Inhibitors of Bruton's tyrosine kinase for the treatment of solid tumors
View Patent ↗Described herein are irreversible Btk inhibitor compounds, and methods for using such irreversible inhibitors in the treatment of diseases and disorders characterized by the presence or development of solid tumors.
1. A method for treating HER2 amplified breast cancer in an individual in need thereof comprising administering to the individual in need thereof a composition comprising a therapeutically-effective amount of a compound of Formula (C1) having the structure:
or a pharmaceutically acceptable salt thereof,
wherein:
Y is selected from alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, and alkylheterocycloalkyl;
R 12 is H or lower alkyl; or
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
G is
wherein R a is H, alkyl, or cycloalkyl; and either
(i) R 7 and R 8 are H; and
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
(ii) R 6 and R 8 are H; and
R 7 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
(iii) R 7 and R 8 taken together form a bond; and
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
2. The method of claim 1 , wherein:
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring.
3. The method of claim 2 , wherein
R 6 and R 8 are H; and
R 7 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
4. The method of claim 3 , wherein:
Y and R 12 taken together form a 6-membered heterocyclic ring.
5. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , further comprising administering an additional therapeutic agent selected from: trastuzumab, paclitaxel, doxorubicin, cyclophosphamide, and cisplatin.
7. The method of claim 1 , further comprising administering trastuzumab.
8. A method for treating HER2 amplified cancer in an individual in need thereof, wherein the HER2 amplified cancer is selected from pancreatic cancer and non-small-cell lung carcinoma, the method comprising administering to the individual in need thereof a composition comprising a therapeutically-effective amount of a compound of Formula (C1) having the structure:
or a pharmaceutically acceptable salt thereof,
wherein:
Y is selected from alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, and alkylheterocycloalkyl;
R 12 is H or lower alkyl; or
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
G is
wherein R a is H, alkyl, or cycloalkyl; and either
(i) R 7 and R 8 are H; and
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
(ii) R 6 and R 8 are H; and
R 7 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
(iii) R 7 and R 8 taken together form a bond; and
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
9. The method of claim 8 , wherein:
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring.
10. The method of claim 9 , wherein
R 6 and R 8 are H; and
R 7 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
11. The method of claim 9 , wherein:
Y and R 12 taken together form a 6-membered heterocyclic ring;
R 6 and R 8 are H; and
R 7 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
12. The method of claim 8 , wherein the compound is
13. The method of claim 8 , further comprising administering an additional therapeutic agent selected from: trastuzumab, paclitaxel, doxorubicin, cyclophosphamide, and cisplatin.
14. The method of claim 8 , further comprising administering trastuzumab.
15. The method of claim 2 , wherein
R 7 and R 8 taken together form a bond; and
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
16. The method of claim 9 , wherein
R 7 and R 8 taken together form a bond; and
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkylC 3 -C 6 cycloalkyl, aryl, C 2 -C 8 heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).
17. The method of claim 8 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein Y is alkyl; or Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring.
19. The method of claim 8 , wherein Y is alkyl; or Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring.
20. The method of claim 18 , wherein
G is
wherein R a is H or alkyl.
21. The method of claim 19 , wherein
G is
wherein R a is H or alkyl.
22. The method of claim 12 , further comprising administering an additional therapeutic agent comprising paclitaxel or gemcitabine, or a combination thereof.