N-substituted bis(fluoroalkyl)-1,4-benzodiazepinone compounds

Patent metadata

Field	Value
Publication number	US-9242940-B2
Application number	US-201314429945-A
Country	US
Kind code	B2
Filing date	Sep 20, 2013
Priority date	Sep 21, 2012
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

Disclosed are compounds of Formula (I): wherein: R 1 is —CH 2 CH 2 CF 3 ; R 2 is —CH 2 CH 2 CF 3 , or —CH 2 CH 2 CH 2 CF 3 ; R 3 is —CH 2 CF 3 , —CH 2 CN, —CH 2 (cyclopropyl), pyridinyl, chloropyridinyl, or tetrahydropyranyl; Ring A is phenyl or pyridinyl; R a , R b , y, and z are defined herein. Also disclosed are methods of using such compounds to inhibit the Notch receptor, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as cancer.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
R 1 is —CH 2 CF 2 CH 3 or —CH 2 CH 2 CF 3 ;
R 2 is —CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 , or —CH 2 CF 2 CH 3 ;
R 3 is —CH 2 CF 3 , —CH 2 CN, —CH 2 (cyclopropyl), pyridinyl, chloropyridinyl, or tetrahydropyranyl;
Ring A is phenyl or pyridinyl;
each R a is independently F, Cl, Br, —CN, —OH, —CH 3 , cyclopropyl, —CF 3 , —CH 2 CF 3 , —OCH 3 , —OCF 3 , and/or —O(cyclopropyl);
or two adjacent R a along with the carbon atoms to which they are attached form a dioxole ring;
each R b is independently F, Cl, —CH 3 , —CF 3 , —CN, and/or —OCH 3 ;
y is zero, 1, or 2; and
z is zero, 1, or 2.

2. The compound according to claim 1 wherein:
Ring A is phenyl.

3. The compound according to claim 1 wherein:
R 2 is —CH 2 CH 2 CF 3 .

4. The compound according to claim 1 wherein:
R 3 is pyridinyl, chloropyridinyl, or tetrahydropyran.

5. The compound according to claim 1 wherein:
R 3 is —CH 2 CF 3 , —CH 2 CN, or —CH 2 (cyclopropyl).

6. The compound according to claim 2 wherein:
R a is —OCH 3 ;
or two adjacent R a along with the carbon atoms to which they are attached form a dioxole ring;
R b is —OCH 3 ;
y is zero, 1, or 2; and
z is zero or 1.

7. A compound according to claim 1 selected from: (2R,3S)-N-((3S)-2-oxo-5-phenyl-1-(2-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (1); (2R,3S)-N-((3S)-1-(5-chloro-2-pyridinyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (2); (2R,3S)-N-((7S)-6-oxo-9-phenyl-5-(2-pyridinyl)-6,7-dihydro-5H-[1,3]dioxolo[4,5-h][1,4]benzodiazepin-7-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (3); (2R,3S)-N-((3S)-2-oxo-5-phenyl-1-(3-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (4); (2R,3S)-N-((3S)-2-oxo-5-phenyl-1-(3-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (5); (2R,3S)-N-(3S)-1-(cyclopropylmethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (6); (2R,3S)-N-((3S)-7-methoxy-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (7); (2R,3S)-N-((3S)-1-(cyclopropylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(2,2-difluoropropyl)-2-(3,3,3-trifluoropropyl)succinamide (8); and (2R,3S)-N-((3S)-1-(cyclopropylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(2,2-difluoropropyl)-3-(3,3,3-trifluoropropyl)succinamide (9).

8. A pharmaceutical composition comprising a compound according to claim 1 ; and a pharmaceutically acceptable carrier.

Assignees

• Bristol Myers Squibb Co

Inventors

• Han Wen-Ching
• Gill Patrice
• Gavai Ashvinikumar V
• Quesnelle Claude A

Classifications

• C07D491/04

  Ortho-condensed systems · CPC title

• C07D243/26

  Preparation from compounds already containing the benzodiazepine skeleton · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/138

  Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) · CPC title