Inhibitors of Bruton's tyrosine kinase and methods of their use

Patent metadata

Field	Value
Publication number	US-10689396-B2
Application number	US-201615374945-A
Country	US
Kind code	B2
Filing date	Dec 9, 2016
Priority date	Dec 10, 2015
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

The present disclosure is directed to compounds of formula I′ and methods of their use and preparation, as well as compositions comprising compounds of formula I′.

First claim

What is claimed:

1. A compound of Formula (I′), pharmaceutically acceptable salts, stereoisomers, isotopes, or N-oxides thereof,

wherein
R 1 is H or C 1-6 alkyl;
R 2 is selected from the group consisting of: C 0-2 alk-piperidinyl; C 0-2 alk-pyrrolidinyl; oxazepanyl; azetidinyl; azepanyl; quinuclidinyl; C 2 alk-imidazolidinyl; C 2 alk-piperazinyl; C 2 alk-morpholinyl; tetrahydropyranyl; and C 0-1 alk-tetrahydrofuranyl; wherein the R 2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of:
(C═O)—C(R 3 )═CR 4 (R 5 ); oxo; halogen; OH; NH 2 ; CN; C 1-6 alkyl; C 1-6 alk-OH; OC 1-6 alkyl; C 1-6 haloalkyl; C 3-6 cycloalkyl; SO 2 C 1-6 alkyl; SO 2 —C 2-6 alkenyl; C 1-2 alk-aryl; (C═O)H; (C═O)C 1-6 alkyl; (C═O)C 1-6 haloalkyl; (C═O)—C 2-6 alkenyl; (C═O)—C 2-6 alkynyl; (C═O)C 3-6 cycloalkyl; (C═O)-phenyl; (C═O)-imidazolyl; (C═O)—C 1-6 alkCN; (C═O)—C 1-6 alk-OH; (C═O)—C 1-6 alk-SO 2 C 1-6 alkyl; (C═O)—C 16 alk-NR 6 R 7 ; (C═O)—C 1-6 alk-O—C 1-6 alkyl wherein the —C 1-6 alk- is optionally substituted with OH, OC 1-6 alkyl, or NR 6 R 7 ; (C═O)C 0-1 alk-heterocycloalkyl wherein the -alk- is optionally substituted with oxo and the heterocycloalkyl is optionally substituted with C 1-6 alkyl; and NH(C═O)—C(R 3 )═CR 4 (R);

wherein
R 3 is selected from the group consisting of: H, CN, halogen, C 1-6 haloalkyl, and C 1-6 alkyl;
R 4 and R 5 are each independently selected from the group consisting of: H; halogen; C 1-6 alkyl; CH 2 OH; C 1-6 alk-OC 1-6 alkyl; OC 1-6 alkyl; C 1-4 alk-NR 6 R 7 ; C 3-6 cycloalkyl substituted with NH 2 or CH 3 ; oxetanyl substituted with CH 3 ; 1-acetylpyrrolidin-2-yl; CH 2 -pyrrolidinyl; CH 2 -piperidinyl; C(CH 3 ) 2 -piperidinyl; CH 2 -morpholinyl; C(CH 3 ) 2 -morpholinyl; CH 2 -(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl; C(CH 3 ) 2 NH(CH 2 CH 2 OCH 3 ); CH 2 SO 2 CH 3 ; CH 2 NHSO 2 CH 3 ; NH(C═O)C 1-6 alkyl; and linker-PEG-Biotin; and
R 6 and R 7 are each independently selected from the group consisting of: H, C 1-6 alkyl, cyclopropyl, (C═O)H, and CN;
A is selected from the group consisting of: a bond, phenyl; naphthalenyl, pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzothiophenyl; and pyrazolyl; wherein the A is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: C 1-6 alkyl, halogen, OC 1-6 alkyl, (C═O)C 1-6 alkyl, and C 1-6 haloalkyl;
E is selected from the group consisting of: —O—, a bond, (C═O)—NH, CH 2 , and CH 2 —O; and
G is selected from the group consisting of: H, C 1-6 alkyl; C 1-6 haloalkyl; C 1-6 alk-OC 1-6 alkyl; NR 6 R 7 ; SO 2 C 1-6 alkyl; OH; C 3-6 cycloalkyl; phenyl; thiophenyl; pyrimidinyl; pyridyl; pyridazinyl; benzofuranyl; heterocycloalkyl that contains an oxygen heteroatom; phenyl-CH 2 —O-phenyl; wherein the phenyl, thiophenyl, pyrimidinyl, pyridyl, pyridazinyl, or benzofuranyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 alkyl-OC 1-6 alkyl, C 3-6 cycloalkyl, CN, OH, NH 2 , N(CH 3 ) 2 , C 1-6 alk-OC 1-6 alkyl, SO 2 C 1-6 -alkyl, (C═O)—NR 6 R 7 , SF 5 , and (C═O)C 1-6 alkyl.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 1 , wherein R 2 is piperidinyl, CH 2 CH 2 -piperidinyl, pyrrolidinyl, CH 2 -pyrrolidinyl, or CH 2 CH 2 -pyrrolidinyl.

4. The compound of claim 1 , wherein R 2 is substituted with (C═O)—C(R 3 )═CR 4 (R 5 ).

5. The compound of claim 4 , wherein R 3 is H.

6. The compound of claim 1 , wherein R 4 is H and R 5 is H.

7. The compound of claim 1 , wherein A is pyridyl.

8. The compound of claim 1 , wherein A is substituted with CH 3 O.

9. The compound of claim 1 , wherein E is O.

10. The compound of claim 1 , wherein G is phenyl.

11. The compound of claim 1 , wherein G is pyridyl.

12. The compound of claim 1 , wherein R 1 is H; R 2 is piperidinyl substituted with 1 or 2 substituents wherein one of the substituents is (C═O)—C(R 3 )═CR 4 (R 5 ), wherein R 3 , R 4 , and R 5 are each H; A is phenyl or pyridyl substituted with CH 3 ; E is O; and G is phenyl.

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R,E)-N-(1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4I-oxo-4,5-dihydro-3H-1-thia-3,

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Arora Nidhi
• Bacani Genesis M
• Barbay Joseph Kent
• Bembenek Scott D
• Cai Min
• Chen Wei
• Deckhut Charlotte Pooley
• Edwards James P
• Ghosh Brahmananda
• Hao Baoyu
• Kreutter Kevin D
• Li Gang
• Tichenor Mark S
• Venable Jennifer D
• Wei Jianmei
• Wiener John J M
• Wu Yao
• Zhu Yaoping
• Zhang Feihuang
• Zhang Zheng
• Xiao Kun

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D495/16 Primary

  Peri-condensed systems · CPC title

• A61P37/02

  Immunomodulators · CPC title