Indole carboxamide compounds

Patent metadata

Field	Value
Publication number	US-2016115126-A1
Application number	US-201514921347-A
Country	US
Kind code	A1
Filing date	Oct 23, 2015
Priority date	Oct 24, 2014
Publication date	Apr 28, 2016
Grant date	—

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

1 . A compound of Formula (I):

or a salt thereof, wherein:
X is CR 4 or N;
A is:
(i)

(ii)

(iii)

(iv)

(v)

(vi) —CHR 8 (pyridinyl) wherein each pyridinyl is substituted with R 6 and R 9 ;

Q 1 is —NR 7 Q 2 , —CR 10 R 10 NR 7 Q 2 , —C(O)NR 7 (C 1-4 alkyl substituted with zero or 1 R 11 ), —CH═CH 2 , —CH═C(CN)S(O) 2 CH 3 , —S(O) 2 CH═CR 10 R 10 , —NR 7 (dichlorotriazinyl), —NR 7 (quinazolin-4-yl substituted with zero or 1 R 11 ), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substituted with zero to two substituents independently selected from F, Cl, —CH 3 , —CN, and —OCH 3 ;
Q 2 is —CN, —C(O)(C 1-4 alkyl substituted with zero or 1 R 11 , —C(O)(C 3-6 cycloalkyl substituted with zero or 1 R 11 , —C(O)(C 5-6 cycloalkenyl), —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), —C(O)C≡CSi(CH 3 ) 3 , 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 H, F, Cl, I, —CN, or —CH 3 ;
R 4 is H, F, —OH, —O(C 1-4 alkyl), —O(C 1-4 alkyl)-O—(C 1-2 alkyl), —O(CH 2 ) 1-3 (phenyl), —O(CH 2 ) 1-3 (methoxyphenyl), or —O(CH 2 ) 1-3 (morpholinyl);
R 5 is H, F, Cl, or —CH 3 ;
R 6 is H, F, Cl, —CF 3 , or C 1-3 alkoxy;
each R 6a is independently H or F;
R 7 , at each occurrence, is independently H, C 1-4 alkyl, or cyclopropyl;
R 8 is H or C 1-4 alkyl;
R 9 is —CH═CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —C≡CH, or —C≡CCH 3 ;
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:
R 3 is H, F, or Cl;
R 4 is H, F, —OH, —O(C 1-2 alkyl), —OCH 2 CH 2 OCH 3 , —OCH 2 (phenyl), —OCH 2 (methoxyphenyl), or —OCH 2 CH 2 (morpholinyl);
R 5 is H, F, or —CH 3 ;
R 6 is H or F;
R 7 is H or C 1-3 alkyl;
R 8 is H or —CH 3 ;
R 9 is —CH═CH 2 or —C≡CCH 3 ;
Q 1 is —N(CH 3 )C(O)CH═CH 2 , —N(CH 3 )S(O) 2 CH═CH 2 , —C(O)NHCH 2 CN, —C(CH 3 ) 2 NHS(O) 2 CH═CH 2 , —CH 2 NHC(O)CH═CH 2 , —CH 2 NHS(O) 2 CH═CH 2 , —NHC(O)CH 2 CN, —NHC(O)CH 2 CH 3 , —NHC(O)CH═CH 2 , —NHC(O)C(CH 3 )═CH 2 , —NHC(O)CH═C(CH 3 ) 2 , —NHC(O)CH═CHCH 3 , —NHC(O)CH═CHCH 2 N(CH 3 ) 2 , —NHC(O)(cyclohexenyl), —NHC(O)(cyclopropyl), —NHC(O)(cyanocyclopropyl), —NHS(O) 2 CH═CH 2 , —S(O) 2 CH═CH 2 , —CH═C(CN)S(O) 2 CH 3 , —NH(dichlorotriazinyl), —NH(fluoroquinazolin-4-yl), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substituted with zero to two substituents independently selected from F, Cl, —CH 3 , —CN, and —OCH 3 ; and
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≡C(CH 3 ) 2 OH, —C(O)C≡CSi(CH 3 ) 3 , —C(O)(cyclopropyl), or —C(O)C≡C(phenyl).

3 . The compound according to claim 1 or a salt thereof, wherein:
X is CR 4 .

4 . The compound according to claim 1 or a salt thereof, wherein:
Q 1 is —NR 7 Q 2 , —CR 10 R 10 NR 7 Q 2 , —S(O) 2 CH═CR 10 R 10 , —NR 7 (dichlorotriazinyl), 1H-pyrrol-2(5H)-on-1-yl, or 3-methylenepyrrolidin-2-on-1-yl;
Q 2 is —CN, —C(O)(C 5-6 cycloalkenyl), —C(O)CH═CHR 10 , —C(O)CR 10 ═CH 2 , —C(O)CR 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), —C(O)C≡CSi(CH 3 ) 3 , or —S(O) 2 CH═CH 2 ;
R 3 is H, F, or Cl; and
R 4 is H or F.

5 . The compound according to claim 1 or a salt thereof, wherein A is:

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

7 . The compound according to claim 1 or a salt thereof, wherein A is:
(i)

(ii)

(iii)

8 . The compound according to claim 1 or a salt thereof, wherein A is —CHR 8 (pyridinyl) wherein each pyridinyl is substituted with R 6 and R 9 .

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

10 . The compound according to claim 9 or a salt thereof, wherein
A is:
(i)

 or
(ii)

11 . The compound according to claim 1 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≡C(CH 3 ) 2 OH, —C(O)C≡CSi(CH 3 ) 3 , —C(O)(cyclopropyl), or —C(O)C≡C(phenyl);
R 7 is H or —CH 3 ; and
R 6 is H, F, or —CH 3 .

12 . The compound according to claim 1 having the structure:

13 . The compound according to claim 1 having the structure:

14 . The compound according to claim 1 or a salt thereof, wherein said compound is selected from: 4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (1); 2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (2); 5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (3); 2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (4); 4-(3-acrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (5); (E)-4-(3-(but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (6); 4-(3-acrylamido-2-methylphenyl)-2-methyl-

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Qingjie
• Watterson Scott Hunter
• Batt Douglas G
• Ahmad Saleem
• Beaudoin Bertrand Myra
• Gong Hua
• Guo Weiwei
• Macor John E
• Ngu Khehyong
• Tebben Andrew J
• Tino Joseph A

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D209/18 Primary

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title