Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds

Inventors: Yufen Zhao (Pennington, NJ); Ashvinikumar V. Gavai (Princeton Junction, NJ); Patrice Gill (Levittown, PA); Soong-Hoon Kim (Titusville, NJ); Brian E. Fink (Yardley, PA); Libing Chen (Newtown, PA); Mark G. Saulnier (Higganum, CT); Wen-Ching Han (Newtown, PA)

Assignee: Bristol-Myers Squibb Company

A61K31/5513 A61K45/06 C07D243/24

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Quick Facts

Patent No.: US 9,427,442
App. No.: 14/429,958
Granted: Aug 30, 2016
Kind: B2

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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.

Claims (25)

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.

Continuity (2)

Provisional Application 61703937 · Sep 21, 2012

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