US2008300241A9PendingUtilityA9
Tricyclic quinolinone and tricyclic quinoline androgen receptor modulator compounds and methods
Est. expiryFeb 23, 2021(expired)· nominal 20-yr term from priority
Inventors:Robert I. HiguchiLin ZhiDonald S. KaranewskyAnthony W. ThompsonThomas Raymond CaferroNeelakandha S. ManiJyun-Hung ChenMarquis CummingsJames P. EdwardsMark E. AdamsCharlotte Deckhut
A61P 5/26A61P 43/00A61P 35/00A61P 5/28A61P 5/00A61P 17/10A61P 17/00A61P 15/08A61P 15/10Y02P20/582C07D 498/04A61P 17/14C07D 498/14A61P 19/10A61P 13/08
49
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Claims
Abstract
Non-steroidal tricyclic quinolinone and tricyclic quinoline compounds and compositions that are agonists, partial agonists and/or antagonists for androgen receptors (AR), their preparation and their uses are described.
Claims
exact text as granted — not AI-modified1 . A compound having the formula:
wherein:
R 1 is selected from the group consisting of hydrogen, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 , S(O) n R 9 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted;
R 2 is selected from the group consisting of hydrogen, F, Cl, Br, I, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) n R 9 , NR 10 R 11 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted;
R 3 and R 4 each independently is selected from the group consisting of hydrogen, OR 9 , S(O) n R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; or
R 3 and R 4 taken together form a three to eight membered saturated or unsaturated carbocyclic or heterocyclic ring; or
R 3 and R 5 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; or
R 3 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; or
R 3 and R 13 taken together form a three to eight membered saturated or unsaturated heterocyclic ring;
R 5 and R 6 each independently are selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; or
R 5 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; or
R 5 and R 13 taken together form a three to eight membered saturated or unsaturated heterocyclic ring; or
R 6 and R 13 taken together form a three to eight membered saturated or unsaturated heterocyclic ring;
R 7 is selected from the group consisting of hydrogen, F, Cl, Br, I, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl, OR 9 , S(O) n R 9 , NR 10 R 11 , C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups are optionally substituted;
R 8 is selected from the group consisting of hydrogen, F, Cl, Br, I, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl, OR 9 , S(O) n R 9 , NR 10 R 11 , C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups are optionally substituted;
R 9 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl and arylalkyl groups are optionally substituted;
R 10 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl, arylalkyl, CO 2 R 12 , C(O)R 12 , SO 2 R 12 and S(O)R 12 , wherein the alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl and arylalkyl groups are optionally substituted;
R 11 and R 12 each independently is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl and arylalkyl groups are optionally substituted;
R 13 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted;
R 16 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, COR 17 , CO 2 R 17 and CONR 12 R 17 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;
R 17 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl and C 1 -C 8 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;
R 18 is selected from the group consisting of hydrogen, F, Br, Cl, I, CN, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, OR 16 , NR 16 R 17 , SR 16 , CH 2 R 16 , COR 17 , CO 2 R 17 , CONR 16 R 17 , SOR 17 and SO 2 R 17 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;
R 19 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted;
m is selected from the group consisting of 0, 1 and 2;
n is selected from the group consisting of 0, 1 and 2;
V is O or S;
W is selected from the group consisting of O, S(O) n , NH, N{R 13 }, N{C(Y)R 11 } and N{SO 2 R 11 };
X and Z each independently is selected from the group consisting of O, S(O) n , NH, N{R 11 }, N{C(Y)R 11 }, N{SO 2 R 12 } and N{S(O)R 12 }; and
Y is selected from the group consisting of O, S, N{R 19 } and N{OR 19 };
and pharmaceutically acceptable salts thereof.
2 . The compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, F, Cl, OR 9 , NR 10 R 11 , S(O) n R 9 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
3 . The compound of claim 2 , wherein R 1 is selected from the group consisting of hydrogen, F, Cl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
4 . The compound of claim 3 , wherein R 1 is selected from the group consisting of hydrogen, F and optionally substituted C 1 -C 4 alkyl.
5 . The compound of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, F, Cl, Br, I, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) n R 9 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl and alkenyl groups are optionally substituted.
