Heterocyclic compound

Abstract

Provided is a compound or a salt thereof, which has an excellent JAK inhibitory action, and is useful as a prophylactic or therapeutic agent for autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's syndrome, multiple sclerosis, systemic lupus erythematosus, etc.), cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.) and the like. The present invention relates to a compound represented by the formula (I) wherein each symbol is as defined in the present specification, or a salt thereof.

1 . A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is an optionally substituted C 1-6  alkyl group, or an optionally substituted cyclic group; 
         R 2  is a hydrogen atom or a cyano group; 
         R 3  is an optionally substituted C 1-3  alkyl group; 
         R 4  is a substituent; and 
         R 5  is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6  alkyl group, an optionally substituted C 1-6  alkoxy group, or an acyl group, or a salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 R 1  is
 (1) a C 1-6  alkyl group optionally substituted by 1 to 5 substituents selected from
 (a) a halogen atom, 
 (b) a C 3-8  cycloalkyl group optionally substituted by 1 to 3 C 1-6  alkyl groups, 
 (c) an oxetanyl group optionally substituted by 1 to 3 C 1-6  alkyl groups, 
 (d) a C 1-6  alkoxy-carbonyl group, 
 (e) a carbamoyl group, 
 (f) a hydroxy group, and 
 (g) a cyano group, 
 
 (2) a C 3-10  cycloalkyl group optionally substituted by 1 to 3 C 1-6  alkyl groups, or 
 (3) a C 6-14  aryl group optionally substituted by 1 to 3 substituents selected from
 (a) a halogen atom, 
 (b) a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, and 
 (c) a cyano group; 
 
   R 2  is a hydrogen atom or a cyano group;   R 3  is a C 1-3  alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6  alkoxy group;   R 4  is
 (1) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a halogen atom, 
 (b) a cyano group, 
 (c) a hydroxy group, 
 (d) an amino group optionally mono- or di-substituted by C 1-6  alkyl-carbonyl group(s), 
 (e) a carbamoyl group optionally mono- or di-substituted by C 1-6  alkyl group(s), and 
 (f) a C 1-6  alkoxy group, 
 
 (2) a C 3-10  cycloalkyl group, 
 (3) a C 6-14  aryl group optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group, 
 (b) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s), and 
 (c) a carbamoyl group optionally mono- or di-substituted by C 1-6  alkyl group(s), 
 
 (4) a 5- or 6-membered non-aromatic heterocyclic group having one oxygen atom, 
 (5) a pyrazolyl group, a pyridyl group, a pyrimidinyl group or a pyrazinyl group, each of which is optionally substituted by 1 to 3 C 1-6  alkyl groups, 
 (6) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, 
 (7) a halogen atom, 
 (8) a cyano group, 
 (9) a group represented by the formula: 
   
       
         
           
           
               
               
           
         
         wherein 
         R 6  and R 7  are each independently a C 1-6  alkyl group; or 
         R 6  and R 7  form, together with the adjacent carbon atom, cyclobutane, cyclohexane, azetidine, tetrahydropyran or tetrahydrothiopyran, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom, a carbamoyl group optionally mono- or di-substituted by C 1-6  alkyl group(s), a C 1-6  alkyl-carbonyl group, a C 1-6  alkylsulfonyl group and an oxo group; 
         R 12  is a C 1-6  alkyl group; 
         R 8  and R 9  are each independently
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 3-8  cycloalkyl group and a C 1-6  alkoxy group, 
 (iii) a C 3-10  cycloalkyl group optionally substituted by 1 to 3 halogen atoms, 
 (iv) a C 6-14  aryl group optionally substituted by 1 to 3 halogen atoms, 
 (v) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, 
 (vi) a C 6-14  aryloxy group optionally substituted by 1 to 3 halogen atoms, 
 (vii) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, 
 (viii) a C 1-6  alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, 
 (ix) a C 1-6  alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms, 
 (x) a carbamoyl group optionally mono- or di-substituted by C 1-6  alkyl group(s) optionally substituted by 1 to 3 halogen atoms, 
 (xi) an aromatic heterocyclic group, or 
 (xii) a 5- or 6-membered non-aromatic heterocyclic group having one oxygen atom; or 
 
         R 8  and R 9  form, together with the adjacent nitrogen atom,
 (i) an aromatic nitrogen-containing heterocycle optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, 
 (b) a hydroxy group, 
 (c) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, and 
 (d) a halogen atom, or 
 
