Androgen receptor modulators and methods for their use

Patent metadata

Field	Value
Publication number	US-11059795-B2
Application number	US-202016852810-A
Country	US
Kind code	B2
Filing date	Apr 20, 2020
Priority date	Oct 18, 2018
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The present invention relates to compounds of formula (I)-(VI) and/or (A)-(H-I), or any subgenera thereof, or a pharmaceutically acceptable salt, tautomer or stereoisomer. The compounds of the present disclosure are useful in modulating androgen receptor activity and for treating cancer including prostate cancer.

First claim

What is claimed is:

1. A compound having the structure of formula (A-I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
C is a 5- to 7-membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member;
X is a bond, —(CR 5 R 6 ) t —, or —NR 7 ;
Y is a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—;
Z is a bond, —CH 2 —, —O—, or —NH—;
W is a bond, —CH 2 —, —C(CH 3 )H—, —C(═O)—, —N(R 7 )CO—, or —CONR 7 —;
V is —CH 2 — and L is halogen, —NH 2 , or —CF 3 ; or
V is —CH 2 CH 2 — and L is halogen or —NH 2 ;
R 1 and R 2 are each independently hydrogen, halogen, —CN, —CF 3 , methyl, or —CONH 2 ;
R 3 is selected from —CN, C 1 -C 3 alkoxy, —CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, —S(C 1 -C 3 alkyl), —SO 2 (C 1 -C 3 alkyl), —NH 2 , —(C 1 -C 3 alkyl)NH 2 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , —CH 2 NHSO 2 CH 3 , —CH 2 N(CH 3 )SO 2 CH 3 , —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), —N(CH 3 )COO(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), or —N(CH 3 )COO(C 1 -C 3 alkyl);
R 5 and R 6 are each independently hydrogen, halogen, —OH, or C 1 -C 3 alkyl;
R 7 is H or C 1 -C 6 alkyl;
n1 and n2 are each independently 0, 1, or 2;
n3 is 1, 2, 3, 4 or 5; and
t is 0, 1 or 2.

2. The compound of claim 1 , wherein C, which is substituted with (R 3 )n3, is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl.

3. The compound of claim 2 , wherein C, which is substituted with (R 3 )n3, is selected from

wherein R 3a is C 1 -C 3 alkyl.

4. The compound of claim 1 , wherein:
X is —(CR 5 R 6 ) t —;
Y and Z are each —O—;
V is —CH 2 — or —CH 2 CH 2 —; and
L is halogen.

5. The compound of claim 4 , wherein:
R 5 and R 6 are each independently hydrogen, or C 1 -C 3 alkyl;
W is —CH 2 — or —C(CH 3 )H—;
V is —CH 2 CH 2 —; and
R 1 and R 2 are each independently hydrogen, halogen, or —CN.

6. The compound of claim 1 , wherein:
at least one R 3 is selected from —CN, C 1 -C 3 alkoxy, —CONH 2 , —NHSO 2 CH 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , or —SO 2 CH 3 and the other R 3 , if present, is selected from —CN, —CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —S(C 1 -C 3 alkyl), —SO 2 (C 1 - C 3 alkyl), —NH 2 , —(C 1 -C 3 alkyl)NH 2 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , —N(CH 3 )SO 2 CH 3 , SO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , —CH 2 NHSO 2 CH 3 , —CH 2 N(CH 3 )SO 2 CH 3 , —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), —N(CH 3 )COO(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), or —N(CH 3 )COO(C 1 -C 3 alkyl).

7. The compound of claim 1 , wherein:
X is a bond or —(CR 5 R 6 ) t ;
W is a bond, —CH 2 —, or —C(CH 3 )H—;
Y is —O—;
Z is —O—;
V is —CH 2 — or —CH 2 CH 2 —; and
L is halogen.

8. The compound of claim 1 , wherein the compound has the structure of formula (G-II)

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
C is

X is —(CR 5 R 6 ) t —;
Y is —O—;
Z is —O—;
W is —CH 2 — or —C(CH 3 )H—;
V is —CH 2 CH 2 —;
L is halogen;
R 1 and R 2 are each independently Cl or —CN;
at least one R 3 is selected from —CN, C 1 -C 3 alkoxy, —CONH 2 , —NHSO 2 CH 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , or —SO 2 CH 3 and the other R 3 , if present, is selected from —CN, —CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —S(C 1 -C 3 alkyl), —SO 2 (C 1 -C 3 alkyl), —NH 2 , —(C 1 -C 3 alkyl)NH 2 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , —CH 2 NHSO 2 CH 3 , —CH 2 N(CH 3 )SO 2 CH 3 , —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), —N(CH 3 )COO(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), or —N(CH 3 )COO(C 1 -C 3 alkyl);
R 5 and R 6 are each independently hydrogen or methyl;
n1 and n2 are each independently 0, 1, or 2;
n3 is 1 or 2; and
t is 1.

9. The compound of claim 8 , wherein:
at least one R 3 is selected from —NHSO 2 CH 3 , —NHSO 2 CH 2 CH 3 , or —SO 2 CH 3 and the other R 3 , if present, is selected from —CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 (C 1 -C 3 alkyl), —NH 2 , —(C 1 -C 3 alkyl)NH 2 , —NHSO 2 CH 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), —N(CH 3 )COO(C 1 -C 3 alkyl), —NHCO(C 1 -C 3 alkyl), or —N(CH 3 )COO(C 1 -C 3 alkyl).

10. A compound selected from the group consisting of:

Assignees

• Essa Pharma Inc
• Univ British Columbia
• Provincial Health Services Authority

Inventors

• Zhou Han-Jie
• Virsik Peter
• Andersen Raymond John
• Sadar Marianne Dorothy

Classifications

• A61P13/08

  of the prostate · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D333/34

  Sulfur atoms · CPC title

• C07D307/64

  Sulfur atoms · CPC title