INHIBITORS OF BRUTON'S TYROSINE KINASE
Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are describeded, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
1 . A compound of Formula (VIa) or (VIb) having the structure:
wherein:
ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
W is —C(R 2 )— or —N—;
X is —C(R 2 )— or —N—;
Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene;
Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
each R 2 is independently H, substituted or unsubstituted C 1 -C 4 alkyl, —CN, or halogen;
each R 3 is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl;
R 5 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 10a is H, substituted or unsubstituted C 1 -C 4 alkyl; and
t is 1, 2, or 3;
or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof;
provided that
i) when the compound is of Formula (VIa), W is N, and R 10a is H; then X is other than C-Et or N; and
ii) when W is N.
2 - 6 . (canceled)
7 . The compound of claim 1 , wherein ring A is phenyl.
8 . The compound of claim 1 , wherein Y is absent, —CH 2 O—, —OCH 2 —, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene.
9 . The compound of claim 1 , wherein Z is substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl.
10 - 11 . (canceled)
12 . The compound of claim 1 , wherein ring A is substituted or unsubstituted C 1 -C 12 heteroaryl.
13 . The compound of claim 12 , wherein ring A is pyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl.
14 . The compound of claim 1 , wherein X is —C(H)—.
15 . The compound of claim 1 , wherein X is —N—.
16 . The compound of claim 1 , wherein W is —C(H)—.
17 . The compound of claim 1 , wherein W is —N—.
18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
19 . A method for treating an autoimmune disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1 .
20 . The method of claim 19 , wherein the autoimmune disease is selected from rheumatoid arthritis or lupus.