Substituted pyrrolines as kinase inhibitors

• US 20070213386A1
• Filed: 05/08/2007
• Published: 09/13/2007
• Est. Priority Date: 06/05/2002
• Status: Active Grant

• Current Assignee: Bruce Conway, Bruce Maryanoff, David Mccomsey, Han-Cheng Zhang, Hong Ye, Keith Demarest, Kimberly White, Leonard Hecker
• Original Assignee: Bruce Conway, Bruce Maryanoff, David Mccomsey, Han-Cheng Zhang, Hong Ye, Keith Demarest, Kimberly White, Leonard Hecker
• Inventors: Ye, Hong, Demarest, Keith, Zhang, Han-Cheng, White, Kimberly, Maryanoff, Bruce, Conway, Bruce, Hecker, Leonard, McComsey, David
• Granted Patent: US 7,759,380 B2
• Time in Patent Office: Days
• US Class Current: 514/403
• 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 phenyl, naphthyl, thienyl or benzothienyl.

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

C_1-6alkyl-R⁵, —

C_2-6alkenyl-R⁵, —

C_2-6alkynyl-R⁵, -aryl-R⁶ or -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 hydrogen, —

C_1-4alkyl-R⁵, —

C_2-4alkenyl-R⁵, —

C_2-6alkynyl-R⁵, -phenyl-R⁶, -naphthyl-R⁶, -pyridinyl-R⁶, -pyrimidinyl-R⁶, -quinolinyl-R⁶ or -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 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)—

NH₂, —

O—

C(O)—

NH(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—

(C_1-4)alkyl-O—

(C_1-4)alkyl-NH(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_1-4alkyl), —

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 or —

(C_1-4)alkyl-heteroaryl-R⁶.

6. The compound of claim 1 wherein R⁵ is 1 to 2 substituents independently selected from hydrogen, —

O—

(C_1-4)alkyl, —

C(O)H, —

N—

R⁷, —

(C_1-4)alkyl-N—

R⁷, hydroxy, -heterocyclyl-R⁶ or —

(C_1-4)alkyl-heterocyclyl-R⁶.

7. The compound of claim 1 wherein R⁵ is 1 to 2 substituents independently selected from 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 or -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 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, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, halo, —

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

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

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 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 or —

(C_1-4)alkyl-heteroaryl-R⁸.

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

C_1-6alkyl, —

C_2-6alkenyl, —

C_2-6alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-N(C_1-6alkyl)₂ or —

(C_1-4)alkyl-heteroaryl-R⁸.

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

C_1-6alkyl, —

C_2-6alkenyl, —

C_2-6alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-N(C_1-6alkyl)₂ or —

(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 hydrogen, —

C_1-4alkyl, —

(C_1-4)alkyl-(halo)_1-3 or —

(C_1-4)alkyl-OH;

with the proviso that, when R⁸ is attached to a carbon atom, R⁸ is further selected from —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, halo, —

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

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

C_1-4alkyl.

15. The compound of claim 1 wherein R² is one substituent attached to a carbon or nitrogen atom selected from 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-R⁵, -aryl-R⁶ or —

(C_1-4)alkyl-N—

R⁷;

with the proviso that, when R² is attached to a carbon atom, R² is further selected from —

C_1-4alkoxy-R⁵, —

N—

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

16. The compound of claim 1 wherein R² is one substituent attached to a carbon or nitrogen atom selected from hydrogen or —

C_1-4alkyl-R⁵;

with the proviso that, when R² is attached to a carbon atom, R² is further selected from —

C_1-4alkoxy-R⁵, halogen or hydroxy.

17. The compound of claim 1 wherein R² is one substituent attached to a carbon or nitrogen atom selected from hydrogen or —

C_1-4alkyl-R⁵;

with the proviso that, when R² is attached to a carbon atom, R² is further selected from —

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

18. The compound of claim 1 wherein R⁹ is 1 to 2 substituents independently selected from hydrogen, —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

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

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

20. The compound of claim 1 wherein R³ is 1 to 4 substituents attached to a carbon atom independently selected from 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-R⁹, —

C(NH)—

NH₂, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R⁹, —

C(O)—

O-aryl-R⁸, —

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 or -heteroaryl-R⁸.

21. The compound of claim 1 wherein R³ is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen or halogen.

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

23. The compound of claim 1 wherein R⁴ is 1 to 4 substituents attached to a carbon atom independently selected from 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)—

NH₂, —

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 or -heteroaryl-R⁸.

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

C_1-4alkyl-R¹⁰ or halogen.

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

C_1-4alkyl-R¹⁰ or chlorine.

26. The compound of claim 1 wherein R¹⁰ is 1 to 2 substituents independently selected from hydrogen, —

NH₂, —

NH(C_1-4alkyl), —

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

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

28. The compound of claim 1 wherein R¹¹ is selected from hydrogen, —

C_1-4alkyl-R¹⁰, —

C_2-4alkenyl-R¹⁰, —

C_2-4alkynyl-R¹⁰, —

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

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

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

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

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

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

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

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