6 . The compound of claim 5 , wherein R 2 is selected from the group consisting of hydrogen, F, Cl, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
7 . The compound of claim 6 , wherein R 2 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl and C 1 -C 2 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
8 . The compound of claim 7 , wherein R 2 is CF 3 .
9 . The compound of claim 1 , wherein:
R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or R 3 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring.
10 . The compound of claim 9 , wherein R 3 and R 6 taken together form a four to six membered saturated or unsaturated carbocyclic ring.
11 . The compound of claim 9 , wherein R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
12 . The compound of claim 1 , wherein R 6 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted.
13 . The compound of claim 12 , wherein R 6 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, C 2 -C 4 alkynyl and C 2 -C 4 alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, alkynyl and alkenyl groups are optionally substituted.
14 . The compound of claim 13 , wherein R 6 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
15 . The compound of claim 12 , wherein R 6 is selected from the group consisting of aryl, arylalkyl and heteroaryl, wherein the aryl, arylalkyl and heteroaryl groups are optionally substituted.
16 . The compound of claim 1 , wherein R 5 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl and alkenyl groups are optionally substituted.
17 . The compound of claim 16 , wherein R 5 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
18 . The compound of claim 17 , wherein R 5 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
19 . The compound of claim 18 , wherein R 5 is hydrogen or CF 3 .
20 . The compound of claim 1 , wherein R 7 is selected from the group consisting of hydrogen, F, Cl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl, groups are optionally substituted.
21 . The compound of claim 1 , wherein R 8 is selected from the group consisting of hydrogen, F, Cl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl, groups are optionally substituted.
22 . The compound of claim 21 , wherein R 7 and R 8 each is hydrogen or optionally substituted C 1 -C 2 alkyl.
23 . The compound of claim 1 , wherein R 9 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
24 . The compound of claim 23 , wherein R 9 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl.
25 . The compound of claim 1 , wherein R 10 is selected from the group consisting of hydrogen, S(O)R 12 , SO 2 R 12 , C(O)R 12 , CO 2 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
26 . The compound of claim 25 , wherein R 10 is selected from the group consisting of hydrogen, S(O)R 12 , SO 2 R 12 , C(O)R 12 and CO 2 R 12 .
27 . The compound of claim 1 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
28 . The compound of claim 27 , wherein R 4 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 2 alkyl.
29 . The compound of claim 1 , wherein R 13 is selected from the group consisting of CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CH 2 CF 3 , CH 2 CF 2 Cl, CH 2 CCl 2 F, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, cycloalkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted; or
R 6 and R 13 taken together form a five to seven membered saturated or unsaturated heterocyclic ring.
30 . The compound of claim 29 , wherein R 13 is selected from the group consisting of CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CH 2 CF 3 , CH 2 CF 2 Cl, CH 2 CCl 2 F, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, C 2 -C 4 alkenyl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl and aryl groups are optionally substituted; or
R 6 and R 13 taken together form a five to six membered saturated or unsaturated heterocyclic ring.
31 . The compound of claim 30 , wherein R 13 is selected from the group consisting of CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CH 2 CF 3 , CH 2 CF 2 Cl, CH 2 CCl 2 F, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, allyl; or
R 6 and R 13 taken together form a five membered saturated or unsaturated heterocyclic ring.
32 . The compound of claim 1 , wherein R 18 is selected from the group consisting of hydrogen, F, Cl, OR 16 , SR 16 , NR 16 R 11 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
33 . The compound of claim 32 , wherein R 18 is selected from the group consisting of hydrogen, F, Cl, OR 16 , SR 16 and NR 16 R 17 .
34 . The compound of claim 33 , wherein R 18 is selected from the group consisting of hydrogen, F, Cl and OR 16 .
35 . The compound of claim 1 , wherein R 19 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
36 . The compound of claim 35 , wherein R 19 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl.
37 . The compound of claim 1 , wherein m is 0 or 1.
38 . The compound of claim 37 , wherein m is 1.
39 . The compound of claim 1 , wherein W is selected from the group consisting of NH, N{R 13 }, N{C(Y)R 11 } and N{SO 2 R 11 }.
40 . The compound of claim 39 , wherein W is NH or N{R 13 }.
