Amide compounds as PGE2 receptor antagonists

Abstract

The present invention relates to compounds of general formula I or pharmaceutically acceptable salts thereof as PGE2 receptor antagonists. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a series of novel amide compounds as PGE2 receptor antagonists, which can be used to treat PGE2-mediated diseases or conditions, such as pain, inflammation, cancer (immunotherapy) and neurodegenerative diseases, and also includes related compound preparations and methods of use thereof. Background Art

[0002] The present invention relates to amides or pharmaceutically acceptable salts thereof, pharmaceutically acceptable prodrugs, compound preparations containing such components and medical uses thereof. The compounds of the present invention have the activity of prostaglandin E2 (PGE2) receptor antagonists and can be used to treat or alleviate cancer, pain, inflammation and other inflammation-related diseases, such as arthritis / rheumatoid arthritis, skin inflammation, vascular inflammation, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), brain injury, neuropathic pain, hypertension, ischemic or hemorrhagic injury, kidney disease / transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, chronic prostatitis, glomerulonephritis, allergies, pelvic inflammatory disease, sarcoidosis, vasculitis, interstitial cystitis, premature birth, autoimmune diseases, neuroinflammation after epileptic seizures, endometriosis, etc.

[0003] Prostaglandins are mediators of pain, fever and other inflammation-related symptoms. In particular, prostaglandin E2 (PGE2) is the most important eicosanoid detected in inflammatory diseases. In addition, PGE2 is also considered to be an important component of the immunosuppressive environment caused by many solid tumors (Whiteside, "Expert Opinion on Biological Therapy", 2010, 1019-1035). PGE2 receptor 2 (EP2) and receptor 4 (EP4) have been shown to be expressed in tumor cells of various cancers (including colon cancer, prostate cancer and breast cancer). EP2 / EP4 gene knockout, as well as the use of EP2 / EP4 antagonists to block the signaling pathways of PGE2 / EP2 and PGE2 / EP4, have been shown to be effective interventions for the treatment of various cancers (including colon cancer, malignant gliomas and neuroblastomas). Recent studies have found that hepatic stellate cells can increase the number of Th17 cells and regulatory T cells through the PGE2 / EP2 pathway (Li et al., "Journal of Translational Medicine", 2017, 75). Therefore, EP2 / EP4 antagonists could improve or synergistically enhance the anti-tumor effects of checkpoint inhibitors such as anti-CTLA4, anti-PD-L1, or anti-PD-1 antibodies.

[0004] The present invention relates to a series of novel amide derivatives as PGE2 receptor antagonists (especially EP2 / EP4 antagonists), methods for treating PGE2-mediated diseases (especially cancer, pain, inflammation and neurodegenerative diseases), and certain compound preparations of these ingredients. Summary of the invention

[0005] The present invention includes compounds shown in general formula I or pharmaceutically acceptable salts thereof as PGE2 receptor antagonists

[0006]

[0007] Where:

[0008] R 1 Indicates -CO2H, -C(O)NHS(O)2R 7 、-NHC(O)NHSO2R 7 , -1H-tetrazolyl, -P(O)(OH)2, -1,2,4-oxadiazole-5(4H)-1 or -tetrazolyl-5(4H)-1;

[0009] Y is N, CR 3 or It is a chemical bond;

[0010] R 2 , R 3 are independently selected from the following groups: halogen, hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Fluorinated cycloalkyl, C 1-6 Fluoroalkyl, or R 2 , R 3 and the carbon atoms connected to both form a 3-6 membered carbon ring which can be optionally replaced by R e substituted, or a 3-6 membered ring containing one or two heteroatoms such as S, O or NR b , where R b Selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 1-6 Fluoroalkyl, C 0-6 Alkylene-aryl, C 0-6 Alkylene-heteroaryl, C(O)C 1-6 Alkyl, C(O)aryl, S(O)2C 1-6 Alkyl, S(O)2C 3-6 Cycloalkyl, S(O)2aryl;

[0011] X does not exist or is halogen, -CN, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or OC 1-6 Halogenated alkyl.

[0012] Select from the following structures:

[0013]

[0014] Z is O, S or NR 8 ;X 1 N or CR 4 ;

[0015] X 2 , X 3 N, CR are independently 4 or with -Y 2 -Ar 2 Connected carbon atoms, provided that X 2 or X 3 At least one of them is with -Y 2 -Ar 2 connected carbon atoms;

[0016] X 4 O, S, N, NR 5 or CR 5 ;

[0017] X 5 O, S, N, CR 6 or -C(O)-;

[0018] X 6 , X 7 and X 8 are independently N or C;

[0019] Y 2 -C(O)-, -(CR a R 1a ) n -, -CH=CH, -C≡C-, -O-, -S-, S(O)2-, -S(O)2NR b -、-NR b S(O)2-、-C(O)NR b -、-NR b C(O)-、NR b C(O)NR b -、NR b S(O)2NR b -, -NRb-, or Y 2 does not exist, and Ar 2 Directly with X 2 or X 3 connected;

[0020] Y 1 -O-, -S-, -NR b-, -C(O)- or -CR a R 1a -;

[0021] Y 3 For-(CR a 2) m -;

[0022] n and m are independently 0, 1, 2 or 3; r is 1 or 2;

[0023] Each R a and R 1a are independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, or two R a and R 1a Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl or heterocyclic group;

[0024] Each R 4 , R 5 and R 6 are independently hydrogen, alkyl, halogen, -OR 8 、-NR 8 R 9 、-SR 8 、-S(O)2NR 8 R 9 、-S(O)2R 11 、-CN、C 3-6 Cycloalkyl, -C 0-6 Alkylene-aryl, -C 0-6 Alkylene-heteroaryl or haloalkyl;

[0025] Ar 1 ,Ar 2 Each independently selected from: -OR 8 、-SR 8 NR 8 R 9 , C 1-10 Alkyl, C 1-10 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-aryl, -C 0-6 Alkylene-heteroaryl and -C 0-6 Alkylene-heterocyclyl, or C 3-6 A fused analog of a cycloalkyl group; wherein Ar 1 and Ar 2 1-3 R e Group substitution;

[0026] Two Ar atoms on adjacent carbon atoms2 Together with carbon atoms, they can form a 3-6-membered carbocyclic ring, a 4-8-membered bicyclic ring, a C5-C 10 Aromatic ring (optionally with one or more R e Replacement), C2-C 90 Heteroaromatic ring (optionally replaced by one or more R e substituted), or contain one, two or three heteroatoms (such as S, O or NR b ) of a 3-6 membered ring, a 4-8 membered bicyclic ring or a 5-8 membered spiro ring;

[0027] Each R e are independently halogen, hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 1-6 Fluoroalkyl, -C2-C9 alkynyl, -C 0-6 Alkylene-heterocyclyl, -C 0-6 Alkylene-aryl, -C 0-6 Alkylene-heteroaryl, SF5, -C 0-6 Alkylene-OR 8 , -C 0-6 Alkylene-P(O)Me2, -C 0-6 -Alkylene-NR 8 R 9 , -C 0-6 Alkylene-C(O)NR 8 R 9 , -C 0-6 Alkylene-SR 8 , -C 0-6 Alkylene-S(O)2NR 8 R 9 , -C 0-6 Alkylene-S(O)2R 10 or -C 0-6 Alkylene -CN, where C 1-6 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, -C 0-6 Alkylene-cycloalkyl, -C 0-6 Alkylene-heterocyclyl, -C 0-6 Alkylene-aryl and -C 0-6 Alkylene-heteroaryl; R e Can be one, two or three R v replace;

[0028] R v are independently alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, halogen, -OR 8 、-NR8 R 9 、-CN、-C(O)R 10 、-C(O)NR 8 R 9 、-NR 8 C(O)R 10 、-NR 8 C(O)OR 9 、-NR 10 C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O)2R 10 、-S(O)R 10 、-SR 8 、-S(O)2NR 8 R 9 、-S(O)NR 8 R 9 、-NR 8 S(O)R 10 、-NR 8 S(O)2R 10 or -NR 10 S(O)2NR 8 R 9 ; wherein the alkyl group can be optionally replaced by -OR 8 or -NR 8 R 9 Substitution, cycloalkyl and heterocyclyl may be optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl;

[0029] R 7 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, aryl and heteroaryl groups;

[0030] Each R 8 and R 9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl may be selectively substituted by one, two or three groups selected from halogen, alkyl and haloalkyl; or R 8 and R 9 Together with the one or more atoms to which they are attached, they form a heterocyclic group, which may be optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl;

[0031] Each R 10are independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl may be selectively substituted with one, two or three groups selected from halogen, alkyl and haloalkyl;

[0032] Select from the following structures:

[0033]

[0034] Can be one or more R e replace.

[0035] In one embodiment, Select from the following structures:

[0036]

[0037]

[0038]

[0039]

[0040] In one embodiment, a compound of Formula II or a pharmaceutically acceptable salt thereof is provided:

[0041]

[0042] Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0043] In one embodiment, the present invention also provides a compound of formula III or a pharmaceutically acceptable salt thereof:

[0044]

[0045] Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0046] In one embodiment, the present invention also provides a compound of formula IV or a pharmaceutically acceptable salt thereof:

[0047]

[0048] Where: X 5 N or CR 6 ; R 2 , R 3 , R 5 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition is as shown in Formula I. In one embodiment, a compound of Formula V or a pharmaceutically acceptable salt thereof is provided:

[0049]

[0050] Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0051] In one embodiment, the present invention further provides a compound of formula VI or a pharmaceutically acceptable salt thereof:

[0052]

[0053] Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0054] In one embodiment, the present invention also provides a compound of formula VII or a pharmaceutically acceptable salt thereof:

[0055]

[0056] Where: X 4 O or S; R 2 , R 3 , Y 1 , Y 2 ,Ar1 and Ar 2 The definition of is as shown in the general formula I.

[0057] In one embodiment, a compound of Formula VIII or a pharmaceutically acceptable salt thereof is provided:

[0058]

[0059] Where X 4 O or S; R 2 , R 3 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0060] In one embodiment, a compound of Formula IX or a pharmaceutically acceptable salt thereof is provided:

[0061]

[0062] Where X 4 , X 5 N or CR respectively 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition is as shown in Formula I. In one embodiment, the present invention also provides a compound of Formula X or a pharmaceutically acceptable salt thereof:

[0063]

[0064] Where X 4 , X 5 N or CR respectively 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition is as shown in Formula I. In one embodiment, a compound of Formula XI or a pharmaceutically acceptable salt thereof is provided:

[0065]

[0066] Where X 4 , X 5 N or CR respectively 6 ; R 6, Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0067] In one embodiment, the present invention also provides a compound of Formula XII or a pharmaceutically acceptable salt thereof:

[0068]

[0069] Where X 4 , X 5 N or CR respectively 6 ; R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0070] In one embodiment, the present invention also provides a compound of formula XIII or a pharmaceutically acceptable salt thereof:

[0071]

[0072]

[0073] Where X 4 , X 5 N or CR respectively 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in general formula I. t is 0, 1 or 2.

[0074] In one embodiment, the present invention also provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:

[0075]

[0076] Where X 4 , X 5 N or CR respectively 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in general formula I. t is 0, 1 or 2.

[0077] In one embodiment, the present invention also provides a compound of formula XV or a pharmaceutically acceptable salt thereof:

[0078]

[0079] Where X 4 , X 5 N or CR respectively 6 ; R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I. t and q are 0, 1 or 2 respectively.

[0080] In one embodiment, the present invention also provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof:

[0081]

[0082] Where X 4 , X 5 N or CR respectively 6 ; R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in general formula I. t is 0, 1 or 2.

[0083] In one embodiment, the present invention also provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof:

[0084]

[0085] Where X 4 , X 5 N or CR respectively 6 ; R 2 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

[0086] In some embodiments, the compound of Formula I-Formula XVII is selected from the following compounds or pharmaceutically acceptable salts thereof:

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[0174] The present invention also includes a prodrug of the inventive compound. The prodrug can be selected from esters or amides.

[0175] The present invention also includes a compound preparation, which is prepared by mixing the compound of the present invention with one or more physiologically acceptable carriers or excipients.

[0176] The invention also includes a compound of the invention or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.

[0177] The present invention also includes a method of treating a human or animal disease mediated by the action of PGE2 receptors - the method comprising administering to a subject an effective amount of an inventive compound.

[0178] The present invention also includes the use of the inventive compounds to prepare therapeutic agents for treating diseases mediated by PGE2 receptors. DETAILED DESCRIPTION

[0179] definition

[0180] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight chain (i.e., unbranched), branched, cyclic hydrocarbon group or combinations thereof having a specified number of carbon atoms (i.e., C1-10 means 1 to 10 carbon atoms), which may be fully saturated, monounsaturated or polyunsaturated, and may include divalent and polyvalent groups. Examples of saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl-methyl and other groups, homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl and other substances. Unsaturated alkyl refers to an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are referred to as "higher alkyl groups." Alkyl groups may be optionally substituted with one or more halogen atoms.

[0181] The term "haloalkyl" refers to an alkyl group as described above in which one or more hydrogen atoms have been replaced by a halogen atom.

[0182] The term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which can be straight chain, branched chain, Z- or E-, or a combination thereof. Examples of alkenyl include CH3CH=CH-, CH2=CHCH2- and CH(CH3)2CH=CH-.

[0183] The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from an alkyl group, examples of which include but are not limited to -CH2CH2CH2CH2-, -CH=CH-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Alkylene groups may be optionally substituted with one or more substituents described herein, respectively, and include groups having "cis" and "trans" orientations or "E" and "Z" orientations. Typically, an alkyl (or alkylene) group has 1 to 24 carbon atoms; in the present invention, those groups having 10 or fewer carbon atoms are preferred. "Lower alkyl" or "lower alkylene" are short chain alkyl or alkylene groups, typically having eight or fewer carbon atoms. Alkylene groups may be optionally substituted with one or more halogen atoms.

[0184] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which can be a straight chain, a branched chain, or a combination thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, etc. Alkynyl can be selectively substituted with one or more halogen atoms.

[0185] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups.

[0186] The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups. The alkyl or aryl moieties of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

[0187] The term "cycloalkyl" or "carbocycloalkyl" refers to a monocyclic, bicyclic or spirobicyclic carbocycle, each ring having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group, wherein the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. Spirobicyclic carbocycles are bicyclic (only two rings) or have a bicyclic moiety as part of a larger ring system; in either case, the two rings are connected by a defined single common carbon atom. Cycloalkyl groups may be optionally substituted with one or more halogen atoms.

[0188] The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. 1-6 Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and the like.

[0189] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with other terms refers to a stable straight chain, branched chain, cyclic hydrocarbon group or combination thereof, consisting of at least one carbon atom and at least one heteroatom, wherein the heteroatom is selected from O, N, P, Si and S; wherein the nitrogen (N), phosphorus (P) and sulfur (S) atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom O, N, P, S and Si may be located at any interior position of the heteroalkyl group, or at the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may appear consecutively, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heterocycloalkylene" by itself or as part of another substituent refers to a divalent group derived from a heteroalkyl group, examples of which include, but are not limited to, -CH2-CH2-S, -CH2-CH2-, and -CH2-S-CH2-CH2-NH-CH2-. For heterocycloalkylene, heteroatoms may also occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heterocycloalkylene linking groups, the direction in which the molecular formula of the linking group is written does not imply the orientation of the linking group. For example, the molecular formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-. As described above, the heteroalkyl groups used herein also include those groups that are connected to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR' and / or -S02R'. When listing "heteroalkyl" and further listing specific heteroalkyl groups (such as -NR'R", etc.), the terms "heteroalkyl" and -NR'R" should be understood as not being redundant or mutually exclusive; the specific heteroalkyl groups are listed for clarity of definition. Therefore, the term "heteroalkyl" in the present invention should not be interpreted as excluding specific heteroalkyl groups (such as -NR'R").

[0190] The term "cycloalkoxy" refers to a cycloalkyl group as defined above bonded to an oxygen atom, such as cyclopropyloxy.

[0191] The term "haloalkoxy" refers to an alkoxy group as described above wherein one or more hydrogen atoms have been replaced by a halogen atom.

[0192] The term "aryl" refers to a monocyclic or bicyclic aromatic ring containing only carbon atoms. A "fused analog" of an aryl group refers to an aryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclyl group, with the point of attachment being on the aromatic portion. Examples of aryl groups and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.

[0193] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, each ring containing 5 to 6 atoms. A "fused analog" of a heteroaryl refers to a heteroaryl fused to a monocyclic cycloalkyl or monocyclic heterocyclyl, with the point of attachment being on the aromatic portion. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furano(2,3-b)pyridinyl, quinolyl, indolyl, isoquinolyl, and the like.

[0194] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring system containing at least one heteroatom selected from N, S and O, each ring having 3 to 10 atoms, and the point of attachment can be carbon or nitrogen. "Heterocyclyl" includes "fused analogs", i.e., monocyclic heterocycles fused to heterocycles, carbocycles, aryls, heteroaryls, and the point of attachment is located on the non-aromatic portion. Examples of "heterocyclyl" and fused analogs thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, tetrahydrothiazolyl, dioxolanyl, oxazolidinyl, decahydroquinolinyl, piperidinyl, 4-piperidonyl, quinuclidinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptane, azabicyclooctanyl, azabicyclononanyl, azaspiroheptane, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H3'Hspiro[cyclopropane-1,2'-pyrrolidinyl], hexahydro-1H-pyrazinyl, hexahydro-1 H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxazolospironyl, oxazolospiroctyl, diazospilonyl, oxazolobicycloheptyl, hexahydropyrrolidinyl, 4(1H0-oxide, tetrahydro-2H-thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide, bicycloheptynyl, 2,3-dihydrofuran(2,3-b)pyridinyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, hexahydro-1H-pyrrolidine, dihydroindolinyl, and the like. The term also includes non-aromatic partially unsaturated monocyclic rings such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through nitrogen.

[0195] The alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups described in the definition are unsubstituted or substituted by at least one substituent (selected from the above substituents). The substituents are selected from: halogen atoms, alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, haloalkyl groups with 1 to 4 carbon atoms, haloalkoxy groups with 1 to 4 carbon atoms, cyano groups, alkynyl groups with 2 to 6 carbon atoms, alkanoyl groups with 1 to 5 carbon atoms, cycloalkyl groups with 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups with 7 to 10 carbon atoms, and arylcarbonyl groups; two adjacent -X groups may be selectively connected at Together, they form an alkylene or alkenylene chain having 3 or 4 carbon atoms, an aminocarbonyl group, an alkenyl group having 2 to 5 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an aminosulfinyl group, an aminosulfonyl group, a hydroxyl group, -SF5, -P(O)Me2, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms, an alkoxysulfonyl group having 1 to 4 carbon atoms, a Alkanoylamino having 1 to 4 carbon atoms, alkanoyl(alkyl)amino having 1 to 6 carbon atoms, alkanoylaminoalkyl having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, alkanoyl(alkyl)aminoalkyl having 1 to 6 carbon atoms in the alkanoyl and each alkyl moieties, alkylsulfonylamino having 1 to 4 carbon atoms, mono- or dialkylaminocarbonyl having 1 to 6 carbon atoms, mono- or dialkylaminosulfinyl having 1 to 6 carbon atoms, mono- or dialkylaminosulfonyl having 1 to 6 carbon atoms, aminoalkyl having 1 to 4 carbon atoms, mono- or dialkylamino having 1 to 6 carbon atoms, mono- or dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, aralkyl having 7 to 10 carbon atoms, heteroaralkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroaralkyloxy having 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonylamino having 1 to 4 carbon atoms.

[0196] Unless otherwise indicated, the term "halogen" by itself or as part of other substituents refers to fluorine, chlorine, bromine or iodine atoms. In addition, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl. For example, the term "halo (C1-C4) alkyl" includes but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0197] "Prodrug" refers to a formulation that is converted into a parent drug in vivo. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, a prodrug is bioavailable after oral administration, while the parent drug is not. The solubility of the prodrug in the compound formulation is also improved compared to the parent drug. Examples of prodrugs include, but are not limited to, any compound of Formula I; the compound is administered in the form of an ester ("prodrug") so that it can pass through the cell membrane when water solubility is not conducive to fluidity, and once it enters the cell where water solubility is favorable to it, the compound will be metabolically hydrolyzed to a carboxylic acid, i.e., an active entity. Examples of prodrugs also include short peptides (polyamino acids) bonded to an acid group, wherein the peptide will display the active ingredient after metabolism.

[0198] Optical isomers-diastereomers-geometric isomers-tautomers

[0199] The compounds of the present invention may contain one or more asymmetric centers and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to encompass all such isomeric forms of the compounds.

[0200] Some compounds of the present invention contain olefinic double bonds, including both E-type and Z-type geometric isomers (unless otherwise specified).

[0201] Some compounds may contain one or more cyclic ring systems and may exist as cis- and trans-isomers. The present invention is intended to encompass all such cis- and trans-isomers.

[0202] Some compounds of the present invention may have different hydrogen attachment points, which are called tautomers; for example, a ketone and its enol form are called keto-enol tautomers. Various tautomers and mixtures thereof are also included in the compounds of the present invention.

[0203] The compounds described herein can be separated into diastereomeric pairs of enantiomers by methods such as fractional crystallization from a suitable solvent (e.g., MeOH or EtOAc or a mixture thereof). The pairs of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, for example, using an optically active amine or acid as a resolving agent or separating on a chiral HPLC column.

[0204] Alternatively, any enantiomer of a compound described herein may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0205] Stable isotope labeled analogs

[0206] In the compounds of the present invention, one or more protons (hydrogen atoms) may be replaced by deuterium atoms to provide deuterated analogs, which may have better pharmacokinetic properties or pharmacological activities.

[0207] Salts and their preparations

[0208] The compounds of the present invention can be used as free bases or salts.

[0209] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic or organic bases, inorganic or organic acids). Salts prepared from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc salts, etc., especially ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tris(hydroxymethyl)methylamine, tromethamine and the like.

[0210] When the compound of the present invention is alkaline, pharmaceutically acceptable non-toxic inorganic and organic acids can be used to prepare salts. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. In particular, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

[0211] It will be understood that the compounds of the present invention described herein also include pharmaceutically acceptable salts.

[0212] Oral preparations can also be hard capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate or kaolin); or soft capsules in which the active ingredient is mixed with water or an oily medium (such as peanut oil, liquid paraffin or olive oil).

[0213] Aqueous suspensions contain the active substance and excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents can be naturally occurring phosphatides (such as lecithin) or condensation products of alkylene oxides with fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain fatty alcohols (such as heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (such as polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (such as ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (such as sucrose, saccharin or aspartame).

[0214] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (such as liquid paraffin). The oil suspension may contain a thickener such as beeswax, solid paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents may also be added to prepare a palatable oral preparation. In order to preserve these ingredients, an antioxidant (such as ascorbic acid) may be added.

[0215] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water can be used as the active ingredient, mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are as described above. Other excipients, such as sweeteners, flavoring agents and coloring agents, can also be added.

[0216] The compound preparation of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture of the two. Suitable emulsifiers can be naturally occurring phospholipids (such as soybean lecithin, lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan monooleate), and condensation products of partial esters and ethylene oxide (such as polyoxyethylene sorbitan monooleate). Emulsions may also contain sweeteners and flavorings.

[0217] Sweeteners such as glycerol, propylene glycol, sorbitol or sucrose may be added to syrups and elixirs. Such preparations may also contain analgesics, preservatives, flavoring agents and coloring agents. The compound preparation may be in the form of sterile water for injection or oil suspension. Such suspensions can be prepared according to known techniques using the above-mentioned appropriate dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in non-toxic diluents or solvents for parenteral administration, such as solutions in 1,3-butanediol. The carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0218] The compounds of the present invention can also be administered intranasally or by inhalation, usually in the form of dry powder (alone or mixed, such as a dry blend with lactose; or as mixed component particles, such as mixed with phospholipids such as lecithin) via a dry powder inhaler, or in the form of an aerosol spray via a pressurized container, pump, injector, nebulizer (type I nebulizer using electrohydrodynamic principle to generate fine mist is recommended) or sprayer; with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The powder for intranasal administration may contain a bioadhesive, such as chitosan or cyclodextrin.

[0219] The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound of the invention which includes ethanol, aqueous ethanol or a suitable substitute for dispersing, solubilizing or prolonging the release of the active substance, a propellant as a solvent and optionally a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

[0220] Prior to use in dry powder or suspension formulations, the drug product is micronized to a particle size suitable for administration by inhalation (usually less than 5 microns).

[0221] To this end, any suitable comminution method may be used, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[0222] Capsules (e.g., capsules made of gelatin or HPMC), blisters and cartridges for use in inhalers or insufflators can be formulated to contain a powder mix of the compound of the invention, an appropriate powder base such as lactose or starch, and a modifier such as L-leucine, mannitol or magnesium stearate. Lactose can be in anhydrous or monohydrate form, the latter being recommended. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0223] When a suitable solution preparation is used in an atomizer that generates fine mist using the electrohydrodynamic principle, each spray contains 1 to 20 mg of the compound of the present invention and the spray volume is 1 to 100 L. Conventional preparations include the compound of formula (A): propylene glycol, sterile water, ethanol and sodium chloride. Propylene glycol can also be replaced by solvents such as glycerol and polyethylene glycol.

[0224] In the preparation for inhalation / intranasal administration of the present invention, appropriate flavors (such as menthol and levomenthol) or sweeteners (such as saccharin or saccharin sodium) may be added.

[0225] Preparations for inhalation / intranasal administration can be formulated into immediate-release and / or sustained-release preparations using materials such as polylactic-co-glycolic acid (PGLA). Sustained-release preparations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release dosage forms.

[0226] When dry powder inhalers and aerosol sprays are used for administration, the dosage unit is determined by a valve (whose function is to provide a metered unit dose). The device according to the present invention is usually designed to administer a metered dose, or a "puff" containing 1 pg to 1 mg of the compound of the present invention. The total daily dose is usually 1 pg to 1 mg, which can be administered once or in divided doses throughout the day (the latter is more common).

[0227] The compounds of the present invention may also be administered rectally in the form of suppositories. These preparations may be prepared by mixing the drug with a suitable non-irritating excipient; such excipients are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0228] For topical application, ointments, creams, gels, solutions or suspensions containing the compounds of the invention may be used. (For the purposes of this application, topical applications shall include mouthwashes and gargles.)

[0229] The above-mentioned conditions can be effectively treated by administration at a dosage of about 0.01 to 140 mg / kg body weight per day or about 0.5 mg to 7 g per patient per day. For example, administration of the relevant compound at a dosage of about 0.01 to 50 mg / kg body weight per day or about 0.5 mg to 3.5 g per patient per day can effectively treat the condition (recommended 2.5 mg to 1 g per patient per day).

[0230] When the active ingredient is combined with a carrier material to form a single dosage form, the amount used will vary depending on the subject being treated and the specific route of administration. For example, a human oral dosage form may contain 0.5 mg to 5 g of active ingredient, compounded with an appropriate amount (approximately 5% to 95% of the total dosage form) of carrier material. Dosage unit forms generally contain about 1 to 500 mg of active ingredient (usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg).

[0231] However, it will be appreciated that the specific dosage administered to any particular patient will depend upon a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0232] application

[0233] The compounds of the present invention are antagonists of PGE2 receptors and are therefore useful in treating PGE2-mediated diseases or conditions.

[0234] The present invention also includes a method for treating cancer using an effective dose of the compound of the present invention or simultaneously using an effective dose of other drugs; the combination therapy includes chemotherapeutic drugs, PI3K / AKT pathway inhibitors, endocrine / hormone drugs, and immunotherapy drugs, such as anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) antibodies, anti-programmed death ligand 1 (anti-PDL1) antibodies, anti-programmed cell death protein 1 (anti-PD1) antibodies, indoleamine-2,3-dioxygenase (IDO) inhibitors, tryptophan-2,3-dioxygenase (TDO) inhibitors, EP1 / EP3 agonists and antimetabolites.

[0235] In another aspect of the invention, the cancer treated is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer. In a more specific aspect of the invention, a method for treating cancer and / or generating a memory immune response is provided, comprising administering a compound of the invention.

