Tetra-aryl cyclobutane inhibitors of androgen receptor action for the treatment of hormone refractory cancer

Patent metadata

Field	Value
Publication number	US-9868705-B2
Application number	US-201415023159-A
Country	US
Kind code	B2
Filing date	Sep 25, 2014
Priority date	Sep 27, 2013
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

The present disclosure provides tetra-substituted cyclobutane inhibitors of Androgen Receptor Action, and methods of using such inhibitors, for the treatment of hormone-refractory cancers.

First claim

The invention claimed is:

1. A compound having the formula:

wherein each ring system,

is

each R 1 and R 2 is independently selected from (a) F, (b) Cl, (c) Br, (d) I, (e) —C 1 -C 8 alkyl, (f) —C 2 -C 8 alkenyl, (g) —C 2 -C 8 alkynyl, (h) —C 3 -C 8 cycloalkyl, (i) —C 3 -C 8 cycloalkenyl, (j) —C 8 cycloalkynyl, (k) phenyl, (l) a 7 to 10-membered saturated, unsaturated, or aromatic fused bicyclic carbocyle, (m) a 3 to 10-membered saturated, unsaturated, or aromatic heterocycle or fused bicyclic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, (n) —OR 3 , (o) —NR 3 R 3 , (p) —CN, (q) —N 3 , (r) —SR 3 , (s) —SOR 3 , (t) —SO 2 R 3 , (u) —COOR 3 , (v) —COR 3 , (w) —CONR 3 R 3 , (x) —NR 3 COR 3 —, (y) —NR 3 CONR 3 R 3 , (z) (C 1 -C 8 alkyl)OR 3 , (aa) —(C 1 -C 8 alkyl)NR 3 R 3 , (bb) —(C 1 -C 8 alkyl)SR 3 , (cc) —(C 1 -C 8 alkyl)SOR 3 , (dd) —(C 1 -C 8 alkyl)SO 2 R 3 , (ee) —(C 1 -C 8 alkyl)COOR 3 , (ff) —(C 1 -C 8 alkyl)COR 3 , (gg) —(C 1 -C 8 alkyl)CONR 3 R 3 , (hh) —(C 1 -C 8 alkyl)NR 3 COR 3 , and (ii) —(C 1 -C 8 alkyl)NR 3 CONR 3 R 3 ,
wherein each of (e) through (j) immediately recited above is optionally substituted with one or more F, Cl, Br, I, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), or —N(C 1 -C 8 alkyl) 2 and
wherein each of (k) through (l) immediately recited above is optionally substituted with one or more R 4 or R 5 ;
each R 3 is independently selected from (a) H, (b) —C 1 -C 8 alkyl, (c) —C 2 -C 8 alkenyl, (d) —C 2 -C 8 alkynyl, (e) —C 3 -C 8 cycloalkyl, (f) —C 3 -C 8 cycloalkenyl, (g) —C 8 cycloalkynyl, (h) phenyl, (i) naphthyl, (j) —C 1 -C 8 alkyl(phenyl), and (k) —C 1 -C 8 alkyl(naphthyl), wherein each of (b) through (k) immediately recited above is optionally substituted with one or more R 5 ;
each R 4 is independently selected from (a) F, (b) Cl, (c) Br, (d) I, (e) —C 1 -C 8 alkyl, (f) —C 2 -C 8 alkenyl, (g) —C 2 -C 8 alkynyl, (h) —C 3 -C 8 cycloalkyl, (i) —C 3 -C 8 cycloalkenyl, and (j) —C 8 cycloalkynyl, wherein each of (e) through (j) immediately recited above is optionally substituted with one or more R 5 ;
each R 5 is independently selected from (a) F, (b) Cl, (c) Br, (d) I, (e) —OH, (f) —NH 2 , (g) —CN, (h) —SH, (i) —COOH, (j) —CHO, (k) —CONH 2 , (l) —O(—C 1 -C 8 alkyl), (m) —NH(—C 1 -C 8 alkyl), (n) —N(—C 1 -C 8 alkyl) 2 , (o) —S(—C 1 -C 8 alkyl), (p) —COO(—C 1 -C 8 alkyl), (q) —CO(—C 1 -C 8 alkyl), (r) —CONH(—C 1 -C 8 alkyl), and (s) —CON(—C 1 -C 8 alkyl) 2 ,
each Ar is independently selected from (a) phenyl, (b) naphthyl, (c) a 5 or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, and (d) a 7 to 10-membered heteroaromatic ring or fused bicyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof,
wherein each of (a) through (d) immediately recited above is optionally substituted with one or more (a) F, (b) Cl, (c) Br, (d) I, (e) —C 1 -C 8 alkyl, (f) —C 2 -C 8 alkenyl, (g) —C 2 -C 8 alkynyl, (h) —C 3 -C 8 cycloalkyl, (i) —C 3 -C 8 cycloalkenyl, (j) —C 8 cycloalkynyl, (k) phenyl, (l) —OR 6 , (m) —NR 6 R 6 , (n) —CN, (o) —N 3 , -(p) —SR 6 , (q) —SOR E , (r) —SO 2 R 6 , (s) —COOR 6 , (t) —COR 6 , (u) —CONR 6 R 6 , (v) NR 6 COR 6 —, and (w) —NR 6 CONR 6 R 6 ,
wherein each of (e) through (k) immediately recited above is optionally substituted with one or more F, Cl, Br, I, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), and —N(C 1 -C 8 alkyl) 2 ;
each R 6 is independently selected from (a) H, (b) —C 1 -C 8 alkyl, (c) —C 2 -C 8 alkenyl, (d) —C 2 -C 8 alkynyl, (e) —C 3 -C 8 cycloalkyl, (f) —C 3 -C 8 cycloalkenyl, (g) —C 8 cycloalkynyl, (h) phenyl, (i) naphthyl, (j) —C 1 -C 8 alkyl(phenyl), and (k) —C 1 -C 8 alkyl(naphthyl), wherein each of (b) through (i) immediately recited above is optionally substituted with one or more R 7 ; and
each R 7 is independently selected from one or more (a) F, (b) Cl, (c) Br, (d) I, (e) —OH, (f) —NH 2 , (g) —CN, (h) —SH, (i) —COOH, (j) —CHO, (k) —CONH 2 , (l) —O(—C 1 -C 8 alkyl), (m) —NH(—C 1 -C 8 alkyl), (n) —N(—C 1 -C 8 alkyl) 2 , (o) —S(—C 1 -C 8 alkyl), (p) —COO(—C 1 -C 8 alkyl), (q) —CO(—C 1 -C 8 alkyl), (r) —CONH(—C 1 -C 8 alkyl), and (s) —CON(—C 1 -C 8 alkyl) 2 ;
or an enantiomer, diastereomer, or tautomer of said compound, or a pharmaceutically acceptable, salt of said compound, of said enantiomer of said compound, of said diastereomer of said compound, or of said tautomer of said compound.

