IP Library › Granted Patent US 9,868,705

Granted Patent B2

US 9,868,705 · App. 15/023,159 · Granted Jan 16, 2018

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

Inventors: John Katzenellenbogen (Urbana, IL); Donald McDonnell (Chapel Hill, NC); John D. Norris (Raleigh, NC); Alexander Parent (Medford, MA); Julie Pollock (Henrick, VA); Jillian Gunther (Houston, TX); Kathryn E. Carlson (Champaign, IL); Teresa Martin (Champaign, IL)

Assignees: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; DUKE UNIVERSITY

C07D239/48 C07D213/24 C07D213/74 C07D239/26 C07D239/30 C07D239/34 C07D239/47 C07D239/52 C07D239/54 C07D239/58 C07D241/12 C07D241/16 C07D241/18 C07D401/14 C07D403/08 C07D403/14 C07D407/08 C07D409/14 F01K5/02 F23G5/04 F23K1/04 F23K3/00 F23K2201/20 F23K2203/103

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,868,705
App. No.: 15/023,159
Granted: Jan 16, 2018
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (158)

1. A compound having the formula:

wherein each ring system,

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 ;

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 6 , (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 ;

3. 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 , (ft) —(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 ;

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 6 , (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 ;

4. 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 ;

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 6 , (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 ;

5. 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 ;

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 6 , (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 ;

6. A compound according to claim 1 wherein

each of R 1 and R 2 are independently selected from (a) F, (b) Cl, (c) —C 1 -C 8 alkyl, (d) —C 3 -C 8 cycloalkyl, (e) phenyl, (f) a 7 to 10-membered saturated, unsaturated, or aromatic fused bicyclic carbocyle, (g) 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, (h) —OR 3 , (i) —NR 3 R 3 , (j) —CN, (k) —SR 3 , (l) —SOR 3 , (m) —SO 2 R 3 , (n) —COOR 3 , (o) —COR 3 , (p) —CONR 3 R 3 , (q) —NR 3 COR 3 —, (r) —NR 3 CONR 3 R 3 , (s) —(C 1 -C 8 alkyl)OR 3 , (t) —(C 1 -C 8 alkyl)NR 3 R 3 , (u) —(C 1 -C 8 alkyl)SR 3 , (v) —(C 1 -C 8 alkyl)SOR 3 , (w) —(C 1 -C 8 alkyl)SO 2 R 3 , (x) —(C 1 -C 8 alkyl)COOR 3 , (y) —(C 1 -C 8 alkyl)COR 3 , (z) —(C 1 -C 8 alkyl)CONR 3 R 3 , (aa) —(C 1 -C 8 alkyl)NR 3 COR 3 , and (bb) —(C 1 -C 8 alkyl)NR 3 CONR 3 R 3 ,

wherein each of (c) or (d) immediately recited above is optionally substituted with one or more F, Cl, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), or —N(C 1 -C 8 alkyl) 2 and

wherein each of (e) through (g) immediately recited above is optionally substituted with one more R 4 or R 5 ;

each R 3 is independently selected from (a) H, (b) —C 1 -C 8 alkyl, (c) —C 3 -C 8 cycloalkyl, (d) phenyl, (e) naphthyl, (f) —C 1 -C 8 alkyl(phenyl), and (g) —C 1 -C 8 alkyl(naphthyl), wherein each of (b) through (g) immediately recited above is optionally substituted with one or more R 5 ;

each R 4 is independently selected from one or more (a) F, (b) Cl, (c) —C 1 -C 8 alkyl, and (d) —C 3 -C 8 cycloalkyl, wherein each of (c) or (d) immediately recited above is optionally substituted with one or more R 5 ;

each R 5 is independently selected from one or more (a) F, (b) Cl, (c) —OH, (d) —NH 2 , (e) —CN, (f) —SH, (g) —COOH, (h) —CHO, (i) —CONH 2 , (j) —O(—C 1 -C 8 alkyl), (k) —NH(—C 1 -C 8 alkyl), (l) —N(—C 1 -C 8 alkyl) 2 , (m) —S(—C 1 -C 8 alkyl), (n) —COO(—C 1 -C 8 alkyl), (o) —CO(—C 1 -C 8 alkyl), (p) —CONH(—C 1 -C 8 alkyl), and (q) —CON(—C 1 -C 8 alkyl) 2 ,

