Fused heterocyclic kinase inhibitors

• US 20050288290A1
• Filed: 06/24/2005
• Published: 12/29/2005
• Est. Priority Date: 06/28/2004
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Cai, Zhen-wei, Borzilleri, Robert M., Chen, Zhong, Huynh, Tram N., Kim, Kyoung S., Vaccaro, Wayne, Chen, Xiao-Tao
• Application Number:
  US11/167,043
• Publication Number:
  US 20050288290A1
• Time in Patent Office: Days
• US Class Current: 514/243
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 473/00 : Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/30 : attached in position 6, e.g. hypoxanthine
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

In general, the instant invention comprises compounds of Formulas I and II including pharmaceutically acceptable salts thereof. The compounds of the invention are useful as protein kinase inhibitors and therefore are useful for treating cancer and other protein kinase mediated diseases.

Claims

1. A compound having the formula I or II

2. The compound according to claim 1 wherein R¹ is an optionally substituted C₁ to C₆ alkyl, alkenyl, alkynyl, optionally substituted C₃ to C₇ cycloalkyl, C₃ to C₇ heterocycloalkyl, optionally substituted phenyl, optionally substituted biphenyl, or a C₅ to C₁₁ optionally substituted monocyclic or bicyclic heteroaryl.

3. The compound according to claim 2 wherein R¹ is selected from the group consisting of phenyl, optionally substituted with Cl, F, OCH₃, alkyl, alkenyl, alkynyl, hydroxy, cyano, amido, phenoxy, CH₂CN, benzyl, NHCO₂CH₃;

biphenyl, pyridyl, azepanyl, pyrazolyl, thiazolyl, indolyl, indazolyl, indenyl, cyclopropyl, isopropyl, phenylethyl, aminoalkyl, benzyl, amidoalkyl, morpholine, or furanylmethyl.

4. The compound according to claim 1 wherein R² is H, methyl, alkoxy, halo, haloalkyl, or cyano.

5. The compound according to claim 1 wherein R⁴ is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrrolidinyl, an optionally substituted pyridyl-N-oxy, or an optionally substituted pyridinone.

6. The compound according to claim 5 wherein said phenyl, pyridyl, pyridinone, or N-oxy pyridyl is substituted with hydroxyl, halo, C₁ to C₄alkyl, C₃ to C₇ cycloalkyl, —

COCH₃, alkoxy, amino, heterocycloalkyl, aminoalkylamino, cyano, alkylthio, phenyl or alkylaminoalkoxy.

7. The compound according to claim 6 wherein said substituent is F, Br, Cl, methyl, pentyl, methoxy, phenyl, morpholinyl, NH², or NHCHNH₂.

8. The compound according to claim 1 wherein A is

9. The compound according to claim 8 wherein R¹⁹ is H or CN;

R¹⁶ and R¹⁷ are independently H, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, or —

C(O)₂R²⁹ wherein R²⁹ is C₁ to C₄ alkyl; and

R¹⁸ is H.

10. The compound according to claim 8 wherein R²² and R⁶¹ are H.

11. The compound according to claim 8 wherein R⁶⁸, R⁶⁹ and R⁷⁰ are H;

R²⁰ is C₁ to C₄ alkyl;

alkenyl;

alkynyl;

C₅ to C₆ heterocycloaryl;

CO(CH₂)₁R⁴¹, and R⁴¹ is C₁ to C₄ alkyl, haloalkyl, amino, alkylamino, C₅ to C₇ heterocycloalkyl, or C₅ to C₇ heteroaryl;

C(O)₂R²⁹ wherein R²⁹ is ethyl;

CN;

alkoxy;

phenylmethyl;

alkylaminoalkynyl;

alkylaminoalkyl, hydroxyalkyl;

or methoxyalkyl.

12. The compound according to claim 8 wherein A is

13. The compound according to claim 1 wherein Y is O or S.

14. The compound according to claim 1 wherein B is O.

15. The compound according to claim 1 wherein Z is —

CR¹³R¹⁴ or NR¹⁵ wherein R¹³, R¹⁴, and R¹⁵ are each H or R¹³ and R¹⁴ together with the carbon to which they are attached form a cyclopropyl.

16. The compound according to claim 1 wherein R⁴ is phenyl.

17. The compound according to claim 1 wherein R⁴ is pyridyl.

18. The compound according to claim 1 wherein R⁴ is pyrrolidinyl.

19. The compound according to claim 1 wherein R⁴ is pyridyl-N-oxy.

20. The compound according to claim 1 wherein R⁴ is pyridinone.

21. The compound according to claim 12 wherein R²⁰ is —

COCH₂—

R, wherein R is amino, pyrrolidine, or piperazine.

22. The compound according to claim 12 wherein R²⁰ is pyridine or thiazole.

23. The compound according to claim 12 wherein R²⁰ is is —

COC(Cl)₃, or CONHCH₂pyridine.

24. The compound according to claim 12 wherein R²⁰ is CH₂piperidine, CH₂phenyl, —

C≡

C-amino, cyano, —

CO₂CH₃, —

CH₂OH, CH₂OMe, hydroxyethyl, —

CHOH(CH₂)₂OH, or CH(OCH₃)CH₃.

25. The compound according to claim 1 having an IC50 value of less than about 5 μ

M.

26. The compound according to claim 1 having an IC50 value of less than about 1 μ

M.

27. A method for treating cancer comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound having the formula I or II according to claim 1.

28. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

29. The method of claim 18, further comprising administering to said patient at least one other anticancer agent.