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

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

• wherein
• R1 is H or C1-6alkyl;
• R2 is selected from the group consisting of:
• C0-2alk-piperidinyl;
• C0-2alk-pyrrolidinyl;
• oxazepanyl;
• azetidinyl;
• azepanyl;
• quinuclidinyl;
• C2alk-imidazolidinyl;
• C2alk-piperazinyl;
• C2alk-morpholinyl;
• tetrahydropyranyl;
• and C0-1alk-tetrahydrofuranyl;
• wherein the R2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of:
• (C═O)—C(R3)═CR4(R5);
• oxo;
• halogen;
• OH;
• NH2;
• CN;
• C1-6alkyl;
• C1-6alk-OH;
• OC1-6alkyl;
• C1-6haloalkyl;
• C3-6cycloalkyl;
• SO2C1-6alkyl;
• SO2—C2-6alkenyl;
• C1-2alk-aryl;
• (C═O)H;
• (C═O)C1-6alkyl;
• (C═O)C1-6haloalkyl;
• (C═O)—C2-6alkenyl;
• (C═O)—C2-6alkynyl;
• (C═O)C3-6cycloalkyl;
• (C═O)-phenyl;
• (C═O)-imidazolyl;
• (C═O)—C1-6alkCN;
• (C═O)—C1-6alk-OH;
• (C═O)—C1-6alk-SO2C1-6alkyl;
• (C═O)—C1-6alk-NR6R7;
• (C═O)—C1-6alk-O—C1-6alkyl wherein the —C1-6alk- is optionally substituted with OH, OC1-6alkyl, or NR6R7;
• (C═O)C0-1alk-heterocycloalkyl wherein the -alk- is optionally substituted with oxo and the heterocycloalkyl is optionally substituted with C1-6alkyl;
• and NH(C═O)—C(R3)═CR4(R5);
• wherein
• R3 is selected from the group consisting of:
• H, CN, halogen, C1-6haloalkyl, and C1-6alkyl;
• R4 and R5 are each independently selected from the group consisting of:
• H;
• halogen;
• C1-6alkyl;
• CH2OH;
• C1-6alk-OC1-6alkyl;
• OC1-6alkyl;
• C1-4alk-NR6R7;
• C36cycloalkyl substituted with NH2 or CH3;
• oxetanyl substituted with CH3;
• 1-acetylpyrrolidin-2-yl;
• CH2-pyrrolidinyl;
• CH2-piperidinyl;
• C(CH3)2-piperidinyl;
• CH2-morpholinyl;
• C(CH3)2-morpholinyl;
• CH2-(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl;
• C(CH3)2NH(CH2CH2OCH3);
• CH2SO2CH3;
• CH2NHSO2CH3;
• NH(C═O)C1-6alkyl;
• and linker-PEG-Biotin;
• and
• R6 and R7 are each independently selected from the group consisting of:
• H, C1-6alkyl, 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:
• C1-6alkyl, halogen, OC1-6alkyl, (C═O)C1-6alkyl, and C1-6haloalkyl;
• E is selected from the group consisting of:
• —O—, a bond, (C═O)—NH, CH2, and CH2—O;
• and
• G is selected from the group consisting of:
• H, C1-6alkyl;
• C1-6haloalkyl;
• C1-6alk-OC1-6alkyl;
• NR6R7;
• SO2C1-6alkyl;
• OH;
• C3-6cycloalkyl;
• phenyl;
• thiophenyl;
• pyrimidinyl;
• pyridyl;
• pyridazinyl;
• benzofuranyl;
• heterocycloalkyl that contains an oxygen heteroatom;
• phenyl-CH2—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, C1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, OC1-6alkyl, OC1-6alkyl-OC1-6alkyl, C3-6cycloalkyl, CN, OH, NH2, N(CH3)2, C1-6alk-OC1-6alkyl, SO2C1-6alkyl, (C═O)—NR6R7, SF5, and (C═O)C1-6alkyl;
• and
• stereoisomers or isotopic variants thereof;
• and pharmaceutically acceptable salts thereof.