IP Library › Granted Patent US 10,023,556

Granted Patent B2

US 10,023,556 · App. 15/261,041 · Granted Jul 17, 2018

Androgen receptor modulators and uses thereof

Inventors: Nicholas D. Smith (San Diego, CA); Celine Bonnefous (San Diego, CA); Jackaline D. Julien (Del Mar, CA)

C07D401/04 A61K31/437 A61K31/444 A61K31/4439 A61K31/4545 A61K31/4709 A61K31/4725 A61K31/496 A61K31/497 A61K31/506 A61K31/5025 A61K31/513 A61K31/5377 A61K31/541 A61K31/635 A61K45/06 C07D401/14 C07D405/14 C07D409/14 C07D413/14 C07D417/14 C07D471/04 C07D487/04

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Quick Facts

Patent No.: US 10,023,556
App. No.: 15/261,041
Granted: Jul 17, 2018
Kind: B2

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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.

Claims (105)

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 piperazinyl;

said optional substituents being 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 piperazinyl optionally substituted with at least one C 1-6 alkyl, fluorinated C 1-6 alkyl, or —C(O)—(C 1-6 alkyl) .

12. 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-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile;

5-(5-(4-Fluoro-3-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile;

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-methyl-picolinonitrile;

5-(5-(3-Fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile;

5-(5-(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-(2-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-(2-Fluoro-4-(3 -(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3 - (trifluoromethyl)- picolinonitrile;

3-Methyl-5-(8-oxo-6-thioxo-5-(4-(2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile;

3-Methyl-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-picolinonitrile;

5-(5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

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

13. A pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier or excipient and (b) a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 13 , wherein the compound is