41 . The compound of claim 1 , wherein X is selected from the group consisting of O, S, NH and N{R 11 }.
42 . The compound of claim 41 , wherein X is O or S.
43 . The compound of claim 1 , wherein Y is O or S.
44 . The compound of claim 43 , wherein Y is O.
45 . The compound of claim 1 , wherein Z is selected from the group consisting of NH, N{R 11 } and O.
46 . The compound of claim 45 , wherein Z is NH or N{R 11 }.
47 . The compound of claim 1 , wherein V is S.
48 . The compound of claim 1 , wherein V is O.
49 . The compound of claim 1 , wherein:
R 1 is selected from the group consisting of hydrogen, F, Cl, OR 9 , S(O) n R 9 , NR 10 R 11 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; R 2 is selected from the group consisting of hydrogen, F, Cl, Br, I, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) n R 9 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl and alkenyl groups are optionally substituted; R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or R 3 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; R 5 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl and alkenyl groups are optionally substituted; R 6 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; or R 6 and R 13 taken together form a five to seven membered saturated or unsaturated heterocyclic ring.
50 . The compound of claim 49 , wherein:
R 7 is selected from the group consisting of hydrogen, F, Cl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; R 8 is selected from the group consisting of hydrogen, F, Cl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; R 13 is selected from the group consisting of CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CH 2 CF 3 , CH 2 CF 2 Cl, CH 2 CCl 2 F, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are optionally substituted; or R 6 and R 13 taken together form a five to seven membered saturated or unsaturated heterocyclic ring; and R 18 is selected from the group consisting of hydrogen, F, Cl, OR 16 , SR 16 , NR 16 R 17 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
51 . The compound of claim 50 , wherein:
m is 0 or 1; W is selected from the group consisting of NH, N{R 13 }, N{C(Y)R 11 } and N{SO 2 R 11 }; X is selected from the group consisting of O, S, NH and N{R 11 }; Y is O or S; and Z is selected from the group consisting of NH, N{R 11 } and O.
52 . The compound of claim 1 , wherein said compound is represented by formula (II).
53 . The compound of claim 1 , wherein said compound is represented by formula (III).
54 . The compound of claim 1 , wherein said compound is represented by formula (IV).
55 . A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and a compound of formula: wherein: R 1 is selected from the group consisting of hydrogen, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 , S(O) n R 9 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; R 2 is selected from the group consisting of hydrogen, F, Cl, Br, I, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) n R 9 , NR 10 R 11 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; R 3 and R 4 each independently is selected from the group consisting of hydrogen, OR 9 , S(O) n R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; or R 3 and R 4 taken together form a three to eight membered saturated or unsaturated carbocyclic or heterocyclic ring; or R 3 and R 5 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; or R 3 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; or R 3 and R 13 taken together form a three to eight membered saturated or unsaturated heterocyclic ring; R 5 and R 6 each independently are selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted; or R 5 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring; or R 5 and R 13 taken together form a three to eight membered saturated or unsaturated heterocyclic ring; or R 6 and R 13 taken together form a three to eight membered saturated or unsaturated heterocyclic ring; R 7 is selected from the group consisting of hydrogen, F, Cl, Br, I, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl, OR 9 , S(O) n R 9 , NR 10 R 11 , C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups are optionally substituted; R 8 is selected from the group consisting of hydrogen, F, Cl, Br, I, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl, OR 9 , S(O) n R 9 , NR 10 R 11 , C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups are optionally substituted; R 9 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl and arylalkyl groups are optionally substituted; R 10 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl, arylalkyl, CO 2 R 12 , C(O)R 12 , SO 2 R 12 and S(O)R 12 , wherein the alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl and arylalkyl groups are optionally substituted; R 11 and R 12 each independently is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl and arylalkyl groups are optionally substituted; R 13 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted; R 16 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, COR 17 , CO 2 R 17 and CONR 12 R 17 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; R 17 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl and C 1 -C 8 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; R 18 is selected from the group consisting of hydrogen, F, Br, Cl, I, CN, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, OR 16 , NR 16 R 17 , SR 16 , CH 2 R 16 , COR 17 , CO 2 R 17 , CONR 16 R 17 , SOR 17 and SO 2 R 17 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; R 19 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted; m is selected from the group consisting of 0, 1 and 2; n is selected from the group consisting of 0, 1 and 2; V is O or S; W is selected from the group consisting of O, S(O) n , NH, N{R 13 }, N{C(Y)R 11 } and N{SO 2 R 11 }; X and Z each independently is selected from the group consisting of O, S(O) n , NH, N{R 11 }, N{C(Y)R 11 }, N{SO 2 R 12 } and N{S(O)R 12 }; and Y is selected from the group consisting of O, S, N{R 19 } and N{OR 19 }; and pharmaceutically acceptable salts thereof.
