Substituted pyrrolines as kinase inhibitors

• US 20040054180A1
• Filed: 06/04/2003
• Published: 03/18/2004
• 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., White, Kimberly, McComsey, David F., Conway, Bruce, Hecker, Leonard R., Zhang, Han Cheng
• Granted Patent: US 7,232,906 B2
• Time in Patent Office: Days
• US Class Current: 544/333
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : 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 R is selected from the group consisting of phenyl, naphthyl, thienyl and benzothienyl.

3. The compound of claim 1 wherein R¹ is selected from the group consisting of hydrogen, —

C_1-6alkyl-R⁵, —

C_2-6alkenyl-R⁵, —

C_2-6alkynyl-R⁵, -aryl-R⁶ and -heteroaryl-R⁶;

wherein a heteroaryl ring carbon atom forms the point of attachment to the indole nitrogen atom.

4. The compound of claim 1 wherein R¹ is selected from the group consisting of hydrogen, —

C_1-4alkyl-R⁵, —

C_2-4alkenyl-R⁵, —

C_2-6alkynyl-R⁵, -phenyl-R⁶, -naphthyl-R⁶, -pyridinyl-R⁶, -pyrimidinyl-R⁶, -quinolinyl-R⁶ and -benzothienyl-R⁶;

wherein a pyridinyl, pyrimidinyl, quinolinyl or benzothienyl ring carbon atom forms the point of attachment to the indole nitrogen atom.

5. The compound of claim 1 wherein R⁵ is 1 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-O—

(C_1-4)alkyl, —

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, —

O—

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

NH₂, —

O—

(C_1-4)alkyl-SO₂—

NH(C_1-4alkyl), —

O—

(C_1-4)alkyl-SO₂—

N(C_1-4alkyl)₂, —

O—

C(O)H, —

O—

C(O)—

(C_1-4)alkyl, —

O—

C(O)—

N H₂, —

O—

C(O)—

N H(C_1-4alkyl), —

O—

C(O)—

N(C_1-4alkyl)₂, —

O—

(C_1-4)alkyl-C(O)H, —

O—

(C_1-4)alkyl-C(O)—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-CO₂H, —

O—

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl, —

O-(C_1-4)alkyl-C(O)—

NH₂, —

O—

(C_1-4)alkyl-C(O)—

NH(C_1-4alkyl), —

O—

(C_1-4)alkyl-C(O)—

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(NH)—

NH₂, —

C(O)—

NH(C_1-4alkyl), —

C(O)—

N(C_1-4alkyl)₂, —

SH, —

S—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-OH, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-NH₂, —

S—

(C₁₄)alkyl-O—

(C_1-4)alkyl-N H(C_1-4alkyl), —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-N(C_1-4alkyl)₂, —

S—

(C_1-4)alkyl-NH(C_1-4alkyl), —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4-alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

N—

R⁷, —

(C_1-4)alkyl-N—

R⁷, cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl-R⁶, —

(C_1-4)alkyl-cycloalkyl-R⁶, -heterocyclyl-R⁶, —

(C_1-4)alkyl-heterocyclyl-R⁶, -aryl-R⁶, —

(C_1-4)alkyl-aryl-R⁶, -heteroaryl-R⁶ and —

(C_1-4)alkyl-heteroaryl-R⁶.

6. The compound of claim 1 wherein R⁵ is 1 to 2 substituents independently selected from the group consisting of hydrogen, -O—

(C_1-4)alkyl, —

C(O)H, —

N—

R⁷, —

(C_1-4)alkyl-N—

R⁷, hydroxy, -heterocyclyl-R⁶ and —

(C_1-4)alkyl-heterocyclyl-R⁶.

7. The compound of claim 1 wherein R⁵ is 1 to 2 substituents independently selected from the group consisting of hydrogen, —

O—

(C_1-4)alkyl, —

C(O)H, —

N—

R⁷, —

(C_1-4)alkyl-N—

R⁷, hydroxy, -pyrrolidinyl-R⁶, -morpholinyl-R⁶, -thiazolidinyl-R⁶, —

(C_1-4)alkyl-piperidinyl-R⁶ and -piperazinyl-R⁶.

