Heteroaryl amide compound

Abstract

Provided is a compound useful as a therapeutic drug for inflammatory disease and / or cancer.　The present inventors studied compounds having an inhibitory effect on AIM2 inflammasome pathway activation and confirmed that a heteroaryl amide compound has an inhibitory effect on AIM2 inflammasome pathway activation, thereby completing the present invention. The heteroaryl amide compound according to the present invention has an inhibitory effect on AIM2 inflammasome pathway activation, and can be used as a therapeutic agent for inflammatory disease and / or cancer.

Claims

The compound or salt thereof described in formula (I). (In the formula, A 1 、 A 2 and A 3 in combination [A 1 、 A 2 、 A 3 is [CR A , CH, N], [CR A , N, CH], [N, CH, CH], [CR A , N, N], [N, CH, N] or [N, N, N], R A H, C 1-3 It is an alkyl or halogen, R 1 is a base represented by formula (II), formula (III), or formula (IV), X 1 , X 2 and X 3 combination [X 1 , X 2 , X 3 ] is [CH, CH, CH], [N, CH, CH], [CH, N, CH] or [CH, CH, N], Y 1 is C, CH, or N, and Y 2 and Y 3 These are C, CH, CH2, N, or NH, independently of each other. Z 1 , Z 2 and Z 3 These are C, CH, CH2, N, or NH, independently of each other. Y 1 ...Y 2 , Y 2 ...Y 3 , Z 1 ...Z 2 and Z 2 ...Z 3 The dotted lines in the diagram represent single or double bonds that are independent of each other. R 1A is H or C 1-3 It is alkyl, R 1B and R 1C H and C are independent of each other. 1-3 Alkyl, halogen, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 It is a haloalkyl or cyano compound. R 2 may be a substituted aryl, may be substituted thienyl, may be substituted benzothiophenyl, or -NR 2A R 2B And, i) R 2A is H or C 1-3 It is alkyl, R 2B is -CH2-CH(R 2C )-R 2D And, R 2C H, C 1-3 It is alkyl or OH, R 2D is an aryl or heteroaryl that may be substituted, Or, ii) R 2A and R 2B is the R 2A and R 2B It combines with N to form a group represented by formula (V), W 1 and W 2 Each of these is independent of the bond, CH2, O, NH, NC. 1-3 Alkyl or S(=O) n And, n is 0, 1, or 2. R 2E is an optionally substituted aryl or optionally substituted heteroaryl, R 2F and R 2G These are H and C, which are independent of each other. 1-3 Alkyl, halogen, C 1-3 Haloalkyl, OH, cyano, or -C 1-3 It is alkylene-OH, R 3A is H or possibly C 1-3 It is alkyl, R 3B H is C, which may be substituted. 1-6 Alkyl, possibly substituted C 3-8 A cycloalkyl, an optionally substituted 4- to 8-membered saturated heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, R 3A and R 3B is the R 3A and R 3B It combines with the N to which it binds to form a substituted 4- to 8-membered nitrogen-containing saturated heterocycline, which may be condensed with an aryl or heteroaryl. A 1 , A 2 and A 3 combination [A 1 , A 2 , A 3 ] is [CR A The compound or salt thereof according to claim 1, wherein the compound is N,N. R A is H or F, R 1 is a group represented by formula (II), formula (IIIa), formula (IIIb), or formula (IVa), R 1B and R 1C H and C are independent of each other. 1-3 Alkyl, halogen, C 1-3 It is a haloalkyl or cyano compound. R 2 is 2-thienyl or -NR 2A R 2B and i) R 2A C 1-3 It is alkyl, R 2B -CH2-CH(R 2C )-R 2D And, R 2C is H, or C 1-3 is alkyl, R 2D Is it a heteroaryl? Or, ii) R 2A and R 2B R 2A and R 2B It combines with N to form a group represented by formula (V), W 1 and W 2 Each of these is independent of the bond, CH2, O, NC 1-3 Alkyl or S(=O) n And, n is 2, R 2E 1 to 3 R 2H An aryl or 1 to 3 R may be substituted. 2H It is a heteroaryl which may be substituted with R 2F and R 2G H and C are independent of each other. 1-3 It is an alkyl or halogen, R 2H Each of them operates independently, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, C 1-6 Haloalkyl, -OC 1-6 Alkyl or phenyl, R 3A is H or C 1-3 It is alkyl, R 3B H, 1-2 R 3C C is replaced by 1-6 Alkyl, 1-2 R 3D C is replaced by 3-8 Cycloalkyl, 1-2 R 3E A 4- to 8-membered saturated heterocycline or 1-2 R which may be substituted. 3F It is a heteroaryl that may be substituted with, Or, R 3A and R 3B R 3A and R 3B It combines with N to form 1-2 R 3G It forms a 4-8 member nitrogen-containing saturated heterocycline which may be substituted with, and the nitrogen-containing saturated heterocycline may be condensed with a heteroaryl, R 3C Each of these is independent of OH, -C(=O)NH2, and -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2, R 3H A 4- to 8-member saturated heterocycline or R which may be substituted. 