2. A compound having the formula:

wherein
each R 1 and R 2 is independently selected from (a) F, (b) Cl, (c) Br, (d) I, (e) —C 1 -C 8 alkyl, (f) —C 2 -C 8 alkenyl, (g) —C 2 -C 8 alkynyl, (h) —C 3 -C 8 cycloalkyl, (i) —C 3 -C 8 cycloalkenyl, (j) —C 8 cycloalkynyl, (k) phenyl, (l) a 7 to 10-membered saturated, unsaturated, or aromatic fused bicyclic carbocyle, (m) a 3 to 10-membered saturated, unsaturated, or aromatic heterocycle or fused bicyclic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, (n) —OR 3 , (o) —NR 3 R 3 , (p) —CN, (q) —N 3 , (r) —SR 3 , (s) —SOR 3 , (t) —SO 2 R 3 , (u) —COOR 3 , (v) —COR 3 , (w) —CONR 3 R 3 , (x) —NR 3 COR 3 —, (y) —NR 3 CONR 3 R 3 , (z) —(C 1 -C 8 alkyl)OR 3 , (aa) —(C 1 -C 8 alkyl)NR 3 R 3 , (bb) —(C 1 -C 8 alkyl)SR 3 , (cc) —(C 1 -C 8 alkyl)SOR 3 , (dd) —(C 1 -C 8 alkyl)SO 2 R 3 , (ee) —(C 1 -C 8 alkyl)COOR 3 , (ff) —(C 1 -C 8 alkyl)COR 3 , (gg) —(C 1 -C 8 alkyl)CONR 3 R 3 , (hh) —(C 1 -C 8 alkyl)NR 3 COR 3 , and (ii) —(C 1 -C 8 alkyl)NR 3 CONR 3 R 3 ,
wherein each of (e) through (j) immediately recited above is optionally substituted with one or more F, Cl, Br, I, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), or —N(C 1 -C 8 alkyl) 2 and
wherein each of (k) through (l) immediately recited above is optionally substituted with one or more R 4 or R 5 ;
each R 3 is independently selected from (a) H, (b) —C 1 -C 8 alkyl, (c) —C 2 -C 8 alkenyl, (d) —C 2 -C 8 alkynyl, (e) —C 3 -C 8 cycloalkyl, (f) —C 3 -C 8 cycloalkenyl, (g) —C 8 cycloalkynyl, (h) phenyl, (i) naphthyl, (j) —C 1 -C 8 alkyl(phenyl), and (k) —C 1 -C 8 alkyl(naphthyl), wherein each of (b) through (k) immediately recited above is optionally substituted with one or more R 5 ;
each R 4 is independently selected from (a) F, (b) Cl, (c) Br, (d) I, (e) —C 1 -C 8 alkyl, (f) —C 2 -C 8 alkenyl, (g) —C 2 -C 8 alkynyl, (h) —C 3 -C 8 cycloalkyl, (i) —C 3 -C 8 cycloalkenyl, and (j) —C 8 cycloalkynyl, wherein each of (e) through (j) immediately recited above is optionally substituted with one or more R 5 ;
each R 5 is independently selected from (a) F, (b) Cl, (c) Br, (d) I, (e) —OH, (f) —NH 2 , (g) —CN, (h) —SH, (i) —COOH, (j) —CHO, (k) —CONH 2 , (l) —O(—C 1 -C 8 alkyl), (m) —NH(—C 1 -C 8 alkyl), (n) —N(—C 1 -C 8 alkyl) 2 , (o) —S(—C 1 -C 8 alkyl), (p) —COO(—C 1 -C 8 alkyl), (q) —CO(—C 1 -C 8 alkyl), (r) —CONH(—C 1 -C 8 alkyl), and (s) —CON(—C 1 -C 8 alkyl) 2 ,
each Ar is independently selected from (a) phenyl, (b) naphthyl, (c) a 5 or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, and (d) a 7 to 10-membered heteroaromatic ri

Assignees

• Univ Illinois
• Univ Duke

Inventors

• Katzenellenbogen John
• Mcdonnell Donald
• Norris John D
• Parent Alexander
• Pollock Julie
• Gunther Jillian
• Carlson Kathryn E
• Martin Teresa

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• F23K1/04

  Heating fuel prior to delivery to combustion apparatus · CPC title

• F23B99/00

  Subject matter not provided for in other groups of this subclass · CPC title

• C07D409/08

  linked by a carbon chain containing alicyclic rings · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title