[0236] synthesis

[0237] The compounds of the present invention can be prepared according to the following synthetic scheme:

[0238] Reaction 1

[0239]

[0240] Reaction 2

[0241]

[0242] Reaction 3

[0243]

[0244] Reaction 4

[0245]

[0246] Reaction 5

[0247]

[0248] Reaction 6

[0249]

[0250] Reaction 7

[0251]

[0252] Biological activity evaluation

[0253] 1. The HEK-293CNG (cyclic nucleotide gated) cell line expresses a modified CNG channel (which causes cell membrane depolarization due to increased intracellular cAMP levels, and depolarization can be detected using fluorescent membrane potential dyes). The cell line is designed to express human EP2 (PTGER2) or EP4 (EP4R). The resulting cell line ACTOne TM PTGER2 or ACTOne TM EP4R and fluorescent membrane potential dyes were purchased from eEnzyme (Gaithersburg, MD, USA) and used for current assays. Briefly, cells were plated at 1.2 × 10 4Cells were plated in 20 μL of DMEM containing 2% fetal bovine serum (FBS, VWR International), 1x penicillin / streptomycin (GenClone), 0.2 μg / mL puromycin (InvivoGen), and 50 μg / mL G418 (InvivoGen) per well (384-well plate, Greiner). The next day, cells were dye loaded with 1x dye loading solution (eENZYME) at 20 μL / well according to the supplier's instructions. The cells were cultured in the dark for 2 hours at room temperature (RT), and then pre-read using a CLARIOstar microplate reader (BMG LABTECH, Germany) according to the following filter settings to obtain background signals: excitation wavelength = 530 / 20 nm, emission wavelength = 590 / 20 nm. Next, serial dilutions of the compound (along with the DMSO control) were added to the well plate (5 μL / well), cultured at room temperature for 15 minutes, and then 5 μL PGE2 was added to each well to a final concentration of 5 nM. The plate was then incubated at room temperature for an additional 30 minutes before a final read using the same instrument settings. The background-subtracted signal was used to calculate the IC 50 All test wells were repeated once.

[0254] 2. Human EP2 and EP4 reporter gene detection kits were purchased from Cayman Chemical (Ann Arbor, Michigan, USA). The detection was performed according to the provided instruction manual. Briefly, during reverse transfection, 6.0 x 10 4 293T cells (ATCC) were seeded into each well of the provided strip plate coated with a proprietary transfection complex containing DNA constructs for expression of human EP2 or EP4 and a cAMP response element-regulated secreted alkaline phosphatase (SEAP) reporter gene. Each well contained 200 μL of DMEM supplemented with 2% FBS and incubated at 37°C in a 5% CO2 environment for 20-24 hours. At the end of the incubation period, the medium was carefully removed and 150 μL of pre-warmed serum-free medium was added. PGE2 and the test compound were simultaneously prepared at 4 times the desired final concentration and 50 μL was added to each assigned well, resulting in a final PGE2 concentration of 13 nM (EP2 detection) and 2 nM (EP4 detection), respectively. After 6-8 hours of incubation, 10 μL of the medium in each well was transferred to the corresponding well on a new well plate, which was then sealed and incubated at 65°C for 30 minutes. After the incubation period, the well plate was cooled to room temperature and 50 μL of SEAP substrate was added to each well. The luminescent signal was measured using a CLARIOstar microplate reader.

[0255] Table 1 shows the activity of selected compounds of the invention in the EP2 antagonist assay. 50The value is the half inhibitory concentration (A: IC 50 ≤100nM; B:IC 50 Between 100nM and 1000nM; C: IC 50 ≥1000nM).

[0256] Table 1 EP2 antagonist activity

[0257]

[0258]

[0259]

[0260] Table 2 shows the activity of selected compounds of the invention in the EP4 antagonist assay. 50 The value is the half inhibitory concentration (A: IC 50 ≤100nM; B:IC 50 Between 100nM and 1000nM; C: IC 50 >1000nM).

[0261] Table 2 EP4 antagonist activity

[0262]

[0263] Abbreviations

[0264] The following abbreviations have the indicated meanings. EA: ethyl acetate; CIP: 2-chloro-1,3-dimethylimidazolium hexafluorophosphate; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL: diisobutylaluminum hydride; DCM: dichloromethane; DIEA / DIPEA: diisopropylethylamine; DMAP: N,N-dimethylaminopyridine; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DMPE: 1,2-bis(dimethylphosphino)ethane; DMS O: dimethyl sulfoxide; dppb: 1,4-bis(diphenylphosphino)butane; dppe: 1,2-bis(diphenylphosphino)ethane; dppf: 1,1'-bis(diphenylphosphino)ferrocene; dppm: 1,1'-bis(diphenylphosphino)methane; DIAD: diisopropyl azodicarboxylate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HATU: 2-(7-azabenzotriazole)-1,1,3,3-tetramethyluronium hexafluorophosphate; HMPA : hexamethylphosphoramide; IPA: isopropanol; LDA: lithium diisopropylamide; LHMDS: lithium bis(hexamethyldisilazide)amide; LAH: lithium aluminum hydride; NCS: N-chlorosuccinimide; PE: petroleum ether; PyBOP: benzotriazol-1-yloxytripyrrolidino hexafluorophosphate; SGC: silica gel column chromatography; TDA: tri(2-(2-methoxyethoxy)ethyl)amine; DCM: dichloromethane; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; NCS: N-chlorosuccinimide; NMI: 1-methylimidazole; NMM: N-methylmorpholine; NMP: N-methylpyrrolidine; PPh3: triphenylphosphine; rt / RT: room temperature; sat.: saturated; T3P: propylphosphonic anhydride; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; MTBE: methyl tert-butyl ether; NBS: N-bromosuccinimide; DMA: N,N-dimethylacetamide; * in the structure: undetermined R or S chiral center.

[0265] LCMS conditions:

[0266] Column: Xtimate C18, 3mm, 4.6 x 50mm.

[0267] Mobile phase: 0.03% trifluoroacetic acid-water solution and 0.03% trifluoroacetic acid-acetonitrile solution;

[0268] Gradient: 5% to 95% acetonitrile in 6.5 min;

[0269] Flow rate: 1 mL / min;

[0270] Mass spectrometer: Waters UPLC-PDA-3100 (SQD3100) single quadrupole mass spectrometer.

[0271] The content of the present invention will be more easily understood with reference to the following examples. These examples are given to illustrate the present invention, but not to limit its scope.

[0272] Example 1

[0273] 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0274]

[0275] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid methyl ester

[0276]

[0277] To a mixture of 5-bromo-1H-indole-7-carboxylic acid methyl ester (500 mg, 1.97 mmol) and Cs2CO3 (769 mg, 2.36 mmol) in anhydrous DMF (10 mL) at 0°C, 1-(bromomethyl)-4-(trifluoromethyl)benzene (564 mg, 2.36 mmol) was added. The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was poured into 100 mL of ice water and extracted with 3 x 50 mL of ethyl acetate. The combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 10:1) to obtain the target compound (500 mg) as a white solid. LCMS (ES+): 412.20 [M+1] + .

[0278] Step 2 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

[0279]

[0280] To a solution of the product of step 1 (500 mg, 1.21 mmol) in MeOH / H2O (10 mL / 2.0 mL) was added LiOH·H2O (254 mg, 6.06 mmol) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. After cooling to 0°C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH to 6. The reaction mixture was extracted with 3x 30 mL of ethyl acetate. The combined organic layers were washed with 20 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound (479 mg) as a white solid. LCMS (ESI): 398.22 [M+1] + .

[0281] Step 3 Methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate

[0282]

[0283] To a mixture of the product of step 2 (398 mg, 1.0 mmol), methyl 4-(aminomethyl)benzoate (215 mg, 1.3 mmol) and HATU (456 mg, 1.2 mmol) in anhydrous DMF (100 mL) at 0°C, DIPEA (0.52 mL, 3.0 mmol) was added. Stir overnight at room temperature, then add 100 mL of water to quench the reaction mixture, and extract with 3 x 100 mL of ethyl acetate. Rinse the combined organic layer with 100 mL of saturated brine, dry over anhydrous Na2SO4, and concentrate. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.5 g) as a white solid. LCMS (ESI): 547.29 [M+1] + .

[0284] Step 4: Methyl 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate

[0285]

[0286] At 70°C, a mixture of the product of step 3 (30 mg, 0.06 mmol), (4-fluorophenyl)boronic acid (38 mg, 0.28 mmol), Pd(dppf)2Cl2 (4 mg, 0.01 mmol) and K2CO3 (38 mg, 0.17 mmol) in EtOH / H2O (5 ml / 0.05 ml) was stirred under nitrogen for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (27 mg) as a yellow solid. LCMS (ESI): 561.49 [M+1] + .

[0287] Step 5 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0288]

[0289] To a solution of the product of step 4 (42 mg, 0.07 mmol) in MeOH / H2O (5 mL / 0.5 mL), LiOH·H2O (16 mg, 0.37 mmol) was added. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the mixture was then treated with 6N hydrochloric acid to adjust pH≈6. The reaction mixture was then extracted with 3x 20 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to obtain the target compound (10.1 mg) as a white solid. LCMS (ESI): 547.40 [M+1] + . 1 H NMR spectrum: (500MHz, DMSO-d6)δ:9.00(t,J=5.9Hz,1H),7.99(d,J=1.7Hz,1H),7.83(d,J=8.1Hz,2H),7.79-7.70(m,2H),7.63(d,J=3.1Hz, 1H),7.56-7.48(m,3H),7.29(dt,J=8.9,4.8Hz,4H),6.98(d,J=8.0Hz,2H),6.72(d,J=3.2Hz,1H),5.72(s,2H),4.41(d,J=5.9Hz,2H).

[0290] Example 2

[0291] 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0292]

[0293] Using phenylboronic acid (15 mg) and the product of step 3 of Example 1 (30 mg) as starting materials, the same procedure as steps 4 and 5 of Example 1 was followed to obtain the target product (9 mg) as a white solid. LCMS (ESI): 529.4 [M+1] + .

[0294] 1 H NMR spectrum: (500MHz,CDCl3)δ:9.00(t,J=6.0Hz,1H),8.23(s,1H),8.02(d,J=1.8Hz,1H),7.84(d,J=8.0Hz,2H),7.81–7.75(m,1H),7.73(d,J=7.5Hz,2H),7.64(d,J=3.1Hz,1H), 7.53(d,J=1.7Hz,2H),7.47(t,J=7.7Hz,2H),7.33(d,J=3.2Hz,1H),7.28(d,J=7.9Hz, 2H), 6.99 (d, J = 8.0Hz, 2H), 6.73 (d, J = 3.1Hz, 1H), 5.72 (s, 2H), 4.41 (d, J = 5.8Hz, 2H).

[0295] Example 3

[0296] (R)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0297]

[0298] Using (R)-4-(1-aminoethyl)benzoic acid methyl ester and the product of step 2 of Example 1 (30 mg) as starting materials, the same procedures as steps 3, 4, and 5 of Example 1 were followed to obtain the target product (19 mg) as a white solid. LCMS (ESI): 561.3 [M+1] + .

[0299] Example 4

[0300] (R)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0301]

[0302] Starting from phenylboronic acid (55 mg), the same procedure as in Example 3 was followed to obtain the target product (19 mg) as a white solid. LCMS (ES+): 543.4 [M+1] + .

[0303] Example 5

[0304] 4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)-benzoic acid

[0305]

[0306] Using methyl 4-(1-aminocyclopropyl)benzoate and 4-fluorophenyl)boronic acid (37 mg) as starting materials, the same procedures as in Steps 3, 4, and 5 of Example 1 were followed to obtain the target product (7.4 mg) as a white solid. MS (ESI): 573.41 [M+1] + .

[0307] 1 H NMR spectrum: (500MHz, DMSO-d6)δ:9.27(s,1H),8.03(d,J=1.8Hz,1H),7.85–7.79(m,2H),7.77(d,J=8.2Hz,2H),7.62–7.58(m,3H),7.53(d,J=3.1Hz,1H) ,7.35–7.30(m,2H),7.22(d,J=8.2Hz,2H),6.93(d,J=7.9Hz,2H),6.73(d ,J=3.1Hz,1H),5.73(s,2H),1.20(q,J=5.1Hz,2H),0.95(q,J=5.0Hz,2H).

[0308] Example 6

[0309] 4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0310]

[0311] Starting from phenylboronic acid (15 mg), the same procedure as in Example 5 was followed to obtain the target product (0.85 mg) as a white solid. LCMS (ESI): 555.5 [M+1] + .

[0312] 1H NMR spectrum: (500MHz, DMSO-d6) δ12.77 (s, 1H), 9.29 (s, 1H), 8.09 (s, 2H), 8.06 (d, J = 1.8 Hz, 1H), 7.78 (t, J = 7.4 Hz, 4H), 7.64 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 3.2 Hz, 1H),7.50(t,J=7.7Hz,2H),7.36(t,J=7.4Hz,1H),7.23(d,J=8.2Hz,2H),6.95(d,J=8.0H z, 2H), 6.75 (d, J = 3.1Hz, 1H), 5.74 (s, 2H), 1.25 (d, J = 11.7Hz, 2H), 0.86 (d, J = 7.1Hz, 2H).

[0313] Example 7

[0314] 4-((5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0315]

[0316] Using (3-cyanophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 1 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 554.3 [M+1] + .

[0317] 1 H NMR (500MHz, DMSO) δ8.97(d,J=6.1Hz,1H),8.22(s,1H),8.15–8.07(m,2H),7.83(d,J=8.0Hz,2H),7.79(d,J=7.7Hz,1H),7.71–7.64(m,2H),7.60 (d,J=1.9Hz,1H),7.54(d,J=8.1Hz,2H),7.27(d,J=7.8Hz,2H),6.98(d,J=8.0Hz,2H),6.75(d,J=3.1Hz,1H),5.74(s,2H),4.43(d,J=5.8Hz,2H).

[0318] Example 8

[0319] 4-((5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0320]

[0321] Using (3,4-difluorophenyl)boronic acid as the starting material, the same steps as in Example 1 were followed to obtain the target product as a white solid. MS (ESI): 565.5 [M+1] + .

[0322] 1 H NMR spectrum: (500MHz, DMSO-d6)δ8.97(t,J=5.9Hz,1H),8.05(d,J=1.9Hz,1H),7.83(dd,J=7.6,5.7Hz,3H),7.65(d,J=3.1Hz,1H ),7.55–7.50(m,4H),7.31–7.24(m,2H),6.97(d,J=8.0Hz,2H),6.73(d,J=3.1Hz,1H),5.73(s,2H),4.42(d,J=5.8Hz,2H).

[0323] Example 9

[0324] 4-((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0325]

[0326] Using (3,5-difluorophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 1 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0327] 1 H NMR spectrum: (500MHz, CDCl3) δ: 12.77 (s, 1H), 8.97 (t, J = 5.9 Hz, 1H), 8.13 (d, J = 1. 9Hz,1H),7.84(d,J=8.0Hz,2H),7.67(d,J=3.2Hz,1H),7.59(d,J=1.9Hz,1H), 7.52(t,J=9.0Hz,4H),7.28(d,J=8.0Hz,2H),7.18(tt,J=9.2,2.4Hz,1H),6.9 7(d,J=8.0Hz,2H), 6.75(d,J=3.2Hz,1H), 5.74(s,2H), 4.44(d,J=5.8Hz,2H).

[0328] Example 10

[0329] 4-((1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)methyl)benzoic acid

[0330]

[0331] Using (3-(trifluoromethyl)phenyl)boronic acid as the starting material, the same steps as in Example 1 were followed to obtain the target product as a white solid. MS (ESI): 597.5 [M+1] + .

[0332] 1 H NMR spectrum: (500MHz, DMSO-d6)δ12.84(s,1H),9.02(t,J=6.0Hz,1H),8.14(d,J=1.8H z,1H),8.09–8.00(m,2H),7.83(d,J=8.0Hz,2H),7.72–7.68(m,2H),7.66(d,J=3 .3Hz,1H),7.59(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,2H),7.29(d,J=7.9Hz,2H),6 .98(d,J=8.0Hz,2H), 6.77(d,J=3.1Hz,1H), 5.74(s,2H), 4.44(d,J=5.8Hz,2H).

[0333] Embodiment 11

[0334] 4-((5-(3-Fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0335]

[0336] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid (15 mg) as the starting material, the same procedure as in Example 1 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 615.4 [M+1] + .

[0337] 1H NMR(500MHz,DMSO-d6)δ12.84(s,1H),9.00(t,J=6.0Hz,1H),8.20(s,1H),7 .96(d,J=10.0Hz,2H),7.83(d,J=7.7Hz,2H),7.68(d,J=3.3Hz,1H),7.63(d ,J=9.6Hz,2H),7.53(d,J=8.0Hz,2H),7.28(d,J=7.8Hz,2H),6.97(d,J=7.9 Hz, 2H), 6.77 (d, J = 3.1Hz, 1H), 5.75 (d, J = 4.3Hz, 2H), 4.45 (d, J = 5.8Hz, 2H).

[0338] Example 12

[0339] (R)-4-(1-(5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0340]

[0341] Using (3-cyanophenyl)boronic acid (39 mg) as the starting material, the same procedure as in Example 3 was followed to obtain the target product (11 mg) as a white solid. LCMS (ESI): 568.4 [M+1] + .

[0342] Embodiment 13

[0343] (R)-4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0344]

[0345] Using (3,4-difluorophenyl)boronic acid (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as Example 3 was followed to obtain the target product (25 mg) as a white solid. LCMS (ES+): 579.4 [M+1] + .

[0346] Embodiment 14

[0347] (R)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0348]

[0349] Using (3,5-difluorophenyl)boronic acid (42 mg) as the starting material, the same procedure as in Example 3 was followed to obtain the target product (15 mg) as a white solid. LCMS (ESI): 579.4 [M+1] + .

[0350] Embodiment 15

[0351] (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)ethyl)benzoic acid

[0352]

[0353] Using (3-(trifluoromethyl)phenyl)boronic acid (51 mg) as the starting material, the same procedure as in Example 3 was followed to obtain the target product (12 mg) as a white solid. LCMS (ESI): 611.4 [M+1] + .

[0354] Example 16

[0355] (R)-4-(1-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0356]

[0357] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as steps 4 and 5 of Example 3 was followed to obtain the target product (25 mg) as a white solid. LCMS (ES+): 629.2 [M+1] + .

[0358] Embodiment 17

[0359] 4-(1-(5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0360]

[0361] Using (3-cyanophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 5 was followed to obtain the target product (0.85 mg) as a white solid. LCMS (ESI): 580.5 [M+1] + .

[0362] Embodiment 18

[0363] 4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0364]

[0365] Using (3,4-difluorophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 5 was followed to obtain the target product (0.85 mg) as a white solid. LCMS (ESI): 591.5 [M+1] + .

[0366] Embodiment 19

[0367] 4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0368]

[0369] Using (3,5-difluorophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 5 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 591.4 [M+1] + .

[0370] 1 H NMR (500MHz, DMSO-d6) δ12.77(s,1H),9.26(s,1H),8.17(d,J=1.8Hz,1H),7.77(d,J=8.4Hz,2H),7.70(d,J=1.9Hz,1H),7.62–7.55(m ,6H),7.23(d,J=8.4Hz,3H),6.93(d,J=8.0Hz,2H),6.75(d,J=3.1Hz,1H),5.75(s,2H),1.22(t,J=3.6Hz,2H),0.99(q,J=5.0Hz,2H).

[0371] Embodiment 20

[0372] 4-(1-(1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0373]

[0374] Using (3-(trifluoromethyl)phenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 5 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 623.4 [M+1] +.

[0375] 1 H NMR (500MHz, DMSO-d6) δ12.78(s,1H),9.30(s,1H),8.17(d,J=1.8Hz,1H),8.12(d,J=8.2Hz,2H),7.79–7.68(m,5H),7.60(d,J=8.2Hz,2H),7.5 7(d,J=3.2Hz,1H),7.23(d,J=8.3Hz,2H),6.94(d,J=8.0Hz,2H),6.77(d,J=3.1Hz,1H),5.75(s,2H),1.23–1.20(m,2H),0.97(q,J=5.1Hz,2H).

[0376] Embodiment 21

[0377] 4-(1-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0378]

[0379] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid (15 mg) as the starting material, the same procedure as in Example 5 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 641.4 [M+1] + .

[0380] 1 H NMR(500MHz,DMSO-d6)δ11.16(s,1H),9.20(s,1H),8.21(d,J=1.8Hz,1H),8.04–7.98(m,2H),7.75(d,J=7.9Hz,2H),7.70–7.64(m,2H),7.61 –7.58(m,3H),7.12(d,J=8.0Hz,2H),6.93(d,J=7.9Hz,2H),6.77(d,J=3.1Hz,1H),5.73(s,2H),1.15(q,J=5.0Hz,2H),0.91(t,J=3.6Hz,2H).

[0381] Embodiment 22

[0382] 4-((4-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0383]

[0384] Using 4-bromo-1H-indole-7-carboxylic acid methyl ester and (3-cyanophenyl)boronic acid as starting materials, the same procedures as steps 1, 2, 3, 4, and 5 of Example 1 were followed to obtain the target product (2.8 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0385] Embodiment 23

[0386] 4-((4-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0387]

[0388] Using (4-fluorophenyl)boronic acid (30 mg) as the starting material, the same procedure as in Example 22 was followed to obtain the target product (28.8 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0389] Embodiment 24

[0390] 4-((1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)methyl)benzoic acid

[0391]

[0392] Using (3-(trifluoromethyl)phenyl)boronic acid (95 mg) as the starting material, the same procedure as in Example 22 was followed to give the desired product (28.8 mg) as a white solid.

[0393] LCMS(ESI):597.41[M+1] + .

[0394] Embodiment 25

[0395] 4-((4-(4-Fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0396]

[0397] Using (4-fluorophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 22 was followed to obtain the target product (0.85 mg) as a white solid. LCMS (ESI): 547.5 [M+1] + .

[0398] Embodiment 26

[0399] 4-((4-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0400]

[0401] Using phenylboronic acid as the starting material, the same procedure as in Example 22 was followed to obtain the target product (14.6 mg) as a white solid. LCMS (ESI): 529.41 [M+1] + .

[0402] Embodiment 27

[0403] 4-((4-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0404]

[0405] Using (3,5-difluorophenyl)boronic acid (43 mg) as the starting material, the same procedure as in Example 22 was followed to obtain the target product (21 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0406] Embodiment 28

[0407] 4-((4-(3-Fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0408]

[0409] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid (104 mg) as the starting material, the same procedure as in Example 22 was followed to obtain the target product (37.3 mg) as a white solid. LCMS (ESI): 615.35 [M+1] + .

[0410] Embodiment 29

[0411] (R)-4-(1-(4-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0412]

[0413] Using 4-bromo-1H-indole-7-carboxylic acid methyl ester, (R)-4-(1-aminoethyl)benzoic acid methyl ester and phenylboronic acid as starting materials, the same procedures as steps 1, 2, 3, 4 and 5 of Example 1 were followed to obtain the target product as a white solid. LCMS (ESI): 543.3 [M+1]+ .

[0414] Embodiment 30

[0415] (R)-4-(1-(4-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0416]

[0417] Using (3-cyanophenyl)boronic acid (39 mg) as the starting material, the same procedure as in Example 29 was followed to obtain the target product (23 mg) as a white solid. LCMS (ESI): 568.4 [M+1] + .

[0418] Embodiment 31

[0419] (R)-4-(1-(4-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0420]

[0421] Using (3,4-difluorophenyl)boronic acid (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as Example 29 was followed to obtain the target product (25 mg) as a white solid. LCMS (ESI): 579.4 [M+1] + .

[0422] Embodiment 32

[0423] (R)-4-(1-(4-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0424]

[0425] Using (3,5-difluorophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 29 was followed to obtain the target product (21 mg) as a white solid. LCMS (ESI): 579.3 [M+1] + .

[0426] Embodiment 33

[0427] (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)ethyl)benzoic acid

[0428]

[0429] Using (3-(trifluoromethyl)phenyl)boronic acid (51 mg) as the starting material, the same procedure as in Example 29 was followed to obtain the target product (23 mg) as a white solid. LCMS (ESI): 611.4 [M+1] + .

[0430] Embodiment 34

[0431] (R)-4-(1-(4-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0432]

[0433] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as Example 29 was followed to obtain the target product (25 mg) as a white solid. LCMS (ESI): 629.5 [M+1] + .

[0434] Embodiment 35

[0435] (R)-4-(1-(4-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0436]

[0437] Using (4-fluorophenyl)boronic acid (63 mg) as the starting material, the same procedure as in Example 29 was followed to give the desired product (7.5 mg) as a white solid.

[0438] LCMS(ESI):561.32[M+1] + .

[0439] Embodiment 36

[0440] 4-(1-(4-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0441]

[0442] Using 4-bromo-1H-indole-7-carboxylic acid methyl ester, 4-(1-aminocyclopropyl)benzoic acid methyl ester and phenylboronic acid as starting materials, the same procedures as steps 1, 2, 3, 4 and 5 of Example 1 were followed to obtain the target product as a white solid. LCMS (ESI): 555.3 [M+1] + .

[0443] Embodiment 37

[0444] 4-(1-(4-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0445]

[0446] Using (3-cyanophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 36 was followed to obtain the target product (7.8 mg) as a white solid. LCMS (ESI): 580.3 [M+1] + .

[0447] Embodiment 38

[0448] 4-(1-(4-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0449]

[0450] Using (3,4-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 36 was followed to obtain the target product as a white solid. LCMS (ESI): 591.5 [M+1] + .

[0451] Embodiment 39

[0452] 4-(1-(4-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0453]

[0454] Using (3,5-difluorophenyl)boronic acid (15 mg) as the starting material, the same procedure as in Example 36 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 591.2 [M+1] + .

[0455] Embodiment 40

[0456] 4-(1-(1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0457]

[0458] Using (3-(trifluoromethyl)phenyl)boronic acid as the starting material, the same procedures as in Steps 3, 4, and 5 of Example 36 were followed to obtain the target product as a white solid. LCMS (ESI): 623.5 [M+1]+ .

[0459] Embodiment 41

[0460] 4-(1-(4-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0461]

[0462] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid as the starting material, the same procedure as in Example 36 was followed to obtain the target product as a white solid. LCMS (ESI): 641.5 [M+1] + .

[0463] Embodiment 42

[0464] 4-(1-(4-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)-benzoic acid

[0465]

[0466] Using (4-fluorophenyl)boronic acid (61.3 mg) as the starting material, the same procedure as in Example 36 was followed to obtain the target product (13.7 mg) as a white solid. LCMS (ESI): 573.35 [M+1] + .

[0467] Embodiment 43

[0468] 4-((5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0469]

[0470] Step 1 Methyl 4-(1-(5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate

[0471]

[0472] At 120°C, a mixture of methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate (30 mg, 0.06 mmol), aniline (30 mg, 0.36 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.2 mg, 0.012 mmol), Pd2(dba)3 (3.2 mg, 0.006 mmol) and Cs2CO3 (60 mg, 0.18 mmol) in 1,4-dioxane (5 mL) was stirred under nitrogen for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (2.0 mg) as a yellow solid. LCMS(ESI):584.3[M+1] + .

[0473] Step 2 4-(1-(5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0474]

[0475] The same procedure as in step 5 of Example 1 was followed to obtain the target product as a white solid. LCMS (ESI): 570.3 [M+1] + .

[0476] Embodiment 44

[0477] 4-(1-(4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0478]

[0479] Using methyl 4-(1-aminocyclopropyl)benzoate, 4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid and aniline (65 mg) as starting materials, the same procedure as in Example 43 was followed to obtain the target product (22 mg) as a white solid. LCMS (ES+): 570.4 [M+1] + .

[0480] 1H NMR spectrum: (500 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.31 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.39-7.35 (m, 1H), 7.34-7.25 (m, 4H), 7.16 (d, J = 8.2 Hz, 2H), 6.96-6.86 (m, 5H), 5.74 (s, 2H), 1.20-1.15 (m, 2H), 0.98-0.94 (m, 2H).

