GLP-1 receptor agonists and uses thereof

1. A compound of Formula 1 ,

or a pharmaceutically acceptable salt thereof, wherein R is F, Cl, or —CN;

p is 0 or 1;

Ring A is phenyl or a 6-membered heteroaryl;

m is 0, 1, 2, or 3;

each R 1 is independently selected from 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;

R 2 is H or —C 1-3 alkyl, wherein alkyl is substituted with 0 to 1 OH;

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;

X-L is N—CH 2 , CHCH 2 , or cyclopropyl;

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 , —SO 2 —N(R N ) 2 , —N(C=(O)(R N ) 2 , —N(C=O)(R N ), 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 , 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. The compound of claim 1 , wherein the compound is a compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein R is F;

p is 0 or 1;

Ring A is phenyl or pyridinyl;

m is 0, 1, or 2;

each R 1 is independently selected from 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;

R 2 is H or CH 3 ;

X-L is N—CH 2 , or cyclopropyl;

Y is CH or N;

Z 3 is —CR z or N; and

R z is H, F, Cl, or —CH 3 .

3. The compound of claim 2 , wherein the compound is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein

Ring A is phenyl or pyridinyl;

m is 0, 1, or 2;

each R 1 is independently selected from F, Cl, or —CN;

R 2 is H or CH 3 ; and

Y is CH or N.

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

5. The compound of claim 3 , wherein R 4 is —CH 2 —R 6 , wherein R 6 is the 5-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substitutents as valency allows independently selected from:

0 to 2 halogens, wherein the halogen is independently selected from F and Cl,

0 to 1 —OCH 3 , and

0 to 1 —CH 3 , —CH 2 CH 3 , —CF 3 , or —CH 2 CH 2 OCH 3 ; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 3 , wherein R 2 is H, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein the compound is

2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; or

2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 3 , wherein R 2 is CH 3 , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein the compound is 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yllmethyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

2-({4-R2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yllmethyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

2-({4-R2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; or

2-({4-R2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

10. A crystal form (Form I) of anhydrous 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid having a powder X-ray diffraction pattern (CuKa radiation) comprising at least two characteristic peaks, in terms of 2θ, selected from at 3.7±0.2°; 7.3±0.2°; 8.5±0.2°; 10.1±0.2°; 14.7±0.2°; and 16.9±0.2°.

11. The crystal form of claim 10 having a powder X-ray diffraction pattern comprising peaks, at least three characteristic peaks, in terms of 2θ, selected from at 3.7±0.2°; 7.3±0.2°; 8.5±0.2°; 10.1±0.2°; 14.7±0.2°; and 16.9±0.2°.

12. A crystal form (Form A) of anhydrous 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt of 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2 having a powder X-ray diffraction pattern (CuKα radiation) comprising at least two characteristic peaks, in terms of 2θ, selected from at 7.7±0.2°; 15.2±0.2°; 15.7±0.2°; and 17.6±0.2°.

13. The crystal form of claim 12 having a powder X-ray diffraction pattern comprising at least three characteristic peaks, in terms of 2θ, selected from at 7.7±0.2°; 15.2±0.2°; 15.7±0.2°; and 17.6±0.2°.

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

15. A pharmaceutical composition comprising the crystal form of claim 10 and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising the crystal form of claim 12 and a pharmaceutically acceptable excipient.