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. In addition, reversible inhibitors of Btk are also described. 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 . A compound of Formula (IV) having the structure:
wherein:
ring A is C 6 -C 12 aryl or C 3 -C 12 heteroaryl;
X is substituted or unsubstituted C 2 -C 4 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl or substituted or unsubstituted C 3 -C 12 heteroaryl;
L 1 is —N(R 2 )C(O)— or —C(O)N(R 2 )—;
R 1 is C 6 -C 12 aryl or C 3 -C 12 heteroaryl, which may optionally be substituted with at least one R 3 ;
R 2 is H or C 1 -C 4 alkyl;
R 3 is halogen, —CF 3 , —CN, —NO 2 , —OR 6 , —N(R 11 )(R 12 ), substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;
R 6 is H or L-J-W;
R 7 and R 8 are independently H or L-J-W; or R 7 and R 8 taken together form a bond;
L and J are each independently a bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene, substituted or unsubstituted C 2 -C 7 heterocycloalkylene, substituted or unsubstituted C 6 -C 12 arylene, substituted or unsubstituted C 3 -C 12 heteroarylene, —CO—, —O—, or —S—;
W is H, or NR 25 R 26 ;
R 9 is H, or substituted or unsubstituted C 1 -C 6 alkyl;
R 10 is halogen, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy;
R 11 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;
R 12 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;
R 25 and R 26 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 3 -C 12 heteroaryl; or R 25 and R 26 together with the nitrogen atom to which they are attached form a C 2 -C 9 heterocycloalkyl;
p is 0, 1, or 2;
or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
2 . The compound of claim 1 , wherein L 1 is —C(O)N(H)—.
3 . The compound of claim 2 , wherein R 1 is C 3 -C 12 heteroaryl substituted with one R 3 .
4 . The compound of claim 3 , wherein R 1 is azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, or thiophenyl.
5 . The compound of claim 4 , wherein R 1 is pyridyl, thiazolyl or oxazolyl.
6 . The compound of claim 3 , wherein R 3 is CN, Me, Et, n-Pr, i-Pr, cyclopropyl, or CF 3 .
7 . The compound of claim 1 , wherein each of R 6 , R 7 , and R 8 is H; or R 6 is H, and R 7 and R 8 taken together form a bond.
8 . The compound of claim 1 , wherein R 25 is substituted or unsubstituted C 3 -C 6 cycloalkyl.
9 . The compound of claim 8 , wherein R 25 is cyclopropyl.
10 . The compound of claim 1 , wherein R 26 is H or Me.
11 . The compound of claim 1 , wherein p is 0.
12 . The compound of claim 1 , wherein ring A is phenyl.
13 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient.
14 . The pharmaceutical composition of claim 13 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, and rectal administration.
15 . A method for treating a disease or condition selected from an autoimmune disease or condition, a heteroimmune disease or condition, an inflammatory disease or condition, or mastocytosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
16 . The method of claim 15 , wherein the disease or condition is an autoimmune disease or condition selected from rheumatoid arthritis or lupus.
17 . A method for treating a cancer comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1 .
18 . The method of claim 17 , wherein the cancer is a B-cell proliferative disorder.
19 . The method of claim 18 , wherein the B-cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
20 . A method for treating osteoporosis or a bone resorption disorder comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1 .