HETEROARYL COMPOUNDS AND USES THEREOF

• US 20100016296A1
• Filed: 04/20/2009
• Published: 01/21/2010
• Est. Priority Date: 10/19/2007
• Status: Active Grant

• Current Assignee: Celgene Avilomics Research Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Avila Therapeutics Inc. (Bristol-Myers Squibb Company)
• Inventors: Ghosh, Shomir, Tester, Richland W., Kluge, Arthur F., Singh, Juswinder, Petter, Russell C.
• Granted Patent: US 7,989,465 B2
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• 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 5/00 : Drugs for disorders of the endocrine system
• 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 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: Y02P 20/582 : Recycling of unreacted starting or intermediate materials

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims

1. A compound selected from the group consisting of:

2. A composition comprising a compound according to claim 1, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

3. The composition according to claim 2, in combination with an additional therapeutic agent.

4. The composition according to claim 3, wherein the additional therapeutic agent is a chemotherapeutic agent.

5. A method for inhibiting one or more of ErbB1, ErbB2, ErbB3, or ErbB4, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

6. The method according to claim 5, wherein the one or more of ErbB1, ErbB2, or ErbB4, or a mutant thereof, activity is inhibited irreversibly.

7. The method according to claim 5, wherein the one or more of ErbB1, ErbB2, or ErbB4, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys797 of ErbB1, Cys805 of ErbB2 or Cys803 of ErbB4.

8. A method for treating an ErbB1-, ErbB2-, ErbB3-, or ErbB4-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

9. The method according to claim 8, wherein the disorder is a carcinoma selected from breast cancer, glioblastoma, lung cancer, cancer of the head and neck, colorectal cancer, bladder cancer, non-small cell lung cancer, squamous cell carcinoma, salivary gland carcinoma, ovarian carcinoma, or pancreatic cancer.

10. The method according to claim 8, wherein the disorder is selected from neurofibromatosis type I (NF1), neurofibromatosis type II (NF2) Schwann cell neoplasms (e.g. MPNST'"'"'s), or a Schwannoma.

11. A method for inhibiting one or more TEC-kinases, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

12. The method according to claim 11, wherein the TEC-kinase, or a mutant thereof, activity is inhibited irreversibly.

13. The method according to claim 12 wherein the TEC-kinase is selected from one or more of TEC, ITK or BMX.

14. The method according to claim 13, where the one or more of TEC, ITK or BMX activity is inhibited irreversibly by colvalently modifying Cys 449 of TEC, Cys 442 of ITK or Cys 496 of BMX.

15. A method for treating a TEC-kinase-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

16. The method according to claim 15, wherein the disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a hyperproliferative disease, an immunological-mediated diseases a disease of the respiratory tract, a disease of the bone and joints, a skin disorder, a gastrointestinal disorder, a systemic disease, or allograft rejection.

17. A method for inhibiting BTK, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

18. The method according to claim 17, wherein the BTK, or a mutant thereof, activity is inhibited irreversibly.

19. The method according to claim 18, wherein the BTK, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 481 of BTK.

20. A method for treating a BTK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

21. The method according to claim 20, wherein the disorder is an autoimmune disease, a heteroimmune disease, an inflammatory disease, a cancer, a disease of the bone and joints, or a thromboembolic disorder.

22. The method according to claim 21, wherein the disorder is selected from rheumatoid arthritis, multiple sclerosis, B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, non-Hodgkin'"'"'s lymphoma, multiple myeloma, bone cancer, bone metastasis, osteoporosis, irritable bowel syndrome, Crohn'"'"'s disease, lupus, or disorders associated with renal transplant.

23. A method for inhibiting JAK3, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

24. The method according to claim 23, wherein the JAK3, or a mutant thereof, activity is inhibited irreversibly.

25. The method according to claim 24, wherein the JAK3, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 909 of JAK3.

26. A method for treating a JAK3-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

27. The method according to claim 26, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a neurodegenerative disorder, or a solid or hematologic malignancy.

28. A compound of formula V:

30. The compound of claim 28, wherein T is selected from:

31. The compound of claim 28, wherein R^t is biotin.

32. The compound of claim 28, wherein R^t is biotin sulfoxide.

33. The compound of claim 28, wherein R^t is a radioisotope.

34. The compound of claim 28, wherein R^t is a fluorescent label.

35. The compound of claim 28 having one of the following structures:

29. A compound of formula VI or VII:

36. A method comprising the steps of:

(a) providing one or more tissues, cell types, or a lysate thereof, obtained from a patient administered at least one dose of a compound of formula I;

37. The method of claim 36, further comprising the step of adjusting the dose of the compound of formula I to increase occupancy of the protein kinase.

38. The method of claim 36, further comprising the step of adjusting the dose of the compound of formula I to decrease occupancy of the protein kinase.

39. The method of claim 36, wherein the measuring step is carried out by one of the following:

flow cytometry, Western blot, or ELISA.