Androgen receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9481664-B2
Application number	US-201514656031-A
Country	US
Kind code	B2
Filing date	Mar 12, 2015
Priority date	Feb 16, 2010
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

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 pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of Formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, said composition formulated in a dosage form suitable for delivering a therapeutically effective amount of the compound when administered in a single dosage form or in a divided dosage form multiple times over the span of one day:

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, C 1 -C 6 alkoxy, or C 1 -C 6 heteroalkyl;
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 ; and
(i) L 1 is —O—, —S—, —OC(═O)—, or —OC(═O)O—; and
(ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;
or
R 5 is L 1 -R 7 ; and L 1 is —O—, —S—, —OC(═O)—, or —OC(═O)O—;
R 6 and R 7 are independently optionally substituted piperidinyl;
said optional substituents including at least one of alkyl, fluoroalkyl, —CN, halo, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , alkoxy, fluoroalkoxy, -(alkyl)sulfonyl, -(alkylene)-OH, or —C(O)-(alkyl);
each R 9 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 10 is C 1 -C 6 alkyl; and
R 11 is independently H or C 1 -C 4 alkyl.

2. The pharmaceutical composition of claim 1 , wherein
both R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
X is S; 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; and
R 6 and R 7 are independently piperidinyl optionally substituted with at least one alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , -(alkyl)sulfonyl, -(alkylene)-OH, or —C(O)(C 1-6 alkyl.

3. The pharmaceutical composition of claim 2 , wherein:
each R 4 is independently hydrogen, halogen, —CN, —NO 2 , —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy;
R 5 is -L 1 -L 2 -R 6 ; and
(i) L 1 is —O— or —S—; and
(ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;
or R 5 is -L 1 -R 7 ; and L 1 is —O— or —S.

4. The pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has the structure of Formula (II):

wherein,

m is 2;
one R A is —CN, —NO 2 , —S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —CO 2 R 9 , or —C(═O)N(R 9 ) 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;
each R 4 is independently hydrogen, halogen, 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 ; and (i) L 1 is —O—; and (ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;
or
R 5 is L 1 -R 7 ; and L 1 is —O—;
or is a pharmaceutically acceptable salt, or N-oxide thereof.

5. The pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has the structure of Formula (VI):

wherein,
one R A is —CN, —NO 2 , —S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —CO 2 R 9 , or —C(═O)N(R 9 ) 2 ;
and the other R A is H, halogen, —OH, 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;
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,
R 6 and R 7 are piperidinyl optionally substituted with at least one alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , -(alkyl)sulfonyl, -(alkylene)-OH, or —C(O)—(C 1-6 alkyl;
or is a pharmaceutically acceptable salt, or N-oxide thereof.

6. A pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has a structure of Formula (VIIIa):

wherein,
R A is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl.

7. The pharmaceutical composition of claim 1 , wherein:
X is S;
R 4 is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 fluoroalkoxy, or C 1 -C 3 alkoxy; and
R 6 and R 7 are independently piperidinyl optionally substituted with at least one alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), -(alkyl)sulfonyl, -(alkylene)-OH, —C(O)—(C 1-6 alkyl), or carbamoyl.

8. The pharmaceutical composition of claim 7 , wherein the compound of Formula (VIIIa) has the structure of Formula (IXa):

or is a pharmaceutically acceptable salt, or N-oxide thereof.

9. The pharmaceutical composition of claim 8 , wherein:
L 2 is C 1 -C 6 alkylene;
R 6 or R 7 are independently piperidinyl optionally substituted with at least one alkyl, —C(O)—O-(alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), -(alkyl)sulfonyl, -(alkylene)-OH, —CH 2 —C(O)—(C 1-6 alkyl), or carbamoyl.

10. The pharmaceutical composition of claim 9 , wherein: R A is —CH 3 or CF 3 .

11. The pharmaceutical composition 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;

Assignees

• Aragon Pharmaceuticals Inc

Inventors

• Smith Nicholas D
• Bonnefous Celine
• Julien Jackaline D

Classifications

• A61P5/26

  Androgens · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title