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

Patent metadata

Field	Value
Publication number	US-2016016908-A1
Application number	US-201414770499-A
Country	US
Kind code	A1
Filing date	Mar 12, 2014
Priority date	Mar 14, 2013
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present invention relates to novel compounds, pharmaceutical compositions containing such compounds and to their use in therapy.

First claim

1 . A compound of formula (I)

or a salt thereof
wherein:
R 1 is C 1-4 alkyl;
R 2 is C 1-4 alkyl, C 3-7 cycloalkyl, —CH 2 CF 3 , —CH 2 OCH 3 or heterocyclyl;
R 3 is —CH 2 F, —CH 2 OH or —CH 2 OC(O)CH 3 ;
R 4 when present is H, 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 , —OCH 2 CH 2 OH, —B—C 3-7 cycloalkyl, —B-phenyl, —B-heterocyclyl or —B-heteroaromatic, wherein the C 3-7 cycloalkyl, phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from ═O, C 1-6 alkyl, C 1-6 alkoxy, halo, —NH 2 , —CO 2 H, —C(O)C 1-6 alkyl, —C(O)NHC 1-6 alkyl, cyano, —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , C 3-7 cycloalkyl, phenyl, heterocyclyl and heteroaromatic;
R 5 when present is H, halo, hydroxy or C 1-6 alkoxy;
A is —NH—, —O—, —S—, —SO—, —SO 2 —, —N(C 1-4 alkyl)- or —NC(O)(CH 3 )—;
B is a bond, —O—, —N(R 8 )—, S, —SO—, —SO 2 —, —SO 2 N(R 8 )—, —CH 2 —, —C(O)—, —CO 2 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —C(O)N(R 8 )CH 2 — or —C(O)N(R 8 )CH 2 CH 2 —;
V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents independently selected from C 1-6 alkyl, fluorine, chlorine, C 1-6 alkoxy, hydroxy, cyclopropyl, cyano, —CO 2 CH 3 , heterocyclyl, —CO 2 H, —CH 2 NR 6 R 7 , —NR 6 R 7 , —C(O)NR 6 R 7 , —NR 6 C(O)R 7 , —CF 3 , —NO 2 , —CH 2 OCH 3 , —CH 2 OH, —CH(OH)CH 3 , —SO 2 CH 3 , —CH 2 heterocyclyl, —OCH 2 CH 2 NHC(O)CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —C(O)NHheteroaromatic, —C(O)NHCH 2 heterocyclyl, —C(O)NHCH 2 CH 2 OH, —C(O)NHCH 2 CH 2 NH 2 , —C(O)NHCH 2 CH 2 SO 2 Me, —C(O)NHCH 2 CH(OH)CH 3 , —C(O)heterocyclyl and —C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionally substituted by —OH;
R 6 , R 7 , R 8 , R 9 and R 10 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; and that the compound of formula (I) is not 1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone or 1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one.

2 . A compound or a salt thereof according to claim 1 which is a racemic mixture of formula (Ia)

or a salt thereof.

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

or a salt thereof.

4 . A compound or a salt thereof according to any preceding claim wherein R 1 is methyl or ethyl.

5 . A compound or a salt thereof according to claim 4 wherein R 1 is methyl.

6 . A compound or a salt thereof according to any one of the preceding claims wherein R 2 is C 1-4 alkyl, C 3-7 cycloakyl, —CH 2 CF 3 or —CH 2 OCH 3 .

7 . A compound or a salt thereof according to claim 6 wherein R 2 is methyl, ethyl or cyclopropyl.

8 . A compound or a salt thereof according to claim 7 wherein R 2 is cyclopropyl.

9 . A compound or a salt thereof according to any one of the preceding claims wherein R 3 is methyl.

10 . A compound or a salt thereof according to any one of the preceding claims wherein R 4 is H, 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 , —C(O)NHCH 2 CH 2 CN, —B—CH 3 , —B—CH(CH 3 ) 2 , —B—CH 2 CH 3 , —B-phenyl, —B-heterocyclyl or —B-heteroaromatic, wherein the phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from ═O, —CH 3 , —CH 2 CH 3 , —OCH 3 , —NH 2 , —C(O)NHCH 3 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 OCH 3 and —CO 2 H.

11 . A compound or a salt thereof according to claim 10 wherein R 4 is H, 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 , —C(O)NHCH 2 CH 2 CN, —B—CH 3 , —B—CH(CH 3 ) 2 , —B—CH 2 CH 3 , —B-phenyl, —B-piperidinyl, —B-morpholinyl, —B-piperazinyl, —B-2,5-diazabicyclo[2.2.2]octan-2-yl, —B-8-oxa-3-azabicyclo[3.2.1]octan-3-yl, —B-3,8-diazabicyclo[3.2.1]octan-3-yl, —B-pyrrolidinyl, —B-3,6-dihydro-2H-pyran, —B-1,2,3,6-tetrahydropyridinyl, —B-tetrahydrofuranyl, —B-tetrahydro-2H-thiopyran1,1,dioxide, —B-pyrazolyl or —B-pyridinyl wherein the phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from ═O, —CH 3 , —CH 2 CH 3 , —OCH 3 , —NH 2 , —C(O)NHCH 3 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 OCH 3 and —CO 2 H.

12 . A compound or a salt thereof according to claim 11 wherein R 4 is C(O)NH 2 .

13 . A compound or a salt thereof according to claim 11 wherein R 4 is H, —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH 2 CH 2 OCH 3 , -morpholinyl, -piperazinyl, -3,6-dihydro-2H-pyran, -1,2,3,6-tetrahydropyridinyl, -pyrazolyl, —C(O)NH-tetrahydro-2H-pyran, —C(O)NH-pyridinyl or —C(O)NH-pyrazolyl wherein the heterocyclyl or heteroaromatic ring is optionally substituted by —CH 2 CH 2 OCH 3 .

14 . A compound or a salt thereof according to claim 13 wherein R 4 is H, —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH 2 CH 2 OCH 3 ,

15 . A compound or a salt thereof according to any one of claims 1 - 9 wherein R 4 is selected from:
(i) —C(O)NHC 1-6 alkyl
(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 ;
(vii) —C(O)N(R 8 )C 1-4 alkyleneCN); and
(viii) —B-heterocyclyl or —B-heteroaromatic in which B is —C(O)NH, —C(O)NHCH 2 — or —C(O)NHCH 2 CH 2 —.

16 . A compound or a salt thereof according to any one of the preceding claims wherein B is a bond, —O—, —NH— —C(O)NH— or —SO 2 —.

17 . A compound or a salt thereof according to any one of the preceding claims wherein R 5 is H, fluoro, hydroxy or —OCH 3 .

18 . A compound or a salt thereof according to claim 16 wherein R 5 is H.

19 . A compound or a salt thereof according to any one of the preceding claims wherein A is —NH—, —O— or N(CH 3 ).

20 . A compound or a salt thereof according to claim 19 wherein A is NH—.

21 . A compound or a salt thereof according to any one of the preceding claims wherein V is phenyl or heteroaromatic, either of 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, —CO 2 H, —CH 2 NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —CO 2 CH 3 , piperazinyl and morpholinyl.

22 . A compound or a salt thereof according to claim 21 wherein V is phenyl, pyridinyl, pyrimidinyl, imidazopyridinyl, quinolinyl, thienyl, thiazolyl, oxazolyl and pyrazinyl, any of which ma

Assignees

• Glaxosmithkline Intelectual Property No 2 Ltd
• Glaxosmithkline Ip No 2 Ltd

Inventors

• Amans Dominique
• Atkinson Stephen John
• Harrison Lee Andrew
• Hirst David Jonathan
• Law Robert Peter
• Lindon Matthew
• Preston Alexander
• Seal Jonathan Thomas
• Wellaway Christopher Roland

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D487/08

  Bridged systems · CPC title