 (ii) a non-aromatic nitrogen-containing heterocycle optionally forming a fused ring, a bridged ring or a Spiro ring, which is optionally substituted by 1 to 5 substituents selected from
 (a) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (A) a halogen atom, 
 (B) a hydroxy group, 
 (C) a cyano group, 
 (D) a C 1-6  alkylsulfonyl group, 
 (E) an amino group optionally mono- or di-substituted by substituent(s) selected from a C 1-6  alkyl group, a C 1-6  alkyl-carbonyl group, a C 1-6  alkoxy-carbonyl group and a C 1-6  alkylsulfonyl group, 
 (F) a C 1-6  alkoxy group, 
 (G) azetidinyl group, pyrrolidinyl group, piperidyl group or morpholinyl group, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom and an oxo group, and 
 (H) a pyrazolyl group, 
 
 (b) a hydroxy group, 
 (c) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, 
 (d) a halogen atom, 
 (e) a C 1-6  alkyl-carbonyl group, 
 (f) a C 1-6  alkoxy-C 1-6  alkyl-carbonyl group, 
 (g) an oxo group, 
 (h) a C 1-6  alkylsulfonyl group, 
 (i) a C 3-10  cycloalkylsulfonyl group, 
 (j) an amino group optionally mono- or di-substituted by alkyl group(s), and 
 (k) a cyano group; 
 
 
         R 10  and R 11  are each independently
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 3-8  cycloalkyl group and a C 1-6  alkoxy group, 
 (iii) a C 3-10  cycloalkyl group optionally substituted by 1 to 3 halogen atoms, 
 (iv) a C 6-14  aryl group optionally substituted by 1 to 3 halogen atoms, 
 (v) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, 
 (vi) a C 6-14  aryloxy group optionally substituted by 1 to 3 halogen atoms, 
 (vii) a alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, 
 (viii) a C 1-6  alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, 
 (ix) a C 1-6  alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms, 
 (x) a carbamoyl group optionally mono- or di-substituted by C 1-6  alkyl group(s) optionally substituted by 1 to 3 halogen atoms, 
 (xi) an aromatic heterocyclic group, or 
 (xii) a 5- or 6-membered non-aromatic heterocyclic group having one oxygen atom; or 
 
         R 10  and R 11  form, together with the adjacent nitrogen atom,
 (i) an aromatic nitrogen-containing heterocycle optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, 
 (b) a hydroxy group, 
 (c) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, and 
 (d) a halogen atom, or 
 
 (ii) a non-aromatic nitrogen-containing heterocycle optionally forming a fused ring or a spiro ring, which is optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a C 1-6  alkoxy group, 
 (b) a hydroxy group, 
 (c) a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms, 
 (d) a halogen atom, 
 (e) a C 1-6  alkyl-carbonyl group, 
 (f) a C 1—-6  alkoxy-C 1-6  alkyl-carbonyl group, and 
 (g) an oxo group, or 
 
 (10) a C 3-8  cycloalkenyl group; and 
 
         R 5  is a hydrogen atom, or a salt thereof. 
       
     
     
         3 . 3-Amino-7-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)-5-((2S)-3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one or a salt thereof. 
     
     
         4 . 3-Amino-5-(dicyclopropylmethyl)-7-(1-methyl-5-(morpholin-4-yl)-1H-pyrazol-3-yl)-1H-pyrazol-3-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one or a salt thereof. 
     
     
         5 . 3-Amino-5-(dicyclopropylmethyl)-7-(5-((2R)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-3-5 yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one or a salt thereof. 
     
     
         6 . A medicament comprising the compound or salt according to  claim 1 . 
     
     
         7 . The medicament according to  claim 6 , which is a Janus kinase inhibitor. 
     
     
         8 . The medicament according to  claim 6 , which is an agent for the prophylaxis or treatment of autoimmune disease. 
     
     
         9 . The medicament according to  claim 8 , wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's syndrome, or multiple sclerosis. 
     
     
         10 . The compound or salt according to  claim 1  for use in the prophylaxis or treatment of autoimmune disease. 
     
     
         11 . The compound or salt according to  claim 10 , wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's syndrome, or multiple sclerosis. 
     
     
         12 . A method of inhibiting Janus kinase in a mammal, which comprises administering an effective amount of the compound or salt according to  claim 1  to the mammal. 
     
     
         13 . A method for the prophylaxis or treatment of autoimmune disease, which comprises administering an effective amount of the compound or salt according to  claim 1  to the mammal. 
     
     
         14 . The treatment method according to  claim 13 , wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's syndrome, or multiple sclerosis. 
     
     
         15 . Use of the compound or salt according to  claim 1  for the production of an agent for the prophylaxis or treatment of autoimmune disease. 
     
     
         16 . Use according to  claim 15 , wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's syndrome, or multiple sclerosis.