Indole compounds and pharmaceutical use thereof

Abstract

The invention provides a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof: wherein each symbol is as described in the specification. The invention also provides a method for the treatment or prophylaxis of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection or the like in a mammal by administering the compound or pharmaceutically acceptable salt thereof or solvate thereof to the mammal.

1 . A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is 
         (1) a hydrogen atom, 
         (2) a hydroxy group, or 
         (3) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s); 
         R 2  and R 3  are the same or different and each is 
         (1) a hydrogen atom, or 
         (2) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group; and 
 
         R 4  is a group represented by 
       
       
         
           
           
               
               
           
         
         which is bonded to the 5-position or the 6-position of the indole ring, 
         wherein 
         R 5  is 
         (1) a hydrogen atom, or 
         (2) a C 1-6  alkyl group, and 
         R 6  is 
         (1) a hydrogen atom, 
         (2) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group, 
 (c) a carboxy group, 
 (d) a C 1-6  alkoxy-carbonyl group, 
 (e) a C 6-10  aryl group, 
 (f) a C 6-10  aryloxy group, 
 (g) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s), 
 (h) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by C 1-6  alkyl group(s), and 
 (i) a 5- or 6-membered saturated heterocyclic group, 
 
         (3) a C 1-6  alkoxy group, 
         (4) a C 6-10  aryl group, or 
         (5) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group, or 
 
         R 5  and R 6  form, together with the nitrogen atom they are bonded to, a 5- or 6-membered cyclic amine (said cyclic amine is optionally condensed with 5- or 6-membered unsaturated heterocycle) optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkyl group, 
 (c) a C 1-6  alkoxy group, and 
 (d) a C 1-6  alkoxy-carbonyl group; 
 
         R 7  is 
         (1) a hydrogen atom, or 
         (2) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group, and 
 (c) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s), and 
 
         R 8  is 
         (1) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
 (c) a C 3-6  cycloalkyl group optionally substituted by C 1-6  alkoxy group(s), 
 (d) a C 6-10  aryl group, 
 (e) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by oxo group(s), 
 (f) a 5- to 8-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (i) a hydroxy group, 
 (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy group, and 
 (iv) an oxo group, 
 
 (g) a C 3-6  cycloalkyloxy group, 
 (h) a C 6-10  aryloxy group, 
 (i) a 5- or 6-membered unsaturated heterocyclyloxy group, 
 (j) a 5- or 6-membered saturated heterocyclyloxy group, and 
 (k) an amino group optionally mono- or di-substituted by substituents selected from
 (i) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6  alkoxy group, 
 (ii) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy-carbonyl group optionally substituted by C 6-10  aryl group(s), and 
 (iv) a C 3-6  cycloalkyl-carbonyl group optionally substituted by C 1-6  alkoxy group(s), 
 
 
         (2) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
         (3) a C 3-6  cycloalkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group, 
 
         (4) a C 6-10  aryl group optionally substituted by C 1-6  alkyl group(s) optionally substituted by 1 to 3 halogen atoms, 
         (5) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s) optionally substituted by C 6-10  aryl group(s), 
         (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by C 1-6  alkyl group(s), 
         (7) a 5- or 6-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group, 
 (b) a C 1-6  alkyl-carbonyl group, and 
 (c) an oxo group, 
 
         (8) a C 3-6  cycloalkyloxy group, or 
         (9) a C 6-10  aryl-carbonyl group, or 
         R 7  and R 8  form, together with the nitrogen atom and carbon atom they are bonded to, a 5- or 6-membered cyclic amine substituted by an oxo group and optionally further substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkyl group optionally substituted by hydroxy group(s), 
 (c) a C 1-6  alkoxy group, and 
 (d) a C 3-6  cycloalkyl group. 
 