[0481] Embodiment 45

[0482] 4-((5-(Methyl(phenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0483]

[0484] Using N-methylaniline (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as Example 43 was followed to obtain the target product (5 mg) as a white solid. LCMS (ES+): 558.3 ​​[M+1] + .

[0485] 1 H NMR spectrum: (500MHz, DMSO-d6) δ: 12.79 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 7.87–7.77 (m, 2H), 7.58 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7. 20–7.13(m,2H),7.06(d,J=2.1Hz,1H),7.01(d,J=8.0Hz,2H),6.77(d,J=8.1Hz,2H),6.73 (t, J=7.2Hz, 1H), 6.61 (d, J=3.2Hz, 1H), 5.66 (s, 2H), 4.35 (d, J=5.7Hz, 2H), 3.28 (s, 3H).

[0486] Embodiment 46

[0487] 4-(1-(4-(methyl(phenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0488]

[0489] Using N-methylaniline (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as Example 43 was followed to obtain the target product (25 mg) as a white solid. LCMS (ES+): 584.5 [M+1] + .

[0490] 1 H NMR spectrum: (500MHz, DMSO-d6)δ:12.79(s,1H),9.13(s,1H),7.77(d,J=8.4Hz,2H) ,7.60(d,J=8.1Hz,2H),7.42(d,J=7.9Hz,1H),7.33(d,J=3.2Hz,1H),7.21(dt, J=7.8,3.6Hz,4H),6.95(dd,J=7.9,2.0Hz,3H),6.85–6.82(m,2H),6.06(d,J=3 .3Hz,1H),5.69(s,2H),5.33(t,J=5.0Hz,1H),3.41(s,3H),0.96–0.83(m,4H).

[0491] Embodiment 47

[0492] 4-((5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0493]

[0494] Using aniline (15 mg) and the product of step 3 of Example 1 (20 mg) as starting materials, the same procedure as Example 43 was followed to obtain the target product (17 mg) as a white solid. LCMS (ES+): 544.4 [M+1] + .

[0495] 1 H NMR spectrum: (500MHz, DMSO-d6)δ:12.87(s,1H),8.90(t,J=6.0Hz,1H),7.97(s,1H), 7.83(d,J=8.1Hz,2H),7.56(d,J=8.1Hz,2H),7.51(d,J=3.2Hz,1H),7.44(d,J= 2.1Hz,1H),7.29(d,J=8.0Hz,2H),7.18(t,J=7.8Hz,2H),7.07–6.99(m,4H),6. 73(t,J=7.3Hz,1H), 6.54(d,J=3.1Hz,1H), 5.60(s,2H), 4.34(d,J=6.0Hz,2H).

[0496] Embodiment 48

[0497] 4-(1-(4-(methyl(phenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0498]

[0499] Using N-methylaniline (15 mg) as the starting material, the same procedure as in Example 43 was followed to obtain the target product (0.85 mg) as a white solid. LCMS (ESI): 598.6 [M+1] + .

[0500] Embodiment 49

[0501] 4-(1-(5-phenoxy-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0502]

[0503] At 120°C, a mixture of methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate (30 mg, 0.06 mmol), phenol (30 mg, 0.36 mmol), CuI (10 mg, 0.06 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (12 mg, 0.06 mmol) and K3PO4 (38 mg, 0.18 mmol) in 1,4-dioxane (5 mL) was placed in nitrogen and stirred for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (MeOH:DCM=25:1) to give the target compound (5.0 mg) as a yellow solid. LCMS(ESI):571.3[M+1] + .

[0504] Embodiment 50

[0505] (S)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0506]

[0507] Using (S)-4-(1-aminoethyl)benzoic acid methyl ester and the product of step 2 of Example 1 as starting materials, the same procedures as steps 3, 4, and 5 of Example 1 were followed to obtain the target product as a white solid. LCMS (ESI): 561.3 [M+1] + .

[0508] Embodiment 51

[0509] (S)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0510]

[0511] Using (S)-methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoate (30 mg) and phenylboronic acid as starting materials, the same procedure as in Example 1 was followed to obtain the target product (12 mg) as a white solid. LCMS (ES+): 543.4 [M+1] + .

[0512] Embodiment 52

[0513] (S)-4-(1-(5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0514]

[0515] Using (S)-methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoate (30 mg) and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 1 was followed to obtain the target product (12 mg) as a white solid. LCMS (ESI): 568.2 [M+1] + .

[0516] Embodiment 53

[0517] (S)-4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0518]

[0519] Using (S)-methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoate (30 mg) and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 1 was followed to obtain the target product (12 mg) as a white solid. LCMS (ESI): 579.0 [M+1] + .

[0520] 1H NMR(500MHz,DMSO-d6)δ12.82(s,1H),8.88(d,J=7.8Hz,1H),8.04(d,J=1.8Hz ,1H),7.87(d,J=8.3Hz,2H),7.87–7.79(m,1H),7.65(d,J=3.2Hz,1H),7.63–7. 52(m,2H),7.53–7.45(m,3H),7.44(d,J=8.3Hz,2H),6.95(d,J=8.0Hz,2H),6. 72(d,J=3.1Hz,1H),5.66(s,2H),5.06(p,J=7.2Hz,1H),1.26(d,J=7.0Hz,3H).

[0521] Embodiment 54

[0522] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0523]

[0524] Using (3,5-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 50 was followed to obtain the target product as a white solid. LCMS (ESI): 579.4 [M+1] + .

[0525] Embodiment 55

[0526] (S)-4-(1-(1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indole-7-amido)ethyl)benzoic acid

[0527]

[0528] Using (3-(trifluoromethyl)phenyl)boronic acid as the starting material, the same procedure as in Example 50 was followed to obtain the target product as a white solid. LCMS (ESI): 611.4 [M+1] + .

[0529] Embodiment 56

[0530] (S)-4-(1-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0531]

[0532] Using (3-fluoro-5-(trifluoromethyl)benzene)boronic acid as the starting material, the same procedure as in Example 50 was followed to obtain the target product as a white solid. LCMS (ES+): 629.2 [M+1] + .

[0533] Embodiment 57

[0534] 4-((4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0535]

[0536] Step 1 Methyl 4-((4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate

[0537]

[0538] At 110°C, a mixture of methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate (30 mg), aniline (30 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.2 mg), Pd2(dba)3 (3.2 mg) and Cs2CO3 (60 mg) in 1,4-dioxane (5 mL) was stirred for 3 hours under nitrogen. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (22.0 mg) as a yellow solid. LCMS(ESI):558.3[M+1] + .

[0539] Step 2 4-((4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0540]

[0541] The same procedure as in step 5 of Example 1 was followed to obtain the target product (12.0 mg) as a white solid. LCMS (ESI): 544.2 [M+1] + .

[0542] 1H NMR (500MHz, DMSO-d6) δ12.85 (s, 1H), 8.70 (t, J = 6.1Hz, 1H), 8.29 (s, 1H), 7.86–7. 81(m,2H),7.52(d,J=8.2Hz,2H),7.46(d,J=3.3Hz,1H),7.34–7.27(m,4H),7.27–7. 22(m,2H),7.19(d,J=8.0Hz,1H),6.97(d,J=8.0Hz,2H),6.93(tt,J=7.3,1.3Hz,1H ), 6.89 (d, J = 3.2Hz, 1H), 6.83 (d, J = 8.1Hz, 1H), 5.72 (s, 2H), 4.38 (d, J = 6.0Hz, 2H).

[0543] Embodiment 58

[0544] 4-((4-morpholine-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0545]

[0546] Starting from methyl 4-((4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate (30 mg) and morpholine, the same procedure as in Example 57 was followed to give the target product (10 mg) as a white solid. LCMS (ESI): 538.2 [M+1] + .

[0547] Embodiment 59

[0548] 4-((4-(4-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0549]

[0550] Using methyl 4-((4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate (30 mg) and 1-methylpiperazine as starting materials, the same procedure as in Example 01 was followed to obtain the target product (12 mg) as a white solid. LCMS (ESI): 551.2 [M+1] + .

[0551] Embodiment 60

[0552] (R)-4-(1-(4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0553]

[0554] Using (R)-methyl 4-(1-(4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoate (30 mg) and aniline as starting materials, the same procedure as in Example 01 was followed to obtain the target product (14 mg) as a white solid. LCMS (ESI): 558.3 ​​[M+1] + .

[0555] Embodiment 61

[0556] 4-(1-(4-((3-cyanophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0557]

[0558] Using 3-aminobenzonitrile (40 mg) as the starting material, the same procedure as in Example 44 was followed to obtain the target product (14 mg) as a white solid. LCMS (ES+): 595.5 [M+1] + .

[0559] Embodiment 62

[0560] 4-(1-(4-((4-cyanophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0561]

[0562] Starting from 4-aminobenzonitrile (40 mg), the same procedure as in Example 44 was followed to obtain the target product (16 mg) as a white solid. LCMS (ES+): 595.5 [M+1] + .

[0563] Embodiment 63

[0564] 4-(1-(4-((3,4-difluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropylbenzoic acid

[0565]

[0566] Using 3,4-difluoroaniline (40 mg) as the starting material, the same procedure as in Example 44 was followed to obtain the target product (17 mg) as a white solid. LCMS (ES+): 606.4 [M+1] + .

[0567] Embodiment 64

[0568] 4-(1-(4-((4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0569]

[0570] Step 1: 4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid methyl ester

[0571]

[0572] To a mixture of methyl 4-bromo-1H-indole-7-carboxylate (500 mg) and Cs2CO3 (769 mg) in anhydrous DMF (10 mL) at 0°C, 1-(bromomethyl)-4-(trifluoromethyl)benzene (564 mg, 2.36 mmol) was added. The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was poured into 100 mL of ice water and extracted with 3 x 50 mL of ethyl acetate. The combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 10:1) to obtain the target compound (500 mg) as a white solid. LCMS (ESI): 412.2 [M+1] + .

[0573] Step 2 4-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

[0574]

[0575] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2.0 mL) was added LiOH·H2O (254 mg) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. After cooling to 0°C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH to 6. The reaction mixture was extracted with 3x 30 mL of ethyl acetate. The combined organic layers were washed with 20 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound (479 mg) as a white solid. LCMS (ESI): 398.2 [M+1] + .

[0576] Step 3 Methyl 4-(1-(4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate

[0577]

[0578] To a mixture of the product of step 2 (398 mg), methyl 4-(1-aminocyclopropyl)benzoate (215 mg) and HATU (456 mg) in anhydrous DMF (100 mL) at 0°C, DIPEA (0.52 mL, 3.0 mmol) was added. Stir overnight at room temperature, then quench the reaction mixture by adding 100 mL of water and extract with 3 x 100 mL of ethyl acetate. Rinse the combined organic layer with 100 mL of saturated brine, dry over anhydrous Na2SO4 and concentrate. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.5 g) as a white solid. LCMS (ESI): 571.1 [M+1] + .

[0579] Step 4: Methyl 4-(1-(4-((4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate

[0580]

[0581] At 120°C, a mixture of methyl 4-(1-(4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoate (30 mg, 0.06 mmol), 4-fluoroaniline (30 mg, 0.36 mmol), xanthene (6.2 mg, 0.012 mmol), Pd2(dba)3 (3.2 mg, 0.006 mmol) and Cs2CO3 (60 mg, 0.18 mmol) in 1,4-dioxane (5 mL) was stirred under nitrogen for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (2.0 mg) as a yellow solid. LCMS (ESI): 602.3 [M+1] + .

[0582] Step 5 4-(1-(4-((4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0583]

[0584] To a solution of the product of step 4 (42 mg) in MeOH / H2O (5 mL / 0.5 mL), LiOH·H2O (16 mg) was added. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 20 mL of ethyl acetate. The combined organic layers were washed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to obtain the target compound (12.1 mg) as a white solid. LCMS (ESI): 588.4 [M+1] + .

[0585] 1 H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.27(s,1H),7.75(d,J=8.3Hz,2H),7.59(d,J=8.1Hz,2H),7.37(d,J=3.2Hz,1H),7.31-7.22(m,3H), 7.20-7.13(m,4H),6.94(d,J=8.1Hz,2H),6.88(d,J=3.3Hz,1H),6.76(d,J=8.0Hz,1H),5.74(s,2H),1.21-1.16(m,2H),0.99-0.95(m,2H).

[0586] Embodiment 65

[0587] 4-(1-(4-((3-chloro-4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0588]

[0589] Using 3-chloro-4-fluoroaniline (70 mg) as the starting material, the same procedure as in Example 64 was followed to obtain the target product (25 mg) as a white solid. LCMS (ESI): 622.1 [M+1] + .

[0590] 1HNMR(400MHz, DMSO-d6)δ8.97(s,1H),8.45(s,1H),7.76(d,J=8.1Hz,2H),7.59(d,J=8.1Hz,2H),7.40(d,J=3.2Hz,1H),7.36–7.30(m,3H ),7.24–7.16(m,3H),6.97–6.92(m,2H),6.88(d,J=7.9Hz,1H),6.83(d,J=3.2Hz,1H),5.74(s,2H),1.21–1.15(m,2H),0.99–0.93(m,2H).

[0591] Embodiment 66

[0592] 4-(1-(4-((3,5-difluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0593]

[0594] Using 3,5-difluoroaniline (40 mg) as the starting material, the same procedure as in Example 64 was followed to give the desired product (25 mg) as a white solid.

[0595] LCMS(ESI):606.3[M+1] + . 1 H NMR (400MHz, DMSO) δ9.05(s,1H),8.79(s,1H),7.77(d,J=8.2Hz,2H),7.60(s,1H),7.44(d,J=3.3Hz,1H),7.37(s,1H),7.20(d,J=8.3 Hz,2H),7.04(d,J=7.9Hz,1H),6.94(s,1H),6.79-6.75(m,3H),6.61-6.57(m,1H),5.74(s,2H),1.19-1.16(m,2H),0.96-0.94(m,2H).

[0596] Embodiment 67

[0597] 4-(1-(4-((3-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0598]

[0599] Using 3-fluoroaniline (40 mg) as the starting material, the same procedure as in Example 64 was followed to give the desired product (25 mg) as a white solid.

[0600] LCMS(ESI):588.47[M+1] + . 1 H NMR (400MHz, DMSO) δ9.00(s,1H),8.54(s,1H),7.76(d,J=8.1Hz,2H),7.59(d,J= 8.1Hz,2H),7.41(d,J=3.4Hz,1H),7.34(d,J=8.0Hz,1H),7.32–7.27(m,1H),7.1 9(d,J=8.1Hz,2H),7.08-7.05(m,1H),7.01–6.92(m,4H),6.84(d,J=3.2Hz,1H), 6.70-6.66(m,1H),5.75(d,J=9.2Hz,2H),1.20-1.14(m,2H),0.98-0.94(m,2H).

[0601] Embodiment 68

[0602] 4-((4-((3-cyanophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0603]

[0604] Using 3-aminobenzonitrile and methyl 4-(aminomethyl)benzoate hydrochloride as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 569.2 [M+1] + .

[0605] 1 HNMR(400MHz, DMSO-d6)δ8.76(t,J=5.9Hz,1H),8.65(s,1H),7.83(d,J=8.5Hz,2H),7.55–7.42(m, 6H),7.31–7.21(m,4H),7.01–6.97(m,3H),6.78(d,J=3.2Hz,1H),5.71(s,2H),4.41-4.35(m,2H).

[0606] Embodiment 69

[0607] 4-((4-((3,5-difluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0608]

[0609] Using 3,5-difluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 580.2 [M+1] + .

[0610] 1 HNMR (400MHz, DMSO-d6) δ8.78(t,J=6.0Hz,1H),8.74(s,1H),7.83(d,J=8.0Hz,2H),7.55–7.50(m,3H),7.30(d,J=8.0H z,2H),7.25(d,J=7.9Hz,1H),7.01–6.97(m,3H),6.77–7.74(m,3H),6.61–6.58(m,1H),5.70(s,2H),4.42-4.36(m,2H).

[0611] Embodiment 70

[0612] 4-(1-(4-((3-chloro-4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0613]

[0614] Using 3-chloro-4-fluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride as starting materials, the same procedure as in Example 64 was followed to obtain the desired product (25 mg) as a white solid. LCMS (ESI): 596.2 [M+1] + .

[0615] 1 HNMR(400MHz, DMSO-d6)δ8.02–7.97(m,2H),7.47(d,J=8.0Hz,2H),7.24–7.21(m,3H),7.19–7.15(m,2H),7.11-7.06(m,1H),7.06–7. 00(m,1H),6.97(d,J=8.0Hz,2H),6.76(d,J=8.0Hz,1H),6.57(d,J=3.2Hz,1H),5.89(t,J=5.8Hz,1H),5.72(s,2H),4.43-4.38(m,2H).

[0616] Embodiment 71

[0617] ((4-((4-Chloro-3-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amidoamido)methyl)benzoic acid

[0618]

[0619] Using 4-chloro-3-fluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 596.4 [M+1] + .

[0620] 1 H NMR (400MHz, DMSO-d6) δ8.69(t,J=6.0Hz,1H),8.63(s,1H),7.80(d,J=7.6Hz,2H),7.56(d,J=8.1Hz,2H),7.51(d,J=3.3Hz,1H),7.41(t,J=8.7Hz,1H) ,7.24–7.15(m,3H),7.04–6.98(m,1H),7.01(dd,J=8.7,2.8Hz,3H),6.92( d,J=7.9Hz,1H),6.77(d,J=3.2Hz,1H),5.70(s,2H),4.33(d,J=5.9Hz,2H).

[0621] Embodiment 72

[0622] 4-((4-((3-Fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0623]

[0624] Using 3-fluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 562.2 [M+1] + .

[0625] 1 HNMR(400MHz,DMSO-d6)δ8.74(t,J=6.0Hz,1H),8.49(s,1H),7.82(d,J=8.1Hz, 2H),7.52(d,J=8.1Hz,2H),7.48(d,J=3.2Hz,1H),7.28(dd,J=7.9,4.7Hz,3H), 7.22(d,J=8.0Hz,1H),7.02(dd,J=8.1,2.0Hz,1H),6.99–6.90(m,4H),6.81(d, J=3.3Hz,1H),6.66(td,J=8.5,2.5Hz,1H),5.70(s,2H),4.37(d,J=6.0Hz,2H).

[0626] Embodiment 73

[0627] ((4-((4-chlorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0628]

[0629] Using 4-chloro-aniline and methyl 4-(aminomethyl)benzoate hydrochloride as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 578.3 [M+1] + .

[0630] 1 HNMR (400MHz, DMSO-d6) δ8.69(t,J=6.1Hz,1H),8.40(s,1H),7.83(d,J=7.8Hz,2H),7.53(d,J=8.1Hz,2H),7.47(d,J=3.3Hz,1H),7.32(d, J=8.7Hz,2H),7.26(d,J=7.7Hz,2H),7.20(d,J=3.6Hz,2H),6.99(d,J=8.0Hz,2H),6.86–6.80(m,2H),5.71(s,2H),4.37(d,J=6.0Hz,2H).

[0631] Embodiment 74

[0632] (S)-4-(1-(4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0633]

[0634] Using aniline and (S)-methyl 4-(1-aminoethyl)benzoic acid as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 558.2 [M+1] + .

[0635] 1HNMR(400MHz, DMSO-d6)δ12.66(s,1H),8.60(d,J=8.0Hz,1H),8.26(s,1H),7.88–7.81(m,2H),7.48–7.44(m,3H),7.41(d,J=8.2Hz,2H),7.29(dd,J= 8.5,7.2Hz,2H),7.24–7.21(m,2H),7.14(d,J=8.0Hz,1H),6.95–6.88(m,3 H),6.88–6.80(m,2H),5.65(s,2H),5.07–5.01(m,1H),1.24-1.22(m,3H).

[0636] Embodiment 75

[0637] 4-((5-(3-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0638]

[0639] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid methyl ester

[0640]

[0641] To a mixture of 5-bromo-1H-indole-7-carboxylic acid methyl ester (500 mg) and Cs2CO3 (769 mg) in anhydrous DMF (10 mL) at 0°C, 1-(bromomethyl)-4-(trifluoromethyl)benzene (564 mg) was added. The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was poured into 100 mL of ice water and extracted with 3 x 50 mL of ethyl acetate. The combined organic layer was washed with 50 mL of brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 10:1) to obtain the target compound (500 mg) as a white solid. LCMS (ESI): 412.2 [M+1] + .

[0642] Step 2 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

[0643]

[0644] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2 mL) was added LiOH·H2O (254 mg) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the reaction mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 30 mL of ethyl acetate. The combined organic layers were washed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound (479 mg) as a white solid. LCMS (ESI): 398.2 [M+1] + .

[0645] Step 3 Methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate

[0646]

[0647] To a mixture of the product of step 2 (398 mg), methyl 4-(aminomethyl)benzoate (215 mg) and HATU (456 mg) in anhydrous DMF (10 mL) at 0°C, DIPEA (0.52 mL) was added. Stir overnight at room temperature, then add 10 mL of water to quench the reaction mixture, and extract with 3 x 100 mL of ethyl acetate. Rinse the combined organic layers with 10 mL of brine, dry over anhydrous Na2SO4, and concentrate. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.5 g) as a white solid. LCMS (ESI): 545.1 [M+1] + .

[0648] Step 4: Methyl 4-((5-(3-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoate

[0649]

[0650] A mixture of the product of step 3 (30 mg), (3-chlorophenyl)boronic acid (38 mg), Pd(dppf)2Cl2 (4 mg) and K2CO3 (38 mg) in EtOH / H2O (5 mL / 1 mL) was stirred at 70°C under nitrogen for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (27 mg) as a yellow solid. LCMS (ESI): 577.2 [M+1] + .

[0651] Step 5 4-((5-(3-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0652]

[0653] To a solution of the product of step 4 (42 mg) in MeOH / H2O (5 mL / 0.5 mL), LiOH·H2O (16 mg) was added. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 20 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to obtain the target compound (10.1 mg) as a white solid. LCMS (ESI): 577.2 [M+1] + .

[0654] 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.01(t,J=5.9Hz,1H),8.08(d,J=1.7Hz,1H),7.87-7.77(m,3H),7.72(d,J=7.7Hz,1H),7.66(d,J=3.1Hz,1H),7 .58-7.44(m,4H),7.40(dd,J=7.9,2.1Hz,1H),7.29(d,J=8.1Hz,2H),6.98( d, J=8.0Hz, 2H), 6.75 (d, J=3.1Hz, 1H), 5.74 (s, 2H), 4.44 (d, J=5.8Hz, 2H).

[0655] Embodiment 76

[0656] 4-((5-(3-methoxyphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0657]

[0658] Using 3-methoxyphenylboronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product (9 mg) as a white solid. LCMS (ESI): 559.2 [M+1] + .

[0659] 1HNMR(400MHz,DMSO-d6)δ12.85(s,1H),9.02(t,J=5.9Hz,1H),8.03(d,J=1.7H z,1H),7.87–7.82(m,2H),7.64(d,J=3.2Hz,1H),7.56–7.51(m,3H),7.38(t,J =7.9Hz,1H),7.33–7.25(m,4H),6.98(d,J=8.1Hz,2H),6.91(dd,J=8.2,2.5Hz ,1H),6.74(d,J=3.1Hz,1H),5.73(s,2H),4.43(d,J=5.9Hz,2H),3.83(s,3H).

[0660] Embodiment 77

[0661] ((5-(3-cyano-5-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0662]

[0663] Using (3-cyano-5-fluorophenyl)boronic acid (98 mg) as the starting material, the same procedure as in Example 75 was followed to obtain the target product (20 mg) as a white solid. LCMS (ESI): 572.5 [M+1] + .

[0664] 1 HNMR (400MHz, DMSO-d6) δ8.97(t,J=5.9Hz,1H),8.21(d,J=1.8Hz,1H),8.15(d,J= 1.7Hz,1H),8.05-8.01(m,1H),7.85(d,J=8.2Hz,2H),7.83–7.78(m,1H),7.69(d, J=3.2Hz,1H),7.67(d,J=1.9Hz,1H),7.55(d,J=8.1Hz,2H),7.30(d,J=8.1Hz,2H) ,6.99(d,J=8.0Hz,2H),6.77(d,J=3.2Hz,1H),5.76(s,2H),4.46(d,J=5.8Hz,2H).

[0665] Embodiment 78

[0666] 4-((5-(Pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0667]

[0668] Starting from pyridine-3-boronic acid, the same procedure as in Example 75 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 530.2 [M+1] + .

[0669] 1 HNMR(400MHz,DMSO-d6)δ12.89(s,1H),9.00(t,J=5.9Hz,1H),8.97(d,J=2.3Hz,1H),8.5 5(dd,J=4.7,1.6Hz,1H),8.19–8.08(m,2H),7.84(d,J=8.1Hz,2H),7.67(d,J=3.2Hz,1H), 7.58(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,2H),7.49(dd,J=8.0,4.7Hz,1H),7.30(d,J=8.2 Hz,2H),6.99(d,J=8.0Hz,2H),6.76(d,J=3.2Hz,1H),5.74(s,2H),4.43(d,J=5.8Hz,2H).

[0670] Embodiment 79

[0671] 4-((5-(3-cyano-4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0672]

[0673] Using (3-cyano-4-fluorophenyl)boronic acid (98 mg) as the starting material, the same procedure as in Example 75 was followed to obtain the target product (20 mg) as a white solid. LCMS (ESI): 572.5 [M+1] + .

[0674] 1HNMR(400MHz,DMSO-d6)δ8.96(t,J=5.9Hz,1H),8.30-8.28(m,1H),8.16-8.13(m, 1H),8.11(d,J=1.8Hz,1H),7.84(d,J=8.0Hz,2H),7.66(d,J=3.2Hz,1H),7.63(t, J=9.0Hz,1H),7.59(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,2H),7.29(d,J=8.0Hz,2H) ,6.98(d,J=8.1Hz,2H),6.75(d,J=3.2Hz,1H),5.74(s,2H),4.43(d,J=5.9Hz,2H).

[0675] Embodiment 80

[0676] 4-((5-(Pyridin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0677]

[0678] Starting from pyridine-4-boronic acid (79.0 mg), the same procedure as in Example 75 was followed to obtain the target product (15 mg) as a white solid. LCMS (ESI): 530.5 [M+1] + .

[0679] 1 HNMR(400MHz,DMSO-d6)δ9.03(t,J=6.0Hz,1H),8.68–8.60(m,2H),8.22(d, J=1.8Hz,1H),7.85(d,J=8.0Hz,2H),7.80–7.75(m,2H),7.68(d,J=3.2Hz,1H ),7.66(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,2H),7.30(d,J=8.0Hz,2H),6.99 (d,J=8.0Hz,2H),6.79(d,J=3.1Hz,1H),5.74(s,2H),4.43(d,J=5.8Hz,2H).

[0680] Embodiment 81

[0681] 4-((5-(4-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0682]

[0683] Using (4-cyanophenyl)boronic acid (48.0 mg) as the starting material, the same procedure as in Example 75 was followed to obtain the target product (22 mg) as a white solid. LCMS (ESI): 554.5 [M+1] + .

[0684] 1 HNMR(400MHz,DMSO-d6)δ9.02(t,J=5.9Hz,1H),8.16(d,J=1.8Hz,1H),7.97(d ,J=8.4Hz,2H),7.93(d,J=8.4Hz,2H),7.85(d,J=8.0Hz,2H),7.67(d,J=3.2Hz ,1H),7.61(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,2H),7.30(d,J=8.1Hz,2H),6.9 9(d,J=8.0Hz,2H),6.78(d,J=3.2Hz,1H),5.74(s,2H),4.43(d,J=5.8Hz,2H).

[0685] Embodiment 82

[0686] 4-((5-(3-Carbamoylphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0687]

[0688] Using 3-aminocarbonylphenylboronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 572.2 [M+1] + .

