Amide compounds as prostaglandin E2 (PGE2) receptor antagonists

Abstract

The present invention relates to a series of novel amide compounds as PGE2 receptor antagonists, which can treat PGE2-mediated diseases or conditions, such as pain, inflammation, cancer (immunotherapy) and neurodegenerative diseases, and further includes related combination preparations and methods of use thereof.

Description

[Technical field]

[0001] The present invention relates to novel amide compounds used as antagonists of the PGE2 receptor. These novel amide compounds are effective in treating diseases and conditions mediated by PGE2, such as pain, inflammation, cancer (immunotherapy), and neurodegenerative diseases. Also included are related combination preparations and methods of use thereof. [Background technology]

[0002] The present invention relates to amides or their pharma- ceutically acceptable salts, pharma-ceutically acceptable prodrugs, combination preparations containing such components, and their medical uses. The compounds of the present invention have prostaglandin E2 (PGE2) receptor antagonist activity 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, allergy, pelvic inflammation, nodal disease, 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. Prostaglandin E2 (PGE2) is the most predominant isoeicosanic acid detected in inflammatory diseases. PGE2 is also considered to be an important component of the immunosuppressive environment of many solid tumors (Non-Patent Document 1). It has been demonstrated that PGE2 receptor 2 (EP2) and receptor 4 (EP4) are expressed in tumor cells of several types of cancers (including colon cancer, prostate cancer and breast cancer). Blocking the PGE2 / EP2 and PGE2 / EP4 signaling pathways using EP2 / EP4 gene knockout and EP2 / EP4 antagonists has been proven to be an effective intervention for treating several cancers (including colon cancer, malignant glioma and neuroblastoma). Recent studies have shown that hepatic stellate cells can increase the number of Th17 cells and regulatory T cells via the PGE2 / EP2 pathway (Non-Patent Document 2). Therefore, EP2 / EP4 antagonists can improve or synergistically enhance the anti-tumor effect of checkpoint inhibitors (e.g., anti-CTLA4, anti-PD-L1 or anti-PD-1 antibodies). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Whiteside, Expert Opinion in Biological Therapy, 2010, 1019-1035 [Non-Patent Document 2] Li at al., J. transl. Med., 2017, 75 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention relates to a series of novel amide derivatives as PGE2 receptor antagonists (particularly EP2 / EP4 antagonists), methods for treating PGE2-mediated diseases (particularly cancer, pain, inflammation and neurodegenerative diseases), and combination preparations of some of these components. [Means for solving the problem]

[0006] (explanation) The present invention includes a compound of formula I or a pharma- ceutically acceptable salt thereof as a PGE2 receptor antagonist. [ka] In the formula: R 1 -CO2H, -C(O)NHS(O)2R 7 , -NHC(O)NHSO2R 7 , -1H-tetrazole group, -P(O)(OH)2, -1,2,4-oxadiazol-5(4H)-one or -tetrazol-5(4H)-one, Y, N, CR 3 or [ka] represents a chemical bond, R 2 , R 3 are independently halogen, hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Fluorocycloalkyl groups, C 1-6 Fluoroalkyl group or R 2 , R 3 and a 3- to 6-membered carbocyclic ring, which is optionally R e or comprises a 3-6 membered ring, which may contain 1 or 2 heteroatoms, such as S, O or NR b where R b is hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 Fluorocycloalkyl groups, C 1-6 Fluoroalkyl group, C 0-6 Alkylene group-aryl group, C 0-6 Alkylene-Heteroaryl, C(O)C 1-6 Alkyl groups, C(O)aryl groups, S(O)2C 1-6Alkyl group, S(O)2C 3-6 S(O) is independently selected from a cycloalkyl group, an S(O)aryl group, X is absent or each independently represents halogen, -CN, C 1-6 Alkyl group, OC 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl group or OC 1-6 It is a halogenated alkyl group.

[0007] [ka] are independently selected from the following structures: [ka] Z is O, S or NR 8 and X 1 is N or CR 4 and X 2 , X 3 are independently N, CR 4 or -Y 2 -Ar 2 A carbon atom connected to X 2 Or X 3 At least one of them is -Y 2 -Ar 2 provided that the carbon atom is connected to X 4 are O, S, N, and NR 5 or CR 5 and X 5 are O, S, N, and CR. 6 or -C(O)-, X 6 , X 7 and X 8 are each 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 X 2 Or X 3 Directly connected to Y 1 -O-, -S-, -NR b -, -C(O)- or -CR a R 1a - and Y 3 is -(CR a 2) m - and n and m are each independently 0, 1, 2, or 3; r is 1 or 2; Each R a and R 1a are independently hydrogen, halogen, or C 1-6 Alkyl group or C 1-6 or two R a and R 1a together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocyclic group; Each R 4 , R 5 and R 6 are each independently hydrogen, an alkyl group, a halogen, or -OR 8 , -NR 8 R 9 , -SR 8 , -S(O)NR 8 R 9 , -S(O)2R 11 , -CN,C 3-6 Cycloalkyl groups, -C 0-6 Alkylene group-aryl group, -C 0-6 an alkylene group-heteroaryl group or a halogenated alkyl group; Ar 1 , Ar 2 are -OR 8 , -SR8 , N.R. 8 R 9 , C 1-10 Alkyl group, C 1-10 Halogenated alkyl groups, -C 0-6 Alkylene group -C 3-6 Cycloalkyl groups, -C 0-6 Alkylene group-aryl group, -C 0-6 Alkylene group-heteroaryl group and -C 0-6 Alkylene group-heterocyclic group, or C 3-6 are independently selected from fused analogs of cycloalkyl groups, where Ar 1 and Ar 2 are 1-3 R e Substituted with a group, Two Ar on adjacent carbon atoms 2 is a 3-6 membered carbocyclic ring, a 4-8 membered bicyclic ring, a C5-C 10 Aromatic ring (optionally one or more R e may be substituted with), C2-C 90 Heteroaromatic ring (optionally multiple R e or 1, 2 or 3 heteroatoms, (e.g., S, O or NR b ) containing 3-6 membered rings, 4-8 membered bicyclo or 5-8 membered spiro rings (e.g., S, O or NR b containing one, two or three heteroatoms such as Each R e are independently halogen, hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Fluorocycloalkyl groups, C 1-6 Fluoroalkyl group, -C2-C9 alkynyl group, -C 0-6 Alkylene group-heterocyclic group, -C 0-6 Alkylene group-aryl group, -C 0-6 Alkylene group-heteroaryl group, SF5, -C 0-6 Alkylene group -OR 8 , -C 0-6 Alkylene group -P(O)Me2, -C 0-6 -Alkylene group -NR 8 R 9 , -C0-6 Alkylene group -C(O)NR 8 R 9 , -C 0-6 Alkylene group -SR 8 , -C 0-6 Alkylene group -S(O)NR 8 R 9 , -C 0-6 Alkylene group -S(O)R 10 Or -C 0-6 An alkylene group, -CN, where C 1-6 Alkyl group, C 2-9 Alkenyl group, C 2-9 Alkynyl group, -C 0-6 Alkylene group-cycloalkyl group, -C 0-6 Alkylene group-heterocyclic group, -C 0-6 Alkylene group-aryl group and -C 0-6 The alkylene-heteroaryl group is R e 1, 2 or 3 R v may be substituted with R v each independently represents an alkyl group, a halogenated alkyl group, a cycloalkyl group, a cycloalkyl group-alkyl group, a heterocyclic group, a heterocyclic group-alkyl group, a 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)NR 8 R 9 , -S(O)NR 8 R 9 , -NR 8 S(O)R 10 , -NR 8 S(O)2R10 or -NR 10 S(O)2NR 8 R 9 wherein the alkyl group is optionally -OR 8 or -NR 8 R 9 and the cycloalkyl and heterocyclic groups are optionally substituted with one, two or three groups independently selected from halogen, alkyl and halogenated alkyl groups; R 7 is C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 independently selected from a halogen ring-alkyl group, an aryl group, and a heteroaryl group; Each R 8 and R 9 are each independently hydrogen, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally substituted with one, two, or three groups independently selected from halogen, an alkyl group, and a halogenated alkyl group; 8 and R 9 together with the atom or atoms to which they are attached form a heterocyclic group, which is optionally substituted with one, two or three groups independently selected from halogen, alkyl and halogenated alkyl groups; Each R 10 are each independently an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally substituted with one, two, or three groups independently selected from halogen, an alkyl group, and a halogenated alkyl group; [ka] is selected from the following structures: [ka] [ka] may optionally be one or more R e may be substituted.

[0008] In one embodiment, [ka] are independently selected from the following structures: [ka]

[0009] [ka]

[0010] [ka]

[0011] [ka]

[0012] In one embodiment, there is provided a compound of formula II, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0013] In one embodiment, the present invention further provides a compound of formula III, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0014] In one embodiment, the present invention further provides a compound of formula IV or a pharma- ceutically acceptable salt thereof: [ka] In the formula: X 5 is N or CR 6 and R 2 , R 3 , R 5 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0015] In one embodiment, there is provided a compound of formula V, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0016] In one embodiment, the present invention further provides a compound of formula VI, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 5 is N or CR 6 and R2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0017] In one embodiment, the present invention further provides a compound of formula VII or a pharma- ceutically acceptable salt thereof: [ka] In the formula: X 4 is O or S, R 2 , R 3 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0018] In one embodiment, there is provided a compound of formula VIII, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 is O or S, R 2 , R 3 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0019] In one embodiment, there is provided a compound of formula IX or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2is defined as in Formula I.

[0020] In one embodiment, the present invention further provides compounds of formula X, or pharma- ceutically acceptable salts thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0021] In one embodiment, there is provided a compound of formula XI, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0022] In one embodiment, the present invention further provides a compound of formula XII or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0023] In one embodiment, the present invention further provides a compound of formula XIII or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I. t is 0, 1 or 2.

[0024] In one embodiment, the present invention further provides a compound of formula XIV or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I. t is 0, 1 or 2.

[0025] In one embodiment, the present invention further provides a compound of formula XV, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I. t and q are each 0, 1 or 2.

[0026] In one embodiment, the present invention further provides a compound of formula XVI or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I. t is 0, 1 or 2.

[0027] In one embodiment, the present invention further provides a compound of formula XVII or a pharma- ceutically acceptable salt thereof: [ka] In the formula, X 4 , X 5 are each independently N or CR 6 and R 2 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 is defined as in Formula I.

[0028] In some embodiments, the compound of Formula I-XVII is independently selected from the following compounds or pharma- ceutically acceptable salts thereof: [ka]

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[0114] [ka] Effect of the Invention

[0115] The present invention further includes prodrugs of the compounds of the invention, which may be selected as ethers or amides.

[0116] The present invention further includes combination preparations prepared by mixing the compounds of the invention with one or more physiologically acceptable carriers or excipients.

[0117] The present invention further includes the inventive compounds or pharma- ceutically acceptable derivatives thereof for use in human or veterinary medicine.

[0118] The present invention further includes a method for treating a human or animal disease mediated by PGE2 receptor activity, which method comprises administering to a subject an effective dosage of a compound of the invention.

[0119] The present invention further includes the use of the compounds of the invention to create therapeutic agents for treating diseases mediated by the action of the PGE2 receptor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0120] definition Unless otherwise indicated, the term "alkyl group" by itself or as part of another substituent means straight chain (i.e., unbranched), branched chain, cyclic hydrocarbon groups, or combinations thereof, having the specified number of carbon atoms (i.e., C1-10 represents 1 to 10 carbon atoms), which may be fully saturated, monounsaturated, or highly unsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon groups include, but are not limited to, radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl-methyl, homologs and isomers of such materials as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. By unsaturated alkyl group is meant an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethylene, 2-isopropenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butyne, and higher homologs and isomers. Alkyl groups limited to hydrocarbon groups are referred to as "higher alkyl groups." Alkyl groups may be optionally substituted with one or more halogen atoms.

[0121] The term "halogenated alkyl group" refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been replaced with a halogen atom.

[0122] The term "alkenyl group" means a carbon chain containing at least one carbon-carbon double bond, which may be linear, branched, Z- or E-, or combinations thereof. Examples of alkenyl groups include CH3CH=CH-, CH2=CHCH2-, and CH(CH3)2CH=CH-.

[0123] The term "alkylene group" 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-. The alkylene group may be optionally substituted with one or more substituents as described herein, and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Typically, an alkyl (or alkylene) group will have 1-24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl group" or "lower alkylene group" is a short chain alkyl or alkylene group, typically having 8 or fewer carbon atoms. The alkylene group may be optionally substituted with one or more halogen atoms.

[0124] The term "alkynyl" means a carbon chain that contains at least one carbon-carbon triple bond, and may be linear, branched, or combinations thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. Alkynyl groups may be optionally substituted with one or more halogen atoms.

[0125] The term "alkylamino" refers to an amino group substituent which is further substituted with one or two alkyl groups.

[0126] The term "aminoalkyl" refers to an alkyl group substituent that is further substituted with one or more amino groups. The term "hydroxyalkyl" refers to an alkyl group substituent that is further substituted with one or more hydroxyl groups. The alkyl or aryl portion of the alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl and alkylcarbonylalkyl groups may be optionally substituted with one or more substituents.

[0127] The term "cycloalkyl group" or "carbocycloalkyl group" refers to a monocyclic, bicyclic, or spirocyclic bicyclic carbocycle, each ring having from 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl group refers to a monocyclic group fused with an aryl or heteroaryl group, where the point of attachment is located on the non-aromatic portion. Examples of cycloalkyl groups and their fused analogs include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthalene, decahydronaphthyl, indanyl, and the like. A spirocyclic bicyclic carbocycle may be bicyclic (only two rings) or one bicyclic moiety may be part of a larger ring system, in either case the two rings are linked by a single shared carbon atom that is limited. A cycloalkyl group may be optionally substituted with one or more halogen atoms.

[0128] The term "alkoxy group" means 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.

[0129] Unless otherwise indicated, the term "heteroalkyl group" by itself or in combination with other terms means a stable linear, branched, or cyclic hydrocarbon group, or combinations thereof, composed of at least one carbon atom and at least one heteroatom, independently selected from O, N, P, Si, and S, where the nitrogen (N), phosphorus (P), and sulfur (S) atoms may be optionally oxidized, while the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder 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 occur consecutively, e.g., -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heterocycloalkylene group" 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, -CH-CH-S, -CH-CH-, and -CH-S-CH-CH-NH-CH-. For heterocycloalkylene groups, heteroatoms can occupy one or two chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heterocycloalkylene linking groups, the direction of the formula of the linking group does not imply the orientation of the linking group. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-. As noted above, heteroalkyl groups as used herein further include groups that are linked to the remainder of the molecule through a heteroatom, such as, for example, -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR' and / or -SOR'.When a "heteroalkyl group" is recited and a specific heteroalkyl group (e.g., -NR'R") is further recited, it should be understood that the terms "heteroalkyl group" and -NR'R" are not mutually exclusive, and the specific heteroalkyl group is recited to provide a clearer definition. Therefore, the term "heteroalkyl group" in the present invention should not be interpreted as not including the specific heteroalkyl group (e.g., -NR'R").

[0130] The term "cycloalkoxy" refers to a cycloalkyl group, as defined above, attached to an oxygen atom, such as a cyclopropyloxy group.

[0131] The term "halogenated alkoxy group" means an alkoxy group as defined above, in which one or more hydrogen atoms have been replaced with a halogen atom.

[0132] The term "aryl group" means a monocyclic or bicyclic aromatic ring containing only carbon atoms. A "fused analog" of an aryl group means an aryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclic group, where the point of attachment is located on the aromatic portion. Examples of aryl groups and their fused analogs include phenyl, naphthalene, indanyl, indenyl, tetrahydronaphthalene, 2,3-dihydrobenzofuryl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.

[0133] The term "heteroaryl group" means at least one monocyclic or bicycloaromatic ring containing a heteroatom independently selected from N, O, and S, and each ring containing 5 to 6 atoms. A "fused analog" of a heteroaryl group means a heteroaryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclic group, where the point of attachment is on the aromatic portion. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazole, thiadiazoyl, thienyl, imidazolyl, triazolyl, tetrazole, furyl, triazine, thienyl, pyrimidinyl, pyrazidinyl, pyrazinyl, benzoxazolyl, benzothienyl, benzimidazolyl, benzofuryl, benzothienyl, furyl(2,3-b)pyridyl, quinoline, indolyl, isoquinolinyl, and the like.

[0134] The term "heterocyclic group" means at least one monocyclic, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring system containing a heteroatom selected from N, S and O, each ring having from 3 to 10 atoms, and whose attachment points may be carbon or nitrogen gas. "Heterocyclic group" includes "fused analogs", i.e., monocyclic heterocycles fused with heterocycles, carbocycles, aryl groups, and heteroaryl groups, whose attachment points are located on the non-aromatic portion. Examples of "heterocyclic groups" and fused analogs thereof are aziridinyl groups, pyrrolylalkyl groups, piperidine groups, piperazine groups, imidazolylalkyl groups, imidazolylpyridyl groups, tetrahydrothienyl groups, dioxolane groups, oxazolylalkyl groups, decahydroquinoline groups, piperidine groups, 4-piperidinone groups, quinine groups, thiomorpholine groups, thiomorpholine 1,1-dioxide, morpholinyl groups, nitrogen heterocycloheptanes, oxygen nitrogen heterocycloheptanes, azabicyclohexane groups, azabicycloheptylalkyl groups, azabicyclooctyl groups, azabicyclohexane ... nonyl group, azaspiroheptyl group, dihydro-1H,3H,5H-oxazolyl[3,4-c]oxazolyl group, tetrahydro-1'H3'Hspirocyclic[cyclopropane-1,2'-pyrrolylalkyl group], hexahydro-1H-pyrazinyl group, hexahydro-1H-pyrrolyl[2,1-c][1,4]oxazyl group, octahydroindolizinyl group, oxazolylspirononyl group, oxazolylspirooctyl group, diazospinonyl group, oxazolylbicycloheptyl group, hexahydropyrrolylalkyl group, 4(1H0-oxide, tetrahydro-2H-thiopyranyl group 1-oxide, tetrahydro-2H-thiopyranyl group 1,1-dioxide, bicycloheptynyl group, 2,3-dihydrofuryl (2,3-b)pyridyl group, benzoxazirine group, tetrahydroquinoline group, tetrahydroisoquinolinyl group, hexahydro-1H-pyrrolidine, dihydroindolyl group, etc. The term further includes some unsaturated monocyclic rings that are non-aromatic, such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidinyl-2,4-diketones (N-substituted uracils) linked via the nitrogen.

[0135] The alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups mentioned in the definitions are unsubstituted or substituted with at least one substituent selected from the substituents mentioned above. The substituent is selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogenated alkyl group having 1 to 4 carbon atoms, a halogenated alkoxy group having 1 to 4 carbon atoms, a cyano group, an alkynyl group having 2 to 6 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 7 ring atoms, a heteroaryl group, an aryl group, an aralkyloxy group having 7 to 10 carbon atoms, and an arylcarbonyl group, and two adjacent -X groups may be selectively linked, an alkylene group or alkenylene group 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 hydroxylalkyl 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 alkoxycarbonyl group having 1 to 4 carbon atoms, an aryl ... an alkoxyalkyl group having from 1 to 4 carbon atoms, an alkoxysulfonyl group having from 1 to 4 carbon atoms, an alkanoyl amino group having from 1 to 4 carbon atoms, an alkanoyl (alkyl) amino group having from 1 to 6 carbon atoms, an alkanoyl amino alkyl group having from 1 to 6 carbon atoms in both the alkanoyl group and the alkyl group moiety, an alkanoyl (alkyl) amino alkyl group having from 1 to 6 carbon atoms in both the alkanoyl group and the alkyl group moiety, an alkylsulfonyl amino group having from 1 to 4 carbon atoms, a single- or dialkylamino carbonyl group having from 1 to 6 carbon atoms, a single- or dialkylamino sulfinyl group having from 1 to 6 carbon atoms, a single- or dialkylamino sulfonyl group having from 1 to 6 carbon atoms, an amino alkyl group having from 1 to 4 carbon atoms, a single- or dialkylamino group having from 1 to 6 carbon atoms, and a single- or dialkylamino alkyl group having from 1 to 6 carbon atoms in each alkyl group moiety;It may form an aralkyl group having 7 to 10 carbon atoms, a heteroaralkyl group having 1 to 4 carbon atoms in the alkyl group portion, a heteroaralkyloxy group having 1 to 4 carbon atoms in the alkoxy group portion, and an alkylsulfonyl group or amino group having 1 to 4 carbon atoms.

