Somatostatin modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-11072598-B2
Application number	US-201916572453-A
Country	US
Kind code	B2
Filing date	Sep 16, 2019
Priority date	Mar 16, 2017
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

Described herein are compounds 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

The invention claimed is:

1. A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

wherein:
R 1 is —NR 2 R 3 ;
R 2 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
R 3 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
or R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 2 -C 4 alkenyl;
each R 6 and R 7 is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 3 -C 5 heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 heteroaryl, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , —NR 15 C(═O)OR 15 , —OC(═O)N(R 15 ) 2 , —NR 15 C(═O)N(R 15 ) 2 , —NR 15 C(═O)NR 15 OR 15 , —C(R 15 )═N—OR 15 , —SR 15 , —S(═O)R 14 , —SO 2 R 14 , or —SO 2 N(R 15 ) 2 ;
or R 6 and an adjacent R 7 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 5-membered or 6-membered ring;
R 8 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 3 -C 5 heterocycloalkyl, —CN, —OH, —OR 14 , —CO 2 R 15 , —CH 2 CO 2 R 15 , —C(═O)N(R 15 ) 2 , —CH 2 C(═O)N(R 15 ) 2 , —N(R 15 ) 2 , —CH 2 N(R 15 ) 2 , —NR 15 C(═O)R 15 , —CH 2 NR 15 C(═O)R 14 , —SR 14 , —S(═O)R 14 , —SO 2 R 14 , or —SO 2 N(R 15 ) 2 ;
R 9 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 3 -C 5 heterocycloalkyl, —CN, —OH, —O-(substituted or unsubstituted C 1 -C 4 alkyl), or —O— (substituted or unsubstituted C 1 -C 4 fluoroalkyl);
X 1 is N or C—R 10 ;
R 10 is hydrogen, F, Cl, Br, —CN, —N(R 15 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkyl, or C 1 -C 4 fluoroalkoxy;

X 2 is C—R 7 or N;
X 3 is C—R 7 or N;
R 11 is hydrogen;
R 12 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 5 heterocycloalkyl that has 1 O atom;
or R 11 and R 12 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl;
R 13 is hydrogen, —OR 15 , —N(R 15 ) 2 , —CN, —CO 2 R 15 , —C(═O)N(R 15 ) 2 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
or R 12 and R 13 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 4- to 7-membered saturated N-containing heterocyclic ring;
each R 14 is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; and
each R 15 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
or two R 15 on the same N atom are taken together with the N atom to which they are attached to form an substituted or unsubstituted N-containing heterocycle.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
R 2 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, or C 3 -C 6 cycloalkyl; and
R 3 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, or C 3 -C 6 cycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
R 2 is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CN; and
R 3 is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CN, or —CH 2 CF 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
R 3 is hydrogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
R 11 is hydrogen;
R 12 is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl;
or R 11 and R 12 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted azepanyl; and
R 13 is hydrogen, —OH, —OCH 3 , —OCH 2 CH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CN, —C(═O)OCH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , or —CF 3 ;
or R 12 and R 13 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted monocyclic 4- to 7-membered heterocyclic ring selected from substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted azepan

Assignees

• Crinetics Pharmaceuticals Inc

Inventors

• Han Sangdon
• Kim Sun Hee
• Zhu Yunfei

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title