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

Patent metadata

Field	Value
Publication number	US-10800792-B2
Application number	US-201916413417-A
Country	US
Kind code	B2
Filing date	May 15, 2019
Priority date	Dec 10, 2015
Publication date	Oct 13, 2020
Grant date	Oct 13, 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 method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by Bruton's tyrosine kinase activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I′), and 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 1-6 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 5 );
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 method of claim 1 , wherein the disease, disorder, or medical condition mediated by Bruton's tyrosine kinase is rheumatoid arthritis.

3. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by Bruton's tyrosine kinase activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound 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,5 S)-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,5 S)-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,5 S)-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,5 S)-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-methyl oxetan-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)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R)-5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(S,E)-N-(1-(4-Hydroxybut-2-enoyl)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-(2-Chloroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;
(R,E)-N-(1-(4-Aminobut-2-enoy

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