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. 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. A compound of Formula (D) having the structure:
wherein:
L a is CH 2 , O, NH or S;
Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O) x , OS(═O) x , NRS(═O) x , where x is 1 or 2;
R 7 and R 8 are each H; or
R 7 and R 8 taken together form a bond;
R 6 is H;
R is H or C 1 -C 6 alkyl; or pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein L a is O.
3. The compound of claim 2 , wherein Ar is phenyl.
4. The compound of claim 3 , wherein:
Z is C(═O), NHC(═O), or S(═O) 2 .
5. The compound of claim 4 , wherein:
Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or
Y is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.
6. The compound of claim 1 selected from among:
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one; N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)propiolamide; 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-yn-1-one; 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one ;N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)ethyl)propiolamide;N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-methylpropiolamide;1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene;1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide; 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)cyclohexyl)ethenesulfonamide;1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one ;3-(4-phenoxyphenyl)-1-(1-(vinylsulfonyl)pyrrolidin-3-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine ;3-(4-phenoxyphenyl)-1-(1-(vinylsulfonyl)piperidin-4-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine;N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-methylacrylamide;N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)acrylamide;N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)ethenesulfonamide; and N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-methylethenesulfonamide.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
8. The compound of claim 1 having the formula 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.
9. The compound of claim 1 having the formula N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidini-1-yl)cyclohexyl)acrylamide.
10. The compound of claim 1 having the formula 1-(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.
11. The compound of claim 1 having the formula 1-(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one.
12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 8 , and a pharmaceutically acceptable excipient.
13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 9 , and a pharmaceutically acceptable excipient.
14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 10 , and a pharmaceutically acceptable excipient.
15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 11 , and a pharmaceutically acceptable excipient.