INHIBITORS OF BRUTON'S TYROSINE KINASE
Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, 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 - 22 . (canceled)
23 . The compound of claim 24 having the structure:
24 . A compound of Formula (D5) having the structure:
wherein:
L a is O or S;
Ar is an unsubstituted phenyl;
Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring, or
Y is a 4-, 5-, 6-, or 7-membered monocyclic nitrogen-containing heterocycloalkyl ring;
Z is C(═O), OC(═O), NHC(═O), S(═O) x , or NHS(═O) x , where x is 2;
R 8 is H; R 7 is H, unsubstituted C 1 -C 4 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, or C 1 -C 4 alkyl(phenyl); or
R 7 and R 8 taken together form a bond;
R 6 is H, unsubstituted C 1 -C 4 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, or C 1 -C 4 alkyl(phenyl); and pharmaceutically acceptable salts thereof.
25 . The compound of claim 24 , wherein L a is O.
26 . The compound of claim 24 , wherein:
Z is C(═O), NHC(═O), or S(═O) 2 .
27 . The compound of claim 24 , wherein:
each of R 7 and R 8 is H; or
R 7 and R 8 taken together form a bond.
28 . The compound of claim 24 , wherein:
each of R 6 and R 8 is H.
29 . A pharmaceutical composition comprising a compound of claim 24 and a pharmaceutically acceptable excipient.
30 . A pharmaceutical composition comprising a compound of claim 25 and a pharmaceutically acceptable excipient.
31 . A pharmaceutical composition comprising a compound of claim 26 and a pharmaceutically acceptable excipient.
32 . A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable excipient.
33 . A pharmaceutical composition comprising a compound of claim 28 and a pharmaceutically acceptable excipient.
34 . A pharmaceutical composition comprising a compound of claim 23 and a pharmaceutically acceptable excipient.
35 . A method of treating cancer in a subject comprising administering to the subject having cancer a compound of claim 24 or pharmaceutically acceptable salts thereof.
36 . The method of claim 35 wherein the cancer is selected from diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis.
37 . The method of claim 36 wherein the cancer is diffuse large B cell lymphoma.
38 . A method of treating an autoimmune disease in a subject comprising administering to the subject having an autoimmune disease a compound of claim 24 or pharmaceutically acceptable salts thereof.
39 . The method of claim 38 wherein the autoimmune disease is inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Grave's disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encepthalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisi, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arthritis, temporal arthritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial, cystitis, neuromyotonia, scleroderma, and vulvodynia.
40 . The method of claim 39 wherein the autoimmune disease is inflammatory bowel disease.
41 . The method of claim 39 wherein the autoimmune disease is rheumatoid arthritis.
42 . The method of claim 39 wherein the autoimmune disease is multiple sclerosis.