IP Library › Granted Patent US 9,108,944

Granted Patent B2

US 9,108,944 · App. 13/579,009 · Granted Aug 18, 2015

Androgen receptor modulators and uses thereof

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

Assignee: ARAGON PHARMACEUTICALS, INC.

C07D401/04 C07D401/14 C07D405/14 C07D471/04 C07D487/04

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Quick Facts

Patent No.: US 9,108,944
App. No.: 13/579,009
Granted: Aug 18, 2015
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 (178)

1. A compound of Formula (Ia), or a pharmaceutically acceptable salt, or N-oxide 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, 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—, —S(═O)—, —S(═O) 2 —, —NH—, —N(CH 3 )—; —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—, —OC(═O)—OC(═O)O—, —OC(═O)NH—, —NHS(═O) 2 —, or —S(═O) 2 NH—; and

(ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;

R 5 is L 1 -R 7 ; and L 1 is —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O) 2 —, or —S(═O) 2 NH—;

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 compound of claim 1 , or a pharmaceutically acceptable salt, or N-oxide thereof, 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 compound of claim 2 , or a pharmaceutically acceptable salt, or N-oxide thereof, 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—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHS(═O) 2 —, or —S(═O) 2 NH—; 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—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O) 2 —, or —S(═O) 2 NH.

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

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—, or —C(═O)NH—; and (ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;

R 5 is L 1 -R 7 ; and L 1 is —O—, or —C(═O)NH—;

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

5. The compound 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. The compound of claim 1 , wherein the compound is:

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;

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-(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;

4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(1-methylpiperidin-4-yl)benzamide;

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

7. A compound of claim 1 of Formula (VIIIa), or a pharmaceutically acceptable salt, or N-oxide thereof:

wherein,

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

8. The compound of claim 1 , or a pharmaceutically acceptable salt, or N-oxide thereof, 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.

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

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

10. The compound of claim 9 , or a pharmaceutically acceptable salt, or N-oxide thereof, 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.

11. The compound of claim 10 , or a pharmaceutically acceptable salt, or N-oxide thereof, wherein:

R A is —CH 3 or CF 3 .

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-(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-(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-(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-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

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

13. A compound of claim 1 , or a pharmaceutically acceptable salt, or N-oxide thereof, wherein the compound is