Pyrimidyl cyclopentanes as AKT protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9409886-B2
Application number	US-201314086717-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Jul 5, 2007
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present invention provides compounds of Formula I, including tautomers, resolved enantiomers, diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof.

Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

First claim

The invention claimed is:

1. A compound of the Formula 10:

and enantiomers and salts thereof, wherein:
G is phenyl, naphthalene, a 5-6 membered heteroaryl or a 9-10 membered bicyclic heteroaryl wherein the phenyl, naphthalene, 5-6 membered heteroaryl or 9-10 membered bicyclic heteroaryl is optionally substituted with one to four R a groups;
R 1 and R 1a are independently selected from H, Me, Et, —CH═CH 2 , —CH 2 OH, CF 3 , CHF 2 or CH 2 F;
R 2 is H, —OH, —OMe or F;
R 2a is H, Me or F, or
R 2 and R 2a are oxo;
R 3 is H, Me, Et, or CF 3 ;
R 4 is H, 4-6 membered heterocycle, cyclopropylmethyl or C 1 -C 4 alkyl optionally substituted with F, —OH or —O(C 1 -C 3 alkyl);
R 5 and R 5a are independently selected from H and C 1 -C 4 alkyl, or R 5 and R 5a together with the atom to which they are attached form a carbonyl group, a 5-6 membered cycloalkyl or a 5-6 membered heterocycle, wherein the heterocycle has an oxygen heteroatom;
each R a is independently halogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, —O—(C 1 -C 6 -alkyl), CF 3 , —OCF 3 , S(C 1 -C 6 -alkyl), CN, phenyl, —OCH 2 -phenyl, NH 2 , —NO 2 , —NH—(C 1 -C 6 -alkyl), —N—(C 1 -C 6 -alkyl) 2 , piperidine, pyrrolidine, pyrazole, pyridine, 2-aminopyrimidine, CH 2 F, CHF 2 , —OCH 2 F, —OCHF 2 , —OH, —SO 2 (C 1 -C 6 -alkyl), C(O)NH 2 , C(O)NH(C 1 -C 6 -alkyl), and C(O)N(C 1 -C 6 -alkyl) 2 ; and
j is 1 or 2; and when j is 2, the j ring carbon opposite NR 4 may be replaced with an O heteroatom.

2. The compound of claim 1 , wherein R 2 is selected from H, —OH, —OMe or F;
R 2a is selected from H, Me or F;
R 4 is H, 4-6 membered heterocycle, cyclopropylmethyl or C 1 -C 4 alkyl optionally substituted with —OH or —O(C 1 -C 3 alkyl);
R 5 and R 5a are independently selected from H and C 1 -C 4 alkyl; and
j is 1 or 2.

3. The compound of claim 1 , wherein R 3 is H.

4. The compound of claim 1 , wherein R 5 is H.

5. The compound of claim 1 , wherein R 5a is H.

6. The compound of claim 1 , wherein R 5 is methyl.

7. The compound of claim 1 , wherein R 5a is methyl.

8. The compound of claim 1 , wherein R 5 is ethyl.

9. The compound of claim 1 , wherein R 5a is ethyl.

10. The compound of claim 1 , wherein R 5 and R 5a together with the atom to which they are attached form a 5-6 membered cycloalkyl.

11. The compound of claim 1 , wherein R 5 and R 5a together with the atom to which they are attached form a 5-6 membered heterocycle, wherein the heterocycle has an oxygen heteroatom.

12. The compound of claim 1 , wherein R 1 is methyl.

13. The compound of claim 1 , wherein R 1 is methyl in the (R) configuration.

14. The compound of claim 1 , wherein R 1a is H.

15. The compound of claim 1 , wherein R 1a is methyl.

16. The compound of claim 1 , wherein R 1 is H.

17. The compound of claim 1 , wherein R 1 is ethyl.

18. The compound of claim 1 , wherein R 1 is CH═CH 2 .

19. The compound of claim 1 , wherein R 1 is CH 2 OH.

20. The compound of claim 1 , wherein R 1 is CH 2 F.

21. The compound of claim 13 , wherein R 1a is H.

22. The compound of claim 1 , wherein R 2a is H.

23. The compound of claim 1 , wherein R 2 is F.

24. The compound of claim 1 , wherein R 2 is OH.

25. The compound of claim 1 , wherein R 2a is F.

26. The compound of claim 1 , wherein R 2 is F.

27. The compound of claim 1 , wherein R 2 is —OMe.

28. The compound of claim 1 , wherein G is selected from 4-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl and 4-cyclopropylphenyl.

29. The compound of claim 1 , wherein G is selected from 4-chlorophenyl, 4-bromophenyl, 4-cyclopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-benzamide, 4-(methylsulfonyl)phenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl or 3-fluoro-4-cyanophenyl.

30. The compound of claim 1 , wherein R 4 is C 1 -C 4 alkyl optionally substituted with OH or O(C 1 -C 3 alkyl).

31. The compound of claim 1 , wherein R 4 is selected from methyl, ethyl, isopropyl, isobutyl, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 C(CH 3 ) 2 OH and CH 2 CH 2 OCH 3 .

32. The compound of claim 1 , wherein R 4 is cyclopropylmethyl.

33. The compound of claim 1 , wherein R 4 is a 4-6 membered heterocycle.

34. The compound of claim 1 , wherein R 4 is tetrahydropyranyl.

35. The compound of claim 1 , wherein R 4 is H.

36. The compound of claim 1 , wherein R 4 is C 1 -C 4 alkyl optionally substituted with F.

37. The compound of claim 1 , wherein R 4 is CH 2 CF 3 , CH 2 CH 2 F or CH 2 CHF 2 .

38. The compound of claim 1 , wherein j is 1.

39. The compound of claim 1 , wherein j is 2.

40. The compound of claim 1 , wherein G is 4-chlorophenyl, 4-bromophenyl, 4-cyclopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-benzamide, 4-(methylsulfonyl)phenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-cyanophenyl, 4-chloro-2,5-difluorophenyl, 4-chloro-2-fluorophenyl, 4-bromo-2-fluorophenyl, 4-bromo-3-fluorophenyl, 3-chlorophenyl, 2-fluoro-4-methylphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 4-fluoro-3-trifluoromethylphenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-fluorophenyl, 2-fluoro-4-methoxyphenyl, 4-(1H-pyrazol-4-yl)phenyl, biphenyl-4-yl, 4-(2-aminopyrimidin-5-yl)phenyl, 4-tert-butylphenyl, 2,3-difluoro-4-(trifluoromethyl)phenyl, 2-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, and 3-fluoro-4-(trifluoromethoxy)phenyl.

41. A pharmaceutical composition comprising a compound as claimed in claim 1 .

42. A method of inhibiting the activity of AKT protein kinase in a mammal, which comprises administering to said mammal an effective amount of a compound as claimed in claim 1 .

43. A kit, wherein said kit comprises:
a) a first pharmaceutical composition comprising a compound as claimed in claim 1 ; and
b) instructions for use.

44. The compound of claim 1 selected from the group consisting of:
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone;
(S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone;
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone;
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2((S)-piperidin-2-yl)ethanone;
(S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone;
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Bencsik Josef
• Blake James F
• Graham James M
• Hentemann Martin F
• Kallan Nicholas C
• Mitchell Ian S
• Schlachter Stephen T
• Spencer Keith L
• Xiao Dengming
• Xu Rui
• Welch Mike
• Liang Jun
• Safina Brian S

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title