[0136] Unless otherwise specified, the term "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromo, or iodine atom. The term "halogenated alkyl group" includes monohalogenated alkyl groups and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4) alkyl group" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0137] By "prodrug" is meant a formulation that is converted to the parent drug in the body. Prodrugs are usually useful because, in some cases, they may be easier to administer than the parent drug. For example, the prodrug is bioavailable after oral administration, whereas the parent drug is not. The solubility of the prodrug in the complex formulation is also improved compared to the parent drug. Examples of prodrugs include, but are not limited to, any compound in Formula I, which is administered in the form of an ether ("prodrug"), which facilitates crossing cell membranes where water solubility is unfavorable for mobility, but once inside a cell where water solubility is favorable, the compound is metabolized and broken down into a carboxylic acid, the active entity. Examples of prodrugs further include peptides (polyamino acids) bound to an acid group, where the peptide exhibits the active moiety after being metabolized.

[0138] Optical Isomers - Diastereoisomers - Geometric Isomers - Tautomers The compounds of the present invention may contain one or more asymmetric centers and therefore may be presented in the form of racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomeric isomers, and the present invention is intended to cover all such isomeric forms of the compounds.

[0139] Some of the compounds in the present invention contain an ethylenic double bond (unless otherwise specified), and include two geometric isomers, E and Z isomers.

[0140] Some of the compounds may contain one or more cyclic ring systems and may exist in cis and trans isomeric forms, and the present invention is intended to cover all such cis and trans isomers.

[0141] Some compounds of the present invention may have different points of hydrogen attachment, called tautomers, for example, a keto and its enol form are called keto-enol tautomers. Various tautomers and mixtures thereof are included in the compounds of the present invention.

[0142] The compounds described herein can be separated into diastereoisomeric pairs of enantiomers by methods such as fractional crystallization from a suitable solvent (e.g., MeOH or EtOAc or mixtures thereof). The enantiomer pairs thus obtained may be separated into single stereoisomers by conventional methods, such as using optically active ammonium or acids as resolving agents or by separation on a chiral HPLC column.

[0143] Alternatively, any enantiomer of a compound described herein may be obtained by stereodirected synthesis using optically pure starting materials or reagents of known structural type.

[0144] Stable isotope marker analogues In the compounds of the invention, one or more atoms (hydrogen atoms) can be replaced with deuterium atoms to provide deuterated analogs, which may have better pharmacokinetic characteristics or pharmacological activity.

[0145] Salts and their preparations The compounds of the present invention can be used as free bases or as salts.

[0146] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic alkalis or acids, including inorganic or organic alkalis, inorganic or organic acids. Salts prepared from inorganic alkalis include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salts, manganous, potassium, sodium, zinc salts, and the like, particularly the ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharma- ceutically acceptable organic non-toxic alkalis include salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cycloammonium and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolammonium, ethylenediamine, N-ethyl-morpholinyl, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydroxylammonium, isopropylammonium, lysine, methylglucosamine, morpholinyl, piperazine, piperidine, polyammonium resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylammonium, tri(hydroxymethyl)methylamine, tromethamine, and the like.

[0147] When the compound of the present invention is basic, salts can be prepared using pharma- ceutically acceptable non-toxic inorganic and organic acids. Such acids include acetic acid, besylic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucose acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxylethanesulfonic 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, paratoluenesulfonic acid, etc. In particular, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0148] It will be understood that the compounds of the invention described herein also include pharma- ceutically acceptable salts.

[0149] Oral administration formulations may be hard capsules, in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or soft capsules, in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0150] The aqueous suspension contains an active material and an excipient suitable for the preparation of the aqueous suspension, such as a suspension aid, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyethylene pyrrolidine keto, gum tragacanth and gum arabic, and the dispersant or wetting agent may be a naturally occurring phospholipid (for example, lecithin fat) or a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), or a condensation product of an ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethyleneoxycetanol), or a condensation product of an ethylene oxide with a fatty acid and a partial ether derived from a hexitol (for example, polyoxyethylene sorbitan monooleate), or a condensation product of an ethylene oxide with a fatty acid and a partial ether derived from a hexitol anhydride (for example, polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (e.g., ethyl or n-propyl parahydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., trehalose, saccharin, or aspartame).

[0151] Oil suspensions can be prepared by suspending the active ingredient in olive oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (e.g., liquid paraffin). Oil suspensions may contain thickening agents such as beeswax, hard paraffin or cetanol. The above sweeteners and flavorings can also be added to prepare a palatable oral preparation. Antioxidants (e.g., ascorbic acid) can be added to preserve these ingredients.

[0152] Dispersible powders and particles suitable for preparing aqueous suspensions by adding water can be mixed with dispersing or wetting agents, suspension aids, and one or more preservatives as active ingredients. Suitable dispersing or wetting agents and suspension aids are described above. Other excipients, such as sweeteners, flavorings, and colorings, can also be added.

[0153] The composite preparation of the present invention may take the form of an oil-in-water emulsion. The oil phase may take olive oil (e.g., olive oil or peanut oil), mineral oil (e.g., liquid paraffin), or a mixture of both. Suitable emulsifiers may be naturally occurring phospholipids (e.g., soybean phospholipid, lecithin fat), ethers or partial ethers derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial ethers with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners and flavoring agents.

[0154] Syrups and elixirs may contain sweetening agents, such as glycerin, propylene glycol, sorbitol or trehalose. Such preparations may further contain analgesics, preservatives, flavorings and coloring agents. The composite preparations may take the form of sterile injectable aqueous or oily suspensions. Such suspensions may be prepared according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending aids. The sterile injectable preparations may be sterile injectable solutions or suspensions prepared in non-toxic diluents or solvents for parenteral administration, such as solutions in 1,3-butanediol. Acceptable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as solvents or suspension media. For this purpose, any mild fixed oil may be used, including synthetic monoglyceride ethers or diglycerides. In addition, fatty acids such as oleic acid may be used to prepare injectables.

[0155] The compounds of the present invention can be administered intranasally or by inhalation, usually in the form of dry powder (either alone or in admixture, e.g., in a dry admixture with lactose, or as mixed component particles, e.g., mixed with phospholipids such as lecithin fat) in a dry powder inhaler, or in the form of an aerosol spray from a pressurized container, pump, injector, nebulizer (I-type nebulizers, which generate a fine mist on the electrodynamic principle, are recommended) or nebulizer, with or without a suitable propellant, e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Powders for intranasal administration may contain bioadhesives, e.g., chitosan or cyclodextrin.

[0156] The pressurized container, pump, injector, nebulizer or atomizer contains a solution or suspension of the compound of the invention, including ethanol, aqueous ethanol or a suitable substitute to disperse, solubilize or prolong active ingredient release, and a propellant as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

[0157] Before being used in a dry powder or suspension formulation, the drug product is first micronized to a particle size suitable for inhaled administration (usually less than 5 microns).

[0158] To this end, any suitable comminuting method may be employed, for example spiral jet milling, fluidized bed jet milling, formation of nanoparticles by supercritical fluid processing, high pressure homogenization or spray drying.

[0159] Capsules for use in inhalers or insufflators (e.g., capsules made from gelatin or HPMC), blisters and curd-type injections can be prepared from a powder mix containing the compound of the invention, a suitable 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 preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, trehalose and trehalose.

[0160] When using a solution formulation suitable for a nebulizer that generates a fine mist by electrodynamic principles, one spray contains 1-20 mg of the compound of the present invention, and the spray volume is 1-100 L. A typical formulation contains the compound of formula (A): propylene glycol, sterile water, ethanol and sodium chloride. Propylene glycol may be replaced by solvents such as glycerin and polyethylene glycol.

[0161] Suitable essences (eg, menthol and levomenthol) or sweeteners (eg, saccharin or saccharin sodium) may be added to formulations of the invention for inhaled / intranasal administration.

[0162] Formulations for inhalation / intranasal administration can be prepared using materials such as polylactic acid-hydroxyl acetate (PGLA) to produce immediate and / or sustained release formulations. Sustained release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release dosage forms.

[0163] When administered using dry powder inhalers and aerosol sprays, the dosage unit is determined by a valve whose role is to provide a metered unit dose. Devices compatible with the present invention are typically designed to administer a metered dose or "one spray" containing 1 pg to 1 mg of the compound of the present invention. The total daily dose is typically 1 pg to 1 mg and may be administered all at once or in divided doses throughout the day (the latter being the more common).

[0164] The compounds of the present invention may be administered rectally in the form of a plug. These preparations may be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature, allowing the drug to melt and be expelled in the rectum. Such materials include cocoa butter and polyethylene glycol.

[0165] When applied topically, salves, ointments, gels, solutions or suspensions containing the compounds of the present invention may be used. (For purposes of this application, topical administration is intended to include mouthwashes and gargles.) The above conditions can be effectively treated when administered at a dose of about 0.01-140 mg / kg of body weight per day or about 0.5 mg-7 g per patient per day. For example, the Related Compounds can be effectively treated when administered at a dose of about 0.01-50 mg / kg of body weight per day or about 0.5 mg-3.5 g per patient per day (2.5 mg-1 g per patient per day is recommended).

[0166] When the active ingredient and the carrier material are combined to produce a single dosage form, the dosage will vary depending on the subject to be treated and the particular mode of administration. For example, a formulation for oral administration to humans may contain 0.5 mg to 5 g of active ingredient, which is then mixed with an appropriate dosage amount (approximately 5% to 95% of the total dosage amount) of the 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).

[0167] However, it will be understood that the specific dosage for any particular patient will depend on a number of factors, including age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination and the severity of the particular disease being treated. EXAMPLES

[0168] The compounds of the present invention are antagonists of the PGE2 receptor and are therefore capable of treating diseases or conditions mediated by PGE2.

[0169] The present invention further includes a method for treating cancer using an effective dose of the compound of the present invention or in combination with an effective dose of other drugs, including radiochemotherapeutic drugs, PI3K / AKT pathway inhibitors, endocrine / hormonal drugs, and immunotherapeutic 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, indolylammonium-2,3-bisoxygenase (IDO) inhibitors, tryptophan-2,3-bisoxygenase (TDO) inhibitors, EP1 / EP3 agonists and antimetabolites.

[0170] In other aspects of the invention, the cancer to be treated is independently selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, renal cancer, liver cancer, lung cancer, myeloma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer. In more specific embodiments of the invention, methods of treating cancer and / or generating a memory immune response are provided comprising administration of a compound of the invention.

[0171] synthesis The compounds of the present invention may be prepared by the following synthetic scheme: [ka]

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] Biological activity evaluation 1. The HEK-293 CNG (cyclic nucleotide controlled) cell line expresses modified CNG channels that depolarize the cell membrane in response to elevated cAMP levels in the cell membrane, a depolarization that can be detected using fluorescent membrane potential dyes, and is engineered to express human EP2 (PTGER2) or EP4 (EP4R). The resulting cell line is ACTOne. TM PTGER2 or ACTOne TM EP4R and fluorescent membrane potential dyes were both purchased from eEnzyme Inc. (Gaethersburg, MD, USA) and used for the current detection. Briefly, at the time of detection, cells were cultured at 1.2 x 10 4Cells were seeded at 1000 cells / well (384-well plate, Greiner) in 20 μL of DMEM containing 2% fetal bovine serum (FBS, VWR International), 1x penicillin / streptomycin (GenClone), 0.2 μg / mL purinomicin (InvivoGen) and 50 μg / mL G418 (InvivoGen). The next day, cells were dye-applied at 20 μL / well using 1x dye-applying solution (eENZYME) according to the supplier's instructions. After 2 h of incubation at room temperature (RT) in the dark, cells were pre-read using a CLARIOstar microplate reader (BMG LABTECH, Germany) following the following filter setup to obtain background signals at excitation wavelength = 530 / 20 nm, emission wavelength = 590 / 20 nm. Then, serial dilutions of compounds (along with DMSO control) were added to the well plate (5 μL / well) and incubated at room temperature for 15 min before adding 5 μL PGE2 to each well for a final concentration of 5 nM. The plate is then incubated at room temperature for 30 minutes and a final reading is taken with the same instrument setup. The signal after background subtraction is IC 50 The value is used to calculate the sigma-based ...

[0179] 2. Human EP2 and EP4 report gene test kits are purchased from Cayman Chemical Company (Annenberg, Michigan, USA). Detection is performed according to the provided manual. Briefly, upon reverse transfection, 6.0 x 10 4293T cells (ATCC) were seeded into each well on the provided bar plate, which was coded for a unique transfection complex (containing a DNA construct for expressing human EP2 or EP4) and a secreted alkaline phosphatase (SEAP) reporter gene regulated by a cAMP response element. Each well contained 200μL DMEM supplemented with 2% FBS and incubated at 37℃ and 5% CO2 for 20-24 hours. After incubation, the medium was carefully removed and 150μL pre-warmed serum-free medium was added. PGE2 and detection compounds were simultaneously placed at 4 times the required final concentration, and 50μL was added to each distributed well, so that the final concentration of PGE2 was 13nM (EP2 detection) and 2nM (EP4 detection), respectively. After incubation for 6-8 hours, 10μL medium in each well was transferred to the corresponding well on a new well plate, sealed, and incubated at 65℃ for 30 minutes. After the incubation period, the well plates are cooled to room temperature and 50 μL SEAP substrate is added to each well. The luminescence signal is measured using a CLARIOstar microplate reader.

[0180] Table 1 shows the activity of selected compounds of the present invention in detecting EP2 antagonists. IC 50 Values ​​are the concentration of DMSO for half inhibition (A: IC 50 ≦ 100nM; B:IC 50 is between 100nM and 1000nM; C:IC 50 ≥ 1000nM).

[0181] [Table 1-1] [Table 1-2]

[0182] Table 2 shows the activity of selected compounds of the present invention in detecting EP4 antagonists. IC 50 Values ​​are the concentration of DMSO for half inhibition (A: IC 50 ≦ 100nM; B:IC 50 is between 100nM and 1000nM; C:IC 50≧1000nM.

[0183] [Table 2]

[0184] Abbreviation The following abbreviations have the indicated meanings: EA: ethyl acetate; CIP: 2-chloro-1,3-dimethylimidazolium hexafluorophosphate; DBU: 1,8-diazabicyclo[5.4.0]undeca-7-alkene; DIBAL: diisobutylaluminium hydride; DCM: dichloromethane; DIEA / DIPEA: diisopropylethylamine; DMAP: N,N-dimethylaminopyridyl; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylamide; dmpe: 1,2-bis(dimethyl phosphine)ethane;DMSO: dimethylsulfoxide;dppb: 1,4-bis(diphenylphosphine)butane;dppe: 1,2-bis(diphenylphosphine)ethane;dppf: 1,1'-bis(diphenylphosphine)ferrocene;dppm: 1,1'-bis(diphenylphosphine)methane;DIAD: diisopropyl azodicarboxylate;EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;HATU: hexafluorophosphate Acid 2-(7-azabenzotriazole)-1,1,3,3-tetramethyluronium salt;HMPA: Hexamethylphosphamide;IPA: Isopropyl alcohol;LDA: Diisopropyl lithium amide;LHMDS: Bis(hexamethyldisiloxane) lithium amide;LAH: Lithium aluminum hydride;NCS: N-chlorosuccinimide;PE: Petroleum ether;PyBOP: Benzotriazol-1-yloxytrispyrolylalkylhexafluoro Phosphate salts; 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-methylimidazolyl; NMM: N-methylmorpholinyl; NMP: N-methylpyrrolidine; PPh3: triphenylphosphine; rt / RT: room temperature; sat.: saturated; T3P: propylphosphonic anhydride; TCFH: N,N,N',N'-tetramethylchloroxamidamide hexafluorophosphate; MTBE: methyl t-butyl ether; NBS: N-bromosuccinimide; DMA: N,N-dimethylacetamide; * in structures: R or S chiral center not determined.

[0185] LCMS conditions: Chromatography column: Xtimate C18, 3mm, 4.6 x 50mm. Mobile phase: 0.03% trifluoroacetic acid-water solution and 0.03% trifluoroacetic acid-acetonitrile solution; Gradient: 5% to 95% acetonitrile within 6.5 min; Flow rate: 1 mL / min; Mass spectrometer: Waters UPLC-PDA-3100 (SQD3100) single quadrupole rod mass spectrometer.

[0186] The present invention will be more readily understood with reference to the following examples, which are intended to illustrate the present invention but are not intended to limit its scope.

[0187] Example 1 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka]

[0188] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylate methyl [ka] To a mixture of methyl 5-bromo-1H-indolyl-7-carboxylate (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 ice water and extracted with 3 x 50 mL ethyl acetate. The combined organic layers were washed with 50 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 10:1) to give the target compound (500 mg) as a white solid. LCMS (ES+): 412.20 [M+1] + .

[0189] Step 2: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylic acid [ka] To a solution of the product of step 1 (500 mg, 1.21 mmol) in MeOH / HO (10 mL / 2.0 mL) was added LiOH·HO (254 mg, 6.06 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound (479 mg) as a white solid. LCMS (ESI): 398.22 [M+1] + .

[0190] Step 3: Methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoate [ka] 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) was added DIPEA (0.52 mL, 3.0 mmol) at 0 °C. After stirring at room temperature overnight, the reaction mixture was quenched by adding 100 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 100 mL saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.5 g) as a white solid. LCMS (ESI): 547.29 [M+1] + .

[0191] Step 4: Methyl 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoate [ka] 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 with nitrogen gas for 2 h at 70 °C. After concentrating the reaction mixture, it was purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (27 mg) as a yellow solid. LCMS (ESI): 561.49 [M+1] + .

[0192] Step 5 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] To a solution of the product of step 4 (42 mg, 0.07 mmol) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH·H2O (16 mg, 0.37 mmol). The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the mixture was treated with 6N hydrochloric acid to adjust the pH ≒ 6. Then, the reaction mixture was extracted with 3 x 20 mL ethyl acetate. The combined organic layers were washed with 20 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the target compound (10.1 mg) as a white solid. LCMS (ESI): 547.40 [M+1] + . (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).

[0193] Example 2 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from phenylboronic acid (15 mg) and the product of step 3 of Example 1 (30 mg), the same steps as steps 4 and 5 of Example 1 were carried out to obtain the target product (9 mg) as a white solid. LCMS (ESI): 529.4 [M+1] + . 1H NMR spectrum: (500 MHz, CDCl3) δ: 9.00 (t, J = 6.0 Hz, 1H), 8.23 ​​(s, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.81 - 7.75 (m, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 3.1 Hz, 1H), 7.53 (d, J = 1.7 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 3.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 3.1 Hz, 1H), 5.72 (s, 2H), 4.41 (d, J = 5.8 Hz, 2H).

[0194] Example 3 (R)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (R)-4-(1-aminoethyl)methyl benzoate and the product of step 2 of Example 1 (30 mg), the same steps as steps 3, 4, and 5 of Example 1 were carried out to obtain the target product (19 mg) as a white solid. LCMS (ESI): 561.3 [M+1] + .

[0195] Example 4 (R)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from phenylboronic acid (55 mg), the same procedure as in Example 3 was followed to give the target product (19 mg) as a white solid. LCMS (ES+): 543.4 [M+1] + .