[0689] 1 HNMR (400MHz, DMSO-d6) δ12.83(s,1H),9.03(t,J=5.9Hz,1H),8.25(t,J=1.8Hz,1H ),8.13–8.08(m,2H),7.90(dd,J=8.4,6.5Hz,1H),7.86–7.82(m,3H),7.64(d,J=3.2 Hz,1H),7.61(d,J=1.8Hz,1H),7.58–7.51(m,3H),7.42(s,1H),7.30(d,J=8.0Hz,2H ), 6.99 (d, J = 8.0Hz, 2H), 6.76 (d, J = 3.2Hz, 1H), 5.72 (s, 2H), 4.44 (d, J = 5.9Hz, 2H).

[0690] Embodiment 83

[0691] 4-((5-(3-aminosulfonylphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0692]

[0693] Using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 608.2 [M+1] + .

[0694] 1 HNMR(400MHz,DMSO-d6)δ12.79(s,1H),9.07(t,J=5.9Hz,1H),8.19(t,J=1.8Hz,1H), 8.08(d,J=1.8Hz,1H),7.97(dt,J=7.8,1.4Hz,1H),7.84(d,J=8.0Hz,2H),7.79(dt,J= 7.8,1.4Hz,1H),7.70–7.64(m,2H),7.60–7.51(m,3H),7.41(s,2H),7.30(d,J=8.1Hz, 2H),7.00(d,J=8.0Hz,2H),6.78(d,J=3.2Hz,1H),5.72(s,2H),4.43(d,J=5.9Hz,2H).

[0695] Embodiment 84

[0696] 4-((5-(3-(Methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0697]

[0698] Using 3-(methylsulfonyl)phenylboronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. MS (ESI): 607.2 [M+1] + .

[0699] 1HNMR (400MHz, DMSO-d6) δ12.84(s,1H),9.06(t,J=5.9Hz,1H),8.25(d,J=1.9Hz,1H),8.16(d, J=1.7Hz,1H),8.13–8.08(m,1H),7.92–7.86(m,1H),7.84(d,J=8.0Hz,2H),7.76(t,J=7.8Hz,1 H),7.66(d,J=3.2Hz,1H),7.62(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,2H),7.30(d,J=8.0Hz,2H), 7.00(d,J=8.0Hz,2H),6.78(d,J=3.1Hz,1H),5.73(s,2H),4.44(d,J=5.8Hz,2H),3.31(s,3H).

[0700] Embodiment 85

[0701] 4-((5-(3-(2-hydroxypropan-2-yl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0702]

[0703] Using 3-(2-hydroxypropan-2-yl)phenylboronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 587.2 [M+1] + .

[0704] 1 HNMR(400MHz,DMSO-d6)δ12.83(s,1H),9.03(t,J=6.0Hz,1H),8.01(d,J=1.7Hz,1 H),7.87–7.79(m,3H),7.63(d,J=3.2Hz,1H),7.57–7.52(m,4H),7.44(dt,J=7.7,1 .5Hz,1H),7.39(t,J=7.6Hz,1H),7.31(d,J=8.0Hz,2H),7.00(d,J=8.1Hz,2H),6. 75(d,J=3.1Hz,1H),5.72(s,2H),5.07(s,1H),4.43(d,J=5.9Hz,2H),1.50(s,6H).

[0705] Embodiment 86

[0706] 4-((5-(2-Hydroxyphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0707]

[0708] Using 2-hydroxyphenylboronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 545.2 [M+1] + .

[0709] 1 HNMR (400MHz, CDCl3) δ7.94 (dd, J=7.9, 6.1Hz, 2H), 7.86–7.82 (m, 1H), 7.46–7.41 (m, 3H), 7.32–7.24 (m, 2H), 7.25–7. 13(m,4H),7.01(d,J=7.6Hz,2H),6.98–6.89(m,2H),6.69–6.64(m,1H),5.68(d,J=5.2Hz,2H),4.37(d,J=5.7Hz,2H).

[0710] Embodiment 87

[0711] 4-((5-(2-Fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0712]

[0713] Using 2-fluorophenylboronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. MS (ESI): 547.2 [M+1] + .

[0714] 1 HNMR (400MHz, DMSO-d6) δ12.85(s,1H),8.97(t,J=5.9Hz,1H),7.94(d,J=1.8Hz,1H),7.84(d,J=8.1Hz,2H),7.65(dd,J=5.7,2.4Hz,1H),7. 55(d,J=8.1Hz,2H),7.43–7.37(m,2H),7.35-7.30(m,4H),7.01(d,J=8.1Hz,2H),6.75(d,J=3.2Hz,1H),5.72(s,2H),4.40(d,J=5.9Hz,2H).

[0715] Embodiment 88

[0716] 4-((5-(3,5-dichlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0717]

[0718] Using (3,5-dichlorobenzene)boronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 599.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.98(t,J=5.9Hz,1H),8.14(s,1H),7.88–7.78(m,4H),7.66(d,J=3.2Hz,1H),7.59(d,J=1.7Hz,1H) ,7.56–7.47(m,3H),7.28(d,J=8.0Hz,2H),6.97(d,J=8.0Hz,2H),6.75(d,J=3.1Hz,1H),5.75(s,2H),4.45(d,J=5.9Hz,2H).

[0719] Embodiment 89

[0720] 4-((1-(4-(trifluoromethyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-indole-7-amido)methyl)benzoic acid

[0721]

[0722] Using (2-(trifluoromethyl)benzene)boronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 597.5 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.92 (t, J=6.0Hz, 1H), 7.86-7.82 (m, 3H), 7.74 -7.69(m,2H),7.66(d,J=3.2Hz,1H),7.61(t,J=7.7Hz,1H),7.57(d,J=8.0Hz,2H),7.51(d,J=7.7Hz,1H),7.29( d,J=8.0Hz,2H),7.21(s,1H),7.06(d,J=8.0Hz,2H),6.72(d,J=3.1Hz,1H),5.72(s,2H),4.38(d,J=5.9Hz,2H).

[0723] Embodiment 90

[0724] 4-((5-(2-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0725]

[0726] Using (2-chlorobenzene)boronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 563.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.94(t,J=6.0Hz,1H),7.90–7.76(m,3H),7.66(d,J=3.2Hz,1H),7.57(m,3H),7.53-7.51(m,1H) ,7.48–7.35(m,2H),7.35–7.24(m,3H),7.05(d,J=8.0Hz,2H),6.74(d,J=3.1Hz,1H),5.72(s,2H),4.40(d,J=5.8Hz,2H).

[0727] Embodiment 91

[0728] 4-((5-(4-chloro-3-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0729]

[0730] Using (4-chloro-3-fluorophenyl)boronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 581.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.99(t,J=6.0Hz,1H),8.10(s,1H),7.91–7.78(m,3H),7.72–7.61(m,3H),7.58(1,1H),7.53(d ,J=8.0Hz,2H),7.30(d,J=8.0Hz,2H),6.98(d,J=8.0Hz,2H),6.75(d,J=3.1Hz,1H),5.74(s,2H),4.44(d,J=5.8Hz,2H).

[0731] Embodiment 92

[0732] 4-((5-(o-Tolyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0733]

[0734] Starting from o-toluene boronic acid (45 mg), the same procedure as in Example 75 was followed to obtain the target product (40 mg) as a white solid. LCMS (ESI): 543.5 [M+1] + .

[0735] 1 HNMR (400MHz, DMSO-d6) δ12.83(s,1H),8.92(t,J=6.0Hz,1H),7.83(d,J=8.1Hz,2H),7.70(d,J=1.7Hz,1H),7.63(d,J=3.2Hz,1H),7.56(d,J=8.1 Hz,2H),7.34–7.23(m,6H),7.20(d,J=1.7Hz,1H),7.06(d,J=8.0Hz,2H) ,6.70(d,J=3.2Hz,1H),5.72(s,2H),4.39(d,J=5.9Hz,2H),2.29(s,3H).

[0736] Embodiment 93

[0737] 4-((5-(2-aminophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0738]

[0739] Starting from (2-aminophenyl)boronic acid (45 mg), the target product was obtained as a white solid by the same procedure as in Example 75. LCMS (ESI): 544.5 [M+1] + .

[0740] 1 HNMR(400MHz,DMSO-d6)δ8.93(t,J=6.0Hz,1H),7.84(d,J=8.2Hz,2H),7.73(d ,J=1.7Hz,1H),7.62(d,J=3.2Hz,1H),7.58(d,J=8.0Hz,2H),7.34–7.25(m,3H ),7.08-7.02(m,7.6,1.6Hz,4H),6.76(d,J=8.0,1H),6.70(d,J=3.1Hz,1H),6 .64(t,J=7.4,1.2Hz,1H),5.72(s,2H),4.88(brs,2H),4.39(d,J=5.9Hz,2H).

[0741] Embodiment 94

[0742] 4-((5-(3-chloro-4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0743]

[0744] Using (3-chloro-4-fluorophenyl)boronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 581.5 [M+1] + .

[0745] 1 HNMR (400MHz, DMSO-d6) δ8.97(t,J=6.0Hz,1H),8.06(d,J=1.9Hz,1H),7.95(dd,J=7.1,2.4Hz,1H),7.84(d,J=7.8Hz,2H),7.76-7.73(m,1H),7. 65(d,J=3.2Hz,1H),7.54-7.49(m,4H),7.29(d,J=7.7Hz,2H),6.98(d,J=8.0Hz,2H),6.74(d,J=3.2Hz,1H),5.74(s,2H),4.43(d,J=5.8Hz,2H).

[0746] Embodiment 95

[0747] 4-((5-(3-chloro-5-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0748]

[0749] Using (3-chloro-5-fluorophenyl)boronic acid (38 mg) as the starting material, the same procedure as in Example 75 was followed to obtain the target product (12 mg) as a white solid. LCMS (ESI): 581.5 [M+1] + .

[0750] 1HNMR(400MHz,DMSO-d6)δ12.84(s,1H),8.97(t,J=5.9Hz,1H),8.14(d,J=1.8Hz,1H),7 .84(d,J=8.1Hz,2H),7.71(d,J=1.7Hz,1H),7.67(d,J=3.2Hz,1H),7.63(d,J=10.1,1H ),7.59(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,2H),7.38(d,J=8.6,1H),7.29(d,J=8.0Hz, 2H), 6.98 (d, J = 8.0Hz, 2H), 6.75 (d, J = 3.2Hz, 1H), 5.75 (s, 2H), 4.45 (d, J = 5.8Hz, 2H).

[0751] Embodiment 96

[0752] 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[0753]

[0754] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid methyl ester

[0755]

[0756] At 0 ° C, to a mixture of 5-bromo-1H-indole-7-carboxylic acid methyl ester (5.0 g) and Cs2CO3 (21.5 g) in anhydrous DMF (100 mL), 1-(bromomethyl)-4-(trifluoromethyl)benzene (5.7 g) was added. The reaction mixture was then heated to room temperature and stirred for 6 hours. The reaction mixture was poured into 100 mL of ice water and extracted with 3x 50 mL of ethyl acetate. The reaction mixture was then introduced into an NH4Cl aqueous solution. The solid was collected by filtration and dried, and then dissolved in EA / PE (60 / 180 mL). The solution was filtered through diatomaceous earth on filter paper and concentrated to obtain the target product as a white solid (crude, 5.1 g). LCMS (ESI): 413 [M+1] + .

[0757] The solid was collected by filtration and dried, and then purified by silica gel column chromatography (EA / PE ratio is 1 / 3) to obtain the target product isomer 1 (5.1 g) and isomer 2 as a white solid. LCMS (ES+): 413 [M+1] + .

[0758] Isomer 1: R f=0.5(EA / PE=1 / 5). 1 H NMR (400MHz, CDCl3) δ8.19–8.03(m,2H),7.99(d,1H),7.49(d,2H),7.08(d,2H),6.06(s,2H),3.82(s,3H).

[0759]

[0760] Isomer 2: R f =0.2(EA / PE=1 / 5). 1 H NMR (400MHz, CDCl3) δ8.15(d,1H),8.01(d,1H),7.92(s,1H),7.63(d,2H),7.41(d,2H),5.76(s,2H),4.02(s,3H).

[0761] Step 2 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[0762]

[0763] Using the product of step 1 and 4-fluorophenylboronic acid as starting materials, the same procedures as steps 2 and 5 of Example 75 were followed to obtain the target product as a white solid. LCMS (ESI): 548 [M+1] + .

[0764] 1 HNMR(400MHz, CDCl3)δ8.21(s,1H),8.01(m,3H),7.60(s,1H),7.56–7.42(m,5H) ,7.15(t,2H),7.09(d,2H),6.09(s,1H),6.00(s,2H),4.52(d,2H),3.92(s,1H).

[0765] Embodiment 97

[0766] 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[0767]

[0768] Starting from phenylboronic acid, the target product was obtained as a white solid by the same procedure as in Example 96. LCMS (ESI): 530 [M+1] + .

[0769] 1HNMR(400MHz, CDCl3)δ8.22(s,1H),8.05-8.00(m,3H),7.64(d,1H),7.61–7.52(m,3H),7. 46(s,4H),7.37(s,2H),7.11(s,2H),6.10(s,1H),6.00(s,1H),4.52(s,1H),3.92(s,1H).

[0770] Embodiment 98

[0771] 4-((5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[0772]

[0773] Using (3-cyanophenyl)boronic acid as the starting material, the same procedure as in Example 96 was followed to obtain the target product as a white solid. LCMS (ESI): 555 [M+1] + .

[0774] 1 HNMR(400MHz,DMSO-d6)δ9.27(t,1H),8.42–8.33(m,2H),8.33–8.27(m,1H),8.15(d,1H),7.94(d, 1H),7.84(d,3H),7.70(dd,1H),7.53(d,2H),7.34(d,2H),7.05(d,2H),5.31(s,2H),4.53(d,2H).

[0775] Embodiment 99

[0776] 4-((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[0777]

[0778] Using (3,5-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 96 was followed to obtain the target product as a white solid. LCMS (ESI): 566 [M+1] + .

[0779] 1HNMR(400MHz,DMSO-d6)δ9.25(t,1H),8.42–8.31(m,2H),7.93(t,1H),7.85(d,2H),7.62–7 .56(m,2H),7.53(d,2H),7.34(d,2H),7.25(tt,1H),7.05(d,2H),5.96(s,2H),4.53(d,2H).

[0780] Embodiment 100

[0781] (S)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[0782]

[0783] Using phenylboronic acid and (S)-methyl 4-(1-aminoethyl)benzoic acid as starting materials, the same procedure as in Example 96 was followed to obtain the target product as a white solid. LCMS (ESI): 544 [M+1] + .

[0784] Embodiment 101

[0785] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[0786]

[0787] Using (3,5-difluorophenyl)boronic acid and (S)-methyl 4-(1-aminoethyl)benzoic acid as starting materials, the same procedure as in Example 96 was followed to obtain the target product as a white solid. LCMS (ESI): 580 [M+1] + .

[0788] Embodiment 102

[0789] 4-((1-(3-chlorobenzyl)-5-(3-cyanophenyl)-1H-indole-7-amido)methyl)benzoic acid

[0790]

[0791] Using 1-(bromomethyl)-3-chlorobenzene and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 622.12 [M+1] + .

[0792] 1HNMR (400MHz, DMSO-d6) δ9.07(d,J=5.9Hz,1H),8.22(s,1H),8.17–8.05(m,2H),7.85(d,J=8.0Hz,2H),7.79(d,J=7. 7Hz,1H),7.73–7.59(m,3H),7.36–7.20(m,4H),6.90(s,1H),6.85–6.69(m,2H),5.63(s,2H),4.47(d,J=5.6Hz,2H).

[0793] Embodiment 103

[0794] 4-((1-(3-chlorobenzyl)-4-(phenylamino)-1H-indole-7-amido)methyl)benzoic acid

[0795]

[0796] Using 1-(bromomethyl)-3-chlorobenzene (70 mg) and aniline (70 mg) as starting materials, the same procedure as in Example 64 was followed to obtain the target product (25 mg) as a white solid. LCMS (ESI): 510.2 [M+1] + .

[0797] 1 HNMR (400MHz, DMSO-d6) δ8.76(t,J=6.0Hz,1H),8.25(s,1H),7.84(d,J=8.0Hz,2H),7.43(d,J=3.2Hz,1H),7.32–7.1 8(m,9H),6.91(t,J=7.2Hz,1H),6.89–6.85(m,2H),6.81(dd,J=12.3,7.7Hz,2H),5.61(s,2H),4.42(d,J=5.9Hz,2H).

[0798] Embodiment 104

[0799] 4-((1-(3-chlorobenzyl)-5-(pyridin-3-yl)-1H-indole-7-amido)methyl)benzoic acid

[0800]

[0801] Using 1-(bromomethyl)-3-chlorobenzene and pyridine-3-biphenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 596.2 [M+1] + .

[0802] 1H NMR (400MHz, DMSO-d6) δ12.85(s,1H),9.08(t,J=5.9Hz,1H),8.97(d,J=2.4Hz,1H),8.55 (dd,J=4.8,1.6Hz,1H),8.14(dt,J=8.1,2.0Hz,1H),8.10(d,J=1.8Hz,1H),7.87(d,J=8.0 Hz,2H),7.65(d,J=3.2Hz,1H),7.59(d,J=1.9Hz,1H),7.49(dd,J=7.9,4.8Hz,1H),7.34( d,J=8.0Hz,2H),7.31–7.21(m,2H),6.92(d,J=2.1Hz,1H),6.82(d,J=7.5Hz,1H),6.75(d,

[0803] J=3.2Hz,1H),5.64(s,2H),4.48(d,J=5.8Hz,2H).

[0804] Embodiment 105

[0805] 4-((1-(3-chlorobenzyl)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[0806]

[0807] Using 1-(bromomethyl)-3-chlorobenzene and phenylboronic acid as starting materials, the target product was obtained as a white solid by the same procedure as in Example 75. MS (ESI): 595.2 [M+1] + .

[0808] 1 HNMR(400MHz,DMSO-d6)δ13.32–12.42(brs,1H),9.09(d,J=7.1Hz,1H),8.02(d,J=7.9Hz,1 H),7.87(d,J=7.8Hz,2H),7.74(d,J=7.8Hz,2H),7.61(d,J=7.8Hz,1H),7.56(d,J=7.9Hz,1 H),7.48(d,J=7.8Hz,2H),7.35(d,J=7.9Hz,3H),7.29–7.23(m,2H),6.94(d,J=8.0Hz,1H), 6.83(d,J=7.6Hz,1H), 6.73(d,J=8.8Hz,1H), 5.63(d,J=7.6Hz,2H), 4.48(t,J=6.4Hz,2H).

[0809] Embodiment 106

[0810] 4-((1-(3-chlorobenzyl)-5-(3,5-difluorophenyl)-1H-indole-7-amido)methyl)benzoic acid

[0811]

[0812] Using 1-(bromomethyl)-3-chlorobenzene and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 531.1 [M+1] + .

[0813] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),9.06(t,J=5.9Hz,1H),8.13(d,J=1.8Hz,1H),7 .87(d,J=8.0Hz,2H),7.65(d,J=3.2Hz,1H),7.60(d,J=1.9Hz,1H),7.54–7.48(m,2H),7 .33(d,J=8.0Hz,2H),7.29–7.22(m,2H),7.19(tt,J=9.2,2.3Hz,1H),6.90(d,J=2.1Hz ,1H),6.79(d,J=7.5Hz,1H),6.74(d,J=3.1Hz,1H),5.64(s,2H),4.48(d,J=5.8Hz,2H).

[0814] Embodiment 107

[0815] 4-((1-(3-chlorobenzyl)-5-(4-fluorophenyl)-1H-indole-7-amido)methyl)benzoic acid

[0816]

[0817] Using 1-(bromomethyl)-3-chlorobenzene and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 513.2 [M+1] + .

[0818] 1HNMR (400MHz, DMSO-d6) δ12.84(s,1H),9.07(t,J=6.0Hz,1H),8.00(d,J=1.8Hz,1H ),7.87(d,J=8.1Hz,2H),7.81–7.74(m,2H),7.62(d,J=3.2Hz,1H),7.51(d,J=1.8H z,1H),7.34(s,1H),7.35–7.25(m,4H),7.24(t,J=7.7Hz,1H),6.91(d,J=2.0Hz,1H ),6.82(d,J=7.5Hz,1H),6.72(d,J=3.2Hz,1H),5.63(s,2H),4.47(d,J=5.9Hz,2H).

[0819] Embodiment 108

[0820] (S)-4-(1-(1-(3-chlorobenzyl)-5-(3-cyanophenyl)-1H-indole-7-amido)ethyl)benzoic acid

[0821]

[0822] Using 1-(bromomethyl)-3-chlorobenzene, (3-cyanophenyl)boronic acid and (S)-methyl 4-(1-aminoethyl)benzoic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product (26 mg) as a white solid. LCMS (ESI): 534.5 [M+1] + .

[0823] 1 HNMR (400MHz, DMSO-d6) δ12.85(s,1H),9.00(d,J=7.6Hz,1H),8.23(d,J=1.9Hz,1H),8.16–8. 04(m,2H),7.88(d,J=8.1Hz,2H),7.81(d,J=7.6Hz,1H),7.71(t,J=7.8Hz,1H),7.63(d,J=3.2H z,1H),7.55(d,J=1.9Hz,1H),7.46(d,J=8.1Hz,2H),7.30–7.18(m,2H),6.87(d,J=2.0Hz,1H) ,6.78(d,J=7.6Hz,1H),6.73(d,J=3.2Hz,1H),5.63–5.49(m,2H),5.07-5.01(m,J=7.1Hz,1H).

[0824] Embodiment 109

[0825] (S)-4-(1-(1-(3-chlorobenzyl)-5-(pyridin-3-yl)-1H-indole-7-amido)ethyl)benzoic acid

[0826]

[0827] Using 1-(bromomethyl)-3-chlorobenzene, (S)-methyl 4-(1-aminoethyl)benzoic acid and pyridine-3-boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 510.5 [M+1] + .

[0828] 1 HNMR(400MHz,DMSO-d6)δ12.84(s,1H),9.03–8.97(m,2H),8.56(d,J=4.7Hz,1H),8.15(d,J= 8.0Hz,1H),8.09(d,J=1.8Hz,1H),7.89(d,J=8.1Hz,2H),7.63(d,J=3.2Hz,1H),7.56–7.49(m ,2H),7.46(d,J=8.1Hz,2H),7.29–7.24(m,1H),7.22(t,J=7.8Hz,1H),6.88(d,J=2.1Hz,1H), 6.79(d,J=7.6Hz,1H),6.74(d,J=3.1Hz,1H),5.65–5.47(m,2H),5.12-5.06(m,J=7.2Hz,1H).

[0829] Embodiment 110

[0830] (S)-4-(1-(1-(3-chlorobenzyl)-5-phenyl-1H-indole-7-amido)ethyl)benzoic acid

[0831]

[0832] Using 1-(bromomethyl)-3-chlorobenzene, (S)-methyl 4-(1-aminoethyl)benzoic acid and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 509.5 [M+1] + .

[0833] 1HNMR (400MHz, DMSO-d6) δ12.84(s,1H),9.03(d,J=7.7Hz,1H),8.01(d,J=1.8Hz,1H),7. 89(d,J=8.2Hz,2H),7.78–7.71(m,2H),7.60(d,J=3.2Hz,1H),7.54–7.43(m,5H),7.35( t,J=7.4Hz,1H),7.29–7.25(m,1H),7.22(t,J=7.8Hz,1H),6.88(d,J=2.0Hz,1H),6.80( d,J=7.6Hz,1H),6.71(d,J=3.1Hz,1H),5.65–5.47(m,2H),5.12-5.06(m,J=7.2Hz,1H).

[0834] Embodiment 111

[0835] (S)-4-(1-(1-(3-chlorobenzyl)-5-(3,5-difluorophenyl)-1H-indole-7-amido)ethyl)benzoic acid

[0836]

[0837] Using 1-(bromomethyl)-3-chlorobenzene, (S)-methyl 4-(1-aminoethyl)benzoic acid and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 545.5 [M+1] + .

[0838] 1 HNMR(400MHz,DMSO-d6)δ12.85(s,1H),8.98(d,J=7.6Hz,1H),8.11(d,J=1.8Hz ,1H),7.88(d,J=8.2Hz,2H),7.63(d,J=3.2Hz,1H),7.57–7.49(m,3H),7.46(d, J=8.2Hz,2H),7.29–7.25(m,1H),7.24–7.17(m,2H),6.86(d,J=2.1Hz,1H),6.7 8(d,J=7.6Hz,1H),6.72(d,J=3.1Hz,1H),5.63–5.51(m,2H),5.11-5.06(m,1H).

[0839] Embodiment 112

[0840] (±)6-(6-Bromo-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)spiro[3.3]heptane-2-carboxylic acid

[0841]

[0842] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid methyl ester

[0843]

[0844] A mixture of methyl 6-bromo-1H-indole-4-carboxylate (3.9 mmol), 4-(trifluoromethyl)thiophenol (4.3 mmol) and tBuOOH (4.29 mmol) was dissolved in MeCN (20.0 mL) at 60°C, followed by the addition of iodine (0.10 mmol, 10 mol%). The reaction mixture was stirred for 1 hour, quenched with saturated aqueous Na2S2O3 (5 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo, and the crude product was purified by column chromatography (with petroleum ether / ethyl acetate as eluent) to give the product as a light yellow solid (1.59 g). LCMS (ESI): 430.2 [M+1] + .

[0845] Step 2 6-Bromo-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-carboxylic acid

[0846]

[0847] To a solution of the product of step 1 (520 mg, 1.21 mmol) in MeOH / H2O (10 mL / 2.0 mL) was added LiOH·H2O (254 mg, 6.06 mmol) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the reaction mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 30 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound (480 mg) as a white solid. LCMS (ESI): 416 [M+1] + .

[0848] Step 3 (±) 6-aminospiro[3.3]heptane-2-carboxylic acid methyl hydrochloride

[0849]

[0850] To a solution of methyl 6-((tert-butyloxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate in THF (10 mL) was added 4M hydrochloric acid in dioxane (1.0 mL). After stirring overnight, the mixture was concentrated (without further purification) to give the title compound (0.52 g) as a white solid. LCMS (ESI): 170 [M+1] + .

[0851] Step 4 (±) 6-(6-bromo-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)spiro[3.3]heptane-2-carboxylic acid methyl ester

[0852]

[0853] To a mixture of the product of step 2 (416 mg), the product of step 32 (266.5 mg) and HATU (456 mg) in anhydrous DMF (10 mL) at 0°C, DIPEA (0.52 mL) was added. Stir overnight at room temperature, then add 100 mL of water to quench the reaction mixture, and extract with 3 x 100 mL of ethyl acetate. Rinse the combined organic layer with 100 mL of saturated brine, dry over anhydrous Na2SO4, and concentrate. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.52 g) as a white solid. LCMS (ESI): 567 [M+1] + .

[0854] Step 5 (±) 6-(6-Bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indole-4-amido)spiro-[3.3]heptane-2-carboxylic acid

[0855]

[0856] To a solution of the product of step 4 (57 mg) in MeOH / H2O (5 mL / 0.5 mL), LiOH·H2O (20 mg) was added. The reaction mixture was stirred at 40°C for 12 hours. Cooled to 0°C, the mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 20 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to obtain the target compound (40 mg) as a white solid. LCMS (ESI): 553.2 [M+1] + .

[0857] 1H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.25(d,J=7.1Hz,1H),7.86(s,1H),7.75(d,J=1.8Hz,1H),7.49(d,J=8.3Hz,2H),7.09(d,J=1.8Hz,1H),7.05(d ,J=8.3Hz,2H),3.99-3.92(m,1H),2.90-2.83(m,1H),2.26–2.08(m,3H),2 .02-1.97(m,2H),1.94-1.90(m,1H),1.73-1.69(m,1H),1.66-1.62(m,1H).

[0858] Embodiment 113

[0859] (±)6-(6-phenyl-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)spiro[3.3]heptane-2-carboxylic acid

[0860]

[0861] Using phenylboronic acid and Example 112 as starting materials, the same procedure as in Steps 4 and 5 of Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 551 [M+1] + .