7. A compound according to claim 6 wherein

each of R 1 and R 2 are independently selected from (a) F, (b) Cl, (c) —C 1 -C 8 alkyl, (d) phenyl, (e) a 7 to 10-membered saturated, unsaturated, or aromatic fused bicyclic carbocyle, (f) 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, (g) —OR 3 , (h) —NR 3 R 3 , (i) —SR 3 , (j) —COOR 3 , (k) —COR 3 , and (l) —CONR 3 R 3 ,

wherein each (c) immediately recited above is optionally substituted with one or more F, Cl, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), or —N(C 1 -C 8 alkyl) 2 and

wherein each (d) through (f) immediately recited above is optionally substituted with one more more R 4 or R 5 ;

each R 3 is independently selected from (a) H, (b) —C 1 -C 8 alkyl, (c) phenyl, and (d) naphthyl, wherein each of (b) through (d) immediately recited above is optionally substituted with one or more R 5 ;

each R 4 is independently selected from one or more (a) F, (b) Cl, (c) —C 1 -C 8 alkyl, (d) —C 3 -C 8 cycloalkyl, wherein each of (c) or (d) immediately recited above is optionally substituted with one or more R 5 ;

each R 5 is independently selected from one or more (a) F, (b) Cl, (c) —OH, (d) —NH 2 , (e) —SH, (f) —COOH, (g) —COCH 3 , (h) —CHO, or (i) —CONH 2 ,

8. A compound according to claim 7 wherein 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 nitrogen,

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 6 , (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 (k) immediately recited above is optionally substituted with one or more R 7 ;

wherein each of (a) through (d) immediately recited above is optionally substituted with one or more (a) F, (b) Cl, (c) —C 1 -C 8 alkyl, (d) —C 3 -C 8 cycloalkyl, (e) phenyl, (f) —OR 6 , (g) —NR 6 R 6 , (h) —CN, (i) —N 3 , -(j) —SR 6 , (k) —SOR 6 , (l) —SO 2 6 3 , (m) —COOR 6 , (n) —COR 6 , (o) —CONR 6 R 6 , (p) —NR 6 COR 6 —, and (q) —NR 6 CONR 6 R 6 ,

wherein each of (c) through (e) immediately recited above is optionally substituted with one or more F, Cl, —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 3 -C 8 cycloalkyl, (d) phenyl, (e) naphthyl, (f) —C 1 -C 8 alkyl(phenyl), and (g) —C 1 -C 8 alkyl(naphthyl), wherein each of (b) through (g) immediately recited above is optionally substituted with one or more R 7 ;

each R 7 is independently selected from one or more (a) F, (b) Cl, (c) —OH, (d) —NH 2 , (e) —CN, (f) —SH, (g) —COOH, (h) —CHO, (i) —CONH 2 , (j) —O(—C 1 -C 8 alkyl), (k) —NH(—C 1 -C 8 alkyl), (l) —N(—C 1 -C 8 alkyl) 2 , (m) —S(—C 1 -C 8 alkyl), (n) —COO(—C 1 -C 8 alkyl), (o) —CO(—C 1 -C 8 alkyl), (p) —CONH(—C 1 -C 8 alkyl), and (q) —CON(—C 1 -C 8 alkyl) 2 ,

9. A compound according to claim 8 wherein each Ar is independently selected from (a) phenyl, (b) naphthyl, (c) pyridyl, (d) pyrimidyl (e) furanyl, (f) thienyl (g) pyrazolyl, (h) pyrazinyl (i) quinolyl, (j) oxazolyl, (k) isoxazolyl, (l) imidazolyl, (m) isothiazolyl, (n) thiazolyl, (o) triazolyl, (p) tetrazolyl, (q) indolyl, (r) benzofuranyl, (s) benzoxazolyl, (t) benzisoxazolyl, and (u) isoquinolinyl,

wherein each of (a) through (u) 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 6 , (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 (k) immediately recited above is optionally substituted with one or more R 7 ;

10. A compound according to claim 9 wherein each Ar is independently selected from (a) phenyl, (b) naphthyl, (c) pyridyl, (d) pyrimidyl (e) furanyl, (f) thienyl (g) pyrazolyl, (h) pyrazinyl (i) quinolyl, (j) oxazolyl, (k) isoxazolyl, (l) imidazolyl, (m) isothiazolyl, (n) thiazolyl, (o) triazolyl, (p) tetrazolyl, (q) indolyl, (r) benzofuranyl, (s) benzoxazolyl, (t) benzisoxazolyl, and (u) isoquinolinyl,

wherein each of (c) through (e) immediately recited above is optionally substituted with one or more F, Cl, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), and —N(C 1 -C 8 alkyl) 2 ;

