteroaryl, themselves or as part of another group, are each independently bound by 0, 1, 2 or 3 R groups. 6 replace; R 3a It is hydrogen; Or R 3a and R 3 These rings, together with the atoms to which they are attached, form 3- to 6-membered carbon rings or heterocycles, which are optionally substituted by one or more groups independently selected from: halogen, cyano, hydroxy, amino, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate and sulfonamide; R 4 It is hydrogen, C 1-6 Alkyl, 3- to 10-membered carbocyclic, carbocyclic alkyl, 3- to 10-membered heterocyclic, heterocyclic alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, -S(O) m R 7 -C(O)NR a R b -NHC(O)OR a -NHC(O)NR a R b -NHC(O)R 7 -OC(O)NR a R b -OC(O)R 7 -NHS(O) m NR a R b Or -NHS(O) m R 7 The alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, whether individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 9 replace; R 5 It is hydrogen, R 5a Or selected from the following structural parts ； R 5a and R 5b Each is C independently 1-6 Alkyl, phenyl, benzyl, or 5- to 7-membered heterocyclic groups; wherein each of the alkyl, phenyl, and heterocyclic groups is independently surrounded by 0 to 3 R groups. 5d replace; R 5c It is C 1-6 Alkyl or 5- to 7-membered carbocyclic group; wherein the C 1-6 Alkyl, phenyl, and heterocyclic groups are each independently bound by 0 to 3 R groups. 5d Replace; and R 5d Each time it appears, it is independently halogenated, OH, alkoxy, oxo, or alkyl; or alternatively, two adjacent Rs. 5d Together with the atoms to which they are attached, they form a carbocyclic moiety; R 6 It includes halogenated, cyano, hydroxyl, amino, oxo, nitro, and -S(O) groups. m R 12 C 1-6 Alkyl, alkoxy, haloalkyl, haloalkoxy, haloaminoalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered carbocyclic or 3- to 7-membered heterocyclic; wherein the alkyl, aryl, heteroaryl, carbocyclic or heterocyclic group, either itself or as part of another group, is independently bounded by 0, 1 or 2 R groups. 10 replace; R 7 Each is C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Halogenated alkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, either individually or as part of another group, are each independently bound by 0, 1, 2, or 3 R groups. 11 replace; R 8a and R 8b Each time it appears, it is independently of halogen, cyano, hydroxyl, amino, oxo, C. 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, or haloalkoxy; R 9 Each group independently represents a halogenated, cyano, hydroxyl, amino, oxo, nitro, or C group. 1-6 Alkyl, alkoxy, haloalkyl, haloalkoxy, haloaminoalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered carbocyclic or 3- to 7-membered heterocyclic; wherein the alkyl, aryl, heteroaryl, carbocyclic or heterocyclic group, either itself or as part of another group, is independently bounded by 0, 1 or 2 R groups. 13 replace; R 10 It is halogenated, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, or sulfonamide; R 11 Each time it appears, it is independently of halogen, cyano, hydroxyl, amino, oxo, C. 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, or haloalkoxy; R 12 It is -N(R) x R y C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; R 13 It is halogenated, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, or sulfonamide; R a and R b Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or alkoxyalkyl; or alternatively, R a and R b Together with the atoms to which they are attached, they form a 3- or 8-membered carbon ring or heterocyclic ring; wherein the aryl and heteroaryl groups, either individually or as part of another group, are each independently substituted by one or more groups independently selected from: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate, and sulfonamide; and said carbocyclic and heterocyclic groups, either themselves or as part of another group, are each independently substituted by one or more groups independently selected from: halogen, cyano, hydroxy, amino, oxo, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amide, carbamate and sulfonamide; R e It is OH, amino, amide, carbamate, sulfonamide, C 1-4 Alkyl, Halogenated, C 1-4 Halogenated alkyl or C 3-6 cycloalkyl; R f It is H, CH3, CH2CH3 or C(O)OCH2CH3; R g Selected from CH3, CH2CCl3, phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, ;and R x and R y Each is independently hydrogen or C 1-6 alkyl; Or its pharmaceutically acceptable salt.

2. The compound of claim 1, wherein the compound of formula (Ia) or (Ib) is represented by structural formula (IIa), (IIb), (IIc), or (IId): (IIa)、 (IIb)、 (IIc) or (IId).

3. The compound of claim 1, wherein the compound of formula (Ia) or (Ib) is represented by structural formula (IIIa), (IIIb), (IIIc), or (IIId): (IIIa)、 (IIIb)、 (IIIc) or (IIId).

4. The compound of claim 1, wherein the compound of formula (Ia) or (Ib) is represented by structural formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf): (IVa)、 (IVb)、 (IVc)、 (IVd)、 (IVe) or (IVf).

5. The compound of claim 1, wherein R 1 Selected from 。 6. The compound of claim 1, wherein R 3a It is hydrogen; and R 3 It is hydrogen or selected from the following structural parts 。 7. The compound of claim 1, wherein R 4 It is hydrogen or selected from the following structural parts 。 8. The compound of claim 1, wherein R 5 Is it H or R? 5a And R 5a It is methyl, ethyl, isopropyl, n-butyl, isopentyl, or a structural moiety selected from the following: 。 9. The compound of claim 1, wherein X is C 1-4 Alkylene; and Y is either covalent or O.