[0196] Example 5 4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)-benzoic acid [ka] Starting from 4-(1-aminocyclopropyl)benzoic acid methyl ester and 4-fluorophenyl)boronic acid (37 mg), the same steps as steps 3, 4, and 5 of Example 1 were carried out to obtain the target product (7.4 mg) as a white solid. MS (ESI): 573.41 [M+1] + . 1 H NMR spectrum: (500 MHz, DMSO-d6) δ: 9.27 (s, 1 H), 8.03 (d, J = 1.8 Hz, 1 H), 7.85 - 7.79 (m, 2 H), 7.77 (d, J = 8.2 Hz, 2 H), 7.62 - 7.58 (m, 3 H), 7.53 (d, J = 3.1 Hz, 1 H), 7.35 - 7.30 (m, 2 H), 7.22 (d, J = 8.2 Hz, 2 H), 6.93 (d, J = 7.9 Hz, 2 H), 6.73 (d, J = 3.1 Hz, 1 H), 5.73 (s, 2 H), 1.20 (q, J = 5.1 Hz, 2 H), 0.95 (q, J = 5.0 Hz, 2 H).

[0197] Example 6 4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from phenylboronic acid (15 mg), the same procedure as in Example 5 was carried out to give the target product (0.85 mg) as a white solid. LCMS (ESI): 555.5 [M+1] + . 1 H NMR spectrum: (500 MHz, DMSO-d6) δ 12.77 (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 = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 1.25 (d, J = 11.7 Hz, 2H), 0.86 (d, J = 7.1 Hz, 2H).

[0198] Example 7 4-((5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-cyanophenyl)boronic acid (15 mg), the same procedure as in Example 1 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 554.3 [M+1] + . 1H NMR (500 MHz, DMSO-d6) δ 8.97 (d, J = 6.1 Hz, 1H), 8.22 (s, 1H), 8.15 - 8.07 (m, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.60 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H).

[0199] Example 8 4-((5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid, the same steps as in Example 1 were carried out to obtain the target product as a white solid. MS(ESI): 565.5 [M+1] + . 1 H NMR spectrum: (500 MHz, DMSO-d6) δ 8.97 (t, J = 5.9 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 7.6, 5.7 Hz, 3H), 7.65 (d, J = 3.1 Hz, 1H), 7.55 - 7.50 (m, 4H), 7.31 - 7.24 (m, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 3.1 Hz, 1H), 5.73 (s, 2H), 4.42 (d, J = 5.8 Hz, 2H) 。

[0200] Example 9 4-((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid (15 mg), the same procedure as in Example 1 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + . 1 H NMR spectrum::(500 MHz, CDCl3) δ: 12.77 (s, 1 H), 8.97 (t, J = 5.9 Hz, 1 H), 8.13 (d, J = 1.9 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 3.2 Hz, 1 H), 7.59 (d, J = 1.9 Hz, 1 H), 7.52 (t, J = 9.0 Hz, 4 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.18 (tt, J = 9.2, 2.4 Hz, 1 H), 6.97 (d, J = 8.0 Hz, 2 H), 6.75 (d, J = 3.2 Hz, 1 H), 5.74 (s, 2 H), 4.44 (d, J = 5.8 Hz, 2 H).

[0201] Example 10 4-((1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid, the same steps as in Example 1 were carried out to obtain the target product as a white solid. MS(ESI): 597.5 [M+1] + . 1H NMR spectrum: (500 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.02 (t, J = 6.0 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.72 - 7.68 (m, 2H), 7.66 (d, J = 3.3 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H).

[0202] Example 11 4-((5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (15 mg), the same procedure as in Example 1 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 615.4 [M+1] + . 1H NMR (500 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.00 (t, J = 6.0 Hz, 1H), 8.20 (s, 1H), 7.96 (d, J = 10.0 Hz, 2H), 7.83 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 3.3 Hz, 1H), 7.63 (d, J = 9.6 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 7.9 Hz, 2H), 6.77 (d, J = 3.1 Hz, 1H), 5.75 (d, J = 4.3 Hz, 2H), 4.45 (d, J = 5.8 Hz, 2H).

[0203] Example 12 (R)-4-(1-(5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-cyanophenyl)boronic acid (39 mg), the same procedure as in Example 3 was followed to give the target product (11 mg) as a white solid. LCMS (ESI): 568.4 [M+1] + .

[0204] Example 13 (R)-4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid (15 mg) and the product of step 3 of example 1 (20 mg), the same procedure as in example 3 was carried out to obtain the target product (25 mg) as a white solid. LCMS (ES+): 579.4 [M+1] + .

[0205] Example 14 (R)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid (42 mg), the same procedure as in Example 3 was followed to give the target product (15 mg) as a white solid. LCMS (ESI): 579.4 [M+1] + .

[0206] Example 15 (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid (51 mg), the same procedure as in Example 3 was followed to give the target product (12 mg) as a white solid. LCMS (ESI): 611.4 [M+1] + .

[0207] Example 16 (R)-4-(1-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (15 mg) and the product of step 3 of Example 1 (20 mg), the same steps as steps 4 and 5 of Example 3 were carried out to obtain the target product (25 mg) as a white solid. LCMS (ES+): 629.2 [M+1] + .

[0208] Example 17 4-(1-(5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3-cyanophenyl)boronic acid (15 mg), the same procedure as in Example 5 was carried out to give the target product (0.85 mg) as a white solid. LCMS (ESI): 580.5 [M+1] + .

[0209] Example 18 4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid (15 mg), the same procedure as in Example 5 was followed to give the target product (0.85 mg) as a white solid. LCMS (ESI): 591.5 [M+1] + .

[0210] Example 19 4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid (15 mg), the same procedure as in Example 5 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 591.4 [M+1] + . 1H NMR (500 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.26 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 1.9 Hz, 1H), 7.62 - 7.55 (m, 6H), 7.23 (d, J = 8.4 Hz, 3H), 6.93 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.75 (s, 2H), 1.22 (t, J = 3.6 Hz, 2H), 0.99 (q, J = 5.0 Hz, 2H).

[0211] Example 20 4-(1-(1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid (15 mg), the same procedure as in Example 5 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 623.4 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.30 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 8.2 Hz, 2H), 7.79 - 7.68 (m, 5H), 7.60 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 3.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 3.1 Hz, 1H), 5.75 (s, 2H), 1.23 - 1.20 (m, 2H), 0.97 (q, J = 5.1 Hz, 2H).

[0212] Example 21 4-(1-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (15 mg), the same procedure as in Example 5 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 641.4 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.20 (s, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.75 (d, J = 7.9 Hz, 2H), 7.70 - 7.64 (m, 2H), 7.61 - 7.58 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 6.77 (d, J = 3.1 Hz, 1H), 5.73 (s, 2H), 1.15 (q, J = 5.0 Hz, 2H), 0.91 (t, J = 3.6Hz, 2H).

[0213] Example 22 4-((4-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-bromo-1H-indolyl-7-methyl carboxylate and (3-cyanophenyl)boronic acid, the same steps as steps 1, 2, 3, 4, and 5 of Example 1 were carried out to obtain the target product (2.8 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0214] Example 23 4-((4-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (4-fluorophenyl)boronic acid (30 mg), the same procedure as in Example 22 was followed to give the target product (28.8 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0215] Example 24 4-((1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid (95 mg), the same procedure as in Example 22 was carried out to give the target product (28.8 mg) as a white solid. LCMS(ESI):597.41 [M+1] + .

[0216] Example 25 4-((4-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (4-fluorophenyl)boronic acid (15 mg), the same procedure as in Example 22 was carried out to give the target product (0.85 mg) as a white solid. LCMS (ESI): 547.5 [M+1] + .

[0217] Example 26 4-((4-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from phenylboronic acid, the same procedure as in Example 22 was used to give the target product (14.6 mg) as a white solid. LCMS (ESI): 529.41 [M+1] + .

[0218] Example 27 4-((4-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid (43 mg), the same procedure as in Example 22 was carried out to give the target product (21 mg) as a white solid. LCMS (ESI): 565.4 [M+1] + .

[0219] Example 28 4-((4-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (104 mg), the same procedure as in Example 22 was followed to give the target product (37.3 mg) as a white solid. LCMS (ESI): 615.35 [M+1] + .

[0220] Example 29 (R)-4-(1-(4-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-bromo-1H-indolyl-7-carboxylate, (R)-4-(1-aminoethyl)methyl benzoate and phenylboronic acid, the same steps as steps 1, 2, 3, 4 and 5 of Example 1 were carried out to obtain the target product as a white solid. LCMS (ESI): 543.3 [M+1] + .

[0221] Example 30 (R)-4-(1-(4-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-cyanophenyl)boronic acid (39 mg), the same procedure as in Example 29 was carried out to give the target product (23 mg) as a white solid. LCMS (ESI): 568.4 [M+1] + .

[0222] Example 31 (R)-4-(1-(4-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid (15 mg) and the product of step 3 of example 1 (20 mg), the same procedure as in example 29 was carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 579.4 [M+1] + .

[0223] Example 32 (R)-4-(1-(4-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid (15 mg), the same procedure as in Example 29 was carried out to give the target product (21 mg) as a white solid. LCMS (ESI): 579.3 [M+1] + .

[0224] Example 33 (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid (51 mg), the same procedure as in Example 29 was carried out to give the target product (23 mg) as a white solid. LCMS (ESI): 611.4 [M+1] + .

[0225] Example 34 (R)-4-(1-(4-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (15 mg) and the product of step 3 of example 1 (20 mg), the same procedure as in example 29 was carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 629.5 [M+1] + .

[0226] Example 35 (R)-4-(1-(4-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (4-fluorophenyl)boronic acid (63 mg), the same procedure as in Example 29 was performed to give the target product (7.5 mg) as a white solid. LCMS(ESI):561.32 [M+1] + .

[0227] Example 36 4-(1-(4-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from methyl 4-bromo-1H-indolyl-7-carboxylate, methyl 4-(1-aminocyclopropyl)benzoate and phenylboronic acid, the same steps as steps 1, 2, 3, 4 and 5 of Example 1 were carried out to obtain the target product as a white solid. LCMS (ESI): 555.3 [M+1] + .

[0228] Example 37 4-(1-(4-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3-cyanophenyl)boronic acid (15 mg), the same procedure as in Example 36 was carried out to give the target product (7.8 mg) as a white solid. LCMS (ESI): 580.3 [M+1] + .

[0229] Example 38 4-(1-(4-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid, the same steps as in Example 36 were carried out to give the target product as a white solid. LCMS (ESI): 591.5 [M+1] + .

[0230] Example 39 4-(1-(4-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid (15 mg), the same procedure as in Example 36 was carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 591.2 [M+1] + .

[0231] Example 40 4-(1-(1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid, the target product was obtained as a white solid by the same steps as in steps 3, 4, and 5 of Example 36. LCMS (ESI): 623.5 [M+1] + .

[0232] Example 41 4-(1-(4-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid, the same steps as in Example 36 were carried out to give the target product as a white solid. LCMS (ESI): 641.5 [M+1] + .

[0233] Example 42 4-(1-(4-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)-benzoic acid [ka] Starting from (4-fluorophenyl)boronic acid (61.3 mg), the same procedure as in Example 36 was carried out to give the target product (13.7 mg) as a white solid. LCMS (ESI): 573.35 [M+1] + .

[0234] Example 43 4-((5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka]

[0235] Step 1 4-(1-(5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] A mixture of methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoate (30 mg, 0.06 mmol), aniline (30 mg, 0.36 mmol), 4,5-bisdiphenylphosphine-9,9-dimethoxyanthracene (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 with nitrogen gas for 16 hours at 120 °C. The reaction mixture was concentrated and then purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (2.0 mg) as a yellow solid. LCMS (ESI): 584.3 [M+1] + .

[0236] Step 2 4-(1-(5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] The target product was obtained as a white solid in the same manner as in Step 5 of Example 1. LCMS(ESI):570.3 [M+1] + .

[0237] Example 44 4-(1-(4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 4-(1-aminocyclopropyl)benzoic acid methyl ester, 4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylic acid and aniline (65 mg), the same procedure as in Example 43 was followed to give the target product (22 mg) as a white solid. LCMS (ES+): 570.4 [M+1] + . 1H NMR spectrum: (500MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.31 (s, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.59 (d, J = 8.1Hz, 2H), 7.39 - 7.35 (m, 1H), 7.34 - 7.25 (m, 4H), 7.16 (d, J = 8.2Hz, 2H), 6.96 - 6.86 (m, 5H), 5.74 (s, 2H), 1.20 - 1.15 (m, 2H), 0.98 - 0.94 (m, 2H) 。

[0238] Example 45 4-((5-(methyl(phenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from N-methylaniline (15 mg) and the product of step 3 of example 1 (20 mg), the same procedure as in example 43 was carried out to give the target product (5 mg) as a white solid. LCMS (ES+): 558.3 ​​[M+1] + . 1H NMR spectrum: (500 MHz, 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 = 2.1 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 5.66 (s, 2H), 4.35 (d, J = 5.7 Hz, 2H), 3.28 (s, 3H).

[0239] Example 46 4-(1-(4-(methyl(phenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from N-methylaniline (15 mg) and the product of step 3 of example 1 (20 mg), the same procedure as in example 43 was carried out to give the target product (25 mg) as a white solid. LCMS (ES+): 584.5 [M+1] + . 1H NMR spectrum: (500 MHz, DMSO-d6) δ: 12.79 (s, 1H), 9.13 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H), 7.21 (dt, J = 7.8, 3.6 Hz, 4H), 6.95 (dd, J = 7.9, 2.0 Hz, 3H), 6.85 - 6.82 (m, 2H), 6.06 (d, J = 3.3 Hz, 1H), 5.69 (s, 2H), 5.33 (t, J = 5.0 Hz, 1H), 3.41 (s, 3H), 0.96 - 0.83 (m, 4H).

[0240] Example 47 4-((5-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from aniline (15 mg) and the product of step 3 of example 1 (20 mg), the same procedure as in example 43 was carried out to give the target product (17 mg) as a white solid. LCMS (ES+): 544.4 [M+1] + . 1H NMR spectrum: (500 MHz, DMSO-d6) δ: 12.87 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 7.97 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 3.2 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.8 Hz, 2H), 7.07 - 6.99 (m, 4H), 6.73 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 3.1 Hz, 1H), 5.60 (s, 2H), 4.34 (d, J = 6.0 Hz, 2H).

[0241] Example 48 4-(1-(4-(methyl(phenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from N-methylaniline (15 mg), the same procedure as in Example 43 was carried out to give the target product (0.85 mg) as a white solid. LCMS (ESI): 598.6 [M+1] + .

[0242] Example 49 4-(1-(5-phenoxy-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] A mixture of methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-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 stirred with nitrogen gas for 16 hours at 120 °C. 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] + .

[0243] Example 50 (S)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (S)-methyl 4-(1-aminoethyl)benzoate and the product of step 2 of Example 1, the target product was obtained as a white solid in the same manner as steps 3, 4, and 5 of Example 1. LCMS (ESI): 561.3 [M+1] + .

[0244] Example 51 (S)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (S)-4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)methyl benzoate (30 mg) and phenylboronic acid, 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] + .

[0245] Example 52 (S)-4-(1-(5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (S)-4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)methyl benzoate (30 mg) and (3-cyanophenyl)boronic acid, 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] + .

[0246] Example 53 (S-4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (S)-4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)methyl benzoate (30 mg) and (3,4-difluorophenyl)boronic acid, 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] + . 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.88 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.87 - 7.79 (m, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.53 - 7.45 (m, 3H), 7.44 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.1 Hz, 1H), 5.66 (s, 2H), 5.06 (p, J = 7.2 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H).

[0247] Example 54 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid, the same steps as in Example 50 were carried out to give the target product as a white solid. LCMS (ESI): 579.4 [M+1] + .

[0248] Example 55 (S)-4-(1-(1-(4-(trifluoromethyl)benzyl)-5-(3-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-(trifluoromethyl)phenyl)boronic acid, the same steps as in Example 50 were carried out to give the target product as a white solid. LCMS (ESI): 611.4 [M+1] + .

[0249] Example 56 (S)-4-(1-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid, the same steps as in Example 50 were carried out to give the target product as a white solid. LCMS (ES+): 629.2 [M+1] + .

[0250] Example 57 4-((4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka]

[0251] Step 1: Methyl 4-((4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoate [ka] A mixture of methyl 4-(1-(5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoate (30 mg), aniline (30 mg), 4,5-bisdiphenylphosphine-9,9-dimethoxyanthracene (6.2 mg), Pd2(dba)3 (3.2 mg), Cs2CO3 (60 mg) and 1,4-dioxane (5 mL) was stirred with nitrogen gas for 3 hours at 110°C. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (22.0 mg) as a yellow solid. LCMS (ESI): 558.3 ​​[M+1] + .

[0252] Step 2 4-((4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] The target product (12.0 mg) was obtained as a white solid by the same procedure as in step 5 of Example 1. LCMS (ESI): 544.2 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.70 (t, J = 6.1 Hz, 1H), 8.29 (s, 1H), 7.86 - 7.81 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 3.3 Hz, 1H), 7.34 - 7.27 (m, 4H), 7.27 - 7.22 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.93 (tt, J = 7.3, 1.3 Hz, 1H), 6.89 (d, J = 3.2 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.72 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H).

[0253] Example 58 4-((4-morpholinyl-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-((4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoate (30 mg) and morpholinyl, 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] + .

[0254] Example 59 4-((4-(4-Methylpiperazin-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-((4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido) methyl)benzoate (30 mg) and 1-methylpiperazine, the same procedure as in Example 01 was followed to give the target product (12 mg) as a white solid. LCMS (ESI): 551.2 [M+1] + .

[0255] Example 60 (R)-4-(1-(4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from (R)-4-(1-(4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)methyl benzoate (30 mg) and aniline, the same procedure as in Example 01 was followed to give the target product (14 mg) as a white solid. LCMS (ESI): 558.3 ​​[M+1] + .

[0256] Example 61 4-(1-(4-((3-cyanophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 3-aminobenzonitrile (40 mg), the same procedure as in Example 44 was carried out to give the target product (14 mg) as a white solid. LCMS (ES+): 595.5 [M+1] + .

[0257] Example 62 4-(1-(4-((4-cyanophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 4-aminobenzonitrile (40 mg), the same procedure as in Example 44 was carried out to give the target product (16 mg) as a white solid. LCMS (ES+): 595.5 [M+1] + .

[0258] Example 63 4-(1-(4-((3,4-difluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropylbenzoic acid [ka] Starting from 3,4-difluoroaniline (40 mg), the same procedure as in Example 44 was carried out to give the target product (17 mg) as a white solid. LCMS(ES+):606.4 [M+1] + .

[0259] Example 64 4-(1-(4-((4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka]

[0260] Step 1: 4-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylate methyl [ka] To a mixture of methyl 4-bromo-1H-indolyl-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 ice water and extracted with 3 x 50 mL ethyl acetate. The combined organic layers were washed with 50 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 10:1) to give the target compound (500 mg) as a white solid. LCMS (ESI): 412.2 [M+1] + .

[0261] Step 2: 4-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylic acid [ka] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2.0 mL) at room temperature, LiOH·H2O (254 mg) was added. The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound (479 mg) as a white solid. LCMS (ESI): 398.2 [M+1] + .

[0262] Step 3: Methyl 4-(1-(4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoate [ka] 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) was added DIPEA (0.52 mL, 3.0 mmol) at 0 °C. After stirring at room temperature overnight, the reaction mixture was quenched by adding 100 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 100 mL saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.5 g) as a white solid. LCMS (ESI): 571.1 [M+1] + .

[0263] Step 4 4-(1-(4-((4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] A mixture of methyl 4-(1-(4-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoate (30 mg, 0.06 mmol), 4-fluoroaniline (30 mg, 0.36 mmol), 4,5-bisdiphenylphosphine-9,9-dimethoxyanthracene (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 with nitrogen gas for 16 hours at 120 °C. The reaction mixture was concentrated and then purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (2.0 mg) as a yellow solid. LCMS (ESI): 602.3 [M+1] + .

[0264] Step 5 4-(1-(4-((4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] To a solution of the product of step 4 (42 mg) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH·H2O (16 mg). The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the mixture was treated with 6N hydrochloric acid until pH ≒ 6. Then, the reaction mixture was extracted with 3 x 20 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the target compound (12.1 mg) as a white solid. LCMS (ESI): 588.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 8.91 (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).