[0862] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.21(d,J=7.1Hz,1H),7.86(d,J=2.4Hz,1H),7.79(d,J =1.6Hz,1H),7.71(d,J=7.4Hz,2H),7.49(t,J=7.7Hz,4H),7.37(d,J=7.3Hz,1H),7.28(d,J=1 .6Hz,1H),7.09(d,J=8.2Hz,2H),4.04-3.96(m,1H),2.91–2.82(m,1H),2.22-2.16(m,2H),2. 15–2.07(m,1H),2.06–1.96(m,2H),1.95-1.90(m,1H),1.75-1.71(m,1H),1.69-1.65(m,1H).

[0863] Embodiment 114

[0864] (±)6-(6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)spiro[3.3]heptane-2-carboxylic acid

[0865]

[0866] Using (3-cyanophenyl)boronic acid as the starting material, the same procedure as in Example 113 was followed to obtain the target product as a white solid. LCMS (ESI): 576 [M+1] + .

[0867] 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.29–8.15(m,2H),8.15–8.02(m,1H),7.9 6–7.87(m,2H),7.84(d,J=7.7Hz,1H),7.70(t,J=7.8Hz,1H),7.51(d,J=8.3Hz,2H ),7.38(d,J=1.6Hz,1H),7.11(d,J=8.2Hz,2H),4.08-3.97(m,2H),2.95–2.82(m, 1H),2.27–2.10(m,3H),2.09–2.01(m,2H),1.99–1.88(m,1H),1.77–1.62(m,1H).

[0868] Embodiment 115

[0869] (±)6-(6-(3-carbamoylphenyl)-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)spiro[3.3]heptane-

[0870] 2-Carboxylic acid

[0871]

[0872] Using (3-carbamoylphenyl)boronic acid as the starting material, the same procedure as in Example 113 was followed to obtain the target product as a white solid. LCMS (ESI): 594 [M+1] + .

[0873] 1 H NMR (400MHz, DMSO-d6) δ12.15(d,J=2.9Hz,1H),8.31–8.11(m,3H),7.96–7.78(m,4H),7.58(t,J=7.7Hz,1H),7.52(d,J=8.4H z,2H),7.47–7.37(m,2H),7.11(d,J=8.2Hz,2H),4.04–3.97(m,1H),2.27–2.10(m,3H),2.09–1.90(m,3H),1.82–1.66(m,2H).

[0874] Embodiment 116

[0875] 4-((5-(3-(methylcarbamoyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0876]

[0877] Using (3-(methylcarbamoyl)phenyl)boronic acid as the starting material, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 586.2 [M+1] + .

[0878] 1 H NMR (400MHz, DMSO) δ12.23(s,1H),8.37(s,1H),8.23(s,1H),8.09(d,J=7.9Hz,1H),7.92–7.82(m,3H),7.72(d,J=7 .9Hz,1H),7.50(d,J=8.2Hz,2H),7.37(d,J=1.6Hz,1H),7.06(d,J=8.2Hz,2H),1.78(s,6H),1.01(d,J=6.5Hz,4H).

[0879] Embodiment 117

[0880] 4-((6-(3-cyanobenzene)-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)methyl)benzoic acid

[0881]

[0882] Using the product of step 2 of Example 112, methyl 4-(aminomethyl)benzoate and (3-cyanophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 572 [M+1] + .

[0883] 1H NMR (400MHz, DMSO) δ12.23(d,J=2.8Hz,1H),8.73(t,J=6.0Hz,1H),8.25(t,J=1.8Hz,1H),8.13-8.10(m,1H),7.95-7.93(m,2H), 7.88–7.80(m,3H),7.71(t,J=7.8Hz,1H),7.54–7.48(m,3H),7.36(d,J=8.0Hz,2H),7.12(d,J=8.3Hz,2H),4.36(d,J=5.9Hz,2H).

[0884] Embodiment 118

[0885] 2-(3-(6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)bicyclo[1.1.1]pentan-1-yl)

[0886] Acetic acid

[0887]

[0888] Step 1 Ethyl 2-(3-aminobicyclo[1.1.1]pentan-1-yl)acetate hydrochloride

[0889]

[0890] To a solution of ethyl 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetate (0.70 g) in THF (10 mL) was added 4 M hydrochloric acid in dioxane (1 mL). After stirring overnight, the mixture was concentrated (without further purification) to give the title compound (0.5 g) as a white solid. LCMS (ESI): 170.1 [M+1] + .

[0891] Step 2 2-(3-(6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)bicyclo[1.1.1]pentan-1-yl)acetic acid

[0892]

[0893] Using the product of steps 1 and 2 of Example 112 and (3-cyanophenyl)boronic acid as starting materials, the same procedures as Example 75 were followed to obtain the target product as a white solid.

[0894] LCMS(ESI):562.4[M+1] + .

[0895] 1H NMR (400MHz, DMSO) δ12.17(s,1H),8.53(s,1H),8.23(d,J=1.8Hz,1H),8.16–8.01(m,1H),7.98–7.84(m,2H),7.85–7.75(m ,1H),7.69(t,J=7.8Hz,1H),7.50(d,J=8.2Hz,2H),7.40(d,J=1.6Hz,1H),7.10(d,J=8.3Hz,2H),2.43(s,2H),1.82(s,6H).

[0896] Embodiment 119

[0897] 3-((6-(3-cyanobenzene)-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0898]

[0899] Using the product of step 2 of Example 112, methyl 3-(aminomethyl)bicyclo[1.1.1]pentane-1-carboxylate hydrochloride and (3-cyanophenyl)boronic acid as starting materials, the same procedure as step 4 of Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 562 [M+1] + .

[0900] 1 H NMR (400MHz, DMSO-d6) δ12.21–12.17(m,1H),8.22(d,J=1.8Hz,1H),8.16–8.06(m,2H),7.93–7.81(m,3H),7.71(t,J =7.8Hz,1H),7.49(d,J=8.2Hz,2H),7.41(d,J=1.6Hz,1H),7.11(d,J=8.2Hz,2H),3.14(d,J=5.7Hz,2H),1.79(s,6H).

[0901] Embodiment 120

[0902] 4-((6-(3-cyanobenzene)-1-methyl-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)methyl)benzoic acid

[0903]

[0904] Step 1: 6-Bromo-1-methyl-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-carboxylic acid methyl ester

[0905]

[0906] To a solution of the product of step 1 of Example 112 (91 mg) in DMF (5 mL) at 0°C, NaH (18 mg) was added and stirred at room temperature for 0.5 hours. MeI (30 mg) was then added to the reaction mixture. Stir for 2 hours and then 50 mL of water was added. The reaction mixture was extracted 3 times with 50 mL of ethyl acetate, rinsed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the product acid (80 mg). LCMS (ESI): 444 [M+1] + .

[0907] Step 2 4-((6-(3-cyanobenzene)-1-methyl-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)methyl)benzoic acid

[0908]

[0909] Using the product of step 1, methyl 4-(aminomethyl)benzoate and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 586.5 [M+1] + .

[0910] 1 H NMR (400MHz, DMSO-d6) δ8.72(t,J=6.0Hz,1H),8.35(d,J=1.9Hz,1H),8.23–8.16(m,1H),8.13(d,J=1.6Hz,1H),7.94(s,1H),7.89–7.79(m,3H),7 .73-7.68(m,1H),7.56(d,J=1.5Hz,1H),7.50(d,J=8.2Hz,2H),7.35(d, J=8.0Hz,2H),7.12(d,J=8.3Hz,2H),4.35(d,J=5.9Hz,2H),4.00(s,3H).

[0911] Embodiment 121

[0912] 4-((6-(3-Carbamoylphenyl)-1-methyl-3-((4-(trifluoromethyl)phenyl)mercapto)-1H-indole-4-amido)methyl)benzoic acid

[0913]

[0914] Using the product of step 1 of Example 120, methyl 4-(aminomethyl)benzoate and (3-carbamoylphenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 604 [M+1] + .

[0915] 1 H NMR (400MHz, DMSO-d6) δ8.73(t,J=6.0Hz,1H),8.29(d,J=2.0Hz,1H),8.15(s,1H),8.04(d,J=1.5Hz,1H),7.95–7.85(m,2H),7.81(d, J=8.0Hz,2H),7.62–7.54(m,3H),7.52–7.42(m,3H),7.34(d,J=7.9Hz,2H),7.12(d,J=8.3Hz,2H),4.34(d,J=5.9Hz,2H),3.99(s,3H).

[0916] Embodiment 122

[0917] 4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0918]

[0919] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 529.2 [M+1] + .

[0920] 1 HNMR(400MHz,DMSO-d6)δ12.86(s,1H),9.08(t,J=6.0Hz,1H),8.03(d,J=1.8Hz ,1H),7.85(d,J=8.0Hz,2H),7.74(d,J=7.6Hz,2H),7.64(d,J=3.2Hz,1H),7.59( d,J=7.8Hz,1H),7.55(d,J=1.8Hz,1H),7.51–7.42(m,3H),7.37–7.29(m,4H),7 .09(d,J=7.8Hz,1H),6.74(d,J=3.2Hz,1H),5.71(s,2H),4.43(d,J=5.9Hz,2H).

[0921] Embodiment 123

[0922] 4-((5-(Pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0923]

[0924] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene and pyridine-3-boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 530.2 [M+1] + .

[0925] 1 HNMR(400MHz,DMSO-d6)δ12.86(s,1H),9.07(t,J=6.0Hz,1H),8.98(d,J=2.4Hz, 1H),8.55(dd,J=4.8,1.5Hz,1H),8.17–8.09(m,2H),7.85(d,J=8.1Hz,2H),7.68 (d,J=3.2Hz,1H),7.59(q,J=3.3Hz,2H),7.53–7.42(m,2H),7.34–7.29(m,3H),7 .09(d,J=7.8Hz,1H),6.76(d,J=3.2Hz,1H),5.72(s,2H),4.43(d,J=5.9Hz,2H).

[0926] Embodiment 124

[0927] 4-((5-(4-Fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0928]

[0929] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 547.2 [M+1] + .

[0930] 1H NMR (400MHz, DMSO-d6) δ12.83 (s, 1H), 9.07 (t, J = 6.0Hz, 1H), 8.00 (s, 1H), 7.8 5(d,J=7.8Hz,2H),7.77(dd,J=8.5,5.4Hz,2H),7.64(d,J=3.2Hz,1H),7.59(d ,J=7.8Hz,1H),7.52(s,1H),7.45(t,J=7.8Hz,1H),7.31(d,J=7.7Hz,5H),7.0 9(d,J=7.8Hz,1H),6.73(d,J=3.1Hz,1H),5.71(s,2H),4.42(d,J=5.8Hz,2H).

[0931] Embodiment 125

[0932] 4-((5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0933]

[0934] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 565.5 [M+1] + .

[0935] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),9.06(t,J=5.9Hz,1H),8.14(s,1H), 7.84(d,J=7.8Hz,2H),7.67(d,J=3.3Hz,1H),7.63–7.56(m,2H),7.52(d,J=8 .2Hz,2H),7.45(t,J=7.9Hz,1H),7.35–7.26(m,3H),7.23–7.15(m,1H),7.07 (d,J=7.8Hz,1H),6.75(d,J=3.2Hz,1H),5.73(s,2H),4.44(d,J=5.9Hz,2H).

[0936] Embodiment 126

[0937] 4-((5-(3-cyanophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)methyl)benzoic acid

[0938]

[0939] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 554.4 [M+1] + .

[0940] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),9.07(t,J=5.9Hz,1H),8.23(d,J=1.9Hz,1H),8.14 (d,J=1.8Hz,1H),8.13–8.08(m,1H),7.84(d,J=8.1Hz,2H),7.80(d,J=7.6Hz,1H),7.70–7 .65(m,2H),7.63(d,J=1.9Hz,1H),7.59(d,J=7.8Hz,1H),7.45(t,J=7.8Hz,1H),7.33–7.2 8(m,3H),7.08(d,J=7.8Hz,1H),6.76(d,J=3.2Hz,1H),5.73(s,2H),4.44(d,J=5.9Hz,2H).

[0941] Embodiment 127

[0942] (S)-4-(1-(5-(3-cyanophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0943]

[0944] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 568.5 [M+1] + .

[0945] 1HNMR(400MHz,DMSO-d6)δ12.83(s,1H),8.98(d,J=7.6Hz,1H),8.24(t,J=1.8Hz,1H ),8.15–8.09(m,2H),7.86(d,J=8.1Hz,2H),7.81(d,J=7.8Hz,1H),7.71(t,J=7.8H z,1H),7.64(d,J=3.2Hz,1H),7.60–7.55(m,2H),7.44-7.41(m,3H),7.26(s,1H),7 .03(d,J=7.8Hz,1H),6.75(d,J=3.2Hz,1H),5.71-5.60(m,2H),5.06-5.01(m,1H).

[0946] Embodiment 128

[0947] (S)-4-(1-(5-(pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0948]

[0949] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and pyridine-3-boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 544.5 [M+1] + .

[0950] 1 HNMR(400MHz,DMSO-d6)δ9.05(d,J=2.3Hz,1H),8.99(d,J=7.6Hz,1H),8.62(dd,J =4.9,1.5Hz,1H),8.29(d,J=8.1,1H),8.13(d,J=1.8Hz,1H),7.87(d,J=8.1Hz,2H ),7.66(d,J=3.2Hz,1H),7.64–7.55(m,3H),7.44(d,J=7.9Hz,3H),7.28(s,1H),7 .04(d,J=7.8Hz,1H),6.76(d,J=3.2Hz,1H),5.75–5.58(m,2H),5.07-5.01(m,1H).

[0951] Embodiment 129

[0952] (S)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0953]

[0954] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and phenylboronic acid (26 mg) as starting materials, the same procedure as in Example 75 was followed to give the target product as a white solid. LCMS (ESI): 543.5 [M+1] + .

[0955] 1 HNMR(400MHz,DMSO-d6)δ12.84(s,1H),9.00(d,J=7.6Hz,1H),8.02(d,J=1.7Hz,1H), 7.87(d,J=8.1Hz,2H),7.78–7.72(m,2H),7.61(d,J=3.2Hz,1H),7.58(d,J=7.8Hz,1H ),7.53–7.47(m,3H),7.44-7.41(m,3H),7.35(t,J=7.4Hz,1H),7.27(s,1H),7.04(d, J=7.8Hz,1H),6.73(d,J=3.1Hz,1H),5.72–5.57(m,2H),5.07-5.01(m,J=7.1Hz,1H).

[0956] Embodiment 130

[0957] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)ethyl)benzoic acid

[0958]

[0959] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 579.5 [M+1] + .

[0960] 1HNMR(400MHz,DMSO-d6)δ12.83(s,1H),8.96(d,J=7.6Hz,1H),8.13(d,J=1.8H z,1H),7.89–7.84(m,2H),7.64(d,J=3.2Hz,1H),7.58(d,J=7.9Hz,1H),7.55–7 .48(m,3H),7.44–7.40(m,3H),7.25(s,1H),7.22-7.18(m,1H),7.03(d,J=7.8 Hz,1H),6.74(d,J=3.2Hz,1H),5.70-5.60(m,2H),5.07-5.01(m,J=7.1Hz,1H).

[0961] Embodiment 131

[0962] 4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0963]

[0964] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, methyl 4-(1-aminocyclopropyl)benzoate and biphenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 555.4 [M+1] + .

[0965] 1 H NMR (400MHz, DMSO) δ12.69 (s, 1H), 9.34 (s, 1H), 8.06 (d, J = 2.0Hz, 1H), 7.80 (t,J=8.1Hz,4H),7.68(d,J=2.0Hz,1H),7.61(d,J=7.9Hz,1H),7.56–7.43(m ,4H),7.37(t,J=7.4Hz,1H),7.33–7.21(m,3H),7.02(d,J=7.8Hz,1H),6.75 (d,J=3.2Hz,1H),5.73(s,2H),1.24(q,J=5.1Hz,2H),1.02(q,J=5.1Hz,2H).

[0966] Embodiment 132

[0967] 4-(1-(5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0968]

[0969] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, methyl 4-(1-aminocyclopropyl)benzoate and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 591.2 [M+1] + .

[0970] 1 H NMR(400MHz,DMSO-d6)δ12.70(s,1H),9.32(s,1H),8.17(d,J=1.8Hz,1H), 7.79(d,J=8.1Hz,2H),7.73(d,J=1.9Hz,1H),7.66–7.52(m,4H),7.48(t,J= 7.8Hz,1H),7.27(d,J=7.8Hz,3H),7.24–7.12(m,1H),7.01(d,J=7.8Hz,1H) ,6.76(d,J=3.1Hz,1H),5.74(s,2H),1.29–1.13(m,2H),1.13–0.95(m,2H).

[0971] Embodiment 133

[0972] 4-(1-(5-(3-cyanophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[0973]

[0974] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, methyl 4-(1-aminocyclopropyl)benzoate and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 580.6 [M+1] + .

[0975] 1H NMR (400MHz, DMSO-d6) δ12.76 (s, 1H), 9.36 (t, J = 2.6Hz, 1H), 8.31 (s, 1H), 8.22 –8.14(m,2H),7.83(d,J=7.7Hz,1H),7.81–7.68(m,4H),7.62(d,J=7.9Hz,1H),7 .56(d,J=3.2Hz,1H),7.49(t,J=7.8Hz,1H),7.34–7.22(m,3H),7.00(d,J=7.8Hz ,1H),6.76(d,J=3.1Hz,1H),5.75(s,2H),1.28–1.24(m,2H),1.08–0.97(m,2H).

[0976] Embodiment 134

[0977] (S)-4-(1-(5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[0978]

[0979] Step 1: 5-bromo-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid methyl ester

[0980]

[0981] To a mixture of 5-bromo-1H-indazole-7-carboxylic acid methyl ester (500 mg) and Cs2CO3 (769 mg) in anhydrous DMF (10 mL) at 0°C, 1-(bromomethyl)-3-(trifluoromethyl)benzene (564 mg) was added. The reaction mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was poured into 100 mL of ice water and extracted with 3 x 50 mL of ethyl acetate. The combined organic layer was washed with 50 mL of brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 10:1) to obtain the target compound (530 mg) as a white solid. LCMS (ESI): 413.2 [M+1] + .

[0982] Step 2 5-Bromo-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid

[0983]

[0984] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2.0 mL) was added LiOH·H2O (254 mg) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. After cooling to 0°C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH to 6. The reaction mixture was then extracted with 3x 30 mL of ethyl acetate. The combined organic layers were washed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound (460 mg) as a white solid. LCMS (ESI): 399.3 [M+1] + .

[0985] Step 3: Methyl (S)-4-(1-(5-bromo-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoate

[0986]

[0987] To a mixture of the product of step 2 (460 mg), methyl (S)-4-(1-aminoethyl)benzoate (233 mg) and HATU (456 mg) in anhydrous DMF (100 mL) at 0°C, DIPEA (0.52 mL) was added. After stirring overnight at room temperature, 100 mL of water was added to quench the reaction mixture, followed by extraction with 3 x 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.6 g) as a white solid. LCMS (ESI): 560.2 [M+1] + .

[0988] Step 4: Methyl (S)-4-(1-(5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoate

[0989]

[0990] At 100°C, a mixture of the product of step 3 (30 mg), (4-fluorophenyl)boronic acid (15 mg), Pd(dppf)2Cl2 (4 mg, 0.01 mmol) and AcOK (16 mg) in 1,4-dioxane / H2O (5 mL / 0.5 mL) was stirred for 1 hour under nitrogen. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (27 mg) as a yellow solid. LCMS (ESI): 576.3 [M+1]+ .

[0991] Step 5 (S)-4-(1-(5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[0992]

[0993] To a solution of the product of step 4 (27 mg) in MeOH / H2O (5 mL / 0.5 mL), LiOH·H2O (16 mg) was added. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 20 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to obtain the target compound (23 mg) as a white solid. LCMS (ESI): 562 [M+1] + .

[0994] 1 HNMR(400MHz,DMSO-d6)δ12.80(s,1H),9.24(d,J=7.6Hz,1H),8.36(s,1H),8.22(s,1H),7.91–7.77(m,5H),7.59(d,J=7.8Hz,1H),7.45 (dd,J=22.7,7.9Hz,3H),7.35(dd,J=16.3,7.6Hz,3H),7.12(d,J=7.8Hz,1H),5.85(s,2H),5.15(p,J=7.1Hz,1H),1.37(d,J=7.1Hz,3H).

[0995] Embodiment 135

[0996] (S)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[0997]

[0998] Starting from phenylboronic acid, the target product was obtained as a white solid by the same procedure as in Example 134. LCMS (ES+): 544.5 [M+1] + .

[0999] 1H NMR(400MHz, DMSO-d6)12.85(s,1H),9.33(d,J=7.6Hz,1H),8.36(s,1H),8.23(d,J=1.7Hz,1H),7.92–7.82(m,3H),7.80(d,J=7.6Hz,2H),7.59(d ,J=7.8Hz,1H),7.57–7.45(m,4H),7.45–7.36(m,2H),7.34(s,1H),7.12 (d,J=7.8Hz,1H),5.84(s,2H),5.20–5.10(m,1H),1.37(d,J=7.0Hz,3H).

[1000] Embodiment 136

[1001] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1002]

[1003] Using (3,5-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 580.5 [M+1] + .

[1004] 1 HNMR (400MHz, DMSO-d6) δ12.84(s,1H),9.21(d,J=7.6Hz,1H),8.38(s,1H),8.35(d,J=1.7Hz,1H),7.87(d,J=8.0Hz,3H),7.63–7.54(m,3H),7 .51–7.40(m,3H),7.32(s,1H),7.27(tt,J=9.3,2.3Hz,1H),7.11(d,J=7.8Hz,1H),5.85(s,2H),5.14(p,J=7.1Hz,1H),1.39(d,J=7.1Hz,3H).

[1005] Embodiment 137

[1006] 4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[1007]

[1008] Using methyl 4-(aminomethyl)benzoate and phenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 530.2 [M+1] + .

[1009] 1 HNMR (400MHz, DMSO-d6) δ12.92(s,1H),9.35(t,J=6.0Hz,1H),8.37(s,1H),8.25(d,J=1.7Hz,1H),7.90–7.83(m,3H),7.79(d,J=7.6Hz,2 H),7.61(d,J=7.8Hz,1H),7.52-7.48(m,3H),7.42–7.36(m,3H),7.36(s,1H),7.18(d,J=7.8Hz,1H),5.93(s,2H),4.53(d,J=5.8Hz,2H).

[1010] Embodiment 138

[1011] 4-((5-(4-Fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[1012]

[1013] Using methyl 4-(aminomethyl)benzoate as the starting material, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 548.5 [M+1] + .

[1014] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.24(d,J=7.6Hz,1H),8.36(s,1H),8.22(s,1H),7.91–7.77(m,5H),7.59(d,J=7.8Hz, 1H),7.50–7.40(m,3H),7.39–7.30(m,3H),7.12(d,J=7.8Hz,1H),5.85(s,2H),5.15(p,J=7.1Hz,1H),1.37(d,J=7.1Hz,3H).

[1015] Embodiment 139

[1016] 4-((5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)benzoic acid

[1017]

[1018] Using (3,5-difluorophenyl)boronic acid and methyl 4-(aminomethyl)benzoate as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 566.4 [M+1] + .

[1019] 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),9.21(d,J=7.6Hz,1H),8.38(s,1H),8.35(d,J=1.7Hz,1H),7.87(d,J=8.0Hz,3H),7.63–7.54(m,3H),7 .51–7.40(m,3H),7.32(s,1H),7.27(tt,J=9.3,2.3Hz,1H),7.11(d,J=7.8Hz,1H),5.85(s,2H),5.14(p,J=7.1Hz,1H),1.39(d,J=7.1Hz,3H).

[1020] Embodiment 140

[1021] 4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)cyclopropyl)benzoic acid

[1022]

[1023] Using methyl 4-(1-aminocyclopropyl)benzoate and phenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 556 [M+1] + .

[1024] 1 H NMR (400MHz, DMSO) δ12.75 (s, 1H), 9.59 (s, 1H), 8.37 (s, 1H), 8.28 (d, J = 1.7Hz,

[1025] 1H),7.85(d,J=7.6Hz,2H),7.81–7.75(m,2H),7.63(d,J=7.8Hz,1H),7.57–7.46(m,3H),

[1026] 7.42(t,J=7.4Hz,1H),7.35(s,1H),7.31–7.26(m,2H),7.10(d,J=7.9Hz,1H),5.93(s,2H),

[1027] 1.33–1.28(m,2H),1.20–1.14(m,2H).

[1028] Embodiment 141

[1029] 4-((5-phenyl-1-(quinolin-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1030]

[1031] Using 2-(bromomethyl)quinoline and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product (21 mg) as a white solid. LCMS (ESI): 512.5 [M+1] + .

[1032] 1 HNMR(400MHz,DMSO-d6)δ8.90(t,J=5.8Hz,1H),8.19(d,J=8.5Hz,1H),8.02(d, J=1.8Hz,1H),7.96–7.89(m,2H),7.75-7.73(m,3H),7.69–7.62(m,3H),7.57(t, J=7.5Hz,1H),7.50(d,J=1.8Hz,1H),7.47(t,J=7.7Hz,2H),7.33(t,J=7.4Hz,1H ),7.06(d,J=7.9Hz,2H),6.79–6.73(m,2H),5.90(s,2H),4.29(d,J=5.7Hz,2H).

[1033] Embodiment 142

[1034] 4-((5-(4-Fluorophenyl)-1-(quinolin-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1035]

[1036] Using 2-(bromomethyl)quinoline and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 530.2 [M+1] + .

[1037] 1HNMR (400MHz, DMSO-d6) δ12.77(s,1H),8.96(t,J=5.9Hz,1H),8.19(d,J=8.5Hz,1H) ,8.01(d,J=1.8Hz,1H),7.94–7.88(m,2H),7.81–7.69(m,3H),7.66–7.59(m,3H),7.5 7(t,J=7.5Hz,1H),7.51(d,J=1.8Hz,1H),7.30(t,J=8.8Hz,2H),7.13(d,J=8.0Hz,2 H), 6.75 (d, J = 3.1Hz, 1H), 6.71 (d, J = 8.6Hz, 1H), 5.91 (s, 2H), 4.33 (d, J = 5.8Hz, 2H).

[1038] Embodiment 143

[1039] (S)-4-(1-(5-phenyl-1-(quinolin-2-methylene)-1H-indole-7-amido)ethyl)benzoic acid

[1040]

[1041] Using 2-(bromomethyl)quinoline, (S)-4-(1-aminoethyl)benzoic acid methyl ester and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product (10 mg) as a white solid. LCMS (ESI): 526.2 [M+1] + .

[1042] 1 HNMR(400MHz,DMSO-d6)δ12.79(s,1H),8.86(d,J=7.6Hz,1H),8.16(d,J=8.6Hz,1H),8.02(s,1 H),7.91(dd,J=11.7,8.4Hz,2H),7.74(t,J=8.6Hz,5H),7.62(d,J=3.2Hz,1H),7.56(t,J=7.5Hz ,1H),7.48(dd,J=15.1,7.5Hz,3H),7.36(d,J=7.5Hz,1H),7.32(d,J=8.2Hz,2H),6.75(d,J=3.1 Hz,1H),6.68(d,J=8.6Hz,1H),5.90–5.78(m,2H),4.97(p,J=7.1Hz,1H),1.02(d,J=6.9Hz,3H).

[1043] Embodiment 144

[1044] (S)-4-(1-(5-(4-fluorophenyl)-1-(quinolin-2-methylene)-1H-indole-7-amido)ethyl)benzoic acid

[1045]

[1046] Using 2-(bromomethyl)quinoline, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 544.2 [M+1] + .

[1047] 1 HNMR(400MHz,DMSO-d6)δ12.73(s,1H),8.84(d,J=7.6Hz,1H),8.16(d,J=8.5Hz,1H),8.00(s, 1H),7.90(t,J=9.4Hz,2H),7.78(dd,J=8.4,5.5Hz,2H),7.73(d,J=8.0Hz,3H),7.63(d,J=3.1 Hz,1H),7.56(t,J=7.5Hz,1H),7.43(s,1H),7.32(dd,J=8.4,5.6Hz,4H),6.74(d,J=3.1Hz,1H ), 6.68 (d, J = 8.6Hz, 1H), 5.84 (d, J = 5.4Hz, 2H), 4.96 (t, J = 7.2Hz, 1H), 1.02 (d, J = 7.1Hz, 3H).

