Substituted phenylcarbamoyl alkylamino arene compounds and N,N′-BIS-arylurea compounds
View Patent ↗Substituted phenylcarbamoyl alkylamino arenes; substituted phenylthiocarbamyl alkylamino arenes; substituted phenylcarbamoyl alkylamino heteroarenes; substituted phenylthiocarbamyl alkylamino heteroarenes; N-substituted aryl, N′-substituted aryl urea compounds; N-substituted aryl, N′-substituted heteroaryl urea compounds; N-substituted aryl, N′-substituted aryl thiourea compounds and N-substituted aryl, N′-substituted heteroaryl thiourea compounds are provided and may find use as androgen receptor modulators. The compounds may find particular use in treating prostate cancer, including castration-resistant prostate cancer and/or hormone-sensitive prostate cancer.
1. A compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl;
Z is S, 0 or NR 5 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl or substituted cycloalkyl;
Y 3 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl, thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl;
T is carbon or nitrogen and can be at any position in the ring;
R 1 is C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d or —C(O)NR e R f , wherein:
R a is a C 1 -C 12 alkyl and R b is H or a C 1 -C 12 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R d is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is a C 1 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl, or R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halo, nitro, alkyl or substituted alkyl;
R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and
if R 1 and R 2 are both hydrogen, T is nitrogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein;
(a) R 1 is —C 1 -C 8 alkyl-NR a R b ;
(b) R 1 is —C 1 -C 8 alkyl-NR a R b and R 2 is halo; or
(c) R 1 is —C 1 -C 8 alkyl-NR a R b , R 2 is halo, and at least one of (i)-(v) applies:
(i) W 1 is CN;
(ii) W 2 is perhaloalkyl;
(iii) Z is S;
(iv) Y 1 and Y 2 are both methyl and
(v) T is C.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
(a) R 1 is —O—C 1 -C 8 alkyl-NR c R d ;
(b) R 1 is —O—C 1 -C 8 alkyl-NR c R d and R 2 is hydrogen; or
(c) R 1 is —O—C 1 -C 8 alkyl-NR c R d , R 2 is hydrogen, and at least one of (i)-(v) applies:
(i) W 1 is CN;
(ii) W 2 is perhaloalkyl;
(iii) Z is S;
(iv) Y 1 and Y 2 are both methyl and
(v) T is C.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
(a) R 1 is —C(O)NR e R f ;
(b) R 1 is —C(O)NR e R f and R 2 is halo; or
(c) R 1 is —C(O)NR e R f , R 2 is halo, and at least one of (i)-(v) applies:
(i) W 1 is CN;
(ii) W 2 is perhaloalkyl or hydrogen;
(iii) Z is S;
(iv) Y 1 and Y 2 are both methyl and
(v) T is C.
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)NR e R f , R 2 is halo, and at least one of (i)-(v) applies:
(i) W 1 is CN;
(ii) W 2 is perhaloalkyl or hydrogen;
(iii) Z is S;
(iv) Y 1 and Y 2 are both methyl and
(v) T is C,
R e is a C 1 -C 12 alkyl and R f is C 1 -C 12 alkyl.
6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)NR e R f , R 2 is halo, and at least one of (i)-(v) applies:
(i) W 1 is CN;
(ii) W 2 is perhaloalkyl or hydrogen;
(iii) Z is S;
(iv) Y 1 and Y 2 are both methyl and
(v) T is C,
wherein R e and R f are taken together with the N to which they are attached to form a heterocyclic ring.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein T is nitrogen.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein at least one of (i)-(iv) applies: (i) W 1 is CN; (ii) W 2 is perhaloalkyl; (iii) Z is S; (iv) R 1 and R 2 are both hydrogen.
9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein at least one of (i)-(iv) applies: (i) W 1 is CN; (ii) W 2 is perhaloalkyl; (iii) Z is S; (iv) R 1 is —C(O)NR e R f ; and (v) R 2 is hydrogen.
10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R e and R f are both hydrogen.
11. The compound of claim 1 , wherein Y 3 is selected from the group consisting of thiocarboxyl, carboxyl, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxy carbonyl.
12. The compound of claim 1 , which is
13. A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13 , wherein the compound of claim 1 is
15. A method of treating prostate cancer in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein the individual has castration-resistant prostate cancer.
17. The method of claim 15 , wherein the individual has hormone-sensitive prostate cancer.
18. The method of claim 15 , wherein the compound is