       
     
     
         2 . A compound represented by the following formula [I-a] or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is 
         (1) a hydrogen atom, 
         (2) a hydroxy group, or 
         (3) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s); 
         R 2  and R 3  are the same or different and each is 
         (1) a hydrogen atom, or 
         (2) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group; 
 
         R 7 ′ is a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group, and 
 (c) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s), and 
 
         R 8  is 
         (1) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
 (c) a C 3-6  cycloalkyl group optionally substituted by C 1-6  alkoxy group(s), 
 (d) a C 6-10  aryl group, 
 (e) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by oxo group(s), 
 (f) a 5- to 8-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (i) a hydroxy group, 
 (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy group, and 
 (iv) an oxo group, 
 
 (g) a C 3-6  cycloalkyloxy group, 
 (h) a C 6-10  aryloxy group, 
 (i) a 5- or 6-membered unsaturated heterocyclyloxy group, 
 (j) a 5- or 6-membered saturated heterocyclyloxy group, and 
 (k) an amino group optionally mono- or di-substituted by substituents selected from
 (i) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6  alkoxy group, 
 (ii) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy-carbonyl group optionally substituted by C 6-10  aryl group(s), and 
 (iv) a C 3-6  cycloalkyl-carbonyl group optionally substituted by C 1-6  alkoxy group(s), 
 
 
         (2) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
         (3) a C 3-6  cycloalkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group, 
 
         (4) a C 6-10  aryl group optionally substituted by C 1-6  alkyl group(s) optionally substituted by 1 to 3 halogen atoms, 
         (5) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s) optionally substituted by C 6-10  aryl group(s), 
         (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by C 1-6  alkyl group(s), 
         (7) a 5- or 6-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group, 
 (b) a C 1-6  alkyl-carbonyl group, and 
 (c) an oxo group, 
 
         (8) a C 3-6  cycloalkyloxy group, or 
         (9) a C 6-10  aryl-carbonyl group, or 
         R 7′  and R 8  form, together with the nitrogen atom and carbon atom they are bonded to, a 5- or 6-membered cyclic amine substituted by an oxo group and optionally further substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkyl group optionally substituted by hydroxy group(s), 
 (c) a C 1-6  alkoxy group, and 
 (d) a C 3-6  cycloalkyl group. 
 
       
     
     
         3 . The compound according to  claim 2 , wherein
 R 1  is a hydrogen atom; and   R 2  and R 3  are the same or different and each is a C 1-6  alkyl group,   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 3 , wherein
 R 7′  is a C 1-6  alkyl group; and   R 8  is a C 1-6  alkyl group substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
 (c) a C 3-6  cycloalkyl group optionally substituted by C 1-6  alkoxy group(s), 
 (d) a C 6-10  aryl group, 
 (e) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by oxo group(s), 
 (f) a 5- to 8-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (i) a hydroxy group, 
 (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy group, and 
 (iv) an oxo group, 
 
 (g) a C 3-6  cycloalkyloxy group, 
 (h) a C 6-10  aryloxy group, 
 (i) a 5- or 6-membered unsaturated heterocyclyloxy group, 
 (j) a 5- or 6-membered saturated heterocyclyloxy group, and 
 (k) an amino group optionally mono- or di-substituted by substituents selected from
 (i) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6  alkoxy group, 
 (ii) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy-carbonyl group optionally substituted by C 6-10  aryl group(s), and 
 (iv) a C 3-6  cycloalkyl-carbonyl group optionally substituted by C 1-6  alkoxy group(s), 
 
   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A compound selected from the following formulas 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . A pharmaceutical composition comprising the compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         7 .- 13 . (canceled) 
     
     
         14 . A method of inhibiting ITK in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         15 . A method for treating or preventing an inflammatory disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         16 . The method according to  claim 15 , wherein the inflammatory disease is rheumatoid arthritis. 
     
     
         17 . A method for treating or preventing an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         18 . A method for treating or preventing an autoimmune disease to a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         19 . The method according to  claim 18 , wherein the autoimmune diseases is rheumatoid arthritis. 
     
     
         20 . A method of suppressing rejection in transplantation in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         21 .- 26 . (canceled)