Substituted indol-5-ol derivatives and their therapeutic applications

1. A compound of the formula (I)

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, wherein;

R is selected from:

(i) hydrogen, amino, alkyl amino;

(ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

(iii) K—Ar;

Ar represents heteroaryl or aryl, each of which is substituted with from 0 to 4 substituents independently chosen from:

(1) halogen, hydroxy, amino, amide, cyano, —COOH, —SO2NH2, oxo, nitro and alkoxycarbonyl; and

(2) C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkanoyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, mono- and di-(C1-C6 alkyl)amino, C1-C6 alkylsulfonyl, mono- and di-(C1-C6alkyl) sulfonamido and mono- and di-(C1-C6 alkyl)aminocarbonyl; phenyl C0-C4 alkyl and (4- to 7-membered heterocycle) C0-C4 alkyl, each of which is substituted with from 0 to 4 secondary substituents independently chosen from halogen, hydroxy, cyano, oxo, imino, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl;

K is selected from

a) O, S, SO, SO2;

b) (CH2)m, m=0-3, —O(CH2)p, p=1-3, —S(CH2)p, p=1-3,—N(CH2)p, p=1-3, —(CH2)pO, p=1-3;

c) NR1

R1 represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, arylalkyl;

(iv) groups of the formula (Ia);

(Ia)

wherein:

R2 represents hydrogen, C1-C4 alkyl, oxo;

X is CH, when R3 is hydrogen; or X—R3 is O; or X is N, R3 represents groups of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 aryl or heteroaryl, (C3-C7cycloalkyl)C1-C4alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkanoyl, C1-C6 alkoxycarbonyl, C2-C6 alkanoyloxy, mono- and di-(C3-C8 cycloalkyl)aminoC0-C4alkyl, (4- to 7-membered heterocycle)C0-C4alkyl, C1-C6 alkylsulfonyl, mono- and di-(C1-C6 alkyl) sulfonamido, and mono- and di-(C1-C6alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH and oxo;

Het is selected from any heterocycle, which is substituted with from 0 to 4 substituents independently chosen from:

(i) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

(ii) halogen, hydroxy, amino, amide, cyano, —COOH, —SO2NH2, oxo, nitro and alkoxycarbonyl,

(iii) aryl;

R11 and R12 are independently selected from: Hydrogen, F, Cl, Br, CN, C1-C4 alkyl, C1-C6 alkoxy;

R13, R14 and R15 are independently selected from Hydrogene, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 aryl or heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkanoyl, C1-C6 alkoxycarbonyl, C2-C6 alkanoyloxy.

2. A pharmaceutical composition comprising at least one compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

3. The composition according to claim 2 , further comprising one or more additional therapeutic agents.

4. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

5. A pharmaceutical composition comprising the compound of claim 4 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

6. The composition according to claim 5 , further comprising one or more additional therapeutic agents.

7. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

8. A pharmaceutical composition comprising the compound of claim 7 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

9. The composition according to claim 8 , further comprising one or more additional therapeutic agents.

10. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

11. A pharmaceutical composition comprising the compound of claim 10 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

12. The composition according to claim 11 , further comprising one or more additional therapeutic agents.

13. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

14. A pharmaceutical composition comprising the compound of claim 13 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

15. The composition according to claim 14 , further comprising one or more additional therapeutic agents.

16. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

17. A pharmaceutical composition comprising the compound of claim 16 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

18. The composition according to claim 17 , further comprising one or more additional therapeutic agents.

19. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

20. A pharmaceutical composition comprising the compound of claim 19 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

21. The composition according to claim 20 , further comprising one or more additional therapeutic agents.

22. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

23. A pharmaceutical composition comprising the compound of claim 22 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

24. The composition according to claim 23 , further comprising one or more additional therapeutic agents.

25. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

26. A pharmaceutical composition comprising the compound of claim 25 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

27. The composition according to claim 26 , further comprising one or more additional therapeutic agents.

28. The compound with the formula;

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

29. A pharmaceutical composition comprising the compound of claim 28 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

30. The composition according to claim 29 , further comprising one or more additional therapeutic agents.

31. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

32. A pharmaceutical composition comprising the compound of claim 31 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

33. The composition according to claim 32 , further comprising one or more additional therapeutic agents.

34. The compound with the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

35. A pharmaceutical composition comprising the compound of claim 34 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

36. The composition according to claim 35 , further comprising one or more additional therapeutic agents.

37. A method of inhibiting kinase activity, comprising contacting a kinase with a compound of claim 1 whereby kinase activity is inhibited.

38. A method of treating cancer, comprising contacting the tumor cell with a compound of claim 1 , wherein the cancer is a leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

39. A method of claim 38 , in which the concentration of the pharmaceutical composition of resulting in a 50% reduction in the net tumor volume increase in xenograft models is from 0.01, to 1.9 μM.

40. A method of claim 38 , in which the leukemia is chronic myeogenous leukemia (CML).