Prodrugs of 1,4-benzodiazepinone compounds

Patent metadata

Field	Value
Publication number	US-9273075-B2
Application number	US-201314429930-A
Country	US
Kind code	B2
Filing date	Sep 20, 2013
Priority date	Sep 21, 2012
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

Disclosed are compounds of Formula (I) and salts thereof, wherein: a) R 1 is H or CH 3 , and R 2 is R y ; or b) R 1 is Rx and R 2 is H; wherein R x and R y are disclosed herein. Also disclosed are methods of using such compounds to inhibit the Notch receptor, and pharmaceutical compositions comprising such compounds. These compounds are prodrugs of compounds that 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:
a) R 1 is H or —CH 3 , and R 2 is R y ; or
b) R 1 is R x and R 2 is H;
R x is: —CH 2 OC(O)—(CH 2 ) n —(CR a R b ) n —X;
X is —NR e R f , —OP(═O)(OH) 2 ,

R a and R b are independently H and/or C 1-3 alkyl, or together with the carbon atom to which they are attached form a C 3-5 cycloalkyl ring;
each n is independently zero and/or 1;
R y is Z or —S—Z;
Z is C 1-6 alkyl substituted with —NR c R d and/or —CO 2 R g ;
R c and R d are independently H and/or C 1-4 alkyl, or together with the nitrogen to which they are attached form a heterocycle containing 1 to 2 nitrogen atoms, wherein said heterocycle is substituted with zero to 2 substituents independently selected from —OH, C 1-4 alkyl, and/or NR e R f ;
R e and R f are independently H and/or C 1-4 alkyl; and
R g is H or C 1-4 alkyl;
or a salt thereof.

2. A compound according to claim 1 or a salt thereof, wherein:
R x is: —CH 2 OC(O)C(CH 3 ) 2 NH 2 , —CH 2 OC(O)CH(CH 3 )NH 2 , —CH 2 OC(O)CH(CH(CH 3 ) 2 )NH 2 ,

 and
R y is: —SCH 2 CH 2 NH 2 , —SCH 2 CH 2 N(CH 3 ) 2 , —SCH 2 CH(NH 2 )C(O)OH, —SCH 2 CH(NH 2 )C(O)OCH 3 , —CH 2 NHCH 2 CH(CH 3 ) 2 ,

3. The compound according to claim 2 or a salt thereof, wherein R 1 is H and R 2 is R y .

4. The compound according to claim 3 or a salt thereof, wherein R y is —SCH 2 CH 2 NH 2 , —SCH 2 CH(NH 2 )C(O)OH, or

5. The compound according to claim 2 or a salt thereof, wherein R 1 is —CH 3 and R 2 is R y .

6. The compound according to claim 5 or a salt thereof, wherein R y is —CH 2 NHCH 2 CH(CH 3 ) 2 , —SCH 2 CH 2 NH 2 , —SCH 2 CH 2 N(CH 3 ) 2 , —SCH 2 CH(NH 2 )C(O)OH, —SCH 2 CH(NH 2 )C(O)OCH 3 ,

7. The compound according to claim 5 or a salt thereof, wherein R 1 is R x and R 2 is H.

8. The compound according the claim 1 selected from: ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl (4-(phosphonooxy)phenyl)acetate (1); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl 4-((phosphonooxy)methyl)benzoate (2); (3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl 3-(2,4-dimethyl-6-(phosphonooxy)phenyl)-3-methylbutanoate (3); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl 2-methylalaninate (4); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl L-alaninate (5); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl L-valinate (6); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl) hexanoyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl 1-aminocyclopropanecarboxylate (7); (2S,3R)—N-((2-aminoethyl)sulfanyl)-N′-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (8); S-(((2S,3R)-6,6,6-trifluoro-3-(((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-L-cysteine (9); (2S,3R)—N-((isobutylamino)methyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (10); (2S,3R)—N-((2-aminoethyl)sulfanyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (11); S-(((2S,3R)-6,6,6-trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-L-cysteine (12); (2S,3R)—N-((2-(dimethylamino)ethyl)sulfanyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (13); Methyl S-(((2S,3R)-6,6,6-trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-L-cysteinate (14); (2R,3S)—N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-N′-((4-methyl-1-piperazinyl)methyl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (15); (2R,3S)—N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-N′-(1-piperidinylmethyl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (16); (2S,3R)—N-((4-amino-1-piperidinyl)methyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (17); (2S,3R)—N-((4-(dimethylamino)-1-piperidinyl)methyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (18); (2S,3R)—N-((4-hydroxy-1-piperidinyl)methyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (19); (2S,3R)—N-((3-hydroxy-1-pyrrolidinyl)methyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl) succinamide (20); (2S,3R)—N-((3-(dimethylamino)-1-pyrrolidinyl)methyl)-N′-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl) succinamide (21); (2R,3S)—N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-N′-(1-pyrrolidinylmethyl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (22); and salts thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

Assignees

• Bristol Myers Squibb Co

Inventors

• Gavai Ashvinikumar V
• Han Wen-Ching
• Fink Brian E
• Guarino Victor R

Classifications

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• A61K45/06

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

• C07D243/26

  Preparation from compounds already containing the benzodiazepine skeleton · CPC title

• C07F9/12

  with hydroxyaryl compounds · CPC title

• A61P35/02

  specific for leukemia · CPC title