IP Library › Granted Patent US 7,524,840

Granted Patent B2

US 7,524,840 · App. 11/244,251 · Granted Apr 28, 2009

7,8-disubstituted pyrazolobenzodiazepines

Assignee: Hoffmann-La Roche Inc.

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Quick Facts

Patent No.: US 7,524,840
App. No.: 11/244,251
Granted: Apr 28, 2009
Kind: B2

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Abstract

The present invention provides compounds of formula I wherein R 1 , R 2 , R 3 , R 4 , and R 5 are described herein. The invention also provides syntheses for preparation of such compounds and pharmaceutical compositions containing them. The invention further provides methods for inhibiting kinases, in particular CDK2, for inhibiting angiogenesis, and for treating cancers, in particular breast, colon, prostate, and lung cancer.

Claims (181)

1. A compound of formula IV,

wherein

R 1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R 6 ) 2 , or (OCH 2 CH 2 ) n OCH 3 ;

R 2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R 6 ) 2 , (OCH 2 CH 2 ) n OCH 3 , O(CH 2 ) m NR 7 R 8 , or

is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR 6 ;

or R 1 and R 2 together form a 5-membered heterocyclic ring;

R 3 is hydrogen or alkyl;

R 4 is hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy;

each R 6 is independently hydrogen or alkyl;

R 7 and R 8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R 7 and R 8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;

each n is independently 1, 2, or 3; and

m is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein R 2 is

3. A compound of claim 2 , wherein R 1 is halogen.

4. A compound of claim 1 , wherein R 1 is cyano.

5. A compound of claim 1 , wherein R 2 is O(CH 2 ) m NR 7 R 8 .

6. A compound of claim 5 , wherein R 7 and R 8 together with the N atom to which they are attached form a 6-membered heterocycle.

7. A compound of claim 6 , wherein R 1 is halogen.

8. A compound of claim 7 , selected from the group consisting of:

5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-(3-(4-morpholinyl)propoxy))-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine;and

7-bromo-5-(2-chlorophenyl)-1,2-dihydro-8-(3-(4-morpholinyl)propoxy))-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

9. A compound of claim 6 , wherein R 1 is cyano.

10. A compound of claim 9 , selected from the group consisting of:

5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(3-(4-morpholinyl)propoxy))-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine; and

5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(2-(4-methyl-1-piperazinyl)ethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

11. A compound of claim 5 , wherein R 7 and R 8 are each independently hydrogen, alkyl, or alkoxyalkyl.

12. A compound of claim 11 , wherein R 1 is halogen.

13. A compound of claim 11 , wherein R 1 is cyano.

14. A compound of claim 13 , which is 5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

15. A compound of claim 1 , wherein R 2 is N(R 6 ) 2 .

16. A compound of claim 15 , wherein R 1 is halogen.

17. A compound of claim 16 , which is 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-N,N-dimethylamino-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

18. A compound of claim 15 , wherein R 1 is cyano.

19. A compound of claim 1 , wherein R 2 is halogen, alkyl, or alkyl substituted by halogen.

20. A compound of claim 19 , wherein R 1 is alkyl.

21. A compound of claim 20 , selected from the group consisting of:

8-chloro-5-(2-chlorophenyl)-1,2-dihydro-3,7-dimethyl-pyrazolo[3,4-b][1,4]benzodiazepine; and

5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-pyrazolo[3,4-b][1,4]benzodiazepine.

22. A compound of claim 19 , wherein R 1 is halogen.

23. A compound of claim 19 , wherein R 1 is alkoxy.

24. A compound of claim 23 , selected from the group consisting of:

5-(2-chlorophenyl)-1,2-dihydro-8-fluoro-7-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-8-trifluoromethyl-pyrazolo[3,4-b][1,4]benzodiazepine; and

8-chloro-5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

25. A compound of claim 1 , wherein R 2 is hydroxy, alkoxy, or alkoxy substituted by halogen.

26. A compound of claim 25 , wherein R 1 is halogen.

27. A compound of claim 26 , selected from the group consisting of:

7-chloro-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine;

7-bromo-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-pyrazolo [3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-ethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine; and

5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-(1-methylethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

28. A compound of claim 27 , which is 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

29. A compound of claim 25 , wherein R 1 is alkoxy.

30. A compound of claim 29 , selected from the group consisting of:

5-(2-chlorophenyl)-1,2-dihydro-7,8-dimethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine;

1,2-dihydro-7,8-dimethoxy-5-(2-methoxyphenyl)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-(1-methylethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine; and

5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-(1-methylethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

31. A compound of claim 25 , wherein R 1 is alkyl.

32. A compound of claim 31 , which is 5-(2-chlorophenyl)-1,2-dihydro-3,7-dimethyl-8-methoxy-pyrazolo[3,4-b][1,4]benzodiazepine.

33. A compound of claim 25 , wherein R 1 is O(CH 2 ) n OCH 3 .

34. A compound of claim 33 , which is 5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

35. A compound of claim 25 , wherein R 1 is cyano.

36. A compound of claim 35 , which is 5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

37. A compound of claim 25 , wherein R 1 is NH 2 C(O).

38. A compound of claim 1 , wherein R 2 is phenyl.

39. A compound of claim 38 , wherein R 1 is alkoxy.

40. A compound of claim 39 , which is 5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-8-phenyl-pyrazolo[3,4-b][1,4]benzodiazepine.

41. A compound of claim 1 , wherein R 2 (OCH 2 CH 2 ) n OCH 3 .

42. A compound of claim 41 , wherein R 1 is halogen.

43. A compound of claim 42 , which is 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

44. A compound of claim 41 , wherein R 1 is alkoxy.

45. A compound of claim 44 , which is 5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine.

46. A compound of claim 41 , wherein R 1 is cyano.

47. A compound of claim 46 , selected from the group consisting of:

5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,41,4]benzodiazepine; and

5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-3-methyl-pyrazolo[3,4-b][1,41,4]benzodiazepine.

48. A compound of claim 1 , wherein R 1 and R 2 together form a dioxolane ring.

49. A compound of claim 48 , which is 5-(2-chlorophenyl)-8,10-dihydro-7-methyl-1,3-dioxolo[4,5-h]pyrazolo[3,4-b][1,4]benzodiazepine.

50. A compound of claim 1 , wherein R 3 is hydrogen.

51. A compound of claim 50 , selected from the group consisting of:

5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methyl-pyrazolo[3,4-b][1,4]benzodiazepine; and

5-(2-chlorophenyl)-1,2-dihydro-7-cyano-8-methoxy- pyrazolo[3,4-b][1,4]benzodiazepine.

52. A pharmaceutical composition of claim 1 , comprising:

(A) a therapeutically effective amount of a compound of formula IV,

wherein

R 1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R 6 ) 2 , or (OCH 2 CH 2 ) n OCH 3 ;

R 2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R 6 ) 2 , (OCH 2 CH 2 ) n OCH 3 , O(CH 2 ) m NR 7 R 8 , or

is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR 6 ;

or R 1 and R 2 together form a 5-membered heterocyclic ring;

R 3 is hydrogen or alkyl;

R 4 is hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy;

each R 6 is independently hydrogen or alkyl;

each n is independently 1, 2, or 3; and

m is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof; and

(B) a pharmaceutically acceptable carrier.

53. A process for preparing a compound of formula IV,

said process comprising

(a) converting a benzodiazepine lactam of formula I

to a thiolactam of formula II

(b) reacting the thiolactam of formula II with the dimethyl acetal of N,N-dimethyl acetamide to form a compound of formula III

and wherein, in the above formulas,

R 1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R 6 ) 2 , or (OCH 2 CH 2 ) n OCH 3 ;

R 2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R 6 ) 2 , (OCH 2 CH 2 ) n OCH 3 , O(CH 2 ) m NR 7 R 8 , or

is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR 6 ;

or R 1 and R 2 together form a 5-membered heterocyclic ring;

R 3 is hydrogen or alkyl;

R 4 is hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy;

each R 6 is independently hydrogen or alkyl;

each n is independently 1, 2, or 3; and

m is 2, 3, or 4.

54. A process for preparing a compound of formula IV,

said process comprising

(a) converting of a benzodiazepine lactam of formula I

to the corresponding O-methyl ether of formula V

(b) reacting the ether of formula V with the dimethyl acetal of N,N-dimethyl acetamide to form a compound of formula VI

wherein, in the above formulas,

R 1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R 6 ) 2 , or (OCH 2 CH 2 ) n OCH 3 ;

R 2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R 6 ) 2 , (OCH 2 CH 2 ) n OCH 3 , O(CH 2 ) m NR 7 R 8 , or

is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR 6 ;

or R 1 and R 2 together form a 5-membered heterocyclic ring;

R 3 is hydrogen or alkyl;

R 4 is hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy;

each R 6 is independently hydrogen or alkyl;

each n is independently 1, 2, or 3; and

m is 2, 3, or 4.

55. A process of preparing a compound of formula IV,

said process comprising

(a) reacting a compound of formula X

with an amino-chloro-pyrazole derivative of formula XIII

to form a compound of formula XIV

(b) reacting the compound of formula XIV in the presence of diisobutyl aluminum hydride and a nickel catalyst to produce a compound of formula IV;

and wherein, in the above formulas,

R 1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R 6 ) 2 , or (OCH 2 CH 2 ) n OCH 3 ;

R 2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R 6 ) 2 , (OCH 2 CH 2 ) n OCH 3 , O(CH 2 ) m NR 7 R 8 , or

is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR 6 ;

or R 1 and R 2 together form a 5-membered heterocyclic ring;

R 3 is hydrogen or alkyl;

R 4 is hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy;

each R 6 is independently hydrogen or alkyl;

each n is independently 1, 2, or 3; and

m is 2, 3, or 4.

56. A compound of formula XIV

wherein

R 1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R 6 ) 2 , or (OCH 2 CH 2 ) n CH 3 ;

R 2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R 6 ) 2 , (OCH 2 CH 2 ) n OCH 3 , O(CH 2 ) m NR 7 R 8 , or

is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR 6 ;

or R 1 and R 2 together form a 5-membered heterocyclic ring;

R 4 is hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy;

each R6 is independently hydrogen or alkyl;

each n is independently 1, 2, or 3; and

m is 2, 3, or 4.

57. A compound of claim 56 , selected from the group consisting of:

5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7,8-dimethoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

8-chloro-5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3,7-dimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

1,2-dihydro-7,8-dimethoxy-5-(2-methoxyphenyl)-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-8,10-dihydro-7-methyl-1,3-dioxolo[4,5-h]pyrazolo[3,4-b][1,4]benzodiazepine; and

7-chloro-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine.

58. A compound of claim 56 , selected from the group consisting of:

5-(2-chlorophenyl)-1,2-dihydro-8-fluoro-7-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-1-(2-propenyl)-8-trifluoromethyl-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-8-phenyl- 1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-methoxyethoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

8-chloro-5-(2-chlorophenyl)-1,2-dihydro-3,7-dimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)- 1,2-dihydro-7-methoxy-8-(1-methylethoxy)-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine;

5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-(1-methylethoxy)-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine; and

5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methoxyethoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine.

Continuity (2)

Provisional Application 6061817400 · Oct 13, 2004

Related Publication 20060079511A1 · Apr 13, 2006