Indolinone hydrazides as c-Met inhibitors

• US 20060009493A1
• Filed: 06/25/2004
• Published: 01/12/2006
• Est. Priority Date: 07/02/2003
• Status: Abandoned Application

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Do, Steven, Ramphal, John, Mattson, Matthew N., Tang, Peng Cho, Nelson, Christopher, Zhang, Fang-Jie, Wei, Chung Chen, Cui, Jingrong, Yang, Guang, Koenig, Marcel, Vojkovsky, Tomas
• Application Number:
  US10/875,508
• Publication Number:
  US 20060009493A1
• Time in Patent Office: Days
• US Class Current: 514/339
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/40 Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to compounds of the formulae (I)-(XII), wherein R₁-R₇₁, A, B, X, Y, G, L and Z are defined herein, and their pharmaceutically acceptable salts. These compounds modulate the activity of c-Met and are therefore expected to be useful in the prevention and treatment of c-Met related disorders such as cancer.

Claims

1. A compound of the Formula I:

9. The compound of claim 1, wherein R₁ is H;

R₂ and R₃ combine to form a heteroalicyclic ring; and

G is —

NR₆₉C(O)—

, —

(O)CNR₆₉—

, —

SO₂—

or —

NR₆₉SO₂—

;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein R₁ is H or alkyl;

R₂ and R₃ combine to form a heteroalicyclic ring; and

G is absent;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9, wherein n is 1;

and R₄ and R₅ are H or alkyl;

or a pharmaceutically acceptable salt thereof.

28. A method for treating a c-Met related disorder comprising administering to an organism in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the c-Met related disorder is a cancer.

30. The method of claim 29, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, gastric cancer, head cancer, neck cancer, melanoma, renal cancer, leukemia, myeloma, and sarcoma.

31. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

2. A compound of the Formula III:

12. The compound of claim 2, wherein R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ are H;

n is 1; and

Y is H or alkyl;

or a pharmaceutically acceptable salt thereof.

3. A compound of the Formula IV:

13. The compound of claim 3, wherein R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are H;

and n is 1;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein A and B are CR₆₉;

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 3, wherein R₂₄ and R₂₅ are independently H, alkyl, halogen, aryl, heteroalicyclic, S(O)_pR₆₉, (CH₂)_mSO₂(CH₂)_zR₇₀, NO₂, C(O)R₆₉, (CH₂)_zOR₇₀ or (CH₂)_zCO₂R₆₉;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15, wherein R₂₈ is (CH₂)_mNR₇₁, (CH₂)_mOR₇₁, NHC(O)R₇₀, halo, (CH₂)_mSO₂(CH₂)_zR₆₉;

R₂₉ is H;

or R₂₈ and R₂₉ are on adjacent carbons and, together with the carbon atoms to which they are attached form a dioxolane ring;

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16, wherein n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

4. A compound of the Formula V:

5. A compound of the Formula VI:

18. The compound of claim 5, wherein R₃₀ and R₃₁ are independently H, alkyl, halogen, (CH₂)COR₆₉, or (CH₂)_zCO₂R₆₉;

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein R₃₄ is halo, (CH₂)_zOR₇₀, NO₂ or CN;

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19, wherein n is 1;

and R₂₆ and R₂₇ are independently H or alkyl;

or a pharmaceutically acceptable salt thereof.

6. A compound of the Formula VII:

21. The compound of claim 6, wherein R₃₅, R₃₆ and R₃₇ are independently H, alkyl or halogen;

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein R₃₈ and R₃₉ are H;

and n is o or 1;

or a pharmaceutically acceptable salt thereof.

7. A compound of the Formula VIII or IX:

23. The compound of claim 7, wherein R₄₃, R₄₅ and R₄₆ are H;

and n is 1;

or a pharmaceutically acceptable salt thereof.

8. A compound of the Formula X, XI or XII:

24. The compound of claim 8, wherein R₅₈ and R₅₉ are H;

and n is 1;

or a pharmaceutically acceptable salt thereof.

25. A method for treating a c-Met related disorder comprising administering to an organism in need thereof a therapeutically effective amount of a compound of the Formula II:

26. The method of claim 25, wherein the c-Met related disorder is a cancer.

27. The method of claim 26, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, gastric cancer, head cancer, neck cancer, melanoma, renal cancer, leukemia, myeloma, and sarcoma.

32. A pharmaceutical composition comprising one or more compounds of the formula (I) and (III)-(XII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.