Substituted pyrrolines as kinase inhibitors

• US 20040059113A1
• Filed: 06/04/2003
• Published: 03/25/2004
• Est. Priority Date: 06/05/2002
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Ye, Hong, Demarest, Keith, Maryanoff, Bruce E., Zhang, Han-Cheng, Conway, Bruce R.
• Granted Patent: US 6,987,110 B2
• Time in Patent Office: Days
• US Class Current: 544/238
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

Claims

1. A compound of Formula (I):

2. The compound of claim 1 wherein R¹ is selected from the group consisting of pyridinyl-R⁵, pyrimidinyl-R⁵, benzothienyl-R⁵ and quinolinyl-R⁵ ring attached to the indole nitrogen atom via a ring carbon atom.

3. The compound of claim 1 wherein R⁵ is up to 4 substituents independently selected from the group consisting of hydrogen, —

(C_1-4)alkyl-R⁶, —

(C_2-4)alkenyl-R⁶, —

(C_2-4)alkynyl-R⁶, —

O—

(C_1-4)alkyl-R⁶, —

O—

C(O)H, —

O—

C(O)—

(C_1-4)alkyl-R⁶, —

O—

C(O)—

NH₂, —

O—

C(O)—

NH(C_1-4alkyl), —

O—

C(O)—

N(C_1-4alkyl)₂, —

C(O)H, —

C(O)—

(C_1-4)alkyl-R⁶, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R⁶, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH(C_1-4alkyl), —

C(O)—

N(C_1-4alkyl)₂, —

SH, —

S—

(C_1-4)alkyl-R⁶;

—

SO₂—

(C_1-4)alkyl-R⁶, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

N—

R⁷, cyano, halo, hydroxy, nitro, -cycloalkyl-R⁸, -heterocyclyl-R⁹, -aryl-R⁸ and -heteroaryl-R⁹.

4. The compound of claim 1 wherein R⁵ is up to 4 substituents independently selected from the group consisting of hydrogen and —

(C_1-4)alkyl-R⁶.

5. The compound of claim 1 wherein R⁵ is 1 substituent selected from the group consisting of hydrogen and —

(C_1-4)alkyl-R⁶.

6. The compound of claim 1 wherein R⁶ is up to 2 substituents independently selected from the group consisting of hydrogen, —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-NH₂, —

O—

(C_1-4)alkyl-NH(C_1-4alkyl), —

O—

(C_1-4)alkyl-N(C_1-4alkyl)₂ —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH(C_1-4alkyl), —

C(O)—

N(C_1-4alkyl)₂, —

S—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

N—

R⁷, cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.

7. The compound of claim 1 wherein R⁶ is up to 2 substituents independently selected from the group consisting of hydrogen, —

N—

R⁷, hydroxy and -heteroaryl.

8. The compound of claim 1 wherein R⁶ is up to 2 substituents independently selected from the group consisting of hydrogen, —

N—

R⁷, hydroxy and -tetrazolyl.

9. The compound of claim 1 wherein R⁷ is 2 substituents independently selected from the group consisting of hydrogen, —

(C_1-4)alkyl-R¹⁰, —

(C_2-4)alkenyl-R¹⁰, —

(C_2-4)alkynyl-R¹⁰, —

C(O)—

(C_1-4)alkyl-R¹⁰, —

C(O)—

O—

(C_1-4)alkyl-R¹⁰, —

C(O)—

NH₂, —

C(O)—

NH((C_1-4alkyl), —

C(O)—

N(C_1-4alkyl)₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

C(N)—

NH₂, -cycloalkyl-R⁸, -heterocyclyl-R⁹, -aryl-R⁸ and -heteroaryl-R⁹.

10. The compound of claim 1 wherein R⁷ is 2 substituents independently selected from the group consisting of hydrogen and —

(C_1-4)alkyl-R¹⁰.

11. The compound of claim 1 wherein R⁸ is up to 5 substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl, —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkoxy-(halo)_1-3, —

(C_1-4)alkyl-OH, cyano, halo, hydroxy and nitro.

12. The compound of claim 1 wherein R⁸ is hydrogen.

13. The compound of claim 1 wherein R⁹ is up to 5 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —

C_1-4alkyl, —

(C_1-4)alkyl-(halo)_1-3 and —

(C_1-4)alkyl-OH;

with the proviso that, when R⁹ is attached to a carbon atom, R⁹ is further selected from the group consisting of —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, —

(C_1-4)alkoxy-(halo)_1-3, cyano, halo, hydroxy and nitro.

