GLP-1 receptor agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-12331041-B2
Application number	US-202318513752-A
Country	US
Kind code	B2
Filing date	Nov 20, 2023
Priority date	Jun 15, 2018
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

Abstract

Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-, 5-aza-, and 7-aza-benzimidazoles as GLP-1R agonists, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

First claim

The invention claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein A is A1 or A2,

and wherein
each R 1 is independently halogen, —CN, —C 1-3 alkyl, or —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl is substituted with 0 to 3 F atoms;
m is 0, 1, 2, or 3;
X-L is N—CH 2 , CHCH 2 , or cyclopropyl;
Y is CH or N;
Z A1 is CH or CR 2 ;
Z A2 is CH, CR 2 , or N;
Z A3 is CH, CR 2 , or N, provided that Z A2 and Z A3 are not simultaneously N; and further provided that one of Z A2 and Z A3 is N when X-L is N—CH 2 ;
each R 2 is F;
each R 3 is independently F, —OH, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, or —C 3-4 cycloalkyl, or 2 R 3 s may together cyclize to form —C 3-4 spirocycloalkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1-OH;
q is 0, 1, or 2;
R 4 is-C 1-3 alkyl, —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 , wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 , and wherein said alkylene of —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 and said cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 ;
R 5 is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 1 oxo (═O),
0 to 1 —CN,
0 to 2 F atoms, and
0 to 2 substituents independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O ;

R 6 is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 halogens,
0 to 1 substituent selected from —OR O and —N(R N ) 2 , and
0 to 2 -C 1-3 alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms, and
0 to 1 —OR O ;

each R O is independently H, or —C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
each R N is independently H, or —C 1-3 alkyl;
Z 1 , Z 2 , and Z 3 are each —CR Z , or
one of Z 1 , Z 2 , and Z 3 is N and the other two are —CR Z ; and
each R Z is independently H, F, Cl, or —CH 3 .

2. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein A is A1 or A2,

and wherein
each R 1 is independently halogen, —CN, —C 1-3 alkyl, or —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl is substituted with 0 to 3 F atoms;
m is 0, 1, 2, or 3;
X-L is N—CH 2 , CHCH 2 , or cyclopropyl;
Y is CH or N;
Z A1 is N;
Z A2 is CH, CR 2 , or N;
Z A3 is CH, CR 2 , or N, provided that Z A2 and Z A3 are not simultaneously N; and further provided that one of Z A2 and Z A3 is N when X-L is N—CH 2 ;
each R 2 is independently F, Cl, or —CN;
each R 3 is independently F, —OH, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, or —C 3-4 cycloalkyl, or 2 R 3 s may together cyclize to form —C 3-4 spirocycloalkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1-OH;
q is 0, 1, or 2;
R 4 is-C 1-3 alkyl, —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 , wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 , and wherein said alkylene of —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 and said cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 ;
R 5 is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 1 oxo (═O),
0 to 1 —CN,
0 to 2 F atoms, and
0 to 2 substituents independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O ;

R 6 is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 halogens,
0 to 1 substituent selected from —OR O and —N(R N ) 2 , and
0 to 2-C 1-3 alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms, and
0 to 1 —OR O ;

each R O is independently H, or —C 1-3 alkyl, wherein C 13 alkyl may be substituted with 0 to 3 F atoms;
each R N is independently H, or —C 1-3 alkyl;
Z 1 , Z 2 , and Z 3 are each —CR Z , or
one of Z 1 , Z 2 , and Z 3 is N and the other two are —CR Z ; and
each R Z is independently H, F, Cl, or —CH 3 .

3. The compound of claim 1 , wherein Z A2 is CH or CR 2 ; and Z A3 is N; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein Z A2 is CH or CR 2 ; and Z A3 is N; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein Z A2 is N and Z A3 is CH or CR 2 , or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 , wherein Z A2 is N and Z A3 is CH or CR 2 , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein X is N, L is CH 2 , and Y is CH or N, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein X is N, L is CH 2 , and Y is CH or N, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 3 , wherein X is N, L is CH 2 , and Y is CH or N, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 4 , wherein X is N, L is CH 2 , and Y is CH or N, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 5 , wherein X is N, L is CH 2 , and Y is CH or N, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 6 , wherein X is N, L is CH 2 , and Y is CH or N, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method for trea

Assignees

• Pfizer

Inventors

• Aspnes Gary Erik
• Bagley Scott W
• Conn Edward L
• Curto John M
• Edmonds David J
• Flanagan Mark E
• Futatsugi Kentaro
• Griffith David A
• Huard Kim
• Limberakis Chris
• Mathiowetz Alan M
• Piotrowski David W
• Ruggeri Roger B

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title