[1048] Embodiment 145

[1049] ((1-([1,1'-Biphenyl]-3-methylene)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[1050]

[1051] Using 3-(bromomethyl)-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 537.3 [M+1] + .

[1052] 1HNMR (400MHz, DMSO-d6) δ9.12–9.05(m,1H),7.99(s,1H),7.86–7.79(m,2H),7.72(d,J=7.7Hz,2H),7.65(d,J=3.2Hz,1H),7.55– 7.49(m,4H),7.48–7.40(m,4H),7.36–7.24(m,6H),6.88(d,J=7.7Hz,1H),6.71(d,J=3.1Hz,1H),5.68(s,2H),4.46–4.38(m,2H).

[1053] Embodiment 146

[1054] 4-((1-(3-methoxybenzyl)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[1055]

[1056] Using 1-(bromomethyl)-3-methoxybenzene and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 491.4 [M+1] + .

[1057] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),9.07(t,J=6.0Hz,1H),8.00(s,1H),7.85(d,J=8.1Hz,2 H),7.74(d,J=7.7Hz,2H),7.58(d,J=3.2Hz,1H),7.55(s,1H),7.47(t,J=7.6Hz,2H),7.34(d,J= 7.4Hz,1H),7.31(d,J=8.2Hz,2H),7.13(t,J=7.9Hz,1H),6.81–6.77(m,1H),6.70(d,J=3.2Hz, 1H),6.47–6.44(m,1H),6.42(d,J=7.6Hz,1H),5.59(s,2H),4.49(d,J=5.9Hz,2H),3.65(s,3H).

[1058] Embodiment 147

[1059] 4-((1-([1,1'-biphenyl]-4-methylene)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[1060]

[1061] Using 4-(bromomethyl)-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 537.5 [M+1] + .

[1062] 1 HNMR (400MHz, DMSO-d6) δ9.07(t,J=6.0Hz,1H),8.01(d,J=1.7Hz,1H),7.85(d,J=7.9Hz,2H),7.74(d,J=7.6Hz,2H),7.65(d,J=3.2Hz,1H),7.59(d, J=7.6Hz,2H),7.55(s,1H),7.51–7.40(m,6H),7.40–7.30(m,4H),6.96(d ,J=8.0Hz,2H),6.72(d,J=3.1Hz,1H),5.65(s,2H),4.51(d,J=5.9Hz,2H).

[1063] Embodiment 148

[1064] 4-((1-([1,1'-biphenyl]-4-methylene)-5-(4-fluorophenyl)-1H-indole-7-amido)methyl)benzoic acid

[1065]

[1066] Using 4-(bromomethyl)-1,1'-biphenyl and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 555.3 [M+1] + .

[1067] 1 H NMR spectrum: (400MHz, DMSO-d6) δ12.85 (s, 1H), 9.05 (t, J = 6.0 Hz, 1H), 7.98 (s, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.78–7.72 (m, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.51 (s, 1H),7.46(d,J=8.0Hz,2H),7.42(t,J=7.6Hz,2H),7.38–7.31(m,3H),7.29(t,J=8.7Hz ,2H),6.94(d,J=7.9Hz,2H),6.70(d,J=3.1Hz,1H),5.64(s,2H),4.50(d,J=5.9Hz,2H).

[1068] Embodiment 149

[1069] 4-((1-([1,1'-biphenyl]-4-methylene)-5-(3,5-difluorophenyl)-1H-indole-7-amido)methyl)benzoic acid

[1070]

[1071] Using 4-(bromomethyl)-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 573.4 [M+1] + .

[1072] 1 HNMR (400MHz, DMSO-d6) δ12.86 (s, 1H), 9.04 (t, J = 6.0Hz, 1H), 8.12 (s, 1H), 7. 84(d,J=8.0Hz,2H),7.68(d,J=3.2Hz,1H),7.61(s,1H),7.58(d,J=7.7Hz,2H), 7.53–7.49(m,2H),7.48–7.41(m,4H),7.39–7.32(m,3H),7.22–7.14(m,1H),6. 93(d,J=8.0Hz,2H),6.73(d,J=3.1Hz,1H),5.67(s,2H),4.53(d,J=5.9Hz,2H).

[1073] Embodiment 150

[1074] (S)-4-(1-(1-([1,1'-biphenyl]-4-methylene)-5-phenyl-1H-indole-7-amido)ethyl)benzoic acid

[1075]

[1076] Using 4-(bromomethyl)-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and biphenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 551.4 [M+1] + .

[1077] 1HNMR(400MHz,DMSO-d6)δ12.84(s,1H),8.98(d,J=7.8Hz,1H),7.98(s,1H),7.89 (d,J=8.0Hz,2H),7.73(d,J=7.7Hz,2H),7.63(d,J=3.2Hz,1H),7.54(d,J=7.7Hz, 2H),7.52–7.45(m,5H),7.44–7.39(m,4H),7.36–7.29(m,2H),6.93(d,J=8.0Hz,2 H),6.70(d,J=3.1Hz,1H),5.58(s,2H),5.22–5.14(m,1H),1.32(d,J=7.0Hz,3H).

[1078] Embodiment 151

[1079] (S)-4-(1-(1-([1,1'-biphenyl]-4-methylene)-5-(4-fluorophenyl)-1H-indole-7-amido)ethyl)benzoic acid

[1080]

[1081] Using 4-(bromomethyl)-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (4-fluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 569.5 [M+1] + .

[1082] 1 HNMR(400MHz,DMSO-d6)δ12.85(s,1H),8.97(d,J=7.8Hz,1H),7.97(d,J=1.8Hz,1H),7.8 9(d,J=8.1Hz,2H),7.79–7.73(m,2H),7.63(d,J=3.2Hz,1H),7.54(d,J=7.7Hz,2H),7.50( d,J=8.1Hz,2H),7.46(d,J=1.9Hz,1H),7.44–7.39(m,4H),7.35–7.27(m,3H),6.92(d,J= 8.0Hz,2H),6.69(d,J=3.1Hz,1H),5.58(s,2H),5.22–5.14(m,1H),1.32(d,J=7.0Hz,3H).

[1083] Embodiment 152

[1084] (S)-4-(1-(1-([1,1'-biphenyl]-4-methylene)-5-(3,5-difluorophenyl)-1H-indole-7-amido)ethyl)benzoic acid

[1085]

[1086] Using 4-(bromomethyl)-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 587.5 [M+1] + .

[1087] 1 HNMR (400MHz, DMSO-d6) δ8.93(d,J=7.8Hz,1H),8.09(d,J=1.9Hz,1H),7.88(d,J=8.0Hz,2H),7.66(d,J=3.2Hz,1H),7.57–7.47(m,7H),7.45–7.37 (m,4H),7.36–7.29(m,1H),7.22–7.13(m,1H),6.91(d,J=8.0Hz,2H),6.7 1(d,J=3.1Hz,1H),5.58(s,2H),5.22–5.14(m,1H),1.34(d,J=7.0Hz,3H).

[1088] Embodiment 153

[1089] 4-((4-(phenylamino)-1-(quinoline-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1090]

[1091] Starting from 2-(bromomethyl)quinoline, methyl 4-(aminomethyl)benzoate and aniline, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 527.2 [M+1] + .

[1092] 1HNMR(400MHz,DMSO-d6)δ8.66(t,J=6.1Hz,1H),8.27(s,1H),8.16(d,J=8.5Hz,1H),7.91(dd,J=15 .3,8.3Hz,2H),7.72(t,J=7.7Hz,1H),7.60(d,J=7.9Hz,2H),7.55(t,J=7.5Hz,1H),7.44(d,J=3.3H z,1H),7.30(t,J=7.7Hz,2H),7.24(d,J=7.9Hz,2H),7.18(d,J=8.0Hz,1H),7.13(d,J=8.0Hz,2H),6 .95–6.87(m,2H),6.84(d,J=8.0Hz,1H),6.65(d,J=8.5Hz,1H),5.89(s,2H),4.30(d,J=5.9Hz,2H).

[1093] Embodiment 154

[1094] 4-((1-([1,1'-biphenyl]-4-methylene)-4-(phenylamino)-1H-indole-7-amido)methyl)benzoic acid

[1095]

[1096] Using 4-(bromomethyl)-1,1'-biphenyl, methyl 4-(aminomethyl)benzoate and aniline as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 552.2 [M+1] + .

[1097] Embodiment 155

[1098] 4-((1-(3-methoxybenzyl)-4-(phenylamino)-1H-indole-7-amido)methyl)benzoic acid

[1099]

[1100] Using 1-(bromomethyl)-3-methoxybenzene, methyl 4-(aminomethyl)benzoate and aniline as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 506.2 [M+1] + .

[1101] 1HNMR (400MHz, DMSO-d6) δ8.77(t,J=6.0Hz,1H),8.24(s,1H),7.83(d,J=8.1Hz,2H),7.40(d,J=3.2Hz,1H),7.31-7.26(m,4H),7.26–7.16(m,3H),7.1 2(t,J=7.9Hz,1H),6.91(t,J=7.2Hz,1H),6.86–6.80(m,2H),6.80–6.76(m ,1H),6.50–6.37(m,2H),5.59(s,2H),4.44(d,J=6.0Hz,2H),3.65(s,3H).

[1102] Embodiment 156

[1103] 4-((1-(naphthalene-2-methylene)-4-(phenylamino)-1H-indole-7-amido)methyl)benzoic acid

[1104]

[1105] Using 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and aniline as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 622.1 [M+1] + .

[1106] 1 HNMR(400MHz,DMSO-d6)δ8.71-8.66(m,1H),8.25(s,1H),7.89–7.81(m,1H), 7.78–7.70(m,4H),7.51(d,J=3.3Hz,1H),7.49–7.44(m,2H),7.41(s,1H),7.3 4–7.26(m,4H),7.23(d,J=7.9Hz,2H),7.16(d,J=8.0Hz,1H),7.10–7.06(m,1 H),6.96–6.85(m,2H),6.81(d,J=8.0Hz,1H),5.77(s,2H),4.45–4.41(m,2H).

[1107] Embodiment 157

[1108] 4-((5-(3,5-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)methyl)benzoic acid

[1109]

[1110] Using 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 548.3 [M+1] + .

[1111] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),9.17(t,J=5.9Hz,1H),8.39(s,1H),8.36(d,J=1.7Hz,1H),7.92–7.82(m,2H),7.77-7.74( m,3H),7.60–7.53(m,2H),7.51–7.41(m,3H),7.30–7.21(m,4H),7.11(dd,J=8.5,1.7Hz,1H),6.04(s,2H),4.55(d,J=5.7Hz,2H).

[1112] Embodiment 158

[1113] (S)-4-(1-(1-(3-methoxybenzyl)-4-(phenylamino)-1H-indole-7-amido)ethyl)benzoic acid

[1114]

[1115] Using 1-(bromomethyl)-3-methoxybenzene (100 mg), (S)-4-(1-aminoethyl)benzoic acid methyl ester (100 mg) and aniline (70 mg) as starting materials, the same procedure as in Example 64 was followed to obtain the target product (25 mg) as a white solid. LCMS (ESI): 622.1 [M+1] + .

[1116] 1HNMR(400MHz,DMSO-d6)δ12.79(s,1H),8.69(d,J=7.9Hz,1H),8.22(s,1H),7.86(d,J=8.1Hz,2H),7 .52–7.37(m,3H),7.32–7.26(m,2H),7.25–7.20(m,2H),7.16(d,J=8.0Hz,1H),7.09(t,J=7.9Hz,1H ),6.90(t,J=7.2Hz,1H),6.86–6.81(m,2H),6.79–6.73(m,1H),6.44–6.41(m,1H),6.39(d,J=7.6Hz ,1H),5.60–5.54(m,1H),5.50–5.44(m,1H),5.15–5.07(m,1H),3.65(s,3H),1.31(d,J=7.1Hz,3H).

[1117] Embodiment 159

[1118] 4-((1-(naphthalene-2-methylene)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[1119]

[1120] Using 2-(bromomethyl)naphthalene and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 511.4 [M+1] + .

[1121] 1 HNMR(400MHz,DMSO-d6)δ8.98(t,J=5.9Hz,1H),8.02(s,1H),7.89–7.82(m,1H),7.79–7.70(m,6H),7.69(d,J=3.2Hz,1H),7.51(s,1H),7.49–7.43( m,4H),7.41(s,1H),7.33(t,J=7.4Hz,1H),7.24(d,J=7.9Hz,2H),7.10(d ,J=8.5Hz,1H),6.74(d,J=3.1Hz,1H),5.79(s,2H),4.45(d,J=5.8Hz,2H).

[1122] Embodiment 160

[1123] 4-((5-(4-Fluorophenyl)-1-(naphthalene-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1124]

[1125] Using 2-(bromomethyl)naphthalene and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 529.5 [M+1] + .

[1126] 1 HNMR(400MHz,DMSO-d6)δ12.79(s,1H),8.95(t,J=5.9Hz,1H),7.98(s,1H),7.86–7.81(m,1H),7.77–7.70(m,6H),7.69(d,J=3.1Hz,1H),7.49–7.43 (m,3H),7.39(s,1H),7.27(t,J=8.7Hz,2H),7.22(d,J=7.9Hz,2H),7.08(d ,J=8.5Hz,1H),6.72(d,J=3.2Hz,1H),5.78(s,2H),4.44(d,J=5.8Hz,2H).

[1127] Embodiment 161

[1128] 4-((5-(3,5-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1129]

[1130] Using 2-(bromomethyl)naphthalene and (3,5-difluorophenyl)boronic acid (50 mg) as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 547.4 [M+1] + .

[1131] 1 HNMR(400MHz,DMSO-d6)δ12.81(s,1H),8.92(t,J=5.9Hz,1H),8.12(d,J=1.9Hz, 1H),7.86–7.81(m,1H),7.75(d,J=8.5Hz,1H),7.73–7.69(m,4H),7.55(d,J=1.9 Hz,1H),7.50–7.43(m,4H),7.37(s,1H),7.20(d,J=7.9Hz,2H),7.18–7.12(m,1H ),7.08–7.04(m,1H),6.74(d,J=3.2Hz,1H),5.80(s,2H),4.45(d,J=5.8Hz,2H).

[1132] Embodiment 162

[1133] (S)-4-(1-(1-(naphthylacetamide-2-methylene)-5-phenyl-1H-indole-7-amido)ethyl)benzoic acid

[1134]

[1135] Using 2-(bromomethyl)naphthalene, (S)-4-(1-aminoethyl)benzoic acid methyl ester and biphenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 525.2 [M+1] + .

[1136] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.89(d,J=7.5Hz,1H),8.01(d,J=1.8Hz,1H),7.82(t,J=6.9Hz,3H),7.74(t,J=7.1Hz,4H),7.67(d,J= 3.2Hz,1H),7.52–7.31(m,9H),7.06(d,J=8.5Hz,1H),6.73(d,J=3.2Hz,1H),5.84–5.63(m,2H),5.11(p,J=7.2Hz,1H),1.12(d,J=7.0Hz,3H).

[1137] Embodiment 163

[1138] (S)-4-(1-(5-(4-fluorophenyl)-1-(naphthalene-2-methylene)-1H-indole-7-amido)ethyl)benzoic acid

[1139]

[1140] Using 2-(bromomethyl)naphthalene, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 543.5 [M+1] + .

[1141] 1HNMR (400MHz, DMSO-d6) δ8.87(d,J=7.6Hz,1H),7.98(d,J=1.8Hz,1H),7.84-7.82(m,J=7.5Hz,3H),7.77-7.1(m,4H),7.68(d,J=3.2 Hz,1H),7.47-7.44(m,6H),7.31(t,J=8.7Hz,2H),7.05(d,J=8.5,1H),6.72(d,J=3.1Hz,1H),5.81–5.62(m,2H),5.12-5.07(m,1H).

[1142] Embodiment 164

[1143] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indole-7-amido)ethyl)benzoic acid

[1144]

[1145] Using 2-(bromomethyl)naphthalene, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 561.5 [M+1] + .

[1146] 1 HNMR (400MHz, DMSO-d6) δ12.81 (s, 1H), 8.83 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 1. 8Hz,1H),7.84-7.79(m,3H),7.76–7.69(m,3H),7.53–7.43(m,5H),7.40(d, J=8.1Hz,2H),7.37(s,1H),7.20-7.16(m,1H),7.04(d,J=8.5,1H),6.74(d, J=3.2Hz,1H),5.80–5.65(m,2H),5.12-5.06(m,1H),1.13(d,J=7.0Hz,3H).

[1147] Embodiment 165

[1148] 4-((1-(naphthalene-2-methylene)-5-phenyl-1H-indazole-7-amido)methyl)benzoic acid

[1149]

[1150] Using 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and phenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 512.4 [M+1] + .

[1151] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),9.21(t,J=5.9Hz,1H),8.37(s,1H),8.23(d,J=1.7Hz,1H),7.87–7.81(m,2H),7. 78–7.44(m,10H),7.38(t,J=7.4Hz,1H),7.30(d,J=8.0Hz,3H),7.15-7.10(m,1H),6.03(s,2H),4.55(d,J=5.8Hz,2H).

[1152] Embodiment 166

[1153] 4-((5-(4-Fluorophenyl)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)methyl)benzoic acid

[1154]

[1155] Using 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 530.6 [M+1] + .

[1156] 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),9.20(t,J=5.9Hz,1H),8.37(s,1H),8.22(d,J=1.7Hz,1H),7.87–7 .71(m,8H),7.51–7.42(m,3H),7.37–7.19(m,5H),7.15-7.09(m,1H),6.03(s,2H),4.54(d,J=5.8Hz,2H).

[1157] Embodiment 167

[1158] (S)-4-(1-(1-(naphthalene-2-methylene)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1159]

[1160] Step 1 5-bromo-1-(naphthalene-2-methylene)-1H-indazole-7-carboxylic acid methyl ester

[1161]

[1162] At 0°C, 2-(bromomethyl)naphthalene (564mg) was added to a mixture of 5-bromo-1H-indazole-7-carboxylic acid methyl ester (500mg) and Cs2CO3 (769mg) in anhydrous DMF (10mL). The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was poured into 100mL ice water and extracted with 3x 50mL ethyl acetate. The combined organic layer was rinsed with 50mL brine and concentrated after drying over anhydrous Na2SO4. The residue was then purified by silica gel column chromatography (ratio of petroleum ether / ethyl acetate was 100:0-10:1) to obtain the target compound isomer 1 (500mg, fast elution) and isomer 2 (positional isomer) as a white solid.

[1163] Isomer 1 (target compound): LCMS (ES+): 395.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.41-8.34(m,2H),7.88-7.76(m,4H),7.48(dt,J=6.4, 3.4Hz, 2H), 7.43 (s, 1H), 7.02 (dd, J = 8.5, 1.8Hz, 1H), 6.02 (s, 2H), 3.79 (s, 3H).

[1164]

[1165] Isomer 2: LCMS (ES+): 395.1 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ8.70(s,1H),8.34(d,J=1.9Hz,1H),7.91(ddd,J=14.8,8.9, 5.5Hz, 6H), 7.57–7.50 (m, 2H), 7.47 (dd, J=8.5, 1.8Hz, 1H), 5.92 (s, 2H), 3.89 (s, 3H).

[1166] Step 2 5-Bromo-1-(naphthalene-2-methylene)-1H-indazole-7-carboxylic acid

[1167]

[1168] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2 mL) was added LiOH·H2O (254 mg) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. After cooling to 0°C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH to 6. The reaction mixture was extracted with 3x 30 mL of ethyl acetate. The combined organic layers were washed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound (479 mg) as a white solid. LCMS (ESI): 381.1 [M+1] + .

[1169] Step 3 (S)-methyl 4-(1-(5-bromo-1-(naphthalene-2-methylene)-1H-indazole-7-amido)ethyl)benzoate

[1170]

[1171] To a mixture of the product of step 2 (398 mg), methyl (S)-4-(1-aminoethyl)benzoate (215 mg) and HATU (456 mg) in anhydrous DMF (10 mL) at 0°C, DIPEA (0.52 mL) was added. After stirring overnight at room temperature, 10 mL of water was added to quench the reaction mixture, followed by extraction with 3 x 100 mL of ethyl acetate. The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.5 g) as a white solid. LCMS (ESI): 542.1 [M+1] + .

[1172] Step 4: Methyl (S)-4-(1-(1-(naphthalene-2-methylene)-5-phenyl-1H-indazole-7-amido)ethyl)benzoate

[1173]

[1174] A mixture of the product of step 3 (30 mg), phenylboronic acid (38 mg), Pd(dppf)2Cl2 (4 mg) and K2CO3 (38 mg) in EtOH / H2O (5 mL / 1 mL) was stirred at 70°C under nitrogen for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (27 mg) as a yellow solid. LCMS (ESI): 540.2 [M+1] + .

[1175] Step 5 (S)-4-(1-(1-(naphthalene-2-methylene)-5-phenyl-1H-indazole-7-amide)ethyl)benzoic acid

[1176]

[1177] To a solution of the product of step 4 (42 mg) in MeOH / H2O (5 mL / 0.5 mL), LiOH·H2O (16 mg) was added. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the mixture was then treated with 6N hydrochloric acid to adjust pH≈6. The reaction mixture was then extracted with 3x 20 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to obtain the target compound (10.1 mg) as a white solid. LCMS (ESI): 526.2 [M+1] + .

[1178] 1 HNMR(400MHz,DMSO-d6)δ12.83(s,1H),9.12(d,J=7.6Hz,1H),8.36(s,1H),8.22(s,1H),7.86-7.82(m,3H),7.79-7.72( m,5H),7.54-7.46(m,7H),7.39(t,J=7.4Hz,1H),7.09(d,J=8.5Hz,1H),5.96(s,2H),5.22(p,J=7.1Hz,1H),1.25(s,3H).

[1179] Embodiment 168

[1180] (S)-4-(1-(5-(4-fluorophenyl)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)ethyl)benzoic acid

[1181]

[1182] Using (4-fluorophenyl)boronic acid as the starting material, the same procedure as in Example 167 was followed to obtain the target product as a white solid. LCMS (ESI): 544.4 [M+1] + .

[1183] 1HNMR(400MHz,DMSO-d6)δ12.83(s,1H),9.10(d,J=7.6Hz,1H),8.36(s,1H),8.20(s,1H),7.88–7.78(m,5H),7.76–7.70(m ,3H),7.50–7.42(m,5H),7.34(t,J=8.8Hz,2H),7.11–7.05(m,1H),5.96(s,2H),5.25–5.16(m,1H),1.24(d,J=6.9Hz,3H).

[1184] Embodiment 169

[1185] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)ethyl)benzoic acid

[1186]

[1187] Using (3,5-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 167 was followed to obtain the target product as a white solid. LCMS (ESI): 562.6 [M+1] + .

[1188] 1 HNMR(400MHz, DMSO-d6)δ12.83(s,1H),9.06(d,J=7.6Hz,1H),8.38(s,1H),8.34(s,1H),7.88–7.78(m,4H),7.76–7.69(m,2H),7. 60–7.53(m,2H),7.51–7.41(m,5H),7.30–7.20(m,1H),7.11–7.02(m,1H),5.96(s,2H),5.24–5.16(m,1H),1.26(d,J=7.1Hz,3H).

[1189] Embodiment 170

[1190] (S)-4-(1-(1-(3-chlorobenzyl)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1191]

[1192] Using 1-(bromomethyl)-3-chlorobenzene, (S)-4-(1-aminoethyl)benzoic acid methyl ester and biphenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 510.3 [M+1] + .

[1193] 1 H NMR(400MHz, DMSO)12.85(s,1H),9.26(d,J=7.6Hz,1H),8.35(s,1H),8.23(d,J=1.6Hz,1H),7.90(d,J=8.1Hz,2H),7.84–7.76(m,3H),7.56–7.47(m ,4H),7.40(t,J=7.4Hz,1H),7.31–7.25(m,1H),6.95(d,J=2.1Hz,1H),6.8 4(d,J=7.6Hz,1H),5.78(s,2H),5.24–5.14(m,1H),1.41(d,J=7.0Hz,3H).

[1194] Embodiment 171

[1195] 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-amido)methyl)benzoic acid

[1196]

[1197] Step 1 Methyl 5-bromo-1H-benzo[d]imidazole-7-carboxylate

[1198]

[1199] To a mixture of methyl 2,3-diamino-5-bromobenzoate (1.0 g) in MeCN (20 mL) at room temperature, 1.2 equivalents (eq.) of triethoxymethane and 10 mol% I2 were added. The mixture was stirred at room temperature for 10 minutes, and then poured into 100 mL of water. The brown solid was filtered and dried to obtain the target compound (1.0 g). LCMS (ESI): 255 [M+1] + .

[1200] Step 2: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylic acid methyl ester

[1201]

[1202] At room temperature, to a mixture of 5-bromo-1H-benzodiimidazole-7-carboxylic acid methyl ester (1.0 g) and 1-(bromomethyl)-3-chlorobenzene in DMF (50 mL), 2.0 equivalents of CsCO were added. Stirred at room temperature for 4 hours, 200 mL was added. The reaction mixture was extracted with 3x50 mL ethyl acetate, rinsed with brine, dried over anhydrous NaSO and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain the target product isomer 1 (0.86 g, fast elution) and isomer 2.

[1203] Isomer 1: 1 H NMR (400MHz, DMSO) δ8.63(s,1H),8.20(d,J=2.0Hz,1H),7.71(d,J=2.0Hz,1H),7.65(d,J =8.1Hz,2H),7.08(d,J=8.0Hz,2H),5.83(s,2H),3.67(s,3H).LCMS(ESI):415.289[M+1] + .

[1204] Isomer 2: 1 H NMR (400MHz, DMSO) δ8.64(s,1H),8.16(t,J=1.5Hz,1H),7.85(d,J=1.9Hz,1H),7.73(d,J =7.9Hz,2H),7.49(d,J=8.0Hz,2H),5.71(s,2H),3.91(s,3H).LCMS(ESI):415.289[M+1] + .

[1205] Step 3 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylic acid

[1206]

[1207] To a solution of the product of step 1 (500 mg, 1.21 mmol) in MeOH / H2O (10 mL / 2.0 mL) was added LiOH·H2O (254 mg, 6.06 mmol) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. Cooled to 0°C, the reaction mixture was then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was then extracted with 3x 30 mL of ethyl acetate. The combined organic layers were rinsed with 20 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio of 100:0 to 10:1) to obtain the target compound as a white solid. LCMS (ESI): 399 [M+1] + .

[1208] Step 4 Methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-amido)methyl)benzoate

[1209]

[1210] To a mixture of the product of step 3 (398 mg), methyl 4-(aminomethyl)benzoate (215 mg) and HATU (456 mg) in anhydrous DMF (100 mL) at 0°C, DIPEA (0.52 mL) was added. Stir overnight at room temperature, then quench the reaction mixture by adding 100 mL of water and extract with 3 x 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio of 100:0 to 5:1) to obtain the target compound (0.5 g) as a white solid. LCMS (ESI): 546 [M+1] + .

[1211] Step 5 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-amido)-methyl)benzoic acid

[1212]

[1213] Using the product of step 4 and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 530 [M+1] + .

[1214] 1 H NMR (400MHz, CDCl3) δ9.11(t,J=5.9Hz,1H),8.58(s,1H),8.11(d,J=1.7Hz,1H),7.86(d,J=8.0Hz,2H),7.77(d,J=7.6Hz,2H),7.70(d,J=1.7Hz,1H), 7.55(d,J=8.1Hz,2H),7.48(t,J=7.6Hz,2H),7.36(t,J=7.4Hz,1H),7.31( d,J=8.1Hz,2H),7.10(d,J=8.0Hz,2H),5.84(s,2H),4.44(d,J=5.7Hz,2H).

[1215] Embodiment 172

[1216] 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-amido)methyl)benzoic acid

[1217]

[1218] Using the product of step 4 of Example 171 and (4-fluorophenyl)boronic acid as starting materials, the target product was obtained as a white solid by following the same procedure as Example 171. LCMS (ESI): 548 [M+1] + .

