4-Heteroaryl-3-heteroarylidenyl-2-indolinones and their use as protein kinase inhibitors

• US 20020187978A1
• Filed: 06/29/2001
• Published: 12/12/2002
• Est. Priority Date: 06/30/2000
• Status: Active Grant

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Huang, Ping, Tang, Peng Cho, Wei, Chung Chen, Cui, Jingrong
• Granted Patent: US 6,635,640 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

The present invention relates to certain 4-heteroaryl-3-heteroarylidenyl-2-indolinones compounds and their physiologically acceptable salts which modulate the activity of protein kinases (“PKs”), in particular CDK2. The compounds of the present invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical composition containing these compounds and methods of preparing these compounds are also described.

Claims

1. A compound comprising the chemical structure:

2. The compound of claim 1, wherein R¹ and R² are hydrogen.

3. The compound of claim 1, wherein Het is:

4. The compound of claim 3, wherein Het is 4-pyridyl or 5-pyrimidinyl.

5. The compound of claim 1, wherein Het is:

6. The compound of claim 5, wherein Het is piperidin-4-yl.

7. The compound of claim 1, wherein Het is:

8. The compound of claim 1, wherein Het is:

9. The compound of claim 1, wherein Het is:

10. The compound of claim 1, wherein Q is:

11. The compound of claim 10, wherein:

R²³ is selected from the group consisting of hydrogen, unsubstituted lower alkyl, —

C(O)OR²⁶, —

C(O)NR²⁸R²⁹ or R²³ combined with R²⁴ form —

(CH₂)₅— and

—

CH═

CH—

CR³⁴═

CH—

where R²⁶ is hydrogen or unsubstituted lower alkyl;

R³⁴ is selected from the group consisting of hydrogen and —

O(CH₂)NR²⁸R²⁹ and R²⁸ and R²⁹ are independently selected from the group consisting of hydrogen, unsubstituted lower alkyl and, R²⁸ and R²⁹ combined, form a group selected from the group consisting of —

(CH₂)₂N(R³⁰)(CH₂)₂—

,

—

(CH₂)₂O(CH₂)₂— and

—

(CH₂)₅—

, wherein R³⁰ is selected from the group consisting of hydrogen and unsubstituted lower alkyl

12. The compound of claim 11, wherein R²⁴ and R²⁵ are independently selected from the group consisting of:

hydrogen;

unsubstituted lower alkyl;

aryl optionally substituted with a group selected from the group consisting of halo, unsubstituted lower alkoxy;

morpholino and 4-formylpiperidinyl;

—

(CH₂)_nC(O)NR²⁸R²⁹;

—

(CH₂)_nC(O)OR²⁶;

—

(CH₂)_nNR²⁸R²⁹;

—

(CH₂)_nOR²⁶,

—

C(O)NH(CH₂)_nNR²⁸R²⁹;

—

O(CH₂)_nNR²⁸R²⁹;

—

O(CH₂)_nOR²⁶, and, when R²⁴ is not combined with R²³, R²⁴ an R²⁵ combined form a group selected from the group consisting of;

—

(CH₂)₂OC(O)—

;

—

(CH₂)₂N(R³⁰)C(O)—

;

—

(CH₂)₅—

; and

—

CH═

CH—

CH═

CH—

;

where R²⁶ is selected from the group consisting of hydrogen and unsubstituted lower alkyl;

R²⁸ and R²⁹are independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower alkyl substituted with a phenyl or a pyridyl group or, combined, a group selected from the group consisting of —

(CH₂)₅—

, —

(CH₂)₂NR³⁰(CH₂)₂— and

—

(CH₂)₂O(CH₂)₂—

where R³⁰ is selected from the group consisting of hydrogen, unsubstituted lower alkyl and

—

C(O)R²⁶ where R²⁶ is as defined above.

