Indolinone derivatives as protein kinase/phosphatase inhibitors

• US 7,071,332 B2
• Filed: 12/02/2003
• Issued: 07/04/2006
• Est. Priority Date: 06/02/2000
• Status: Expired due to Fees

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Harris, G. Davis, Li, Xiaoyuan, Tang, Peng Cho
• Primary Examiner(s): Saeed, Kamal A.
• Assistant Examiner(s): PAVIGLIANITI, ANTHONY JOSEPH
• Application Number:
  US10/725,277
• Publication Number:
  US 20040147586A1
• Time in Patent Office: 945 Days
• Field of Search: 544/144, 544/131, 548/455, 546/277.7
• US Class Current: 544/144
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/02 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 209/34 in position 2
• 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 relates to certain 2-indolinone compounds which modulate the activity of protein kinases (“PKs”) and phosphatases. The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

Claims

1. A compound having a structure set forth in formula (I):

2. The compound of claim 1, wherein:

(a) R₁ is selected from the group consisting of hydrogen and optionally substituted alkyl;

(b) R₂ and R₃ are each independently selected from the group consisting of hydrogen, halogen, carboxylic acid, optionally substituted heteroaryl, and optionally substituted phenyl; and

(c) R₇ is selected from the group consisting of lower alkyl substituted with a morpholinyl ring, a pyrrolidinyl ring or dialkylamino and lower alkoxy substituted with a morpholinyl ring, a pyrrolidinyl ring or dialkylamino.

3. The compound of claim 2 wherein:

(a) R₁ is selected from the group consisting of hydrogen;

(b) R₂ is hydrogen, halogen, phenyl, or carboxylic acid; and

(c) R₃ is hydrogen, halogen, carboxylic acid, optionally substituted pyridyl, and phenyl optionally substituted with lower alkoxy or halogen; and

(d) R₇ is lower alkyl substituted with a morpholinyl ring, a pyrrolidinyl ring a or dialkylamino.

4. The compound of claim 3 wherein R₇ is selected from the group consisting of 3-diethylaminopropyl and 3-pyrrolidin-1-yl-propyl.

5. The compound of claim 3 wherein:

(a) R₁ is selected from the group consisting of hydrogen;

(b) R₂ is hydrogen, halogen, phenyl, or carboxylic acid;

(c) R₃ is hydrogen, halogen, carboxylic acid, optionally substituted pyridyl, and phenyl optionally substituted with lower alkoxy or halogen; and

(d) R₇ is lower alkoxy substituted with a morpholinyl ring, a pyrrolidinyl ring a or dialkylamino.

6. The compound of claim 5, wherein R₇ is selected from the group consisting of 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-pyrrolidin-1-yl-ethoxy, and 2-morpholin-4-yl-ethoxy.

7. A compound selected from the group consisting of:

3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

5-bromo-3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro-indol-2-one,

3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro-indol-2-one,

3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro-indol-2-one,

5-phenyl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one

5-bromo-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro-indol-2-one,

3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

5-bromo-3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro-indol-2-one,

3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

5-bromo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-phenyl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

5-bromo-3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro-indol-2-one,

3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro-indol-2-one,

3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

5-bromo-3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro-indol-2-one,

3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro-indol-2-one,

3-[5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

2-oxo-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-ylmethylene]-2,3-dihydro-1H-indol-5-carboxylic acid,

2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-dihydro-1H-indole-5-carboxylic acid,

2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-dihydro-1H-indole-6-carboxylic acid,

4-(2-hydroxy-ethyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-pyridin-3-yl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-(4-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-(3-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-(2-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-(4-fluoro-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid,

3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid,

3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro-indol-2-one,

4-(2-hydroxy-ethyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-6-pyridin-3-yl-1,3-dihydro-indol-2-one,

6-(4-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-(3-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

6-(2-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one,

and 6-(4-fluoro-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one;

or a pharmaceutically acceptable salt thereof.