[1219] 1 H NMR (400MHz, DMSO) δ12.87(s,1H),9.11(s,1H),8.60(s,1H),8.11(d,J=1.7Hz,1H),7.89–7.78(m,4H),7.69(d,J =1.7Hz,1H),7.55(d,J=8.1Hz,2H),7.36–7.27(m,4H),7.11(d,J=8.0Hz,2H),5.85(s,2H),4.45(d,J=5.8Hz,2H).

[1220] Embodiment 173

[1221] 4-((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-amido)methyl)benzoic acid

[1222]

[1223] Using the product of step 4 of Example 171 and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as Example 171 was followed to obtain the target product as a white solid. LCMS (ESI): 566 [M+1] + .

[1224] 1 H NMR (400MHz, DMSO) δ12.87(s,1H),9.12(t,J=5.9Hz,1H),8.72(d,J=2.1Hz,1H),8.26(d,J=1.7Hz,1H),7.87(d,J=8.0Hz,2H),7.79(d, J=1.8Hz,1H),7.64–7.53(m,4H),7.31(d,J=8.0Hz,2H),7.27–7.19(m,1H),7.11(d,J=8.0Hz,2H),5.88(s,2H),4.47(d,J=5.8Hz,2H).

[1225] Embodiment 174

[1226] ((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)methyl)benzoic acid

[1227]

[1228] Step 1 5-Bromo-3-nitro-2-((4-(trifluoromethyl)benzyl)amino)benzoic acid

[1229]

[1230] A solution of 5-bromo-2-chloro-3-nitrobenzoic acid (600 mg, 2.14 mmol), DIPEA (1.1 g, 8.56 mmol) and (4-(trifluoromethyl)phenyl)methanamine (905 mg, 4.28 mmol) in 1,4-dioxane (6 mL) was stirred at 90°C for 16 hours. The reaction solution was poured into water, acidified to pH = 4 with aqueous hydrochloric acid (6N), and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with 30 mL of brine, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated to obtain the target compound (800 mg) as a brown solid. LCMS (ESI): 419 [M+1] + .

[1231] Step 2 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid

[1232]

[1233] To a mixture of Zn (5.9 g, 89.47 mmol) in AcOH (20 mL) at 50 ° C, add a solution of the product of step 1 (800 mg, 1.91 mmol) in AcOH (10 mL) and let stand for 5 minutes. The reaction mixture was stirred at 50 ° C for 1 hour. The mixture was cooled to 0 ° C, filtered and rinsed with AcOH (5 mL). The organic layer was concentrated and diluted with DCM (20 mL). At room temperature, tert-butyl nitrite (197 mg, 1.91 mmol) was added to the above solution. The resulting solution was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with water and brine (pH = 4), and washed with anhydrous Na 2 SO 4 Dry and filter. Concentrate the filtrate in vacuo to give the title compound (500 mg) as a brown solid. LCMS (ESI): 400 [M+1] + .

[1234] Step 3 Methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)methyl)benzoate

[1235]

[1236] To a solution of DIPEA (259 mg), the product of step 2 (200 mg) and methyl 4-(aminomethyl)benzoate hydrochloride (151 mg) in DMF (6 mL) at 0°C was added HATU (304 mg). Stirred at room temperature for 3 hours, then the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water and brine, then dried over Na2SO4 and filtered. The filtrate was concentrated, and the residue was then placed in MeOH (5 mL) and stirred at room temperature for 30 minutes. The solid was collected by filtration and rinsed with MeOH (3 mL) to obtain the target compound (180 mg) as a brown solid. LCMS (ESI): 547 [M+1] + .

[1237] Step 4 Methyl 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)methyl)benzoate

[1238]

[1239] K2CO3 (45 mg), PdCl2(dppf) (8.0 mg), methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]imidazole-7-amido)methyl)benzoate (60 mg), and phenylboronic acid (27 mg) were mixed in 1,4-dioxane / H2O (1.8 mL, 5 / 1). The mixture was stirred at 70°C under argon for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA=5:1) to obtain the target compound (40 mg) as a yellow solid. LCMS (ESI): 545 [M+1] + .

[1240] Step 5 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)methyl)benzoic acid

[1241]

[1242] The product of step 4 (40.0 mg) and LiOH.H2O (31 mg) were mixed in tetrahydrofuran / 1,4-dioxane / H2O (6 mL, 2 / 3 / 1) at room temperature. The resulting mixture was stirred at 50°C for 5 hours. The reaction solution was poured into water and acidified to pH = 6 with aqueous hydrochloric acid (6N). The solid was collected by filtration and rinsed with water to obtain the target compound (20 mg) as a light yellow solid. LCMS (ESI): 531 [M+1] + .

[1243] 1 HNMR(400MHz,DMSO-d6)δ9.40(t,J=6.0Hz,1H),8.55(s,1H),8.10(s,1H),7.88(t,J=7.1Hz,4H),7.61-7.50(m ,4H),7.44(t,J=7.4Hz,1H),7.37(d,J=8.0Hz,2H),7.16(d,J=8.0Hz,2H),6.30(s,2H),4.55(d,J=5.9Hz,2H).

[1244] Embodiment 175

[1245] 4-(5-(4-Fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)methyl)benzoic acid

[1246]

[1247] Using the product of step 4 of Example 174 and (4-fluorophenyl)boronic acid as starting materials, the same procedure as Example 174 was followed to obtain the target product as a white solid. LCMS (ESI): 549.5 [M+1] + .

[1248] 1 HNMR(400MHz,DMSO-d6)δ12.88(s,1H),9.39(t,J=5.9Hz,1H),8.54(s,1H),8.07(s,1H),7.98–7.91(m,2H),7.90–7.8 6(m,2H),7.56(d,J=8.0Hz,2H),7.38-7.35(m,6.5Hz,4H),7.16(d,J=8.0Hz,2H),6.30(s,2H),4.55(d,J=5.8Hz,2H).

[1249] Embodiment 176

[1250] ((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)methyl)benzoic acid

[1251]

[1252] Using the product of step 4 of Example 174 and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as Example 174 was followed to obtain the target product as a white solid. LCMS (ESI): 567.5 [M+1] + .

[1253] 1 HNMR(400MHz,DMSO-d6)δ9.36(t,J=6.0Hz,1H),8.70(s,1H),8.15(s,1H),7.88(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),7 .56(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),7.33-7.28(m,1H),7.16(d,J=8.0Hz,2H),6.31(s,2H),4.56(d,J=5.8Hz,2H).

[1254] Embodiment 177

[1255] 4-((1-(naphthalene-1-methylene)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[1256]

[1257] Using 1-(bromomethyl)naphthalene and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 511.2 [M+1] + .

[1258] 1 HNMR(400MHz,DMSO-d6)δ12.75(s,1H),8.91(t,J=6.0Hz,1H),8.08–8.04(m, 2H),8.01–7.96(m,1H),7.83(d,J=8.2Hz,1H),7.76(d,J=7.7Hz,2H),7.62–7 .53(m,5H),7.52–7.45(m,3H),7.35-7.28(m,2H),6.92(d,J=8.0Hz,2H),6.7 5(d,J=3.2Hz,1H),6.32(d,J=7.1Hz,1H),6.15(s,2H),4.07(d,J=5.9Hz,2H).

[1259] Embodiment 178

[1260] (±)4-((5-phenyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-7-amido)methyl)benzoic acid

[1261]

[1262] Using 1-(1-chloroethyl)-4-(trifluoromethyl)benzene and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 543.4 [M+1] + .

[1263] 1 HNMR(400MHz,DMSO-d6)δ9.17–9.06(m,1H),7.99(s,1H),7.89(d,J=7.8Hz, 2H),7.77–7.69(m,3H),7.55(d,J=8.1Hz,2H),7.51–7.44(m,3H),7.41(d,J =7.9Hz,2H),7.34(t,J=7.3Hz,1H),7.09(d,J=8.0Hz,2H),6.76(s,1H),6.3 2–6.23(m,1H),4.62–4.55(m,1H),4.47–4.39(m,1H),1.82(d,J=7.1Hz,3H).

[1264] Embodiment 179

[1265] (S)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)ethyl)benzoic acid

[1266]

[1267] Using (S)-4-(1-aminoethyl)benzoic acid methyl ester and the product of step 2 of Example 174 as starting materials, the target product was obtained as a yellow solid by the same procedure as Example 174. LCMS (ESI): 545.5 [M+1] + .

[1268] 1HNMR(400MHz,DMSO-d6)δ12.85(s,1H),9.25(d,J=7.8Hz,1H),8.52(s,1H), 8.02(s,1H),7.91(d,J=7.9Hz,2H),7.86(d,J=7.7Hz,2H),7.54(t,J=7.6Hz ,2H),7.51–7.46(m,4H),7.44(t,J=7.3Hz,1H),7.10(d,J=7.9Hz,2H),6.34 –6.23(m,1H),6.19–6.09(m,1H),5.22–5.12(m,1H),1.37(d,J=7.0Hz,3H).

[1269] Embodiment 180

[1270] (S)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)ethyl)benzoic acid

[1271]

[1272] Using (4-fluorophenyl)boronic acid, (S)-4-(1-aminoethyl)benzoic acid methyl ester and the product of step 2 of Example 174 as starting materials, the same procedure as Example 174 was followed to obtain the desired product (36 mg) as a yellow solid. LCMS (ESI): 563.4 [M+1] + .

[1273] 1 HNMR(400MHz, DMSO-d6)δ12.85(s,1H),9.24(d,J=7.7Hz,1H),8.52(s,1H),8.00(s,1H),7.95–7.86(m,4H),7.52–7.44(m,4H ),7.41–7.33(m,2H),7.10(d,J=8.0Hz,2H),6.30–6.24(m,1H),6.18–6.10(m,1H),5.22–5.12(m,1H),1.37(d,J=6.9Hz,3H).

[1274] Embodiment 181

[1275] (S)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazole-7-amido)ethyl)

[1276] benzoic acid

[1277]

[1278] Using (3,5-difluorophenyl)boronic acid, (S)-4-(1-aminoethyl)benzoic acid methyl ester and the product of step 2 of Example 174 as starting materials, the target product was obtained as a yellow solid by following the same procedure as Example 174. LCMS (ESI): 581.5 [M+1] + .

[1279] 1 HNMR (400MHz, DMSO-d6) δ12.84(s,1H),9.21(d,J=7.8Hz,1H),8.66(s,1H),8.06(s,1H),7.91(d,J=7.9Hz,2H),7.69(d,J=7.9Hz,2H),7.5 3–7.43(m,4H),7.34–7.27(m,1H)7.10(d,J=7.9Hz,2H),6.33–6.24(m,1H),6.19–6.10(m,1H),,5.22–5.12(m,1H),1.40(d,J=7.0Hz,3H).

[1280] Embodiment 182

[1281] 4-((4-((4-Fluorophenyl)amino)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)methyl)benzoic acid

[1282]

[1283] Using methyl 4-bromo-1H-indazole-7-carboxylic acid, 2-(bromomethyl)naphthalene and methyl 4-(aminomethyl)benzoate as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 545.5 [M+1] + .

[1284] 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.89–8.82(m,1H),8.81(s,1H),8.45(s,1H),7.87–7.80(m,1H),7.79–7.67(m,4H),7.51–7.43(m,3H), 7.40(d,J=8.0Hz,1H),7.35–7.28(m,4H),7.22(t,J=8.8Hz,2H),7.13-7.08(m,1H),6.63(d,J=8.0Hz,1H),6.01(s,2H),4.50(d,J=5.9Hz,2H).

[1285] Embodiment 183

[1286] ((4-((4-Fluorophenyl)amino)-1-(naphthalene-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1287]

[1288] Using 2-(bromomethyl)naphthalene and methyl 4-(aminomethyl)benzoate as starting materials, the same procedure as in Example 64 was followed to obtain the target product as a white solid. LCMS (ESI): 544 [M+1] + .

[1289] 1 H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.67(t,J=6.0Hz,1H),8.23(s,1H),7.89–7.82(m ,1H),7.79–7.67(m,4H),7.56–7.39(m,4H),7.32–7.21(m,4H),7.18–7.11(m,3H),7.12 -7.06(m,1H),6.87(d,J=3.2Hz,1H),6.69(d,J=8.0Hz,1H),5.77(s,2H),4.43(d,J=5.9Hz,2H).

[1290] Embodiment 184

[1291] 4-((1-((4'-Fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indazole-7-amido)methyl)benzoic acid

[1292]

[1293] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 556 [M+1] + .

[1294] 1H NMR(400MHz,)δ12.88(s,1H),9.30(d,J=6.1Hz,1H),8.36(s,1H),8.24(d,J=1.7Hz,1H),7.91–7.83(m,3H),7.79(d,J=7.4Hz,2H),7.66– 7.57(m,2H),7.52(t,J=7.7Hz,2H),7.47–7.36(m,5H),7.26(t,J=8.9Hz,2H),7.00(d,J=8.0Hz,2H),5.90(s,2H),4.60(d,J=5.9Hz,2H).

[1295] Embodiment 185

[1296] 4-((1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indazole-7-amido)methyl)benzoic acid

[1297]

[1298] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (4-fluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 574 [M+1] + .

[1299] 1 H NMR (400MHz, DMSO) δ12.87(s,1H),9.29(t,J=6.0Hz,1H),8.34(s,1H),8.21(d,J=1.7Hz,1H),7.88–7.78(m,5H),7.64–7.57(m ,2H),7.41(t,J=8.4Hz,4H),7.37–7.29(m,2H),7.29–7.20(m,2H),6.98(d,J=8.3Hz,2H),5.89(s,2H),4.59(d,J=5.9Hz,2H).

[1300] Embodiment 186

[1301] 4-((5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indazole-7-amido)methyl)benzoic acid

[1302]

[1303] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 592 [M+1] + .

[1304] 1 H NMR (400MHz, DMSO) δ12.88(s,1H),9.29(t,J=6.0Hz,1H),8.38–8.33(m,2H),7.93(d,J=1.8Hz,1H),7.87–7.82(m,2H) ,7.64–7.54(m,4H),7.45–7.36(m,4H),7.29–7.20(m,3H),6.96(d,J=8.1Hz,2H),5.90(s,2H),4.60(d,J=5.9Hz,2H).

[1305] Embodiment 187

[1306] 4-((5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indazole-7-amido)methyl)benzoic acid

[1307]

[1308] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 592 [M+1] + .

[1309] 1 H NMR (400MHz, DMSO) δ12.86(s,1H),9.27(t,J=6.0Hz,1H),8.35(s,1H),8.27(d,J=1.7Hz,1H),7.93–7.82(m,4H),7.6 8–7.51(m,4H),7.41(t,J=8.0Hz,4H),7.29–7.20(m,2H),6.97(d,J=8.0Hz,2H),5.89(s,2H),4.60(d,J=5.9Hz,2H).

[1310] Embodiment 188

[1311] 4-((1-([1,1'-biphenyl]-4-methylene)-5-(3,4-difluorophenyl)-1H-indole-7-amido)methyl)benzoic acid

[1312]

[1313] Using 4-(bromomethyl)-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 573.5 [M+1] + .

[1314] 1 HNMR(400MHz, DMSO-d6)δ12.84(s,1H),9.02(t,J=6.0Hz,1H),8.03(s,1H),7.87–7.76(m,3H),7.65(d,J=3.2Hz,1H),7.61–7.49 (m,5H),7.48–7.39(m,4H),7.38–7.29(m,3H),6.93(d,J=8.0Hz,2H),6.71(d,J=3.1Hz,1H),5.65(s,2H),4.51(d,J=5.8Hz,2H).

[1315] Embodiment 189

[1316] (S)-4-(1-(1-(naphthalene-2-methyl)-5-phenyl-1H-benzo[d][1,2,3]triazole-7-amido)ethyl)benzoic acid

[1317]

[1318] Using naphthalene-2-ylmethylamine and (S)-4-(1-aminoethyl)benzoic acid methyl ester as starting materials, the same procedure as in Example 174 was followed to obtain the target product as a white solid. LCMS (ESI): 527.5 [M+1] + .

[1319] 1 HNMR(400MHz, DMSO-d6)δ8.92(d,J=7.8Hz,1H),8.02-8.00(m,1H),7.90–7.83(m,2H),7.78–7.71(m,2H),7.62(d,J=3.2Hz,1H),7.53–7.45 (m,5H),7.45–7.41(m,2H),7.37-7.32(m,1H),6.95(d,J=8.0Hz,2H),6.78–6.70(m,1H),5.65(s,2H),5.08-5.00(m,1H),1.26-1.21(m,3H).

[1320] Embodiment 190

[1321] 4-((1-([1,1'-biphenyl]-4-methylene)-5-phenyl-1H-indazole-7-amido)methyl)benzoic acid

[1322]

[1323] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product (20 mg) as a white solid. LCMS (ESI): 538.3 [M+1] + .

[1324] 1 HNMR(400MHz,DMSO-d6)δ12.88(s,1H),9.32(t,J=6.0Hz,1H),8.36(s,1H),8.24(d,J=1.7Hz,1H), 7.92–7.74(m,5H),7.62–7.32(m,12H),7.01(d,J=8.0Hz,2H),5.90(s,2H),4.61(d,J=5.9Hz,2H).

[1325] Embodiment 191

[1326] 4-((1-([1,1'-biphenyl]-4-methylene)-5-(4-fluorophenyl)-1H-indazole-7-amido)methyl)benzoic acid

[1327]

[1328] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-1,1'-biphenyl and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 556.5 [M+1] + .

[1329] 1 H NMR(400MHz, DMSO-d6)δ12.87(s,1H),9.31(t,J=6.0Hz,1H),8.36(s,1H),8.22(d,J=1.7Hz,1H),7.93–7.74(m,5H), 7.62-7.58(m,2H),7.49–7.41(m,6H),7.38–7.30(m,3H),7.00(d,J=8.0Hz,2H),5.89(s,2H),4.60(d,J=5.8Hz,2H).

[1330] Embodiment 192

[1331] 4-((1-([1,1'-biphenyl]-4-methylene)-5-(3,5-difluorophenyl)-1H-indazole-7-amido)methyl)benzoic acid

[1332]

[1333] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 574.5 [M+1] + .

[1334] 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.30(t,J=5.9Hz,1H),8.40–8.35(m,2H),7.94(d,J=1.8Hz,1H),7.88(d,J=8.0Hz,2H),7.63– 7.54(m,4H),7.47–7.41(m,6H),7.35(t,J=7.3Hz,1H),7.28-7.21(m,1H),6.99(d,J=8.0Hz,2H),5.91(s,2H),4.62(d,J=5.9Hz,2H).

[1335] Embodiment 193

[1336] 4-((1-([1,1'-biphenyl]-4-methylene)-5-(3,4-difluorophenyl)-1H-indazole-7-amido)methyl)benzoic acid

[1337]

[1338] Using 5-bromo-1H-indazole-7-carboxylic acid methyl ester, 4-(bromomethyl)-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 574.5 [M+1] + .

[1339] 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.31(d,J=5.9Hz,1H),8.37(s,1H),8.28(d,J=1.7Hz,1H),7.95–7.84(m,4H),7 .71–7.51(m,4H),7.44(t,J=7.4Hz,6H),7.37-7.33(m,1H),7.00(d,J=8.0Hz,2H),5.90(s,2H),4.61(d,J=5.8Hz,2H).

[1340] Embodiment 194

[1341] (S)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1342]

[1343] Using 1-(bromomethyl)-4-(trifluoromethyl)benzene as the starting material, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 562.5 [M+1] + .

[1344] 1 HNMR (400MHz, DMSO-d6) δ12.85(s,1H),9.19(d,J=7.8Hz,1H),8.36(s,1H),8.22(d,J=1.7Hz,1H),7.90(d,J=8.0Hz,2H),7.86–7.81(m,2H),7.80( d,J=1.7Hz,1H),7.49(d,J=7.9Hz,4H),7.36(t,J=8.8Hz,2H),7.03(d,J= 8.0Hz,2H),5.98–5.77(m,2H),5.22–5.12(m,1H),1.37(d,J=7.1Hz,3H).

[1345] Embodiment 195

[1346] (S)-4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1347]

[1348] Using 1-(bromomethyl)-4-(trifluoromethyl)benzene and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product (76 mg) as a white solid. LCMS (ESI): 580.6 [M+1] + .

[1349] 1 HNMR(400MHz, DMSO-d6)δ12.83(s,1H),9.16(d,J=7.8Hz,1H),8.35(s,1H),8.26(d,J=1.7Hz,1H),7.94–7.84(m,3H),7.81(d,J=1.8Hz,1H), 7.68–7.61(m,1H),7.60–7.53(m,1H),7.51–7.43(m,4H),7.01(d,J=8. 0Hz,2H),5.95–5.77(m,2H),5.20–5.10(m,1H),1.36(d,J=7.2Hz,3H).

[1350] Embodiment 196

[1351] 4-((S)-1-(1-((R)-1-(naphthalen-2-yl)ethyl)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1352]

[1353] Step 1 (R)-5-bromo-1-(1-(naphthalen-2-yl)ethyl)-1H-indazole-7-carboxylic acid methyl ester

[1354]

[1355] A mixture of methyl 5-bromo-1H-indazole-7-carboxylate (300 mg, 1.18 mmol) and (S)-1-(naphthalen-2-yl)ethan-1-ol (304 mg, 1.76 mmol) was degassed and purged with argon three times. THF (10 mL), TBP (428 mg, 2.11 mmol) and DIAD (357 mg, 1.76 mmol) were added to the mixture at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (EA / PE ratio of 0-20%) to obtain the target compound (270 mg) as a colorless oil. LCMS (ESI): 409.5 [M+1] + .

[1356] 1H NMR (400MHz, CDCl3) δ8.15(s,1H),8.04(d,J=2.0Hz,1H),7.85(d,J=2.0Hz,1H),7.78-7.64(m,3H),7.46( s,1H),7.45-7.37(m,2H),7.11(d,J=8.5,1H),6.66(q,J=6.9Hz,1H),3.86(s,3H),2.11(d,J=6.9Hz,3H).

[1357] Step 2 4-((S)-1-(1-((R)-1-(naphthalen-2-yl)ethyl)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1358]

[1359] The product of step 1 (200 mg) was used as a starting material and the same procedure as in Example 167 was followed to obtain the target product (60 mg) as a white solid. LCMS (ESI): 540.5 [M+1] + .

[1360] 1 H NMR (400MHz, DMSO-d6) δ9.34(d,J=8.2Hz,1H),8.36(s,1H),8.20(s,1H),7.87–7.74(m,6H),7.59(d,J=8.6Hz,1H),7.50(d,J=13.8,5 H),7.46–7.35(m,4H),7.10(d,J=8.5Hz,1H),6.45(q,J=6.8Hz,1H),5.43-5.35(m,1H),1.97(d,J=6.9Hz,3H),1.58(d,J=6.9Hz,3H).

[1361] Embodiment 197

[1362] 4-((S)-1-(1-((S)-1-(naphthylacetamido-2-yl)ethyl)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1363]

[1364] Using (R)-1-(naphthylacetamide-2-yl)ethan-1-ol as the starting material, the same procedure as in Example 196 was followed to obtain the target product as a white solid. LCMS (ESI): 540.5 [M+1] + .

[1365] 1H NMR (400MHz, DMSO-d6) δ12.86(s,1H),9.18(d,J=7.3Hz,1H),8.39(s,1H),8.20(d,J=1.7H z,1H),7.99(d,J=8.2Hz,2H),7.88–7.82(m,2H),7.80(d,J=8.6Hz,1H),7.77–7.72(m,2H), 7.69(d,J=1.7Hz,1H),7.62(d,J=8.3Hz,2H),7.57–7.44(m,5H),7.43–7.32(m,1H),7.19( s,1H),6.46–6.36(m,1H),5.35–5.24(m,1H),1.94(d,J=6.9Hz,3H),1.27(d,J=7.1Hz,3H).

[1366] Embodiment 198

[1367] (S)-4-(1-(1-([1,1'-biphenyl]-4-methyl)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1368]

[1369] Using 4-(bromomethyl)-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product (23 mg) as a white solid. LCMS (ESI): 552.5 [M+1] + .

[1370] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.24(d,J=7.9Hz,1H),8.35(s,1H),8.22(d,J=1.7Hz,1H),7.93(d,J=8.0Hz,2H),7.87–7.75 (m,3H),7.58–7.50(m,6H),7.47–7.32(m,6H),6.98(d,J=8.1Hz,2H),5.92–5.74(m,2H),5.29-5.25(m,1H),1.44(d,J=7.0Hz,3H).

[1371] Embodiment 199

[1372] (S)-4-(1-(1-([1,1'-biphenyl]-4-methyl)-5-(4-fluorophenyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1373]

[1374] Using 4-(bromomethyl)-1,1'-biphenyl as the starting material, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 570.5 [M+1] + .

[1375] 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),9.22(d,J=7.9Hz,1H),8.34(s,1H),8.21(d,J=1.7Hz,1H),7.93(d,J=8.3Hz,2H),7.86–7.78 (m,3H),7.60–7.53(m,4H),7.49–7.32(m,7H),6.98(d,J=8.1Hz,2H),5.91–5.72(m,2H),5.32-5.27(m,1H),,1.44(d,J=7.0Hz,3H).

[1376] Embodiment 200

[1377] (S)-4-(1-(1-([1,1'-biphenyl]-4-methyl)-5-(3,5-difluorophenyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1378]

[1379] Using 4-(bromomethyl)-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product (23 mg) as a white solid. LCMS (ESI): 588.5 [M+1] + .

[1380] 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),9.22(d,J=7.9Hz,1H),8.34(s,1H),8.21(d,J=1.7Hz,1H),7.93(d,J=8.3Hz,2H),7.86–7.78 (m,3H),7.60–7.53(m,4H),7.49–7.32(m,7H),6.98(d,J=8.1Hz,2H),5.91–5.72(m,2H),5.32-5.27(m,1H),,1.44(d,J=7.0Hz,3H).

[1381] Embodiment 201

[1382] (S)-4-(1-(1-([1,1'-biphenyl]-4-methyl)-5-(3,4-difluorophenyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1383]

[1384] Using 4-(bromomethyl)-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 588.4 [M+1] + .

[1385] 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.20(d,J=7.9Hz,1H),8.36(s,1H),8.27(d,J=1.7Hz,1H),7.97–7.87(m,3H),7.82(d,J=1.7 Hz,1H),7.69–7.53(m,6H),7.48–7.31(m,5H),6.97(d,J=8.0Hz,2H),5.91–5.74(m,2H),5.31-5.27(m,1H),1.45(d,J=7.0Hz,3H).

[1386] Embodiment 202

[1387] (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indazole-7-amido)ethyl)benzoic acid

[1388]

[1389] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 570 [M+1] + .

[1390] 1H NMR (400MHz, DMSO) δ12.88 (s, 1H), 9.23 (d, J = 7.9Hz, 1H), 8.35 (s, 1H), 8.22 ( d,J=1.7Hz,1H),7.92(d,J=8.0Hz,2H),7.85–7.76(m,3H),7.63–7.49(m,6H), 7.45–7.34(m,3H),7.26(t,J=8.8Hz,2H),6.97(d,J=8.0Hz,2H),5.87(d,J=1 5.7Hz,1H),5.77(d,J=15.7Hz,1H),5.35–5.24(m,1H),1.44(d,J=7.0Hz,3H).

[1391] Embodiment 203

[1392] (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1393]

[1394] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl as the starting material, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 588 [M+1] + .

[1395] 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.22(d,J=7.9Hz,1H),8.34(s,1H),8.21(d,J=1.7Hz,1H),7.92(d,J=8.3Hz,2H),7.88–7.78(m,3H),7.64– 7.51(m,4H),7.42–7.19(m,4H),6.97(d,J=8.0Hz,2H),5.87(d,J=15.7H z,1H),5.77(d,J=15.7Hz,1H),5.35–5.23(m,1H),1.44(d,J=7.0Hz,3H).

[1396] Embodiment 204

[1397] (S)-4-(1-(5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1398]

[1399] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 606 [M+1] + .