[0265] Example 65 4-(1-(4-((3-chloro-4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 3-chloro-4-fluoroaniline (70 mg), the same procedure as in Example 64 was carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 622.1 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.45 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 3.2 Hz, 1H), 7.36 - 7.30 (m, 3H), 7.24 - 7.16 (m, 3H), 6.97 - 6.92 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 3.2 Hz, 1H), 5.74 (s, 2H), 1.21 - 1.15 (m, 2H), 0.99 - 0.93 (m, 2H).

[0266] Example 66 4-(1-(4-((3,5-difluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 3,5-difluoroaniline (40 mg), the same procedure as in Example 64 was carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 606.3[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.79 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.60 (s, 1H), 7.44 (d, J = 3.3 Hz, 1H), 7.37 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 7.9 Hz, 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).

[0267] Example 67 4-(1-(4-((3-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 3-fluoroaniline (40 mg), the same procedure as in Example 64 was carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 588.47[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.54 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 3.4 Hz, 1H), 7.34(d, J = 8.0 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.08 - 7.05 (m, 1H), 7.01 - 6.92 (m, 4H), 6.84 (d, J = 3.2 Hz, 1H), 6.70 - 6.66 (m, 1H), 5.75 (d, J = 9.2 Hz, 2H), 1.20 - 1.14 (m, 2H), 0.98 - 0.94 (m, 2H).

[0268] Example 68 4-((4-((3-cyanophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-aminobenzonitrile and methyl 4-(aminomethyl)benzoate hydrochloride, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 569.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.76 (t, J = 5.9 Hz, 1H), 8.65 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.55 - 7.42 (m, 6H), 7.31 - 7.21 (m, 4H), 7.01 - 6.97 (m, 3H), 6.78 (d, J = 3.2 Hz, 1H), 5.71 (s, 2H), 4.41-4.35 (m, 2H).

[0269] Example 69 4-((4-((3,5-difluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3,5-difluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride, the same steps as in Example 64 were carried out to give the target product as a white solid. LCMS (ESI): 580.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 6.0 Hz, 1H), 8.74 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.55 - 7.50 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.9 Hz, 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).

[0270] Example 70 4-(1-(4-((3-chloro-4-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 3-chloro-4-fluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride, the same steps as in Example 64 were carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 596.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.02 - 7.97 (m, 2H), 7.47 (d, J = 8.0 Hz, 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 = 8.0 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 5.89 (t, J = 5.8 Hz, 1H), 5.72 (s, 2H), 4.43-4.38 (m, 2H).

[0271] Example 71 ((4-((4-chloro-3-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-chloro-3-fluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 596.4 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 6.0 Hz, 1H), 8.63 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 3.3 Hz, 1H), 7.41 (t, J = 8.7 Hz, 1H), 7.24 - 7.15 (m, 3H), 7.04 - 6.98 (m, 1H), 7.01 (dd, J = 8.7, 2.8 Hz, 3H), 6.92 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 3.2 Hz, 1H), 5.70 (s, 2H), 4.33 (d, J = 5.9 Hz, 2H).

[0272] Example 72 4-((4-((3-fluorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-fluoroaniline and methyl 4-(aminomethyl)benzoate hydrochloride, the same steps as in Example 64 were carried out to give the target product as a white solid. LCMS (ESI): 562.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 6.0 Hz, 1H), 8.49 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.28 (dd, J = 7.9, 4.7 Hz, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.1, 2.0 Hz, 1H), 6.99 - 6.90 (m, 4H), 6.81 (d, J = 3.3 Hz, 1H), 6.66 (td, J = 8.5, 2.5 Hz, 1H), 5.70 (s, 2H), 4.37 (d, J = 6.0 Hz, 2H).

[0273] Example 73 ((4-((4-chlorophenyl)amino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-chloroaniline and methyl 4-(aminomethyl)benzoate hydrochloride, the same steps as in Example 64 were carried out to give the target product as a white solid. LCMS (ESI): 578.3 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 6.1 Hz, 1H), 8.40 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 3.3 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 3.6 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.86 - 6.80 (m, 2H), 5.71 (s, 2H), 4.37 (d, J = 6.0 Hz, 2H).

[0274] Example 74 (S)-4-(1-(4-(phenylamino)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from aniline and (S)-4-(1-aminoethyl)benzoic acid methyl ester, the same procedure as in Example 64 was carried out to give the target product as a white solid. LCMS (ESI): 558.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.66 (s, 1 H), 8.60 (d, J = 8.0 Hz, 1 H), 8.26 (s, 1 H), 7.88 - 7.81 (m, 2 H), 7.48 - 7.44 (m, 3 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.29 (dd, J = 8.5, 7.2 Hz, 2 H), 7.24 - 7.21 (m, 2 H), 7.14 (d, J = 8.0 Hz, 1 H), 6.95 - 6.88 (m, 3 H), 6.88 - 6.80 (m, 2 H), 5.65 (s, 2 H), 5.07 - 5.01 (m, 1 H), 1.24-1.22(m, 3 H).

[0275] Example 75 4-((5-(3-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka]

[0276] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylate methyl [ka] To a mixture of methyl 5-bromo-1H-indolyl-7-carboxylate (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 ice water and extracted with 3 x 50 mL ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 10:1) to give the target compound (500 mg) as a white solid. LCMS (ESI): 412.2 [M+1] + .

[0277] Step 2: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylic acid [ka] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2 mL) at room temperature, LiOH·H2O (254 mg) was added. The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid until pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound (479 mg) as a white solid. LCMS (ESI): 398.2 [M+1] + .

[0278] Step 3: Methyl 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoate [ka] 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) was added DIPEA (0.52 mL) at 0 °C. After stirring at room temperature overnight, the reaction mixture was quenched by adding 10 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 10 mL brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.5 g) as a white solid. LCMS (ESI): 545.1 [M+1] + .

[0279] Step 4: Methyl 4-((5-(3-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoate [ka] A mixture of the product of step 3 (30 mg), (3-chlorobenz)boronic acid (38 mg), Pd(dppf)2Cl2 (4 mg) and K2CO3 (38 mg) in EtOH / H2O (5 mL / 1 mL) was stirred with nitrogen gas for 2 h at 70 °C. After concentrating the reaction mixture, it was purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (27 mg) as a yellow solid. LCMS (ESI): 577.2 [M+1] + .

[0280] Step 5 4-((5-(3-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] To a solution of the product of step 4 (42 mg) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH·H2O (16 mg). The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the mixture was treated with 6N hydrochloric acid until pH ≒ 6. Then, the reaction mixture was extracted with 3 x 20 mL ethyl acetate. The combined organic layers were washed with 20 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the target compound (10.1 mg) as a white solid. LCMS (ESI): 577.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.01 (t, J = 5.9 Hz, 1H), 8.08 (d, J = 1.7 Hz, 1H), 7.87 - 7.77 (m, 3H), 7.72 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 3.1 Hz, 1H), 7.58 - 7.44 (m, 4H), 7.40 (dd, J = 7.9, 2.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H).

[0281] Example 76 4-((5-(3-Methoxyphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-methoxyphenylboronic acid, the same procedure as in Example 75 was carried out to give the target product (9 mg) as a white solid. LCMS (ESI): 559.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.02 (t, J = 5.9 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.56 - 7.51 (m, 3H), 7.38 (t, J = 7.9 Hz, 1H), 7.33 - 7.25 (m, 4H), 6.98 (d, J = 8.1 Hz, 2H), 6.91 (dd, J = 8.2, 2.5 Hz, 1H), 6.74 (d, J = 3.1 Hz, 1H), 5.73 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H).

[0282] Example 77 ((5-(3-cyano-5-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-cyano-5-fluorophenyl)boronic acid (98 mg), the same procedure as in Example 75 was carried out to give the target product (20 mg) as a white solid. LCMS (ESI): 572.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 5.9 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.05-8.01 (m, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.83 - 7.78 (m, 1H), 7.69 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 3.2 Hz, 1H), 5.76 (s, 2H), 4.46 (d, J = 5.8 Hz, 2H).

[0283] Example 78 4-((5-(pyridyl-3-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from pyridyl-3-boronic acid, the same steps as in Example 75 were carried out to give the target product (10 mg) as a white solid. LCMS (ESI): 530.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.00 (t, J = 5.9 Hz, 1H), 8.97 (d, J = 2.3 Hz, 1H), 8.55 (dd, J = 4.7, 1.6 Hz, 1H), 8.19 - 8.08 (m, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.0, 4.7 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 3.2 Hz, 1H), 5.74 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H).

[0284] Example 79 4-((5-(3-cyano-4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-cyano-4-fluorophenyl)boronic acid (98 mg), the same procedure as in Example 75 was carried out to give the target product (20 mg) as a white solid. LCMS (ESI): 572.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 5.9 Hz, 1H), 8.30-8.28 (m, 1H), 8.16-8.13 (m, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 3.2 Hz, 1H), 7.63 (t, J = 9.0 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 3.2 Hz, 1H), 5.74 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H).

[0285] Example 80 4-((5-(pyridyl-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from pyridyl-4-boronic acid (79.0 mg), the same procedure as in Example 75 was followed to give the target product (15 mg) as a white solid. LCMS (ESI): 530.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.03 (t, J = 6.0 Hz, 1H), 8.68 - 8.60 (m, 2H), 8.22 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.80 - 7.75 (m, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H).

[0286] Example 81 4-((5-(4-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (4-cyanophenyl)boronic acid (48.0 mg), the same procedure as in Example 75 was carried out to give the target product (22 mg) as a white solid. LCMS (ESI): 554.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.02 (t, J = 5.9 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 3.2 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 3.2 Hz, 1H), 5.74 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H).

[0287] Example 82 4-((5-(3-carbamoylphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-aminocarbonylphenylboronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 572.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.03 (t, J = 5.9 Hz, 1H), 8.25 (t, J = 1.8 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.90 (dd, J = 8.4, 6.5 Hz, 1H), 7.86 - 7.82 (m, 3H), 7.64 (d, J = 3.2 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.58 - 7.51 (m, 3H), 7.42 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 3.2 Hz, 1H), 5.72 (s, 2H), 4.44 (d, J = 5.9 Hz, 2H).

[0288] Example 83 4-((5-(3-sulfamoylphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 608.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.07 (t, J = 5.9 Hz, 1H), 8.19 (t, J = 1.8 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.97 (dt, J = 7.8, 1.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.79 (dt, J = 7.8, 1.4 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.60 - 7.51 (m, 3H), 7.41 (s, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 3.2 Hz, 1H), 5.72 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H).

[0289] Example 84 4-((5-(3-(methanesulfonyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-(methanesulfonyl)phenylboronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. MS(ESI): 607.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.92 - 7.86 (m, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 3.2 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 3.1 Hz, 1H), 5.73 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H), 3.31 (s, 3H).

[0290] Example 85 4-((5-(3-(2-hydroxylpropan-2-yl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 3-(2-hydroxypropyl-2-yl)phenylboronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 587.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.87 - 7.79 (m, 3H), 7.63 (d, J = 3.2 Hz, 1H), 7.57 - 7.52 (m, 4H), 7.44 (dt, J = 7.7, 1.5 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.72 (s, 2H), 5.07 (s, 1H), 4.43 (d, J = 5.9 Hz, 2H), 1.50 (s, 6H).

[0291] Example 86 4-((5-(2-hydroxyphenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-hydroxylphenylboronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 545.2 [M+1] + . 1 HNMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.9, 6.1 Hz, 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 = 7.6 Hz, 2H), 6.98 - 6.89 (m, 2H), 6.69 - 6.64 (m, 1H), 5.68 (d, J = 5.2 Hz, 2H), 4.37 (d, J = 5.7 Hz, 2H).

[0292] Example 87 4-((5-(2-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-fluorophenylboronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. MS(ESI): 547.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.97 (t, J = 5.9 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.65 (dd, J = 5.7, 2.4 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.43 - 7.37 (m, 2H), 7.35-7.30(m, 4H), 7.01 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 3.2 Hz, 1H), 5.72 (s, 2H), 4.40 (d, J = 5.9 Hz, 2H).

[0293] Example 88 4-((5-(3,5-dichlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3,5-dichlorophenyl)boronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 599.3 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 7.88 - 7.78 (m, 4H), 7.66 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.56 - 7.47 (m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.75 (s, 2H), 4.45 (d, J = 5.9 Hz, 2H).

[0294] Example 89 4-((1-(4-(trifluoromethyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (2-(trifluoromethyl)phenyl)boronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 597.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (t, J = 6.0 Hz, 1H), 7.86 - 7.82 (m, 3H), 7.74 -7.69 (m, 2H), 7.66 (d, J = 3.2 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.1Hz, 1H), 5.72 (s, 2H), 4.38 (d, J = 5.9 Hz, 2H).

[0295] Example 90 4-((5-(2-chlorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (2-chlorobenz)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 563.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.0 Hz, 1H), 7.90 - 7.76 (m, 3H), 7.66 (d, J = 3.2 Hz, 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 = 8.0 Hz, 2H), 6.74 (d, J = 3.1 Hz, 1H), 5.72 (s, 2H), 4.40 (d, J = 5.8 Hz, 2H).

[0296] Example 91 4-((5-(4-chloro-3-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (4-chloro-3-fluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 581.4 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.99 (t, J = 6.0 Hz, 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 = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H).

[0297] Example 92 4-((5-(o-tolyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from o-tolyl boronic acid (45 mg), the same procedure as in Example 75 was carried out to give the target product (40 mg) as a white solid. LCMS (ESI): 543.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.34 - 7.23 (m, 6H), 7.20 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 3.2 Hz, 1H), 5.72 (s, 2H), 4.39 (d, J = 5.9 Hz, 2H), 2.29 (s, 3H).

[0298] Example 93 4-((5-(2-aminophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (2-aminophenyl)boronic acid (45 mg), the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 544.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.0 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.34 - 7.25 (m, 3H), 7.08-7.02 (m, 7.6, 1.6 Hz, 4H), 6.76 (d, J = 8.0, 1H), 6.70 (d, J = 3.1 Hz, 1H), 6.64 (t, J = 7.4, 1.2 Hz, 1H), 5.72 (s, 2H), 4.88 (brs, 2H), 4.39 (d, J = 5.9 Hz, 2H).

[0299] Example 94 4-((5-(3-chloro-4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-chloro-4-fluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 581.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 6.0 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.95 (dd, J = 7.1, 2.4 Hz, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.76-7.73 (m, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.54-7.49 (m, 4H), 7.29 (d, J = 7.7 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 3.2 Hz, 1H), 5.74 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H).

[0300] Example 95 4-((5-(3-chloro-5-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-chloro-5-fluorophenyl)boronic acid (38 mg), the same procedure as in Example 75 was carried out to give the target product (12 mg) as a white solid. LCMS (ESI): 581.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.97 (t, J = 5.9 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 1.7 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 10.1, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.6, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.2 Hz, 1H), 5.75 (s, 2H), 4.45 (d, J = 5.8 Hz, 2H).

[0301] Example 96 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka]

[0302] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-carboxylate methyl [ka] To a mixture of methyl 5-bromo-1H-indolyl-7-carboxylate (5.0 g) and Cs2CO3 (21.5 g) in anhydrous DMF (100 mL) at 0° C., 1-(bromomethyl)-4-(trifluoromethyl)benzene (5.7 g) was added. The reaction mixture was then heated to room temperature and stirred for 6 h. The reaction mixture was poured into 100 mL ice water and extracted with 3 x 50 mL ethyl acetate. The reaction mixture was then poured into aqueous NH4Cl.

[0303] Filter, collect the solid, dry, and dissolve in EA / PE (60 / 180 mL). Filter the solution through diatomaceous earth and concentrate to give the target product (crude, 5.1 g) as a white solid. LCMS (ESI): 413 [M+1] + .

[0304] Filtration, collection of the solid, drying, and purification by silica gel column chromatography (EA / PE ratio 1 / 3) gave the target product isomer 1 (5.1 g) and isomer 2 as a white solid. LCMS (ES+): 413 [M+1] + .

[0305] Isomer 1: R f =0.5 (EA / PE=1 / 5). 1 H NMR (400 MHz, CDCl3) δ 8.19 - 8.03 (m, 2H), 7.99 (d, 1H), 7.49 (d, 2H), 7.08 (d, 2H), 6.06 (s, 2H), 3.82 (s, 3H). [ka] Isomer 2: R f =0.2 (EA / PE=1 / 5). 1 H NMR (400 MHz, CDCl3) δ 8.15 (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). Step 2 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from the product of step 1 and 4-fluorophenylboronic acid, the target product was obtained as a white solid in the same manner as in steps 2 and 5 of Example 75. LCMS (ESI): 548 [M+1] + . 1 HNMR (400 MHz, CDCl3) δ 8.21 (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).

[0306] Example 97 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from phenylboronic acid, the same steps as in Example 96 were carried out to give the target product as a white solid. LCMS (ESI): 530 [M+1] + . 1 HNMR (400 MHz, CDCl3) δ 8.22 (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).

[0307] Example 98 4-((5-(3-cyanophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-cyanophenyl)boronic acid, the same steps as in Example 96 were carried out to give the target product as a white solid. LCMS (ESI): 555 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.27 (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).

[0308] Example 99 4-((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid, the same procedure as in Example 96 was carried out to give the target product as a white solid. LCMS (ESI): 566 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.25 (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).

[0309] Example 100 (S)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from phenylboronic acid and (S)-4-(1-aminoethyl)benzoic acid methyl ester, the same procedure as in Example 96 was carried out to give the target product as a white solid. LCMS (ESI): 544 [M+1]+ .

[0310] Example 101 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid and (S)-4-(1-aminoethyl)methyl benzoate, the target product was obtained as a white solid in the same manner as in Example 96. LCMS (ESI): 580 [M+1] + .

[0311] Example 102 4-((1-(3-chlorobenzyl)-5-(3-cyanophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz and (3-cyanophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 622.12 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 5.9 Hz, 1H), 8.22 (s, 1H), 8.17 - 8.05 (m, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.7 Hz, 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 = 5.6 Hz, 2H).

[0312] Example 103 4-((1-(3-chlorobenzyl)-4-(phenylamino)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz (70 mg) and aniline (70 mg), the same procedure as in Example 64 was carried out to give the target product (25 mg) as a white solid. LCMS (ESI): 510.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.76 (t, J = 6.0 Hz, 1H), 8.25 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 3.2 Hz, 1H), 7.32 - 7.18 (m, 9H), 6.91 (t, J = 7.2 Hz, 1H), 6.89 - 6.85 (m, 2H), 6.81 (dd, J = 12.3, 7.7 Hz, 2H), 5.61 (s, 2H), 4.42 (d, J = 5.9 Hz, 2H).

[0313] Example 104 4-((1-(3-chlorobenzyl)-5-(pyridyl-3-yl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz and pyridyl-3-boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 596.2 [M+1] + . 1H NMR (400MHz, DMSO-d6)δ 12.85(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 = 8.0Hz, 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, J = 3.2Hz, 1H), 5.64(s, 2H), 4.48(d, J = 5.8Hz, 2H).

[0314] Example 105 4-((1-(3-chlorobenzyl)-5-phenyl-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz and phenylboronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. MS (ESI): 595.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 13.32 - 12.42 (brs, 1H), 9.09 (d, J = 7.1 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.9 Hz, 3H), 7.29 - 7.23 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.63 (d, J = 7.6 Hz, 2H), 4.48 (t, J = 6.4 Hz, 2H).

[0315] Example 106 4-((1-(3-chlorobenzyl)-5-(3,5-difluorophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz and (3,5-difluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 531.1 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.29 - 7.22 (m, 2H), 7.19 (tt, J = 9.2, 2.3 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 3.1 Hz, 1H), 5.64 (s, 2H), 4.48 (d, J = 5.8 Hz, 2H).

[0316] Example 107 4-((1-(3-chlorobenzyl)-5-(4-fluorophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz and (4-fluorophenyl)boronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 513.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.81 - 7.74 (m, 2H), 7.62 (d, J = 3.2 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.34 (s, 1H), 7.35 - 7.25 (m, 4H), 7.24 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 5.63 (s, 2H), 4.47 (d, J = 5.9 Hz, 2H).

