Carbazole carboxamide compounds

Patent metadata

Field	Value
Publication number	US-2016200710-A1
Application number	US-201414392355-A
Country	US
Kind code	A1
Filing date	Jun 25, 2014
Priority date	Jun 25, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

Disclosed are compounds of Formula (I); and salts thereof, wherein: Formula (II); Q is: R 1 is —C(CH 3 )2OH, —NHC(=0)C(CH 3 ) 3 , —N(CH3)2, or —CH 2 R d ; R 2 is CI or —CH 3 ; R 3 is H, F, or —CH 3 ; R a is H or —CH 3 ; R b is H, F, CI, or —OCH3 R c is H or F; and Rd is —OH, —OCH3, —NHC(=0)CH3, or fORMULA (III), Also disclosed are methods of using such compounds as inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

First claim

1 . A compound of Formula (I):

or a salt thereof, wherein:
Q is:

R 1 is —C(CH 3 ) 2 OH, —NHC(═O)C(CH 3 ) 3 , —N(CH 3 ) 2 , or —CH 2 R d ;
R 2 is Cl or —CH 3 ;
R 3 is H, F, or —CH 3 ;
R a is H or —CH 3 ;
R b is H, F, Cl, or —OCH 3 ;
R c is H or F;and
R d is —OH, —OCH 3 , —NHC(═O)CH 3 , or

2 . The compound according to claim 1 or a salt thereof, wherein:
Q is:

3 . The compound according to claim 1 or a salt thereof, wherein:
R a is —CH 3 ;
R b is F, Cl, or —OCH 3 ; and
R c is F.

4 . The compound according to claim 1 or a salt thereof, wherein:
R 2 is —CH 3 .

5 . The compound according to claim 1 wherein:
Q is:

and
R 1 is C(CH 3 ) 2 OH.

6 . The compound according to claim 1 or a salt thereof, wherein:
Q is:

R 2 is —CH 3 ; and
R 3 is H.

7 . The compound according to claim 1 wherein said compound is selected from: 4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (1 and 2); 4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (3); 4-(3-(S)-(8-fluoro-1-methyl(d 3 )-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (4); 4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (5); 4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (6); 7-(2-hydroxypropan-2-yl)-4-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (7); 4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (8); 4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (9); 7-(2-hydroxypropan-2-yl)-4-(3-(7-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (10); 7-(2-hydroxypropan-2-yl)-4-(3-(6-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (11); 7-(2-hydroxypropan-2-yl)-4-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (12); 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (13); 4-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (14); 4-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (15); 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-pivalamido-9H-carbazole-1-carboxamide (16); 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(methoxymethyl)-9H-carbazole-1-carboxamide (17); 4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(methoxymethyl)-9H-carbazole-1-carboxamide (18); 4-(3-(4-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (19); 4-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (20); 4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (21); 4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (22 and 23); 4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-5-methyl-9H-carbazole-1-carboxamide (24); 4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-5-methyl-9H-carbazole-1-carboxamide (25); 4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-8-methyl-9H-carbazole-1-carboxamide (26); 4-(3-(S)-(8-fluoro-1-methyl(d 3 )-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-5-methyl-9H-carbazole-1-carboxamide (27); 4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (28); 7-(dimethylamino)-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (29); 7-(acetamidomethyl)-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (30); 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(pyrrolidin-1-ylmethyl)-9H-carbazole-1-carboxamide (31); 4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(methoxymethyl)-9H-carbazole-1-carboxamide (32); 8-fluoro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (33); and salts thereof.

8 . A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

9 . (canceled)

10 . (canceled)

11 . A method of treating an autoimmune disease or a chronic inflammatory disease, comprising administering to a mammalian patient a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12 . The method according to claim 11 wherein said autoimmune disease or a chronic inflammatory disease is selected from lupus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, encephalomyelitis, and vascular disease.

Assignees

• Bristol Myers Squibb Co

Inventors

• Ko Soo Sung
• Batt Douglas G
• Bertrand Myra Beaudoin
• Delucca George
• Langevine Charles M
• Liu Qingjie
• Srivastava Anurag S
• Watterson Scott Hunter

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title