GLP-1 receptor agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-11512070-B2
Application number	US-202017085534-A
Country	US
Kind code	B2
Filing date	Oct 30, 2020
Priority date	Dec 16, 2016
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

Abstract

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

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently F, Cl, —CN, —CH 3 , or —CF 3 ;
m is 0, 1, 2, or 3;
each R 2 is independently F, Cl, or —CN;
p is 0, 1 or 2;
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;
Y is CH or N;
R 3 is —CH 3 ;
q is 0 or 1; and
R 4 is —CH 2 CH 2 OCH 3 , C 1-3 alkylene-R 5 , or C 1-3 alkylene-R 6 ,
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 is CH or N;
Z 2 and Z 3 are each independently —CR Z or N, provided that when Z 1 or Z 3 is N, then Z 2 is —CR Z ; and
each R Z is independently H, F, Cl, or —CH 3 .

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z 1 , Z 2 , and Z 3 are each CR Z .

3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z 1 , Z 2 , and Z 3 are each CH.

4. The compound or pharmaceutically acceptable salt thereof of claim 2 , wherein R 4 is —CH 2 —R 5 ; R 5 is a 4- to 5-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 F atoms, and
0 to 1 substituent selected from —OCH 3 and —CH 2 OCH 3 .

5. The compound or pharmaceutically acceptable salt thereof of claim 2 , wherein R 4 is —CH 2 —R 5 ; and the heterocycloalkyl of R 5 is a monovalent radical of

wherein the 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 independently 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 .

6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is —CH 2 —R 5 ; the heterocycloalkyl of R 5 is a monovalent radical of

wherein the heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows each independently selected from:
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 independently substituted with 0 to 3 substituents as valency allows each independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O .

7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is —CH 2 —R 5 ; and the heterocycloalkyl of R 5 is a monovalent radical of

and wherein the heterocycloalkyl may be substituted with 0 to 1 substituent as valency allows selected from:
—CN,
F atom, and
0 to 1 substituent independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1 alkyl may be substituted with 0 to 3 substituents as valency allows with:
0 to 3 F atoms,
0 to 1 —CN, or
0 to 1 —OR O .

8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is —CH 2 —R 5 ; and the heterocycloalkyl of R 5 is a monovalent radical of

and wherein the heterocycloalkyl may be substituted as valency allows with 0 to 1 methyl, wherein said methyl may be substituted with 0 to 3 F atoms.

9. The compound or pharmaceutically acceptable salt thereof of claim 2 , wherein R 4 is —CH 2 —R 5 ; and the heterocycloalkyl of R 5 is a monovalent radical of

and wherein the heterocycloalkyl may be substituted as valency allows with 0 to 1 methyl, wherein said methyl may be substituted with 0 to 3 F atoms.

10. The compound or pharmaceutically acceptable salt thereof of claim 3 , wherein R 4 is —CH 2 —R 5 ; and the heterocycloalkyl of R 5 is a monovalent radical of

and wherein the heterocycloalkyl may be substituted as valency allows with 0 to 1 methyl, wherein said methyl may be substituted with 0 to 3 F atoms.

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

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

13. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 7 , and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 8 , and a pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 9 , and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 10 , and a pharmaceutically acceptable excipient.

Assignees

• Pfizer

Inventors

• Aspnes Gary Erik
• Bagley Scott W
• Curto John M
• Dowling Matthew S
• Edmonds David
• Flanagan Mark E
• Futatsugi Kentaro
• Griffith David A
• Huard Kim
• Ingle Gajendra
• Jiao Wenhua
• Limberakis Chris
• Mathiowetz Alan M
• Piotrowski David W
• Ruggeri Roger B

Classifications

• A61P17/06

  Antipsoriatics · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title