Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases

• US 8,143,293 B2
• Filed: 04/18/2008
• Issued: 03/27/2012
• Est. Priority Date: 04/20/2007
• Status: Expired due to Fees

• Current Assignee: Deciphera Pharmaceuticals, LLC (Deciphera Pharmaceuticals, Inc.)
• Original Assignee: Deciphera Pharmaceuticals, LLC (Deciphera Pharmaceuticals, Inc.)
• Inventors: Flynn, Daniel L., Petillo, Peter A., Kaufman, Michael D.
• Primary Examiner(s): Andres, Janet L
• Assistant Examiner(s): Robinson, Binta M
• Application Number:
  US12/105,408
• Publication Number:
  US 20080261965A1
• Time in Patent Office: 1,439 Days
• Field of Search: 546/275.4, 546/271.1, 546/256, 546/278.7, 546/278.4, 514/406, 514/341
• US Class Current: 514/341
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, leukemias, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocyclosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

Claims

1. A compound of the formula Ia

2. The compound of claim 1 having formula Ib

3. The compound of claim 2 having formula Ic

4. The compound of claim 2 having formula Id

5. The compound of claim 2 having formula Ie

6. The compounds of claim 1, wherein each D is individually selected from the group consisting of C, CH, N-Z3, and N, such that the resultant ring is a pyrazole.

7. The compound of claim 6 having formula Ig

8. The compound of claim 7 having the formula Ih

9. The compound of claim 7 having the formula Ii

10. The compound of claim 6 having formula Il

11. The compound of claim 10 having formula If

12. A pharmaceutical composition comprising a compound of claim 1, together with a pharmaceutically acceptable carrier, optionally containing an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.

13. A compound selected from the group consisting of

1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(3-(trifluoromethyl)phenyl)urea,

1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-(trifluoromethyl) pyridin-3-yl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,

1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,

1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(3-tert-butyl-1-(2-(dimethylamino)ethyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(1-methylcyclopentyl) isoxazol-5-yl)urea,

1-(3-cyclopentylisoxazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(1-cyclopentyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,

1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)-3-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropylpyridin-3-yl)urea,

1-(1-cyclopentyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(benzo[d]isoxazol-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(3-tert-butylisoxazol-5-yl)-3-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea,

1-(5-tert-butyl-2-methylfuran-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-fluorobenzo[d]thiazol-2-yl)urea,

1-(1-tert-butyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-(2-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,

1-(5-ethylpyridin-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,

1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(1-isopropyl-1H-imidazol-4-yl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(2-methyl-5-(trifluoromethyl)pyridin-3-yl)urea,

1-(1-tert-butyl-5-methyl-1H-pyrazol-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,

1-(2-tert-butyl-4-morpholinopyrimidin-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyridin-3-yl)urea and pharmaceutically acceptable salts and tautomers thereof.

14. A compound selected from the group consisting of

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-1H-pyrazol-4-yl)urea,

1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)phenyl)urea,

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(5-fluoropyridin-3-yl)urea,

1-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(3-isopropylisoxazol-5-yl)urea, and

1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(5-methylpyridin-3-yl)urea.

15. The compound 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)pheny)urea and pharmaceutically acceptable salts and tautomers thereof.

16. The compound 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea and pharmaceutically acceptable salts and tautomers thereof.

17. The compound 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(1-isopropyl-1H-imidazol-4-yl)urea and pharmaceutically acceptable salts and tautomers thereof.

18. The compound 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea and pharmaceutically acceptable salts and tautomers thereof.

19. The compound 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea and pharmaceutically acceptable salts and tautomers thereof.

20. The compound 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(1-isopropyl-1H-pyrazol-4-yl)urea and pharmaceutically acceptable salts and tautomers thereof.

21. The compound 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(5-fluoropyridin-3-yl)urea and pharmaceutically acceptable salts and tautomers thereof.

22. The compound 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy) phenyl)-3-(5-methylpyridin-3-yl)urea and pharmaceutically acceptable salts and tautomers thereof.