Substituted pyrroline kinase inhibitors

• US 7,488,826 B2
• Filed: 03/03/2004
• Issued: 02/10/2009
• Est. Priority Date: 03/27/2003
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Zhang, Han-Cheng, Ye, Hong, Maryanoff, Bruce E.
• Primary Examiner(s): Morris; Patricia L
• Application Number:
  US10/792,522
• Publication Number:
  US 20040192718A1
• Time in Patent Office: 1,805 Days
• Field of Search: 546/112, 546/113
• US Class Current: 546/113
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 471/04 : Ortho-condensed systems

Abstract

The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors 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 R_a, —

C_1-4alkyl-R_a, —

C_2-4alkenyl-R_a, —

C_2-4alkynyl-R_a and cyano.

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-R⁸, -cycloalkyl-R⁶, -aryl-R⁶.

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

C_1-4alkyl-R⁵and -aryl-R⁶.

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—

(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, and -aryl-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, —

N—

R⁷ and hydroxy.

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, —

N—

R⁷and hydroxy.

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 and —

(C_1-4)alkyl-aryl-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 and oxo.

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, -aryl-R⁸ and —

(C_1-4)alkyl-aryl-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)-aryl-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 and oxo.

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 and oxo.

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 and hydroxy.

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)-aryl-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 and -aryl-R⁸.

19. The compound of claim 1 wherein R 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)-aryl-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 and -aryl-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 and -cycloalkyl, -aryl.

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 Y and Z are independently selected from the group consisting of O, S, (H,OH) and (H,H);

with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H).

29. The compound of claim 1 wherein Y and Z are independently selected from the group consisting of O and (H,H);

with the proviso that one of Y and Z is O, and the other is selected from the group consisting of O and (H,H).

30. The compound of claim 1 wherein Y and Z are independently selected from O.

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