Compounds and methods for regulating insulin secretion

Patent metadata

Field	Value
Publication number	US-12486258-B2
Application number	US-202217991792-A
Country	US
Kind code	B2
Filing date	Nov 21, 2022
Priority date	Mar 20, 2017
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

Disclosed herein are methods for inducing insulin secretion in a glucose-dependent manner and compounds for use in these methods.

First claim

The invention claimed is:

1 . A method of modulating insulin secretion comprising contacting a β-cell with a compound having the structure of Formula I:

wherein the “dashed” bond is a single or double bond;
X 1 and X 2 are independently selected at each occurrence from C(R 2 ) and N, wherein two vicinal R 2 groups may together form an optionally aromatic five- or six membered fused ring;
Y is selected from —C(O)N(R 3 )—, —N(R 3 )C(O)—, —SO 2 N(R 3 )—, and —N(R 3 )SO 2 —;
Z 1 and Z 2 are independently CH 2 , O, N, CHR 5 , CR 5 , or NR 5 ;
R 1 is selected from aryl, heteroaryl, heterocyclyl, and —(C(R 3)2 )-heterocyclyl optionally substituted with one or more substituents independently selected from alkyl, alkenyl, hydroxyalkyl, ether, acyl, and halogen, and wherein any two vicinal substituents of R 1 may together form a five- or six-optionally aromatic membered ring;
R 2 is selected from hydrogen, alkyl, alkoxy, —CN, —NH 2 , —(CH 2 ) 1-4 NH 2 , —(CH 2 ) 1-4 N 3 , —(CH 2 ) 1-4 NHC(O)CH 3 ; and
R 3 is independently selected at each occurrence from hydrogen and alkyl optionally substituted with one to three groups independently selected from halogen, and wherein a substituent of R 1 and any R 4 may together form a fused five- or six-membered ring optionally substituted with one two three groups Cl, F, OH, CN, N, O, or S;
R 4 is a five- or six-membered aromatic heterocycle optionally substituted with one or more alkyl, halogen, alkoxy, and wherein any two vicinal substituents may together form an optionally aromatic five- or six-membered fused ring optionally substituted with alkyl, N, O, S, or C(═O); and wherein R 3 may together with R 2 of X 1 form a five- or six membered optionally substituted fused ring;
R 5 is independently at each occurrence hydrogen or alkyl, and R 5 and R 2 of X 2 may together form a five- or six-membered fused ring; and
R Q is independently selected at each occurrence a bivalent optionally aromatic heterocycles;
or a pharmaceutically acceptable form thereof;
wherein insulin secretion from said B-cell occurs only when blood glucose levels exceed normoglycemic conditions.

2 . The method according to claim 1 , wherein said blood glucose levels are greater than about 5 mM.

3 . The method according to claim 1 , wherein said blood glucose levels are greater than about 7 mM.

4 . The method according to claim 1 , wherein said blood glucose levels are greater than about 10 mM.

5 . The method according to claim 1 , wherein said blood glucose levels are greater than about 12 mM.

6 . The method according to claim 1 , wherein said normoglycemic conditions comprise a blood glucose concentration from about 3.5 mM to about 7 mM.

7 . A method for modulating insulin secretion comprising contacting cells with a compound having the structure of Formula I:

wherein the “dashed” bond is a single or double bond;
X 1 and X 2 are independently selected at each occurrence from C(R 2 ) and N, wherein two vicinal R 2 groups may together form an optionally aromatic five- or six membered fused ring;
Y is selected from —C(O)N(R 3 )—, —N(R 3 )C(O)—, —SO 2 N(R 3 )—, and —N(R 3 )SO 2 —;
Z 1 and Z 2 are independently CH 2 , O, N, CHR 5 , CR 5 , or NR 5 ;
R 1 is selected from aryl, heteroaryl, heterocyclyl, and —(C(R 3)2 )-heterocyclyl optionally substituted with one or more substituents independently selected from alkyl, alkenyl, hydroxyalkyl, ether, acyl, and halogen, and wherein any two vicinal substituents of R 1 may together form a five-or six-optionally aromatic membered ring;
R 2 is selected from hydrogen, alkyl, alkoxy, —CN, —NH 2 , —(CH 2 ) 1-4 NH 2 , —(CH 2 ) 1-4 N 3 , —(CH 2 ) 1-4 NHC(O)CH 3 ; and
R 3 is independently selected at each occurrence from hydrogen and alkyl optionally substituted with one to three groups independently selected from halogen, and wherein a substituent of R 1 and any R 4 may together form a fused five- or six-membered ring optionally substituted with one two three groups Cl, F, OH, CN, N, O, or S;
R 4 is a five- or six-membered aromatic heterocycle optionally substituted with one or more alkyl, halogen, alkoxy, and wherein any two vicinal substituents may together form an optionally aromatic five- or six-membered fused ring optionally substituted with alkyl, N, O, S, or C(═O);
and wherein R 3 may together with R 2 of X 1 form a five- or six membered optionally substituted fused ring;
R 5 is independently at each occurrence hydrogen or alkyl, and R 5 and R 2 of X 2 may together form a five- or six-membered fused ring; and
R Q is independently selected at each occurrence a bivalent optionally aromatic heterocycles;
or a pharmaceutically acceptable form thereof.

8 . The method of claim 7 , wherein said compound is Compound 8 having the structure:

9 . The method of claim 7 , wherein R 1 is aryl.

10 . The method of claim 9 , wherein the aryl is a substituted phenyl, where one or more substituents are selected from alkyl, cyano, or morpholinyl.

11 . The method of claim 7 , wherein R 1 is heteroaryl.

12 . The method of claim 7 , wherein R 1 is —(C(R 3)2 )-heterocyclyl.

13 . The method of claim 7 , wherein R 2 is alkyl or alkoxy.

14 . The method of claim 7 , wherein Y is selected from —NR 4 C(O)—, —C(O)NR 4 .

15 . The method according claim 7 , wherein said compound is selected from

Assignees

• Broad Inst Inc
• Massachusetts Gen Hospital
• Inst Carlos Slim De La Salud A C

Inventors

• Burns Sean M
• Wagner Bridget K
• Vetere Amedeo

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D261/08

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

• C07D237/08

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

• C07D231/12

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

• C07D213/30

  Oxygen atoms · CPC title