[1400] 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.19(s,1H),8.39–8.32(m,2H),7.94–7.85(m,3H),7.63–7.51(m,6H),7.37(d,J=8.0Hz,2H),7.2 6(t,J=8.6Hz,3H),6.96(d,J=8.0Hz,2H),5.88(d,J=15.7Hz,1H),5.76(d,J=15.6Hz,1H),5.29(t,J=7.2Hz,1H),1.46(d,J=7.0Hz,5H).

[1401] Embodiment 205

[1402] (S)-4-(1-(5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1403]

[1404] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 606 [M+1] + .

[1405] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.19(d,J=7.9Hz,1H),8.35(s,1H),8.26( d,J=1.7Hz,1H),7.91(d,J=8.1Hz,3H),7.83(d,J=1.7Hz,1H),7.67–7.51(m,6H), 7.37(d,J=8.1Hz,2H),7.26(t,J=8.8Hz,2H),6.96(d,J=8.0Hz,2H),5.87(d,J=1 5.7Hz, 1H), 5.76 (d, J = 15.7Hz, 1H), 5.29 (t, J = 7.4Hz, 1H), 1.45 (d, J = 7.0Hz, 3H).

[1406] Embodiment 206

[1407] 4-(1-(1-(3-chlorobenzyl)-5-(3-cyanophenyl)-1H-indole-7-amido)cyclopropyl)benzoic acid

[1408]

[1409] Using 1-(bromomethyl)-3-chlorobenzene, methyl 4-(1-aminocyclopropyl)benzoate and (3-cyanophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 546 [M+1] + .400MHz

[1410] 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),9.37(s,1H),8.30(s,1H),8.17(d,J=6.0Hz,2H),7.85–7.78(m,3H),7.78–7.6 8(m,2H),7.55(d,J=3.2Hz,1H),7.34–7.24(m,4H),6.88(s,1H),5.66(s,2H),1.31–1.22(m,3H),1.14–1.08(m,2H).

[1411] Embodiment 207

[1412] (S)-4-(1-(1-([1,1'-biphenyl]-4-methyl)-5-(3,4-difluorophenyl)-1H-indole-7-amido)ethyl)benzoic acid

[1413]

[1414] Using 4-(bromomethyl)-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 587.4 [M+1] + .

[1415] 1HNMR (400MHz, DMSO-d6) δ12.86(s,1H),8.96(d,J=7.8Hz,1H),8.04(s,1H),7.90(d,J=8.0Hz,2H),7.87–7.80(m,1H),7.67(d,J=3.2Hz,1H),7.61–7. 50(m,7H),7.47–7.41(m,4H),7.37–7.32(m,1H),6.93(d,J=7.9Hz,2H),6. 72(d,J=3.1Hz,1H),5.60(s,2H),5.24–5.15(m,1H),1.35(d,J=7.0Hz,3H).

[1416] Embodiment 208

[1417] 4-((1-((4'-Fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indole-7-amido)methyl)benzoic acid

[1418]

[1419] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and phenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 555.2 [M+1] + .

[1420] 1 HNMR(400MHz,DMSO-d6)δ9.06(t,J=6.0Hz,1H),8.02(s,1H),7.84(d,J=8.0Hz,2H),7.75(d,J=7.7Hz,2H),7.67–7.59(m,3H),7.57(d,J=1.8Hz,1H),7 .52–7.42(m,4H),7.36(dd,J=7.7,4.4Hz,3H),7.26(t,J=8.7Hz,2H),6.95( d,J=8.1Hz,2H),6.73(d,J=3.1Hz,1H),5.66(s,2H),4.52(d,J=5.8Hz,2H).

[1421] Embodiment 209

[1422] 4-((1-((4'-Fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indole-7-amido)methyl)benzoic acid

[1423]

[1424] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (4-fluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product (28.8 mg) as a white solid. LCMS (ESI): 573.2 [M+1] + .

[1425] 1 HNMR(400MHz, DMSO-d6)δ9.05(t,J=6.0Hz,1H),8.00(s,1H),7.84(d,J=8.0Hz,2H),7.77(dd,J=8.5,5.5Hz,2H),7.67–7.59(m,3H),7.53(s,1H), 7.45(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.33-7.24(m,4H),6.95(d, J=8.0Hz,2H),6.72(d,J=3.1Hz,1H),5.66(s,2H),4.52(d,J=5.8Hz,2H).

[1426] Embodiment 210

[1427] 4-((5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indole-7-amido)methyl)benzoic acid

[1428]

[1429] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 591.2 [M+1] + .

[1430] 1 H NMR (400MHz, DMSO-d6) δ9.03(t,J=6.0Hz,1H),8.13(s,1H),7.83(d,J=7.9Hz,2H ),7.67(d,J=3.2Hz,1H),7.62(q,J=5.3Hz,3H),7.51(d,J=8.1Hz,2H),7.44(d,J= 7.9Hz,2H),7.35(d,J=8.0Hz,2H),7.25(t,J=8.7Hz,2H),7.18(t,J=9.3Hz,1H), 6.93(d,J=8.0Hz,2H),6.75(d,J=3.1Hz,1H),5.68(s,2H),4.53(d,J=5.9Hz,2H).

[1431] Embodiment 211

[1432] 4-((5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indole-7-amido)methyl)benzoic acid

[1433]

[1434] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 591.2 [M+1] + .

[1435] 1 HNMR(400MHz, DMSO-d6)δ12.81(s,1H),8.96(t,J=5.9Hz,1H),7.99(d,J=1.8Hz,1H),7.82–7.72(m,3H),7.60(d,J=3.2Hz,1H),7.60–7.41(m,5H),7 .38(d,J=7.9Hz,2H),7.29(d,J=7.9Hz,2H),7.19(t,J=8.8Hz,2H),6.87(d ,J=7.9Hz,2H),6.66(d,J=3.1Hz,1H),5.61(s,2H),4.46(d,J=5.8Hz,2H).

[1436] Embodiment 212

[1437] (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indole-7-amido)ethyl)benzoic acid

[1438]

[1439] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and biphenylboronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 569.2 [M+1] + .

[1440] 1HNMR(400MHz,DMSO-d6)δ12.85(s,1H),9.00(d,J=7.9Hz,1H),8.01(d,J=1.8Hz ,1H),7.93–7.86(m,2H),7.76(d,J=7.6Hz,2H),7.67–7.56(m,3H),7.54–7.46(m ,5H),7.38(dd,J=13.5,7.6Hz,3H),7.26(t,J=8.8Hz,2H),6.94(d,J=8.0Hz,2H ),6.72(d,J=3.1Hz,1H),5.59(s,2H),5.23-5.19(m,1H),1.35(d,J=7.0Hz,3H).

[1441] Embodiment 213

[1442] (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indole-7-amido)ethyl)benzoic acid

[1443]

[1444] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (4-fluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 587.2 [M+1] + .

[1445] 1 HNMR (400MHz, DMSO-d6) δ12.73(s,1H),8.98(d,J=7.9Hz,1H),7.99(d,J=1.8Hz,1H),7.89(d, J=8.4Hz,2H),7.82–7.74(m,2H),7.65(d,J=3.2Hz,1H),7.63–7.56(m,2H),7.52(s,1H),7.51 –7.46(m,2H),7.40(d,J=8.0Hz,2H),7.33(t,J=8.8Hz,2H),7.26(t,J=8.8Hz,2H),6.93(d,J= 8.0Hz,2H),6.71(d,J=3.1Hz,1H),5.59(s,2H),5.20(p,J=7.4Hz,1H),1.35(d,J=7.0Hz,3H).

[1446] Embodiment 214

[1447] (S)-4-(1-(5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indole-7-amido)ethyl)benzoic acid

[1448]

[1449] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,5-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 605.2 [M+1] + .

[1450] 1 HNMR(400MHz, DMSO-d6)δ12.83(s,1H),8.95(d,J=7.8Hz,1H),8.12(d,J=1.8Hz,1H),7.89(d,J=7.9Hz,2H),7.67(d,J=3.2Hz,1H),7.63–7.48(m,7H) ,7.39(d,J=7.9Hz,2H),7.30–7.16(m,3H),6.92(d,J=7.9Hz,2H),6.73(d, J=3.2Hz,1H),5.68–5.53(m,2H),5.23-5.17(m,1H),1.37(d,J=7.0Hz,3H).

[1451] Embodiment 215

[1452] (S)-4-(1-(5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indole-7-amido)ethyl)benzoic acid

[1453]

[1454] Using 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 605.2 [M+1] + .

[1455] 1HNMR(400MHz,DMSO-d6)δ12.82(s,1H),8.95(d,J=7.9Hz,1H),8.04(s,1H),7 .94–7.78(m,3H),7.66(d,J=3.2Hz,1H),7.65–7.54(m,3H),7.55–7.47(m,4H ),7.40(d,J=8.0Hz,2H),7.26(t,J=8.8Hz,2H),6.92(d,J=8.0Hz,2H),6.71( d,J=3.1Hz,1H),5.73–5.51(m,2H),5.23-5.17(m,1H),1.36(d,J=7.0Hz,3H).

[1456] Embodiment 216

[1457] 4-((5-(3,4-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indole-7-amido)methyl)benzoic acid

[1458]

[1459] Using 2-(bromomethyl)naphthalene and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 547.5 [M+1] + .

[1460] 1 HNMR(400MHz, DMSO-d6)δ12.80(s,1H),8.92(t,J=5.9Hz,1H),8.03(s,1H),7.85–7.81(m,1H),7.80–7.68(m,6H),7.59–7.52(m,1H),7.51–7.4 8(m,2H),7.47–7.42(m,2H),7.38(s,1H),7.21(d,J=8.0Hz,2H),7.10– 7.03(m,1H),6.73(d,J=3.1Hz,1H),5.79(s,2H),4.44(d,J=5.7Hz,2H).

[1461] Embodiment 217

[1462] (S)-4-(1-(5-(3,4-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indole-7-amido)ethyl)benzoic acid

[1463]

[1464] Using 2-(bromomethyl)naphthalene, (S)-4-(1-aminoethyl)benzoic acid methyl ester and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as Example 75 was followed to obtain the target product as a white solid. LCMS (ESI): 561.5 [M+1] + .

[1465] 1 HNMR(400MHz,DMSO-d6)δ8.84(d,J=7.6Hz,1H),8.02(s,1H),7.85–7.76(m ,4H),7.75–7.69(m,2H),7.68(d,J=3.2Hz,1H),7.60–7.49(m,2H),7.47–7. 42(m,3H),7.40(d,J=8.0Hz,2H),7.36(s,1H),7.06–7.01(m,1H),6.72(d, J=3.1Hz,1H),5.80–5.64(m,2H),5.12–5.04(m,1H),1.11(d,J=7.0Hz,3H).

[1466] Embodiment 218

[1467] 4-((5-(3,4-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)methyl)benzoic acid

[1468]

[1469] Using methyl 4-(aminomethyl)benzoate and (3,4-difluorophenyl)boronic acid as starting materials, the same procedure as in Example 167 was followed to obtain the target product as a white solid. LCMS (ESI): 548.5 [M+1] + .

[1470] 1 HNMR(400MHz, DMSO-d6)δ12.81(s,1H),9.20(t,J=5.9Hz,1H),8.37(s,1H),8.26(d,J=1.7Hz,1H),7.91–7.81(m,3H),7.76–7.69(m,4H) ,7.65–7.59(m,1H),7.58–7.49(m,1H),7.48–7.42(m,3H),7.28(d,J=8.0Hz,2H),7.13–7.07(m,1H),6.02(s,2H),4.54(d,J=5.7Hz,2H).

[1471] Embodiment 219

[1472] (S)-4-(1-(5-(3,4-difluorophenyl)-1-(naphthalene-2-methylene)-1H-indazole-7-amido)ethyl)benzoic acid

[1473]

[1474] Using (3,4-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 167 was followed to obtain the target product as a white solid. LCMS (ESI): 562.4 [M+1] + .

[1475] 1 HNMR(400MHz, DMSO-d6)δ12.83(s,1H),9.09(d,J=7.6Hz,1H),8.38(s,1H),8.27(d,J=1.7Hz,1H),7.93–7.81(m,4H),7.80–7.71(m ,3H),7.68–7.54(m,2H),7.50–7.43(m,5H),7.09(dd,J=8.5,1.8Hz,1H),5.97(s,2H),5.21(p,J=7.1Hz,1H),1.26(d,J=6.8Hz,3H).

[1476] Embodiment 220

[1477] (S)-4-(1-(5-(3,4-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)benzoic acid

[1478]

[1479] Using (3,4-difluorophenyl)boronic acid as the starting material, the same procedure as in Example 134 was followed to obtain the target product as a white solid. LCMS (ESI): 580 [M+1] + .

[1480] 1 HNMR(400MHz,DMSO-d6)δ12.84(s,1H),9.22(d,J=7.6Hz,1H),8.38(s,1H),8.28(d,J=1.7Hz,1H),8.00–7.86(m,3H),7.69– 7.54(m,3H),7.51–7.40(m,3H),7.33(s,1H),7.13(d,J=7.7Hz,1H),5.86(s,2H),5.21–5.10(m,1H),1.39(d,J=7.0Hz,3H).

[1481] Embodiment 221

[1482] (1r,4r)-4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)cyclohexane-1-carboxylic acid

[1483]

[1484] Step 1 5-phenyl-1H-indazole-7-carboxylic acid methyl ester

[1485]

[1486] At 70°C, a mixture of 5-bromo-1H-indazole-7-carboxylic acid methyl ester (0.8 g), phenylboronic acid (4.0 g), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (0.27 g) and potassium acetate (4.8 g) in 1,4-dioxane / water (80 mL / 8 mL) was stirred in nitrogen for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: = 5:1) to obtain the target compound (0.78 g) as a yellow solid. LCMS (ESI): 253.22 [M+1] + .

[1487] Step 2: 5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid methyl ester

[1488]

[1489] A mixture of the product of step 1 (0.77 g) and cesium carbonate (3.0 g) in anhydrous N,N-dimethylformamide (30 mL) was stirred at room temperature for 1 hour, and then treated with 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.1 g). The mixture was then stirred at room temperature for 2 hours, and the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: = 10: 1) to obtain the target compound (1.0 g) as a yellow solid. LCMS (ESI): 411.32 [M+1] + .

[1490] Step 3 5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid

[1491]

[1492] To a solution of the product of step 2 (1.0 g) in acetonitrile / water (30 mL / 15 mL) was added lithium hydroxide monohydrate (2.1 g) at room temperature. The reaction mixture was stirred at 80°C for 1 hour. The mixture was cooled to 0°C and then treated with 6N hydrochloric acid until pH ≈ 6. The reaction mixture was extracted with 3 x 50 mL of ethyl acetate. The combined organic layers were washed with 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound (0.95 g) as a white solid. LCMS (ESI): 397.15 [M+1] + .

[1493] Step 4: Methyl (1r,4r)-4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)cyclohexane-1-carboxylate

[1494]

[1495] At 0°C, HATU (72 mg) was added to a mixture of the product of step 3 (50 mg), (1r, 4r)-4-(aminomethyl)cyclohexane-1-carboxylic acid hydrochloride methyl ester (31 mg) and DIPEA (49 mg) in DMF (10 mL). The mixture was then stirred at room temperature for 1 hour, and 5 mL of water was added, followed by stirring at room temperature for 1 hour. The solid was then collected by filtration, rinsed with water and air-dried to obtain the target compound (60 mg) as a white solid. LCMS (ESI): 550.22 [M+1] + .

[1496] Step 5 (1r,4r)-4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)methyl)cyclohexane-1-carboxylic acid

[1497]

[1498] To a solution of the product of step 4 (60 mg) in acetonitrile / water (10 mL / 5 mL) was added lithium hydroxide monohydrate (106 mg) at room temperature. The reaction mixture was stirred at 70°C for 1 hour. Then it was cooled to room temperature and the mixture was treated with 6N hydrochloric acid until pH ≈ 6. The solid was collected by filtration, rinsed with water and air-dried to obtain the target compound (52 mg) as a white solid. LCMS (ESI): 536.32 [M+1] + .

[1499] 1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.75-8.68(m,1H),8.37(s,1H),8.26-8.20(m, 1H),7.82–7.76(m,3H),7.61(d,J=7.8Hz,1H),7.55–7.47(m,3H),7.44–7.36(m,2H),7 .22(d,J=7.7Hz,1H),5.98(s,2H),3.10(t,J=6.2Hz,2H),2.13-2.07(m,1H),1.90–1.8 0(m,2H),1.74–1.65(m,2H),1.45-1.35(m,1H),1.24–1.14(m,2H),0.98–0.84(m,2H).

[1500] Embodiment 222

[1501] (±)(1r,4r)-4-1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)cyclohexane-1-carboxylic acid

[1502]

[1503] Step 1: Methyl (1r,4r)-4-(methoxy(methyl)carbamoyl)cyclohexane-1-carboxylate

[1504]

[1505] In a 40mL screw cap vial, (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (1.86g), 1,1'-carbonyldiimidazole (2.1g) and dichloromethane (50mL) were added and stirred for 1 hour. N,O-dimethylhydroxylamine hydrochloride (1.94g) was added and stirred at room temperature for 12 hours. Water (100mL) was then added. The reaction mixture was extracted with dichloromethane (3x 50mL). The organic layer was rinsed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether: ethyl acetate: 0-30%) to give an oily product (2.3g). LCMS (ESI): 230.4 [M+1] + .

[1506] Step 2 (1r,4r)-4-acetylcyclohexane-1-carboxylic acid methyl ester

[1507]

[1508] After cooling to 0°C, methylmagnesium bromide (15 mL, 1 M in tetrahydrofuran) was added to a mixture of the product of step 1 (2.3 g) in tetrahydrofuran (40 mL). The reaction mixture was stirred at room temperature for 12 hours. Ammonium chloride (aqueous solution; 100 mL) was then added. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was rinsed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether: ethyl acetate: 0-15%) to give an oily product (1.7 g). LCMS (ES+): 185.2 [M+1] + .

[1509] Step 3 (±)(1r,4r)-4-(-1-aminoethyl)cyclohexane-1-carboxylic acid methyl hydrochloride

[1510]

[1511] A mixture of the product of step 2 (368 mg, 1.0 eq.), ammonium formate (630 mg) and palladium (37 mg) in methanol (10 mL) was stirred at 70 ° C for 12 hours. The reaction mixture was directly concentrated in vacuo, then poured into 100 mL of water and extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and filtered, then treated with 1 mL of hydrochloric acid (4 M in 1,4-dioxane). The mixture was concentrated in vacuo to give a crude product. LCMS (ES+): 186.3 [M+1] + .

[1512] Step 4 (±)(1r,4r)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)cyclohexane-1-carboxylic acid methyl ester

[1513]

[1514] A mixture of 5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid (40 mg, 0.1 mmol), the product of step 3 (1.2 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg) and DIPEA (39 mg) in anhydrous DMF (10 mL) was stirred at room temperature for 12 hours. Water (100 mL) was added and the mixture was extracted with 3 x 50 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: = 0-40%) to obtain the target product (55 mg) as an oil. LCMS (ES+): 564.6 [M+1] + .

[1515] Step 5 (±)(1r,4r)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)cyclohexane-1-carboxylic acid

[1516]

[1517] The product of step 4 (55 mg) and lithium hydroxide monohydrate (42 mg) were dissolved in tetrahydrofuran / water (6 mL / 4 mL) solution. Stir at 40 ° C for 12 hours, then acidify the reaction mixture with 2 mL of 6M hydrochloric acid and remove tetrahydrofuran in vacuo. The reaction mixture was then extracted with 3x50 mL of ethyl acetate. The combined extracts were rinsed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product (50 mg). LCMS (ES+): 549.6 [M+1] + .

[1518] Examples 223 and 224

[1519] (1S,4r)-4-((S)-1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)cyclohexane-1-carboxylic acid (1R,4r)-4-((R)-1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazole-7-amido)ethyl)cyclohexane-1-carboxylic acid

[1520]

[1521] Example 222 was analyzed under the following conditions to obtain Examples 223 and 224:

[1522] Column type: CHIRALPAK IB N-5, 5mm, 250mm x 4.6mm

[1523] Mobile phase: n-hexane / ethanol (70:30) + 0.2% trifluoroacetic acid

[1524] Flow rate: 1 mL / min.

[1525] Example 223: retention time 5.188 minutes;

[1526] Example 224: Retention time was 8.485 minutes.

Claims

1. A compound of general formula I or a pharmaceutically acceptable salt thereof: Where: R 1 Indicates -CO2H, -C(O)NHS(O)2R 7 、-NHC(O)NHSO2R 7 , -1H-tetrazolyl, -P(O)(OH)2, -1,2,4-oxadiazole-5(4H)-1 or -tetrazolyl-5(4H)-1; Y is N, CR 3 or is a chemical bond; R 2 , R 3 are independently selected from the following groups: halogen, hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Fluorinated cycloalkyl, C 1-6 Fluoroalkyl, or R 2 , R 3 and carbon atoms connected to both of them to form a 3-6 membered carbocyclic ring which may be optionally replaced by R e substituted, or a 3-6 membered ring containing one or two heteroatoms such as S, O or NR b , where R b Selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 1-6 Fluoroalkyl, C 0-6 Alkylene-aryl, C 0-6 Alkylene-heteroaryl, C(O)C 1-6 Alkyl, C(O)aryl, S(O)2C 1-6 Alkyl, S(O)2C 3-6 Cycloalkyl, S(O)2aryl; X does not exist or is halogen, -CN, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or OC 1-6 Haloalkyl; Select from the following structures: Z is O, S or NR 8 ; X 1 N or CR 4 ; X 2 , X 3 N, CR, and 4 or with -Y 2 -Ar 2 Connected carbon atoms, provided that X 2 or X 3 At least one of them is with -Y 2 -Ar 2 connected carbon atoms; X 4 O, S, N, NR 5 or CR 5 ; X 5 is O, S, N, CR 6 or -C(O)-; X 6 , X 7 and X 8 are independently N or C; Y 2 -C(O)-, -(CR a R 1a ) n -, -CH=CH-, -C≡C-, -O-, -S-, S(O)2-, -S(O)2NR b -、-NR b S(O)2-、-C(O)NR b -、-NR b C(O)-、NR b C(O)NR b -、NR b S(O)2NR b -, -NRb-, or Y 2 does not exist, and Ar 2 Directly with X 2 or X 3 connected; Y 1 -O-, -S-, -NR b -, -C(O)- or -CR a R 1a -; Y 3 For-(CR a 2) m -; n and m are independently 0, 1, 2 or 3; r is 1 or 2; Each R a and R 1a are independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, or two R a and R 1a Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl or heterocyclic group; Each R 4 , R 5 and R 6 are independently selected from: hydrogen, alkyl, halogen, -OR 8 、-NR 8 R 9 、-SR 8 、-S(O)2NR 8 R 9 、-S(O)2R 11 、-CN、C 3-6 Cycloalkyl, -C 0-6 Alkylene-aryl, -C 0-6 Alkylene-heteroaryl or haloalkyl; Ar 1 ,Ar 2 Each independently selected from the following groups: -OR 8 、-SR 8 NR 8 R 9 , C 1-10 Alkyl, C 1-10 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-aryl, -C 0-6 Alkylene-heteroaryl and -C 0-6 Alkylene-heterocyclyl, or C 3-6 A fused analog of a cycloalkyl group; wherein, Ar 1 and Ar 2 Each independently by 1-3 R e Group substitution; Two Ar atoms on adjacent carbon atoms 2 Together with carbon atoms, they can form a 3-6-membered carbocyclic ring, a 4-8-membered bicyclic ring, a C5-C 10 Aromatic ring (optionally with one or more R e Replacement), C2-C 90 Heteroaromatic ring (optionally replaced by one or more R e substituted), or contain one, two or three heteroatoms (such as S, O or NR b ) of a 3-6 membered ring, a 4-8 membered bicyclic ring or a 5-8 membered spiro ring; Each R e are independently halogen, hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Fluorinated cycloalkyl, C 1-6 Fluoroalkyl, -C2-C9 alkynyl, -C 0-6 Alkylene-heterocyclyl, -C 0-6 Alkylene-aryl, -C 0-6 Alkylene-heteroaryl, SF5, -C 0-6 Alkylene-OR 8 , -C 0-6 Alkylene-P(O)Me2, -C 0-6 -Alkylene-NR 8 R 9 , -C 0-6 Alkylene-C(O)NR 8 R 9 , -C 0-6 Alkylene-SR 8 , -C 0-6 Alkylene-S(O)2NR 8 R 9 , -C 0-6 Alkylene-S(O)2R 10 or -C 0-6 Alkylene -CN, where C 1-6 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, -C 0-6 Alkylene-cycloalkyl, -C 0-6 Alkylene-heterocyclyl, -C 0-6 Alkylene-aryl and -C 0-6 Alkylene-heteroaryl; R e Can be one, two or three R v replace; R v are independently alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, halogen, -OR 8 、-NR 8 R 9 、-CN、-C(O)R 10 、-C(O)NR 8 R 9 、-NR 8 C(O)R 10 、-NR 8 C(O)OR 9 、-NR 10 C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O)2R 10 、-S(O)R 10 、-SR 8 、-S(O)2NR 8 R 9 、-S(O)NR 8 R 9 、-NR 8 S(O)R 10 、-NR 8 S(O)2R 10 or -NR 10 S(O)2NR 8 R 9 ; wherein the alkyl group can be optionally replaced by -OR 8 or -NR 8 R 9 Substitution, cycloalkyl and heterocyclyl may be optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; R 7 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, aryl and heteroaryl groups; Each R 8 and R 9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl may be selectively substituted by one, two or three groups selected from halogen, alkyl and haloalkyl; or R 8 and R 9 Together with the one or more atoms to which they are attached, they form a heterocyclic group, which may be optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; Each R 10 are independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl may be selectively substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; Select from the following structures: Can be one or more R e replace.

2. The compound according to claim 1, characterized in that The compound of general formula I is or a pharmaceutically acceptable salt thereof, wherein X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

3. The compound according to claim 1, characterized in that The compound of general formula I is Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

4. The compound according to claim 1, characterized in that The compound of general formula I is Where: X 5 N or CR 6 ; R 2 , R 3 , R 5 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in Formula I.

5. The compound according to claim 1, characterized in that The compound of general formula I is Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

6. The compound according to claim 1, characterized in that The compound of general formula I is Where X 5 N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

7. The compound according to claim 1, characterized in that The compound of general formula I is Where: X 4 NR 5 , O or S; R 2 , R 3 , R 5 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

8. The compound according to claim 1, characterized in that The compound of general formula I is Where X 4 NR 5 , O or S; R 2 , R 3 , R 5 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

9. The compound according to claim 1, characterized in that The compound of general formula I is Where X 4 , X 5 are independently N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

10. The compound according to claim 1, characterized in that The compound of general formula I is Where X 4 , X 5 are independently N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

11. The compound according to claim 1, characterized in that The compound of general formula I is Where X 4 , X 5 are independently N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in the general formula I.

12. The compound according to claim 1, characterized in that The compound of general formula I is Where X 4 , X 5 are independently N or CR 6 ; R 2 , R 3 , R 6 , Y 1 , Y 2 ,Ar 1 and Ar 2 The definition of is as shown in general formula I; t is 0, 1 or 2; q is 1, 2 or 3.

13. The compound according to claim 1, characterized in that The compound is selected from the compounds described in the "Instructions" and Examples section of the present invention, pages 11 to 97.

14. A method for treating a human or animal disease mediated by PGE2 receptor action, by administering to a subject an effective dose of a compound according to claims 1 to 13; wherein the disease or condition is selected from cancer, pain, neurodegenerative disease, osteoarthritis, rheumatoid arthritis, endometriosis and kidney disease.

15. A method for treating a cancer subject by administering to the subject an effective dose of a compound according to claims 1 to 13, wherein the antibody is selected from anti-CTLA4, anti-PD-L1, anti-PD-1 antibodies; or is used in combination with small molecule drugs such as kinase inhibitors, A2A receptor antagonists, IDO inhibitors, TDO inhibitors, HDAC inhibitors, PI3K / AKT pathway inhibitors, endocrine / hormone drugs, other chemotherapeutic drugs or antimetabolites.

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