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, selected from:
a compound according to formula III
where the bond represented by “-----” is a single or double bond,
R 20 is (a) phenyl substituted with C 1 -C 3 perfluoroalkyl, halo, or pentafluorosulfanyl,
(b) thiophenyl substituted with C 1 -C 3 alkyl, or (c) cycloalkyl substituted with C 1 -C 3 perfluoroalkyl,
R 23 is (a) phenyl mono- or di-substituted with substituents selected from halo, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, pentafluorosulfanyl, cyano, —C(O)Oalkyl, or —C(O)N(H)alkyl, (b) cycloalkyl, or
(c) heterocycloalkyl,
R 24 and R 25 are absent if the bond represented by “-----” is a double bond, or R 24 and R 25 independently are hydrogen, deuterium, C 1 -C 3 perhaloalkyl, halo, or cyano, or R 24 and R 25 together form —CH 2 —, and
R 26 and R 27 independently are hydrogen, deuterium, or halo,
wherein if R 24 -R 27 are hydrogen, then R 20 is not halo-substituted phenyl, and
if R 24 -R 27 are hydrogen and R 23 is phenyl mono- or di-substituted with substituents selected from halo, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, pentafluorosulfanyl, cyano, —C(O)Oalkyl, or —C(O)N(H)alkyl, then R 20 is (a) pentafluorosulfanyl-substituted phenyl, (b) thiophenyl substituted with C 1 -C 3 alkyl, or (c) cycloalkyl substituted with C 1 -C 3 perfluoroalkyl.
2. The compound of claim 1 , wherein R 20 is:
phenyl substituted with —SF 5 or —F; or
thiophenyl substituted with —CH 3 ; or
cyclohexyl substituted with —CF 3 .
3. The compound of claim 2 , wherein R 20 is phenyl or cyclohexyl and is substituted at the C4 position.
4. The compound of claim 1 , wherein R 23 is:
phenyl substituted with —CF 3 ; or
phenyl disubstituted with two halo substituents, halo and —CF 3 , halo and —CH 3 , or halo and cyano; or
cyclohexyl; or
heterocyclohexyl.
5. The compound of claim 4 , wherein R 23 is disubstituted phenyl and the two substituents are para to one another.
6. The compound of claim 1 , wherein at least one of R 24 -R 27 is other than hydrogen.
7. The compound of claim 1 , wherein the compound is:
8. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive, and a compound of claim 1 .
9. A method for treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
10. The method of claim 9 , 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.
11. A compound, or a stereoisomer, pharmaceutically acceptable salt, or ester thereof, wherein the compound is:
where each R independently is C 1 -C 3 perfluoroalkyl, halo, pentafluorosulfanyl, —C(O)Oalkyl, or C(O)N(H)alkyl; and R 28 is O, N(CH 3 ), or CH 2 .
12. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive, and a compound of claim 11 .
13. A method for treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 11 .
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.
15. The compound of claim 1 , wherein R 23 is phenyl disubstituted with halo and —CF 3 , and the two substituents are para to one another.
16. The compound of claim 1 , wherein R 20 is phenyl substituted at the C3 position.