SUBSTITUTED PYRROLINE KINASE INHIBITORS

• US 20090176806A1
• Filed: 03/11/2009
• Published: 07/09/2009
• Est. Priority Date: 05/08/2002
• Status: Active Grant

• Current Assignee: Bruce E. Maryanoff, Bruce R. Conway, David F. Mccomsey, David O'Neill, Gee-Hong Kuo, Han-Cheng Zhang, Hong Ye, Keith Demarest, Lan Shen
• Original Assignee: Bruce E. Maryanoff, Bruce R. Conway, David F. Mccomsey, David O'Neill, Gee-Hong Kuo, Han-Cheng Zhang, Hong Ye, Keith Demarest, Lan Shen
• Inventors: Ye, Hong, Demarest, Keith, Maryanoff, Bruce E., Kuo, Gee-Hong, O'Neill, David, Zhang, Han-Cheng, McComsey, David F., Shen, Lan, Conway, Bruce R.
• Granted Patent: US 7,781,450 B2
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 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 39/00 General protective or antinoxious agents
• 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 7/10 : Antioedematous agents; Diuretics
• 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 471/04 : Ortho-condensed systems

Abstract

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

Claims

1. A compound of Formula (I):

2. The compound of claim 1 wherein R_a is selected from the group consisting of azaindolyl, indazolyl, benzofuryl, benzothienyl, dibenzofuryl, dibenzothienyl, quinolinyl, pyrrolo[1,2-b]pyrazolyl and pyrazolo[1,5-a]pyridin-2-yl.

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

C_1-4alkyl-R⁵, —

C_2-4alkenyl-R⁵, —

C_2-4alkynyl-R⁵, —

C(O)—

(C_1-4)alkyl-R⁹, —

C(O)-aryl-R⁸, —

C(O)—

O—

(C_1-4)alkyl-R⁹, —

C(O)—

O-aryl-R⁸, —

C(O)—

NH(C_1-4alkyl-R⁹), —

C(O)—

NH(aryl-R⁸), —

C(O)—

N(C_1-4alkyl-R⁹)₂, —

SO₂—

(C_1-4)alkyl-R⁹, —

SO₂-aryl-R³, -cycloalkyl-R⁵, -heterocyclyl-R⁶, -aryl-R⁶ and -heteroaryl-R⁶;

wherein heterocyclyl and heteroaryl are attached to the azaindole nitrogen atom in the one position via a heterocyclyl or heteroaryl ring carbon atom.

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

C_1-4alkyl-R⁵, -aryl-R⁶ and -heteroaryl-R⁶;

wherein heteroaryl is attached to the azaindole nitrogen atom in the one position via a heteroaryl ring carbon atom.

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

C_1-4alkyl-R⁵ and -naphthyl-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, —

O-aryl-R⁶, —

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, cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl-R⁶, -heterocyclyl-R⁶, -aryl-R⁶ and -heteroaryl-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, —

O-aryl-R⁶, —

N—

R⁷, hydroxy and -heteroaryl-R⁵.

8. 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-aryl-R⁶, —

N—

R⁷, hydroxy, -imidazolyl-R⁶, -triazolyl-R⁶ and -tetrazolyl-R⁶.

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, —

C_1-4alkyl, —

C_2-4alkenyl, —

C_2-4alkynyl, —

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_1-4)alkyl)₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

(C_1-4)alkyl-N—

R⁷, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkyl-OH, -aryl-R⁸, —

(C_1-4)alkyl-aryl-R⁸ and —

(C_1-4)alkyl-heteroaryl-R⁸;

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

C_1-4alkoxy, —

(C_1-4)alkoxy-(halo)_1-3, —

SH, —

S—

(C_1-4)alkyl, —

N—

R⁷, cyano, halo, hydroxy, nitro, oxo and -heteroaryl-R⁸.

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

C_1-4alkyl, —

C_2-4alkenyl, —

C_2-4alkynyl, —

(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_1-4alkyl), —

(C_1-4)alkyl-N(C_1-4alkyl)₂, —

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

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, —

(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_1-4alkyl, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl) and —

SO₂—

N(C_1-4alkyl)₂.

12. 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.

13. 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.

14. The compound of claim 1 wherein R⁶, R⁸ and R⁹ are hydrogen.

15. The compound of claim 1 wherein R² is one substituent attached to a carbon or nitrogen atom 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 and —

(C_1-4)alkyl-N—

R⁷;

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

C_1-4alkoxy-R⁵, —

N—

R⁷, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R⁶ and -heteroaryl-R⁶.

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

C_1-4alkyl-R⁵, —

C_2-4alkenyl-R⁵, —

C_2-4alkynyl-R⁵, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R⁹, -cycloalkyl-R⁶, -aryl-R⁶ and —

(C_1-4)alkyl-N—

R⁷;

with the proviso that, when R² is attached to a nitrogen atom, a quaternium salt is not formed; and

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

C_1-4alkoxy-R⁵, —

N—

R⁷, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R⁶ and -heteroaryl-R⁶.

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

C_1-4alkyl-R⁵ and -aryl-R⁶;

with the proviso that when R² is attached to a nitrogen atom, a quaternium salt is not formed; and

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

N—

R⁷, halogen, hydroxy and -heteroaryl-R⁶.

18. The compound of claim 1 wherein R³ is 1 to 3 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)—

NH₂, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl-R⁹, —

C(O)—

O-aryl-R⁸, —

SO₂—

(C_1-8)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.

19. The compound of claim 1 wherein R³ is one substituent attached to a carbon atom 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, —

CO₂H, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, halogen, hydroxy and nitro.

20. The compound of claim 1 wherein R³ is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —

C_1-4alkyl-R¹⁰, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, halogen and hydroxy.

21. 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)—

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

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, —

CO₂H, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.

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, C_1-4alkoxy-R¹⁰, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, halogen and hydroxy.

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, C_1-4alkoxy-R¹⁰, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, chlorine, fluorine and hydroxy.

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 1 to 2 substituents independently selected from the group consisting of hydrogen and (halo)_1-3.

27. The compound of claim 1 wherein R¹⁰ is 1 to 2 substituents independently selected from the group consisting of hydrogen and (fluoro)₃.

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

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

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