13. The compound of claim 1, wherein Q is 3,5-dimethyl-4-(4-methylpiperazin-1-yl-carbonyl)-1H-pyrrol-2-yl, 5-(methyl-3H-imidazol-4-yl)-1H-pyrrol-2-yl, 3-methyl-4-(4-methylpiperidin-1-yl-carbonyl)-1H-pyrrol-2-yl, 3,5-dimethyl-1H-pyrrol-2-yl, 3-(2-carboxyethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl, 3-(2-carboxyethyl)-5-methyl-1H-pyrrol-2-yl, 3-(2-carboxyethyl)-5-ethyl-1H-pyrrol-2-yl, 3-(2-carboxyethyl)-4-ethoxycarbonyl-5-methyl-1H-pyrrol-2-yl, 4-(2-carboxyethyl)-3,5-dimethyl-1H-pyrrol-2-yl, 4-(carboxymethyl)-3,5-dimethyl-1H-pyrrol-2-yl, indol-2-yl, 4,5,6,7-tetrahydroindol-2-yl, 5-(2-morpholin-4-ylethyloxy)indol-2-yl, 3-(carboxy)-5-methyl-1H-pyrrol-2-yl, 5-carboxy-3-methyl-1H-pyrrol-2-yl, 3-(3-morpholin-4-ylpropyl)-4,5,6,7-tetrahydroindol-2-yl, 4-(2-diethylaminoethylaminocarbonyl)-3,5-dimethyl-1H-pyrrol-2-yl, 4-(4-methylpiperazin-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrol-2-yl, 5-(4-methylpiperazin-1-ylcarbonyl)-3-methyl-1H-pyrrol-2-yl, 5-(ethoxycarbonyl)-4,5,6,7-tetrahydro-2H-isoindol-3-yl, 4-(pyridin-4-ylaminocarbonyl)-3-phenyl-5-methyl-1H-pyrrol-2-yl, 5-methylthiophen-2-yl, 3-(2-carboxyethyl)-5-ethoxycarbonyl-4-methyl-1H-pyrrol-2-yl, 3-(2-carboxyethyl)-4-carboxy-1H-pyrrol-2-yl, 3-(4-hydroxyphenyl)-4-ethoxycarbonyl-1H-pyrrol-2-yl, 4-(morpholin-4-ylcarbonyl)-3-methyl-1H-pyrrol-2-yl, 4-(piperidin-1-ylcarbonyl)-3-methyl-1H-pyrrol-2-yl, 3-(2-carboxyethyl)-5-(ethoxycarbonyl)-4-methyl-1H-pyrrol-2-yl, 3-(2-carboxyethyl)-4-(carboxy)-1H-pyrrol-2-yl, 3-(methyl)-4-(benzylaminocarbonyl)-1H-pyrrol-2-yl, 3-methyl-4-(pyridin-4-ylmethylaminocarbonyl)-1H-pyrrol-2-yl, 3-methyl-4-[3-(2-oxopyrrolidin-1-yl)propyl-aminocarbonyl)-1H-pyrrol-2-yl, 5-methyl-4-ethoxycarbonyl-3-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrrol-2-yl, or 3,5-dimethyl-4-(4-methylpiperazin-1-ylaminocarbonyl)-1H-pyrrol-2-yl.

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

15. The compound of claim 14, wherein Het is pyridin-4-yl.

16. The compound of claim 14, wherein Het is piperidin-4-yl.

17. The compound of claim 1, wherein Q is selected from the group consisting of:

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

19. A pharmaceutical composition comprising a compound or salt of claim 15 and a pharmaceutically acceptable carrier or excipient.

20. A pharmaceutical composition comprising a compound or salt of claim 16 and a pharmaceutically acceptable carrier or excipient.

21. A method for treating a protein kinase related disorder comprising administering to an organism in need thereof a therapeutically effective amount of a compound or salt of claim 1.

22. A method for treating a protein kinase related disorder comprising administering to an organism in need thereof a therapeutically effective amount of a compound or salt of claim 15.

23. A method for treating a protein kinase related disorder comprising administering to an organism in need thereof a therapeutically effective amount of a compound or salt of claim 16.

24. The method of claim 21, 22, or 23 wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase related disorder and a serine-threonine kinase related disorder.

25. The method of claim 21, 22, or 23 wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder, a flk related disorder, a CDK related disorder, a Met kinase related disorder and a Src kinase related disorder.

26. The method of claim 21, 22, or 23 wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi'"'"'s sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.

27. The method of claim 21, 22, or 23 wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder.

28. The method of claim 21, 22, or 23 wherein said protein kinase related disorder is a CDK-related disorder.

29. The method of claim 21, 22, or 23 wherein said organism is a human.