Androgen receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-2016376252-A1
Application number	US-201615261041-A
Country	US
Kind code	A1
Filing date	Sep 9, 2016
Priority date	Feb 16, 2010
Publication date	Dec 29, 2016
Grant date	—

Abstract

Described herein are compounds that are androgen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such androgen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon androgen receptors.

First claim

What is claimed is:

1 . A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:

wherein,
ring A is pyridinyl;
m is 1, 2, 3 or 4;
each R A is independently halogen, —CN, —NO 2 , —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , —N(R 11 )S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —OC(═O)R 10 , —CO 2 R 9 , —N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy;
both R 1 are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;
X is S or O;
ring B is phenyl;
n is 1 or 2;
each R 4 is independently hydrogen, halogen, —CN, —NO 2 , —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , —N(R 11 )S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —OC(═O)R 10 , —CO 2 R 9 , —OCO 2 R 10 , —N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —OC(═O)N(R 9 ) 2 , —NR 11 C(═O)N(R 9 ) 2 , —NR 11 C(═O)R 10 , —NR 11 C(═O)OR 10 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy;
R 5 is -L 1 -L 2 -R 6 or L 1 -R 7 ; wherein
(i) L 1 is —O—; and
(ii) L 2 is C 1 -C 6 alkylene;
R 6 and R 7 are independently an optionally substituted heterocycloalkyl selected from the group consisting of morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, 1,1-dioxothiomorphinyl, and thiomorpholinyl;
said optional substituents including at least one of C 1-6 alkyl, C 1-6 fluoroalkyl, —C(O)—(C 1-6 alkyl), —C(O)—O—(C 1-6 alkyl); —CH 2 —C(O)—O—(C 1-6 alkyl), —(C 1-6 alkyl)sulfonyl, —(C 2-6 alkylene)-OH, or carbamoyl;
each R 9 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 10 is independently C 1 -C 6 alkyl; and
R 11 is independently H or C 1 -C 4 alkyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is S; both R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and each R A is independently halogen, —CN, —NO 2 , —OH, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently hydrogen, halogen, —CN, —NO 2 , —OH, C 1 -C 4 alkyl, C 1-4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy.

4 . The compound of claim 3 , wherein
m is 2 one R A is —CN, or —NO 2 ; and the other R A is halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy; n is 1; R 4 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy.

5 . The compound of claim 4 , wherein the compound of Formula (Ia) has the structure of Formula (VI):

wherein,
R 4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy;
or is a pharmaceutically acceptable salt thereof.

6 . The compound of claim 5 , wherein the compound of Formula (Ia) has the structure of Formula (IXa):

or is a pharmaceutically acceptable salt thereof.

7 . The compound of claim 6 , wherein:
R A is CH 3 , —CF 3 , or OCH 3 .

8 . The compound of claim 6 , wherein R 5 is -L 1 -L 2 -R 6 and L 2 is C 1 -C 3 alkylene.

9 . The compound of claim 6 , wherein R 5 is L 1 -R 7 .

10 . The compound of claim 1 , wherein:
R A is CH 3 , —CF 3 , or OCH 3 ; both R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; n is 0 or 1; and R 4 is hydrogen or fluoro.

11 . The compound of claim 1 , wherein R 6 or R 7 is piperidinyl optionally substituted with at least one C 1-6 alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —(C 1-6 alkyl)sulfonyl, —(C 2-6 alkylene)-OH, —C(O)—(C 1-6 alkyl), or carbamoyl.

12 . The compound of claim 1 , wherein the compound is
3-Methyl-5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; 5-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(3-Fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(2-Fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(2-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile; 5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 3-Methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; 5-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(8-Oxo-5-(4-((1-propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(4-((1-isobutyrylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; Ethyl 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxylate; 5-(5-(4-((1-Acetylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile; 5-(5-(4-((1-Ethylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile; 5-(5-(4-((1-(2-Hydroxyethyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile; 5-(5-(4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(4-((1-(Methylsulfonyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; 5-(5-(4-((1-Isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; Ethyl 2-(4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidin-1-yl)acetate; 4-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxamide; or a pharmaceutically acceptable salt, or N-oxide thereof.

13 . The compound of claim 1 , wherein R 6 or R 7 is piperazinyl optionally substituted with at least one C 1-6 alkyl, fluorinated C 1-6 alkyl, or C(O)—(C 1-6 alkyl).

14 . The compound of claim 1 , wherein the compound is:
5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(2-(4-methylp

Assignees

• Aragon Pharmaceuticals Inc

Inventors

• Smith Nicholas D
• Bonnefous Celine
• Julien Jackaline D

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title