Fluoroalkyl-1,4-benzodiazepinone compounds

Inventors: Ashvinikumar V. Gavai (Princeton Junction, NJ); Weifang Shan (Princeton, NJ); James Aaron Balog (Lambertsville, NJ); Claude A. Quesnelle (Skillman, NJ); Wen-Ching Han (Newtown, PA); George V. DeLucca (Pennington, NJ); Daniel O'Malley (New Hope, PA); Brian E. Fink (Yardley, PA)

Assignee: Bristol-Myers Squibb Company

C07D243/24 A61K31/5513 A61K45/06 C07D401/04 C07D401/12 C07D413/12 C07D413/14 C07D491/056

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,133,139
App. No.: 14/429,941
Granted: Sep 15, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed are compounds of Formula (I): wherein: R 2 is phenyl, fluorophenyl, chlorophenyl, trifluorophenyl, methylisoxazolyl, or pyridinyl; R 3 is H, CH 3 , CH 2 (cyclopropyl), pyridinyl, chloropyridinyl, or methoxypyridinyl: and 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 (23)

1. A compound of Formula (I):

wherein:

R 2 is phenyl, fluorophenyl, chlorophenyl, trifluorophenyl, methylisoxazolyl, or pyridinyl;

R 3 is H, —CH 3 , —CH 2 (cyclopropyl), pyridinyl, chloropyridinyl, or methoxypyridinyl;

each R a is independently F, Cl, —CH 3 , —OCH 3 , —CN, 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, —CHF 2 , and/or —CF 3 ;

y is zero, 1, or 2; and

z is zero, 1, or 2.

2. The compound according to claim 1 wherein:

R 2 is phenyl, fluorophenyl, chlorophenyl, or trifluorophenyl.

3. The compound according to claim 1 wherein:

R 2 is methylisoxazolyl.

4. The compound according to claim 1 wherein:

R 2 is pyridinyl.

5. The compound according to claim 1 wherein:

R 3 is H or —CH 3 .

6. The compound according to claim 1 wherein:

R 3 is —CH 2 (cyclopropyl), pyridinyl, chloropyridinyl, or methoxypyridinyl.

7. A compound according to claim 1 selected from: (2R,3R)—N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (1); (2R,3R)-3-(4-fluorophenyl)-N-((3 S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (2); (2R,3R)—N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(2,3,4-trifluorophenyl)-2-(3,3,3-trifluoropropyl)succinamide (3); (2R,3R)—N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (4); (2R,3R)—N1-((S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (5); (2R,3R)—N1-((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (6); (2R,3R)—N1-((S)-1-(cyclopropylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (7); (2R,3R)—N1-((S)-1-(cyclopropylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)succinamide (8); (2R,3R)-3-(3-methylisoxazol-4-yl)-N1-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-(3,3,3-trifluoropropyl) succinamide (9); (2R,3R)—N1-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(pyridin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (10); (2R,3R)-3-(3-methyl-4-isoxazolyl)-N-((3S)-2-oxo-5-phenyl-1-(2-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (11); (2R,3R)—N-((3S)-2-oxo-5-phenyl-1-(2-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (12); (2R,3R)-3-(3-methyl-4-isoxazolyl)-N-((7S)-6-oxo-9-phenyl-6,7-dihydro-5H-[1,3]dioxolo[4,5-h][1,4]benzodiazepin-7-yl)-2-(3,3,3-trifluoropropyl)succinamide (13); (2R,3R)—N-((3S)-1-(5-methoxy-2-pyridinyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(3-methyl-4-isoxazolyl)-2-(3,3,3-trifluoropropyl) succinamide (14); (2R,3R)—N-((3S)-1-(5-methoxy-2-pyridinyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (15); (2R,3R)—N-((3S)-1-(6-methoxy-2-pyridinyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (16); (2R,3R)—N1-((S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (17); (2R,3R)—N1-((S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (18); (2R,3R)—N1-((S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (19); (2R,3R)—N1-((S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (20); (2R,3R)—N1-((S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl) succinamide (21); (2R,3R)—N-((3S)-1-(5-chloro-2-pyridinyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (22); (2R,3R)—N-((3S)-1-(5-chloro-2-pyridinyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(3-methyl-4-isoxazolyl)-2-(3,3,3-trifluoropropyl)succinamide (23); (2R,3R)—N1-((S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (24); (2R,3R)—N1-((S)-7-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (25); (2R,3R)—N1-((S)-9-cyclopropoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (26); (2R,3R)—N1-((S)-5-(4-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (27); (2R,3R)—N1-((S)-9-methyl-2-oxo-5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (28); (2R,3R)—N1-((S)-9-methyl-2-oxo-5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (29); (2R,3R)—N1-((S)-9-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (30); (2R,3R)—N1-((S)-5-(3-chlorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (31); (2R,3R)—N1-((S)-5-(3-chlorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (32); (2R,3R)—N1-((S)-5-(4-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinamide (33); (2R,3R)—N1-((S)-5-(3-(difluoromethyl)phenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl) succinamide (34); (2R,3R)—N1-((S)-9-cyclopropoxy-5-(3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-phenyl-2-(3,3,3-trifluoropropyl)succinamide (35); and (2R,3R)-3-(4-chlorophenyl)-N1-((S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-(3,3,3-trifluoropropyl)succinamide (36).

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

9. A method of treating a disease or disorder wherein the disease or disorder is breast cancer, the method comprising administering to a mammalian patient at least one compound according claim 1 and/or at least one salt thereof.

10. The method according to claim 9 , further comprising administering sequentially or concurrently one or more addition agents selected from dasatinib, paclitaxel, tamoxifen, dexamethasone, and carboplatin.

Continuity (2)

Provisional Application 61703928 · Sep 21, 2012

Related Publication 20150218111A1 · Aug 6, 2015