Aminoheteroaryl compounds as protein kinase inhibitors

• US 20060178374A1
• Filed: 08/26/2005
• Published: 08/10/2006
• Est. Priority Date: 08/26/2004
• Status: Abandoned Application

• Current Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Cui, Jingrong Jean, Jia, Lei, Shen, Hong, Nambu, Mitchell David, Tran-Dube, Michelle, Funk, Lee Andrew, Pairish, Mason Alan, Kung, Pei-Pei, Meng, Jerry Jialun
• Application Number:
  US11/213,038
• Publication Number:
  US 20060178374A1
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

Aminoheteroaryl compounds are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.

Claims

1. A compound of formula 1

2. The compound of claim 1, wherein Y is CR¹ and R¹ is hydrogen.

3. The compound of claim 1, wherein R² is hydrogen.

4. The compound of claim 1, wherein the compound has formula 1a

5. The compound of claim 1, selected from the group consisting of:

34. A method of treating abnormal cell growth in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound, salt, hydrate or solvate of claim 1.

35. The method of claim 34, wherein the abnormal cell growth is cancer.

36. The method of claim 35, wherein the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'"'"'s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, and combinations thereof.

37. The method of claim 34, wherein the method further comprises co-administering an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, anti-androgens and mixtures thereof.

6. A compound of formula 2

7. The compound of claim 6, wherein each R² is hydrogen.

8. The compound of claim 6, wherein each R¹¹ and R¹² is independently hydrogen or C_1-6 alkyl optionally substituted by one or more R³ groups.

9. The compound of claim 6, wherein R¹⁰ is —

C(O)R⁴ or —

(CR⁶R⁷)_nC(O)NR⁴R⁵, and each hydrogen in R¹⁰ is optionally substituted by R³.

10. The compound of claim 6 selected from the group consisting of:

11. A compound of formula 3a or 3b

12. The compound of claim 11, wherein R¹⁰ and R¹² are hydrogen.

13. The compound of claim 11, wherein each R² is hydrogen.

14. The compound of claim 11 selected from the group consisting of:

15. A compound of formula 4a or 4b

16. The compound of claim 15, wherein R² is hydrogen.

17. The compound of claim 15, wherein R¹⁰ and R¹¹ are independently hydrogen or C_1-6 alkyl optionally substituted by one or more R³ groups.

18. The compound of claim 15, wherein A is phenyl.

19. The compound of claim 15 selected from the group consisting of:

20. A compound of formula 5

21. The compound of claim 20, wherein each R² is hydrogen.

22. The compound of claim 20 selected from the group consisting of:

23. A compound selected from the group consisting of:

24. A compound selected from the group consisting of:

25. A compound selected from the group consisting of:

26. A compound selected from the group consisting of:

27. A compound selected from the group consisting of:

28. A compound selected from the group consisting of:

29. A compound selected from the group consisting of:

30. A compound selected from the group consisting of:

31. A compound selected from the group consisting of:

32. A compound selected from the group consisting of:

33. 3-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-(piperazin-1-ylcarbonyl)phenyl] pyridin-2-amine at least 95% free of 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-(piperazin-1-ylcarbonyl)phenyl] pyridin-2-amine.