CYCLOPROPANE AMIDES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES

• US 20100120806A1
• Filed: 10/29/2009
• Published: 05/13/2010
• Est. Priority Date: 10/29/2008
• Status: Active Grant

• Current Assignee: Deciphera Pharmaceuticals, LLC (ONO Pharmaceutical Company Limited)
• Original Assignee: Deciphera Pharmaceuticals, LLC (ONO Pharmaceutical Company Limited)
• Inventors: Flynn, Daniel L., Petillo, Peter A., Kaufman, Michael D.
• Granted Patent: US 8,278,331 B2
• Time in Patent Office: Days
• US Class Current: 514/274
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 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 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 403/04 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

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, solid tumors, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, 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, diabetic retinopathy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocytosis, mast cell leukemia, and diseases caused by PDGFR-α kinase, PDGFR-β kinase, c-KIT kinase, cFMS kinase, c-MET kinase, and oncogenic forms, aberrant fusion proteins and polymorphs of any of the foregoing kinases.

Claims

1. Compounds of the formula Ia

2. Compounds of claim 1 wherein

3. Compounds of claim 2 having formula Ib

4. Compounds of claim 3 having formula Ic

5. Compounds of claim 3 having formula Id

6. Compounds of claim 3 having formula Ie

7. Compounds of claim 2 having formula If

8. Compounds of claim 7 having formula Ig

9. Compounds of claim 7 having formula Ih

10. Compounds of claim 7 having formula Ii

11. Compounds of claim 2 having formula Ij

12. Compounds of claim 11 having formula Ik

13. Compounds of claim 11 having formula Il

14. Compounds of claim 11 having formula Im

15. Compounds of claim 2 having formula In

16. Compounds of claim 15 having formula Io

17. Compounds of claim 15 having formula Ip

18. Compounds of claim 15 having formula Iq

19. Compounds of claim 2 having formula Ir

20. Compounds of claim 19 having formula Is

21. Compounds of claim 19 having formula It

22. Compounds of claim 19 having formula Iu

23. Compounds of claim 2 having formula Iv

24. Compounds of claim 23 having formula Iw

25. Compounds of claim 23 having formula Ix

26. Compounds of claim 23 having formula Iy

27. Compounds of claim 2 having formula Iz

28. Compounds of claim 27 having formula Iaa

29. Compounds of claim 27 having formula Ibb

30. Compounds of claim 27 having formula Icc

31. Compounds of claim 2 having formula Idd

32. Compounds of claim 31 having formula Iee

33. Compounds of claim 31 having formula Iff

34. Compounds of claim 31 having formula Igg

35. Compounds of claim 2 having formula Ihh

36. Compounds of claim 35 having formula Iii

37. Compounds of claim 35 having formula Ijj

38. Compounds of claim 35 having formula Ikk

40. A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by the kinase activity of PDGFR-α

kinase, PDGFR-β

kinase, c-KIT kinase, cFMS kinase, or c-MET kinase and oncogenic forms, aberrant fusion proteins and polymorphs thereof, comprising the step of administering to the mammal a compound of claim 1.

41. A method of claim 40 wherein said kinase is c-MET protein kinase, and any fusion protein, mutation and polymorphs thereof.

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

43. A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, or diseases characterized by angiogenesis, such as solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, 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 retinopathies, diabetic retinopathy, age-related macular degeneration and hypereosinophilic syndrome, rheumatoid arthritis, asthma, chronic obstructive pulmonary, mastocytosis, mast cell leukemia, or diseases caused by PDGFR-α

kinase, PDGFR-β

kinase, c-KIT kinase, cFMS kinase, c-MET kinase, and oncogenic forms, aberrant fusion proteins and polymorphs of any of the foregoing kinases, comprising the step of administering to such individual a compound of claim 1.

44. The method of claim 43, said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.

39. A compound selected from the group consisting of N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′

-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′

-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea, N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′

-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-fluorophenyl)-N′

-(5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide, 2-(4-fluorophenyl)-N-(5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-ylcarbamoyl)acetamide, N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide, N-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide, N-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-fluorophenyl)-N-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide, and pharmaceutically acceptable salts, solvates, hydrates and tautomers thereof.