Therapeutic compounds
The invention provides compounds of Formula (I) and (IV): as described herein, as well as salts thereof. The compounds have anti-cancer properties and/or chemosensitization properties.
1. A compound of formula (I):
wherein:
R 1 is (C 1 -C 6 )alkoxy or NR a R b ;
R 2 is cyano, (C 1 -C 6 )alkoxycarbonyl or —C(O)NR e R f ;
R 3 is halo, cyano, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxycarbonyl;
each of R 6 , R 7 and R 8 is independently hydrogen, halo, cyano, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxycarbonyl;
R c and R d are independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl or arylcarbonyl; or R c and R d taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
R e and R f are independently hydrogen or (C 1 -C 6 )alkyl; or R c and R d taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
R 4 and R 5 are each hydrogen; or R 4 is (C 1 -C 6 )alkyl and R 5 is cyano;
R a and R b are independently hydrogen or (C 1 -C 6 )alkyl; or R a and R b taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
wherein any aryl or heteroaryl of R 3 , R 6 , R 7 or R 8 is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, CF 3 , OCF 3 , OCHF 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, aryloxy, NR g R h , benzyloxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy; and
each R g and R h is independently hydrogen or (C 1 -C 6 )alkyl; or R g and R h taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
or a salt thereof.
2. A compound of formula (II):
wherein:
R 1 is (C 1 -C 6 )alkoxy or NR a R b ;
R 2 is cyano, or (C 1 -C 6 )alkoxycarbonyl;
R 3 is halo, (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, cyano, or (C 1 -C 6 )alkoxycarbonyl;
R 4 and R 5 are each hydrogen; or R 4 is (C 1 -C 6 )alkyl and R 5 is cyano; and
each R a and R b is independently hydrogen or (C 1 -C 6 )alkyl; or R a and R b taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
wherein any aryl of R 3 is optionally substituted with one or more groups independently selected from halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy;
or a salt thereof.
3. The compound of claim 1 wherein the compound of formula (I) is a compound of formula (III):
wherein:
R 1 is (C 1 -C 6 )alkoxy or NR a R b ;
R 2 is cyano, or (C 1 -C 6 )alkoxycarbonyl;
R 3 is halo, (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, cyano, or (C 1 -C 6 )alkoxycarbonyl;
R 4 and R 5 are each hydrogen; or R 4 is (C 1 -C 6 )alkyl and R 5 is cyano; and
each R a and R b is independently hydrogen or (C 1 -C 6 )alkyl; or R a and R b taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
wherein any aryl of R 3 is optionally substituted with one or more groups independently selected from halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy;
or a salt thereof.
4. The compound of claim 1 wherein R 1 is NR a R b .
5. The compound of claim 1 wherein R 1 is ethoxy or isopropoxy.
6. The compound of claim 1 wherein R 1 is piperidino.
7. The compound of claim 1 wherein R 1 is morpholino, piperazino or diethylamino.
8. The compound of claim 1 wherein R 2 is ethoxycarbonyl, isopropoxycarbonyl, or cyano.
9. The compound of claim 1 wherein R 3 is aryl, which is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, CF 3 , OCF 3 , OCHF 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, aryloxy, NR g R h , benzyloxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy.
10. The compound of claim 1 wherein R 3 is bromo, n-propyl, 4-t-butylphenyl, phenyl, 3,5-dimethoxyphenyl, 3,5-dihydroxyphenyl, 3-hydroxy-5-methoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 1,2,3-trimethoxyphenyl, indol-5-yl, benzoxazol-5-yl, benzofuran-5-yl, indazol-5-yl, 3,4-methylenedioxyphenyl, quinolin-5-yl, 4-methoxy-3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 3-benzyloxy-4-trifluoromethylphenyl, 4-(diethylamino)phenyl, 3,5-dichlorophenyl, 4-phenoxyphenyl, naphthyl, 4-acetylphenyl or 4-isopropyl-2-methoxyphenyl.
11. The compound of claim 1 wherein R 3 is phenyl, which is optionally substituted with one or more (C 1 -C 6 )alkyl groups.
12. The compound of claim 1 wherein R 3 is bromo, propyl, phenyl, 4-tert-butylphenyl, 3-methoxy,5-hydroxyphenyl, 3,5-dihydroxyphenyl, or 3,5-dimethoxyphenyl.
13. The compound of claim 1 wherein R 4 and R 5 are each hydrogen.
14. The compound of claim 1 wherein R 4 is (C 1 -C 6 )alkyl and R 5 is cyano.
15. The compound of claim 1 which is
or a salt thereof.
16. The compound of claim 1 which is
or a salt thereof.
17. The compound of claim 1 which is
or a salt thereof.
18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 1 , and a pharmaceutically acceptable diluent or carrier.
19. A therapeutic method for treating cancer in a mammal wherein the activity of Bcl-2 protein is implicated and antagonism of its action is desired comprising administering a compound of formula (I):
wherein:
R 1 is (C 1 -C 6 )alkoxy or NR a R b ;
R 1 is cyano, (C 1 -C 6 )alkoxycarbonyl or —C(O)NR e R f ;
each of R 3 , R 6 , R 7 and R 8 is independently hydrogen, halo, cyano, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxycarbonyl;
R c and R d are independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl or arylcarbonyl; or
R c and R d taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
R e and R f are independently hydrogen or (C 1 -C 6 )alkyl; or R c and R d taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
R 4 and R 5 are each hydrogen; or R 4 is (C 1 -C 6 )alkyl and R 5 is cyano;
R a and R b , are independently hydrogen or (C 1 -C 6 )alkyl; or R a and R b taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
wherein any aryl or heteroaryl of R 3 , R 6 , R 7 or R 8 is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, CF 3 , OCF 3 , OCHF 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, aryloxy, NR g R h , benzyloxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy; and
each R g and R h is independently hydrogen or (C 1 -C 6 )alkyl; or R g and R h taken together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, or morpholino ring;
or a pharmaceutically acceptable salt thereof to the mammal.
20. The compound of claim 2 which is
or a salt thereof.
21. The method of claim 19 wherein the cancer is acute lymphoblastic leukemia, an acute myelogenous leukemia, a chronic lyphocytic leukemia, breast cancer, colon cancer, liver cancer, lung cancer, pancreatic cancer, or prostate cancer.