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

1. A 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. The compound according to claim 1 which is a racemic mixture of formula (Ia)

or a pharmaceutically acceptable salt thereof.

3. The compound or a salt thereof according to claim 2 , which is an enantiomer of formula (Iaa)

or a pharmaceutically acceptable salt thereof.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein R 1 is methyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein R 2 is cyclopropyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein R 3 is methyl.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein R 4 is hydroxy, fluoro, cyano, —CO 2 H, —CONH 2 , —OSO 2 CF 3 , —C(O)NHCH 2 CH 2 OH, —C(O)NHCH 2 C(CH 3 )OH, —C(O)NHCH 2 CH 2 OCH 3 , —C(O)NHCH 2 CH 2 NHCH 3 , —C(O)NHCH 2 CH 2 SO 2 CH 3 , or —C(O)NHCH 2 CH 2 CN.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7 wherein R 4 is —CONH 2 .

9. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein R 4 is selected from:

(ii) —C(O)N(R 8 )C 1-4 alkyleneOH;

(iii) —C(O)N(R 8 )C 1-4 alkyleneOCH 3 ;

(iv) —C(O)NHCH(CH 2 OH) 2 ;

(v) —C(O)N(R 8 )C 1-4 alkyleneNR 6 R 7 ;

(vi) —C(O)N(R 8 )C 1-4 alkyleneSO 2 CH 3 ; and

(vii) —C(O)N(R 8 )C 1-4 alkylene(CN).

10. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein R 5 is H.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein A is —NH—.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein V is pyrimidinyl optionally substituted by 1 or 2 C 1-6 alkyl groups.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein W is CH; X is C; Y is C; and Z is CH.

14. A pharmaceutical composition which comprises the compound or a pharmaceutically acceptable salt thereof as defined in claim 3 and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 3 wherein V is

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1 which is 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-3-methyl-4-(pyrimidin-2-ylamino)-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-(2-hydroxyethyl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-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; and

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