Selective serine/threonine kinase inhibitors

• US 7,687,506 B2
• Filed: 04/12/2004
• Issued: 03/30/2010
• Est. Priority Date: 04/11/2003
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Taunton, Jack, Zhang, Chao, Cohen, Michael, Shokat, Kevan
• Primary Examiner(s): Kifle; Bruck
• Application Number:
  US10/552,847
• Publication Number:
  US 20070082884A1
• Time in Patent Office: 2,178 Days
• Field of Search: 544/280, 514/265.1
• US Class Current: 514/265.1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Inhibition of protein kinases having one or more cysteine residues within the ATP binding site is effected by contacting the kinase, per se or in a cell or subject, with an inhibitory-effective amount of a compound having a heterocyclic core structure comprised of two or more fused rings containing at least one nitrogen ring atom, and an electrophilic substituent that is capable of reacting with a cysteine residue within the ATP binding site of a kinase. Preferred compounds include certain pyrrolopyrimidines and oxindoles having such an electrophilic substituent and optionally an aromatic or heteroaromatic substituent that is capable of interacting with a threonine or smaller residue located in the gatekeeper position of the kinase. Kinases lacking such cysteine residues may be engineered or modified so that they are capable of being inhibited by such compounds by replacing a valine or other amino acid residue within the ATP binding site by a cysteine residue.

Claims

1. A compound having the formula (IA):

2. A compound according to claim 1 in which R² is hydrogen.

3. A compound according to claim 1 in which R² is a group having the formula (CH₂)_bR^b.

4. A compound according to claim 3 in which b is 0.

5. A compound according to claim 4 in which R² is an optionally substituted phenyl group.

6. A compound according to claim 1 in which E is an olefin attached to a nitro or cyano.

7. A compound according to claim 1 in which E is —

C(O)(CH₂)_nR′

in which R′

is a halogen and n is 0 or an integer from 1 to 6.

8. A compound according to claim 7 in which n is 0.

9. A compound according to claim 7 in which n is 1.

10. A compound according to claim 1 in which E is —

(CH₂)_mC(O)R′

in which m is 0 or an integer from 1 to 6 and R′

is a halogen.

11. A compound according to claim 10 in which m is 0.

12. A compound according to claim 10 in which m is 1.

13. A compound according to any of claims 7-12 in which R′

is chloro.

14. A compound according to any of claims 7-12 in which R′

is fluoro.

15. A compound according to claim 1 in which E is —

C(O)CH═

CH₂.

16. A compound according to claim 1 in which E is —

CH═

CHC(O)OR′

where R′

is an optionally substituted aliphatic, aromatic, or heterocyclic moiety.

17. A compound according to claim 1 in which R′

is methyl.

18. A compound according to claim 1 in which E is —

CH═

C(O)N″

R′

″

where R″ and

R′

″

are optionally substituted aliphatic, aromatic, or heterocyclic moieties.

19. A pharmaceutical composition comprising the composition according to claim 1 and a pharmaceutically acceptable carrier.

20. A compound according to claim 1 in which E is —

CH═

CH—

C(O)—

OCH₃.

21. A compound according to claim 1 in which R⁵ is hydrogen.

22. A compound according to claim 1 in which R⁴ is an aliphatic optionally substituted with one or more unprotected polar groups.

23. A compound according to claim 1 in which R⁴ is an aliphatic optionally substituted with hydroxyl.

24. A compound according to claim 1 in which R⁴ is —

(CH₂)₃—

OH.

25. A compound according to claim 1 in which R² is —

(CH₂)_bR^b, wherein b is 0, and wherein R^b is an aromatic optionally substituted with one or more groups selected from lower alkyl, halogen, substituted alkyl, nitro, alkoxy, phenoxy, and sulfonamido.

26. A compound according to claim 25 in which R^b is an aromatic group substituted with lower alkyl.

27. A compound according to claim 25 in which R^b is tolyl.

28. A compound according to claim 25 in which R^b is p-tolyl.

29. A compound according to claim 25 in which

R⁴ is an aliphatic optionally substituted with hydroxyl;

R⁵ is hydrogen; and

E is —

CH═

CH—

C(O)—

OCH₃ or —

CO(CH₂)_nR′

, wherein n is 1 and R′

is chloro or fluoro.

30. A compound according to claim 25 in which

R⁴ is an aliphatic optionally substituted with hydroxyl;

R⁵ is hydrogen; and

E is —

CO(CH₂)R′

, wherein n is 1 and R′

is chloro or fluoro.

31. A compound according to claim 1 having the formula:

32. A compound according to claim 1 having the formula:

33. A compound according to claim 1 having the formula: