Heterocyclic GLP-1 agonists

1. A method of treating type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound selected from:

121a

144a

145a

146a

and

146b

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound is administered orally.

3. The method of claim 1 , further comprising administering an additional therapy or therapeutic agent to the patient.

4. The method of claim 3 , wherein the additional therapy or therapeutic agent is an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent to treat non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

5. The method of claim 4 , wherein the anti-diabetic agent is a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose linked transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic peptide (GIP), an insulin or insulin analogue, an alpha glucosidase inhibitor, a sodium-glucose linked transporter 1 (SGLT1) inhibitor, or a combination thereof.

6. The method of claim 5 , wherein the biguanide is metformin.

7. The method of claim 4 , wherein the anti-obesity agent is neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine/dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, a sodium-glucose cotransporter 1 (SGLT-1) inhibitor, or a combination thereof.

8. The method of claim 4 , wherein the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or a combination thereof.

9. The method of claim 4 , wherein the agent to treat NASH is selected from the group consisting of an FXR agonist, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21) agonist, a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, or a combination thereof.

10. The method of claim 9 , wherein the acetyl-CoA carboxylase (ACC) inhibitor is PF-05221304.

11. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound is:

13. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound is:

15. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is:

17. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is:

19. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the compound is: