Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof

Patent metadata

Field	Value
Publication number	US-10766877-B2
Application number	US-201916713601-A
Country	US
Kind code	B2
Filing date	Dec 13, 2019
Priority date	Jun 5, 2018
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

Described herein are compounds that are melanocortin subtype-2 receptor (MC2R) modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of MC2R activity.

First claim

What is claimed is:

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

wherein:
V is N;
R a is selected from the group consisting of hydrogen, halogen, —OR 8 , —CN, —N(R 7 ) 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, and unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein any substituted group of R a is substituted with one or more R 9 groups;
R b and R c are each independently selected from the group consisting of hydrogen, halogen, —OR 8 , —CN, —N(R 7 ) 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, and unsubstituted or substituted C 1 -C 6 heteroalkyl, wherein any substituted group of R b and R c is substituted with one or more R 9 groups;
R B is unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, unsubstituted or substituted C 1 -C 7 alkyl, unsubstituted or substituted C 1 -C 7 fluoroalkyl, or unsubstituted or substituted C 1 -C 6 heteroalkyl, wherein if R B is substituted then R 8 is substituted with R d , R e and R f ;
R d is selected from the group consisting of hydrogen, halogen, —OR 8 , —CN, —N(R 7 ) 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted C 2 -C 7 heterocycloalkyl, unsubstituted or substituted phenyl, and or unsubstituted or substituted monocyclic heteroaryl, wherein any substituted group of R d is substituted with one or more R 9 groups;
R e and R f are each independently selected from the group consisting of hydrogen, halogen, —OR 8 , —CN, —N(R 7 ) 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, and unsubstituted or substituted C 1 -C 6 heteroalkyl, wherein any substituted group of R d is substituted with one or more R 9 groups;
X 1 is CR 6 ;
R 2 and R 3 are hydrogen;
or R 2 and R 3 are taken together with the carbon atom to which they are attached to form —C(═O)—;
R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted —(C 1 -C 6 alkyl)-carbocycle, and unsubstituted or substituted —(C 1 -C 6 alkyl)-heterocycle, wherein any substituted group of R 4 is substituted with one or more halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R 7 ) 2 , —CN, —CO 2 R 8 , —C(═O)N(R 7 ) 2 , —SR 8 , —S(═O)R 10 , —S(═O) 2 R 10 , —NR 7 C(═O)R 8 , —NR 7 SO 2 R 10 , —SO 2 R 10 , or —SO 2 N(R 7 ) 2 ;
R 6 is H or F;
each R 7 is independently selected from the group consisting of hydrogen, substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
or two R 7 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle;
each R 8 is independently selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
each R 9 is independently hydrogen, halogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 1 -C 4 alkoxy, unsubstituted or substituted C 1 -C 4 fluoroalkyl, unsubstituted or substituted C 1 -C 4 fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO 2 R 8 , —CH 2 CO 2 R 8 , —C(═O)N(R 7 ) 2 , —C(═O)N(R 7 ) 01 e, —CH 2 C(═O)N(R 7 ) 2 , —N(R 7 ) 2 , —CH 2 N(R 7 ) 2 , —C(R 8 ) 2 N(R 7 ) 2 , —NR 7 C(═O)R 8 , —CH 2 NR 7 C(═O)R 8 , —NR 7 C(═O)N(R 7 ) 2 , —NR 7 C(═O)N(R 7 ) 2 , C(R 8 )═N(R 7 )—OR 8 , —SR 8 , —S(═O)R 10 , —SO 211 10 , or —SO 2 N(R 7 ) 2 ; and
each R 10 is independently selected from the group consisting unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R a is selected from the group consisting of hydrogen, halogen, —OR 8 , —CN, —N(R 7 ) 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, and unsubstituted or substituted C 1 -C 6 heteroalkyl, wherein any substituted group of R a is substituted with one or more R 9 groups; and
R b and R c are each independently selected from the group consisting of hydrogen, halogen, —OR 8 , —N(R 7 ) 2 , and unsubstituted or substituted C 1 -C 6 alkyl, wherein any substituted group of R b and R c is substituted with one or more R 9 groups.

3. The compound of claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R a is —OR 8 ; and
R b and R c are each hydrogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic carbocycle, and unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms, wherein any substituted group of R 4 is substituted with one or more halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms, —N(R 7 ) 2 , —OR 8 , —CN, —CO 2 R 8 , —C(═O)N(R 7 ) 2 , —S(═O)R 10 , —S(═O) 2 R 10 , —NR 7 C(═O)R 8 , —NR 7 SO 2 R 10 , —SO 2 R 10 , or —SO 2 N(R 7 ) 2 .

5. The compound of claim 4 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R 4 is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-2 N atoms and 0 or 1 O or S atoms, wherein any substituted group of R 4 is substituted with one or more halogen, unsubstituted or substituted C 1 -C 6 alkyl, —N(R 7 ) 2 , —OR 8 , or —CN.

6. The compound of claim 4 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R 4 is hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R B is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted polycyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted bicyclic heterocycle, or unsubstituted or substituted polycyclic heterocycle, wherein if R B is substituted then R B is substituted with R d , R e and R f .

8. The compound of claim 7 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R B is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl

Assignees

• Crinetics Pharmaceuticals Inc

Inventors

• Han Sangdon
• Zhu Yunfei
• Kim Sun Hee
• Zhao Jian

Classifications

• C07D453/02

  containing not further condensed quinuclidine ring systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D241/04 Primary

  having no double bonds between ring members or between ring members and non-ring members · CPC title