[0317] Example 108 (S)-4-(1-(1-(3-chlorobenzyl)-5-(3-cyanophenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz, (3-cyanophenyl)boronic acid and (S)-4-(1-aminoethyl)benzoic acid methyl ester, the same procedure as in Example 75 was followed to give the target product (26 mg) as a white solid. LCMS (ESI): 534.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.00 (d, J = 7.6 Hz, 1H), 8.23 ​​(d, J = 1.9 Hz, 1H), 8.16 - 8.04 (m, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.30 - 7.18 (m, 2H), 6.87 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 5.63 - 5.49 (m, 2H), 5.07-5.01 (m, J = 7.1 Hz, 1H).

[0318] Example 109 (S)-4-(1-(1-(3-chlorobenzyl)-5-(pyridyl-3-yl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz, (S)-methyl 4-(1-aminoethyl)benzoate and pyridyl-3-boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 510.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.03 - 8.97 (m, 2H), 8.56 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.29 - 7.24 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 3.1 Hz, 1H), 5.65 - 5.47 (m, 2H), 5.12-5.06 (m, J = 7.2 Hz, 1H).

[0319] Example 110 (S)-4-(1-(1-(3-chlorobenzyl)-5-phenyl-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz, (S)-methyl 4-(1-aminoethyl)benzoate and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 509.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.03 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.78 - 7.71 (m, 2H), 7.60 (d, J = 3.2 Hz, 1H), 7.54 - 7.43 (m, 5H), 7.35 (t, J = 7.4 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 3.1 Hz, 1H), 5.65 - 5.47 (m, 2H), 5.12-5.06 (m, J = 7.2 Hz, 1H).

[0320] Example 111 (S)-4-(1-(1-(3-chlorobenzyl)-5-(3,5-difluorophenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz, (S)-methyl 4-(1-aminoethyl)benzoate and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 545.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.57 - 7.49 (m, 3H), 7.46 (d, J = 8.2 Hz, 2H), 7.29 - 7.25 (m, 1H), 7.24 - 7.17 (m, 2H), 6.86 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 3.1 Hz, 1H), 5.63 - 5.51 (m, 2H), 5.11-5.06 (m, 1H).

[0321] Example 112 (±) 6-(6-bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)spiro[3.3]heptane-2-carboxylic acid [ka] Step 1: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-carboxylate methyl [ka] A mixture of methyl 6-bromo-1H-indolyl-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, and iodine (0.10 mmol, 10 mol%) was added. The reaction mixture was stirred for 1 h, 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 (eluting with petroleum ether / ethyl acetate) to give the product (1.59 g) as a pale yellow solid. LCMS (ESI): 430.2 [M+1]+ .

[0322] Step 2: 6-Bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-carboxylic acid [ka] 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 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid until pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound (480 mg) as a white solid. LCMS (ESI): 416 [M+1] + .

[0323] Step 3 (±) 6-Aminospiro[3.3]heptane-2-carboxylate methyl ester hydrochloride [ka] To a solution of methyl 6-(6-((t-butoxycarbonyl)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 (no further purification was necessary) to give the target compound (0.52 g) as a white solid. LCMS (ESI): 170 [M+1] + .

[0324] Step 4 (±) 6-(6-bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)spiro[3.3]heptane-2-carboxylate methyl [ka] 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) was added DIPEA (0.52 mL) at 0 °C. After stirring overnight at room temperature, the reaction mixture was quenched by adding 100 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 100 mL saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.52 g) as a white solid. LCMS (ESI): 567 [M+1] + .

[0325] Step 5 (±) 6-(6-bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)spiro-[3.3]heptane-2-carboxylic acid [ka] To a solution of the product of step 4 (57 mg) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH·H2O (20 mg). The reaction mixture was stirred at 40 °C for 12 h. After cooling to 0 °C, the mixture was treated with 6N hydrochloric acid until pH ≒ 6. Then, the reaction mixture was extracted with 3 x 20 mL ethyl acetate. The combined organic layers were washed with 20 mL saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the target compound (40 mg) as a white solid. LCMS (ESI): 553.2 [M+1] + . 1H NMR (400MHz, DMSO-d6)δ 12.12(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).

[0326] Example 113 (±) 6-(6-phenyl-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)spiro[3.3]heptane-2-carboxylic acid [ka] Starting from phenylboronic acid and Example 112, the same steps as Steps 4 and 5 of Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 551 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.21 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.7 Hz, 4H), 7.37 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 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).

[0327] Example 114 (±) 6-(6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)spiro[3.3]heptane-2-carboxylic acid [ka] Starting from (3-cyanophenyl)boronic acid, the same steps as in Example 113 were carried out to give the target product as a white solid. LCMS (ESI): 576 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.29 - 8.15 (m, 2H), 8.15 - 8.02 (m, 1H), 7.96 - 7.87 (m, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 8.2 Hz, 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).

[0328] Example 115 (±) 6-(6-(3-carbamoylphenyl)-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)spiro[3.3]heptane-2-carboxylic acid [ka] Starting from (3-carbamoylphenyl)boronic acid, the same procedure as in Example 113 was carried out to give the target product as a white solid. LCMS (ESI): 594 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (d, J = 2.9 Hz, 1H), 8.31 - 8.11 (m, 3H), 7.96 - 7.78 (m, 4H), 7.58 (t, J = 7.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 - 7.37 (m, 2H), 7.11 (d, J = 8.2 Hz, 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).

[0329] Example 116 4-((5-(3-(methylcarbamoyl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from (3-(methylcarbamoyl)phenyl)boronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 586.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.37 (s, 1H), 8.23 ​​(s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.92 - 7.82 (m, 3H), 7.72 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 8.2 Hz, 2H), 1.78 (s, 6H), 1.01 (d, J = 6.5 Hz, 4H).

[0330] Example 117 4-((6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)methyl)benzoic acid [ka] Starting from the product of step 2 of Example 112, methyl 4-(aminomethyl)benzoate and (3-cyanophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 572 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.23 (d, J = 2.8 Hz, 1H), 8.73 (t, J = 6.0 Hz, 1H), 8.25 (t, J = 1.8 Hz, 1H), 8.13 - 8.10 (m, 1H), 7.95 - 7.93 (m, 2H), 7.88 - 7.80 (m, 3H), 7.71 (t, J = 7.8 Hz, 1H), 7.54 - 7.48 (m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.36 (d, J = 5.9 Hz, 2H).

[0331] Example 118 2-(3-(6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)bicyclo[1.1.1]pentan-1-yl)acetic acid [ka]

[0332] Step 1 Ethyl 2-(3-aminobicyclo[1.1.1]pentan-1-yl)acetate hydrochloride [ka] To a solution of ethyl 2-(3-((t-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetate (0.70 g) in THF (10 mL) was added 4M hydrochloric acid in dioxane (1 mL). After stirring overnight, the mixture was concentrated (no further purification was necessary) to give the target compound (0.5 g) as a white solid. LCMS (ESI): 170.1 [M+1] + .

[0333] Step 2: 2-(3-(6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)bicyclo[1.1.1]pentan-1-yl)acetic acid [ka] Starting from the product of steps 1 and 2 of Example 112 and (3-cyanophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 562.4 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.53 (s, 1H), 8.23 ​​(d, J = 1.8 Hz, 1H), 8.16 - 8.01 (m, 1H), 7.98 - 7.84 (m, 2H), 7.85 - 7.75 (m, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 2.43 (s, 2H), 1.82 (s, 6H).

[0334] Example 119 3-((6-(3-cyanophenyl)-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] Starting from the product of step 2 of example 112, methyl 3-(aminomethyl)bicyclo[1.1.1]pentane-1-carboxylate hydrochloride and (3-cyanophenyl)boronic acid, the same procedure as step 4 of example 75 was carried out to give the target product as a white solid. LCMS (ESI): 562 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.21 - 12.17 (m, 1H), 8.22 (d, J = 1.8 Hz, 1H), 8.16 - 8.06 (m, 2H), 7.93 - 7.81 (m, 3H), 7.71 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 3.14 (d, J = 5.7 Hz, 2H), 1.79 (s, 6H).

[0335] Example 120 4-((6-(3-cyanophenyl)-1-methyl-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)methyl)benzoic acid [ka]

[0336] Step 1: 6-bromo-1-methyl-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-carboxylate methyl [ka] 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 h. Then, MeI (30 mg) was added to the reaction mixture. After stirring for 2 h, 50 mL water was added. The reaction mixture was extracted three times with 50 mL ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the product acid (80 mg). LCMS (ESI): 444 [M+1] + .

[0337] Step 2 4-((6-(3-cyanophenyl)-1-methyl-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)methyl)benzoic acid [ka] Starting from the product of step 1, methyl 4-(aminomethyl)benzoate and (3-cyanophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 586.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.23 ​​- 8.16 (m, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H), 7.89 - 7.79 (m, 3H), 7.73-7.68 (m, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.35 (d, J = 5.9 Hz, 2H), 4.00 (s, 3H).

[0338] Example 121 4-((6-(3-carbamoylphenyl)-1-methyl-3-((4-(trifluoromethyl)phenyl)thio)-1H-indolyl-4-amido)methyl)benzoic acid [ka] Starting from the product of step 1 of example 120, methyl 4-(aminomethyl)benzoate and (3-carbamoylphenyl)boronic acid, the target product was obtained as a white solid in the same manner as in example 75. LCMS (ESI): 604 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.73 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.04 (d, J = 1.5 Hz, 1H), 7.95 - 7.85 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.62 - 7.54 (m, 3H), 7.52 - 7.42 (m, 3H), 7.34 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 3.99 (s, 3H).

[0339] Example 122 4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene and phenylboronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 529.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.08 (t, J = 6.0 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.51 - 7.42 (m, 3H), 7.37 - 7.29 (m, 4H), 7.09 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H), 5.71 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H).

[0340] Example 123 4-((5-(pyridyl-3-yl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene and pyridyl-3-boronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 530.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.55 (dd, J = 4.8, 1.5 Hz, 1H), 8.17 - 8.09 (m, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.59 (q, J = 3.3 Hz, 2H), 7.53 - 7.42 (m, 2H), 7.34 - 7.29 (m, 3H), 7.09 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 5.72 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H).

[0341] Example 124 4-((5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene and (4-fluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 547.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.77 (dd, J = 8.5, 5.4 Hz, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.7 Hz, 5H), 7.09 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H), 5.71 (s, 2H), 4.42 (d, J = 5.8 Hz, 2H).

[0342] Example 125 4-((5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 565.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.67 (d, J = 3.3 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.35 - 7.26 (m, 3H), 7.23 - 7.15 (m, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H), 5.73 (s, 2H), 4.44 (d, J = 5.9 Hz, 2H).

[0343] Example 126 4-((5-(3-cyanophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene and (3-cyanophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 554.4 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.07 (t, J = 5.9 Hz, 1H), 8.23 ​​(d, J = 1.9 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.70 - 7.65(m, 2H), 7.63 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.33 - 7.28 (m, 3H), 7.08 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 5.73 (s, 2H), 4.44 (d, J = 5.9 Hz, 2H).

[0344] Example 127 (S)-4-(1-(5-(3-cyanophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and (3-cyanophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 568.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.24 (t, J = 1.8 Hz, 1H), 8.15 - 8.09 (m, 2H), 7.86 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.44-7.41 (m, 3H), 7.26 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H), 5.71-5.60 (m, 2H), 5.06-5.01 (m, 1H).

[0345] Example 128 (S)-4-(1-(5-(pyridyl-3-yl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and pyridyl-3-boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 544.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.3 Hz, 1H), 8.99 (d, J = 7.6 Hz, 1H), 8.62 (dd, J = 4.9, 1.5 Hz, 1H), 8.29 (d, J = 8.1, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 3.2 Hz, 1H), 7.64 - 7.55 (m, 3H), 7.44 (d, J = 7.9 Hz, 3H), 7.28 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 5.75 - 5.58 (m, 2H), 5.07-5.01 (m, 1H).

[0346] Example 129 (S)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and boronic acid (26 mg), the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 543.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.00 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.78 - 7.72 (m, 2H), 7.61 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.53 - 7.47 (m, 3H), 7.44-7.41 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.27 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H), 5.72 - 5.57 (m, 2H), 5.07-5.01 (m, J = 7.1 Hz, 1H).

[0347] Example 130 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, (S)-methyl 4-(1-aminoethyl)benzoate and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 579.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.96 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 7.9 Hz, 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 = 3.2 Hz, 1H), 5.70-5.60 (m, 2H), 5.07-5.01 (m, J = 7.1 Hz, 1H).

[0348] Example 131 4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, methyl 4-(1-aminocyclopropyl)benzoate and biphenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 555.4 [M+1] + . 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 9.34 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.80 (t, J = 8.1 Hz, 4H), 7.68 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.56 - 7.43 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.33 - 7.21 (m, 3H), 7.02 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H), 5.73 (s, 2H), 1.24 (q, J = 5.1 Hz, 2H), 1.02 (q, J = 5.1 Hz, 2H).

[0349] Example 132 4-(1-(5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, methyl 4-(1-aminocyclopropyl)benzoate and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 591.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.32 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 1.9 Hz, 1H), 7.66 - 7.52 (m, 4H), 7.48 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 3H), 7.24 - 7.12 (m, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 3.1 Hz, 1H), 5.74 (s, 2H), 1.29 - 1.13 (m, 2H), 1.13 - 0.95 (m, 2H).

[0350] Example 133 4-(1-(5-(3-cyanophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-(trifluoromethyl)benzene, methyl 4-(1-aminocyclopropyl)benzoate and (3-cyanophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 580.6 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 9.36 (t, J = 2.6 Hz, 1H), 8.31 (s, 1H), 8.22 - 8.14 (m, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.81 - 7.68 (m, 4H), 7.62 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.34 - 7.22 (m, 3H), 7.00 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 3.1 Hz, 1H), 5.75 (s, 2H), 1.28 - 1.24 (m, 2H), 1.08 - 0.97 (m, 2H).

[0351] Example 134 (S)-4-(1-(5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka]

[0352] Step 1: 5-Bromo-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-carboxylate methyl [ka] To a mixture of methyl 5-bromo-1H-indazolyl-7-carboxylate (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 h. The reaction mixture was poured into 100 mL ice water and extracted with 3 x 50 mL ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 10:1) to give the target compound (530 mg) as a white solid. LCMS(ESI): 413.2 [M+1] + .

[0353] Step 2: 5-Bromo-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-carboxylic acid [ka] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2.0 mL) at room temperature, LiOH·H2O (254 mg) was added. The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound (460 mg) as a white solid. LCMS (ESI): 399.3 [M+1] + .

[0354] Step 3: (S)-4-(1-(5-bromo-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid methyl ester [ka] To a mixture of the product of step 2 (460 mg), (S)-4-(1-aminoethyl)methylbenzoate (233 mg) and HATU (456 mg) in anhydrous DMF (100 mL) was added DIPEA (0.52 mL) at 0 °C. After stirring overnight at room temperature, the reaction mixture was quenched by adding 100 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 100 mL brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.6 g) as a white solid. LCMS (ESI): 560.2 [M+1] + .

[0355] Step 4: (S)-4-(1-(5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid methyl ester [ka] 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 with nitrogen gas for 1 h at 100 °C. After concentrating the reaction mixture, it was purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (27 mg) as a yellow solid. LCMS (ESI): 576.3 [M+1] + .

[0356] Step 5: (S)-4-(1-(5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] To a solution of the product of step 4 (27 mg) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH·H2O (16 mg). The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the mixture was treated with 6N hydrochloric acid until pH ≒ 6. Then, the reaction mixture was extracted with 3 x 20 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the target compound (23 mg) as a white solid. LCMS (ESI): 562 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.24 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.91 - 7.77 (m, 5H), 7.59 (d, J = 7.8 Hz, 1H), 7.45 (dd, J = 22.7, 7.9 Hz, 3H), 7.35 (dd, J = 16.3, 7.6 Hz, 3H), 7.12 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 5.15 (p, J = 7.1 Hz, 1H), 1.37 (d, J = 7.1 Hz, 3H).

[0357] Example 135 (S)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from phenylboronic acid, the same procedure as in Example 134 was used to give the target product as a white solid. LCMS (ES+): 544.5 [M+1] + . 1H NMR (400 MHz, DMSO-d6) 12.85 (s, 1H), 9.33 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 8.23 ​​(d, J = 1.7 Hz, 1H), 7.92 - 7.82 (m, 3H), 7.80 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.57 - 7.45 (m, 4H), 7.45 - 7.36 (m, 2H), 7.34 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 5.84 (s, 2H), 5.20 - 5.10 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H).

[0358] Example 136 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid, the same procedure as in Example 134 was carried out to give the target product as a white solid. LCMS (ESI): 580.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.21 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.0 Hz, 3H), 7.63 - 7.54 (m, 3H), 7.51 - 7.40 (m, 3H), 7.32 (s, 1H), 7.27 (tt, J = 9.3, 2.3 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 5.14 (p, J = 7.1 Hz, 1H), 1.39 (d, J = 7.1Hz, 3H).

[0359] Example 137 4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from methyl 4-(aminomethyl)benzoate and phenylboronic acid, the same procedure as in Example 134 was carried out to give the target product as a white solid. LCMS (ESI): 530.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 9.35 (t, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.90 - 7.83 (m, 3H), 7.79 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 - 7.48 (m, 3H), 7.42 - 7.36 (m, 3H), 7.36 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.93 (s, 2H), 4.53 (d, J = 5.8 Hz, 2H).

[0360] Example 138 4-((5-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from methyl 4-(aminomethyl)benzoate, the same procedure as in Example 134 was used to give the target product as a white solid. LCMS (ESI): 548.5 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.24 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.91 - 7.77 (m, 5H), 7.59 (d, J = 7.8 Hz, 1H), 7.50 - 7.40 (m, 3H), 7.39 - 7.30 (m, 3H), 7.12 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 5.15 (p, J = 7.1 Hz, 1H), 1.37 (d, J = 7.1 Hz, 3H).

[0361] Example 139 4-((5-(3,5-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid and methyl 4-(aminomethyl)benzoate, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 566.4 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.21 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.0 Hz, 3H), 7.63 - 7.54 (m, 3H), 7.51 - 7.40 (m, 3H), 7.32 (s, 1H), 7.27 (tt, J = 9.3, 2.3 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 5.14 (p, J = 7.1 Hz, 1H), 1.39 (d, J = 7.1Hz, 3H).

[0362] Example 140 4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from methyl 4-(1-aminocyclopropyl)benzoate and phenylboronic acid, the same steps as in Example 134 were carried out to give the target product as a white solid. LCMS (ESI): 556 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.59 (s, 1H), 8.37 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.81 - 7.75 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.57 - 7.46 (m, 3H), 7.42 (t, J = 7.4 Hz, 1H), 7.35 (s, 1H), 7.31 - 7.26 (m, 2H), 7.10 (d, J = 7.9 Hz, 1H), 5.93 (s, 2H), 1.33 - 1.28 (m, 2H), 1.20 - 1.14 (m, 2H).

[0363] Example 141 4-((5-phenyl-1-(quinolin-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)quinoline and phenylboronic acid, the same procedure as in Example 75 was followed to give the target product (21 mg) as a white solid. LCMS (ESI): 512.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.90 (t, J = 5.8 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.75-7.73 (m, 3H), 7.69 - 7.62 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.79 - 6.73 (m, 2H), 5.90 (s, 2H), 4.29 (d, J = 5.7 Hz, 2H).

[0364] Example 142 4-((5-(4-fluorophenyl)-1-(quinolin-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)quinoline and (4-fluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 530.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.81 - 7.69 (m, 3H), 7.66 - 7.59 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.30 (t, J = 8.8 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 5.91 (s, 2H), 4.33 (d, J = 5.8 Hz, 2H).

[0365] Example 143 (S)-4-(1-(5-phenyl-1-(quinolin-2-ylmethyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 2-(bromomethyl)quinoline, (S)-4-(1-aminoethyl)methyl benzoate and phenylboronic acid, the same procedure as in Example 75 was followed to give the target product (10 mg) as a white solid. LCMS (ESI): 526.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.86 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H), 7.91 (dd, J = 11.7, 8.4 Hz, 2H), 7.74 (t, J = 8.6 Hz, 5H), 7.62 (d, J = 3.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.48 (dd, J = 15.1, 7.5 Hz, 3H), 7.36 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H), 5.90 - 5.78 (m, 2H), 4.97 (p, J = 7.1 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H).

