Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders

• US 20060183900A1
• Filed: 10/28/2005
• Published: 08/17/2006
• Est. Priority Date: 10/29/2004
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Lin, Ronghui, Connolly, Peter J., Huang, Shenlin, Middleton, Steven A., Emanuel, Stuart L.
• Granted Patent: US 7,855,205 B2
• Time in Patent Office: Days
• US Class Current: 544/331
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides pyrimidinyl substituted fused-pyrrolyl compounds of Formula (I) and pharmaceutical compositions comprising the compounds and methods of synthesis and use thereof. The compounds are kinase inhibitors useful in treating or ameliorating a kinase mediated, angiogenesis-mediated or hyperproliferative disorder. The invention thus also provides a therapeutic or prophylactic method of use for the compounds and/or pharmaceutical compositions to treat such disorders.

Claims

1. A compound of Formula (1):

2. The compound of claim 1, wherein the compound is a compound of Formula (Ia):

3. The compound of any of claim 1 or 2, wherein

R₂ is selected from C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl or C_1-8alkyl substituted with C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally substituted on each of C_3-8cycloalkyl, aryl, heteroaryl and heterocyclyl with one or more of C_1-8alkyl, C_1-8alkoxy, —

N—

, —

NHC(O)—

or —

C(O)—

,

wherein C_1-8alkyl and C_1-8alkoxy are each optionally substituted with one or more of C_1-8alkoxy, NH₂, NH(C_1-8alkyl), N(C_1-8alkyl)₂, NH(C_1-8alkyl-C_1-8alkoxy), N(C_1-8alkyl-C_1-8alkoxy)₂, nitro, cyano, halogen, hydroxy, C_3-8cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally substituted on each of C_3-8cycloalkyl, aryl, heteroaryl and heterocyclyl with one or more of C_1-8alkyl, C_1-8alkoxy, C_1-8alkyl(C_1-8alkoxy), C_1-8alkyl(halogen)_1-3, C_1-8alkoxy(halogen)_1-3, C_1-8alkyl(hydroxy), C_1-8alkoxy(hydroxy), CO₂H, CO₂(C_1-8alkyl), COH, C(O)(C_1-8alkyl), NH₂, NH(C_1-8alkyl), N(C_1-8alkyl)₂, cyano, halogen, hydroxy, nitro,

wherein N is substituted with two substituents each selected from hydrogen or C_1-8alkyl, and

wherein NHC(O) and C(O) are each substituted on C(O) with C_1-8alkyl.

4. The compound of any of claim 1 or 2, wherein R₃ is selected from hydrogen, C_1-8alkyl, C_1-8alkyl(C_1-8alkoxy), C_1-8alkyl(halogen)_1-3, C_1-8alkyl(hydroxy), CO₂H, CO₂(C_1-8alkyl), COH, C(O)(C_1-8alkyl), hydroxy, C_1-8alkyl-NH₂, C_1-8alkyl-NH(C_1-8alkyl), C_1-8alkyl-N(C_1-8alkyl)₂, C_1-8alkyl(hydroxy)-NH(C_1-8alkyl), C_1-8alkyl(hydroxy)-N(C_1-8alkyl)₂ or SO₂(C_1-8alkyl).

5. The compound of any of claim 1 or 2, wherein R₄ is selected from hydrogen, C_1-8alkyl, C_1-8alkyl(halogen)_1-3, C_1-8alkyl(hydroxy), hydroxy, C_1-8alkyl-NH₂, C_1-8alkyl-NH(C_1-8alkyl) or C_1-8alkyl-N(C_1-8alkyl)₂.

6. The compound of any of claim 1 or 2, wherein

R₂ is selected from C_3-8cycloalkyl, aryl, heterocyclyl or C_1-8alkyl substituted with C_3-8cycloalkyl, optionally substituted on each of C_3-8cycloalkyl, aryl and heterocyclyl with one or more of C_1-8alkyl, C_1-8alkoxy, —

N—

, —

NHC(O)—

or —

C(O)—

,

wherein C_1-8alkyl and C_1-8alkoxy are each optionally substituted with one or more of NH(C_1-8alkyl), N(C_1-8alkyl)₂, halogen, hydroxy or heterocyclyl, optionally substituted on heterocyclyl with one or more of C_1-8alkyl,

wherein N is substituted with two substituents each selected from hydrogen or C_1-8alkyl, and

wherein NHC(O) and C(O) are each substituted on C(O) with C_1-8alkyl;

R₃ is selected from hydrogen, C_1-8alkyl, C_1-8alkyl(hydroxy), C(O)(C_1-8alkyl), C_1-8alkyl-NH(C_1-8alkyl), C_1-8alkyl-N(C_1-8alkyl)₂, C_1-8alkyl(hydroxy)-N(C_1-8alkyl)₂ or SO₂(C_1-8alkyl); and

R₄ is selected from hydrogen or C_1-8alkyl.

7. The compound of any of claim 1 to 6, wherein the compound is an isolated form thereof.

8. The compound of claim 7, wherein the compound or a form thereof is an inhibitor of ATP-protein kinase interactions.

9. The compound of claim 8, wherein the protein kinase is selected from a serine/threonine kinase or a tyrosine kinase.

10. The compound of claim 9, wherein the protein kinase is selected from CDK, VEGF-R2, HER2, Aurora-A or RET.

11. The compound of any of claim 1 to 6, wherein the form of said compound is a pharmaceutical composition or medicament comprising one or more of said compound.

12. A pharmaceutical composition comprising an effective amount of a compound of any of claim 1 to 6 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.

14. A process for preparing a pharmaceutical composition comprising the step of admixing a compound of any of claim 1 to 6 and a pharmaceutically acceptable carrier.

15. A method for using a compound of any of claim 1 to 6 for inhibiting unregulated kinase activity comprising contacting the kinase domain with one or more of the compounds.

16. The method of claim 15, wherein the kinase domain is a kinase receptor.

17. The method of claim 15, wherein the unregulated activity is increased or unregulated kinase expression or signaling leading to unregulated cell proliferation.

18. The method of any of claim 15 to 17, wherein the kinase is selected from CDK, VEGF-R2, HER2, Aurora-A or RET.

19. A method for treating or ameliorating a kinase mediated disorder in a patient in need thereof comprising administering to the patient an effective amount of a compound of any of claim 1 to 6.

20. The method of claim 19, wherein the kinase is selected from CDK, VEGF-R2, HER2, Aurora-A or RET.

21. The method of claim 19, wherein the kinase mediated disorder is selected from cancers and associated pathologies, disorders and diseases associated with unregulated cellular mitosis, unregulated cell proliferation and upregulated kinase activity.

22. The method of claim 21, wherein cancer is selected from glioma cancers, epidermoid cancers, head and neck cancers, lung cancers, breast cancers, colorectal cancers, prostate cancers, gastric cancers, esophageal cancers, papillocarcinomas, Kaposi'"'"'s sarcoma, leukemias and lymphomas;

and associated pathologies is selected from abnormal cell proliferation, unregulated cell proliferation, tumor growth, tumor vascularization, metastatic cancer cell invasion and migration, angiopathy, angiogenesis or chemotherapy-induced alopecia.

23. The method of claim 21, wherein disorders and diseases associated with unregulated cellular mitosis, unregulated cell proliferation and upregulated kinase activity is selected from acute inflammation, chronic inflammation, osteoarthritis, synovial pannus invasion in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, retinal vessel proliferation, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, bone diseases, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, cachexia, septic shock, fibroproliferative and differentiative skin diseases or disorders, papilloma formation, psoriasis, dermatitis, eczema, seborrhea, central nervous system diseases, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, depression, heart disease, hemangioma atheroma, occular diseases, macular degeneration, diseases of the cornea, glaucoma, autoimmune disease, viral infections, cytomegalovirus, atherosclerosis, transplantation-induced vasculopathies, neointima formation, allergic-asthma, lung fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disorder, acute, subacute or chronic forms of glomerulonephritis, glomerulosclerosis, congenital multicystic renal dysplasia, kidney fibrosis, diabetic retinopathy, rheumatoid arthritis or arterial restenosis.

24. The method of claim 19, wherein the effective amount of the compound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

25. The method of claim 24, wherein the amount of the compound is effective to induce remission of a chronic form of a cancer.

26. The method of claim 24, wherein the amount of the compound is effective at a low dose to inhibit unregulated kinase activity.

27. The method of claim 19, wherein the method further comprises the use of one or more of the compound in the preparation of a composition or medicament for use in treating or ameliorating a kinase mediated disorder in the patient.

28. A process for preparing a compound of any of claim 1 to 6 comprising the steps of

29. A process for preparing a compound of any of claim 1 to 6 comprising the steps of

30. A process for preparing a compound of any of claim 1 to 6 comprising the steps of