Substituted pyrrolines as kinase inhibitors

US 6,987,110 B2
Filed: 06/04/2003
Issued: 01/17/2006
Est. Priority Date: 06/05/2002
Status: Expired due to Fees

First Claim

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1. A compound of Formula (I):

whereinR¹is selected from the group consisting of a pyridinyl-R⁵, pyrimidinyl-R⁵, pyrazinyl-R⁵, furyl-R⁵, thienyl-R⁵, benzofuryl-R⁵, benzothienyl-R⁵, quinolinyl-R⁵and isoquinolinyl-R⁵ring attached to the indole nitrogen atom via a ring carbon atom;

R²is selected from the group consisting of —

C_1-8alkyl-R⁶, —

C_2-8alkenyl-R⁶, —

C_2-8alkynyl-R⁶, —

C(O)H, —

C(O)—

(C_1-8)alkyl-R⁶, —

C(O)—

NH₂, —

C(O)—

NH(C_1-8alkyl), —

C(O)—

N(C_1-8alkyl)₂, —

C(O)—

NH(aryl), —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, —

C(O)-aryl, —

C(O)-heteroaryl, —

CO₂H, —

C(O)—

O—

(C_1-8)alkyl-R⁶, —

C(O)—

O-aryl, —

SO₂—

(C_1-8)alkyl-R⁶, —

SO₂-aryl, -cycloalkyl-R⁸, -heterocyclyl-R⁹(attached to the indole nitrogen atom via a ring carbon atom), -aryl-R⁸and -heteroaryl-R⁹(attached to the indole nitrogen atom via a ring carbon atom);

R³is up to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —

C_1-8alkyl-R¹⁰, —

C_2-8alkenyl-R¹⁰, —

C_2-8alkynyl-R¹⁰, —

C_1-8alkoxy-R¹⁰, —

C(O)H, —

C(O)—

(C_1-8)alkyl-R¹⁰, —

C(O)—

NH₂, —

C(O)—

NH(C_1-8alkyl), —

C(O)—

N(C_1-8alkyl)₂, —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, —

C(O)-aryl, —

C(O)-heteroaryl, —

C(NH)—

NH₂, —

CO₂H, —

C(O)—

O—

(C_1-8)alkyl-R¹⁰, —

C(O)—

O—

aryl, —

SO₂—

(C_1-8)alkyl-R¹⁰, —

SO₂-aryl, —

N—

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

R⁴is up to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —

C_1-8alkyl-R¹⁰, —

C_2-8alkenyl-R¹⁰, —

C_2-8alkynyl-R¹⁰, —

C_1-8alkoxy-R¹⁰, —

C(O)H, —

C(O)—

(C_1-8)alkyl-R¹⁰, —

C(O)—

NH₂, —

C(O)—

NH(C_1-8alkyl), —

C(O)—

N(C_1-8alkyl)₂, —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, —

C(O)-aryl, —

C(O)-heteroaryl, —

C(NH)—

NH₂, —

CO₂H, —

C(O)—

O—

(C_1-8)alkyl-R¹⁰, —

C(O)—

O-aryl, —

SH, —

S—

(C_1-8)alkyl-R¹⁰, —

SO₂—

(C_1-8)alkyl-R¹⁰, —

SO₂-aryl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-8alkyl), —

SO₂—

N(C_1-8alkyl)₂, —

N—

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

R⁵is up to 4 substituents independently selected from the group consisting of hydrogen, —

(C_1-8)alkyl-R⁶, —

(C_2-8)alkenyl-R⁶, —

(C_2-8)alkynyl-R⁶, —

O—

(C_1-8)alkyl-R⁶, —

O—

C(O)H, —

O—

C(O)—

(C_1-8)alkyl-R⁶, —

O—

C(O)—

NH₂, —

O—

C(O)—

NH(C_1-8alkyl), —

O—

C(O)—

N(C_1-8alkyl)₂, —

C(O)H, —

C(O)—

(C_1-8)alkyl-R⁶, —

CO₂H, —

C(O)—

O—

(C_1-8)alkyl-R⁶, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH(C_1-8alkyl), —

C(O)—

N(C_1-8alkyl)₂, —

SH, —

S—

(C_1-8)alkyl-R⁶;