14. The compound of claim 1 wherein R⁹ is hydrogen.

15. The compound of claim 1 wherein R² is selected from the group consisting of —

C_1-4alkyl-R⁶, —

C_2-4alkenyl-R⁶, —

C_2-4alkynyl-R⁶, —

C(O)H, —

C(O)—

(C_1-4)alkyl-R⁶, —

C(O)—

NH₂, —

C(O)—

NH(C_1-4alkyl), —

C(O)—

N((C_1-4alkyl)₂, —

C(O)—

NH(aryl), —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, —

C(O)-aryl, —

C(O)-heteroaryl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R⁶, —

C(O)—

O—

aryl, —

SO₂—

(C_1-4)alkyl-R⁶, —

SO₂-aryl, -cycloalkyl, -heterocyclyl (attached to the indole nitrogen atom via a ring carbon atom), -aryl and -heteroaryl (attached to the indole nitrogen atom via a ring carbon atom).

16. The compound of claim 1 wherein R² is selected from the group consisting of —

C_1-4alkyl-R⁶ and heteroaryl.

17. The compound of claim 1 wherein R³ is up to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —

C_1-4alkyl-R¹⁰, —

C_2-4alkenyl-R¹⁰, —

C_2-4alkynyl-R¹⁰, —

C_1-4alkoxy-R¹⁰, —

C(O)H, —

C(O)—

((C_1-4)alkyl-R¹⁰, —

C(O)—

NH₂, —

C(O)—

NH(C_1-4alkyl), —

C(O)—

N(C_1-4alkyl)₂, —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, —

C(O)-aryl, —

C(O)-heteroaryl, —

C(NH)—

NH₂, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R¹⁰, —

C(O)—

O-aryl, —

SO₂—

(C_1-4)alkyl-R¹⁰, —

SO₂-aryl, —

N—

R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.

18. The compound of claim 1 wherein R³ is hydrogen.

19. The compound of claim 1 wherein R⁴ is up to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —

C_1-4alkyl-R¹⁰, —

C_2-4alkenyl-R¹⁰, —

C_2-4alkynyl-R¹⁰, —

C_1-4alkoxy-R¹⁰, —

C(O)H, —

C(O)—

(C_1-4)alkyl-R¹⁰, —

C(O)—

NH₂, —

C(O)—

NH((C_1-4alkyl), —

C(O)—

N(C_1-4alkyl)₂, —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, —

C(O)-aryl, —

C(O)-heteroaryl, —

C(NH)—

NH₂, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R¹⁰, —

C(O)—

O-aryl, —

SH, —

S—

(C_1-4)alkyl-R¹⁰, —

SO₂—

(C_1-4)alkyl-R¹⁰, —

SO₂-aryl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

N—

R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.

20. The compound of claim 1 wherein R⁴ is hydrogen.

21. The compound of claim 1 wherein R¹⁰ is 1 to 2 substituents independently selected from the group consisting of hydrogen, —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, (halo)_1-3, hydroxy, nitro and oxo.

22. The compound of claim 1 wherein R¹⁰ is hydrogen.

23. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of Formula (Ia):

24. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

25. A method for preparing a composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

26. A method for treating or ameliorating a kinase mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

27. The method of claim 26 wherein the disorder is mediated by selective inhibition of a kinase selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

28. The method of claim 27 wherein the kinase is selected from the group consisting of protein kinase C α

, protein kinase C β

-I, protein kinase C β

-II, protein kinase C γ and

glycogen synthase kinase-3β

.

29. The method of claim 26 wherein the disorder is mediated by dual inhibition of at least two kinases selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

30. The method of claim 29 wherein at least two kinases are selected from the group consisting of protein kinase C α

, protein kinase C β

-II, protein kinase C γ and

glycogen synthase kinase-3β

.

31. The method of claim 26 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 300 mg/kg/day.

32. The method of claim 26 wherein the kinase mediated disorder is selected from the group consisting of cardiovascular diseases, diabetes, diabetes-associated disorders, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and CNS disorders.

33. The method of claim 32 wherein cardiovascular diseases are selected from the group consisting of acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity and age-related macular degeneration.

34. The method of claim 32 wherein diabetes is selected from the group consisting of insulin dependent diabetes and Type II non-insulin dependent diabetes mellitus.

35. The method of claim 32 wherein diabetes-associated disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy.

36. The method of claim 32 wherein inflammatory diseases are selected from the group consisting of vascular permeability, inflammation, asthma, rheumatoid arthritis and osteoarthritis.

37. The method of claim 32 wherein immunological disorders are selected from the group consisting of transplant tissue rejection, HIV-1 and PKC modulated immunological disorders.

38. The method of claim 32 wherein dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness.

39. The method of claim 32 wherein oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy and angiogenesis.

40. The method of claim 32 wherein central nervous system disorders are selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dementia, Alzheimer'"'"'s disease, mood disorders, schizophrenia, manic depression and neurotraumatic, cognitive decline and ischemia-related diseases (as a result of head trauma or transient ischemic stroke).

41. The method of claim 26 further comprising a method for use for a compound of claim 1 as an adjunct to chemotherapy and radiation therapy.

42. The method of claim 26 further comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 24.

43. The method of claim 26 wherein the therapeutically effective amount of a composition of claim 24 is from about 0.001 mg/kg/day to about 300 mg/kg/day.