Substituted tricyclic compounds as protein kinase inhibitors

• US 7,326,712 B2
• Filed: 10/14/2004
• Issued: 02/05/2008
• Est. Priority Date: 10/14/2003
• Status: Expired due to Fees

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Supergen Incorporated (Otsuka Holdings Company Limited), Arizona Board of Regents (University of Arizona)
• Inventors: Bearss, David J., Mahadevan, Daruka, Hurley, Laurence H., Warner, Steven L., Bashyam, Sridevi, Vankayalapati, Hariprasad
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Moore, Susanna
• Application Number:
  US10/965,313
• Publication Number:
  US 20050227992A1
• Time in Patent Office: 1,209 Days
• Field of Search: 544/250, 514/267
• US Class Current: 514/267
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/14 Ortho-condensed systems

Abstract

Protein kinase inhibitors are disclosed having utility in the treatment of protein kinase-mediated diseases and conditions, such as cancer. The compounds of this invention have the following structure:

including steroisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein A is a ring moiety selected from:

and wherein R1, R2, R3, X, Z, L1, Cycl1, L2 and Cycl2 are as defined herein. Also disclosed are compositions containing a compound of this invention, as well as methods relating to the use thereof.

Claims

1. A compound having a structure selected from (II) or (III):

2. The compound of claim 1, wherein the compound has structure (II).

3. The compound of claim 2 wherein L₁ is a direct bond.

4. The compound of claim 3 wherein X is NH and Z is CH.

5. The compound of claim 3 wherein R₁ and R₂ are selected from —

OCH₃, —

OH, —

Cl, —

CF₃ or —

OC(═

O)CH₃, and R₃ is hydrogen or —

NH₂.

6. The compound of claim 3 wherein L₂ is selected from —

C(═

S)NH—

, —

C(═

S)NHCH₂—

, —

NHC(═

S)NH—

, or —

NHC(═

O)NH—

.

7. The compound of claim 2, wherein L₁ is —

NH—

or —

OC(═

S)NH—

.

8. The compound of claim 7, wherein X is NH and Z is CH.

9. The compound of claim 7, wherein R₁ and R₂ are methoxy, and R₃ is hydrogen or —

NH₂.

10. The compound of claim 7, wherein L₂ is selected from —

NHCH₂—

, —

NH—

, —

C(═

S)NH—

, —

NHC(═

S)—

, —

C(═

S)NHCH₂—

, —

NHC(═

S)NH—

, —

NHC(═

O)NH—

or —

S(═

O)₂.

11. The compound of claim 1, wherein the compound has structure (III).

12. The compound of claim 11 wherein L₁ is a direct bond.

13. The compound of claim 12 wherein R₁, R₂ and R₃ are hydrogen.

14. The compound of claim 12 wherein Cycl₁ is:

15. The compound of claim 12 wherein L₂ is selected from —

C(═

S)NH—

, —

C(═

S)—

or —

C(═

S)NHCH₂—

.

16. The compound of claim 12 wherein Cycl₂ is selected from:

17. The compound of claim 11 wherein L₁ is —

NH—

or —

OC(═

S)NH—

.

18. The compound of claim 17 wherein R₁, R₂ and R₃ are hydrogen.

19. The compound of claim 17 wherein Cycl₁ is selected from:

20. The compound of claim 17 wherein L₂ is selected from —

NHC(═

S)NH—

, —

NHC(═

O)—

, —

NH—

or —

NHCH₂—

.

21. The compound of claim 17 wherein Cycl₂ is selected from:

22. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient.