Substituted triazole and imidazole compounds as glucagon-like peptide-1 receptor (GLP-1 r) agonists

Abstract

The present disclosure relates to new substituted triazole and imidazole compounds and pharmaceutically acceptable salts thereof; to their use in medicine; to pharmaceutical compositions containing them; to processes for their preparation; and to intermediates used in such processes. The substituted triazole and imidazole compounds may be useful in the treatment and amelioration of obesity.

Description

[0001] PC073242A

[0002] Substituted Triazole And Imidazole Compounds

[0003] Field of Invention

[0004] Provided herein are new substituted triazole and imidazole compounds that may be useful as glucagon-like peptide-1 receptor (GLP-1R) agonists, compositions containing said compounds, process to make said compounds, and methods comprising administering said compounds to a subject in need thereof.

[0005] Background of the Invention

[0006] Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes are recognized, Type 1 and Type 2. Type 1 diabetes (T1D) develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump. Type 2 diabetes mellitus (referred to generally as T2DM) usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.

[0007] Currently, various pharmacological approaches are available for treating hyperglycemia and subsequently, T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374). These may be grouped into six major classes, each acting through a different primary mechanism: (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Sulphonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema andanemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents, and frequent use may also lead to weight gain and carries a risk of hypoglycemia. (F) sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit reabsorption of glucose in the kidneys and thereby lower glucose levels in the blood. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0008] However, with the exception of GLP-1 R agonists and SGLT2 inhibitors, the drugs have limited efficacy and do not address the most important problems, the declining p-cell function and the associated obesity.

[0009] Obesity is a chronic disease that is highly prevalent in modern society and is associated with numerous medical problems including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a two to fourfold increased risk of coronary artery disease. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. Pharmacological intervention is generally less efficacious and associated with side effects. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.

[0010] Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases associated with T2DM include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia and metabolic dysfunction-associated fatty liver disease (MAFLD).

[0011] MAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. MAFLD and MASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids. The severity of MAFLD / MASH is based on the presence of lipid, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to MASH, a substantial portion does.

[0012] GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier, et al. Biodrugs. 2003; 17 (2): 93-102).In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).

[0013] Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1, liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

[0014] There remains a need for an easily-administered prevention and / or treatment for cardiometabolic and associated diseases.

[0015] Summary of the Invention

[0016] In one embodiment (Embodiment A1), the present invention provides a compound of Formula I:

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] ring A1is phenyl or a 5- or 6-membered heteroaryl;

[0020] each R1is independently halogen, cyano, RAMD, Rcy Rcv1-L1-, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, or Ci-4 fluoroalkoxy, wherein each of the C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0021] each L1is independently C1.4 alkylene optionally subsituted with 1, 2, 3, or 4 substituents each independently selected from halogen, cyano, C1.2 alkyl, and C1.2 fluoroalkyl;each Rcy1is independently phenyl or 5- to 6-membered heteroaryl, each of which is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ram1)(Ram2)-; N(Ram1)(Ram2)-C(=O)-; N(Ram1)(Ram2)-S(=O)2-; Ram2-C(=O)-, or Ram2-S(=O)2-, wherein each of the C3-4 cycloalkyl, (C3-4 cycloalkyl)-Ci-2alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0022] each Ram1is independently H or methyl;

[0023] each Ram2is independently C1.4 alkyl, Rcy2, or Rcy2-L2-, wherein the C1.4 alkyl is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, cyano, C3-4 cycloalkoxy, C3-4 fluorocycloalkoxy, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0024] each L2is independently C1.4 alkylene optionally subsituted with 1, 2, 3, or 4 substituents each independently selected from halogen, cyano, Ci-2alkyl, and Ci-2fluoroalkyl;

[0025] each Rcy2is independently C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, Ce- aryl, or 5- to 10-membered heteroaryl, each of which is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-S(=O)2-, Rd-C(=O)-N(RC)-, Rd-C(=O)-, or Rd-S(=O)2-N(Rc)-, wherein each of the C1.4 alkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, hydroxyl, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0026] RAMDis N(Ram3)(Ram4)-C(=O)-;

[0027] Ram3is H or methyl;

[0028] Ram4is C1.6 alkyl, Rcy3, or Rcy3-L3-, wherein the Ci-e alkyl is optionally subsituted with 1, 2, or 3 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(RC)-, or Rd-S(=O)2-N(Rc)-,;

[0029] each L3is independently C1.4 alkylene optionally subsituted with 1, 2, 3, or 4 substituents each independently selected from halogen, cyano, Ci-2alkyl, and Ci-2fluoroalkyl;

[0030] each Rcy3is independently C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, Ce- aryl, or 5- to 10-membered heteroaryl, each of which is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(Rc)-, or Rd-S(=O)2-N(Rc)-, wherein each of the C1.4 alkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5substituents each independently selected from halogen, cyano, hydroxyl, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0031] each of RL1and RL2is independently H or methyl; or

[0032] RL1and RL2, together with the carbon atom to which they are attached to, optionally form cyclopropyl;

[0033] each of T1and T2is independently N, CH, or CR2;

[0034] each R2is independently halogen, cyano, C1.2 alkyl, C1.2 fluoroalkyl, C1.2 alkoxy, or Ci-2 fluoroalkoxy;

[0035] each of the - bonds (designated as the x bond, y bond, and z bond respectively) represents a single or double bond;

[0036] each R3is independently F, HO-, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 hydroxylalkyl, C1.4 alkoxy, C1.4 fluoroalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4 cycloal kyl)-Ci.2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, cyano, HO-, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0037] T3is C, CRT3or N, provided (1) that when T3is CRT3or N then the y bond is a single bond and that (2) when T3is C then the y bond is a double bond;

[0038] RT3is H or R3;

[0039]

[0040] M-1 M-2

[0041]

[0042] M-3 M-4;

[0043] each of RL3and RL4is independently H or methyl; orRL3and RL4, together with the carbon atom to which they are attached to, optionally form cyclopropyl; or

[0044] RL3and RT3, together with the two carbon atoms to which they are attached to, optionally form cyclopropyl;

[0045] T4is CH, CRT4, or N;

[0046] RT4is halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0047] Y1is -(CRL5RL6)q- or absent;

[0048] each RL5and RL6is independently selected from H and C1.2 alkyl;

[0049] R4is C1.6 alkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein

[0050] the C1.6 alkyl of R4is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-;

[0051] N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(Rc)-, or Rd-S(=O)2-N(Rc)-

[0052] the C3-6 cycloalkyl of R4is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from oxo (=0), hydroxyl, halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, C1.2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)( C(=0)-; N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(

[0053]

[0054] S(=0)2-N(RC)-, wherein each of the C1.4 alkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci.

[0055] 2 alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, hydroxyl, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;

[0056] the 4- to 6-membered heterocycloalkyl of R4is optionally substituted with 1, 2, or 3 substituents each independently selected from oxo (=0), cyano, halogen, H0-, N(Ra)(Rb)-, (Ra)(Rb)N-C(=O)-, Rd-C(=O)-N(Rc)-, N(Ra)(Rb)- S(=0)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-S(=O)2-N(Rc)-, C1.4 alkyl, C1.4 alkoxy, C3-4cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, H0-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;

[0057] the 5- to 6-membered heteroaryl of R4is optionally substituted with 1, 2, or 3 substituents each independently selected from cyano, halogen, H0-, N(Ra)(Rb)-, (Ra)(Rb)N-C(=O)-, Rd-C(=O)-N(Rc)-, (Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd- S(=0)2-, Rd-S(=0)2-N(Rc)-, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, HO-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;

[0058] each Rais independently H, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-C1.4 alkyl-;

[0059] each Rbis independently H or selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce- aryl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of HO-, cyano, C1.4 alkyl, C3-7 cycloalkyl, C1.4 hydroxylalkyl, C1-4 alkyl-S-, HC(=O)-, HO-C(=O)-, C1.4 alkyl-C(=O)-, C1.4 alkyl-O-C(=O)-, H2N-C(=O)-, (C1.4 alkyl)2-N-C(=O)-, C1.4 haloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy;

[0060] or Raand Rbtogether with the N atom to which they are attached form 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, HO-, cyano, oxo, HC(=O)-, HO-C(=O)-, C1.4 alkyl-C(=O)-, C1.4 alkyl-O-C(=O)-, H2N-C(=O)-, (C1.4 alkyl)2-N-C(=O)-, C1.4 alkyl, C1.4 alkoxy, C1.4 hydroxylalkyl, C1.4 haloalkyl, and C1.4 haloalkoxy; each Rcis independently selected from the group consisting of H, C1.4 alkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-;

[0061] each Rdis independently selected from the group consisting of Ci-e alkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, Ce- aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce- aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CF3, cyano, HO-, oxo, C1.4 alkyl-S-, C1.4 alkyl, C1.4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy;

[0062] R5is R5a, R5b, R5c, or R5d:

[0063]

[0064] R5aR5b

[0065]

[0066] each of Z2, Z3, Z4is independently OR8or N, provided (a) that at least one of Z2and Z3in each of R5a, R5b, and R5cis N and provided (b) that at least one of Z2, Z3, and Z4in R5dis N;

[0067] R7is H, Ci-4 alkyl, C1.4 fluoroalkyl, C3-4 cycloalkyl, or (C3-4cycloalkyl)-Ci-2 alkyl-; each of R8is independently H, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 alkoxy, C1.4 fluoroalkoxy, C3-4 cycloalkyl, C3-4 fluorocycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl-;

[0068] m is 0, 1, 2, 3, or 4;

[0069] n is 0, 1, or 2;

[0070] t is 0, 1, 2, or 3; and

[0071] q is 1, 2, or 3.

[0072] The present invention also provides a pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable excipient or carrier.

[0073] The compound of Formula I or a pharmaceutically acceptable salts thereof may modulate (e.g. agonize) the activity of GLP-1 R and may be useful in the treatment, prevention, and amelioration of diseases, disorders and conditions mediated by GLP-1 R.

[0074] The present invention also provides a method for treating or preventing a GLP-1 R-mediated condition, disease, or disorder in a subject (e.g., a mammal or a human), which method includes administering to the subject (e.g., the mammal or human) the compound of Formula I or a pharmaceutically acceptable salt of the compound.

[0075] The present invention also provides the compound of Formula I or a pharmaceutically acceptable salt of the compound for use in treating or preventing a GLP-1 R-mediated condition, disease, or disorder.

[0076] The GLP-1 R-mediated condition, disease, or disorder includes one selected from diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and relatedcomorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0077] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0078] Detailed Description of the Invention

[0079] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0080] A1 A compound of Formula I or a pharmaceutically acceptable salt thereof, as defined above.A2. A compound of embodiment A1 or a pharmaceutically acceptable salt thereof, ring A1is phenyl.

[0081] A3. A compound of embodiment A1 or a pharmaceutically acceptable salt thereof, wherein ring A1is 5- or 6-membered heteroaryl.

[0082] A4. A compound of embodiment A1 or a pharmaceutically acceptable salt thereof, wherein ring A1is 5-membered heteroaryl.

[0083] A5. A compound of embodiment A1 or a pharmaceutically acceptable salt thereof, wherein ring A1is 6-membered heteroaryl.

[0084] A6. A compound of any one of embodiments A1 to A5 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), or a pharmaceutically acceptable salt thereof, wherein each R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy, wherein each of the C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy.

[0085] A7. A compound of any one of embodiments A1 to A6 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein each R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy.

[0086] In some further embodiments, each R1is independently halogen, cyano, C1.4 alkyl, or Ci- 4 fluoroalkyl.

[0087] In some further embodiments, each R1is independently halogen or cyano.

[0088] In some further embodiments, each R1is independently halogen.

[0089] A8. A compound of any one of embodiments A1 to A5 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein one R1is RAMDand each of the other R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C3-4 cycloalkyl, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy.

[0090] A9. A compound of any one of embodiments A1 to A8 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein m is 2 or 3.A10. A compound of any one of embodiments A1 to A8 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein m is 2.

[0091] A11. A compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein:

[0092]

[0093] each R1is independently halogen or cyano.

[0094] A12. A compound of any one of embodiments A1, A3, and A8 to A10 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein:

[0095]

[0096] ml is 1 or 2;

[0097] each R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C3-4 cycloalkyl, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy.

[0098] A13. A compound of any one of embodiments A1 to A12 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein each of RL1and RL2is independently H or methyl.A14. A compound of any one of embodiments A1 to A12 or a pharmaceutically acceptable salt thereof, wherein each of RL1and RL2is H.

[0099] A15. A compound of any one of embodiments A1 to A14 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T1is N.

[0100] A16. A compound of any one of embodiments A1 to A15 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T2is N.

[0101] A17. A compound of any one of embodiments A1 to A14 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T1is N and T2is N.

[0102] A18. A compound of any one of embodiments A1 to A17 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein each R2is independently F, Cl, cyano, C1.2 alkyl, or C1.2 fluoroalkyl.

[0103] In some further embodiments, each R2is independently F, Cl, cyano, methyl, or C1.2 fluoroalkyl.

[0104] In some further embodiments, each R2is independently F or Cl.

[0105] A19. A compound of any one of embodiments A1 to A18 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein n is 0 or 1.

[0106] A20. A compound of any one of embodiments A1 to A19 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein n is 0.

[0107] A21. A compound of any one of embodiments A1 to A20 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T3is CRT3.

[0108] A22. A compound of any one of embodiments A1 to A21 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein RT3is H.

[0109] A23. A compound of any one of embodiments A1 to A22 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein each R3is independently HO-, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 hydroxylalkyl, C3-4 cycloalkyl, or (C3-4 cycloal kyl)-Ci.2 alkyl-, wherein each of the C3-4 cycloalkyl or (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, cyano, HO-, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy.In some further embodiments, each R3is independently C1.4 alkyl, C1.4 fluoroalkyl, C1.4 hydroxylalkyl, C3-4 cycloalkyl, or (C3-4cycloalkyl)-Ci-2 alkyl-.

[0110] In some further embodiments, each R3is independently C1.4 alkyl, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-Ci-2 alkyl-.

[0111] In some further embodiments, each R3is independently C1.4 alkyl.

[0112] A24. A compound of any one of embodiments A1 to A23 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein t is 0, 1 or 2.

[0113] A25. A compound of any one of embodiments A1 to A23 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein t is 0.

[0114] A26. A compound of any one of embodiments A1 to A20 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T3is N.

[0115] A27. A compound of any one of embodiments A1 to A26 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherien Moiety M is Moiety M-1.

[0116] In some further embodiments, T3is CRT3.

[0117] In some further embodiments, T3is N.

[0118] A28. A compound of any one of embodiments A1 to A26 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein Moiety M is Moiety M-2 or Moiety M-3

[0119] In some further embodiments, Moiety M is Moiety M-2.

[0120] In some further embodiments, Moiety M is Moiety M-3.

[0121] A29. A compound of any one of embodiments A1 to A26 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein Moiety M is Moiety M-4.

[0122] A30. A compound of any one of embodiments A1 to A29 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein each of RL3and RL4is independently H or methyl.

[0123] A31. A compound of any one of embodiments A1 to A29 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein each of RL3and RL4is H.

[0124] A32. A compound of any one of embodiments A1 to A29 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein RL3and RT3, together with the two carbon atoms to which they are attached to, optionally form cyclopropyl.A33. A compound of any one of embodiments A1 to A32 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein Y is -(CH2)q- or absent.

[0125] A34. A compound of any one of embodiments A1 to A32 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein Y is -CH2- or absent.

[0126] In some further embodiments, Y is -CH2-.

[0127] In some further embodiments, Y is absent.

[0128] A35. A compound of any one of embodiments A1 to A34 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein:

[0129] R4is 4- to 6-membered heterocycloalkyl that is optionally substituted with 1, 2, or 3 substituents each independently selected from oxo (=0), cyano, halogen, H0-, N(Ra)(Rb)-, N(Ra)(Rb)-C(=O)-, Rd-C(=O)-N(Rc)-, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, H0-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;

[0130] Rais H, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-;

[0131] Rbis H or selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, Ce- aryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (Ce- aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-C1.4 alkyl-;

[0132] or Raand Rbtogether with the N atom to which they are attached form pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of C1.4 alkyl-C(=O)-, (C1.4 alkyl)2-N-C(=0)-, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, and C1.4 haloalkoxy;

[0133] Rcis selected from the group consisting of H, C1.4 alkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-; and

[0134] Rdis selected from the group consisting of Ci-e alkyl, C3-7 cycloalkyl, Ce- aryl, 5 (C3-7 cycloalkyl)-Ci-4 alkyl-, and (Ce- aryl)-Ci-4 alkyl-, wherein each of the selections in the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CF3, cyano, H0-, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy.

[0135] A36. A compound of any one of embodiments A1 to A35 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R4is 4- to 6-membered heterocycloalkyl that is optionally substituted with 1, 2, or 3 substituents each independentlyselected from oxo (=0), halogen, H0-, C1.4 alkyl, Ci.4haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-.

[0136] A37. A compound of any one of embodiments A1 to A36 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R4is 4- to 6-membered heterocycloalkyl that is optionally substituted with 1, 2, or 3 substituents each independently selected from C1.4 alkyl, Ci.4haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-.

[0137] A38. A compound of any one of embodiments A1 to A37 or a pharmaceutically acceptable

[0138] salt thereof (including any further embodiment thereof), wherein R4is selected from

[0139]

[0140]

[0141] In some further embodiments,

[0142]

[0143] In some further embodiments,

[0144]

[0145] In some further embodiments, R4is

[0146]

[0147] In some further embodiments, R4is

[0148]

[0149] A39. A compound of any one of embodiments A1 to A34 or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein:

[0150] R4is 5- to 6-membered heteroaryl that is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, HO-, -NRaRb, -C(=O)-NRaRb, -NRcC(=O)Rd, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituentseach independently selected from halogen, HO-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;

[0151] Rais H, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-;

[0152] Rbis H or selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, Ce- aryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (Ce- aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-C1.4 alkyl-;

[0153] or Raand Rbtogether with the N atom to which they are attached form pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of C1.4 alkyl-C(=O)-, (C1.4 alkyl)2-N-C(=O)-, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, and C1.4 haloalkoxy;

[0154] Rcis selected from the group consisting of H, C1.4 alkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-; and

[0155] Rdis selected from the group consisting of Ci-e alkyl, C3-7 cycloalkyl, Ce- aryl, 5 (C3-7 cycloalkyl)-Ci-4 alkyl-, and (Ce- aryl)-Ci-4 alkyl-, wherein each of the selections in the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CF3, cyano, HO-, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy.

[0156] A40. A compound of any one of embodiments A1 to A34 and A39, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R4is 5- to 6-membered heteroaryl that is optionally substituted with 1, 2, or 3 substituents each independently selected from cyano, halogen, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-.

[0157] A41. A compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T4is N.

[0158] A42. A compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein T4is CH or CRT4.

[0159] A43. A compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R5is R5a.

[0160] In some further embodiments, Z1is O.

[0161] In some further embodiments, Z1is O; Z2is N; and Z3is CR8. In some yet further embodiments, R8is H or C1.4 alkyl. In some still further embodiments, R8is H.

[0162] A44. A compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R5is R5b.A45. A compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R5is R5c.

[0163] A46. A compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein R5is R5d.

[0164] A47. A compound of embodiment A1 or a pharmaceutically acceptable salt thereof, which is 5-[5-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)cyclohexyl]methyl}-4-(4,4-dimethyloxolan-3-yl)-4 / 7-1 ,2,4-triazol-3-yl]-1 ,2-oxazol-3-ol,

[0165]

[0166] or a pharmacutically acceptable salt thereof.

[0167] In some further embodiments, the compound of invention is one of diastereoisomer of 5-[5-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)cyclohexyl]methyl}-4-(4,4-dimethyloxolan-3-yl)-4 / 7-1,2,4-triazol-3-yl]-1,2-oxazol-3-ol, ora pharmacutically acceptable salt thereof.

[0168] In some further embodiments, the compound of invention is 2-[(4-chloro-2-fluorophenyl)methyl]-4-({(1R,4r)-4-[(4-[(3R)-4,4-dimethyloxolan-3-yl]-5-{3-[(4-methoxyphenyl)methoxy]-1 ,2-oxazol-5-yl}-4 / 7-1 ,2,4-triazol-3-yl)methyl]cyclohexyl}oxy)pyrimidine,

[0169]

[0170] or a pharmacutically acceptable salt thereof.

[0171] A48. A compound of embodiment A1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds in the following table:

[0172]

[0173]

[0174] or a pharmaceutically acceptable salt thereof.

[0175] In some further embodiments, the compound of invention is a compound of embodiment A1 , selected from the group consisting of the compounds in the following table:

[0176]

[0177] or a pharmaceutically acceptable salt thereof.

[0178] Any of the compounds described in embodiments A47 to A48, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds in embodiments A47 to A48 or in embodiments A1 to A46, or pharmaceutically acceptable salts thereof.B1 A pharmaceutical composition comprising a compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), and at least one pharmaceutically acceptable excipient.

[0179] C1 A method for treating a condition, disease, or disorder in a subject comprising administering to the subject a compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), or a method for weight management of a subject comprising administering to the subject a compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof), wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youthonset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’sdisease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0180] C2 A method of embodiment C1, further comprising administering an additional therapeutic agent.

[0181] C3 A method of embodiment C1 or C2, wherein the condition, disease, or disorder is obesity.

[0182] C4 A method of embodiment C1 or C2, wherein the method is for weight management.

[0183] In some further embodiments, the weight management is chronic weight management. In some further embodiments, the subject to be treated is overweight [i.e. having a body mass index (BMI) of 27 kg / m2or greater] when the weight management treatment is initiated. In some further embodiments, the subject to be treated is adult. In some yet further embodiments, the adult subject to be treated has an initial BMI of 27 kg / m2or greater in the presence of at least one weight-related comorbid condition (e.g., hypertension, T2DM, or dyslipidemia).

[0184] In some further embodiments, the subject to be treated is obese (i.e. having an BMI of 30 kg / m2or greater) when the weight management treatment is initiated. In some yet further embodiments, the subject to be treated is adult.

[0185] In some further embodiments, the subject to be treated is a pediatric patient. In some yet further embodiments, the pediatric patient to be treated is aged 12 years or older with an initial BMI at the 95thpercentile or greater for age and sex (obese pediatric patient).

[0186] D1. A compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof) for use in treating or preventing a condition, disease, or disorder, or for use in weight management, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onsetT2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).D2 The compound or pharmaceutically acceptable salt thereof for use of embodiment D1 , wherein the compound or pharmaceutically acceptable salt is used in combination with an additional therapeutic agent.

[0187] D3 The compound or pharmaceutically acceptable salt thereof for use of embodiment D1 or D2, wherein the condition, disease, or disorder is obesity.

[0188] D4 The compound or pharmaceutically acceptable salt thereof for use of embodiment D1 or D2, wherein the method is for weight management.

[0189] E1. Use of a compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof) in treating or preventing a condition, disease, or disorder, or in weight management, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early- onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonaryhypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0190] E2 The use of embodiment E1 wherein the compound or pharmaceutically acceptable salt thereof is used in combination with an additional therapeutic agent.

[0191] E3 The use of embodiment E1 or E2, wherein the condition, disease, or disorder is obesity. E4 The use of embodiment E1 or E2, wherein the method is for weight management.

[0192] F1. Use of a compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof) in in manufacturing a medicament for treating or preventing a condition, disease, or disorder, or for weight management, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet- Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia[including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0193] F2 The use of embodiment F1 wherein the compound or pharmaceutically acceptable salt thereof is to be used in combination with an additional therapeutic agent for treating or preventing the condition, disease, or disorder, or for weight management.

[0194] F3 The use of embodiment F1 or F2, wherein the condition, disease, or disorder is obesity.

[0195] F4 The of embodiment F1 or F2, wherein the medicament is for weight management.

[0196] Each of the embodiments described herein (including any further embodiment thereof) may be combined with any other embodiment(s) described herein (including any further embodiment thereof) not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein.G1 A method for modulating (e.g. agonizing) GLP-1 R (either in vitro or in vivo), comprising contacting (including incubating) the GLP-1 R with a compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof (including any further embodiment thereof).

[0197] G2. The method of embodiment G1, wherein said modulating is agonizing.

[0198] Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein.

[0199] Definitions

[0200] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0201] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0202] “Compounds of the invention” include compounds of Formula I, and the novel intermediates used in the preparation thereof. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0203] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0204] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a compound as described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.

[0205] If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

[0206] As used herein, a wavy line,"

[0207]

[0208] denotes a point of attachment of a substituent or moiety to another group or moiety.

[0209] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the ring-forming atoms in the ring that are substitutable (i.e., bonded to one or more hydrogen atoms). For example, as shown in Formulaa-101 below, an R2may be bonded to any one of the substitutable ring-forming atoms of the ring containing the variables T1and T2, each of which bears a hydrogen atom. Where either or both of T1and T2are CH, then these ring-forming carbon atoms are also substitutable and thus an R2from (R2)ncan also be bonded to at these positions. For another example, as shown in Formula a-101 below, an R3may be bonded to any ring-forming atom that is substitutable in the 6-membered ring containing the variable T3(i.e. , bonded to any one of substitutable ringforming atoms of the 6-membered ring containing the variable T3).

[0210]

[0211] As used herein, the term “alkyl” means an acyclic, saturated aliphatic hydrocarbon group which may be straight / linear or branched. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl and terf-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix Cj.j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Ci-s alkyl refers to alkyl of one to eight carbon atoms, inclusive; for another example, Ci-6 alkyl refers to alkyl of one to six carbon atoms, inclusive; for yet another example, C1.4 alkyl refers to alkyl of one to four carbon atoms, inclusive. Representative examples of C1.4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and terf-butyl. For another example, C1.2 alkyl refers to alkyl of one to two carbon atoms, inclusive (i.e., methyl or ethyl). The alkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents, when so specified.

[0212] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual sub-combination of the members of such groups and ranges. For example, the term “C1.4 alkyl” is specifically intended to include Ci alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl. For another example, the term “4- to 6-membered heterocycloalkyl” is specifically intended to include any 4-, 5-, or 6-membered heterocycloalkyl group. For yet another example, the term "C3-6 cycloalkyl” is specifically intended to include any saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3, 4, 5, or 6 ring-forming carbon atoms.As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and pyrrolindinyl is an example of a 5-membered heterocycloalkyl group.

[0213] As used herein, the term “alkoxy” or “alkyloxy” refers to an -O-alkyl group (which can also be shown as alkyl-O-). For example, the term “C1.4 alkoxy” or “C1.4 alkyloxy” refers to an -O-(Ci-4 alkyl) group; for another example, the term “C1.2 alkoxy” or “C1.2 alkyloxy” refers to an -O-(Ci-2alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. The alkoxy or alkyloxy group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents when so specified.

[0214] The term "halo" or "halogen" as used herein, means -F, -Cl, -Br, or -I.

[0215] As used herein, the term “haloalkyl” refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For example, the term “C1.4 haloalkyl” refers to a C1.4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); and the term “C1.2 haloalkyl” refers to a C1.2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). Examples of haloalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -C2F5, -CH2CI and the like.

[0216] As used herein, the term “fluoroalkyl” as used herein means an alkyl as defined herein substituted with one or more fluoro (-F) substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a fluorine atom). For example, the term “C1.2 fluoroalkyl” refers to a C1.2 alkyl group (i.e., methyl or ethyl) having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a fluorine atom); and the term “Ci fluoroalkyl” refers to methyl having 1, 2, or 3 fluorine substituents. Examples of Ci fluoroalkyl include fluoromethyl, difluoromethyl and trifluoromethyl; some examples of C2 fluoroalkyl include 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1 ,2-difluoroethyl, 2,2,2-trifluoroethyl, 1 , 1 ,2-trifluoroethyl, and the like.

[0217] As used herein, the term “cyanoalkyl” as used herein means an alkyl as defined herein substituted with one or more (e.g. 1 or 2) cyano substituents. For example, the term “C1.4 cyanoalkyl” refers to a C1.4 alkyl group (i.e., methyl or ethyl) having one or more (e.g. one or two) cyano substituents. Examples of C1.4 cyanoalkyl include cyanomethyl, 1 -cyanoethyl, 2-cycanoethyl, and the like.

[0218] As used here, the term “haloalkoxy” refers to an -O-haloalkyl group (which can also be shown as haloalkyl-O-). For example, the term “C1.4 haloalkoxy” refers to an -O-(Ci-4 haloalkyl) group; and the term “C1.2 haloalkoxy” refers to an -O-(Ci-2 haloalkyl) group. For yet another example, the term “Ci haloalkoxy” refers to a methoxy group having one, two, or three halogen substituents. An example of haloalkoxy is -OCF3 or -OCHF2.As used here, the term “fluoroalkoxy” refers to an -O-fluoroalkyl group. For example, the term “C1.2 fluoroalkoxy” refers to an -O-(Ci-2 fluoroalkyl) group; and the term “Ci fluoroalkoxy” refers to an -O-(Ci fluoroalkyl) group. Examples of Ci fluoroalkoxy include -O-CH2F, -O-CHF2, and -O-CF3. Some examples of C2 fluoroalkoxy include -O-CH2CHF2, -O-CH2-CHF2, -O-CH2CF3, -O-CF2CH3, and -O-CF2CF3.

[0219] As used herein, the term “hydroxylalkyl” or “hydroxyalkyl” refers to an alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. The term “C1.4 hydroxylalkyl” or “C1.4 hydroxyalkyl” refers to a C1.4 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; and the term “C1.2 hydroxylalkyl” or “C1.2 hydroxyalkyl” refers to a C1.2 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. An example of hydroxylalkyl is -CH2OH or -CH2CH2OH.

[0220] As used herein, the term “halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, and I respectively).

[0221] As used herein, the term "alkenyl" refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, as used herein, the term "C2-20 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 20 carbon atoms; the term "C2-10 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 10 carbon atoms; the term "C3-6 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 3 to 4 carbon atoms; and the term "C2-4 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 4 carbon atoms. For another example, the term "C2-6 alkenyl" means straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. An alkenyl group optionally can be substituted by one or more (e.g. 1 to 5) suitable substituents. When the compounds of Formula I contain an alkenyl group, the alkenyl group may exist as the pure E form, the pure Z form, or any mixture thereof.

[0222] As used herein, the term "alkynyl" refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms. For example, as used herein, the term "C2-6 alkynyl” refers to straight or branched hydrocarbon chain alkynyl radicals as defined above, having 2 to 6 carbon atoms. For another example, the term "C2-20 alkynyl” is used herein to mean straight or branched hydrocarbon chain alkynyl radicals as defined above, having 2 to 20 carbon atoms; the term "C2-10 alkynyl” refers to straight or branched hydrocarbon chain alkynyl radicals as defined above, having 2 to 10 carbon atoms; and the term "C3-6 alkynyl” refers to straight or branchedhydrocarbon chain alkynyl radicals as defined above, having 3 to 6 carbon atoms. An alkynyl group optionally can be substituted by one or more (e.g. 1 to 5) suitable substituents.

[0223] As used herein, the term “cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e. , -C=N (which can also be shown as -CN or NC- or N C-), wherein the point of attachment is through the carbo atom.

[0224] "Hydroxy" or “hydroxyl” as used herein refers to an -OH group (which can be shown as HO-).

[0225] As used herein, the term “oxo” refers to a double bonded oxygen (i.e., =0, which can also be shown as 0=).

[0226] As used herein, the term "cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclics such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclics including spiro, fused, or bridged systems (such as bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl or bicyclo[5.2.0]nonanyl, decahydronaphthalenyl, etc.). The cycloalkyl group has 3 to 15 (e.g., 3 to 14, 3 to 10, 3 to 6, 3 to 4, or 4 to 6) carbon atoms. In some embodiments the cycloalkyl may optionally contain one, two, or more non-cumulative non-aromatic double or triple bonds and / or one to three oxo groups. In some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms. The term "C3-7 cycloalkyl" as used herein, means a saturated or unsaturated (but non-aromatic) cyclic hydrocarbon group containing from 3 to 7 carbons. The term "C3-6 cycloalkyl" as used herein, means a saturated or unsaturated (but non-aromatic) cyclic hydrocarbon group containing from 3 to 6 carbons. The term "C3-4 cycloalkyl" as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 4 carbons. Examples of C3-4 cycloalkyl include cyclopropyl and cyclobutyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (including aryl and heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyridinyl derivatives of cyclopentane (a 5-membered cycloalkyl), cyclopentene, cyclohexane (a 6-membered cycloalkyl), and the like, for example, 6,7-dihydro-5 / 7-cyclopenta[b]pyridinyl, 5, 6,7,8-tetrahydroquinolinyl, or 5,6,7,8-tetrahydroisoquinolinyl, each of which includes a 5-membered or 6-membered cycloalkyl moiety that is fused to a heteroaryl ring (i.e. the pyridinyl ring). The cycloalkyl or C3-4 cycloalkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents when so specified.

[0227] As used herein, the term “halocycloalkyl” refers to a cycloalkyl group having one or more halogen substituents (up to perhalocylcoalkyl, i.e., every hydrogen atom of the cycloalkyl group has been replaced by a halogen atom). For example, the term “C3-4 halocycloalkyl” refers to a C3-4 cycloalkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the cycloalkyl group has been replaced by a halogen atom). Examples of halocycloalkyl groups include 2-fluorocyclopropan-1-yl, 2,2-difluorocyclopropan-1-yl, and the like.As used herein, the term “fluorocycloalkyl” as used herein means a cycloalkyl as defined herein substituted with one or more fluoro (-F) substituents (up to perfluoroalkyl, i.e. , every hydrogen atom of the cycloalkyl group has been replaced by a fluorine atom). For example, the term “C3-4 fluorocycloalkyl” refers to a C3-4 cycloalkyl group (e.g., cyclcopropyl) having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the cycloalkyl group has been replaced by a fluorine atom). Examples of C3-4 fluorocycloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl; some examples of C2 fluoroalkyl include 2-fluorocyclopropan-1-yl, 2,2-difluorocyclopropan-1-yl, and the like.

[0228] As used herein, the term “cycloalkoxy” refers to an -O-cycloalkyl group (which can also be shown as cycloalkyl-O-). For example, the term “C3-4 cycloalkoxy” refers to an -O-(C3-4 cycloalkyl) group. Examples of C3-4 cycloalkoxy include -O-(cyclopryl) and -O-(cyclobutyl), and the like. The cycloalkoxy or C3-4 cycloalkoxy group optionally can be substituted by 1 or more (e.g., 1 to 3) suitable substituents when so specified.

[0229] As used herein, the term “halocycloalkoxy” refers to an -O-halocycloalkyl group (which can also be shown as halocycloalkyl-O-). For example, the term “C3-4 halocycloalkoxy” refers to an -O-(C3-4 halocycloalkyl) group.

[0230] As used herein, the term “fluorocycloalkoxy” refers to an -O-fluorocycloalkyl group (which can also be shown as fluorocycloalkyl-O-). For example, the term “C3-4 fluorocycloalkoxy” refers to an -O-(C3-4 fluorocycloalkyl) group.

[0231] The term "(C3-7 cycloalkyl)-Ci-4 alkyl-" as used herein, means a C3-7 cycloalkyl as defined herein, appended to the parent molecular moiety through a C1.4 alkyl group, as defined herein. The term "(C3-6 cycloalkyl)-Ci-4 alkyl-" as used herein, means a C3-6 cycloalkyl as defined herein, appended to the parent molecular moiety through a C1.4 alkyl group, as defined herein. Some examples of (C3-7 cycloalkyl)-Ci-4 alkyl- include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.

[0232] The term "(C3-6 cycloalkyl)-Ci-2 alkyl-" as used herein, means a C3-6 cycloalkyl as defined herein, appended to the parent molecular moiety through a C1.2 alkyl group, as defined herein. The term "(C3-4 cycloalkyl)-Ci-2 alkyl-" as used herein, means a C3-4 cycloalkyl as defined herein, appended to the parent molecular moiety through a C1.2 alkyl group, as defined herein.

[0233] As used herein, the term “heterocycloalkyl” refers to a monocyclic or polycyclic [including 2 or more rings that are fused together, including spiro, fused, or bridged systems, for example, a bicyclic ring system], saturated or unsaturated, non-aromatic 4- to 15-membered ring system (such as a 4- to 14-membered ring system, 4- to 12-membered ring system, 4- to 10-membered ring system, 5- to 10-membered ring system, 4- to 7-membered ring system, 4-to 6-membered ring system, or 5- to 6-membered ring system), including 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S and N (and optionally P or B when present). The heterocycloalkyl group can also optionally containone or more oxo (i.e. , =0 or 0=) or thiono (i.e. , =S or S=) groups. For example, the term "4- to 10-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 10-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. For another example, the term "4-to 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 6-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. For yet another example, the term "5- or 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5- or 6-membered ring system that comprises one or more ringforming heteroatoms each independently selected from O, S and N. The heterocycloalkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents, when so specified.

[0234] Some examples of 4- to 6-membered heterocycloalkyl include azetidinyl, oxetanyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiazinyl, and tetrahydropyranyl (also known as oxanyl). Some further examples of 4-to 7-heterocycloalkyl include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl (e.g., tetrahydro-2 / 7-pyran-4-yl), imidazolidin-1 -yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4-oxazepan-2-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1 ,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), 2-oxoazepan-3-yl, and the like.

[0235] As used herein, the term "aryl" refers to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. The aryl group has 6 or 10 carbon atoms in the ring(s). Most commonly, the aryl group has 6 carbon atoms in the ring. For example, as used herein, the term “Ce- aryl” means aromatic radicals containing from 6 to 10 carbon atoms such as phenyl or naphthyl. The aryl group is optionally substituted by 1 or more (such as 1 to 5) suitable substituents.

[0236] As used herein, the term “heteroaryl” refers to monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms) each independently selected from O, S and N in at least one ring. The heteroaryl group has 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, the heteroaryl group has 5 to 10 ring-forming atoms including one to four heteroatoms. The heteroaryl group can also contain one to three oxo or thiono (i.e., =S) groups. In some embodiments, the heteroaryl group has 5 to 8 ring-forming atoms including one, two or three heteroatoms. For example, the term "5-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 ring-forming atoms in the monocyclic heteroaryl ring; the term "6-membered heteroaryl” refers to a monocyclicheteroaryl group as defined above with 6 ring-forming atoms in the monocyclic heteroaryl ring; and the term "5- or 6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 or 6 ring-forming atoms in the monocyclic heteroaryl ring. Examples of monocyclic heteroaryls include those with 5 ring-forming atoms including one to three heteroatoms or those with 6 ring-forming atoms including one, two or three nitrogen heteroatoms. Examples of fused bicyclic heteroaryls include two fused 5- and / or 6-membered monocyclic rings including one to four heteroatoms. A heteroaryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents, when so specified.

[0237] Some examples of heteroaryl groups include pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridine-4-yl), pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), pyridazinyl (e.g., pyridazin-3-yl, or pyridazin-4-yl), thienyl, furyl, imidazolyl (e.g., 1 / 7-imidazol-4-yl), pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1 ,2-thiazolyl, 1 ,3-thiazolyl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl), tetrazolyl (e.g., 2 / 7-tetrazol-5-yl), triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,3,4-thiadiazolyl, or 1 ,2,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, benzothiazolyl, 1,2-benzoxazolyl, 1 / 7-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1 / 7-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[2, 1-c][1 , 2 , 4]triazi ny I , imidazo[1 ,5-a]pyrazinyl, imidazo[1 , 2-a] py ri m id i ny 1 , 1 / 7-i ndazoly I , 9 / 7-purinyl, imidazo[1,2-a]pyrimidinyl, [1 ,2,4]triazolo[1 ,5-a]pyridinyl, [1 ,2,4]triazolo[1 ,5-a]pyrimidinyl, [1 ,2,4]triazolo[4,3-b]pyridazinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4-c]pyridazinyl, pyrazolo[1 ,5-a]pyrim idinyl , 6,7-dihydro-5 / 7-pyrrolo[1 ,2-b][1 ,2,4]triazolyl , pyridone, pyrimidone, pyrazinone, pyrimidinone, 7 / 7-imidazol-2(3 / 7)-one, 7 / 7-pyrrole-2, 5-dione, 3-oxo-2 / 7-pyridazinyl, 1 / 7-2-oxo-pyrimidinyl, 1 / 7-2-oxo-pyridinyl, 2,4(1 / 7,3 / 7)-dioxo-pyrimidinyl, 1 / 7-2-oxo-pyrazinyl, and the like.

[0238] The term "(Ce- aryl)-Ci-4 alkyl-" as used herein, means a Ce- aryl group as defined herein, appended to the parent molecular moiety through a C1.4 alkyl group, as defined herein. The (Ce- aryl)-Ci-4 alkyl- group optionally can be substituted by 1 or more (e.g., 1 to 3) suitable substituents, when so specified.

[0239] The term “(5- to 10-membered heteroaryl)-Ci-4 alkyl-" as used herein, means a 5- to 10-membered heteroaryl group as defined herein, appended to the parent molecular moiety through a C1.4 alkyl group, as defined herein. The (5- to 10-membered heteroaryl)-Ci-4 alkylgroup optionally can be substituted by 1 or more (e.g., 1 to 3) suitable substituents, when so specified.

[0240] The term “(4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-" as used herein, means a 54-to 10-membered heterocycloalkyl group as defined herein, appended to the parent molecular moiety through a C1.4 alkyl group, as defined herein. The 4- to 10-membered heterocycloalkyl optionally can be substituted by 1 or more (e.g., 1 to 3) suitable substituents, when so specified.As used herein, the compound of Formula I or pharmaceutically salt thereof as described herein includes optional substitutions and variables. It is understood that the normal valency of each of the designated (optionally substituted) atom or moiety is not exceeded, and that any of the optional substitution results in a stable compound. It is also understood that combinations of optional substituents and / or variables are permissible only if such combinations result in a stable compound.

[0241] As used herein, when a group is described to be optionally substituted, it means that the group can be either unsubstituted or substituted with one or more substituents as specified.

[0242] As used herein, unless otherwise specified, the point of attachment of a substituent can be from any suitable position of the substituent. For example, piperidinyl can be piperidin-1-yl (attached through the N atom of the piperidinyl), piperidin-2-yl (attached through the C atom at the 2-position of the piperidinyl), piperidin-3-yl (attached through the C atom at the 3-position of the piperidinyl), or piperidin-4-yl (attached through the C atom at the 4-position of the piperidinyl). For another example, propanyl (or propyl) can be propan- 1-yl (or 1 -propyl) or propan-2-yl (or 2-propyl).

[0243] As used herein, the point of attachment of a substituent can be specified to indicate the position where the substituent is attached to another moiety. For example, “(C3-7 cycloalkyl)-Ci.

[0244] 4 alkyl-” means the point of attachment occurs at the “C1.4 alkyl” part of the “(C3-7 cycloalkyl)-Ci-4 alkyl-.” For another example, “(C3-4 cycloalkyl)-Ci-2 alkyl-” means the point of attachment occurs at the “C1.2 alkyl” part of the “(C3-4 cycloalkyl)-Ci-2 alkyl-.”

[0245] When a substituted or optionally substituted moiety is described without indicating the atom via which such moiety is bonded to a substituent, then the substituent may be bonded via any appropriate atom in such moiety. For example in a substituted “(C3-4 cycloalkyl)-Ci-2 alkyl-”, a substituent on the (C3-4 cycloalkyl)-Ci-2 alkyl- can be bonded to any carbon atom on the C1.2 alkyl part or on the C3-4 cycloalkyl part of the (C3-4 cycloalkyl)-Ci-2 alkyl. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0246] The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

[0247] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0248] "Excipient" as used herein describes any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.

[0249] Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0250] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0251] The term "therapeutically effective amount" as used herein refers to that amount of the compound (including a pharmaceutically acceptable salt thereof) being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of a GLP-1 R-mediated disease, disorder, or condition (e.g., T2DM or obesity), a therapeutically effective amount refers to that amount which has the effect of relieving to some extent (or, for example, eliminating) one or more symptoms associated with the GLP-1 R-mediated disease, disorder, or condition.

[0252] As used herein, the term, “subject, “individual” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.“Therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder; (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0253] As used herein, treating diabetes (e.g. T2DM) in a diabetic patient (e.g. a patient with T2DM) includes, among other things, improving glycemic control.

[0254] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” GLP-1 R with a compound of the invention includes the administration of a compound of the present invention to a mammal, such as a human, having the GLP-1 R, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the GLP-1 R.

[0255] Salts

[0256] The compounds of the present invention may be isolated and used perse, or when possible, in the form of its pharmaceutically acceptable salt. The term “salts” refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately treating the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed.

[0257] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of the invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid to provide a salt of the compound of the invention that is suitable for administration to a patient, or by reacting the free acid with a suitable organic or inorganic base to provide a salt of the compound of the invention that is suitable for administration to a patient.

[0258] In addition, the compounds of the invention may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I; 2) purifying compounds of Formula I; 3) separating enantiomers of compounds of Formula I; or 4) separating diastereomers of compounds of Formula I.

[0259] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, ammonium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0260] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.For a review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

[0261] Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures

[0262] (i) by reacting a compound of the invention with the desired acid or base;

[0263] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0264] (iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure.

[0265] These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.

[0266] Tautomers

[0267] The compounds of Formula I or salt thereof may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula I may exist in several tautomeric forms, including, e.g., the amide and imidol form, the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of Formula I. Tautomers may exist as mixtures of a tautomeric set in solution. In solid form, one tautomer may predominate. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula I. For example, when one of the following two tautomers of the invention is disclosed in the experimental section herein, those skilled in the art would readily recognize that the invention also includes the other.

[0268]

[0269] Stereoisomers

[0270] The compounds of the present invention may contain asymmetric or chiral centers, and, therefore, exist in two or more stereoisomeric forms. Unless specified otherwise, it is intended that all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the c / s- and trans- forms, as well as mixtures, are embraced within the scope of the invention.

[0271] Stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[0272] The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., D-lactate or L-lysine) or racemic (e.g. DL-tartrate or DL-arginine).

[0273] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0274] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC.

[0275] Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein).

[0276] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneousform of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[0277] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC), on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine (DEA) or isopropylamine. Concentration of the eluent affords the enriched mixture. In the case where SFC is used, the mobile phase may consist of a supercritical fluid, typically carbon dioxide, containing 2-50% of an alcohol, such as methanol, ethanol or isopropanol.

[0278] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.

[0279] In some embodiments, the compounds of the invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of Formula I, II, III, IV, and V may be depicted herein using a solid line ( - ), a wavy line (>~vvv wv)] asolid wedge ( ■ ), a bolded line (^^"), a dotted wedge >

[0280]

[0281] or a hashed line ( ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. The use of either bolded or hashed line to depict bonds to asymmetric carbon atoms is meant to indicate that the stereochemistry at the specific carbon atom is only relative to the stereochemistry at other asymmetric carbon atoms. The use of a wavy line to depict bonds to asymmetric carbon atomsis meant to indicate that the stereochemistry is unknown (unless otherwise specified). It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of the invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

[0282] Where the compounds of the present invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations R and S refer respectively to each stereogenic center in ascending numerical order (1, 2, 3, etc.) according to the conventional IIIPAC number schemes for each molecule. Where the compounds of the present invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form.

[0283] Included within the scope of the claimed compounds of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

[0284] Isotopes

[0285] The present invention includes all pharmaceutically acceptable isotopically labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0286] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l,124l and125l, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[0287] Certain isotopically labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0288] Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.

[0289] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention may be deuterated. MetaSite (moldiscovery.com / software / metasite / ) may be helpful in predicting some metabolic sites on the compounds of the invention.

[0290] Substitution with positron-emitting isotopes, such as11C,18F,150 and13N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0291] Isotopically labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed.

[0292] Pharmaceutically acceptable solvates (including hydrates) in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, de-DMSO.

[0293] Pharmaceutical Compositions

[0294] The present invention also provides a composition (e.g., a pharmaceutical composition) comprising the compound of the invention. Accordingly, in one embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) the compound of the invention and optionally comprising a pharmaceutically acceptable carrier. In addition to the compounds of the invention, the pharmaceutical composition of the invention may also contain, or be co-administered (e.g. simultaneously, sequentially, together, or separately) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein. In one further embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally comprising a pharmaceutically acceptable carrier and, optionally, at least one additional medicinal or pharmaceutical agent (such as an anti-diabetic agent or weight management agent). In oneembodiment, the additional medicinal or pharmaceutical agent is anti-diabetic agent as described below.

[0295] A "pharmaceutical composition" of the invention refers to a mixture of (1) one or more of the compounds of the invention as an active ingredient (e.g. a compound of Formula I or a pharmaceutically acceptable salt, including any solvate, hydrate, solid form, stereoisomer, tautomer, or prodrug) and (2) at least one pharmaceutically acceptable excipient.

[0296] The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0297] As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0298] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0299] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomesand suppositories. The form depends on the intended mode of administration and therapeutic application.

[0300] Some compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0301] Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0302] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.

[0303] In another embodiment, the invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion.

[0304] Injectable preparations (i.e. , sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.

[0305] In another embodiment, the invention comprises a topical dosage form. "Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skinpatches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci. , vol. 88, pp. OSS-OSS, 1000.

[0306] Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e. , absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0307] For intranasal administration, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0308] In another embodiment, the invention comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0309] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011; and Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0310] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0311] For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0312] Liposome-containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0313] Compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0314] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0315] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0316] Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0317] For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0318] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breatheddirectly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0319] A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the invention may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0320] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[0321] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[0322] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. One of ordinary skill in the art would appreciate that the composition may be formulated in sub-therapeutic dosage such that multiple doses are envisioned.

[0323] In one embodiment the composition comprises (a therapeutically effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.Administration and Dosing

[0324] Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound perse or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0325] The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the invention may be administered orally, rectally, vaginally, parenterally, or topically.

[0326] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0327] In another embodiment, the compounds of the invention may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0328] In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

[0329] The dosage regimen for the compounds of the invention and / or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.001 to about 100 mg / kg (i.e., mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the compound of the invention is from about 0.01 to about 30 mg / kg, and in another embodiment, from about 0.03 to about 10 mg / kg, and in yet another embodiment, from about 0.1 to about 3. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.For oral administration, the compositions may be provided in the form of tablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0330] Suitable subjects according to the invention include mammalian subjects. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.

[0331] Therapeutic Methods and Uses

[0332] Another embodiment of the present invention includes a compound of Formula I or a pharmaceutically acceptable salt of the compound for use as a medicament, particularly wherein the medicament is for use in the treatment or prevention of a GLP-1 R-mediated condition, disease, or disorder, including administering to a mammal, such as a human, in need of such treatment.

[0333] Another embodiment of the present invention includes use of a compound of Formula I or a pharmaceutically acceptable salt of the compound as a medicament, particularly wherein the medicament is for use in the treatment or prevention of a GLP-1 R-mediated condition, disease, or disorder, including administering to a mammal, such as a human, in need of such treatment.

[0334] Another embodiment of the present invention includes use of a compound of Formula I or a pharmaceutically acceptable salt of the compound in the manufacture of a medicament for treating or preventing a GLP-1 R-mediated condition, disease, or disorder, including administering to a mammal, such as a human, in need of such treatment a therapeutically effective amount.

[0335] Another embodiment of the present invention includes the compound of invention for use as a medicament, particularly wherein the medicament is for use in treating or preventing a condition, disease, or disorder selected from diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urineincontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0336] Another embodiment of the present invention includes use of the compound of invention as a medicament, particularly wherein the medicament is for use in the treatment or prevention of a condition, disease, or disorder selected from diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such asweight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0337] Another embodiment of the present invention includes use of the compound of invention for the manufacture of a medicament for treating or preventing a condition, disease, or disorder selected from diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [includinghyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0338] In some further embodiments of the methods and uses of the present invention described herein, the condition, disease, or disorder that can be treated or prevented in accordance with the present invention is selected from obesity, T2DM, Heart Failure (e.g.

[0339] HFpEF and HFrEF); CKD; MAFLD, MASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

[0340] The compound of the invention is a GLP-1 receptor agonist. Thus, the present invention further provides a method for modulating (e.g. agonizing) GLP-1 receptor (either in vitro or in vivo), comprising contacting (including incubating) the GLP-1 receptor with the compound of Formula I or a pharmaceutically acceptable salt thereof described herein.

[0341] In some embodiments, the amount of the compound of the invention used in any one of the methods (or uses) of the present invention is effective in modulating GLP-1 receptor.

[0342] Co-administration

[0343] The compounds of the invention may be used alone, or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of the invention, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein.The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0344] A compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0345] The combination agents are administered to a patient (e.g. a mammal or human) in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease / disorder / condition (e.g., T2DM or obesity).

[0346] In some embodiments, a compound of this invention may be co-administered with one or more other agents such as Orlistat, TZDs and other insulin-sensitizing agents, FGF21 analogs, Metformin, Omega-3-acid ethyl esters (e.g., Lovaza), Fibrates, HMG CoA-reductase Inhibitors, Ezetimibe, Probucol, Ursodeoxycholic acid, TGR5 agonists, FXR agonists, Vitamin E, Betaine, Pentoxifylline, CB1 antagonists, Carnitine, / V-acetylcysteine, Reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 as well as those in WO2010023594), Phentermine, Topiramate, GLP-1 receptor agonists, GIP (glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide) receptor agonists, GIP receptor (GIPR) inhibitors and / or antagonists, dual GLP-1 receptor / glucagon receptor agonists (e.g., OPK88003, MEDI0382, JNJ-64565111, NN9277, Bl 456906), dual GLP-1 receptor / GIP receptor agonists [e.g., Tirzepatide (LY3298176), NN9423, NN9541, HS-20094, SCO-094, VK2735, CT-388, GMA-106, CT-868, HRS9531], dual GLP-1receptor / glucagon receptor agonists (e.g. DD-01, PB-718, mazdutide, pemvidutide, pegapamodutide, survodutide, LM-008, IBI-362, AZD9550), dual GLP-1 receptor / GLP-2 receptor agonists (e.g. dapiglutide), dual GLP-1 receptor / amylin receptor agonists (e.g. amycretin), cagrilinitide / semaglutide, GLP-1 receptor agonist / GIP receptor antagonist (maridebart cafraglutide), dual GLP-1 receptor / FGF21 receptor agonists (e.g. HEC-88473, Bl 3006337), triple agonists of the GLP-1 receptor / glucagon receptor / GIP receptor (e.g. retatrutide), triple agonists of the GLP-1 receptor / glucagon receptor / FGF21 receptor (e.g.

[0347] DR10624), NPY2 receptor agonists (e.g. Bl 1820237), activin receptor type-2 B modulators (e.g. bimagrumab), amylin receptor agonists, GPR75 modulators, delta-5 desaturase inhibitors, Angiotensin-receptor blockers, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, ASK1 inhibitors, branched-chain alpha-keto acid dehydrogenase kinase inhibitors (BCKDK inhibitors), inhibitors of CCR2 and / or CCR5, PNPLA3 inhibitors, DGAT1 inhibitors, DGAT2 inhibitors, an FGF21 analog, FGF19 analogs, PPAR agonists, FXR agonists, AM PK activators [e.g., ETC-1002 (bempedoic acid)], SCD1 inhibitors, apelin receptor (APJ) agonists, or myeloperoxidase (MPO) inhibitors.

[0348] Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide, danuglipron, orforglipron, lotiglipron, PF-06954522, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, efpeglenatide, CT-996, ECC5004, XW004, XW014, M DR-001 , ZT002, KN-056, GL0034, GSBR-1290, noiiglutide, RGT-075, TTP-273, HRS-7535, GMA-105, TG103, GZR-18, GX-G6, ecnoglutide, PB-119, QLG2065, beinaglutide, those described in WO2018109607, those described in WO2019239319 (PCT / IB2019 / 054867 filed June 11, 2019), and those described in WO2019239371 (PCT / IB2019 / 054961 filed June 13, 2019).

[0349] Some exemplary GIPR antagonists include the following:

[0350] 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0351] 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-3-carboxylic acid;

[0352] 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-3- carboxylic acid;

[0353] 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0354] 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-3-yl}benzoic acid; 3'-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid;

[0355] 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-DL-prolyl}amino)[1,T-biphenyl]-4-carboxylic acid;2-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyrimidine-5-carboxylic acid;

[0356] 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0357] 6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]naphthalene-2-carboxylic acid; 8-methyl-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]quinoline-2-carboxylic acid;

[0358] 4'-[(1-{[4-(prop-1-en-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0359] 4'-({1-[(4-chlorophenyl)carbamoyl]-DL-prolyl}amino)[1,T-biphenyl]-4-carboxylic acid; 4-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0360] 3',5'-difluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0361] 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0362] 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-3-carboxylic acid;

[0363] 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-3-carboxylic acid;

[0364] 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0365] 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-3-yl}benzoic acid; 3'-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0366] 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1,T-biphenyl]-4-carboxylic acid; 2-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyrimidine-5-carboxylic acid;

[0367] 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0368] 6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]naphthalene-2-carboxylic acid; 8-methyl-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]quinoline-2-carboxylic acid;

[0369] 4'-[(1-{[4-(prop-1-en-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4- carboxylic acid;

[0370] 4'-({1-[(4-chlorophenyl)carbamoyl]-D-prolyl}amino)[1,T-biphenyl]-4-carboxylic acid; 4-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;3',5'-difluoro-4'-[(1 -{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1 , 1 '-biphenyl]-4-carboxylic acid;

[0371] 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4- carboxylic acid;

[0372] 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0373] 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0374] 3-methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0375] 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid;

[0376] 3-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0377] 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]-3-methoxy[1,T-biphenyl]-4-carboxylic acid;

[0378] 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-2-yl}benzoic acid;

[0379] 6-methyl-5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0380] 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0381] 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0382] 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0383] 3-methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0384] 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid;

[0385] 3-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0386] 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]-3-methoxy[1,T-biphenyl]-4-carboxylic acid;

[0387] 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-2-yl}benzoic acid;6-methyl-5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0388] 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0389] 5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0390] 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-2-yl}benzoic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0391] 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0392] 3-methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0393] 4-{5-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-2-yl}benzoic acid; 4'-({1-[(4-cyclobutylphenyl)carbamoyl]-DL-prolyl}amino)[1,T-biphenyl]-4-carboxylic acid; 4-{5-fluoro-6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-3-yljbenzoic acid;

[0394] 4-{5-fluoro-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-3-yl}benzoic acid;

[0395] 4'-[(1-{[4-cyclopropyl-3-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0396] 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid;

[0397] 3-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0398] 2-methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0399] 3-methoxy-4'-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0400] 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]-3-methoxy[1,T-biphenyl]-4-carboxylic acid;

[0401] 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridin-2-yl}benzoic acid;

[0402] 4'-{[3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;

[0403] 4'-{[(frans)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;4'-{[3-methyl-1 -{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1 , 1 '-biphenyl]-4-carboxylic acid;

[0404] 4'-{[(3-frans)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;

[0405] 4'-{[4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;

[0406] 4'-{[(4-c / s)-4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;

[0407] 4'-{[1-({1-[4-(propan-2-yl)phenyl]ethyl}carbamoyl)-DL-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;

[0408] 3-[6-({1-[(4-cyclobutylphenyl)carbamoyl]-DL-prolyl}amino)pyridin-3-yl]benzoic acid; 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4- carboxylic acid;

[0409] 5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine- 2-carboxylic acid;

[0410] 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-2-yl}benzoic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0411] 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid;

[0412] 3-methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0413] 4-{5-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-2-yl}benzoic acid; 4'-({1-[(4-cyclobutylphenyl)carbamoyl]-D-prolyl}amino)[1,T-biphenyl]-4-carboxylic acid; 4-{5-fluoro-6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-3-yljbenzoic acid;

[0414] 4-{5-fluoro-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-3-yl}benzoic acid;

[0415] 4'-[(1-{[4-cyclopropyl-3-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]- 4-carboxylic acid;

[0416] 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid;

[0417] 3-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0418] 2-methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;

[0419] 3-methoxy-4'-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,T-biphenyl]-4-carboxylic acid;4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]-3-methoxy[1,T-biphenyl]-4-carboxylic acid;

[0420] 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-2-yl}benzoic acid;

[0421] 4'-{[(3S)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid;

[0422] 4'-{[(3R)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-L-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid;

[0423] 4'-{[(3R)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid;

[0424] 4'-{[(3S)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-L-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid;

[0425] 4'-{[(4R)-4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid;

[0426] 4'-{[1-({(1S)-1-[4-(propan-2-yl)phenyl]ethyl}carbamoyl)-D-prolyl]amino}[1,T-biphenyl]-4-carboxylic acid; and

[0427] 3-[6-({1-[(4-cyclobutylphenyl)carbamoyl]-D-prolyl}amino)pyridin-3-yl]benzoic acid; or a pharmaceutically acceptable salt thereof.

[0428] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1' / 7-spiro[indazole-5,4'-piperidin]-T-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid, gemcabene, and firsocostat (GS-0976) and phamaceutally acceptable salts thereof.

[0429] Exemplary FXR agonists include tropifexor (2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid), cilofexor (GS-9674), obeticholic acid, LY2562175, Met409, TERN-101 and EDP-305 and pharmaceutically acceptable salts thereof.

[0430] Exemplary KHK inhibitors include [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid and pharmaceutically acceptable salts thereof.

[0431] Exemplary DGAT2 inhibitors include (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide [including its crystalline solid forms (Form 1 and Form 2)]. See U.S. Patent No. 10,071,992.

[0432] Some exemplary BCKDK inhibitors include those described in US Patent Nos.

[0433] 11542270 and 11059833, including the following:

[0434] 5-(5-chloro-4-fluoro 3-methylthiophen-2-yl)-1 / - / -tetrazole;

[0435] 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1 / - / -tetrazole;

[0436] 5-(5-fluoro-3-methylthiophen-2-yl)-1 / - / -tetrazole;

[0437] 5-(5-chloro-3-methylthiophen-2-yl)-1 / - / -tetrazole;5-(3,5-dichlorothiophen-2-yl)-1 / -tetrazole;

[0438] 5-(4-bromo-3-methylthiophen-2-yl)-1 / - / -tetrazole;

[0439] 5-(4-bromo-3-ethylthiophen-2-yl)-1 / 7-tetrazole;

[0440] 5-(4-chloro-3-ethylthiophen-2-yl)-1 / 7-tetrazole;

[0441] 3-chloro-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0442] 3-bromo-5-fluorothieno[3,2- b]thiophene-2-carboxylic acid;

[0443] 3-(difluoromethyl)-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0444] 5,6-difluorothieno[3,2-b]thiophene-2-carboxylic acid; and

[0445] 3,5-difluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0446] or a pharmaceutically acceptable salt thereof.

[0447] Some additional exemplary BCKDK inhibitors include those described in US Patent Application 18 / 060,027, filed November 30, 2022, including the following:

[0448] 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0449] 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0450] 6-chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid;

[0451] 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0452] 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2;

[0453] 3-(3-chloro-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid;

[0454] 3-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0455] 6-chloro-3-(3-ethyl-2,4,5-trifluorophenyl)-1-benzothiophene-2-carboxylic acid; or ammonium 3-(3-ethyl-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylate; or a pharmaceutically acceptable salt thereof.

[0456] In some embodiments, a compound of this invention may be co-administered with one or more anti-diabetic agents. Suitable anti-diabetic agents include insulin, metformin, GLP-1 receptor agonists (e.g., one of those described herein above), an acetyl-CoA carboxylase (ACC) inhibitor (described herein above), SGLT2 inhibitors (described herein above), monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AMPK activators [e.g., ETC-1002 (bempedoic acid)], sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, a-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), a-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARy agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), PPAR a / y agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), protein tyrosinephosphatase- 1B (PTP-1B) inhibitors [e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S. et al., Drug Discovery Today, 12(9 / 10), 373-381 (2007)], SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa) such as those described in WG2010103437, WG2010103438, WG2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001 , insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators such as those described in Demong, D.E. et al., Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in WG2010140092, WO2010128425, WG2010128414, WG2010106457, Jones, R.M. et al., Annual Reports in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high-affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611.

[0457] Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g., PKCa, PKC0, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g., SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILIbeta, and modulators of RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. The Pat., 2010, 20(12), 1627-51.

[0458] The compounds of the present invention may be co-administered with anti-heart failure agents such as ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril), Angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), Angiotensin-receptor neprilysin inhibitors (sacubitril / valsartan), ^channel blocker Ivabradine, Beta-Adrenergic blocking agents (e.g., bisoprolol, metoprolol succinate, carvedilol),Aldosterone antagonists (e.g., spironolactone, eplerenone), hydralazine and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, Indapamide, Metolazone, Triamterene), or digoxin.

[0459] The compounds of the present invention may also be co-administered with cholesterol or lipid lowering agents including the following exemplary agents: HMG CoA reductase inhibitors (e.g., pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates (e.g., gemfibrozil, pemafibrate, fenofibrate, clofibrate); bile acid sequestrants (such as questran, colestipol, colesevelam);

[0460] ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; cholesterol absorption inhibitors (e.g., ezetimibe); nicotinic acid agents (e.g., niacin, niacor, slo-niacin); omega-3 fatty acids (e.g., epanova, fish oil, eicosapentaenoic acid); cholesteryl ester transfer protein inhibitors (e.g., obicetrapib) and PCSK9 modulators [e.g., alirocumab, evolocumab, bococizumab, ALN-PCS (inclisiran)].

[0461] The compounds of the present invention may also be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable anti-hypertensive agents include: alpha-adrenergic blockers; beta-adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos.

[0462] 5,612,359 and 6,043,265); Dual ET / AII antagonist (e.g., compounds disclosed in WO 00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginal agent is ivabradine.

[0463] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.

[0464] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0465] In one embodiment, a compound of invention may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIX™), torsemide (such as DEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such as EDECRIN™); (b) thiazide-type diuretics such as chlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (such as SALURON™), bendroflumethiazide,methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (such as LOZOL™); (c) phthalimidine-type diuretics such as chlorthalidone (such as HYGROTON™), and metolazone (such as ZAROXOLYN™); (d) quinazoline-type diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (such as DYRENIUM™), and amiloride (such as MIDAMOR™ or MODURETIC™).

[0466] In another embodiment, a compound of the invention may be co-administered with a loop diuretic. In still another embodiment, the loop diuretic is selected from furosemide and torsemide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with furosemide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with torsemide which may optionally be a controlled or modified release form of torsemide.

[0467] In another embodiment, a compound of the invention may be co-administered with a thiazide-type diuretic. In still another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be coadministered with chlorothiazide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with hydrochlorothiazide.

[0468] In another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with a phthalimidine-type diuretic. In still another embodiment, the phthalimidine-type diuretic is chlorthalidone.

[0469] Examples of suitable mineralocorticoid receptor antagonists include sprionolactone and eplerenone.

[0470] Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0471] Those skilled in the art will recognize that the compounds of this invention may also be used in conjunction with other cardiovascular or cerebrovascular treatments including Percutaneous Coronary Intervention (PCI), stenting, drug-eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

[0472] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when a compound of this invention and a second therapeutic agent are combined in a single dosage unit they may be formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric-coated. By enteric-coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also,it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that effects a sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric-coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and / or enteric-release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[0473] These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

[0474] Another approach may involve the formulation of a combination product in which both active components are combined with a material that effects a sustained release throughout the gastrointestinal tract of both active ingredients.

[0475] In some embodiments of combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to patients such as mammals (e.g., humans, male or female) by conventional methods.

[0476] Synthetic Methods

[0477] Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.

[0478] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below,other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0479] The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0480] In the preparation of compounds of the invention it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.

[0481] For example, if a compound contains a amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected.

[0482] Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as / V-f-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.

[0483] General Experimental Details

[0484] The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein.Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-Seal™ products from Sigma-Aldrich or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4 molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, / V, / V-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves, and distilled just prior to use. Other commercial solvents and reagents were used without further purification. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing.

[0485] When indicated, reactions were heated by microwave irradiation using Biotage Initiator or Personal Chemistry Emrys Optimizer microwave instruments. Reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under UV light and / or with I2, KMnO4, C0CI2, phosphomolybdic acid, or ceric ammonium molybdate stains. LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. The column eluent was analyzed using a Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 Series instrument using Gemini orXBridge C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid or ammonium hydroxide modifiers. High resolution mass spectra (HRMS) were obtained on an Agilent™ Model 6210 using time of flight method. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 injector, HP-1 column (12 m x 0.2 mm x 0.33 pm), and helium carrier gas. Samples were analyzed on an HP 5973 mass selective detector, scanning from 50 to 550 Da using electron ionization. Purifications were generally performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were generally performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments; ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or-OJ columns; and CO2 mixtures with methanol, ethanol, propan-2-ol, or acetonitrile, alone or modified using trifluoroacetic acidor propan-2-amine. UV detection was used to trigger fraction collection. For syntheses referencing procedures in other Examples or Methods, purifications may vary; in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate RfS or retention times.

[0486] Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (El) or electron scatter (ES) ionization sources. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian, Bruker, or Jeol spectrometers. Chemical shifts are expressed in parts per million (ppm, 8) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-^, 1.94 ppm; dimethyl sulfoxide-cfc, 2.50 ppm; DHO, 4.79 ppm). The peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm cell. Silica gel chromatography was performed primarily using medium-pressure Biotage or ISCO systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values.

[0487] Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0488] Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0489] The terms “concentrated,” “evaporated,” and “concentrated in vacuo" refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60 °C. The abbreviation “min” and “h” stand for “minutes” and “hours” respectively. The term “TLC” refers to thin-layer chromatography, “room temperature or ambient temperature” means a temperature between 18 and 25 °C, “GCMS” refers to gas chromatography-mass spectrometry, “LCMS” refers to liquid chromatography-mass spectrometry, “UPLC” refers to ultra-performance liquid chromatography and “HPLC” refers to high-performance liquid chromatography, “SFC” refers to supercritical fluid chromatography.

[0490] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures.

[0491] Abbreviations

[0492] AcOH is acetic acid;

[0493] BOP is benzotriazol- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0494] BTMG is 2-tert-Butyl-1,1,3,3-tetramethylguanidinecAMP is cyclic adenosine monophosphate

[0495] °C is degrees Celsius;

[0496] GDI is 1,1'-Carbonyldiimidazole

[0497] CDC is deutero-chloroform;

[0498] 5 is chemical shift;

[0499] d is doublet;

[0500] dd is doublet of doublets;

[0501] ddd is doublet of doublet of doublets;

[0502] dt is doublet of triplets;

[0503] DCE is 1,2-dichloroethane;

[0504] DCM is dichloromethane; methylene chloride;

[0505] DMA is / V, / V-dimethylacetamide;

[0506] DMF is / V, / V-dimethylformamide;

[0507] DMSO is dimethyl sulfoxide;

[0508] DMSO-de is deuterodimethylsulfoxide;

[0509] Et2O is diethyl ether;

[0510] EtOAc is ethyl acetate;

[0511] EtOH is ethanol;

[0512] Et3N is triethylamine;

[0513] HATLI is Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium

[0514] HCI is hydrogen chloride;

[0515] HPLC is high pressure liquid chromatography;

[0516] HTRF is homogeneous time-resolved fluorescence;

[0517] iPrOAc is isopropyl acetate;

[0518] [lr((ppy)2(dtbpy)][PF6] is [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,NT]bis[2-(2-pyridinyl- N)phenyl-C]iridium(l II) hexafluorophosphate;

[0519] L is liter;

[0520] LCMS is liquid chromatography mass spectrometry;

[0521] LiOH is lithium hydroxide

[0522] m is multiplet;

[0523] M is molar;

[0524] MeCN is acetonitrile;

[0525] MeNHOMe HCI is N,O-dimethylhydroxylamine hydrochloride;

[0526] MeOD_d4is deuterated methanol;

[0527] MeOH is methanol;

[0528] 2-MeTHF is 2-methyl tetra hydrofuran;

[0529] mg is milligram;

[0530] MgSC is magnesium sulfateMHz is mega Hertz;

[0531] min(s) is minute(s);

[0532] mL is milliliter;

[0533] mmol is millimole;

[0534] mol is mole;

[0535] MS (m / z) is mass spectrum peak;

[0536] MTBE is tert-butyl methyl ether;

[0537] NaBH4sodium borohydride

[0538] NaSC is sodium sulfate

[0539] NH4OH is ammonium hydroxide

[0540] Ni(dtbbpy)Br2 is [4,4'-bis(1 , 1-dimethylethyl)-2,2'-bipyridine] nickel (II) dibromide;

[0541] NMI is N-methylimidazole

[0542] NMR is nuclear magnetic resonance;

[0543] pH is power of hydrogen;

[0544] q is quartet;

[0545] rt is room temperature;

[0546] RT is retention time;

[0547] s is singlet;

[0548] t is triplet;

[0549] TBD is 1,5,7-triazabicyclo[4.40]dec-5-ene

[0550] TCFH is chloro- / V, / V, / V( / V'-tetramethylformamidinium hexafluorophosphate

[0551] THF is tetra hydrofuran;

[0552] pL is microliter;

[0553] pm is micro meter; and

[0554] pmol is micromole.

[0555] EXAMPLES

[0556] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0557] The compounds and intermediates described below were named using the naming convention provided with ChemDraw [such as Version 20.1.1.125, by Revvity Signals (formerly known as PerkinElmer Informatics)] or with ACD / ChemSketch [such as Version 2020.2.1.1, File Version C25H41, Build 121153, by Advanced Chemistry Development, Inc.). The naming convention provided with ChemDraw or ACD / ChemSketch is well known by those skilled in the art and it is believed that the naming convention provided with ChemDraw or with ACD / ChemSketch generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0558] PREPARATIONS

[0559] Preparation P1 (P1a and P1b) describes preparations of some starting materials or intermediates used for the preparation of certain compounds of the invention.

[0560] Preparation P1a / P1b

[0561] methyl (Z)- / V-[(3R)-4,4-dimethyloxolan-3-yl]-3-[(4-methoxyphenyl)methoxy]-1,2-oxazole-5- carboximidothioate (P1a) and methyl (E)- / V-[(3R)-4,4-dimethyloxolan-3-yl]-3-[(4- methoxyphenyl)methoxy]-1,2-oxazole-5-carboximidothioate (P1b)

[0562]

[0563] Step 1. Synthesis of / V-[(3R)-4,4-dimethyloxolan-3-yl]-3-[(4-methoxyphenyl)methoxy]-1,2-oxazole-5-carboxamide (C2)

[0564] A 125 mL round bottom flask was charged with 3-[(4-methoxyphenyl)methoxy]-1,2-oxazole-5-carboxylic acid (2.14 g, 8.57 mmol, C1), DMF (18.8 mL), and GDI (1.39 g, 8.57 mmol). The solution was stirred at room temperature for 1 h and then (R)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (1.00 g, 6.59 mmol), and 1- / V-methylimidazole (596 mg, 0.575 mL, 7.25 mmol) were added. The resultant solution was stirred for 30 min at room temperature. The solution was cooled to 0 °C and then 50 mL of saturated sodium bicarbonate was added dropwise. A white solid precipitated. The resultant solids were filtered, then slurried in water for 15 minutes. The solids were then filtered to afford C2 as a white solid (2.20 g, 6.35 mmol, 96% yield). LCMS m / z: 347.3 [M+H]+; expected for C18H23N2O5: 347.15.1H NMR (400 MHz, DMSO-d6) 58.78 (m, 1H), 7.42 (d, J = 8.59 Hz, 2H), 6.96 (d, J = 8.59 Hz, 2H),6.88 (s, 1 H), 5.21 (s, 2H), 4.21 - 4.28 (m, 1 H), 4.06 (m, 1 H), 3.77 (s, 3H), 3.66 (m, 1 H), 3.48 (m, 2H), 1.07 (s, 3H), 0.91 (s, 3H).

[0565] Step 2. Synthesis of / V-[(3R)-4,4-dimethyloxolan-3-yl]-3-[(4-methoxyphenyl)methoxy]-1,2-oxazole-5-carbothioamide (C3)

[0566] A 100 mL round bottom flask was charged with C2 (2.15 g, 6.21 mmol) and Lawesson's reagent (2.01 g, 4.97 mmol). The flask was sealed with a red septum stopper and evacuated / backfilled 3 times with nitrogen. 1,4-Dioxane (20.7 mL) was added via syringe. The solution was heated to 100 °C and stirred for 45 min. An additional 300 mg of Lawesson's reagent was added and stirred at 100 °C for 20 min. The solution was cooled to room temperature and quenched with water (50 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL). The organic layer was dried over sodium sulfate and concentrated. The crude residue was purified via silica gel chromatography (0-30% EtOAc / heptane gradient) to yield C3 as a viscous yellow oil (2.06 g, 5.68 mmol, 92% yield). LCMS m / z: 361.1 [M-H]'; expected for C18H21N2O4S: 361.13.1H NMR (400 MHz, DMSO-d6) 5 10.63 (m, 1H), 7.41 - 7.44 (m, 2H), 6.94 - 6.97 (m, 2H), 6.83 (s, 1 H), 5.22 (s, 2H), 4.15 - 4.19 (m, 1H), 4.00 - 4.07 (m, 1H), 3.72 - 3.78 (m, 4H), 3.47 - 3.55 (m, 2H), 1.17 (s, 3H), 0.97 (s, 3H).

[0567] Step 3. Synthesis of methyl (Z)- / V-[(3R)-4,4-dimethyloxolan-3-yl]-3-[(4-methoxyphenyl)methoxy]-1,2-oxazole-5-carboximidothioate (P1a) and methyl (E)- / V-[(3R)-4,4-dimethyloxolan-3-yl]-3-[(4-methoxyphenyl)methoxy]-1 ,2-oxazole-5-carboximidothioate (P1 b)

[0568] A 50 mL flask was charged with C3 (0.986 g, 2.72 mmol), acetonitrile (9.07 mL), cesium carbonate (1.77 g, 5.44 mmol), and methyl iodide (772 mg, 0.340 mL, 5.44 mmol) in that respective order. The solution was heated to 60 °C and stirred for 30 min. The solution was cooled to room temperature and 20 mL of water was added. The aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with brine (2 x 20 mL). The organic layer was dried over sodium sulfate and then concentrated. The crude residue was purified via silica gel chromatography (0-35% EtOAc / heptane gradient) to yield P1a and P1b as a mixture of E / Z isomers (815.8 mg, 2.17 mmol, 80% yield). LCMS m / z: 377.6 [M+H]+; expected for C19H24N2O4S: 377.15.1H NMR (400 MHz, DMSO-d6) 57.42 (d, J= 8.6 Hz, 2H), 6.96 (d, J= 8.7 Hz, 2H), 6.70 (s, 0.6H), 6.67 (s, 0.4H), 5.75 (s, 1H), 5.21 (s, 2H), 4.17 - 4.00 (m, 1H), 3.85 -3.80 (m, 1H), 3.76 (s, 3H), 3.68 - 3.63 (m, 1H), 3.58 - 3.45 (m, 2H), 2.41 - 2.37 (m, 3H), 1.07 (s, 1.2H), 0.98 - 0.90 (m, 4.8H).Example 1

[0569] 5-(5-{[(1r,4F?)-4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)cyclohexyl]methyl}-4- [(3F?)-4,4-dimethyloxolan-3-yl]-4 / 7-1,2,4-triazol-3-yl)-1,2-oxazol-3-ol (Compound 1)

[0570]

[0571] Step 1. Synthesis of 2-[(1r,4r)-4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)cyclohexyl]acetohydrazide (C4)

[0572] HATLI (211 mg, 0.55 mmol) in DMF (1.85 mL) was added to a solution of [(1r,4r)-4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)cyclohexyl]acetic acid (140 mg, 0.37 mmol, see WO2022042691 for preparation) in THF (1.85 mL). After 30 minutes, / V-Boc hydrazine (54 mg, 0.41 mmol) was added and the resultant mixture stirred an additional 18 hours. Water (3 mL) was added and the mixture was extracted into ethyl acetate (3 x 5 mL). The combined organics were washed with water (2 x 20 mL) and then brine (20 mL); dried over magnesium sulfate; filtered; and concentrated. The resulting material was diluted with 1, 1,1, 3,3,3-hexafluoro-2-propanol (3 mL) and treated with methanesulfonic acid (0.072 mL, 1.11 mmol). After 30 minutes, the solvent was evaporated, then saturated NaHCCh (5 mL) was added to the residue. The mixture was extracted into DCM (3 x 5 mL) and the combined organics washed with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated to afford C4 as an orange oil (145 mg, 0.37 mmol, quantitative). LCMS m / z 393.2 [M+H]+.Step 2. Synthesis of 2-[(4-chloro-2-fluorophenyl)methyl]-4-({(1R,4r)-4-[(4-[(3R)-4,4-dimethyloxolan-3-yl]-5-{3-[(4-methoxyphenyl)methoxy]-1,2-oxazol-5-yl}-4 / 7-1,2,4-triazol-3-yl)methyl]cyclohexyl}oxy)pyrimidine (Compound 1)

[0573] A 20 mL vial was charged with C4 (70 mg, 0.18 mmol), P1a / P1b (67 mg, 0.18 mmol) and 1-butanol (1.2 mL). Silver trifluoroacetate (39 mg, 0.18 mmol) was then added and the mixture stirred at 23 °C for 10 minutes followed by heating in an aluminum block at 100 °C for 15 hours. Upon cooling to room temperature, the reaction mixture was passed through a 0.45 micron filter, then concentrated to afford C5 as a yellow oil (130mg). LCMS m / z 703.6 [M+H]+. This was used in the next step without further purification.

[0574] Trifluoroacetic acid (0.14 mL, 1.85 mmol) and 1,3-dimethoxybenzene (0.15 mL, 1.11 mmol) were added to a solution of C5 (130 mg) in dichloromethane (0.5 mL). After 2 hours, the reaction mixture was concentrated, and then purified by reverse phase HPLC (retention time 2.48 min) to yield Compound 1 (2.4 mg, 0.004 mmol, 2% yield). Column: Waters XBridge C18 19 x 100 mm, 5 pm; Mobile Phase A: 0.03% NH4OH in water (v / v); Mobile Phase B: 0.03% NH4OH in acetonitrile (v / v). 85.0% H2O / 15.0% acetonitrile linear to 65.0% H2O / 35.0% acetonitrile in 8.5 min, 65.0% H2O / 35.0% acetonitrile linear to 5.0% H2O / 95.0% acetonitrile to 9.0 min, hold at 5% H2O / 95% acetonitrile to 10.0 min. Flow: 25 mL / min. LCMS m / z 583.3 [M+H]+.1H NMR (600 MHz, DMSO-d6) 58.39 (d, J= 5.8 Hz, 1H), 7.44-7.34 (m, 2H), 7.24 (dd, J = 8.0, 2.2 Hz, 1 H), 6.70 (d, J = 5.8 Hz, 1 H), 6.61 (br s, 1 H), 4.89 - 4.73 (m, 2H), 4.32 - 4.20 (m, 2H), 3.55 (m, 2H), 2.91 -2.73 (m, 3H), 2.10- 1.95 (m, 3H), 1.92 - 1.79 (m, 2H), 1.44 -1.30 (m, 2H), 1.19- 1.02 (m, 5H), 0.62 (s, 3H)

[0575] Example AA: Biological assay

[0576] Glucagon-Like Peptide 1 receptor (GLP-1 Remediated agonist activity was determined by monitoring intracellular cyclic adenosine monophosphate (cAMP) levels in a cell-based functional assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP Dynamic Range Assay Kit; Revvity cat # 62AM4PEC) that measures cAMP levels in the cell. The method is a competitive immunoassay between native cAMP produced by the cells and cAMP labelled with the acceptor dye, d2. The two entities compete for binding to a monoclonal anti-cAMP antibody labeled with cryptate. The specific signal is inversely proportional to the concentration of cAMP in the cells.

[0577] The human GLP-1R coding sequence (NCBI Reference Sequence NP_002053.3, including naturally-occurring variant Leu260Phe) was subcloned into pcDNA5-FRT-TO and a clonal CHO cell line stably expressing a low receptor density was isolated using the Flp-ln™ T-Rex™ System, as described by the manufacturer (ThermoFisher). Saturation binding analyses (filtration assay procedure) using125I-GLP-1 (Perkin Elmer) showed that plasma membranes derived from this cell line (designated clone C6) express a low GLP-1R density (Kd: 0.3 nM, Bmax- 240 fmol / mg protein).Test compounds were solubilized to a concentration of 30 mM in 100% dimethyl sulfoxide (DMSO). An 11-point dilution series using 1 in 3.162-fold serial dilutions was created in 100% DMSO with a top concentration of 2 mM. The serially diluted compound was spotted with an Echo Acoustic liquid handler (Beckman Coulter) into a 384-well assay plate (Corning Cat # 3570) at 100 nL / well with duplicate points at each concentration, at a 200x final assay concentration (FAC). The final compound concentration range in the assay was 10 pM to 100 pM, with a final DMSO concentration of 0.5%.

[0578] Frozen assay-ready vials (at 1E7 cells / vial) of CHO-TREX cells stably expressing the Gs-coupled human GLP-1R were thawed, counted, and resuspended in assay buffer consisting of Hank’s Balanced Salt Solution (HBSS, Lonza Cat# 10-527) containing 20 mM (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES, Lonza Cat# 17-737E), 0.1% bovine serum albumin (BSA, Sigma Cat# A7979), and 100 pM 3-isobutyl-1-methylxanthine (IBMX, Sigma Cat # I5879) at a density of 3E5 cells / mL. Cells were added to assay plate (10 pL / well of 3E5 cells / mL stock for 3,000 cells / well final) containing 10 pL / well assay buffer and 100 nL of 200x FAC test compound and incubated at 37°C (95% O2: 5% CO2) for 30 minutes, with microclime lids (Labcyte, Cat No. LLS-0310). Following the 30-minute cell and compound incubation, intracellular cAMP levels were quantified as per Revvity’s protocol (10 pL of d2 and then 10 pL cryptate, incubated for 1 hour at room temperature).

[0579] Emission spectra of samples were measured on a Pherastar plate reader (BMG Labtech Inc) using a HTRF protocol (excitation 320 nm; emission 665 nm and 620 nm). Data were analyzed using the ratio of fluorescence intensity at 620 and 665 nm for each well, extrapolated from the cAMP standard curve to express data as nanomolar (nM) cAMP for each well. Data expressed as nM cAMP were then normalized to control wells using ActivityBase (I DBS data management software). Zero percent effect (ZPE) was defined as nM cAMP generated from vehicle control (0.5% DMSO), while 100% effect, or one hundred percent effect (HPE), was defined as nM cAMP generated from stimulation with 10 nM FAC GLP-1[7-36] agonist. The concentration and % effect values for each compound were plotted by ActivityBase using a four-parameter logistic dose response equation, and the concentration required for 50% effect (EC50) was determined.

[0580] Results:

[0581] Table AA-1. Biological activity for Compound 1

[0582]

[0583] It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention.Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0584] All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

CLAIMSWhat Is Claimed Is:or a pharmaceutically acceptable salt thereof, wherein:ring A1is phenyl or a 5- or 6-membered heteroaryl;each R1is independently halogen, cyano, RAMD, Rcy1, Rcy1-L1-, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, or Ci-4 fluoroalkoxy, wherein each of the C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;each L1is independently C1.4 alkylene optionally subsituted with 1, 2, 3, or 4 substituents each independently selected from halogen, cyano, C1.2 alkyl, and C1.2 fluoroalkyl; each Rcy1is independently phenyl or 5- to 6-membered heteroaryl, each of which is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ram1)(Ram2)-; N(Ram1)(Ram2)-C(=O)-; N(Ram1)(Ram2)-S(=O)2-; Ram2-C(=O)-, or Ram2-S(=O)2-, wherein each of the C3-4 cycloalkyl, (C3-4 cycloalkyl)-Ci-2 alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;each Ram1is independently H or methyl;each Ram2is independently C1.4 alkyl, Rcy2, or Rcy2-L2-, wherein the C1.4 alkyl is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, cyano, C3-4 cycloalkoxy, C3-4 fluorocycloalkoxy, C1.3 alkoxy, or C1.3 fluoroalkoxy;each L2is independently C1.4 alkylene optionally subsituted with 1, 2, 3, or 4 substituents each independently selected from halogen, cyano, C1.2 alkyl, and C1.2 fluoroalkyl; each Rcy2is independently C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, Ce- aryl, or 5- to 10-membered heteroaryl, each of which is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkyl, C1.4fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-S(=O)2-, Rd-C(=O)-N(RC)-, Rd-C(=O)-, or Rd-S(=O)2-N(Rc)-, wherein each of the C1.4 alkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, hydroxyl, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;RAMDis N(Ram3)(Ram4)-C(=O)-;Ram3is H or methyl;Ram4is C1.6 alkyl, Rcy3, or Rcy3-L3-, wherein the Ci-e alkyl is optionally subsituted with 1, 2, or 3 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(RC)-, or Rd-S(=O)2-N(Rc)-,;each L3is independently C1.4 alkylene optionally subsituted with 1, 2, 3, or 4 substituents each independently selected from halogen, cyano, Ci-2alkyl, and Ci-2fluoroalkyl;each Rcy3is independently C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, Ce- aryl, or 5- to 10-membered heteroaryl, each of which is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(Rc)-, or Rd-S(=O)2-N(Rc)-, wherein each of the C1.4 alkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, hydroxyl, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;each of RL1and RL2is independently H or methyl; orRL1and RL2, together with the carbon atom to which they are attached to, optionally form cyclopropyl;each of T1and T2is independently N, CH, or CR2;each R2is independently halogen, cyano, Ci-2alkyl, Ci-2fluoroalkyl, Ci-2alkoxy, or Ci-2fluoroalkoxy;each of the - - bonds (designated as the x bond,y bond, and z bond respectively) represents a single or double bond;each R3is independently F, HO-, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 hydroxylalkyl, C1.4 alkoxy, C1.4 fluoroalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2alkyl-, wherein each of the C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4 cycloal kyl)-Ci-2alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, cyano, HO-, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;T3is C, CRT3or N, provided (1) that when T3is CRT3or N then the y bond is a single bond and that (2) when T3is C then the y bond is a double bond;RT3is H or R3;each of RL3and RL4is independently H or methyl; orRL3and RL4, together with the carbon atom to which they are attached to, optionally form cyclopropyl; orRL3and RT3, together with the two carbon atoms to which they are attached to, optionally form cyclopropyl;T4is CH, CRT4, or N;RT4is halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;Y1is -(CRL5RL6)q- or absent;each RL5and RL6is independently selected from H and Ci-2alkyl;R4is C1.6 alkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, whereinthe C1.6 alkyl of R4is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from hydroxyl, halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)(Rb)-; N(Ra)(Rb)-C(=O)-;N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(Rc)-, or Rd-S(=O)2-N(Rc)-the C3-6 cycloalkyl of R4is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from oxo (=0), hydroxyl, halogen,cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, C1.2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, C1.4 fluoroalkoxy, N(Ra)( C(=O)-; N(Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-C(=O)-N(S(=O)2-N(RC)-, wherein each of the C1.4 alkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci.2alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, hydroxyl, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy;the 4- to 6-membered heterocycloalkyl of R4is optionally substituted with 1, 2, or 3 substituents each independently selected from oxo (=0), cyano, halogen, H0-, N(Ra)(Rb)-, (Ra)(Rb)N-C(=O)-, Rd-C(=O)-N(Rc)-, N(Ra)(Rb)- S(=0)2-, Rd-C(=O)-, Rd-S(=O)2-, Rd-S(=O)2-N(Rc)-, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, H0-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;the 5- to 6-membered heteroaryl of R4is optionally substituted with 1, 2, or 3 substituents each independently selected from cyano, halogen, H0-, N(Ra)(Rb)-, (Ra)(Rb)N-C(=O)-, Rd-C(=O)-N(Rc)-, (Ra)(Rb)-S(=O)2-, Rd-C(=O)-, Rd- S(=0)2-, Rd-S(=O)2-N(Rc)-, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, H0-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;each Rais independently H, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-C1.4 alkyl-;each Rbis independently H or selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce- aryl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of H0-, cyano, C1.4 alkyl, C3-7 cycloalkyl, C1.4 hydroxylalkyl, C1-4 alkyl-S-, HC(=O)-, HO-C(=O)-, C1.4 alkyl-C(=O)-, C1.4 alkyl-O-C(=O)-, H2N-C(=O)-, (C1.4 alkyl)2-N-C(=O)-, C1.4 haloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy;or Raand Rbtogether with the N atom to which they are attached form 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen,HO-, cyano, oxo, HC(=O)-, HO-C(=O)-, Ci-4alkyl-C(=O)-, Ci-4alkyl-O-C(=O)-, H2N-C(=O)-, (Ci-4alkyl)2-N-C(=O)-, Ci-4alkyl, Ci-4alkoxy, Ci-4hydroxylalkyl, Ci-4haloalkyl, and Ci-4haloalkoxy; each Rcis independently selected from the group consisting of H, Ci-4alkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4alkyl-;each Rdis independently selected from the group consisting of Ci-e alkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, Ce- aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4alkyl-, (Ce- aryl)-Ci-4alkyl-, and (5- to 10-membered heteroaryl)-Ci.4alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CF3, cyano, HO-, oxo, Ci-4alkyl-S- , Ci-4alkyl, Ci-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy;R5is R5a, R5b, R5c, or R5d:Z1is O, S, or NR7;each of Z2, Z3, Z4is independently CR8or N, provided (a) that at least one of Z2and Z3in each of R5a, R5b, and R5cis N and provided (b) that at least one of Z2, Z3, and Z4in R5dis N;R7is H, Ci-4alkyl, Ci-4fluoroalkyl, Cs-4cycloalkyl, or (C3-4cycloalkyl)-Ci-2 alkyl-; each of R8is independently H, Ci-4alkyl, Ci-4fluoroalkyl, Ci-4alkoxy, Ci-4fluoroalkoxy, Cs-4cycloalkyl, Cs-4fluorocycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl-;m is 0, 1, 2, 3, or 4;n is 0, 1, or 2;t is 0, 1, 2, or 3; andq is 1, 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A1is phenyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A1is 5- or 6-membered heteroaryl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A1is 5-membered heteroaryl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A1is 6-membered heteroaryl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy, wherein each of the C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, and C3-4 cycloalkoxy is optionally subsituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 cyanoalkyl, C3-4 cycloalkyl, (C3-4cycloalkyl)-Ci-2 alkyl-, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy.

8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein one R1is RAMDand each of the other R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C3-4 cycloalkyl, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein m is 2 or 3.

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein m is 2.

11. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, whereinthe moietyeach R1is independently halogen or cyano.

12. The compound of any one of claims 1, 3, and 8 to 10, or a pharmaceutically acceptable salt thereof, whereineach R1is independently halogen, cyano, C1.4 alkyl, C1.4 fluoroalkyl, C3-4 cycloalkyl, C3-4 cycloalkoxy, C1.4 alkoxy, or C1.4 fluoroalkoxy.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each of RL1and RL2is independently H or methyl.

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each of RL1and RL2is H.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein T1is N.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein T2is N.

17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein T1is N and T2is N.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein each R2is independently F, Cl, cyano, C1.2 alkyl or C1.2 fluoroalkyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein n is 0.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein T3is CRT3.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein RT3is H.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each R3is independently HO-, C1.4 alkyl, C1.4 fluoroalkyl, C1.4 hydroxylalkyl, C3-4 cycloalkyl, or (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C3-4 cycloalkyl or (C^cycloalkyl)-C1.2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, cyano, HO-, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, or C1.3 fluoroalkoxy.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2.

25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein t is 0.

26. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein T3is N.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Moiety M is Moiety M-1.

28. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Moiety M is Moiety M-2 or Moiety M-3.

29. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Moiety M is Moiety M-4.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each of RL3and RL4is independently H or methyl.

31. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each of RL3and RL4is H.

32. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein RL3and RT3, together with the two carbon atoms to which they are attached to, optionally form cyclopropyl.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Y is -(CH2)q- or absent.

34. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Y is -CH2- or absent.

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein:R4is 4- to 6-membered heterocycloalkyl that is optionally substituted with 1, 2, or 3 substituents each independently selected from oxo (=0), cyano, halogen, HO-, N(Ra)(Rb)-, N(Ra)(Rb)-C(=O)-, Rd-C(=O)-N(Rc)-, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, HO-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;Rais H, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-;Rbis H or selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, Ce- aryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (Ce- aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-C1.4 alkyl-;or Raand Rbtogether with the N atom to which they are attached form pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each optionally substituted with 1, 2, 3,4, or 5 substituents each independently selected from the group consisting of C1.4 alkyl-C(=O)-, (C1.4 alkyl)2-N-C(=O)-, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, and C1.4 haloalkoxy;Rcis selected from the group consisting of H, C1.4 alkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-; andRdis selected from the group consisting of Ci-e alkyl, C3-7 cycloalkyl, Ce- aryl, 5 (C3-7 cycloalkyl)-Ci-4 alkyl-, and (Ce- aryl)-Ci-4 alkyl-, wherein each of the selections in the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CF3, cyano, HO-, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy.

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R4is 4- to 6-membered heterocycloalkyl that is optionally substituted with 1, 2, or 3 substituents each independently selected from oxo (=0), halogen, H0-, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R4is 4- to 6-membered heterocycloalkyl that is optionally substituted with 1, 2, or 3 substituents each independently selected from C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-.

38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable saltthereof, wherein R4is selected from39. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein:R4is 5- to 6-membered heteroaryl that is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, HO-, -NRaRb, -C(=O)-NRaRb, -NRcC(=O)Rd, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl-, wherein each of the C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, or (C3-4cycloalkyl)-Ci-2 alkyl- is optionally subsituted with 1, 2, or 3 substituents each independently selected from halogen, HO-, cyano, C1.3 alkyl, C1.3 fluoroalkyl, C1.3 alkoxy, and C1.3 fluoroalkoxy;Rais H, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-;Rbis H or selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, Ce-io aryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (Ce- aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-C1.4 alkyl-;or Raand Rbtogether with the N atom to which they are attached form pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of C1.4 alkyl-C(=O)-, (C1.4 alkyl)2-N-C(=O)-, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, and C1.4 haloalkoxy;Rcis selected from the group consisting of H, C1.4 alkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-Ci-4 alkyl-; andRdis selected from the group consisting of Ci-e alkyl, C3-7 cycloalkyl, Ce- aryl, 5 (C3-7 cycloalkyl)-Ci-4 alkyl-, and (Ce- aryl)-Ci-4 alkyl-, wherein each of the selections in the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CF3, cyano, HO-, C1.4 alkyl, C1.4 haloalkyl, C3-7 cycloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy.

40. The compound of any one of claims 1 to 34 and 39, or a pharmaceutically acceptable salt thereof, wherein R4is 5- to 6-membered heteroaryl that is optionally substituted with 1, 2, or 3 substituents each independently selected from cyano, halogen, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and (C3-4cycloalkyl)-Ci-2 alkyl-.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein T4is N.

42. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein T4is CH or CRT4.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R5is R5a.

44. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R5is R5b.

45. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R5is R5c.

46. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R5is R5d.

47. The compound of claim 1 that is 5-(5-{[(1r,4R)-4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)cyclohexyl]methyl}-4-[(3R)-4,4-dimethyloxolan-3-yl]-4 / 7-1,2,4-triazol-3-yl)-1,2-oxazol-3-ol, or a pharmacutically acceptable salt thereof.

48. The compound of claim 1 , selected from the group consisting of the compounds in the following table:or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising the compound according to any of claims 1 to 48, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

50. A method for treating a condition, disease, or disorder in a subject comprising administering to the subject any of claims 1 to 48, or a pharmaceutically acceptable salt thereof, or a method for weight management of a subject comprising administering to the subject any of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, metabolic dysfunction-associated fatty liver disease [MAFLD, including related diseases such as steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowelsyndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

51. The method of claim 50, further comprising administering an additional therapeutic agent.

52. The method of claim 50 or 51, wherein the condition, disease, or disorder is obesity.

53. The method of claim 50 or 51 , wherein the method is for weight management.

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