—

SO₂—

(C_1-8)alkyl-R⁶, —

SO₂—

NH₂, —

SO₂—

NH(C_1-8alkyl), —

SO₂—

N(C_1-8alkyl)₂, —

N—

R⁷, cyano, halo, hydroxy, nitro, -cycloalkyl-R⁸, -heterocyclyl-R⁹, -aryl-R⁸, and -heteroaryl-R⁹;

R⁶is up to 2 substituents independently selected from the group consisting of hydrogen, —

O—

(C_1-8)alkyl, —

O—

(C_1-8)alkyl-OH, —

O—

(C_1-8)alkyl-NH₂, —

O—

(C_1-8)alkyl-NH(C_1-8alkyl), —

O—

(C_1-8)alkyl-N(C_1-8alkyl)₂, —

C(O)H, —

C(O)—

(C_1-8)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-8)alkyl, —

C(O)—

NH₂, —

C(O)—

NH(C_1-8alkyl), —

C(O)—

N(C_1-8alkyl)₂, —

S—

(C_1-8)alkyl, —

SO₂—

(C_1-8)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-8alkyl), —

SO₂—

N(C_1-8alkyl)₂, —

N—

R⁷, cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl, -heterocyclyl, -aryl, and -heteroaryl;

R⁷is 2 substituents independently selected from the group consisting of hydrogen, —

(C_1-4)alkyl-R¹⁰, —

(C_2-4)alkenyl-R¹⁰, —

(C_2-4)alkynyl-R¹⁰, —

C(O)—

(C_1-4)alkyl-R¹⁰, —

C(O)—

O—

(C_1-4)alkyl-R¹⁰, —

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, -heterocyclyl-R⁹, -aryl-R⁸, and -heteroaryl-R⁹;

R⁸is up to 5 substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl, —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkoxy-(halo)_1-3, —

(C_1-4)alkyl-OH, cyano, halo, hydroxy, and nitro;

R⁹is up to 5 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 R⁹is attached to a carbon atom, R⁹is further selected from the group consisting of —

C_1-4alkoxy, —

NH₂, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, —

(C_1-4)alkoxy-(halo)_1-3, cyano, halo, hydroxy, and nitro; and

, R¹⁰is 1 to 2 substituents independently selected from the group consisting of hydrogen, —

C_1-8alkoxy, —

NH₂, —

NH(C_1-8alkyl), —

N(C_1-8alkyl)₂, cyano, (halo)_1-3, hydroxy, nitro, and oxo;

and pharmaceutically acceptable salts thereof.

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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.

110 Citations

29 Claims

1. A compound of Formula (I):
- whereinR¹is selected from the group consisting of a pyridinyl-R⁵, pyrimidinyl-R⁵, pyrazinyl-R⁵, furyl-R⁵, thienyl-R⁵, benzofuryl-R⁵, benzothienyl-R⁵, quinolinyl-R⁵and isoquinolinyl-R⁵ring attached to the indole nitrogen atom via a ring carbon atom;
  
  R²is selected from the group consisting of —
  
  C_1-8alkyl-R⁶, —
  
  C_2-8alkenyl-R⁶, —
  
  C_2-8alkynyl-R⁶, —
  
  C(O)H, —
  
  C(O)—
  
  (C_1-8)alkyl-R⁶, —
  
  C(O)—
  
  NH₂, —
  
  C(O)—
  
  NH(C_1-8alkyl), —
  
  C(O)—
  
  N(C_1-8alkyl)₂, —
  
  C(O)—
  
  NH(aryl), —
  
  C(O)-cycloalkyl, —
  
  C(O)-heterocyclyl, —
  
  C(O)-aryl, —
  
  C(O)-heteroaryl, —
  
  CO₂H, —
  
  C(O)—
  
  O—
  
  (C_1-8)alkyl-R⁶, —
  
  C(O)—
  
  O-aryl, —
  
  SO₂—
  
  (C_1-8)alkyl-R⁶, —
  
  SO₂-aryl, -cycloalkyl-R⁸, -heterocyclyl-R⁹(attached to the indole nitrogen atom via a ring carbon atom), -aryl-R⁸and -heteroaryl-R⁹(attached to the indole nitrogen atom via a ring carbon atom);
  