8. The compound of claim 1 wherein R⁶ is 1 to 4 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 or —

(C_1-4)alkyl-OH;

with the proviso that, when R⁶ is attached to a carbon atom, R⁶ is further selected from —

C_1-4alkoxy, —

C(O)NH₂, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, halo, —

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

9. The compound of claim 1 wherein R⁶ is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen and —

C_1-4alkyl;

with the proviso that, when R⁶ is attached to a carbon atom, R⁶ is further selected from halo.

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

C_1-6alkyl, —

C_2-6alkenyl, —

C_2-6alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

(C_1-4)alkyl-NH₂, —

(C_1-4)alkyl-NH(C_1-6alkyl), —

(C_1-4)alkyl-N(C_1-6alkyl)₂, —

(C_1-4)alkyl-S-(C_1-4)alkyl, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH(C_1-6alkyl), —

C(O)—

N(C_1-6alkyl)₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-6alkyl), —

SO₂—

N(C_1-6alkyl)₂, —

C(N)—

NH₂, -cycloalkyl-R⁸, —

(C_1-4)alkyl-heterocyclyl-R⁸, -aryl-R⁸, —

(C_1-4)alkyl-aryl-R⁸ and —

(C_1-4)alkyl-heteroaryl-R⁸.

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

C_1-6alkyl, —

C_2-6alkenyl, —

C_2-6alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-N(C_1-6alkyl)₂ and —

(C_1-4)alkyl-heteroaryl-R⁸.

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

C_1-6alkyl, —

C_2-6alkenyl, —

C_2-6alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-N(C_1-6alkyl)₂ and —

(C_1-4)alkyl-furyl-R⁸.

13. The compound of claim 1 wherein R⁸ is 1 to 4 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 R⁸ is attached to a carbon atom, R⁸ is further selected from the group consisting of —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, halo, —

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

14. The compound of claim 1 wherein R⁸ is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen and —

C_1-4alkyl.

The compound of claim 1 wherein R is one substituent attached to a carbon selected from the group consisting of hydrogen, —

C_1-4alkyl-R⁵, —

C_2-4alkenyl-R⁵, —

C_2-4alkynyl-R⁵, —

C(O)H, —

C(O)—

(C_1-4)alkyl-R⁹, —

C(O)—

NH₂, —

C(O)—

NH(C_1-4alkyl-R⁹), —

C(O)—

N(C_1-4alkyl-R⁹)₂, —

C(O)—

NH(aryl-R⁸), —

C(O)-cycloalkyl-R⁸, —

C(O)-heterocyclyl-R⁸, —

C(O)-aryl-R⁸, —

C(O)-heteroaryl-R⁸, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R⁹, —

C(O)—

O-aryl-R⁸, —

SO₂—

(C_1-4)alkyl-R⁹, —

SO₂-aryl-R⁸, -cycloalkyl-R⁶, -aryl-R⁶, —

(C_1-4)alkyl-N—

R⁷, —

C_1-4alkoxy-R⁹, —

N—

R⁷, cyano, halogen, hydroxy, nitro, oxo (wherein oxo is attached to a saturated carbon atom), -heterocyclyl-R⁶ and -heteroaryl-R⁶.

15. The compound of claim 1 wherein R² is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —

C_1-4alkyl-R⁵, —

C_1-4alkoxy-R⁵, halogen and hydroxy.

16. The compound of claim 1 wherein R² is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —

C_1-4alkyl-R⁵, —

C_1-4alkoxy-R⁵, bromine, iodine and hydroxy.

