Bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9296741-B2
Application number	US-201313828285-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	Dec 30, 2011
Publication date	Mar 29, 2016
Grant date	Mar 29, 2016

Abstract

The present invention provides for compounds of formula (I)

wherein A 1 , A 2 , A 3 , A 4 , X 1 , X 2 , Y 1 , L 1 , G 1 , R x , and R y have any of the values defined thereof in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
R x is hydrogen or C 1 -C 3 alkyl;
R y is C 1 -C 3 alkyl, —(C 2 -C 3 alkylenyl)-OH, or C 1 -C 3 haloalkyl;
X 1 is N or CR x1 wherein
R x1 is hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OR ax1 , —C(O)NR bx1 R cx1 , —C(O)R dx1 , S(O) 2 R dx1 , —S(O) 2 NR bx1 R cx1 , G x1 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of OR ax1 , SR ax1 , S(O)R dx1 , S(O) 2 R dx1 NR bx1 R cx1 , —C(O)R ax1 , —C(O)OR ax1 , —C(O)NR bx1 R cx1 , —S(O) 2 NR bx1 R cx1 , and G x1 ;
R ax1 , R bx1 , and R cx1 , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;
R dx1 , at each occurrence, is each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;

X 2 is N or CR x2 ; wherein
R x2 is hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OR ax2 , —C(O)NR bx2 R cx2 , —C(O)R dx2 , —C(O)H, S(O) 2 R dx2 , —S(O) 2 NR bx2 R cx2 , G x2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of OR ax2 , SR ax2 , S(O)R dx2 , S(O) 2 R dx2 , NR bx2 R cx2 , —C(O)R ax2 , —C(O)OR ax2 , —C(O)NR bx2 , —S(O) 2 NR bx2 R cx2 , and G x2 ;
R ax2 , R bx2 , and R cx2 , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G b , or —(C 1 -C 6 alkylenyl)-G b ;
R dx2 , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G b , or —(C 1 -C 6 alkylenyl)-G b ;

