Indole carboxamide compounds
Disclosed are compounds of Formula (I): or a salt thereof, wherein: X is CR 4 or N; R 1 , R 2 , R 3 , R 4 , and A are defined herein. 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.
1. A compound of Formula (I):
or a salt thereof, wherein:
X is CR 4 ;
A is:
Q 2 is —CN, —C(O)(C 1-4 alkyl substituted with zero or 1 R 11 ), —C(O)CR 10 ═CR 10 R 10 , —C(O)C(R 10 )═CHCH 2 N(CH 3 ) 2 , —C(O)C≡CR 7 , —C(O)C≡C(C 1-3 hydroxyalkyl), —C(O)C≡C(phenyl), or —S(O) 2 CH═CHR 10 ;
R 1 is H, —CH 3 , —CF 3 , or phenyl substituted with zero or 1 R 12 ;
R 2 is H, —CH 3 , cyclopropyl, or phenyl substituted with zero or 1 R 12 , provided that zero or one of R 1 and R 2 is phenyl substituted with zero or 1 R 12 ;
R 3 is F, Cl, or I;
R 4 is H, F, —OH, or —OCH 3 ;
R 6 is H, F, or Cl;
each R 6a is independently H or F;
R 7 , at each occurrence, is independently H, C 1-4 alkyl, or cyclopropyl;
R 10 , at each occurrence, is independently H or —CH 3 ;
R 11 is F, Cl, —CN, —CF 3 , or C 1-3 alkoxy; and
R 12 is F, Cl, —CN, —CF 3 , or C 1-3 alkoxy.
2. The compound according to claim 1 or a salt thereof, wherein:
Q 2 is —CN, —C(O)CR 10 ═CR 10 R 10 , —C(O)C≡CR 7 , —C(O)C≡C(phenyl), or —S(O) 2 CH═CHR 10 ;
R 1 is —CH 3 or —CF 3 ;
R 2 is —CH 3 , cyclopropyl, or phenyl substituted with zero or 1 R 12 ;
R 3 is F or Cl;
R 4 is H or F;
R 6 is H or F;
R 7 , at each occurrence, is independently H, C 1-2 alkyl, or cyclopropyl; and
R 12 is F, Cl, —CN, —CF 3 , or —OCH 3 .
3. The compound according to claim 2 or a salt thereof, wherein
A is:
4. The compound according to claim 2 or a salt thereof, wherein:
A is:
5. The compound according to claim 2 or a salt thereof, wherein:
A is:
6. The compound according to claim 2 or a salt thereof, wherein:
Q 2 is —C(O)CH═CH 2 or —C(O)C≡CCH 3 ;
R 1 is —CH 3 ;
R 2 is —CH 3 ;
R 3 is F; and
R 4 is H.
7. The compound according to claim 1 or a salt thereof, wherein said compound is selected from: cis-4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (98); 4-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (165 and 166); 4-(1-acryloylhexahydropyrrolo[3,4-b] pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (167 and 168); 4-(5-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (175 and 176); and 4-(1-(but-2-ynoyl)hexahydropyrrolo[3,4-b] pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (177 and 178).
8. The compound according to claim 1 the structure:
9. The compound according to claim 1 the structure:
10. The compound according to claim 1 the structure:
11. The compound according to claim 1 the structure:
12. The compound according to claim 1 the structure:
13. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.
14. A method for treating a disease comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound according to claim 1 or a pharmaceutically-acceptable salt thereof, wherein said disease is rheumatoid arthritis.