11. A compound according to claim 10 wherein each Ar is independently selected from (a) phenyl, (b) naphthyl, (c) 2-thienyl, (d) 3-thienyl (e) 2-furanyl, and (f) 3-furanyl

wherein

each of (a) through (f) immediately recited above is optionally substituted with one or more (a) F, (b) Cl, (c) —C 1 -C 8 alkyl, (d) —C 3 -C 8 cycloalkyl, (e) phenyl, (f) —OR 6 , (g) —NR 6 R 6 , (h) —CN, -(i) —SR 6 , (j) —SOR 6 , (k) —SO 2 6 3 , (l) —COOR 6 , (m) —COR 6 , (n) —CONR 6 R 6 , (o) —NR 6 COR 6 —, and (p) —NR 6 CONR 6 R 6 ,

wherein each of (c) through (e) immediately recited above is optionally substituted with one or more F, Cl, —OH, —SH, —NH 2 , —NH(C 1 -C 8 alkyl), and —N(C 1 -C 8 alkyl) 2 ;

12. A compound according to claim 1 wherein the following provisos (I) and (II) apply:

(I) the compound is not selected from any of the following compounds (a) through (qq):

or an enantiomer or diastereomer of any of the immediately foregoing compounds;

and

(II) the compound is not selected from a compound represented by the following formula

or stereoisomers, enantiomers or diastereoisomers of compounds represented by the foregoing formula.

13. A compound selected from

or combinations thereof,

14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

15. A method of treating prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 such that the cancer is treated.

16. A method of treating a hormone responsive prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 such that the prostate cancer is treated.

17. A method of treating a hormone refractory prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 such that the prostate cancer is treated.

18. A method of treating a hormone refractory prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 to inhibit the androgen receptor of the tumor cells of the prostate cancer such that the prostate cancer is treated.

19. A method of treating a hormone refractory prostate cancer according to claim 18 in a subject wherein the prostate cancer is characterized by having one or more mutations in the androgen receptors of the prostate cancer cells.

20. A method of treating a hormone refractory prostate cancer according to claim 19 in a subject wherein the prostate cancer is characterized by having one or more mutations in the ligand-binding domain of the androgen receptors of the prostate cancer cells.

21. A method according to claim 20 wherein the one or more mutations of the androgen receptor are selected from T877A, W741C, W741L, L701H, H874Y, and F876L, and combinations thereof.

22. A method according to claim 18 wherein the androgen receptor in the tumor cells is selectively inhibited compared to the androgen receptor in non-tumor cells.

23. A method for inhibiting the subcellular relocalization of an androgen receptor of a prostate cancer cell in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 such that the prostate cancer is treated.

24. A method according to claim 23 wherein the subcellular relocalization of the androgen receptor is subcellular relocation from the cytoplasm to the nucleus.

25. A method for trapping an androgen receptor in the cytoplasm of a prostate cancer cell in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 such that the prostate cancer is treated.

26. A method according to claim 23 wherein the prostate cancer cell is a hormone responsive prostate cancer cell.

27. A method according to claim 23 wherein the prostate cancer cell is a hormone refractory prostate cancer cell.

28. A method according to claim 23 wherein the androgen receptor is characterized as having one or more mutations.

29. A method according to claim 28 wherein the one or more mutations of the androgen receptor is in the ligand-binding domain of the androgen receptor.

30. A method according to claim 29 wherein the one or more mutations of the androgen receptor are selected from T877A, W741C, W741L, L701H, H874Y, and F876, and combinations thereof.

31. A method of treating prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound having the formula:

wherein in each ring system,

each X 1 is —C═;

each of X 2 , X 3 , X 4 , X 5 , and X 6 is independently selected from —CH═, —CR 1 ═, —CR 2 ═, —NH—, —NR 1 —, —NR 2 —, —N═, and —CO—;

such that each ring system (X) contains 1 to 3 nitrogen atoms, each ring system (X) contains no more than 2-CO—, and each ring system (X) contains no more than one of each R 1 and each R 2 ;

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 ;

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 6 , (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 ;

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 20, 2018

From: MCDONNELL, DONALD; NORRIS, JOHN D.

To: DUKE UNIVERSITY

Reel/Frame 044972/0670 →

CONFIRMATORY LICENSE Recorded Jan 29, 2018

From: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 045172/0665 →

Continuity (3)

Provisional Application 61925603 · Jan 9, 2014

Provisional Application 61883231 · Sep 27, 2013

Related Publication 20160229811A1 · Aug 11, 2016