Indole carboxamide compounds

Patent metadata

Field	Value
Publication number	US-9688629-B2
Application number	US-201514921347-A
Country	US
Kind code	B2
Filing date	Oct 23, 2015
Priority date	Oct 24, 2014
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

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.

First claim

The invention claimed is:

1. A compound of Formula (I):

or a salt thereof, wherein:
X is —CR 4 ;
R 1 is —CH 3 or —CF 3 ;
R 2 is —CH 3 or cyclopropyl;
R 3 is F, Cl, or I;
R 4 is H;
A is:

Q 2 is —CN, —C(O)CH═CH 2 , —S(O) 2 CH═CH 2 , —C(O)CH═CHCH 2 N(CH 3 ) 2 , —C(O)C≡CH, —C(O)C≡CCH 3 , —C(O)C≡CCH 2 CH 3 , —C(O) C≡CCH 2 CH 2 CH 3 , —C(O)C≡CC(CH 3 ) 2 OH, —C(O)C≡CSi(CH 3 ) 3 , —C(O)C≡C(cyclopropyl), or —C(O)C≡C(phenyl); and
R 7 is H or —CH 3 .

2. The compound according to claim 1 or a salt thereof, wherein R 3 is F or Cl.

3. The compound according to claim 1 or a salt thereof, wherein R 3 is F.

4. The compound according to claim 1 or a salt thereof, wherein:
R 1 is —CH 3 ;
R 2 is —CH 3 ;
R 3 is F;
Q 2 is —CN, —C(O) CH═CH 2 , —S(O) 2 CH═CH 2 , —C(O)C≡CH, —C(O)C≡CCH 2 CH 3 , —C(O)C≡CCH 2 CH 2 CH 3 , or —C(O)C≡C(cyclopropyl);
R 7 is H.

5. The compound according to claim 1 or a salt thereof, wherein said compound is selected from: (S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (89); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1 -yl)-1 H -indole-7-carboxamide (125); (S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido) piperidin-1-yl)-1H -indole-7-carboxamide (126); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (127); (S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (128); (S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (136); (S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido) piperidin-1-yl)-1H-indole-7-carboxamide (146); (S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (150); (S)-4-(3-(but-2-ynamido) piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (223); (S)-5-fluoro-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (242); and (R)-4-(3-(but-2-ynamido) piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (243).

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

7. A method for treating a disease comprising the administration 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.

8. A pharmaceutical composition comprising a compound according to claim 5 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

9. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to claim 5 or a pharmaceutically-acceptable salt thereof, wherein said disease is rheumatoid arthritis.

10. A compound having the structure:

or a salt thereof.

11. The compound according to claim 10 .

12. A pharmaceutical composition comprising a compound according to claim 10 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

13. A method for treating a disease comprising administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to claim 10 or a pharmaceutically-acceptable salt thereof, wherein said disease is rheumatoid arthritis.

14. A compound having the structure:

or a salt thereof.

15. The compound according to claim 14 .

16. A pharmaceutical composition comprising a compound according to claim 14 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

17. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to claim 14 or a pharmaceutically-acceptable salt thereof, wherein said disease is rheumatoid arthritis.

18. A compound having the structure:

or a salt thereof.

19. The compound according to claim 18 .

20. A pharmaceutical composition comprising a compound according to claim 18 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

21. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to claim 18 or a pharmaceutically-acceptable salt thereof, wherein said disease is rheumatoid arthritis.

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Qingjie
• Watterson Scott Hunter
• Ahmad Saleem

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/4045

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title