2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors

1. A method of treatment of an acute or chronic autoimmune and/or inflammatory condition in a subject in need thereof which comprises administering a therapeutically effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C 1-4 alkyl;

R 2 is methyl, ethyl or cyclopropyl;

R 3 is C 1-4 alkyl;

R 4 when present is hydroxy, halo, cyano, —CO 2 H, —CONH 2 , —OSO 2 CF 3 , —C(O)N(R 8 )C 1-4 alkyleneOH, —C(O)N(R 8 )C 1-4 alkyleneOCH 3 , —C(O)N(R 8 )C 1-4 alkyleneNR 6 R 7 , —C(O)N(R 8 )C 1-4 alkyleneSO 2 CH 3 , —C(O)N(R 8 )C 1-4 alkyleneCN, —C(O)NHOH, —C(O)NHCH(CH 2 OH) 2 , or —OCH 2 CH 2 OH;

R 5 when present is H, halo, hydroxy or C 1-6 alkoxy;

A is —NH— or —O—;

V is pyrimidinyl which may be optionally substituted by 1 or 2 substituents independently selected from C 1-6 alkyl, fluorine, chlorine, —OCH 3 , —OCH(CH 3 ) 2 , hydroxy, cyclopropyl, cyano, —CH 2 NH 2 , —C(O)NHCH 3 , —CO 2 CH 3 , piperazinyl and morpholinyl;

R 6 , R 7 , and R 8 are each independently selected from H and C 1-4 alkyl;

W is CH or N;

X is C or N;

Y is C or N; and

Z is CH or N;

subject to the proviso that no more than 2 of W, X, Y and Z are N.

2. A method of treatment according to claim 1 , wherein the subject is a human.

3. A method according to claim 1 wherein the acute or chronic autoimmune and/or inflammatory condition is psoriasis.

4. A method according to claim 1 wherein the acute or chronic autoimmune and/or inflammatory condition is atopic dermatitis.

5. A method according to claim 1 wherein the acute or chronic autoimmune and/or inflammatory condition is vitiligo.

6. A method according to claim 1 wherein the compound of formula I is a racemic mixture of formula (Ia)

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 , which the compound of formula (I) is an enantiomer of formula (Iaa)

or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1 wherein R 1 is methyl.

9. The method according to claim 1 wherein R 2 is cyclopropyl.

10. The method according to claim 1 wherein R 3 is methyl.

11. The method according to claim 1 wherein R 4 is fluoro, cyano, CO 2 H or —CONH 2 .

12. The method according to claim 1 wherein R 4 is —CONH 2 .

13. The method according to claim 1 wherein R 5 is H.

14. The method according to claim 1 wherein A is —NH—.

15. The method according to claim 1 wherein V is pyrimidinyl optionally substituted by 1 or 2 C 1-6 alkyl groups.

16. The method according to claim 1 wherein V is

17. The method according to claim 1 wherein W is CH; X is C; Y is C; and Z is CH.

18. A method of treatment of an acute or chronic autoimmune and/or inflammatory condition in a subject in need thereof which comprises administering a therapeutically effective amount of a compound selected from:

(2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile;

(2S,3R,4R)-1-Acetyl-2-cyclopropyl-4-((6-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile;

2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinamide;

(2S,3R,4R)-1-Acetyl-4-((3-(2-aminoethoxy)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile;

(2S,3R,4R)-1-acetyl-4-((4-cyano-2-fluorophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-N-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl —N-ethyl-3-methyl-4-((4-m ethylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxyethyl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-N-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-N-(2-methoxyethyl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-N-(oxetan-3-yl)-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxypropyl)-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;

rac-4-(((2S,3R,4R)-1-acetyl-6-(4-acetylpiperazin-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;

rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;

1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;

1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;

1-((2S,3R,4R)-2-ethyl-3-methyl-6-(piperazin-1-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid; and

(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1 wherein the compound of formula (I) is (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide or a pharmaceutically acceptable salt thereof.

20. The method according to claim 4 wherein the compound of formula (I) is (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide or a pharmaceutically acceptable salt thereof.

21. The method according to claim 5 wherein the compound of formula (I) is (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide or a pharmaceutically acceptable salt thereof.