  R³is up to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
  
  C_1-8alkyl-R¹⁰, —
  
  C_2-8alkenyl-R¹⁰, —
  
  C_2-8alkynyl-R¹⁰, —
  
  C_1-8alkoxy-R¹⁰, —
  
  C(O)H, —
  
  C(O)—
  
  (C_1-8)alkyl-R¹⁰, —
  
  C(O)—
  
  NH₂, —
  
  C(O)—
  
  NH(C_1-8alkyl), —
  
  C(O)—
  
  N(C_1-8alkyl)₂, —
  
  C(O)-cycloalkyl, —
  
  C(O)-heterocyclyl, —
  
  C(O)-aryl, —
  
  C(O)-heteroaryl, —
  
  C(NH)—
  
  NH₂, —
  
  CO₂H, —
  
  C(O)—
  
  O—
  
  (C_1-8)alkyl-R¹⁰, —
  
  C(O)—
  
  O—
  
  aryl, —
  
  SO₂—
  
  (C_1-8)alkyl-R¹⁰, —
  
  SO₂-aryl, —
  
  N—
  
  R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl, and -heteroaryl;
  
  R⁴is up to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
  
  C_1-8alkyl-R¹⁰, —
  
  C_2-8alkenyl-R¹⁰, —
  
  C_2-8alkynyl-R¹⁰, —
  
  C_1-8alkoxy-R¹⁰, —
  
  C(O)H, —
  
  C(O)—
  
  (C_1-8)alkyl-R¹⁰, —
  
  C(O)—
  
  NH₂, —
  
  C(O)—
  
  NH(C_1-8alkyl), —
  
  C(O)—
  
  N(C_1-8alkyl)₂, —
  
  C(O)-cycloalkyl, —
  
  C(O)-heterocyclyl, —
  
  C(O)-aryl, —
  
  C(O)-heteroaryl, —
  
  C(NH)—
  
  NH₂, —
  
  CO₂H, —
  
  C(O)—
  
  O—
  
  (C_1-8)alkyl-R¹⁰, —
  
  C(O)—
  
  O-aryl, —
  
  SH, —
  
  S—
  
  (C_1-8)alkyl-R¹⁰, —
  
  SO₂—
  
  (C_1-8)alkyl-R¹⁰, —
  
  SO₂-aryl, —
  
  SO₂—
  
  NH₂, —
  
  SO₂—
  
  NH(C_1-8alkyl), —
  
  SO₂—
  
  N(C_1-8alkyl)₂, —
  
  N—
  
  R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl, and -heteroaryl;
  
  R⁵is up to 4 substituents independently selected from the group consisting of hydrogen, —
  
  (C_1-8)alkyl-R⁶, —
  
  (C_2-8)alkenyl-R⁶, —
  
  (C_2-8)alkynyl-R⁶, —
  
  O—
  
  (C_1-8)alkyl-R⁶, —
  
  O—
  
  C(O)H, —
  
  O—
  
  C(O)—
  
  (C_1-8)alkyl-R⁶, —
  
  O—
  
  C(O)—
  
  NH₂, —
  
  O—
  
  C(O)—
  
  NH(C_1-8alkyl), —
  
  O—
  
  C(O)—
  
  N(C_1-8alkyl)₂, —
  
  C(O)H, —
  
  C(O)—
  
  (C_1-8)alkyl-R⁶, —
  
  CO₂H, —
  
  C(O)—
  
  O—
  
  (C_1-8)alkyl-R⁶, —
  
  C(O)—
  
  NH₂, —
  
  C(NH)—
  
  NH₂, —
  
  C(O)—
  
  NH(C_1-8alkyl), —
  
  C(O)—
  
  N(C_1-8alkyl)₂, —
  
  SH, —
  
  S—
  
  (C_1-8)alkyl-R⁶;
  
  —
  
  SO₂—
  
  (C_1-8)alkyl-R⁶, —
  
  SO₂—
  
  NH₂, —
  
  SO₂—
  
  NH(C_1-8alkyl), —
  
  SO₂—
  
  N(C_1-8alkyl)₂, —
  
  N—
  
  R⁷, cyano, halo, hydroxy, nitro, -cycloalkyl-R⁸, -heterocyclyl-R⁹, -aryl-R⁸, and -heteroaryl-R⁹;
  
  R⁶is up to 2 substituents independently selected from the group consisting of hydrogen, —
  
  O—
  
  (C_1-8)alkyl, —
  
  O—
  
  (C_1-8)alkyl-OH, —
  
  O—
  
  (C_1-8)alkyl-NH₂, —
  
  O—
  
  (C_1-8)alkyl-NH(C_1-8alkyl), —
  
  O—
  
  (C_1-8)alkyl-N(C_1-8alkyl)₂, —
  
  C(O)H, —
  
  C(O)—
  
  (C_1-8)alkyl, —
  
  CO₂H, —
  
  C(O)—
  
  O—
  
  (C_1-8)alkyl, —
  
  C(O)—
  
  NH₂, —
  
  C(O)—
  
  NH(C_1-8alkyl), —
  
  C(O)—
  
  N(C_1-8alkyl)₂, —
  
  S—
  
  (C_1-8)alkyl, —
  
  SO₂—
  
  (C_1-8)alkyl, —
  
  SO₂—
  
  NH₂, —
  
  SO₂—
  
  NH(C_1-8alkyl), —
  
  SO₂—
  
  N(C_1-8alkyl)₂, —
  
  N—
  
  R⁷, cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl, -heterocyclyl, -aryl, and -heteroaryl;
  
  R⁷is 2 substituents independently selected from the group consisting of hydrogen, —
  
  (C_1-4)alkyl-R¹⁰, —
  
  (C_2-4)alkenyl-R¹⁰, —
  
  (C_2-4)alkynyl-R¹⁰, —
  
  C(O)—
  
  (C_1-4)alkyl-R¹⁰, —
  
  C(O)—
  
  O—
  
  (C_1-4)alkyl-R¹⁰, —
  
  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, -heterocyclyl-R⁹, -aryl-R⁸, and -heteroaryl-R⁹;
  
  R⁸is up to 5 substituents independently selected from the group consisting of hydrogen, —
  
  C_1-4alkyl, —
  
  C_1-4alkoxy, —
  
  NH₂, —
  
  NH(C_1-4alkyl), —
  
  N(C_1-4alkyl)₂, —
  
  (C_1-4)alkyl-(halo)_1-3, —
  
  (C_1-4)alkoxy-(halo)_1-3, —
  
  (C_1-4)alkyl-OH, cyano, halo, hydroxy, and nitro;
  
  R⁹is up to 5 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 R⁹is attached to a carbon atom, R⁹is further selected from the group consisting of —
  
  C_1-4alkoxy, —
  
  NH₂, —
  
  NH(C_1-4alkyl), —
  
  N(C_1-4alkyl)₂, —
  
  (C_1-4)alkoxy-(halo)_1-3, cyano, halo, hydroxy, and nitro; and
  
  , R¹⁰is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
  
  C_1-8alkoxy, —
  
  NH₂, —
  
  NH(C_1-8alkyl), —
  
  N(C_1-8alkyl)₂, cyano, (halo)_1-3, hydroxy, nitro, and oxo;
  
  and pharmaceutically acceptable salts thereof.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29)
- - 2. The compound of claim 1 wherein R¹is selected from the group consisting of pyridinyl-R⁵, pyrimidinyl-R⁵, benzothienyl-R⁵and quinolinyl-R⁵ring attached to the indole nitrogen atom via a ring carbon atom.
  - 3. The compound of claim 1 wherein R⁵is up to 4 substituents independently selected from the group consisting of hydrogen, —
    - (C_1-4)alkyl-R⁶, —
      
      (C_2-4)alkenyl-R⁶, —
      
      (C_2-4)alkynyl-R⁶, —
      
      O—
      
      (C_1-4)alkyl-R⁶, —
      
      O—
      
      C(O)H, —
      
      O—
      
      C(O)—
      
      (C_1-4)alkyl-R⁶, —
      
      O—
      
      C(O)—
      
      NH₂, —
      
      O—
      
      C(O)—
      
      NH(C_1-4alkyl), —
      
      O—
      
      C(O)—
      
      N(C_1-4alkyl)₂, —
      
      C(O)H, —
      
      C(O)—
      
      (C_1-4)alkyl-R⁶, —
      
      CO₂H, —
      
      C(O)—
      
      O—
      
      (C_1-4)alkyl-R⁶, —
      
      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-R⁶;
      
      —
      
      SO₂—
      
      (C_1-4)alkyl-R⁶, —
      
      SO₂—
      
      NH₂, —
      
      SO₂—
      
      NH(C_1-4alkyl), —
      
      SO₂—
      
      N(C_1-4alkyl)₂, —
      
      N—
      
      R⁷, cyano, halo, hydroxy, nitro, -cycloalkyl-R⁸, -heterocyclyl-R⁹, -aryl-R⁸and -heteroaryl-R⁹.
  - 4. The compound of claim 1 wherein R⁵is up to 4 substituents independently selected from the group consisting of hydrogen and —
    - (C_1-4)alkyl-R⁶.
  - 5. The compound of claim 1 wherein R⁵is 1 substituent selected from the group consisting of hydrogen and —
    - (C_1-4)alkyl-R⁶.
  - 6. The compound of claim 1 wherein R⁶is up 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-NH₂, —
      
      O—
      
      (C_1-4)alkyl-NH(C_1-4alkyl), —
      
      O—
      
      (C_1-4)alkyl-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(O)—
      
      NH(C_1-4alkyl), —
      
      C(O)—
      
      N(C_1-4alkyl)₂, —
      
      S—
      
      (C_1-4)alkyl, —
      
      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, -heterocyclyl, -aryl and -heteroaryl.
  - 7. The compound of claim 1 wherein R⁶is up to 2 substituents independently selected from the group consisting of hydrogen, —
    - N—
      
      R⁷, hydroxy and -heteroaryl.
  - 8. The compound of claim 1 wherein R⁶is up to 2 substituents independently selected from the group consisting of hydrogen, —
    - N—
      
      R⁷, hydroxy and -tetrazolyl.
  - 9. The compound of claim 1 wherein R⁷is 2 substituents independently selected from the group consisting of hydrogen and —
    - (C_1-4)alkyl-R¹⁰.
  - 10. The compound of claim 1 wherein R⁸is hydrogen.
  - 11. The compound of claim 1 wherein R⁹is hydrogen.
  - 12. The compound of claim 1 wherein R²is selected from the group consisting of —
    - C_1-4alkyl-R⁶, —
      
      C_2-4alkenyl-R⁶, —
      
      C_2-4alkynyl-R⁶, —
      
      C(O)H, —
      
      C(O)—
      
      (C_1-4)alkyl-R⁶, —
      
      C(O)—
      
      NH₂, —
      
      C(O)—
      
      NH(C_1-4alkyl), —
      
      C(O)—
      
      N(C_1-4alkyl)₂, —
      
      C(O)—
      
      NH(aryl), —
      
      C(O)-cycloalkyl, —
      
      C(O)-heterocyclyl, —
      
      C(O)-aryl, —
      
      C(O)-heteroaryl, —
      
      CO₂H, —
      
      C(O)—
      
      O—
      
      (C_1-4)alkyl-R⁶, —
      
      C(O)—
      
      O-aryl, —
      
      SO₂—
      
      (C_1-4)alkyl-R⁶, —
      
      SO₂-aryl, -cycloalkyl, -heterocyclyl (attached to the indole nitrogen atom via a ring carbon atom), -aryl and -heteroaryl (attached to the indole nitrogen atom via a ring carbon atom).
  - 13. The compound of claim 1 wherein R²is selected from the group consisting of —
    - C_1-4alkyl-R⁶and heteroaryl.
  - 14. The compound of claim 1 wherein R³is up 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-R¹⁰, —
      
      C(O)—
      
      NH₂, —
      
      C(O)—
      
      NH(C_1-4alkyl), —
      
      C(O)—
      
      N(C_1-4alkyl)₂, —
      
      C(O)-cycloalkyl, —
      
      C(O)-heterocyclyl, —
      
      C(O)-aryl, —
      
      C(O)-heteroaryl, —
      
      C(NH)—
      
      NH₂, —
      
      CO₂H, —
      
      C(O)—
      
      O—
      
      (C_1-4)alkyl-R¹⁰, —
      
      C(O)—
      
      O-aryl, —
      
      SO₂—
      
      (C_1-4)alkyl-R¹⁰, —
      
      SO₂-aryl, —
      
      N—
      
      R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.
  - 15. The compound of claim 1 wherein R³is hydrogen.
  - 16. The compound of claim 1 wherein R⁴is up 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-R¹⁰, —
      
