Somatostatin modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-2018016252-A1
Application number	US-201715647758-A
Country	US
Kind code	A1
Filing date	Jul 12, 2017
Priority date	Jul 14, 2016
Publication date	Jan 18, 2018
Grant date	—

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

What is claimed is:

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

wherein:
each R a and R b is independently hydrogen, halogen, 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 monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, —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 , —CH(CF 3 )N(R 15 ) 2 , —NR 15 C(═O)R 14 , —CH 2 NR 15 C(═O)R 14 , —SR 14 , —S(═O)R 14 , —SO 2 R 14 , —SO 2 N(R 15 ) 2 or —C(═NOR 15 )R 15 ;
m is 1 or 2; n is 0, 1 or 2;
or if one R a and one R b are on adjacent atoms of ring A then the adjacent R a and R b groups are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;
R B is an unsubstituted or substituted ring B that is an unsubstituted or substituted phenyl or an unsubstituted or substituted pyridinyl, wherein if the ring B is substituted then the ring B is substituted with p R c and q R d ;
each R c and R d is independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —OR 14 , —C(═O)R 15 , —OC(═O)R 15 , —CO 2 R 15 , —CH 2 CO 2 R 15 , —C(═O)N(R 15 ) 2 , —OC(═O)N(R 15 ) 2 , —NR 15 C(═O)N(R 15 ) 2 , —NR 15 C(═O)OR 14 , —NR 15 C(═O)NR 15 OR 14 , —C(═O)NR 15 OR 15 , —CH 2 C(═O)N(R 15 ) 2 , —N(R 15 ) 2 , —CH 2 N(R 15 ) 2 , —CH(CF 3 )N(R 15 ) 2 , —NR 15 C(═O)R 14 , —CH 2 NR 15 C(═O)R 14 , —SR 14 , —S(═O)R 14 , —SO 2 R 14 , —SO 2 N(R 15 ) 2 , —C(═NOR 15 )R 15 , —N(R 15 )SO 2 R 14 , —C(═O)NR 15 S(═O) 2 R 14 , —S(═O) 2 NR 15 C(═O)R 14 , —C(═NR 15 )N(R 15 ) 2 , —NR 15 C(═NR 15 )N(R 15 ) 2 , —NR 15 C(═CR 14 R 15 )N(R 15 ) 2 , —C(═O)NR 15 C(═NR 15 )N(R 15 ) 2 or, —C(═O)NR 15 C(═CR 14 R 15 )N(R 15 ) 2 ;
p is 1 or 2; q is 0, 1 or 2;

or if one R c and one R d are on adjacent atoms of ring B then the adjacent R c and R d groups are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;
R e is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, OH, or —OR 14 ;
each R f is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, or —OR 14 ;
R 1 and R 2 are independently hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 2 -C 6 heterocycloalkyl;
or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form ring C that is an unsubstituted or substituted N-containing C 2 -C 8 heterocycloalkyl;
R 5 is selected from the group consisting of hydrogen, halogen, —OH, —OR 14 , —SR 14 , —S(═O)R 14 , —S(═O) 2 R 14 , —N(R 15 ) 2 , —CN, —C(═O)OR 15 , —C(═O)N(R 15 ) 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, and unsubstituted or substituted C 1 -C 6 fluoroalkyl;
or R 2 and R 5 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;
each R 14 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each R 15 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted 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 unsubstituted or substituted N-containing heterocycle;
wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R s groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, monocyclic carbocycle, monocyclic heterocycle, —CN, —OR 16 , —CO 2 R 16 , —C(═O)N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(═O)R 17 , —SR 16 , —S(═O)R 17 , —SO 2 R 17 , or —SO 2 N(R 16 ) 2 ;
each R 16 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R 16 groups are taken together with the N atom to which they are attached to form a N-containing heterocycle;
each R 17 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
R e is hydrogen, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, —OH, —OCH 3 , —OCH 2 CH 3 , or —OCF 3 ; each R f is independently hydrogen, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, —OH, —OCH 3 , —OCH 2 CH 3 , or —OCF 3 .

3 . The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
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 heteroalkyl, —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 , —CH(CF 3 )N(R 15 ) 2 , —NR 15 C(═O)R 14 , —CH 2 NR 15 C(═O)R 14 , —SR 14 , —S(═O)R 14 , —SO 2 R 14 , —SO 2 N(R 15 ) 2 or —C═N(R 14 )OR 15 ; and each R b 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 heteroalkyl, —CN, —OH, —O-(unsubstituted or substituted C 1 -C 4 alkyl), or —O-(unsubstituted or substituted C 1 -C 4 fluoroalkyl).

4 . The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:
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 heteroalkyl, —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 , or —CH 2 N(R 15 ) 2 ; and each R b is independently hydrogen, halogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 1 -C 4 heteroalkyl, —CN, —O-(unsubstituted or substituted C 1 -C 4 alkyl), or —O-(unsubstituted or substituted C 1 -C

Assignees

• Crinetics Pharmaceuticals Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/08

  for decreasing, blocking or antagonising the activity of the anterior pituitary hormones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title