(Thio, oxo, and seleno) semicarbazone derivatives and their use for treating cancer
The invention provides compounds of formula I and II and salts thereof, wherein R 1 , R 2 , Y, R 3 , and R 4 have any of the meanings described in the specification, as well as compositions comprising such compounds and salts, and methods for treating cancer using such compounds and salts.
1. A compound selected from compounds of formulas (I) and (II):
or a salt thereof, wherein:
R 1 is selected from the group consisting of:
wherein R 1 is optionally substituted with one or more groups independently selected from halo, cyano, —N(R a ) 2 , carboxy, phenyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, (C 4 -C 6 )heterocycloalkyl, (C 2 -C 6 )alkylaminocarbonyl and (C 2 -C 6 )alkanoylamino wherein any phenyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, and (C 3 -C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, —N(R a ) 2 , carboxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, (C 4 -C 6 )heterocycloalkyl, (C 2 -C 6 )alkylaminocarbonyl and (C 2 -C 6 )alkanoylamino;
R 2 is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, —N(R b ) 2 , (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkanoyloxy, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 ) alkylaminocarbonyl, and (C 2 -C 6 ) alkanoylamino;
provided that if R 1 is 2-pyridinyl, then R 2 is not H or (C 1 -C 6 )alkyl;
Y is S, O, Se;
R 3 is selected from H, (C 1 -C 6 )alkyl, piperidinyl, and piperazinyl, which piperidinyl or piperazinyl is optionally substituted with pyridyl;
R 4 is selected from (C 1 -C 6 )alkyl, piperidinyl, and piperazinyl, which piperidinyl or piperazinyl is optionally substituted with pyridyl; or R 3 and each R 4 taken together with the nitrogen to which they are attached form a 3, 4, 5, 6, 7, or 8 membered ring that is optionally substituted with one or more groups independently selected from the group consisting of halo;
each R a is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R a taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each R b is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R b taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each R c is independently selected from the group consisting of H and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy.
2. A compound selected from the group consisting of:
or a salt thereof.
3. A pharmaceutical composition, comprising, a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. An injectable pharmaceutical formulation comprising, a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. A method of inhibiting cancer cell growth in vivo or in vitro, comprising contacting a cancer cell with a compound of claim 1 or a pharmaceutically acceptable salt thereof.
6. A method of treating cancer in an animal comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to the animal.
7. The method of claim 6 , further comprising administering zinc to the animal.
8. The method of claim 6 , wherein the cancer is caused by mutations affecting zinc binding proteins.
9. The method of claim 6 , wherein the cancer is associated with a zinc binding p53 mutation.
10. The method of claim 6 , wherein the cancer is associated with a zinc binding p53 mutation selected from R175, C176, H179, C238, C242, and G245.
11. A pharmaceutical composition, comprising, a compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. An injectable pharmaceutical formulation comprising, a compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of inhibiting cancer cell growth in vivo or in vitro, comprising contacting a cancer cell with a compound of claim 2 or a pharmaceutically acceptable salt thereof.
14. A method of treating cancer in an animal comprising administering a compound of claim 2 or a pharmaceutically acceptable salt thereof to the animal.
15. The method of claim 14 , further comprising administering zinc to the animal.
16. The method of claim 14 , wherein the cancer is caused by mutations affecting zinc binding proteins.
17. The method of claim 14 , wherein the cancer is associated with a zinc binding p53 mutation.
18. The method of claim 14 , wherein the cancer is associated with a zinc binding p53 mutation selected from R175, C176, H179, C238, C242, and G245.
19. A compound selected from compounds of formulas (I) and (II):
or a salt thereof, wherein:
R 1 is selected from the group consisting of:
wherein R 1 is optionally substituted with one or more groups independently selected from halo, cyano, —N(R a ) 2 , carboxy, phenyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, (C 4 -C 6 )heterocycloalkyl, (C 2 -C 6 )alkylaminocarbonyl and (C 2 -C 6 )alkanoylamino wherein any phenyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, and (C 3 -C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, —N(R a ) 2 , carboxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, (C 4 -C 6 )heterocycloalkyl, (C 2 -C 6 )alkylaminocarbonyl and (C 2 -C 6 )alkanoylamino;
R 2 is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, —N(R b ) 2 , (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkanoyloxy, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 ) alkylaminocarbonyl, and (C 2 -C 6 ) alkanoylamino;
provided that if R 1 is 2-pyridinyl, then R 2 is not H or (C 1 -C 6 )alkyl;
Y is S, O, Se;
R 3 and R 4 are each independently selected from H, (C 1 -C 6 )alkyl, piperidinyl, or piperazinyl, which piperidinyl or piperazinyl is optionally substituted with pyridyl; or R 3 and each R 4 taken together with the nitrogen to which they are attached form a 3, 4, 5, 6, 7, or 8 membered ring that is optionally substituted with one or more groups independently selected from the group consisting of halo;
each R a is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R a taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each R b is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R b taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each R C is independently selected from the group consisting of H and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy.
20. A compound selected from compounds of formulas (I) and (II):
or a salt thereof, wherein:
R 1 is selected from the group consisting of:
wherein R 1 is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, —N(R a ) 2 , carboxy, phenyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, (C 4 -C 6 )heterocycloalkyl, (C 2 -C 6 )alkylaminocarbonyl and (C 2 -C 6 )alkanoylamino wherein any phenyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, and (C 3 -C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, —N(R a ) 2 , carboxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, (C 4 -C 6 )heterocycloalkyl, (C 2 -C 6 )alkylaminocarbonyl and (C 2 -C 6 )alkanoylamino;
R 2 is selected from the group consisting of H, phenyl, heteroaryl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl, wherein any phenyl, heteroaryl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl is optionally substituted with one or more groups independently selected from halo, —N(R b ) 2 , (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkanoyloxy, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 ) alkylaminocarbonyl, and (C 2 -C 6 ) alkanoylamino;
Y is S, O, Se;
R 3 and R 4 are each independently is selected from H, (C 1 -C 6 )alkyl, piperidinyl, and piperazinyl, which piperidinyl or piperazinyl is optionally substituted with pyridyl; or R 3 and each R 4 taken together with the nitrogen to which they are attached form a 3, 4, 5, 6, 7, 8, or 9 membered ring that is optionally substituted with one or more groups independently selected from the group consisting of halo;
each R a is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R b taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each R b is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R b taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each R c is independently selected from the group consisting of H and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy.
21. A pharmaceutical composition, comprising, a compound of claim 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. An injectable pharmaceutical formulation comprising, a compound of claim 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
23. A method of inhibiting cancer cell growth in vivo or in vitro, comprising contacting a cancer cell with a compound of claim 20 or a pharmaceutically acceptable salt thereof.
24. A method of treating cancer in an animal comprising administering a compound of claim 20 or a pharmaceutically acceptable salt thereof to the animal.
25. The method of claim 24 , further comprising administering zinc to the animal.
26. The method of claim 24 , wherein the cancer is caused by mutations affecting zinc binding proteins.
27. The method of claim 24 , wherein the cancer is associated with a zinc binding p53 mutation.
28. The method of claim 24 , wherein the cancer is associated with a zinc binding p53 mutation selected from R175, C176, H179, C238, C242, and G245.