US2020123117A1PendingUtilityA1
Androgen receptor modulators and methods for their use
Est. expiryOct 18, 2038(~12.3 yrs left)· nominal 20-yr term from priority
C07D 233/74C07D 263/48C07D 277/56C07D 231/38C07D 263/38C07D 233/84C07D 307/64C07D 271/113C07D 239/42C07D 241/20A61P 35/00C07D 261/08C07D 277/36C07D 277/42C07D 263/46A61P 13/08C07D 333/34C07D 239/38C07D 239/70C07D 239/28C07D 213/76C07D 207/36C07D 263/32C07D 471/04C07D 491/052C07D 307/66C07D 207/34C07D 271/07C07D 237/20C07D 413/12C07D 233/64C07D 233/88C07D 231/18C07D 231/40C07D 263/34C07D 263/40C07D 261/12C07D 261/14C07D 261/10C07D 233/80A61K 31/42A61K 31/4245A61K 31/421A61K 31/4164C07D 233/76
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of formula (IIIA):
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
A and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
C is a 3- to 10-membered ring;
X is a bond, —(CR 5 R 6 ) t —, or —NR 7 ;
Y is a bond, —(CR 8 R 9 ) m —, —O—, —S—, —S(═O)—, —SO 2 —, —NR 7 —, or —N(COCH 3 )—;
W is a bond, —(CR 8a R 9a ) m —, —C(═O)—, —N(R 7 )CO—, —CONR 7 —, or —NSO 2 R 7 —;
Z is a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—;
V is —CH 2 — and L is halogen, —NH 2 , —CHCl 2 , —CCl 3 , 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 , —OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted —(C 1 -C 6 alkyl)-(C 1 -C 6 alkoxy), optionally substituted —(C 1 -C 6 alkyl)-OH, —NR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , optionally substituted —(C 1 -C 6 alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , optionally substituted —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl)-SO 2 NR 14 R 15 , optionally substituted —SO 2 R 16 or optionally substituted —(C 1 -C 6 alkyl)-SO 2 R 16 ;
R 3 is selected from halogen, oxo, ═S, ═NR 16 , —CN, —CF 3 , —OH, —S(C 1 -C 3 alkyl), C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —NR 13 R 14 , —(C 1 -C 3 alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , —(C 1 -C 3 alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , —(C 1 -C 3 alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , —(C 1 -C 3 alkyl)-SO 2 NR 14 R 15 , —SO 2 (C 1 -C 3 alkyl), or —(C 1 -C 6 alkyl)-SO 2 (C 1 -C 3 alkyl);
R 5 and R 6 are each independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or C 1 -C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
R 7 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 8 and R 9 are each independently hydrogen, halogen, or C 1 -C 3 alkyl;
R 8a and R 9a are each independently hydrogen, —OH, halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —NR 13 R 14 , —(C 1 -C 3 alkyl)-NR 13 R 14 , —NR 14 COR 16 , —(C 1 -C 3 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , or —(C 1 -C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
R 13 , R 14 and R 15 are each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
R 16 is hydrogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl, optionally substituted C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl, or phenyl;
each m is independently 0, 1, or 2;
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 the compound has the structure of formula (IVA):
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
A and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
C is a 3- to 10-membered ring;
X is a bond, —(CR 5 R 6 ) t —, or —NR 7 ;
Y and Z are each independently a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—;
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 , —OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted —(C 1 -C 6 alkyl)-(C 1 -C 6 alkoxy), optionally substituted —(C 1 -C 6 alkyl)-OH, —NR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , optionally substituted —(C 1 -C 6 alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , optionally substituted —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl)-SO 2 NR 14 R 15 , optionally substituted —SO 2 R 16 , optionally substituted —(C 1 -C 6 alkyl)-SO 2 R 16 ;
R 3 is selected from halogen, oxo, ═S, ═NR 16 , —CN, —CF 3 , —OH, —S(C 1 -C 3 alkyl), C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —NR 13 R 14 , —(C 1 -C 3 alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , —(C 1 -C 3 alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , —(C 1 -C 3 alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , —(C 1 -C 3 alkyl)-SO 2 NR 14 R 15 , —SO 2 (C 1 -C 3 alkyl), or —(C 1 -C 6 alkyl)-SO 2 (C 1 -C 3 alkyl);
R 5 and R 6 are each independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or C 1 -C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
R 7 is H or C 1 -C 6 alkyl;
R 13 , R 14 and R 15 are each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
R 16 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl;
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.
3 . The compound of claim 2 , wherein C is 5- to 10-membered heteroaryl or aryl.
4 . The compound of claim 3 , wherein C is 5- to 7-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member.
5 . The compound of claim 4 , wherein C, which is substituted with (R 3 )n3, is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl.
6 . The compound of claim 5 , wherein C, which is substituted with (R 3 )n3, is selected from
wherein R 3a is C 1 -C 3 alkyl.
7 . The compound of claim 6 , wherein R 1 and R 2 are each independently C 1 , —CN, —CF 3 , —OH, methyl, methoxy, or —CONH 2 .
8 . The compound of claim 2 , wherein:
A and B are phenyl; X is —(CR 5 R 6 ) t —; Y and Z are each —O—; V is —CH 2 — or —CH 2 CH 2 —; L is halogen; R 1 and R 2 are each independently hydrogen, halogen, —CN, —CF 3 , —OH, or optionally substituted C 1 -C 6 alkyl; R 5 and R 6 are each independently hydrogen, halogen, —OH, or C 1 -C 3 alkyl; and R 16 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl.
9 . The compound of claim 8 , 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.
10 . The compound of claim 1 , wherein the compound has the structure of formula (A-I)
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug 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.
11 . The compound of claim 10 , 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 , —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).
12 . The compound of claim 10 , 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.
13 . The compound of claim 1 , wherein the compound has the structure of formula (G-II)
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug 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.
14 . The compound of claim 13 , 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).
15 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
16 . The compound of claim 15 , wherein the compound is selected from
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
17 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
18 . A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.
19 . A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.
20 . A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.
21 . A pharmaceutical composition comprising a compound of claim 15 and a pharmaceutically acceptable carrier.
22 . A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier.
23 . A method for treating cancer, comprising administering the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug of the compound of claim 1 , to a subject in need thereof.
24 . The method of claim 23 , wherein the cancer is prostate cancer.
25 . The method of claim 24 , wherein the prostate cancer is metastatic castration-resistant prostate cancer.
26 . The method of claim 25 , wherein the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.
27 . The method of claim 24 , wherein the compound is selected from
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.Cited by (0)
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