Substituted pyrrolines as kinase inhibitors

• US 7,232,906 B2
• Filed: 06/04/2003
• Issued: 06/19/2007
• Est. Priority Date: 06/05/2002
• Status: Expired due to Fees

• 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
• Primary Examiner(s): Saeed; Kamal A.
• Application Number:
  US10/454,561
• Publication Number:
  US 20040054180A1
• Time in Patent Office: 1,476 Days
• Field of Search: 546/144, 546/167, 548/455, 548/465
• 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 R¹ is selected from the group consisting of -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.

3. 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)—

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—

(C₁₄)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_1-4-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.

4. 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.

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, —

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.

6. 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.

7. 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.

8. 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.

9. 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.

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-N(C_1-6alkyl)₂ and —

(C_1-4)alkyl-furyl-R⁸.

11. 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.

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 and —

C_1-4alkyl.

13. The compound of claim 1 wherein R² 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-R⁵, —

N—

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

14. 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.

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, bromine, iodine and hydroxy.

16. 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.

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

18. 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, —

C₂alkenyl-R¹⁰, —

C_2-4alkynyl-R¹⁰, —

C_1-4alkoxy-R¹⁰, —

C(O)H, —

C(O)—

(C_1-4alkyl-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_1-4alkyl-R⁹, —

C(O)—

O-aryl-R⁸, —

SO₂—

(C_1-4alkyl-R⁸, —

SO₂-aryl-R⁸, —

N—

R⁷, —

(C_1-4alkyl-N—

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

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 and halogen.

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

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_1-4alkyl-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_1-4alkyl-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 and halogen.

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 chlorine.

24. 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.

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

26. 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.

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

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

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

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

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