[0366] Example 144 (S)-4-(1-(5-(4-fluorophenyl)-1-(quinolin-2-ylmethyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 2-(bromomethyl)quinoline, (S)-4-(1-aminoethyl)methyl benzoate and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 544.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.84 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.90 (t, J = 9.4 Hz, 2H), 7.78 (dd, J = 8.4, 5.5 Hz, 2H), 7.73 (d, J = 8.0 Hz, 3H), 7.63 (d, J = 3.1 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 4H), 6.74 (d, J = 3.1 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H), 5.84 (d, J = 5.4 Hz, 2H), 4.96 (t, J = 7.2 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H).

[0367] Example 145 ((1-([1,1'-biphenyl]-3-ylmethyl)-5-phenyl-1H-indolyl-7-amido) methyl)benzoic acid [ka] Starting from 3-(bromomethyl)-1,1'-biphenyl and phenylboronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 537.3 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.12 - 9.05 (m, 1H), 7.99 (s, 1H), 7.86 - 7.79 (m, 2H), 7.72 (d, J = 7.7 Hz, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.55 - 7.49 (m, 4H), 7.48 - 7.40 (m, 4H), 7.36 - 7.24 (m, 6H), 6.88 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 3.1 Hz, 1H), 5.68 (s, 2H), 4.46 - 4.38 (m, 2H).

[0368] Example 146 4-((1-(3-Methoxybenzyl)-5-phenyl-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-methoxybenzene and phenylboronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 491.4 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 3.2 Hz, 1H), 7.55 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 7.9 Hz, 1H), 6.81 - 6.77 (m, 1H), 6.70 (d, J = 3.2 Hz, 1H), 6.47 - 6.44 (m, 1H), 6.42 (d, J = 7.6 Hz, 1H), 5.59 (s, 2H), 4.49 (d, J = 5.9 Hz, 2H), 3.65 (s, 3H).

[0369] Example 147 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-phenyl-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and phenylboronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 537.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.07 (t, J = 6.0 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.55 (s, 1H), 7.51 - 7.40 (m, 6H), 7.40 - 7.30 (m, 4H), 6.96 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.1 Hz, 1H), 5.65 (s, 2H), 4.51 (d, J = 5.9 Hz, 2H).

[0370] Example 148 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-(4-fluorophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and (4-fluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 555.3 [M+1] + . 1H NMR spectrum: (400 MHz, DMSO-d6) δ 12.85(s, 1H), 9.05(t, J = 6.0Hz, 1H), 7.98(s, 1H), 7.84(d, J = 7.9Hz, 2H), 7.78 - 7.72(m, 2H), 7.64(d, J = 3.2Hz, 1H), 7.57(d, J = 7.6Hz, 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).

[0371] Example 149 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,5-difluorophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 573.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.04 (t, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.7 Hz, 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 = 8.0 Hz, 2H), 6.73 (d, J = 3.1 Hz, 1H), 5.67 (s, 2H), 4.53 (d, J = 5.9 Hz, 2H).

[0372] Example 150 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-phenyl-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl, (S)-4-(1-aminoethyl)methyl benzoate and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 551.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.98 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 7.7 Hz, 2H), 7.52 - 7.45 (m, 5H), 7.44 - 7.39 (m, 4H), 7.36 - 7.29 (m, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 3.1 Hz, 1H), 5.58 (s, 2H), 5.22 - 5.14 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H).

[0373] Example 151 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-(4-fluorophenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl, (S)-4-(1-aminoethyl)methyl benzoate and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 569.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.97 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.79 - 7.73 (m, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 7.7 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.44 - 7.39 (m, 4H), 7.35 - 7.27 (m, 3H), 6.92 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 3.1 Hz, 1H), 5.58 (s, 2H), 5.22 - 5.14 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H).

[0374] Example 152 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,5-difluorophenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl, (S)-methyl 4-(1-aminoethyl)benzoate and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 587.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 3.2 Hz, 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 = 8.0 Hz, 2H), 6.71 (d, J = 3.1 Hz, 1H), 5.58 (s, 2H), 5.22 - 5.14 (m, 1H), 1.34 (d, J = 7.0 Hz, 3H).

[0375] Example 153 4-((4-(phenylamino)-1-(quinolin-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)quinoline, methyl 4-(aminomethyl)benzoate and aniline, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 527.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.1 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 15.3, 8.3 Hz, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 3.3 Hz, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.95 - 6.87 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.89 (s, 2H), 4.30 (d, J = 5.9 Hz, 2H).

[0376] Example 154 4-((1-([1,1'-biphenyl]-4-ylmethyl)-4-(phenylamino)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl, methyl 4-(aminomethyl)benzoate and aniline, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 552.2 [M+1] + .

[0377] Example 155 4-((1-(3-Methoxybenzyl)-4-(phenylamino)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-methoxybenzene, methyl 4-(aminomethyl)benzoate and aniline, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 506.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.77 (t, J = 6.0 Hz, 1H), 8.24 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 3.2 Hz, 1H), 7.31 - 7.26 (m, 4H), 7.26 - 7.16 (m, 3H), 7.12 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 7.2 Hz, 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 = 6.0 Hz, 2H), 3.65 (s, 3H).

[0378] Example 156 4-((1-(naphthalen-2-ylmethyl)-4-(phenylamino)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and aniline, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 622.1 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.71-8.66 (m, 1H), 8.25 (s, 1H), 7.89 - 7.81 (m, 1H), 7.78 - 7.70 (m, 4H), 7.51 (d, J = 3.3 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.41 (s, 1H), 7.34 - 7.26 (m, 4H), 7.23 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.10 - 7.06 (m, 1H), 6.96 - 6.85 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 4.45 - 4.41 (m, 2H).

[0379] Example 157 4-((5-(3,5-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene-4-(aminomethyl)benzoic acid methyl ester and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 548.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.17 (t, J = 5.9 Hz, 1H), 8.39 (s, 1H), 8.36 (d, J = 1.7 Hz, 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, 1.7 Hz, 1H), 6.04 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H).

[0380] Example 158 (S)-4-(1-(1-(3-methoxybenzyl)-4-(phenylamino)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-methoxybenzene (100 mg), (S)-methyl 4-(1-aminoethyl)benzoate (100 mg) and aniline (70 mg), the same procedure as in Example 64 was followed to give the target product (25 mg) as a white solid. LCMS (ESI): 622.1 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.69 (d, J = 7.9 Hz, 1H), 8.22 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.52 - 7.37 (m, 3H), 7.32 - 7.26 (m, 2H), 7.25 - 7.20 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.86 - 6.81 (m, 2H), 6.79 - 6.73 (m, 1H), 6.44 - 6.41 (m, 1H), 6.39 (d, J = 7.6 Hz, 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 = 7.1 Hz, 3H).

[0381] Example 159 4-((1-(naphthalene-2-ylmethyl)-5-phenyl-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene and phenylboronic acid, the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 511.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 5.9 Hz, 1H), 8.02 (s, 1H), 7.89 - 7.82 (m, 1H), 7.79 - 7.70 (m, 6H), 7.69 (d, J = 3.2 Hz, 1H), 7.51 (s, 1H), 7.49 - 7.43 (m, 4H), 7.41 (s, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 3.1 Hz, 1H), 5.79 (s, 2H), 4.45 (d, J = 5.8 Hz, 2H).

[0382] Example 160 4-((5-(4-fluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene and (4-fluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 529.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.98 (s, 1H), 7.86 - 7.81 (m, 1H), 7.77 - 7.70 (m, 6H), 7.69 (d, J = 3.1 Hz, 1H), 7.49 - 7.43 (m, 3H), 7.39 (s, 1H), 7.27 (t, J = 8.7 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 5.78 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H).

[0383] Example 161 4-((5-(3,5-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene and (3,5-difluorophenyl)boronic acid (50 mg), the same procedure as in Example 75 was carried out to give the target product as a white solid. LCMS (ESI): 547.4 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.92 (t, J = 5.9 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.75 (d, J = 8.5 Hz, 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 = 7.9 Hz, 2H), 7.18 - 7.12 (m, 1H), 7.08 - 7.04 (m, 1H), 6.74 (d, J = 3.2 Hz, 1H), 5.80 (s, 2H), 4.45 (d, J = 5.8 Hz, 2H).

[0384] Example 162 (S)-4-(1-(1-(naphthalen-2-ylmethyl)-5-phenyl-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, (S)-4-(1-aminoethyl)methyl benzoate and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 525.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.89 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.82 (t, J = 6.9 Hz, 3H), 7.74 (t, J = 7.1 Hz, 4H), 7.67 (d, J = 3.2 Hz, 1H), 7.52 - 7.31 (m, 9H), 7.06 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 5.84 - 5.63 (m, 2H), 5.11 (p, J = 7.2 Hz, 1H), 1.12 (d, J = 7.0Hz, 3H).

[0385] Example 163 (S)-4-(1-(5-(4-fluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, (S)-4-(1-aminoethyl)methyl benzoate and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 543.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.84-7.82 (m, J = 7.5 Hz, 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 = 8.7 Hz, 2H), 7.05 (d, J = 8.5, 1H), 6.72 (d, J = 3.1 Hz, 1H), 5.81 - 5.62 (m, 2H), 5.12-5.07 (m, 1H).

[0386] Example 164 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, (S)-methyl 4-(1-aminoethyl)benzoate and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 561.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.83 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.84-7.79 (m, 3H), 7.76 - 7.69 (m, 3H), 7.53 - 7.43 (m, 5H), 7.40 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 7.20-7.16 (m, 1H), 7.04 (d, J = 8.5,1H), 6.74 (d, J = 3.2 Hz, 1H), 5.80 - 5.65 (m, 2H), 5.12-5.06 (m, 1H), 1.13 (d, J = 7.0 Hz, 3H).

[0387] Example 165 4-((1-(naphthalen-2-ylmethyl)-5-phenyl-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 512.4 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.21 (t, J = 5.9 Hz, 1H), 8.37 (s, 1H), 8.23 ​​(d, J = 1.7 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.78 - 7.44 (m, 10H), 7.38 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 3H), 7.15-7.10 (m, 1H), 6.03 (s, 2H), 4.55 (d, J = 5.8 Hz, 2H).

[0388] Example 166 4-((5-(4-fluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, methyl 4-(aminomethyl)benzoate and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 530.6 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 8.37 (s, 1H), 8.22 (d, J = 1.7 Hz, 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 = 5.8 Hz, 2H).

[0389] Example 167 (S)-4-(1-(1-(naphthalen-2-ylmethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka]

[0390] Step 1 5-Bromo-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-carboxylic acid [ka] To a mixture of methyl 5-bromo-1H-indazolyl-7-carboxylate (500 mg) and Cs2CO3 (769 mg) in anhydrous DMF (10 mL) was added 2-(bromomethyl)naphthalene (564 mg) at 0 °C. The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was poured into 100 mL ice water and extracted with 3 x 50 mL ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0-10:1) to give the target compound isomer 1 (500 mg, first elution) and isomer 2 (regioisomer) as a white solid. Isomer 1 (target compound): LCMS (ES+): 395.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 8.41 - 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).

[0391] [ka] Isomer 2: LCMS (ES+): 395.1 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.91 (ddd, J = 14.8, 8.9, 5.5 Hz, 6H), 7.57 - 7.50 (m, 2H), 7.47 (dd, J = 8.5, 1.8 Hz, 1H), 5.92 (s, 2H), 3.89 (s, 3H).

[0392] Step 2: 5-Bromo-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-carboxylic acid [ka] To a solution of the product of step 1 (500 mg) in MeOH / H2O (10 mL / 2 mL) at room temperature, LiOH·H2O (254 mg) was added. The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid to adjust the pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound (479 mg) as a white solid. LCMS (ESI): 381.1 [M+1] + .

[0393] Step 3: (S)-4-(1-(5-bromo-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)ethyl)benzoic acid methyl ester [ka] To a mixture of the product of step 2 (398 mg), (S)-4-(1-aminoethyl)methylbenzoate (215 mg) and HATU (456 mg) in anhydrous DMF (10 mL) was added DIPEA (0.52 mL) at 0 °C. After stirring at room temperature overnight, the reaction mixture was quenched by adding 10 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 10 mL brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.5 g) as a white solid. LCMS (ESI): 542.1 [M+1] + .

[0394] Step 4: (S)-4-(1-(1-(naphthalen-2-ylmethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid methyl ester [ka] A mixture of the product of step 3 (30 mg), phenylboronic acid (38 mg), (dppf)2Cl2 (4 mg) and K2CO3 (38 mg) in EtOH / H2O (5 mL / 1 mL) was stirred with nitrogen gas for 2 h at 70 °C. After concentrating the reaction mixture, it was purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (27 mg) as a yellow solid. LCMS (ESI): 540.2 [M+1] + .

[0395] Step 5 (S)-4-(1-(1-(naphthalen-2-ylmethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] To a solution of the product of step 4 (42 mg) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH·H2O (16 mg). The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the mixture was treated with 6N hydrochloric acid to adjust the pH ≒ 6. The reaction mixture was then extracted with 3 x 20 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the target compound (10.1 mg) as a white solid. LCMS (ESI): 526.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.12 (d, J = 7.6 Hz, 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 = 7.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.96 (s, 2H), 5.22 (p, J = 7.1 Hz, 1H), 1.25 (s, 3H).

[0396] Example 168 (S)-4-(1-(5-(4-fluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (4-fluorophenyl)boronic acid, the same procedure as in Example 167 was carried out to give the target product as a white solid. LCMS (ESI): 544.4 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.10 (d, J = 7.6 Hz, 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 = 8.8 Hz, 2H), 7.11 - 7.05 (m, 1H), 5.96 (s, 2H), 5.25 - 5.16 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H).

[0397] Example 169 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid, the same steps as in Example 167 were carried out to give the target product as a white solid. LCMS (ESI): 562.6 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.06 (d, J = 7.6 Hz, 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 = 7.1 Hz, 3H).

[0398] Example 170 (S)-4-(1-(1-(3-chlorobenzyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz, (S)-4-(1-aminoethyl)methyl benzoate and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 510.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) 12.85 (s, 1H), 9.26 (d, J = 7.6 Hz, 1H), 8.35 (s, 1H), 8.23 ​​(d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.84 - 7.76 (m, 3H), 7.56 - 7.47 (m, 4H), 7.40 (t, J = 7.4 Hz, 1H), 7.31 - 7.25 (m, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.78 (s, 2H), 5.24 - 5.14 (m, 1H), 1.41 (d, J = 7.0 Hz, 3H).

[0399] Example 171 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-7-amido)methyl)benzoic acid [ka]

[0400] Step 1: 5-Bromo-1H-benzo[d]imidazole-7-carboxylate methyl [ka] To a mixture of methyl 2,3-diamino-5-bromobenzoate (1.0 g) in MeCN (20 mL) was added 1.2 equivalents (eq.) of triethoxymethane and 10 mol% I2. at room temperature and stirred for 10 min at room temperature, then the mixture was poured into 100 mL of water. The brown solid was filtered and dried to give the target compound (1.0 g). LCMS (ESI): 255 [M+1] + .

[0401] Step 2: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylate methyl [ka] To a mixture of methyl 5-bromo-1H-benzodiimidazole-7-carboxylate (1.0 g) and 1-(bromomethyl)-3-chlorobenzamide in DMF (50 mL) at room temperature, 2.0 equivalents of Cs2CO3 was added and stirred at room temperature for 4 h, followed by addition of 200 mL. The reaction mixture was extracted with 3 x 50 mL ethyl acetate, rinsed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the target product isomer 1 (0.86 g, first elution) and isomer 2. Isomer 1: 1 H NMR (400MHz, DMSO-d6)δ 8.63(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] + . Isomer 2: 1 H NMR (400MHz, DMSO) δ 8.64(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] +.

[0402] Step 3: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylic acid [ka] To a solution of the product of step 1 (500 mg, 1.21 mmol) in MeOH / H2O (10 mL / 2.0 mL) at room temperature, LiOH·H2O (254 mg, 6.06 mmol) was added. The reaction mixture was stirred at 60 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid until pH ≒ 6. The reaction mixture was then extracted with 3 x 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na2SO4, and concentrated. The residue was then purified by silica gel column chromatography (DCM / MeOH ratio 100:0 ~ 10:1) to give the target compound as a white solid. LCMS (ESI): 399 [M+1] + .

[0403] Step 4: 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-7-amido)methyl)benzoate methyl [ka] 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) was added DIPEA (0.52 mL) at 0 °C. After stirring at room temperature overnight, the reaction mixture was quenched by adding 100 mL water and then extracted with 3 x 100 mL ethyl acetate. The combined organic layers were washed with 100 mL brine, dried over anhydrous Na2SO4 and concentrated. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 100:0 ~ 5:1) to give the target compound (0.5 g) as a white solid. LCMS (ESI): 546 [M+1] + .

[0404] Step 5 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-7-amido)methyl)benzoic acid [ka] Starting from the product of step 4 and phenylboronic acid, the same procedure as in example 75 was carried out to give the target product as a white solid. LCMS (ESI): 530 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 9.11 (t, J = 5.9 Hz, 1H), 8.58 (s, 1H), 8.11 (d, J = 1.7 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 5.84 (s, 2H), 4.44 (d, J = 5.7 Hz, 2H).

[0405] Example 172 4-((5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-7-amido)methyl)benzoic acid [ka] Starting from the product of step 4 of example 171 and (4-fluorophenyl)boronic acid, the same steps as in example 171 were carried out to give the target product as a white solid. LCMS (ESI): 548 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.11 (s, 1H), 8.60 (s, 1H), 8.11 (d, J = 1.7 Hz, 1H), 7.89 - 7.78 (m, 4H), 7.69 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.36 - 7.27 (m, 4H), 7.11 (d, J = 8.0 Hz, 2H), 5.85 (s, 2H), 4.45 (d, J = 5.8 Hz, 2H).

[0406] Example 173 4-((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-7-amido)methyl)benzoic acid [ka] Starting from the product of step 4 of example 171 and (3,5-difluorophenyl)boronic acid, the same steps as in example 171 were carried out to give the target product as a white solid. LCMS (ESI): 566 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 1.8 Hz, 1H), 7.64 - 7.53 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.27 - 7.19 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 5.88 (s, 2H), 4.47 (d, J = 5.8 Hz, 2H).

[0407] Example 174 ((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazol-7-amido)methyl)benzoic acid [ka]

[0408] Step 1 5-Bromo-3-nitro-2-((4-(trifluoromethyl)benzyl)amino)benzoic acid [ka] 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)methylamine (905 mg, 4.28 mmol) in 1,4-dioxane (6 mL) was stirred at 90 °C for 16 h. The reaction solution was poured into water and acidified with aqueous hydrochloric acid (6N) to pH = 4, then 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 give the target compound (800 mg) as a brown solid. LCMS (ESI): 419 [M+1] + .

[0409] Step 2: 5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3 triazole-7-carboxylic acid [ka] A solution of the product of step 1 (800 mg, 1.91 mmol) in AcOH (10 mL) was added to a mixture of Zn (5.9 g, 89.47 mmol) in AcOH (20 mL) at 50° C. and allowed to stand for 5 min. The reaction mixture was stirred at 50° C. for 1 h. 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). t-Butyl nitrite (197 mg, 1.91 mmol) was added to the above solution at room temperature. The resulting solution was stirred at room temperature for 30 min and then concentrated in vacuum. The residue was dissolved in ethyl acetate (50 mL), rinsed with water and brine (pH = 4), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuum to give the target compound (500 mg) as a brown solid. LCMS (ESI): 400 [M+1] + .

[0410] Step 3: 4-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazol-7-amido)methyl)benzoate methyl [ka] 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., HATU (304 mg) was added. After stirring at room temperature for 3 h, 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, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was placed in MeOH (5 mL) and stirred at room temperature for 30 min. After filtration, the solid was collected and rinsed with MeOH (3 mL) to give the target compound (180 mg) as a brown solid. LCMS (ESI): 547 [M+1] + .

