Furopyridines as bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-2016016966-A1
Application number	US-201414770922-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

What is claimed is:

1 - 57 . (canceled)

58 . A compound of formula (I):

wherein:
V is N or C—R 2
W is N or C—R 8 ;
X is N, CH or C(CH 3 );
Y is N or C—R 5 ;
Z is N or C—R 15 ;
Q is N or CH;
R 1 is C 1-4 alkyl or deuterated C 1-4 alkyl;
R 2 , when present, is H, OH, C 1-4 alkyl, halo, —CF 3 , —NH 2 , —OC 1-4 alkyl, —NHC(O)H, —NHC(O)C 1-4 alkyl, —N(CH 3 )C(O)C 1-4 alkyl, —NHC(O)NH 2 , —NHC(O)C 1-4 alkyleneNH 2 , —N(CH 3 )C(O)NH 2 , —N(CH 3 )C(O)C 1-4 alkyleneNH 2 , —NHC 2-4 alkyleneOCH 3 , —N(CH 3 )C 2-4 alkyleneOCH 3 , —OC 2-4 alkyleneOCH 3 , —OC 2-4 alkyleneOH or
R 2 is a group selected from -G-CH 2 CH(R 3 )(R 4 ), -G-CH(R 3 )(R 4 ) and -G-R 3 in which
G is NH, N(CH 3 ), O, C(O)NH or NHC(O);
R 3 is phenyl, pyridinyl, C 3-7 cycloalkyl or a heterocycle optionally substituted by ═O; and
R 4 is H or C 1-4 alkyl;

R 5 , when present, is H, C 1-4 alkyl, halo, —CF 3 , CN, OH, —OC 1-4 alkyl, —CH 2 NH 2 , —OCF 3 , —SO 2 CH 3 , —C(O)NHC 1-4 alkyl or —CO 2 H;
R 6 is —NR 11 R 12 or a group

D is CH or N;
E is N, O, CH or SO 2 ;
R 7 , when present, is H, OH, C 1-4 alkyl, —NH 2 , —SO 2 C 1-4 alkyl, —SO 2 phenyl, —SO 2 benzyl, —SO 2 N(CH 3 ) 2 , —NHSO 2 CH 3 , —C(O)C 1-4 alkyl, —C(O)phenyl;
R 8 , when present, is H, C 1-4 alkyl, halo, —CF 3 , CN, OH, —OC 1-4 alkyl, —OC 2-4 alkyleneOC 1-4 alkyl, —OCF 3 , —OC 1-4 alkyleneF, —OC 1-4 alkyleneCHF 2 , —OC 2 , alkyleneOH, —Ophenyl, —OC 1-4 alkylenephenyl, —NHC 3-7 cycloalkyl, —NHC 4-6 alkyleneC 3-7 cycloalkyl, —OC 3-7 cycloalkyl, —OC 1-4 alkyleneC 3-7 cycloalkyl, —NHC 4-6 heterocycle —NHC 1-4 alkyleneC 4-6 heterocycle, —OC 4-6 heterocycle or —OC 1-4 alkyleneC 4-6 heterocycle wherein the C 3-7 cycloalkyl or the C 4-8 heterocycle are each optionally substituted by one or two substituents independently selected from halo, OH, oxo, C 1-4 alkyl and —NH 2 ; or
R 8 and R 2 together with the carbon atoms to which they are attached, form a heterocycle optionally substituted by oxo;
R 9 is H, C 1-4 alkyl, —C(O)NH 2 , —CO 2 CH 3 , —CF 3 , halo, OH, —OC 1-4 alkyl, —CH 2 OH, —C(O)NHCH 3 , —C(O)NH(CH 3 ) 2 , —CH 2 OC 1-4 alkyl or —CH 2 OCH 2 C 3-7 cycloalkyl;
R 10 is H, C 1-4 alkyl, —C(O)NH 2 , —CO 2 CH 3 , —CF 3 , halo, OH, —OC 1-4 alkyl or oxo;
R 11 is H, C 1-4 alkyl or SO 2 CH 3 ;
R 12 is H, C 1-4 alkyl, C 2-4 alkyleneNHR 13 , SO 2 CH 3 , a heterocycle or a heterocycle comprising SO 2 ;
R 13 is H or SO 2 CH 3 ;
R 14 is H or C 1-4 alkyl;
R 15 is H, C 1-4 alkyl or NHC(O)C 1-4 alkyl;
R 16 is H or C 1-4 alkyl; and
n and m are each an integer independently selected from 0, 1 and 2; subject to proviso that no more than 2 of V, W, X, Y and Z are N; or a salt thereof.

59 . A compound or a salt thereof according to claim 58 wherein V is C—R 2 and W is C—R 8 .

