Bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9994581-B2
Application number	US-201415103215-A
Country	US
Kind code	B2
Filing date	Dec 10, 2014
Priority date	Dec 10, 2013
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

The present invention provides for compounds of formula (I) wherein R x , X, Y, Y 1 , L 1 , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 , have any of the values defined 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 comprised of 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 C 1 -C 3 alkyl;
Y 1 is CR y , wherein R is H, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
A 1 is CR 1 , A 2 is CR 2 , A 3 is CR 3 ; and A 4 is N;
A 5 is CR 5 , A 6 is CR 6 , A 7 is CR 7 ; and A 8 is CR 8 ;
R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 , are each independently hydrogen, halogen, NO 2 , G a , C 1 -C 6
haloalkyl, —CN, —OR a , —S(O) 2 R c , —C(O)R a , —C(O)OR a , —S(O) 2 NR a R b , —C(O)NR a R b , NR a R b , —N(R b )S(O) 2 R c , —N(R b )C(O)OR c , —N(R b )C(O)NR a R b , —N(R b )C(O)R c , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkyl; wherein the C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkyl are optionally substituted with one substituent selected from the group consisting of—
CN, —OR a , —S(O) 2 R c , —S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , NR a R b , —N(R b )S(O) 2 R c , —N(R b )C(O)OR c , —N(R b )C(O)NR a R b , —N(R b )C(O)R, and G a ;

X is O;
Y is O;
R 9 and R 10 are each independently hydrogen, halogen, —CN, C 1 -C 6 haloalkyl, G b , C 1 -C 6 alkyl, —OR d , —NR d R e , or —C(O)NR d R e ;
R 11 and R 12 are each independently hydrogen or C 1 -C 3 alkyl;
L 1 is —(CR 13 R 14 ) m —W—(CR 15 R 16 ) n —; wherein —(CR 15 R 16 ) n — is attached to the ring containing A 5 , A 6 , A 7 , and A 8 ; wherein
m is 1, 2, or 3;
n is 0, 1, 2, or 3;
W is a bond, O, N(R 17 ), —CH═CH—, —C(O)—N(R 18 )—, —S(O) 2 —N(R 18 )—, —N(R 18 )—C(O)—, or —N(R 18 )—S(O) 2 —; wherein
R 17 is hydrogen, C 1 -C 6 haloalkyl,
 G c , —S(O) 2 R f , —S(O) 2 N(R g ) 2 , —S(O) 2 N(R g )C(O)R f , —S(O) 2 N(R g )C(O) OR f , —C(O)R f , —C(O)OR f , —C(O)N(R g ) 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkyl; wherein the C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkyl are optionally substituted with one substituent selected from the group consisting of—
 CN, —OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b ,
 NR a R b , —N(R b )S(O) 2 R c , —N(R b )C(O)OR c , —N(R b )C(O)NR a R b , —N(R b )C(O)R c , and G c ; and
R 18 , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, G c , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkyl; wherein the C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkyl are optionally substituted with one substituent selected from the group consisting of —CN, —OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b ,
 NR a R b , —N(R b )S(O) 2 R c , —N(R b )C(O)OR c , —N(R b )C(O)NR a R b , —N(R b )C(O)R c , and G c ;

R 13 and R 14 , at each occurrence, are each independently hydrogen, halogen, —CN, C 1 -C 6 haloalkyl, G b , C 1 -C 6 alkyl, —OR d , —NR d R e , or —C(O)NR d R e ; R 13 and R 14 together may be an oxo group;
R 15 and R 16 , at each occurrence, are each independently hydrogen, halogen, —CN, C 1 -C 6 haloalkyl, G b , C 1 -C 6 alkyl, —OR d , —NR d R e , or —C(O)NR d R e ; R 15 and R 16 together may be an oxo group;

R a and R b , 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 c , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;
R d , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, G b , 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—
CN, —OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , NR a R b , —N(R b )S(O) 2 R c , —N(R b )C(O)OR c , —N(R b )C(O)NR a R b , —N(R b )C(O)R, and G b ;

R e , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G b , or —(C 1 -C 6 alkylenyl)-G b ;
R f , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G c , or —(C 1 -C 6 alkylenyl)-G;
R g , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G c , or —(C 1 -C 6 alkylenyl)-G c ;
G a , G b , and G c , at each occurrence, are each independently phenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 heterocycle, or C 5 -C 6 heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R u groups;
R u , at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —CN, oxo,
NO 2 , —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)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)-SR h , —(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 i ), —(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. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R x is methyl; and
R y is H.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R x is methyl;
R y is H;
R 1 , R 3 , R 5 , R 6 , and R 8 are each independently hydrogen or halogen;
R 7 is hydrogen, halogen, C 1 -C 6 haloalkyl, —OR a , —CN, or unsubstituted C 1 -C 6 alkyl; and
R 2 is hydrogen, —S(O) 2 R c , —C(O)OR a , —S(O) 2 NR a R b ,
NR a R b , —N(R b )S(O) 2 R c , —N(R b )C(O)NR a R b , —N(R b )C(O)R c , or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is substituted with one substituent selected from the group consisting of —OR a and —S(O) 2 R c .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R x is methyl;
R y is H; and
L 1 is —(CR 13 R 14 ) m —W—(CR 15 R 16 ) n —; wherein W is a bond, O, N(R 17 ), —CH═CH—, or —N(R 18 )—C(O)—.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R x is methyl;
R y is H; and
L 1 is —(CR 13 R 14 ) m —W—(CR 15 R 16 ) n —; wherein m is 1, 2, or 3, n is 1 or 2, and W is a bond.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R x is methyl;
R y is H; and
L 1 is —(CR 13 R 14 ) m —W—(CR 15 R 16 ) n —; wherein m is 2, n is 1, and W is O, N(R 17 ), or —CH═CH—.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R x is methyl;
R y is H; and
L 1 is —(CR 13 R 14 ) m —W—(CR 15 R 16 ) n —; wherein m is 2 or 3, n is 0, and W is —CH═CH— or —N(R 18 )—C(O)—.

8. A compound of formula (I-a) or a pharmaceutically acceptable salt thereof,

wherein
n is 1 or 2;
m is 1, 2, or 3;
R x is C 1 -C 3 alkyl;
Y 1 is CR y , wherein R y is H, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
A 1 is CR 1 , A 2 is CR 2 , A 3 is CR 3 ; and A 4 is N;
A 5 is CR 5 , A 6 is CR 6 , A 7 is CR 7 ; and A 8 is CR 8 ;

R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 , are each independently hydrogen, halogen, NO 2 , G a , C 1 -C 6 haloalkyl, —CN, —OR a , —S(O) 2 R c , —C

Assignees

• Abbvie Inc

Inventors

• Wang Le
• Frey Robin R
• Hansen Todd M
• Liu Dachun
• Mcclellan William J
• Mcdaniel Keith F
• Pratt John K
• Wada Carol K

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/4353

  ortho- or peri-condensed with heterocyclic ring systems · CPC title