[0411] Step 4: 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazol-7-amido)methyl)benzoate methyl [ka] K2CO3 (45 mg), PdCl2(dppf) (8.0 mg), 44-((5-bromo-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3 triazole-7-amido)methyl)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 gas for 2 h. The reaction mixture was concentrated and then purified by silica gel column chromatography (PE / EA = 5:1) to give the target compound (40 mg) as a yellow solid. LCMS (ESI): 545 [M+1] + .

[0412] Step 5 4-((5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3 triazol-7-amido)methyl)benzoic acid [ka] At room temperature, 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). The resulting mixture was stirred at 50 °C for 5 h. The reaction solution was poured into water and acidified to pH = 6 with aqueous hydrochloric acid (6N). After filtration, the solid was collected and washed with water to give the target compound (20 mg) as a pale yellow solid. LCMS (ESI): 531 [M+1] + . 1 HNMR (400 MHz, DMSO-d6)δ9.40 (t, J = 6.0 Hz, 1H), 8.55 (s, 1H), 8.10 (s, 1H), 7.88 (t, J = 7.1 Hz, 4H), 7.61-7.50 (m, 4H), 7.44 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.30 (s, 2H), 4.55 (d, J = 5.9 Hz, 2H).

[0413] Example 175 (5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazole-7-amido)methyl)benzoic acid [ka] Starting from the product of step 4 of example 174 and (4-fluorophenyl)boronic acid, the same steps as in example 174 were carried out to give the target product as a white solid. LCMS (ESI): 549.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.39 (t, J = 5.9 Hz, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 7.98 - 7.91 (m, 2H), 7.90 - 7.86 (m, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.38-7.35 (m, 6.5 Hz, 4H), 7.16 (d, J = 8.0 Hz, 2H), 6.30 (s, 2H), 4.55 (d, J = 5.8 Hz, 2H).

[0414] Example 176 ((5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazol-7-amido)methyl)benzoic acid [ka] Starting from the product of step 4 of example 174 and (3,5-difluorophenyl)boronic acid, the same steps as in example 174 were carried out to give the target product as a white solid. LCMS (ESI): 567.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.36 (t, J = 6.0 Hz, 1H), 8.70 (s, 1H), 8.15 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.33-7.28 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.31 (s, 2H), 4.56 (d, J = 5.8 Hz, 2H).

[0415] Example 177 44-((1-(naphthalene-1-ylmethyl)-5-phenyl-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(bromomethyl)naphthalene and phenylboronic acid, the same procedure as in Example 75 was followed to give the target product as a white solid. LCMS (ESI): 511.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.08 - 8.04 (m, 2H), 8.01 - 7.96 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 7.7 Hz, 2H), 7.62 - 7.53 (m, 5H), 7.52 - 7.45 (m, 3H), 7.35-7.28 (m, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.2 Hz, 1H), 6.32 (d, J = 7.1 Hz, 1H), 6.15 (s, 2H), 4.07 (d, J = 5.9 Hz, 2H).

[0416] Example 178 (±) 4-((5-phenyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 1-(1-chloroethyl)-4-(trifluoromethyl)phenyl, phenylboronic acid, the same procedure as in Example 75 was followed to give the target product as a white solid. LCMS (ESI): 543.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.17 - 9.06 (m, 1H), 7.99 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.77 - 7.69 (m, 3H), 7.55 (d, J = 8.1 Hz, 2H), 7.51 - 7.44 (m, 3H), 7.41 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 6.32 - 6.23 (m, 1H), 4.62 - 4.55 (m, 1H), 4.47 - 4.39 (m, 1H), 1.82 (d, J = 7.1 Hz, 3H).

[0417] Example 179 (S)-4-(1-(5-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazole-7-amido)ethyl)benzoic acid [ka] Starting from (S)-methyl 4-(1-aminoethyl)benzoate and the product of step 2 of example 174, the same procedure as in example 174 was carried out to give the target product as a yellow solid. LCMS (ESI): 545.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.25 (d, J = 7.8 Hz, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.51 - 7.46 (m, 4H),7.44 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H),6.34 - 6.23 (m, 1H), 6.19 - 6.09 (m, 1H), 5.22 - 5.12 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H).

[0418] Example 180 (S)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazol-7-amido)ethyl)benzoic acid [ka] Starting from (4-fluorophenyl)boronic acid, (S)-4-(1-aminoethyl)benzoic acid methyl ester and the product of step 2 of example 174, the same procedure as in example 174 was carried out to give the target product (36 mg) as a yellow solid. LCMS (ESI): 563.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.24 (d, J = 7.7 Hz, 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 = 8.0 Hz, 2H), 6.30 - 6.24 (m, 1H), 6.18 - 6.10 (m, 1H), 5.22 - 5.12 (m, 1H), 1.37 (d, J = 6.9 Hz, 3H).

[0419] Example 181 (S)-4-(1-(5-(3,5-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3-triazole-7-amido)ethyl)benzoic acid [ka] Starting from (3,5-difluorophenyl)boronic acid, (S)-4-(1-aminoethyl)methyl benzoate and the product of step 2 of example 174, the same procedure as in example 174 was carried out to give the target product as a yellow solid. LCMS (ESI): 581.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.21 (d, J = 7.8 Hz, 1H), 8.66 (s, 1H), 8.06 (s, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.53 - 7.43 (m, 4H), 7.34 - 7.27 (m, 1H) 7.10 (d, J = 7.9 Hz, 2H), 6.33 - 6.24 (m, 1H), 6.19 - 6.10 (m, 1H),, 5.22 - 5.12 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H).

[0420] Example 182 4-((4-((4-fluorophenyl)amino)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from methyl 4-bromo-1H-indazolyl-7-carboxylate, 2-(bromomethyl)naphthalene and methyl 4-(aminomethyl)benzoate, the target product was obtained as a white solid in the same manner as in Example 64. LCMS (ESI): 545.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (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 = 8.0 Hz, 1H), 7.35 - 7.28 (m, 4H), 7.22 (t, J = 8.8 Hz, 2H), 7.13-7.08 (m, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.01 (s, 2H), 4.50 (d, J = 5.9 Hz, 2H).

[0421] Example 183 ((4-((4-fluorophenyl)amino)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene and methyl 4-(aminomethyl)benzoate, the same steps as in Example 64 were carried out to give the target product as a white solid. LCMS (ESI): 544 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.67 (t, J = 6.0 Hz, 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 = 3.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H).

[0422] Example 184 4-((1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-methyl carboxylate, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 556 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.30 (d, J = 6.1 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.91 - 7.83 (m, 3H), 7.79 (d, J = 7.4 Hz, 2H), 7.66 - 7.57 (m, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.47 - 7.36 (m, 5H), 7.26 (t, J = 8.9 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 5.90 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H).

[0423] Example 185 4-((1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-methyl carboxylate, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 574 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.29 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.88 - 7.78 (m, 5H), 7.64 - 7.57 (m, 2H), 7.41 (t, J = 8.4 Hz, 4H), 7.37 - 7.29 (m, 2H), 7.29 - 7.20 (m, 2H), 6.98 (d, J = 8.3 Hz, 2H), 5.89 (s, 2H), 4.59 (d, J = 5.9Hz, 2H).

[0424] Example 186 4-((5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-methyl carboxylate, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 592 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.29 (t, J = 6.0 Hz, 1H), 8.38 - 8.33 (m, 2H), 7.93 (d, J = 1.8 Hz, 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 = 8.1 Hz, 2H), 5.90 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H).

[0425] Example 187 4-((5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-methyl carboxylate, 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 592 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.27 (t, J = 6.0 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.93 - 7.82 (m, 4H), 7.68 - 7.51 (m, 4H), 7.41 (t, J = 8.0 Hz, 4H), 7.29 - 7.20 (m, 2H), 6.97 (d, J = 8.0 Hz, 2H), 5.89 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H).

[0426] Example 188 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,4-difluorophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 573.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.02 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.87 - 7.76 (m, 3H), 7.65 (d, J = 3.2 Hz, 1H), 7.61 - 7.49 (m, 5H), 7.48 - 7.39 (m, 4H), 7.38 - 7.29 (m, 3H), 6.93 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 3.1 Hz, 1H), 5.65 (s, 2H), 4.51 (d, J = 5.8Hz, 2H).

[0427] Example 189 (S)-4-(1-(1-(naphthalen-2-ylmethyl)-5-phenyl-1H-benzo[d][1,2,3]triazole-7-carboxamido)ethyl)benzoic acid [ka] Starting from naphthalen-2-ylmethylamine and (S)-4-(1-aminoethyl)benzoic acid methyl ester, the same procedure as in Example 174 was carried out to give the target product as a white solid. LCMS (ESI): 527.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.02-8.00 (m, 1H), 7.90 - 7.83 (m, 2H), 7.78 - 7.71 (m, 2H), 7.62 (d, J = 3.2 Hz, 1H), 7.53 - 7.45 (m, 5H), 7.45 - 7.41 (m, 2H), 7.37-7.32 (m, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.78 - 6.70 (m, 1H), 5.65 (s, 2H), 5.08-5.00 (m, 1H), 1.26-1.21 (m, 3H).

[0428] Example 190 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-phenyl-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-methyl carboxylate, 4-(bromomethyl)-1,1'-biphenyl and phenylboronic acid, the same procedure as in Example 134 was used to give the target product (20 mg) as a white solid. LCMS (ESI): 538.3 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.32 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.92 - 7.74 (m, 5H), 7.62 - 7.32 (m, 12H), 7.01 (d, J = 8.0 Hz, 2H), 5.90 (s, 2H), 4.61 (d, J = 5.9 Hz, 2H).

[0429] Example 191 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-(4-fluorophenyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-methyl carboxylate, 4-(bromomethyl)-1,1'-biphenyl and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 556.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.31 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 8.22 (d, J = 1.7 Hz, 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 = 8.0 Hz, 2H), 5.89 (s, 2H), 4.60 (d, J = 5.8 Hz, 2H).

[0430] Example 192 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,5-difluorophenyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-carboxylic acid, 4-(bromomethyl)-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 574.5 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.30 (t, J = 5.9 Hz, 1H), 8.40 - 8.35 (m, 2H), 7.94 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.63 - 7.54 (m, 4H), 7.47 - 7.41 (m, 6H), 7.35 (t, J = 7.3 Hz, 1H), 7.28-7.21 (m, 1H), 6.99 (d, J = 8.0 Hz, 2H), 5.91 (s, 2H), 4.62 (d, J = 5.9 Hz, 2H).

[0431] Example 193 4-((1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,4-difluorophenyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from 5-bromo-1H-indazolyl-7-carboxylic acid, 4-(bromomethyl)-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 574.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.31 (d, J = 5.9 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.95 - 7.84 (m, 4H), 7.71 - 7.51 (m, 4H), 7.44 (t, J = 7.4 Hz, 6H), 7.37-7.33 (m, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.90 (s, 2H), 4.61 (d, J = 5.8 Hz, 2H).

[0432] Example 194 (S)-4-(1-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-4-(trifluoromethyl)phenyl, the same steps as in Example 134 were carried out to give the target product as a white solid. LCMS (ESI): 562.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.19 (d, J = 7.8 Hz, 1H), 8.36 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.86 - 7.81 (m, 2H), 7.80 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 4H), 7.36 (t, J = 8.8 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 5.98 - 5.77 (m, 2H), 5.22 - 5.12 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H).

[0433] Example 195 (S)-4-(1-(5-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 1-(bromomethyl)-4-(trifluoromethyl)phenyl and (3,4-difluorophenyl)boronic acid, the same procedure as in Example 134 was followed to give the target product (76 mg) as a white solid. LCMS (ESI): 580.6 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.16 (d, J = 7.8 Hz, 1H), 8.35 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.94 - 7.84 (m, 3H), 7.81 (d, J = 1.8 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.60 - 7.53 (m, 1H),7.51 - 7.43 (m, 4H), 7.01 (d, J = 8.0 Hz, 2H), 5.95 - 5.77 (m, 2H), 5.20 - 5.10 (m, 1H), 1.36 (d, J = 7.2Hz, 3H).

[0434] Example 196 4-((S)-1-(1-((R)-1-(naphthalen-2-yl)ethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka]

[0435] Step 1: (R)-5-bromo-1-(1-(naphthalen-2-yl)ethyl)-1H-indazolyl-7-carboxylate methyl [ka] A mixture of methyl 5-bromo-1H-indazolyl-7-carboxylate (300 mg, 1.18 mmol) and (S)-1-(naphthalen-2-yl)-1-alcohol (304 mg, 1.76 mmol) was degassed and purged with argon gas three times. At 0°C, THF (10 mL), TBP (428 mg, 2.11 mmol) were added to the above mixture in sequence, and DIAD (357 mg, 1.76 mmol) was added dropwise. The resulting 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 0-20%) to obtain the target compound (270 mg) as a colorless oil. LCMS (ESI): 409.5 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 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 = 6.9 Hz, 1H), 3.86 (s, 3H), 2.11 (d, J = 6.9 Hz, 3H).

[0436] Step 2 4-((S)-1-(1-((R)-1-(naphthalen-2-yl)ethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from the product of step 1 (200 mg), the same procedure as in Example 167 was carried out to give the target product (60 mg) as a white solid. LCMS (ESI): 540.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 8.2 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.87 - 7.74 (m, 6H), 7.59 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 13.8, 5H), 7.46 - 7.35 (m, 4H), 7.10 (d, J = 8.5 Hz, 1H), 6.45 (q, J = 6.8 Hz, 1H), 5.43-5.35 (m, 1H), 1.97 (d, J = 6.9 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H).

[0437] Example 197 4-((S)-1-(1-((S)-1-(naphthalen-2-yl)ethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (R)-1-(naphthaleneacetamid-2-yl)-1-alcohol, the same steps as in Example 196 were carried out to give the target product as a white solid. LCMS (ESI): 540.5 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 9.18 (d, J = 7.3 Hz, 1H), 8.39 (s, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.88 - 7.82 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.69 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 8.3 Hz, 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 = 6.9 Hz, 3H), 1.27 (d, J = 7.1 Hz, 3H).

[0438] Example 198 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and phenylboronic acid, the same procedure as in Example 134 was carried out to give the target product (23 mg) as a white solid. LCMS (ESI): 552.5 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.24 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.87 - 7.75 (m, 3H), 7.58 - 7.50 (m, 6H), 7.47 - 7.32 (m, 6H), 6.98 (d, J = 8.1 Hz, 2H), 5.92 - 5.74 (m, 2H), 5.29-5.25 (m, 1H), 1.44 (d, J = 7.0 Hz, 3H).

[0439] Example 199 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-(4-fluorophenyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl, the same steps as in Example 134 were carried out to give the target product as a white solid. LCMS (ESI): 570.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.22 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.86 - 7.78 (m, 3H), 7.60 - 7.53 (m, 4H), 7.49 - 7.32 (m, 7H), 6.98 (d, J = 8.1 Hz, 2H), 5.91 - 5.72 (m, 2H), 5.32-5.27 (m, 1H),, 1.44 (d, J = 7.0 Hz, 3H).

[0440] Example 200 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,5-difluorophenyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid, the same procedure as in Example 134 was carried out to give the target product (23 mg) as a white solid. LCMS (ESI): 588.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.22 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.86 - 7.78 (m, 3H), 7.60 - 7.53 (m, 4H), 7.49 - 7.32 (m, 7H), 6.98 (d, J = 8.1 Hz, 2H), 5.91 - 5.72 (m, 2H), 5.32-5.27 (m, 1H),, 1.44 (d, J = 7.0 Hz, 3H).

[0441] Example 201 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,4-difluorophenyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid, the same steps as in Example 134 were carried out to give the target product as a white solid. LCMS (ESI): 588.4 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.20 (d, J = 7.9 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.97 - 7.87 (m, 3H), 7.82 (d, 7.69 - 7.53 (m, 6H), 7.48 - 7.31 (m, 5H), 6.97 (d, J = 8.0 Hz, 2H), 5.91 - 5.74 (m, 2H), 5.31-5.27 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H).

[0442] Example 202 (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and phenylboronic acid, the same procedure as in Example 134 was carried out to give the target product as a white solid. LCMS (ESI): 570 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.23 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.85 - 7.76 (m, 3H), 7.63 - 7.49 (m, 6H), 7.45 - 7.34 (m, 3H), 7.26 (t, J = 8.8 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 5.87 (d, J = 15.7 Hz, 1H), 5.77 (d, J = 15.7 Hz, 1H), 5.35 - 5.24 (m, 1H), 1.44 (d, J = 7.0 Hz, 3H).

[0443] Example 203 (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, the same steps as in Example 134 were carried out to give the target product as a white solid. LCMS (ESI): 588 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.22 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.88 - 7.78 (m, 3H), 7.64 - 7.51 (m, 4H), 7.42 - 7.19 (m, 4H), 6.97 (d, J = 8.0 Hz, 2H), 5.87 (d, J = 15.7 Hz, 1H), 5.77 (d, J = 15.7 Hz, 1H), 5.35 - 5.23 (m, 1H), 1.44 (d, J = 7.0 Hz, 3H).

[0444] Example 204 (S)-4-(1-(5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl) methyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 606 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (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 = 8.0 Hz, 2H), 7.26 (t, J = 8.6 Hz, 3H), 6.96 (d, J = 8.0 Hz, 2H), 5.88 (d, J = 15.7 Hz, 1H), 5.76 (d, J = 15.6 Hz, 1H), 5.29 (t, J = 7.2 Hz, 1H), 1.46 (d, J = 7.0 Hz, 5H).

[0445] Example 205 (S)-4-(1-(5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl) methyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 134. LCMS (ESI): 606 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.19 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 3H), 7.83 (d, J = 1.7 Hz, 1H), 7.67 - 7.51 (m, 6H), 7.37 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 8.8 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.87 (d, J = 15.7 Hz, 1H), 5.76 (d, J = 15.7 Hz, 1H), 5.29 (t, J = 7.4 Hz, 1H), 1.45 (d, J = 7.0 Hz, 3H).

[0446] Example 206 4-(1-(1-(3-chlorobenzyl)-5-(3-cyanophenyl)-1H-indolyl-7-amido)cyclopropyl)benzoic acid [ka] Starting from 1-(bromomethyl)-3-chlorobenz, methyl 4-(1-aminocyclopropyl)benzoate and (3-cyanophenyl)biphenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 546 [M+1] + . 400MHz 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.37 (s, 1H), 8.30 (s, 1H), 8.17 (d, J = 6.0 Hz, 2H), 7.85 - 7.78 (m, 3H), 7.78 - 7.68 (m, 2H), 7.55 (d, J = 3.2 Hz, 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).

[0447] Example 207 (S)-4-(1-(1-([1,1'-biphenyl]-4-ylmethyl)-5-(3,4-difluorophenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-1,1'-biphenyl, (S)-methyl 4-(1-aminoethyl)benzoate and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 587.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H),8.96 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.87 - 7.80 (m, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.61 - 7.50 (m, 7H), 7.47 - 7.41 (m, 4H), 7.37 - 7.32 (m, 1H), 6.93 (d, J = 7.9 Hz, 2H), 6.72 (d, J = 3.1 Hz, 1H), 5.60 (s, 2H), 5.24 - 5.15 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H).

[0448] Example 208 4-((1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and phenylboronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 555.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.06 (t, J = 6.0 Hz, 1H), 8.02 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.67 - 7.59 (m, 3H), 7.57 (d, J = 1.8 Hz, 1H), 7.52 - 7.42 (m, 4H), 7.36 (dd, J = 7.7, 4.4 Hz, 3H), 7.26 (t, J = 8.7 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.73 (d, J = 3.1 Hz, 1H), 5.66 (s, 2H), 4.52 (d, J = 5.8 Hz, 2H).

[0449] Example 209 4-((1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (4-fluorophenyl)boronic acid, the same procedure as in Example 75 was followed to give the target product (28.8 mg) as a white solid. LCMS (ESI): 573.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 9.05 (t, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.77 (dd, J = 8.5, 5.5 Hz, 2H), 7.67 - 7.59 (m, 3H), 7.53 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.33-7.24 (m, 4H), 6.95 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.1 Hz, 1H), 5.66 (s, 2H), 4.52 (d, J = 5.8 Hz, 2H).