56 . The pharmaceutical composition of claim 55 , wherein said composition is suitable for enteral, parenteral, suppository or topical administration.
57 . The pharmaceutical composition of claim 55 , wherein R 1 is selected from the group consisting of hydrogen, F, Cl, OR 9 , NR 10 R 11 , S(O) n R 9 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
58 . The pharmaceutical composition of claim 55 , wherein R 2 is selected from the group consisting of hydrogen, F, Cl, Br, I, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) n R 9 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl and alkenyl groups are optionally substituted.
59 . The pharmaceutical composition of claim 55 , wherein:
R 1 is selected from the group consisting of hydrogen, F and optionally substituted C 1 -C 4 alkyl; and R 2 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl and C 1 -C 2 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
60 . The pharmaceutical composition of claim 55 , wherein R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C(Y)OR 11 and C(Y)NR 10 R 11 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or
R 3 and R 6 taken together form a three to eight membered saturated or unsaturated carbocyclic ring.
61 . The pharmaceutical composition of claim 55 , wherein R 6 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl and alkenyl groups are optionally substituted.
62 . The pharmaceutical composition of claim 61 , wherein R 6 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, C 2 -C 4 alkynyl and C 2 -C 4 alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, alkynyl and alkenyl groups are optionally substituted.
63 . The pharmaceutical composition of claim 55 , wherein R 5 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl and C 2 -C 6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl and alkenyl groups are optionally substituted.
64 . The pharmaceutical composition of claim 63 , wherein R 5 is selected from the group consisting of hydrogen, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
65 . The pharmaceutical composition of claim 55 , wherein R 7 and R 8 each independently is selected from the group consisting of hydrogen, F, Cl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
66 . The pharmaceutical composition of claim 55 , wherein:
R 9 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; and R 10 is selected from the group consisting of hydrogen, S(O)R 12 , SO 2 R 12 , C(O)R 12 , CO 2 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
67 . The pharmaceutical composition of claim 55 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
68 . The pharmaceutical composition of claim 55 , wherein R 13 is selected from the group consisting of CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CH 2 CF 3 , CH 2 CF 2 Cl, CH 2 CCl 2 F, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted; or
R 6 and R 13 taken together form a five to seven membered saturated or unsaturated heterocyclic ring.
69 . The pharmaceutical composition of claim 68 , wherein R 13 is selected from the group consisting of CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CH 2 CF 3 , CH 2 CF 2 Cl, CH 2 CCl 2 F, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, allyl; or
R 6 and R 13 taken together form a five membered saturated or unsaturated heterocyclic ring.
70 . The pharmaceutical composition of claim 55 , wherein R 18 is selected from the group consisting of hydrogen, F, Cl, OR 16 , SR 16 , NR 16 R 17 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
71 . The pharmaceutical composition of claim 55 , wherein R 19 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.
72 . The pharmaceutical composition of claim 55 , wherein m is 0 or 1.
73 . The pharmaceutical composition of claim 55 , wherein:
W is selected from the group consisting of NH, N{R 13 }, N{C(Y)R 11 } and N{SO 2 R 11 }; and X is selected from the group consisting of O, S, NH and N{R 11 }.
74 . The pharmaceutical composition of claim 55 , wherein:
Y is O or S; and Z is selected from the group consisting of NH, N{R 11 } and O.
75 . A method of determining the presence of an androgen receptor (AR) in a cell or cell extract, comprising:
(a) labeling a compound of claim 1; (b) contacting the cell or cell extract with said labeled compound; and (c) testing the contacted cell or cell extract to detect said labeled compound, thereby determining the presence of AR.
76 . A method for purifying a sample containing an androgen receptor in vitro, comprising:
(a) contacting said sample with a compound of claim 1; (b) allowing said compound to bind to said androgen receptor to form a bound compound/receptor combination; and (c) isolating said bound compound/receptor combination.
77 . A method of treating an individual having a condition mediated by an androgen receptor, comprising administering to said individual a pharmaceutically effective amount of a compound of claim 1 .
78 . The method of claim 77 , wherein said compound is represented by formula (II).
79 . The method of claim 77 , wherein said compound is represented by formula (III).
80 . The method of claim 77 , wherein said compound is represented by formula (IV).
81 . The method of claim 77 , wherein said condition is selected from among acne, male-pattern baldness, sexual dysfunction, impotence, wasting diseases, hirsutism, hypogonadism, prostatic hyperplasia, osteoporosis, cancer cachexia, and hormone-dependent cancers.
82 . The method of claim 77 , wherein said condition is alleviated with a therapy selected from among male hormone replacement therapy, female androgen replacement therapy and stimulation of hematopoiesis.
83 . A method of modulating an androgen receptor in an individual, comprising administering to said individual an androgen receptor modulating effective amount of a compound of claim 1 .
84 . The method of claim 83 , wherein said individual has a condition mediated by an androgen receptor.
85 . The method of claim 84 , wherein said condition is selected from among acne, male-pattern baldness, sexual dysfunction, impotence, wasting diseases, hirsutism, hypogonadism, prostatic hyperplasia, osteoporosis, cancer cachexia, hormone-dependent cancers and a process mediated by an anabolic agent.
86 . The method of claim 84 , wherein said condition is alleviated with a therapy selected from among male hormone replacement therapy, female androgen replacement therapy and stimulation of hematopoiesis.
87 . The method of claim 83 , wherein said modulation is activation.
88 . The method of claim 87 , wherein said individual has a condition mediated by an androgen receptor.
89 . A method according to claim 88 , wherein said condition is selected from among sexual dysfunction, impotence, wasting diseases, hypogonadism, osteoporosis, cancer cachexia, and a process mediated by an anabolic agent.
90 . The method of claim 88 , wherein said condition is alleviated with a therapy selected from among male hormone replacement therapy, female androgen replacement therapy and stimulation of hematopoiesis.
91 . The method of claim 87 , wherein said compound provides 50% maximal activation of AR at a drug concentration of less than 100 nM.
92 . The method of claim 87 , wherein said compound provides 50% maximal activation of AR at a drug concentration of less than 50 nM.
93 . The method of claim 87 , wherein said compound provides 50% maximal activation of AR at a drug concentration of less than 20 nM.
94 . The method of claim 87 , wherein said compound provides 50% maximal activation of AR at a drug concentration of less than 10 nM.
95 . The method of claim 83 , wherein said modulation is inhibition.
96 . The method of claim 95 , wherein said individual has a condition mediated by an androgen receptor.
97 . The method of claim 96 , wherein said condition is selected from among acne, male-pattern baldness, hirsutism, prostatic hyperplasia, and hormone-dependent cancers.
98 . The method of claim 84 , wherein:
the compound of claim 1 is an AR partial agonist; and said condition is selected from among acne, male-pattern baldness, sexual dysfunction, impotence, wasting diseases, hirsutism, hypogonadism, prostatic hyperplasia, osteoporosis, cancer cachexia, and hormone-dependent cancers.
99 . The method of claim 98 , wherein said condition is alleviated with a therapy selected from among male hormone replacement therapy, female androgen replacement therapy and stimulation of hematopoiesis.
100 . The method of claim 95 , wherein said compound provides 50% maximal inhibition of AR at a drug concentration of less than 100 nM.
101 . The method of claim 95 , wherein said compound provides 50% maximal inhibition of AR at a drug concentration of less than 50 nM.
102 . The method of claim 95 , wherein said compound provides 50% maximal inhibition of AR at a drug concentration of less than 20 nM.
103 . The method of claim 95 , wherein said compound provides 50% maximal inhibition of AR at a drug concentration of less than 10 nM.
104 . A method of treating cancer, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.Cited by (0)
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