      C(O)—
      
      NH₂, —
      
      C(O)—
      
      NH(C_1-4alkyl), —
      
      C(O)—
      
      N(C_1-4alkyl)₂, —
      
      C(O)-cycloalkyl, —
      
      C(O)-heterocyclyl, —
      
      C(O)-aryl, —
      
      C(O)-heteroaryl, —
      
      C(NH)—
      
      NH₂, —
      
      CO₂H, —
      
      C(O)—
      
      O—
      
      (C_1-4)alkyl-R¹⁰, —
      
      C(O)—
      
      O-aryl, —
      
      SH, —
      
      S—
      
      (C_1-4)alkyl-R¹⁰, —
      
      SO₂—
      
      (C_1-4)alkyl-R¹⁰, —
      
      SO₂-aryl, —
      
      SO₂—
      
      NH₂, —
      
      SO₂—
      
      NH(C_1-4alkyl), —
      
      SO₂—
      
      N(C_1-4alkyl)₂, —
      
      N—
      
      R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.
  - 17. The compound of claim 1 wherein R⁴is hydrogen.
  - 18. The compound of claim 1 wherein R¹⁰is 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, nitro and oxo.
  - 19. The compound of claim 1 wherein R¹⁰is hydrogen.
  - 20. The compound of claim 1 wherein the compound of Formula (I) is selected from a compound of Formula (Ia):
21. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
22. A method of preparing a composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
24. A method of treating or ameliorating diabetes or diabetes-associated disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.
25. The method of claim 24 wherein the therapeutically effective amount of the compound is from about 0.001 mg/kg/day to about 300 mg/kg/day.
26. The method of claim 24 wherein diabetes is selected from the group consisting of insulin dependent diabetes and Type II non-insulin dependent diabetes mellitus.
27. The method of claim 24 wherein diabetes-associated disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy.
28. The method of treating or ameliorating diabetes or diabetes-associated disorders comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 21.
29. The method of claim 28 wherein the therapeutically effective amount of the composition is from about 0.001 mg/kg/day to about 300 mg/kg/day.

23. A compound of claim which is 3-[1-(2-hydroxyethyl)-1H-indol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione.

Specification

Resources

Litigation Campaign Assessment

Current Assignee
Janssen Pharmaceutica NV (Johnson & Johnson)
Original Assignee
Janssen Pharmaceutica NV (Johnson & Johnson)
Inventors
Ye, Hong, Demarest, Keith, Maryanoff, Bruce E., Zhang, Han-Cheng, Conway, Bruce R.
Primary Examiner(s)
Richter, Johann
Assistant Examiner(s)
SACKEY, EBENEZER O

Application Number

US10/454,069
Publication Number

US 20040059113A1
Time in Patent Office

958 Days
Field of Search

544/333, 544/335, 544/405, 546/167, 546/176, 546/256, 546/2, 514/252.1, 514/256, 514/307, 514/25
US Class Current

514/252.1
CPC Class Codes

A61P 11/06   Antiasthmatics

A61P 13/12   of the kidneys

A61P 17/00   Drugs for dermatological di...

A61P 17/06   Antipsoriatics

A61P 17/14   for baldness or alopecia

A61P 19/02   for joint disorders, e.g. a...

A61P 25/00   Drugs for disorders of the ...

A61P 25/04   Centrally acting analgesics...

A61P 25/08   Antiepileptics; Anticonvuls...

A61P 25/18   Antipsychotics, i.e. neurol...

A61P 25/24   Antidepressants

A61P 25/28   for treating neurodegenerat...

A61P 27/02   Ophthalmic agents

A61P 29/00   Non-central analgesic, anti...

A61P 3/10   for hyperglycaemia, e.g. an...

A61P 31/18   for HIV

A61P 35/00   Antineoplastic agents

A61P 37/00   Drugs for immunological or ...

A61P 37/06   Immunosuppressants, e.g. dr...

A61P 43/00   Drugs for specific purposes...

A61P 7/02 : Antithrombotic agents; Anti...

A61P 9/00 : Drugs for disorders of the ...

A61P 9/04 : Inotropic agents, i.e. stim...

A61P 9/10 : for treating ischaemic or a...

A61P 9/12 : Antihypertensives

C07D 401/14 : containing three or more he...

C07D 403/14 : containing three or more he...

C07D 409/14 : containing three or more he...

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Substituted pyrrolines as kinase inhibitors

First Claim

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Abstract

110 Citations

29 Claims

Specification

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Substituted pyrrolines as kinase inhibitors

First Claim

1 Assignment

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

110 Citations

29 Claims

Specification

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Use Cases

Quick Links

Others