10. The compound of claim 1, wherein the compound is selected from: 3-(6-methoxypyridin-3-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-2H-indazol-2-yl)propionic acid; 3-Phenylacetic-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-2H-indazol-2-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-((2-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)methyl)-2H-indazol-2-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2H-indazol-2-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)ethyl)-2H-indazol-2-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)pyrazolo[4,3-b]pyridin-1-yl)propionic acid; 3-(5-(2-((4,5-dihydroimidazol-2-yl)amino)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3-yl)propionic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid; 2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3,5-Dichlorophenyl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(quinoxalo-2-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(3,5-Dichlorophenyl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(quinoxalo-2-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; 3-(dibenzo[b,d]furan-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; 3-(3-((dimethylamino)methyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; 3-(quinoxalo-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; 3-(3,5-Dichlorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(dibenzo[b,d]furan-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 6,6,6-Trifluoro-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)hexanoic acid; 3-(3,5-Dichlorophenyl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(quinoxalo-2-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-indazol-1-yl)propionic acid; (R)-3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 2-(((benzyloxy)carbonyl)amino)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-chloropyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3,5-Dichlorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-fluoro-4-methoxyphenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-Cyclopropyl-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)octanoic acid; 3-(2,3-dihydrobenzofuran-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(quinolin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid (48); 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(thiophen-2-yl)propionic acid; 3-(pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-cyanophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-Fluoropyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(dibenzo[b,d]furan-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(4,6-dimethylpyrimidin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-Methylbenzo[d]thiazo-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(4-phenoxyphenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-morpholinophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-(1H-pyrrolo-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-((dimethylamino)methyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(pyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-(2-oxopyrrolidone-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1-propylpyrazole-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-2H-indazol-2-yl)propionic acid; 3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2H-indazol-2-yl)propionic acid; 3-(3-(3,5-dimethylpyrazol-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 4-(4-(benzyloxy)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)butyric acid; 3-(6-methoxypyridin-3-yl)-3-(3-methyl-5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (3S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid; 4-Phenylacetic-2-((5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)methyl)butyric acid; 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(pyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 2-(1-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)cyclopropyl)acetic acid; 3-(2-ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 4-(4-fluorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)butyric acid; 3-(5-methoxypyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(quinoxalo-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(quinolin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid; (S)-3-(6-((2-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)methyl)-2H-indazol-2-yl)-3-(quinolin-3-yl)propionic acid; (3S)-3-(quinolin-3-yl)-3-(6-(2-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid; (S)-3-(3-(2-oxopyrrolidone-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(3-(2-oxopyrrolidone-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-fluoro-6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(quinolin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2H-indazol-2-yl)propionic acid; (3S)-3-(quinolin-3-yl)-3-(6-(3-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)propyl)-2H-indazol-2-yl)propionic acid; 3-(5-(hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(6-(2-hydroxy-2-methylpropoxy)-5-methylpyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]) (-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-Methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-(2-oxopyrrolidone-1-yl)pyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(isoquinoline-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1,8-naphthid-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]) (-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methoxy)-2H-indazol-2-yl)propionic acid; (R)-3-(5-(hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1,8-naphthid-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-oxopyrrolidone-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridin-5-yl)propionic acid; 3-(5-(1,3-dioxolane-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-((dimethylamino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(2-ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(2-ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2,3-dihydro-[1,4]di) Indo[2,3-b]pyridin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(benzo[d]thiazo-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-morpholinopyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-(methylamino)pyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)propionic acid; 3-(6-methoxypyridazine-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(2-methoxypyrimidin-5-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2H-indazol-2-yl)propionic acid; 3-(2-(azacyclobutan-1-yl)pyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-( (5-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(7-ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; Tertiary oxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-morpholinopyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(pyrrolidone-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(aminomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-([1,3]m-dioxacyclopenteno[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(1,3-dioxolane-2-yl)-6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(6-(1H-pyrazol-1-yl)pyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(5-(1,3-dioxolane-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(1,3-dioxolane-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(1-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(1H-pyrazol-5-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(6-morpholinopyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-hydroxypropyl-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(5-(2-hydroxypropyl-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(2-hydroxypropyl-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(6-methoxypyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(5-(2-oxopyrrolidone-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(2-oxopyrrolidone-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(morpholino-4-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(dimethylcarbamoyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-Cyclopropylpyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(azacyclobutane-1-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-((2-(dimethylamino)ethyl)carbamoyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethoxy)-1H-indazol-1-yl)hexanoic acid; 3-(5-(dimethylamino)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-Cyclohexyl-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (R)-3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(methylsulfonamidomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(acetamidomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)propionic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)propionic acid; 4-((6-(2-carboxy-1-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)ethyl)pyrazin-2-yl)amino)butyric acid; 3-(6-methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-indazol-1-yl)propionic acid; (R)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid; (S)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid; (R)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid; (S)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propionic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(1-methyl-1,2,3,4-tetrahydropyridino[2,3-b]pyrazin-6-yl)ethoxy)-1H-indazol-1-yl)propionic acid; (S)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]) Azine-6-yl)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3-yl)propionic acid; and (R)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]) (6-azinyl)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3-yl)propionic acid; Or its pharmaceutically acceptable salt.

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