Somatostatin modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9902703-B2
Application number	US-201615186088-A
Country	US
Kind code	B2
Filing date	Jun 17, 2016
Priority date	Jul 1, 2015
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, that are somatostatin 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 somatostatin activity.

First claim

What is claimed is:

1. A compound that has the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

wherein:
A 1 , A 2 , and A 3 are CR A ;
each R A is independently hydrogen, halogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 1 -C 4 fluoroalkyl, unsubstituted or substituted C 1 -C 4 alkoxy, unsubstituted or substituted C 1 -C 4 fluoroalkoxy, —CN, —OH, —CO 2 R 14 , —C(═O)NR 14 R 15 ,—NR 14 R 15 , —NR 14 C(═O)NHR 15 , —NR 14 C(═O)(C 1 -C 4 alkyl), —C(═NOR 14 )R 15 , —SR 14 , —S(═O)(C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 alkyl), or —SO 2 NR 14 R 15 ;

R 1 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted bicyclic heterocycle, —(C 1 -C 4 alkylene)-(unsubstituted or substituted monocyclic carbocycle or unsubstituted or substituted bicyclic carbocycle), or —(C 1 -C 4 alkylene)-(unsubstituted or substituted monocyclic heterocycle or unsubstituted or substituted bicyclic heterocycle), wherein if R 1 is substituted then R 1 is substituted with 1-2 R 16 and 0-2 R 17 ;
R 2 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted bicyclic heterocycle, —(C 1 -C 4 alkylene)-(unsubstituted or substituted monocyclic carbocycle or unsubstituted or substituted bicyclic carbocycle), or —(C 1 -C 4 alkylene)-(unsubstituted or substituted monocyclic heterocycle or unsubstituted or substituted bicyclic heterocycle), wherein if R 2 is substituted then R 2 is substituted with 1-2 R 18 and 0-2 R 19 ;
R 3 and R 4 are independently hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein any substituted group of R 3 and R 4 is substituted with 1-4 R 20 ;
or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring or an unsubstituted or substituted bicyclic 9- to 12-membered heterocyclic ring, wherein if the heterocyclic ring is substituted then the heterocyclic ring is substituted with 1-4 R 20 ;
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, and unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, wherein any substituted group of R 5 , R 6 , R 7 , and R 8 is substituted with 1-4 R 20 ;
R 9 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or unsubstituted or substituted benzyl, wherein if R 9 is substituted then R 9 is substituted with 1-4 R 20 ;
or R 4 and any one of R 5 , R 7 , or R 9 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring or an unsubstituted or substituted bicyclic 9- to 12-membered heterocyclic ring, wherein if the heterocyclic ring is substituted then the heterocyclic ring is substituted with 1-4 R 20 ;
or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered carbocyclic ring, wherein if the carbocyclic ring is substituted then the carbocyclic ring is substituted with 1-4 R 20 ;
or R 5 and any one of R 7 or R 9 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring or a bicyclic 9- to 12-membered heterocyclic ring, wherein if the heterocyclic ring is substituted then the heterocyclic ring is substituted with 1-4 R 20 ;
or R 7 and R 9 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring or an unsubstituted or substituted bicyclic 9- to 12-membered heterocyclic ring, wherein if the heterocyclic ring is substituted then the heterocyclic ring is substituted with 1-4 R 20 ;
R 10 and R 11 are each independently selected from the group consisting of hydrogen, and unsubstituted or substituted C 1 -C 6 alkyl, wherein any substituted group of R 10 and R 11 is substituted with 1-4 R 20 ;
or R 10 and R 11 are taken together with the carbon atom to which they are attached to form —C(═O);
or R 7 and R 11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring or an unsubstituted or substituted bicyclic 9- to 12-membered heterocyclic ring, wherein if the heterocyclic ring is substituted then the heterocyclic ring is substituted with 1-4 R 20 ;
R 12 is hydrogen, or C 1 -C 4 alkyl;
or R 12 and R 9 are taken together with the intervening atoms to which they are attached to form a monocyclic 4- to 7-membered heterocyclic ring, wherein if the heterocyclic ring is substituted then the heterocyclic ring is substituted with 1-4 R 20 ;
R 13 is hydrogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 1 -C 4 fluoroalkyl, unsubstituted or substituted C 1 -C 4 alkoxy, unsubstituted or substituted C 1 -C 4 fluoroalkoxy, —CN, —CO 2 R 14 , —C(═O)NR 14 R 15 , or —C(═NOR 14 )R 15 ;
each R 14 and R 15 are independently selected from hydrogen, and unsubstituted or substituted C 1 -C 4 alkyl;
each R 16 , R 17 , R 18 and R 19 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 heterocycle, —CN, —OH, —CO 2 R 14 , —C(═O)NR 14 R 15 , —NR 14 R 15 , —NR 14 C(═O)NHR 15 , —NR 14 C(═O) R 15 , —C(═NOR 14 )R 15 , —SR 14 , —S(═O)(C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 alkyl), or —SO 2 NR 14 R 15 , wherein if any group of R 16 , R 17 , R 18 and R 19 is substituted then the substituted group of R 16 , R 17 , R 18 and R 19 is substituted with 1-4 R 20 ;
each R 20 is independently halogen, heterocycle, —CN, —OR 14 , —CO 2 R 14 , —C(═O)NR 14 R 15 , —NR 14 R 15 , —NR 14 C(═O)NHR 15 , —NR 14 C(═O)R 15 , —C(═NOR 14 )R 15 , —SR 14 , —S(═O)(C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 alkyl), or —SO 2 NR 14 R 15 ; and
m is 1, 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
R 3 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen;
R 8 is hydrogen; and
R 12 is hydrogen.

3. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R 10 and R 11 are taken together with the carbon atom to which they are attached to form a C(═O); or
R 10 and R 11 are hydrogen.

4. The compound of claim 1 , wherein the compound of Formula (I) has the structure of Formula (Ia), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

Assignees

• Crinetics Pharmaceuticals Inc

Inventors

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

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/74 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring · CPC title

• A61P5/02

  of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin · CPC title