3I It is a heteroaryl which may be substituted with R 3D Each of them operates independently, C 1-6 Alkyl, OH, or -(C 1-6 It is alkylene)-OH. R ３Ｅ Each of them operates independently, C 1-6 Alkyl, OH, -(C 1-6 It is alkylene)-OH or oxo. R 3F Each of them operates independently, C 1-6 Alkyl or 4-8 member saturated heterocycline, R 3G Each of them operates independently, C 1-6 Alkyl, OH, -(C 1-6 Alkylene)-OH, -C(=O)-C 1-6 Alkyl, -C(=O)-(C 1-6 Alkylene)-OH, -NR 3J R 3K , -C 1-6 Alkilen-NR 3J R 3K , -C 1-6 Alkylene-C(=O)- NR 3J R 3K , oxo, imino, methylimino or 4-8 member saturated heterocyclyl, R 3H Each of them operates independently, C 1-6 Alkyl, OH, or -(C 1-6 It is alkylene)-OH. R 3I Each of them operates independently, C 1-6 It is alkyl, R 3J , R 3K H and C are independent of each other. 1-6 Alkyl, -(C 1-6 Alkylene)-OH or -C(=O)-C 1-6 A compound or salt thereof according to claim 1 or 2, which is alkyl. A 1 , A 2 and A 3 combination [A 1 , A 2 , A 3 ] is [CR A ,N,N], R 1 The base is represented by formula (IIa), R 2 ga-NR 2A R 2B And, R 2A and R 2B R 2A and R 2B It combines with N to form a group represented by formula (V), W 1 CH2 is W 2 The compound or salt thereof according to claim 3, wherein the bond is R A H is, R 1A H is, R 1B and R 1C These are H or halogen, independently of each other. R 2E 1 to 3 R 2H It is a heteroaryl which may be substituted with R 2F and R 2G H is, R 2H Each of them operates independently, C 1-6 Alkyl, halogen, or C 1-6 It is a haloalkyl, R 3A is H or C 1-3 It is alkyl, R 3B 1 to 2 R 3C C is replaced by 1-6 Alkyl, 1-2 R 3D C is replaced by 3-6 Cycloalkyl or 1-2 R 3E A 4-6 member saturated heterocycline which may be substituted, Or, R 3A and R 3B R 3A and R 3B It combines with N to form 1-2 R 3G It forms a 4-6 member nitrogen-containing saturated heterocycline which may be substituted with R 3C Each of them independently becomes OH or R 3H A 4-6 member saturated heterocycline which may be substituted with R ３Ｅ Each of them is independent of OH, -(C 1-6 It is alkylene)-OH or oxo. R 3G Each of them operates independently, C 1-6 Alkyl, OH, -(C 1-6 The compound or salt thereof according to claim 4, which is an alkylene)-OH, oxo, methylimino, or a 4- to 6-membered saturated heterocycline. R 1B and R 1C They are H or F, independently of each other. R 2 ga-NR 2A R 2B And, R 2A and R 2B R 2A and R 2B It combines with N to form a group represented by formula (Va), R 2E is one R 2H It is pyrazole-1-yl or indazole-2-yl, which may be substituted with R 2H It is trifluoromethyl, R 3A is H or C 1-3 It is alkyl, R 3B 1 to 2 R 3C C is replaced by 1-6 Alkyl or 1-2 R 3D Is it cyclobutyl substituted with, Or, R 3A and R 3B R 3A and R 3B It combines with N to form 1-2 R 3G It forms azetidine-1-yl which is substituted with R 3C is OH, R 3D Each of them operates independently, C 1-3 Alkyl, OH, or -(C 1-3 It is alkylene)-OH. R 3G Each of them operates independently, C 1-3 Alkyl, OH, or -(C 1-3 The compound or salt thereof according to claim 5, which is alkylene)-OH. [(2S)-2-(hydroxymethyl)azetidine-1-yl]{6-[(3R)-3-(2H-indazole-2-yl)piperidine-1-yl]-2-[(pyridine-3-yl)amino]pyrimidine-4-yl}methanone, N-(2-hydroxy-2-methylpropyl)-6-[(3R)-3-(2H-indazole-2-yl)piperidine-1-yl]-N-methyl-2-[(pyridine-3-yl)amino]pyrimidine-4-carboxyamide, (2-[(2-fluoropyridine-3-yl)amino]-6-{(3R)-3-[3-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-yl}pyrimidine-4-yl)[(2S)-2-(hydroxymethyl)azetidine-1-yl]methanone, 2-[(2-fluoropyridine-3-yl)amino]-N-[(1s,3S)-3-hydroxy-3-methylcyclobutyl]-6-{(3R)-3-[3-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-yl}pyrimidine-4-carboxamide, 2-[(2-fluoropyridine-3-yl)amino]-N-[(1r,3R)-3-hydroxy-3-methylcyclobutyl]-6-{(3R)-3-[3-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-yl}pyrimidine-4-carboxamide, 2-[(2-fluoropyridine-3-yl)amino]-N-(2-hydroxy-2-methylpropyl)-6-{(3R)-3-[3-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-yl}pyrimidine-4-carboxamide, and N-(2-hydroxy-2-methylpropyl)-6-[(3R)-3-(2H-indazole-2-yl)piperidine-1-yl]-2-[(pyridine-3-yl)amino]pyrimidine-4-carboxyamide The compound or salt thereof according to claim 1, which is a compound or salt thereof selected from the group consisting of the following. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1 to 7, and one or more pharmaceutically acceptable excipients.

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