KINASE INHIBITORS USEFUL FOR THE TREATMENT OF MYLEOPROLIFIC DISEASES AND OTHER PROLIFERATIVE DISEASES

• US 20080269267A1
• Filed: 04/18/2008
• Published: 10/30/2008
• Est. Priority Date: 04/20/2007
• Status: Abandoned Application

• 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.
• Application Number:
  US12/105,302
• Publication Number:
  US 20080269267A1
• Time in Patent Office: Days
• US Class Current: 514/274
• 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, 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, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, a disease caused by c-Met kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by a Raf kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

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 the 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. A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by the kinase activity of c-Abl kinase, bcr-Abl kinase, Flt-3 kinase, VEGFR-2 kinase mutants, c-Met, HER-1. HER-2, HER-3, HER-4, FGFR, c-Kit, Raf kinase, PDGFRα

kinase and PDGFR, kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of administering to the mammal a compound of claim 1.

12. A method of claim 11 wherein said kinase is selected from the group consisting of bcr-Abl fusion protein kinases p210, bcr-Abl fusion protein kinases p190, bcr-Abl fusion protein kinases bearing the T315I gatekeeper mutant in the Abl kinase domain of p210, bcr-Abl fusion protein kinases bearing the T315I gatekeeper mutant in the Abl kinase domain of p190, and other bcr-Abl polymorphs of any of the foregoing kinases.

13. The method of claim 12, wherein said bcr-Abl fusion protein kinases p210 having SEQ ID NO:

3 &

SEQ ID NO;

4, wherein said bcr-Abl fusion protein kinase p190 has SEQ ID NO;

5, wherein said bcr-Abl fusion protein kinases p210 bearing the TB315I mutation in the Abl kinase domain has SEQ ID NO;

6 &

SEQ ID NO;

7, and wherein said bcr-Abl fusion protein kinase p190 bearing the T315I mutation in the Abl kinase domain has SEQ ID NO;

8.

14. A method of claim 11 wherein said kinase is selected from the group consisting of cKit protein kinase, PDGFR-alpha kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

15. A method of claim 11 wherein said kinase is selected from the group consisting of B-Raf V600E protein kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

16. A method of claim 11 wherein said kinase is selected from the group consisting of c-Met protein kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

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

18. 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 disease a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, comprising the step of administering to such individual a compound of claim 1.

19. The method of claim 18, said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.