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 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.