Inhibitors of Bruton's tyrosine kinase
View Patent ↗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 (I) having the structure:
wherein:
L 1 is —N(R 2 )C(O)— or —C(O)N(R 2 )—;
R 1 is C 3 -C 12 heteroaryl, wherein C 3 -C 12 heteroaryl is optionally 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 6 )(R 7 ), 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 4 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 2 -C 9 heterocycloalkyl;
R 5 is substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 2 -C 9 heterocycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a C 2 -C 9 heterocycloalkyl;
R 6 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;
R 7 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;
R 10 is halogen, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy;
m is 1 or 2;
n is 0 or 1; and
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(R 2 )—.
3. The compound of claim 2 , wherein L 1 is —C(O)N(H)—.
4. The compound of claim 1 , wherein R 1 is C 3 -C 12 heteroaryl substituted with one R 3 .
5. The compound of claim 4 , wherein R 1 is pyridyl.
6. The compound of claim 4 , wherein R 1 is thiazolyl or oxazolyl.
7. The compound of claim 4 , wherein R 3 is CN, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl.
8. The compound of claim 1 , wherein R 4 is H.
9. The compound of claim 1 , wherein R 4 is substituted or unsubstituted C 1 -C 6 alkyl.
10. The compound of claim 9 , wherein R 4 is —CH 3 .
11. The compound of claim 1 , wherein R 5 is substituted or unsubstituted C 3 -C 8 cycloalkyl.
12. The compound of claim 11 , wherein R 5 is cyclopropyl.
13. The compound of claim 1 , wherein m is 1.
14. The compound of claim 1 , wherein m is 2.
15. The compound of claim 1 , wherein n is 0.
16. The compound of claim 1 , wherein n is 1.
17. The compound of claim 1 , wherein p is 0.
18. A compound having the structure:
or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
19. Any one of the compounds selected from:
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-ethylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methylthiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-cyclopropylthiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-isopropylthiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-ethylthiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-propylthiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(trifluoromethyl)thiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-cyanothiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(thiazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(oxazol-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyclopropylpyridin-2-yl)benzamide;
R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;
4-(4-amino-1-((1,4 trans)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
4-(4-amino-1-((1,4 trans)-4-((E)-4-(cyclopropyl(methyl)amino)but-2-enamido)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
4-(1-((1,4 trans)-4-acrylamidocyclohexyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
4-(4-amino-1-((1,4 trans)-4-((E)-4-(dimethylamino)but-2-enamido)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
4-(4-amino-1-((1,4 trans)-4-((E)-4-(cyclopropyl(methyl)amino)but-2-enamido)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;
(R,E)-4-(4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide; and
(R,E)-4-(4-amino-1-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
20. 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.