Substituted indazoly(indoly)maleimide derivatives as kinase inhibitors

• US 7,439,363 B2
• Filed: 06/01/2004
• Issued: 10/21/2008
• Est. Priority Date: 06/13/2003
• Status: Expired due to Fees

• Current Assignee: Janssen Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Ye, Hong, Maryanoff, Bruce E., Zhang, Han-Cheng
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): Young; Shawquia
• Application Number:
  US10/858,212
• Publication Number:
  US 20050004201A1
• Time in Patent Office: 1,603 Days
• Field of Search: 548/414, 548/523, 548/361.1, 546/144, 546/159, 546/275.7, 546/277.4
• US Class Current: 546/144
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 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 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings

Abstract

The present invention is directed to novel indazolyl-substituted pyrroline compounds of Formula (I):

R² is selected from the group consisting of —C_1-8alkyl-Z, —C_2-8alkenyl-Z and —C_2-8alkynyl-Z; wherein the —C_1-8alkyl-Z, —C_2-8alkenyl-Z and —C_2-8alkynyl-Z and Z is a 5 to 6 member aromatic monocyclic heteroaryl ring having from 2 to 4 heteroatoms. These compounds are 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. The compounds of Formula (I)

2. The compound of claim 1 wherein R¹ is pyridinyl.

3. The compound of claim 1 wherein R² is selected from the group consisting of —

C_1-4alkyl-Z, —

C_2-4alkenyl-Z and —

C_2-4-alkynyl-Z;

wherein the —

C_1-4alkyl, —

C₂₄alkenyl and —

C_2-4alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4)alkylamino, C_1-4alkyl, C_1-4alkoxy, halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy and hydroxy(C_1-4)alkyl.

4. The compound of claim 1 wherein R² is selected from the group consisting of —

C_1-4alkyl-Z;

wherein the —

C_1-4alkyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4)alkylamino, C_1-4alkyl, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy and hydroxy(C_1-4)alkyl.

5. The compound of claim 1 wherein Z is selected from the group consisting of, imidazole, furazan, isoxazole, isothiazole, thiazole, oxatriazole and tetrazole.

6. The compound of claim 1 wherein Z is selected from the group consisting of imidazole, triazole, oxatriazole and tetrazole.

7. The compound of claim 1 wherein Z is selected from the group consisting of oxatriazole and tetrazole.

8. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, —

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_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), amino-(C_1-4)alkyl- (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkenyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, nitro, aryl, and —

(C_1-4)alkyl-aryl.

9. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, cyano and halogen.

10. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, methoxy, cyano and chloro.

11. The compound of claim 1 wherein R⁵ is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is 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, —

(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-NH₂, —

(C_1-4)alkyl-NH(C_1-4alkyl), —

(C_1-4)alkyl- N(C_1-4alkyl)₂, —

(C_1-4alkyl-(halo)_1-3, —

(C_1-4)alkyl-OH, -aryl, and —

(C_1-4)alkyl-aryl;

with the proviso that, when R⁵ is attached to a carbon atom, R⁵ 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—

R⁶, cyano, halo, hydroxy, and nitro.

12. The compound of claim 1 wherein R⁵ is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is independently selected from the group consisting of —

C_1-4alkyl, —

C_2-4alkenyl, —

(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-(halo)_1-3, —

(C_1-4)alkyl-OH, and —

(C_1-4)alkyl-aryl;

with the proviso that, when R⁵ is attached to a carbon atom, R⁵ is further selected from the group consisting of —

C_1-4alkoxy, —

(C_1-4)alkoxy-(halo)_1-3, —

S—

(C_1-4)alkyl, —

N—

R⁶, halo, and hydroxy.

13. The compound of claim 1 wherein R⁵ is C_1-4alkyl.

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

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