[0450] Example 210 4-((5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 591.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.03 (t, J = 6.0 Hz, 1H), 8.13 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 3.2 Hz, 1H), 7.62 (q, J = 5.3 Hz, 3H), 7.51 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 8.7 Hz, 2H), 7.18 (t, J = 9.3 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.1 Hz, 1H), 5.68 (s, 2H), 4.53 (d, J = 5.9 Hz, 2H).

[0451] Example 211 4-((5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 591.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.82 - 7.72 (m, 3H), 7.60 (d, J = 3.2 Hz, 1H), 7.60 - 7.41 (m, 5H), 7.38 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 3.1 Hz, 1H), 5.61 (s, 2H), 4.46 (d, J = 5.8 Hz, 2H).

[0452] Example 212 (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-4-(1-aminoethyl)methyl benzoate and phenylboronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 569.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.00 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.67 - 7.56 (m, 3H), 7.54 - 7.46 (m, 5H), 7.38 (dd, J = 13.5, 7.6 Hz, 3H), 7.26 (t, J = 8.8 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.1 Hz, 1H), 5.59 (s, 2H), 5.23-5.19 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H).

[0453] Example 213 (S)-4-(1-(1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-5-(4-fluorophenyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-methyl 4-(1-aminoethyl)benzoate and (4-fluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 587.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.98 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.82 - 7.74 (m, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.52 (s, 1H), 7.51 - 7.46 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.8 Hz, 2H), 7.26 (t, J = 8.8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 3.1 Hz, 1H), 5.59 (s, 2H), 5.20 (p, J = 7.4 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H).

[0454] Example 214 (S)-4-(1-(5-(3,5-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl) methyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-methyl 4-(1-aminoethyl)benzoate and (3,5-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 605.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.95 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 3.2 Hz, 1H), 7.63 - 7.48 (m, 7H), 7.39 (d, J = 7.9 Hz, 2H), 7.30 - 7.16 (m, 3H), 6.92 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 3.2 Hz, 1H), 5.68 - 5.53 (m, 2H), 5.23-5.17 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H).

[0455] Example 215 (S)-4-(1-(5-(3,4-difluorophenyl)-1-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 4-(bromomethyl)-4'-fluoro-1,1'-biphenyl, (S)-4-(1-aminoethyl)methyl benzoate and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 605.2 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.95 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.94 - 7.78 (m, 3H), 7.66 (d, J = 3.2 Hz, 1H), 7.65 - 7.54 (m, 3H), 7.55 - 7.47 (m, 4H), 7.40 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.8 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 3.1 Hz, 1H), 5.73 - 5.51 (m, 2H), 5.23-5.17 (m, 1H), 1.36 (d, J = 7.0 Hz, 3H).

[0456] Example 216 4-((5-(3,4-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)methyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene and (3,4-difluorophenyl)boronic acid, the same steps as in Example 75 were carried out to give the target product as a white solid. LCMS (ESI): 547.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.92 (t, J = 5.9 Hz, 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 - 7.48 (m, 2H), 7.47 - 7.42 (m, 2H), 7.38 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.10 - 7.03 (m, 1H), 6.73 (d, J = 3.1 Hz, 1H), 5.79 (s, 2H), 4.44 (d, J = 5.7 Hz, 2H).

[0457] Example 217 (S)-4-(1-(5-(3,4-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indolyl-7-amido)ethyl)benzoic acid [ka] Starting from 2-(bromomethyl)naphthalene, (S)-methyl 4-(1-aminoethyl)benzoate and (3,4-difluorophenyl)boronic acid, the target product was obtained as a white solid in the same manner as in Example 75. LCMS (ESI): 561.5 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.85 - 7.76 (m, 4H), 7.75 - 7.69 (m, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.47 - 7.42 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.36 (s, 1H), 7.06 - 7.01 (m, 1H), 6.72 (d, J = 3.1 Hz, 1H), 5.80 - 5.64 (m, 2H), 5.12 - 5.04 (m, 1H), 1.11 (d, J = 7.0 Hz, 3H).

[0458] Example 218 4-((5-(3,4-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)methyl)benzoic acid [ka] Starting from methyl 4-(aminomethyl)benzoate and (3,4-difluorophenyl)boronic acid, the same steps as in Example 167 were carried out to give the target product as a white solid. LCMS (ESI): 548.5 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 8.37 (s, 1H), 8.26 (d, J = 1.7 Hz, 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 = 8.0 Hz, 2H), 7.13 - 7.07 (m, 1H), 6.02 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H).

[0459] Example 219 (S)-4-(1-(5-(3,4-difluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid, the same procedure as in Example 167 was carried out to give the target product as a white solid. LCMS (ESI): 562.4 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.09 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J = 1.7 Hz, 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, 1.8 Hz, 1H), 5.97 (s, 2H), 5.21 (p, J = 7.1 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H).

[0460] Example 220 (S)-4-(1-(5-(3,4-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)benzoic acid [ka] Starting from (3,4-difluorophenyl)boronic acid, the same procedure as in Example 134 was carried out to give the target product as a white solid. LCMS (ESI): 580 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.22 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.28 (d, J = 1.7 Hz, 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 = 7.7 Hz, 1H), 5.86 (s, 2H), 5.21 - 5.10 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H).

[0461] Example 221 (1r,4r)-4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)cyclohexane-1-carboxylic acid [ka]

[0462] Step 1: Methyl 5-phenyl-1H-indazolyl-7-carboxylate [ka] At 70°C, a mixture of 5-bromo-1H-indazolyl-7-methyl carboxylate (0.8g), phenylboronic acid (4.0g), 1,1'-bis(diphenylphosphine)ferrocene-dichloride palladium(II) dichloromethane complex (0.27g) and potassium acetate (4.8g) in 1,4-dioxane / water (80mL / 8mL) was stirred with nitrogen gas for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate:= 5:1) to give the target compound (0.78g) as a yellow solid. LCMS(ESI):253.22 [M+1] + .

[0463] Step 2: 5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-carboxylate methyl [ka] 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 h, then treated with 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.1 g). After stirring at room temperature for 2 h, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate:= 10:1) to give the target compound (1.0 g) as a yellow solid. LCMS (ESI): 411.32 [M+1] + .

[0464] Step 3: 5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-carboxylic acid [ka] To a solution of the product of step 2 (1.0 g) in acetonitrile / water (30 mL / 15 mL) at room temperature was added lithium hydroxide monohydrate (2.1 g). The reaction mixture was stirred at 80 °C for 1 h. After cooling to 0 °C, the reaction mixture was treated with 6N hydrochloric acid until pH ≒ 6. Then, the reaction mixture was extracted with 3 x 50 mL ethyl acetate. The combined organic layers were washed with 200 mL 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] + .

[0465] Step 4: (1r,4r)-4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)cyclohexane-1-carboxylate methyl [ka] 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-carboxylate methyl hydrochloride (31 mg) and DIPEA (49 mg) in DMF (10 mL). After stirring at room temperature for 1 h, 5 mL water was added and stirring was continued at room temperature for 1 h, followed by filtration, collecting the solid, rinsing with water and air drying to give the target compound (60 mg) as a white solid. LCMS (ESI): 550.22 [M+1] + .

[0466] Step 5. (1r,4r)-4-((5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)methyl)cyclohexane-1-carboxylic acid [ka] To a solution of the product of step 4 (60 mg) in acetonitrile / water (10 mL / 5 mL) at room temperature was added lithium hydroxide monohydrate (106 mg). The reaction mixture was stirred at 70 °C for 1 h. After cooling to room temperature, the mixture was treated with 6N hydrochloric acid until pH ≒ 6. After filtration, the solid was collected, rinsed with water and air-dried to give the target compound (52 mg) as a white solid. LCMS (ESI): 536.32 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (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 = 7.8 Hz, 1H), 7.55 - 7.47 (m, 3H), 7.44 - 7.36 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 5.98 (s, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.13-2.07 (m, 1H), 1.90 - 1.80 (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).

[0467] Example 222 (±) (1r,4r)-4-1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)cyclohexane-1-carboxylic acid [ka]

[0468] Step 1 (1r,4r)-4-(Methoxy(methyl)carbamoyl)cyclohexane 1-carboxylate methyl [ka] In a 40 mL screw cap vial, (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (1.86 g), 1,1'-carbonyldiimidazole (2.1 g) and dichloromethane (50 mL) were added and stirred for 1 h. N,O-dimethylhydroxyammonium hydrochloride (1.94 g) was added and stirred at room temperature for 12 h. Then, water (100 mL) was added. The reaction mixture was extracted with dichloromethane (3 x 50 mL). The organic layer was washed using 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 (2.3 g). LCMS (ESI): 230.4 [M+1] + .

[0469] Step 2 (1r,4r)-4-Acetylcyclohexane-1-carboxylate methyl ester [ka] After cooling to 0°C, methylbromomagnesium (15 mL, 1M 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 h. Then, ammonium chloride (aqueous; 100 mL) was added. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed using 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] + .

[0470] Step 3 (±) (1r,4r)-4-(-1-aminoethyl)cyclohexane-1-carboxylate hydrochloride methyl [ka] 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 h. The reaction mixture was directly concentrated in vacuo, then poured into 100 mL water and extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and then treated with 1 mL hydrochloric acid (4 M in 1,4-dioxane). The mixture was concentrated in vacuo to give the crude product. LCMS (ES+): 186.3 [M+1] + .

[0471] Step 4 (±) (1r,4r)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)cyclohexane-1-carboxylate methyl [ka] At room temperature, a mixture of 5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-carboxylic acid (40 mg, 0.1 mmol), the product of step 3 (1.2 eq.), O-(7-azabenzotriazolyl-1-yl)-N,N,N',N'-tetramethylureauron hexafluorophosphate (114 mg) and DIPEA (39 mg) in anhydrous DMF (10 mL) was stirred for 12 h. Water (100 mL) was added and the mixture was extracted with 3 x 50 mL 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 give the oily target product (55 mg). LCMS (ES+): 564.6 [M+1] + .

[0472] Step 5 (±) (1r,4r)-4-(1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)cyclohexane-1-carboxylic acid [ka] The product of step 4 (55 mg) and lithium hydroxide monohydrate (42 mg) were dissolved in a solution of tetrahydrofuran / water (6 mL / 4 mL). After stirring at 40 °C for 12 h, the reaction mixture was acidified with 2 mL 6M hydrochloric acid and the tetrahydrofuran was removed in vacuo. The reaction mixture was then extracted with 3 x 50 mL ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the target product (50 mg). LCMS (ES+): 549.6 [M+1] + .

[0473] Examples 223 and 224 (1S,4r)-4-((S)-1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)cyclohexane-1-carboxylic acid (1R,4r)-4-((R)-1-(5-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-indazolyl-7-amido)ethyl)cyclohexane-1-carboxylic acid [ka] Example 222 was analyzed under the following conditions to obtain Examples 223 and 224: Column type: CHIRALPAK IB N-5, 5mm, 250mm x 4.6mm Mobile phase: n-hexane / ethanol (70:30) + 0.2% trifluoroacetic acid Flow rate: 1mL / min. Example 223: Retention time is 5.188 minutes; Example 224: Retention time is 8.485 minutes.

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 In the formula: R 1 -CO 2 H, -C(O)NHS(O) 2 R 7 , -NHC(O)NHSO 2 R 7 , -1H-tetrazole group, -P(O)(OH) 2 , -1,2,4-oxadiazol-5(4H)-one or -tetrazol-5(4H)-one, Y, N, CR 3 or 【Chemistry 2】 represents a chemical bond, R 2 , R 3 is halogen, hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Fluorocycloalkyl groups, C 1-6 Fluoroalkyl group or R 2 , R 3 and a 3- to 6-membered carbocyclic ring, which is optionally selected from the carbon atoms attached to both of them, e or comprises a 3-6 membered ring, which ring may contain 1 or 2 heteroatoms, such as S, O or NR b where R b is hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 Fluorocycloalkyl groups, C 1-6 Fluoroalkyl group, C 0-6 Alkylene group-aryl group, C 0-6 Alkylene-Heteroaryl, C(O)C 1-6 Alkyl groups, C(O)Aryl groups, S(O) 2 C 1-6 Alkyl group, S(O) 2 C 3-6 Cycloalkyl groups, S(O) 2 aryl groups, X is absent or is halogen, -CN, C 1-6 Alkyl group, OC 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl group or OC 1-6 It is a halogenated alkyl group. 【Chemistry 3】 are independently selected from the following structures: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 Z is O, S or NR 8 and X 1 is N or CR 4 and X 2 , X 3 are independently N, CR 4 , or -Y 2 -Ar 2 A carbon atom connected to X 2 Or X 3 At least one of them is -Y 2 -Ar 2 provided that the carbon atom is connected to X 4 are O, S, N, and NR 5 or CR 5 and X 5 are O, S, N, and CR. 6 or -C(O)-, X 6 , X 7 and X 8 are each independently N or C; Y 2 -C(O)-, -(CR a R 1a ) n -, -CH=CH, -C≡C-, -O-, -S-, S(O) 2 -, -S(O) 2 NR b -, -NR b S(O) 2 -, -C(O)NR b -, -NR b C(O)-, NR b C(O)NR b -, NR b S(O) 2 NR b -, -NRb-, or Y 2 does not exist and Ar 2 X 2 Or X 3 Directly connected to Y 1 -O-, -S-, -NR b -, -C(O)- or -CR a R 1a - and Y 3 is -(CR a 2 ) m - and n and m are each independently 0, 1, 2, or 3; r is 1 or 2; Each R a and R 1a are independently hydrogen, halogen, or C 1-6 Alkyl group or C 1-6 or two R a and R 1a together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocyclic group; Each R 4 , R 5 and R 6 are each independently hydrogen, an alkyl group, a halogen, or -OR 8 , -NR 8 R 9 , -SR 8 , -S(O) 2 NR 8 R 9 , -S(O) 2 R 11 , -CN,C 3-6 Cycloalkyl groups, -C 0-6 Alkylene group-aryl group, -C 0-6 independently selected from an alkylene group, a heteroaryl group, or a halogenated alkyl group; Ar 1 , Ar 2 are -OR 8 , -SR 8 , N.R. 8 R 9 , C 1-10 Alkyl group, C 1-10 Halogenated alkyl groups, -C 0-6 Alkylene group -C 3-6 Cycloalkyl groups, -C 0-6 Alkylene group-aryl group, -C 0-6 Alkylene group-heteroaryl group and -C 0-6 Alkylene group-heterocyclic group, or C 3-6 are independently selected from fused analogs of cycloalkyl groups, where Ar 1 and Ar 2 are 1-3 R e are independently substituted with groups, Two Ar on adjacent carbon atoms 2 With carbon atoms, it can be 3-6 membered carbocyclic, 4-8 membered bicyclic, C 5 -C 10 Aromatic ring (optionally one or more R e may be substituted with C 2 -C 90 Heteroaromatic ring (optionally multiple R e or 1, 2 or 3 heteroatoms (e.g., S, O or NR b ) can form a 3-6 membered ring, a 4-8 membered bicyclo or a 5-8 membered spiro ring, Each R e are independently halogen, hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Fluorocycloalkyl groups, C 1-6 Fluoroalkyl group, -C 2 -C 9 Alkynyl group, -C 0-6 Alkylene group-heterocyclic group, -C 0-6 Alkylene group-aryl group, -C 0-6 Alkylene-heteroaryl group, SF 5 , -C 0-6 Alkylene group -OR 8 , -C 0-6 Alkylene group -P(O)Me 2 , -C 0-6 -Alkylene group -NR 8 R 9 , -C 0-6 Alkylene group -C(O)NR 8 R 9 , -C 0-6 Alkylene group -SR 8 , -C 0-6 Alkylene group -S(O) 2 NR 8 R 9 , -C 0-6 Alkylene group -S(O) 2 R 10 Or -C 0-6 An alkylene group, -CN, where C 1-6 Alkyl group, C 2-9 Alkenyl group, C 2-9 Alkynyl group, -C 0-6 Alkylene group-cycloalkyl group, -C 0-6 Alkylene group-heterocyclic group, -C 0-6 Alkylene group-aryl group and -C 0-6 Alkylene group-heteroaryl group, R e may optionally contain one, two or three R v may be substituted with R v each independently represents an alkyl group, a halogenated alkyl group, a cycloalkyl group, a cycloalkyl group-alkyl group, a heterocyclic group, a heterocyclic group-alkyl group, a 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) 2 R 10 , -S(O)R 10 , -SR 8 , -S(O) 2 NR 8 R 9 , -S(O)NR 8 R 9 , -NR 8 S(O)R 10 , -NR 8 S(O) 2 R 10 or -NR 10 S(O) 2 NR 8 R 9 wherein the alkyl group is optionally -OR 8 or -NR 8 R 9 and the cycloalkyl and heterocyclic groups are optionally substituted with one, two or three groups independently selected from halogen, alkyl and halogenated alkyl groups; R 7 is C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 independently selected from a halogen ring-alkyl group, an aryl group, and a heteroaryl group; Each R 8 and R 9 are each independently hydrogen, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally substituted with one, two, or three groups independently selected from halogen, an alkyl group, and a halogenated alkyl group; 8 and R 9 together with the atom or atoms to which they are attached form a heterocyclic group, which is optionally substituted with one, two or three groups independently selected from halogen, alkyl and halogenated alkyl groups; Each R 10 are each independently an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally substituted with one, two, or three groups independently selected from halogen, an alkyl group, and a halogenated alkyl group; 【Chemistry 9】 are independently selected from the following structures: 【Chemistry 10】 【Chemistry 11】 is one or more R e or a pharma- ceutically acceptable salt thereof, wherein the compound in formula I is optionally substituted with

2. The compound of formula I is 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, wherein X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

3. The compound of formula I is 【Chemistry 13】 and In the formula, X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

4. The compound of formula I is 【Chemistry 14】 and In the formula: X 5 is N or CR 6 and R 2 , R 3 , R 5 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

5. The compound of formula I is 【Chemistry 15】 and In the formula, X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 The definition of claim 1 is as in formula I.

6. The compound of formula I is 【Chemistry 16】 and In the formula, X 5 is N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

7. The compound of formula I is 【Chemistry 17】 and In the formula: X 4 is NR 5 , O or S; R 2 , R 3 , R 5 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

8. The compound of formula I is 【Chemistry 18】 and In the formula, X 4 is NR 5 , O or S; R 2 , R 3 , R 5 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

9. The compound of formula I is 【Chemistry 19】 and In the formula, X 4 and X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

10. The compound of formula I is 【Chemistry 20】 and In the formula, X 4 and X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

11. The compound of formula I is 【Chemistry 21】 and In the formula, X 4 and X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 The compound according to claim 1, wherein:

12. The compound of formula I is 【Chemical 22】 and In the formula, X 4 and X 5 are each independently N or CR 6 and R 2 , R 3 , R 6 , Y 1 , Y 2 , Ar 1 and Ar 2 2. The compound according to claim 1, wherein: is defined as in formula I; t is 0, 1 or 2; and q is 1, 2 or 3; or a pharma- ceutically acceptable salt thereof.

13. The compound of claim 1, selected from the compounds described in the "Description" section and the exemplary portion (Chemical Formula 29 to Chemical Formula 115) of the present invention, or a pharma- ceutically acceptable salt thereof.

14. 14. A method for treating a human or animal disease mediated by PGE2 receptor activity by administering to a subject an effective dose of a compound, wherein the disease or condition is selected from the group consisting of cancer, pain, neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, endometriosis and renal disease, comprising administering a compound according to any one of claims 1 to 13.

15. The present invention includes a method of treating a subject with cancer by administering thereto an effective dosage of a compound, wherein the antibody is selected from an anti-CTLA4, anti-PD-L1, anti-PD-1 antibody, or a compound according to any of claims 1 to 13 in combination with a small molecule drug, such as a kinase inhibitor, an A2A receptor antagonist, an IDO inhibitor, a TDO inhibitor, an HDAC inhibitor, a PI3K / AKT pathway inhibitor, an endocrine / hormonal drug, other chemotherapeutic drug, or antimetabolic drug.

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