Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds

Patent metadata

Field	Value
Publication number	US-9427442-B2
Application number	US-201314429958-A
Country	US
Kind code	B2
Filing date	Sep 20, 2013
Priority date	Sep 21, 2012
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

Disclosed are compounds of Formula (I): (Formula (I)) wherein: R 1 is —CH 2 CH 2 CF 3 ; R 2 is —CH 2 CH 2 CH 2 F, —CH 2 CF 2 CH 3 , —CH 2 CH 2 CF 3 , —CH 2 CH(CH 3 )CF 3 , —CH 2 CH 2 CF 2 CH 3 , (Formulae (II), (III), (IV), (V) or (VI): R 3 is H or —CH 3 ; Ring A is phenyl or pyridinyl; and R x , R y , 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 CH 2 CF 3 ;
R 2 is —CH 2 CH 2 CH 2 F, —CH 2 CF 2 CH 3 , —CH 2 CH(CH 3 )CF 3 , —CH 2 CH 2 CF 2 CH 3 ,

R 3 is H or —CH 3 ;
Ring A is phenyl or pyridinyl;
each R a is independently F, Cl, —CN, —OH, —CH 3 , cyclopropyl, —CF 3 , —OCH 3 , —OCF 3 , and/or —O(cyclopropyl);
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:
R 3 is H;
Ring A is phenyl;
each R a is independently F, Cl, —CH 3 , cyclopropyl, —OCH 3 , and/or —O(cyclopropyl);
R b is F or —CH 3 ;
y is zero, 1, or 2; and
z is zero or 1.

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

4. The compound according to claim 1 wherein:
R 2 is:

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

6. A compound according to claim 1 selected from: (2R,3S)-3-((3,3-difluorocyclobutyl) methyl)-N-((3S)-9-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (1); (2R,3S)-3-(4,4-difluorocyclohexyl)-N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (2); (2R,3S)—N-((3S)-9-(cyclopropyloxy)-5-(3-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4,4-difluorocyclohexyl)-2-(3,3,3-trifluoropropyl)succinamide (3); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4-(trifluoromethyl)cyclohexyl)-2-(3,3,3-trifluoropropyl)succinamide (4); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4,4-difluorocyclohexyl)-2-(3,3,3-trifluoropropyl)succinamide (5); (2R,3S)-3-((3,3-difluorocyclobutyl)-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (6); (2R,3S)—N-((3S)-9-(cyclopropyloxy)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((3,3-difluorocyclobutyl)methyl)-2-(3,3,3-trifluoropropyl) succinamide (7); (2R,3S)-3-((3,3-difluorocyclobutyl)methyl)-N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (8); (2R,3S)-3-((3,3-difluorocyclobutyl)methyl)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (9); (2R,3S)—N-((3S)-9-chloro-5-(3-methylphenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((3,3-difluorocyclobutyl)methyl)-2-(3,3,3-trifluoropropyl)succinamide (10); (2R,3S)-3-((3,3-difluorocyclobutyl)methyl)-N-((3S)-9-fluoro-5-(3-methylphenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl) succinamide (11); (2R,3S)—N-((3S)-9-cyclopropyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((3,3-difluorocyclobutyl)methyl)-2-(3,3,3-trifluoropropyl)succinamide (12); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((3,3-difluorocyclobutyl)methyl)-2-(3,3,3-trifluoropropyl)succinamide (13); (2R,3S)-3-((3,3-difluorocyclobutyl)methyl)-N-((3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (14); (2R,3S)-3-((3,3-difluorocyclobutyl)methyl)-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (15); (2R,3S)-3-(3-fluoropropyl)-N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (16); (2R,3S)-3-(3-fluoropropyl)-N-((3S)-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (17); (2R,3S)-3-(2,2-difluoropropyl)-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (18); (2R,3S)—N-((3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((2S)-3,3,3-trifluoro-2-methylpropyl)-2-(3,3,3-trifluoropropyl) succinamide (19); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(3-fluoropropyl)-2-(3,3,3-trifluoropropyl)succinamide (20); (2R,3S)-3-(3,3-difluorobutyl)-N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl) succinamide (21); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((2R)-3,3,3-trifluoro-2-methylpropyl)-2-(3,3,3-trifluoropropyl)succinamide (22); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-((2S)-3,3,3-trifluoro-2-methylpropyl)-2-(3,3,3-trifluoropropyl)succinamide (23); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(3,3-difluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (24); and (2R,3S)-3-((1-fluorocyclobutyl)methyl)-N-((3S)-9-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (25).

7. A pharmaceutical composition comprising at least one compound according claim 1 ; and a pharmaceutically acceptable carrier.

Assignees

• Bristol Myers Squibb Co

Inventors

• Zhao Yufen
• Gavai Ashvinikumar V
• Gill Patrice
• Kim Soong-Hoon
• Fink Brian E
• Chen Libing
• Saulnier Mark G
• Han Wen-Ching

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/555

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title

• C07D243/18

  substituted in position 2 by nitrogen, oxygen or sulfur atoms · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title