17. The compound of claim 1 wherein R⁹ 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 and nitro.

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

19. The compound of claim 1 wherein R³ is 1 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-R⁹, —

C(O)—

NH₂, —

C(O)—

NH(C_1-4alkyl-R⁹), —

C(O)—

N(C_1-4alkyl-R⁹)₂, —

C(O)-cycloalkyl-R⁸, —

C(O)-heterocyclyl-R⁸, —

C(O)-aryl-R⁸, —

C(O)-heteroaryl-R⁸, —

C(N H)—

N H₂, —

CO₂H, —

C(O)—

O-(C_1-4)alkyl-R⁹, —

C(O)—

O-aryl-R⁹, —

SO₂—

(C_1-4)alkyl-R⁹, —

SO₂-aryl-R⁸, —

N—

R⁷, —

(C_1-4)alkyl-N—

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

20. The compound of claim 1 wherein R³ is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen and halogen.

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

22. The compound of claim 1 wherein R⁴ is 1 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-R⁹, —

C(O)—

NH₂, —

C(O)—

NH(C_1-4alkyl-R⁹), —

C(O)—

N(C_1-4alkyl-R⁹)₂, —

C(O)-cycloalkyl-R⁸, —

C(O)-heterocyclyl-R⁸, —

C(O)-aryl-R⁸, —

C(O)-heteroaryl-R⁸, —

C(NH)—

N H₂, —

CO₂H, —

C(O)—

O-(C_1-4)alkyl-R⁹, —

C(O)—

O-aryl-R⁸, —

SH, —

S-(C_1-4)alkyl-R¹⁰, —

SO₂—

(C_1-4)alkyl-R⁹, —

SO₂-aryl-R⁸, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl-R⁹), —

SO₂—

N(C_1-4alkyl-R⁹)₂, —

N—

R⁷, —

(C_1-4)alkyl-N—

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

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

C_1-4alkyl-R¹⁰ and halogen.

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

C_1-4alkyl-R¹⁰ and chlorine.

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

NH₂, —

NH(C_1-4alkyl), —

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

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

27. The compound of claim 1 wherein R¹¹ is selected from the group consisting of hydrogen, —

C_1-4alkyl-R¹⁰, —

C_2-4alkenyl-R¹⁰, —

C_2-4alkynyl-R¹⁰, —

C_1-4alkoxy-R¹⁰, -aryl-R⁸, -heteroaryl-R⁸ and halogen.

28. The compound of claim 1 wherein R¹¹ is hydrogen.

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

30. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ib):

31. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ic):

32. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Id):

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

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

35. 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.

40. The method of claim 36 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.

50. The method of claim 36 further comprising a method for use for a compound of claim 1 as an adjunct to chemotherapy and radiation therapy.

51. The method of claim 36 further comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 34.

52. The method of claim 52 wherein the therapeutically effective amount of a composition of claim 34 is from about 0.001 mg/kg/day to about 300 mg/kg/day.

36. The method of claim 36 wherein the disorder is mediated by selective inhibition of a kinase selected from protein kinase C or glycogen synthase kinase-3.

38. The method of claim 36 wherein the disorder is mediated by dual inhibition of at least two kinases selected from protein kinase C or glycogen synthase kinase-3.

41. The method of claim 36 wherein the kinase mediated disorder is selected from cardiovascular diseases, diabetes, diabetes-associated disorders, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders or CNS disorders.

37. The method of claim 37 wherein the kinase is selected from protein kinase C α

, protein kinase C β

-II, protein kinase C γ

or glycogen synthase kinase-3β

.

39. The method of claim 39 wherein at least two kinases are selected from protein kinase C α

, protein kinase C β

-II, protein kinase C γ

or glycogen synthase kinase-3β

.

42. The method of claim 42 wherein cardiovascular diseases are selected from acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity or age-related macular degeneration.

43. The method of claim 42 wherein diabetes is selected from insulin dependent diabetes or Type II non-insulin dependent diabetes mellitus.

44. The method of claim 42 wherein diabetes-associated disorders are selected from impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy or neuropathy.

45. The method of claim 42 wherein inflammatory diseases are selected from vascular permeability, inflammation, asthma, rheumatoid arthritis or osteoarthritis.

46. The method of claim 42 wherein immunological disorders are selected from transplant tissue rejection, HIV-1 or PKC modulated immunological disorders.

47. The method of claim 42 wherein dermatological disorders are selected from psoriasis, hair loss or baldness.

48. The method of claim 42 wherein oncological disorders are selected from cancer or tumor growth, proliferative angiopathy or angiogenesis.

49. The method of claim 42 wherein central nervous system disorders are selected from chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dementia, Alzheimer'"'"'s disease, mood disorders, schizophrenia, manic depression and neurotraumatic, cognitive decline or ischemia-related diseases (as a result of head trauma or transient ischemic stroke).

53. A method of treating or ameliorating a disorder selected from diabetes-associated disorders, dermatological disorders, oncological disorders or central nervous system disorders comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I):

55. The method of claim 55 wherein dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness.

54. The method of claim 55 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.

56. The method of claim 55 wherein oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy and angiogenesis.

57. The method of claim 55 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).