60 . A compound or a salt thereof according to claim 58 wherein R 8 is H, OH, —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH(CH 3 )OCH 3 , —OCH(CH 3 )CH 2 OCH 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CH 2 OH, —NHCH 2 cyclopropyl, —Ocyclopropyl, —OCH 2 cyclopropyl, —Otetrahydrofuranyl, —Ooxetanyl, —OCH 2 tetrahydrofuranyl, —OCH 2 oxetanyl or —OCH 2 CH 2 pyrrolidinyl, wherein the C 3-7 cycloalkyl or the C 4-6 heterocycle are each optionally substituted by one or two substituents independently selected from fluoro and oxo.

61 . A compound or a salt thereof according to claim 58 wherein X is CH; Y is N; Z is CH; and Q is CH.

62 . A compound or a salt thereof according to claim 58 wherein R 1 is methyl.

63 . A compound or a salt thereof according to claim 58 wherein R 2 is H, —OC 1-4 alkyl, —NHC(O)C 1-4 alkyl or —N(CH 3 )C(O)C 1-4 alkyl.

64 . A compound or a salt thereof according to claim 58 wherein R 6 is a group

65 . A compound or a salt thereof according to claim 58 wherein D is N and E is N, O or CH.

66 . A compound or a salt thereof according to claim 58 wherein R 7 is —SO 2 CH 3 .

67 . A compound selected from:
7-[3,4-bis(methyloxy)phenyl]-5-methyl-2-{[4-(methylsulfonyl)-1-piperazinyl]methyl}furo[3,2-c]pyridin-4(5H)-one; (R)—N-(4-(5-methyl-2-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)pyridin-2-yl)acetamide; 7-(3-(benzyloxy)phenyl)-5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)furo[3,2-c]pyridin-4(5H)-one; 7-(3-(benzylamino)phenyl)-5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)furo[3,2-c]pyridin-4(5H)-one; 2-(((2-aminoethyl)amino)methyl)-7-(3,4-dimethoxyphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one; 7-(4-(aminomethyl)phenyl)-5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)furo[3,2-c]pyridin-4(5H)-one; 5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; 7-(3,4-dimethoxyphenyl)-5-methyl-2-(piperidin-1-ylmethyl)furo[3,2-c]pyridin-4(5H)-one; 7-(3,4-dimethoxyphenyl-5-methyl-2-(morpholinomethyl)furo[3,2-c]pyridin-4(5H)-one; (R)-7-(3,4-dimethoxyphenyl)-5-methyl-2-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)furo[3,2-c]pyridin-4(5H)-one; 2-((1,4-diazepan-1-yl)methyl)-7-(3,4-dimethoxyphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one; 5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)-7-(5-(1-phenylethoxy)pyridin-3-yl)furo[3,2-c]pyridin-4(5H)-one; 2-((3,3-difluoropiperidin-1-yl)methyl-5-methyl-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; 5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)-7-(2-((1-phenylethyl)amino)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; 5-methyl-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)-7-(3-((1-phenylethyl)amino)phenyl)furo[3,2-c]pyridin-4(5H)-one; 7-(3,4-dimethoxyphenyl)-5-methyl-2-((3-methylmorpholino)methyl)furo[3,2-c]pyridin-4(5H)-one; N-(4-(2-((3-fluoropiperidin-1-yl)methyl)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)pyridin-2-yl)acetamide; N-(4-(2-((3,3-difluoropiperidin-1-yl)methyl-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)pyridin-2-yl)acetamide; 2-((3-fluoropiperidin-1-yl)methyl)-7-(4-methoxyphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one; 5-methyl-2-(morpholinomethyl)-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; 5-methyl-2-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; (S)-5-methyl-2-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; (R)-5-methyl-2-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; 2-((1,4-oxazepan-4-yl)methyl)-5-methyl-7-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one; (R)-7-(2-(cyclopropylmethoxy)pyridin-4-yl)-5-methyl-2-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)furo[3,2-c]pyridin-4(5H)-one; (R)—N-(4-(5-methyl-2-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)pyridin-2-yl)cyclopropanecarboxamide; (R)—N-(4-(5-methyl-2-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)pyridin-2-yl)propionamide; (R)-7-(2-(2-methoxyethoxy)pyridin-4-yl)-5-meth

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Amans Dominique
• Bamborough Paul
• Barker Michael David
• Bit Rino Antonio
• Brown John Alexander
• Campbell Matthew
• Garton Neil Stuart
• Lindon Matthew J
• Shipley Tracy Jane
• Theodoulou Natalie Hope
• Wellaway Christopher Roland
• Westaway Susan Marie

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/4355

  the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title