GLP-1 receptor agonists and uses thereof
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.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently F, Cl, —CN, —CH 3 , or —CF 3 ;
m is 0 or 1;
R 2 is F;
p is 0, or 1;
q is 0 or 1;
R 3 is 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;
Y is CH or N;
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 and 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 is CH or N;
Z 3 is —CR Z or N; and
each R Z is independently H, F, Cl, or —CH 3 .
2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is —F, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CF 3 , isopropyl, or cyclopropyl.
3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
R 3 is —CH 3 ; and
R 4 is —CH 2 CH 2 OCH 3 , C 1-3 alkylene-R 5 , or C 1-3 alkylene-R 6 .
4. The compound or pharmaceutically acceptable salt thereof of claim 1 , 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 1 , 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.
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 1-3 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. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 8 , and a pharmaceutically acceptable excipient.
11. A compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently F, Cl, —CN, —CH 3 , or —CF 3 ;
m is 0 or 1;
R 2 is F;
p is 0, or 1;
R 3 is —C 1-2 alkyl, wherein —C 1-2 alkyl may be substituted as valency allows with 0 to 3 F atoms;
q is 0 or 1;
Y is CH or N;
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 1-3 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 , and
wherein said alkylene and 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;
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 3 is —CR Z or N; and
each R Z is independently H, F, Cl, or —CH 3 .
12. The compound or pharmaceutically acceptable salt thereof of claim 11 , wherein:
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 .
13. The compound or pharmaceutically acceptable salt thereof of claim 11 , wherein R 4 is —CH 2 —R 5 ; and 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 .
14. The compound or pharmaceutically acceptable salt thereof of claim 11 , 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 .
15. The compound or pharmaceutically acceptable salt thereof of claim 11 , 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 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.
16. The compound or pharmaceutically acceptable salt thereof of claim 11 , 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 1-3 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.
17. The compound or pharmaceutically acceptable salt thereof of claim 11 , 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.
18. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 11 , and a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 17 , and a pharmaceutically acceptable excipient.