Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer
A compound, or a pharmaceutically acceptable salt or ester thereof, according to formula I: R 20 —(Z) b —(Y) c —(R 21 ) a —(X) d —R 22 —R 23 wherein R 20 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; Z is alkanediyl, substituted alkanediyl, cycloalkanediyl, or substituted cycloalkanediyl; Y is S, O, S(═O), —S(═O)(═O)—, or NR 10 , wherein R 10 is H or alkyl; R 21 is alkanediyl, substituted alkanediyl, cycloalkanediyl, substituted cycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl, substituted cycloalkenediyl, alkatrienyl, substituted alkatrienyl; X is —C(═O)—, —S(═O)(═O)—, or —N(H)C(═O)—; R 22 includes at least one divalent amino radical; R 23 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; a, b, c, and d independently are 0 or 1.
1. A compound, or a stereoisomer, pharmaceutically acceptable salt, or ester thereof, according to any one of formulas IV, XVI, or XVII:
wherein R 20 is phenyl substituted with C1-C3 perfluoroalkyl, halo, or pentafluorosulfanyl;
R 24 -R 27 independently are hydrogen, deuterium, or halo;
each R 31 independently is C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, halo, pentafluorosulfanyl, —C(O)Oalkyl, or C(O)N(H)alkyl; and
q is 2 or 3,
wherein if R 24 -R 27 are hydrogen, then R 20 is not halogen-substituted phenyl, and/or
wherein if R 24 -R 27 are hydrogen, then R 20 is not C 1 -C 3 perfluoroalkyl substituted phenyl.
2. The compound of claim 1 , wherein R 20 is phenyl substituted with —SF 5 , or —F.
3. The compound of claim 1 , wherein R 20 is substituted at the C3 or C4 position.
4. The compound of claim 1 , wherein each R 31 independently is C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, or halo.
5. The compound of claim 1 , wherein each R 31 independently is methyl, trifluoromethyl, or chloro.
6. The compound of claim 1 , wherein q is 2, and the R 31 substituents are para to one another.
7. A compound, wherein the compound is:
8. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive, and a compound of claim 1 .
9. A compound, wherein the compound is:
10. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive, and a compound of claim 9 .
11. A method for treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
12. The method of claim 11 , wherein:
the compound is orally administered; or
the method is used in combination with androgen deprivation therapy; or
the compound is co-administered with abiraterone or enzalutamide.
13. A method for treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 9 .
14. The method of claim 13 , wherein:
the compound is orally administered; or
the method is used in combination with androgen deprivation therapy; or
the compound is co-administered with abiraterone or enzalutamide.