Biphenyl compounds as immunomodulators, methods for preparing them, and their applications.

Abstract

The present invention relates to a biphenyl compound represented by formula (I), its preparation method and its application. The present invention also relates to a pharmaceutical composition comprising the compound as an active ingredient. The compound is a novel small molecule immunomodulator with excellent oral absorption characteristics, and can be used to treat and / or prevent various immune-related diseases. [Formula 1] JPEG2024504224000063.jpg86166

Claims

[Claim 1] Formula (I) 【Chemistry 1】 (In the formula, R １ and R ２ However, they can be selected identically or differently from methyl, cyano, fluorine, chlorine, and bromine; R ３ is C １ -C ６ alkyl, C ２ -C ６ alkenyl C １ -C ６ alkyl, C ２ -C ６ alkynyl C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy C １ -C ６ alkyl, mono-C １ -C ６ alkylamino C １ -C ６ alkyl, di-C １ -C ６ alkylamino C １ -C ６ alkyl, C １ -C ６ haloalkoxy C １ -C ６ alkyl, C ３ -C １４ cycloalkyl, 3- to 14-membered heterocycloalkyl, C ３ -C １４ cycloalkyl-C １ -C ４ alkyl, and 3- to 14-membered heterocycloalkyl-C １ -C ４ selected from alkyl; R ４ However, hydrogen and C １ ~C ６ Selected from alkyl, the C １ ~C ６ The alkyl group is optionally substituted with one or more substituents selected from hydroxyl groups and halogens; X is -O- and -N(R ａ ) - Selected from; R ａ However, hydrogen, methyl, ethyl, isopropyl, and C １ ~C ６ Selected from haloalkyls; m is 1, 2, or 3; n is 1, 2, or 3. The compounds listed, their stereoisomers, or pharmaceutically acceptable salts thereof. [Claim 2] R １ and R ２ However, they can be selected from methyl, cyano, fluorine, and chlorine, either identically or differently; R ３ However, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, mono-C １ ~C ６ Alkylamino C １ ~C ６ Alkyl, di-C １ ~C ６ Alkylamino C １ ~C ６ Alkyl, C １ ~C ６ Haloalkoxy C １ ~C ６ Alkyl, C ３ ~C １４ Selected from cycloalkyl and 3- to 14-membered heterocycloalkyl groups; R ４ However, hydrogen and C １ ~C ６ Selected from alkyl, the C １ ~C ６ The alkyl group is optionally substituted with a halogen substituent; X is -O- and -N(R ａ ) - Selected from; R ａ is selected from hydrogen, methyl, ethyl, and C １ to C ６ haloalkyl; m is 1 or 2; n is 1, 2, or 3. The compound described in claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 3] R １ and R ２ However, they can be selected from methyl, cyano, fluorine, and chlorine, either identically or differently; R ３ is C １ to C ６ alkyl, C ２ to C ６ alkenyl C １ to C ６ alkyl, C ２ to C ６ alkynyl C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy C １ to C ６ alkyl, mono-C １ to C ６ alkylamino C １ to C ６ alkyl, di-C １ to C ６ alkylamino C １ to C ６ alkyl, and C １ to C ６ haloalkoxy C １ to C ６ selected from; R ４ However, hydrogen and C １ ~C ６ Selected from alkyl, the C １ ~C ６ The alkyl group is optionally substituted with substituents selected from fluorine, chlorine, and bromine; X is -O- and -N(R ａ ) - Selected from; R ａ However, hydrogen, methyl, ethyl, C １ ~C ６ Fluoroalkyl, and C １ ~C ６ Selected from chloroalkyl; m is 1 or 2; n is 1, 2, or 3. The compound described in claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 4] R １ and R ２ However, they can be selected from methyl, cyano, fluorine, and chlorine, either identically or differently; R ３ However, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl and C １ ~C ６ Haloalkoxy C １ ~C ６ Selected from alkyl groups; R ４ However, hydrogen and C １ ~C ６ Selected from alkyl, the C １ ~C ６ The alkyl group is optionally substituted with substituents selected from fluorine and chlorine; X is -O- and -N(R ａ ) - Selected from; m is 1 or 2; n is 1, 2, or 3; R ａ is methyl, The compound described in claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 5] R １ and R ２ However, they can be selected from methyl, cyano, fluorine, and chlorine, either identically or differently; R ３ However, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl and C １ ~C ６ Haloalkoxy C １ ~C ６ Selected from alkyl groups; R ４ However, hydrogen and methyl are selected; X is -O- and -N(R ａ ) - Selected from; m is 1 or 2; n is 1, 2, or 3; R ａ is methyl, The compound described in claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 6] 4-(2-(2-((2-chloro-3'-(5-(3-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)propyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2'-chloro-3'-(5-(2-(4-(ethoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2'-chloro-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2-chloro-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2'-chloro-3'-(5-(3-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)propyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(5-(2-(4-((difluoromethoxy)methyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(5-((4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-((2-((2,2'-dichloro-3'-(5-((4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)methyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-((2-((2-chloro-3'-(5-((4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)methyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(5-((4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid methyl ester; 4-(2-(2-((2-chloro-2'-fluoro-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2-chloro-3'-(5-(2-(4-((difluoromethoxy)methyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2-chloro-2'-cyano-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-(2-(2-((2'-cyano-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid; 4-((2-((2-chloro-3'-(5-(2-(4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)methyl)bicyclo[2.2.1]heptan-1-carboxylic acid; and 4-(2-(2-((2'-chloro-3'-(5-((4-(methoxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)ethyl)bicyclo[2.2.1]heptan-1-carboxylic acid A compound according to any one of claims 1 to 5, selected from, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 7] A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, a stereoisomer thereof, or a metabolite thereof. [Claim 8] For treating and / or preventing diseases related to target PD-L1, To inhibit the activity of PD-L1, or For use as an immunomodulator that targets the PD-L1 signaling pathway. The pharmaceutical composition according to claim 7. [Claim 9] The pharmaceutical composition according to claim 8, wherein the disease related to the target PD-L1 includes tumors, cancer, or other immune-related diseases. [Claim 10] A drug for treating and / or preventing diseases related to targeted PD-L1, or A drug for inhibiting the activity of PD-L1, or A drug as a PD-L1 inhibitor, or A drug as an immunomodulator to target the PD-L1 signaling pathway. The use of a compound according to any one of claims 1 to 6 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of the compound. [Claim 11] The use according to claim 10, wherein the disease associated with the target PD-L1 includes tumors, cancers, or other immune-related diseases.

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