Y 1 is N or CR u ; wherein R u is hydrogen, C 1 -C 6 alkyl, halogen, or C 1 -C 6 haloalkyl;
A 1 is N or CR 1 , A 2 is N or CR 2 , A 3 is N or CR 3 ; and A 4 is N or CR 4 ; with a proviso that zero, one, two, or three of A 1 , A 2 , A 3 , and A 4 are N;
R 1 , R 3 , and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, CN, or NO 2 ;
R 2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —CN, NO 2 , G 2a , —OR 2a , —OC(O)R 2d , —OC(O)NR 2b R 2c , —SR 2a , —S(O) 2 R 2d , —S(O) 2 NR 2b R 2c , —C(O)R 2d , —C(O)OR 2a , —C(O)NR 2b R 2c , —NR 2b R 2c , —N(R 2e )C(O)R 2d , —N(R 2e )S(O) 2 R 2d , —N(R 2e )C(O)O(R 2d ), —N(R 2e )C(O)NR 2b R 2c , —N(R 2e )S(O) 2 NR 2b R 2c , —(C 1 -C 6 alkylenyl)-G 2a , —(C 1 -C 6 alkylenyl)-OR 2a , —(C 1 -C 6 alkylenyl)-OC(O)R 2d , —(C 1 -C 6 alkylenyl)-OC(O)NR 2b R 2c , —(C 1 -C 6 alkylenyl)-S(O) 2 R 2d , —(C 1 -C 6 alkylenyl)-S(O) 2 NR 2b R 2c , —(C 1 -C 6 alkylenyl)-C(O)R 2d , —(C 1 -C 6 alkylenyl)-C(O)OR 2a , —(C 1 -C 6 alkylenyl)-C(O)NR 2b R 2c , —(C 1 -C 6 alkylenyl)-NR 2b R 2c , —(C 1 -C 6 alkylenyl)-N(R 2e )C(O)R 2d , —(C 1 -C 6 alkylenyl)-N(R 2e )S(O) 2 R 2d , —(C 1 -C 6 alkylenyl)-N(R 2e )C(O)O(R 2a ), —(C 1 -C 6 alkylenyl)-N(R 2e )C(O)NR 2b R 2c , —(C 1 -C 6 alkylenyl)-N(R 2e )S(O) 2 NR 2b R 2c , and —(C 1 -C 6 alkylenyl)-CN;
R 2a , R 2b , R 2c , and R 2e , at each occurrence, are each independently hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 2b , or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of —OR z1 , NR z1 R z2 , —C(O)OR z1 , —C(O)NR z1 R z2 , —S(O) 2 R z1 , —S(O) 2 NR z1 R z2 , and G 2b ;
R 2d , at each occurrence, is independently C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 2b , or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of —OR z1 , NR z1 R z2 , —C(O)OR z1 , —C(O)NR z1 R z2 , —S(O) 2 R z1 , —S(O) 2 NR z1 R z2 , and G 2b ;
R z1 and R z2 , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
G x1 , G x2 , G a , G b , G 2a , and G 2b , at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R v ;
L 1 is absent, CH 2 , C(O), C(H)(OH), (CH 2 ) m O, (CH 2 ) m S(O) n wherein n is 0, 1, or 2; or (CH 2 ) m N(R z ) wherein R z is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, (C 2 -C 3 alkylenyl)-OH, or unsubstituted cyclopropyl;
m is 0 or 1;
G 1 is C 1 -C 6 alkyl, alkoxyalkyl, G 1a or —(C 1 -C 6 alkylenyl)-G 1a ; wherein each G 1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G 1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R w ;
R v and R W , at each occurrence, are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —CN, oxo, —OR h , —OC(O)R i , —OC(O)NR j R k , —SR h , —S(O) 2 R h , —S(O) 2 NR j R k , —C(O)R h , —C(O)-monocyclic heterocycle, —C(O)-monocyclic heteroaryl, —C(O)OR h , —C(O)NR j R k , —NR j R k , —N(R h )C(O)R i , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), —N(R h )C(O)NR j R k , —(C 1 -C 6 alkylenyl)-OR h , —(C 1 -C 6 alkylenyl)-OC(O)R i , —(C 1 -C 6 alkylenyl)-OC(O)NR j R k , —(C 1 -C 6 alkylenyl)-S(O) 2 R h , —(C 1 -C 6 alkylenyl)-S(O) 2 NR j R k , —(C 1 -C 6 alkylenyl)-C(O)R h , —(C 1 -C 6 alkylenyl)-C(O)OR h , —(C 1 -C 6 alkylenyl)-C(O)NR j R k , —(C 1 -C 6 alkylenyl)-NR j R k , —(C 1 -C 6 alkylenyl)-N(R h )C(O)R i , —(C 1 -C 6 alkylenyl)-N(R h )S(O) 2 R i , —(C 1 -C 6 alkylenyl)-N(R h )C(O)O(R 1 ), —(C 1 -C 6 alkylenyl)-N(R h )C(O)NR j R k , or —(C 1 -C 6 alkylenyl)-CN;
R h , R j , R k , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
R i , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
R x is hydrogen or C 1 -C 3 alkyl;
R y is C 1 -C 3 alkyl, —(C 2 -C 3 alkylenyl)-OH, or C 1 -C 3 haloalkyl;
X 1 is N or CR x1 wherein
R x1 is hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OR ax1 , —C(O)NR bx1 R cx1 , —C(O)R dx1 , S(O) 2 R dx1 , —S(O) 2 NR bx1 R cx1 , G x1 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of OR ax1 , SR ax1 , S(O)R dx1 , S(O) 2 R dx1 , NR bx1 R cx1 , —C(O)R ax1 , —C(O)OR ax1 , —C(O)NR bx1 R cx1 , —S(O) 2 NR bx1 R cx1 and G x1 ;
R ax1 , R bx1 , and R cx1 , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;
R dx1 , at each occurrence, is each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;

X 2 is N or CR x2 ; wherein
R x2 is hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OR ax2 , —C(O)NR bx2 R cx2 , —C(O)R dx2 , S(O) 2 R dx2 , —S(O) 2 NR bx2 R cx2 , G x2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of OR ax2 , SR ax2 , S(O)R dx2 , S(O) 2 R dx2 , NR bx2 R cx2 , —C(O)R ax2 , —C(O)OR ax2 , —C(O)NR bx2 R cx2 , —S(O) 2 NR bx2 R cx2 , and G x2 ;
R ax2 , R bx2 , and R cx2 , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G b , or —(C 1 -C 6 alkylenyl)-G b ;
R dx2 , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G b , or —(C 1 -C 6 alkylenyl)-G b ;

Y 1 is N or CR u ; wherein R u is hydrogen, C 1 -C 6 alkyl, halogen, or C 1

Assignees

• Abbvie Inc

Inventors

• Wang Le
• Pratt John K
• Mcdaniel Keith F
• Dai Yujia
• Fidanze Steven D
• Hasvold Lisa
• Holms James H
• Kati Warren M
• Liu Dachun
• Mantei Robert A
• Mcclellan William J
• Sheppard George S
• Wada Carol K

Classifications

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P43/00

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

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title

• A61P39/02

  Antidotes · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title