Indole compounds and pharmaceutical use thereof

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:

and a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method of inhibiting ITK in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby inhibiting ITK in the mammal.

8. A method for treating inflammatory bowel disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating inflammatory bowel disease in the mammal.

9. A method for treating rheumatoid arthritis in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating rheumatoid arthritis in the mammal.

10. A method for treating an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal having an allergic disease selected from the group consisting of atopic dermatitis, asthma, and allergic rhinitis, thereby treating the allergic disease in the mammal.

11. A method for treating systemic lupus erythematosus in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating systemic lupus erythematosus in the mammal.

12. A method for treating psoriasis in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating psoriasis in the mammal.

13. A method of suppressing rejection in transplantation in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby suppressing rejection in transplantation in the mammal.

14. A pharmaceutical composition comprising the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method of inhibiting ITK in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby inhibiting ITK in the mammal.

16. A method for treating inflammatory bowel disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating inflammatory bowel disease in the mammal.

17. A method for treating rheumatoid arthritis in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating rheumatoid arthritis in the mammal.

18. A method for treating an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, to a mammal having an allergic disease selected from the group consisting of atopic dermatitis, asthma, and allergic rhinitis, thereby treating the allergic disease in the mammal.

19. A method for treating systemic lupus erythematosus in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating systemic lupus erythematosus in the mammal.

20. A method for treating psoriasis in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating psoriasis in the mammal.

21. A method of suppressing rejection in transplantation in a mammal, comprising administering a pharmaceutically effective amount of the compound according to claim 5 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby suppressing rejection in transplantation in the mammal.

22. The compound of claim 1 that is

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 that is

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 that is

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 that is t, 572 or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 that is t, 573 or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 that is t, 574 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A method of inhibiting ITK in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby inhibiting ITK in the mammal.

30. A method for treating inflammatory bowel disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating inflammatory bowel disease in the mammal.

31. A method for treating rheumatoid arthritis in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating rheumatoid arthritis in the mammal.

32. A method for treating an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, to a mammal having an allergic disease selected from the group consisting of atopic dermatitis, asthma, and allergic rhinitis, thereby treating the allergic disease in the mammal.

33. A method for treating systemic lupus erythematosus in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating systemic lupus erythematosus in the mammal.

34. A method for treating psoriasis in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 22 - 27 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby treating psoriasis in the mammal.

35. 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 22 - 27 , or a pharmaceutically acceptable salt thereof, to the mammal, thereby suppressing rejection in transplantation in the mammal.

36. The compound of claim 22 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

37. The compound of claim 23 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

38. The compound of claim 24 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

39. The compound of claim 25 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

40. The compound of claim 26 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

41. The compound of claim 27 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

42. The pharmaceutical composition of claim 28 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

43. The method according to claim 29 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

44. The method according to claim 30 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

45. The method according to claim 31 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

46. The method according to claim 32 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

47. The method according to claim 33 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

48. The method according to claim 34 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.

49. The method according to claim 35 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt.