Benzodiazepine bromodomain inhibitor
Benzodiazepine compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and their use in therapy.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
where
R 1 is C 1-3 alkyl;
R 2 is —NR 2a R 2a′ ;
wherein R 2a is hydrogen, and R 2a′ is heterocyclylC 1-4 alkyl,
wherein the heterocyclyl is optionally substituted once by amino, hydroxyl, or methyl;
each R 3 is independently selected from hydrogen, hydroxyl, halo, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, CF 3 , —OCF 3 , —COOR 5 , and —C 1-4 alkylOH;
R 4 is hydroxyl, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, nitro, cyano, CF 3 , —OCF 3 , —COOR 5 ; or —OS(O) 2 C 1-4 alkyl;
R 5 is C 1-3 alkyl; and
n is an integer 1 to 5.
2. The compound or salt according to claim 1 , wherein R 2a′ is selected from heterocyclyl-CH 2 —, heterocyclyl-CH 2 CH 2 —, heterocyclyl-CH 2 CH 2 CH 2 — and heterocyclyl-CH 2 CH 2 CH 2 CH 2 —, wherein the heterocyclyl is optionally substituted once by amino, hydroxyl or methyl.
3. The compound or salt according to claim 2 , wherein heterocyclyl is selected from tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholino and thiomorpholinodioxide, wherein each group is optionally substituted once by amino, hydroxyl or methyl.
4. The compound or salt according to claim 3 , wherein heterocyclyl is selected from:
5. The compound or salt according to claim 1 , wherein n is 1.
6. The compound or salt according to claim 5 , wherein R 3 is 3-fluoro, 4- chloro, 4-fluoro, 4-methoxy or 4-CF 3 .
7. The compound or salt according to claim 6 , wherein R 3 is 4-chloro.
8. The compound or salt according to claim 1 , wherein R 4 is MeO.
9. The compound or salt according to claim 8 , wherein R 4 is 8-MeO.
10. The compound or salt according to claim 1 which is the S-enantiomer.
11. A compound which is:
2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H- [1,2,4]triazolo [4,3-a][1,4]benzodiazepin-4-yl]-N-[2-(4-morpholinyl)ethyl]acetamide;
2-[(4S)-6-(4-chloropheny )-1-methyl-8-(methyloxy)-4H- [1,2,4]triazolo [4,3-a][1,4]benzodiazepin-4-yl]-N-[3-(4-morpholinyl)propyl]acetamide; or
2-[(4S)-6-(4-chlorophenyl)- 1 -methyl-8-(methyloxy)-4H- [1,2,4]triazolo [4,3-a][1,4]benzodiazepin-4-yl]-N-[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]acetamide;
or a salt thereof.
12. A pharmaceutical composition which comprises the compound or salt according to claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients.