WO2026013531A1 - Spiro[2.5]octane compounds - Google Patents

Abstract

The present disclosure relates to new spiro[2.5]octane compounds of formula I 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 spiro[2.5]octane compounds may be useful in the treatment and amelioration of obesity. Formula (I).

Description

Spiro[2.5]octane compounds

This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63/669,493 filed July 10, 2024, the disclosure of which is hereby incorporated by reference in its entirety.

Field of Invention

Provided herein are new spiro[2.5]octane compounds that may be useful as glucagon- like peptide-1 receptor (GLP-1 R) agonists, compositions containing said compounds, process to make said compounds, and methods comprising administering said compounds to a subject in need thereof.

Background of the Invention

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 (T1 D) 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.

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-1 R) 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-1 R 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 and anemia. (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.

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 (3-cell function and the associated obesity.

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.

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).

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.

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).

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.

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

Summary of the Invention

In one embodiment (Embodiment E1), the present invention provides a compound of

Formula I or a pharmaceutically acceptable salt thereof, wherein

A is A1 or A2: and wherein each R¹ is independently halogen, -CN, - Ci-salkyl, or -OCi-salkyl, wherein the alkyl of Ci.₃alkyl and OCi.₃alkyl is unsubstituted or substituted with 1 , 2, or 3 F atoms; each R² is independently halogen, -CN, — Ci_₃alkyl, or -OCi.₃alkyl, wherein the alkyl of Ci-₃alkyl and OCi.₃alkyl is unsubstituted or substituted with 1 , 2, or 3 F atoms m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3;

Z^A1 is CH, CR^A1 , or N;

R^A1 is -F, -Cl, or -CN;

Z^A2 is CH, CR^A2, or N;

R^A2 is -F, -Cl, or -CN;

Z^A3 is CH, CR^A3, or N, provided that Z^A2 and Z^A3 are not simultaneously N;

R^A3 is -F, -Cl, or -CN; each R³ is independently -F, -OH, -CN, — Ci_₃alkyl, -OCi-₃alkyl, or -C_3.4cycloalkyl, wherein each of the — Ci_₃alkyl, -OCi-₃alkyl, and -C_3.4cycloalkyl is independently unsubstituted or substituted with 1 -OH or 1 , 2, or 3 F atoms; q is 0, 1 , or 2;

Y is -Ci-₃alkylene- or absent;

R⁴ is 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with

1 or 2 substituents selected from oxo (=O), -CN, -F, — Ci_₃alkyl, and -OCi-₃alkyl, and wherein each of the — Ci-₃alkyl and -OCi.₃alkyl are independently unsubstituted or substittued with 1 , 2, or 3 substituents each independently selected from -F, -CN, and -OR⁰; and the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from halogen, — Ci -₃alkyl , -OR⁰, and -N(R^N)₃ and wherein - Ci _₃alkyl is unsubstituted or substituted with 1 , 2, or 3 substituents each independently selected from -F, and -OR⁰; each R° is H or-Ci-₃alkyl, wherein Ci-₃alkyl is unsubstituted or substituted with 1 , 2, or 3 F atoms; each R^N is independently H or -Ci-₃alkyl;

Z¹ , Z², and Z³ are each independently -CR^Z, or one of Z¹, Z², and Z³ is N and each of the other two is independently -CR^Z; and each R^z is independently -H, -F, -Cl, or -CH₃.

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.

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. The present invention also provides a method for treating or preventing a GLP-1 R- related 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.

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-related condition, disease, or disorder.

The GLP-1 R-related condition, disease, or disorder includes one selected from diabetes [e.g. Type 1 diabetes mellitus (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), 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, 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).

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.

Detailed Description of the Invention

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.

E1 A compound of Formula I or a pharmaceutically acceptable salt thereof, as defined above.

E2 A compound of embodiment E1 , wherein the compound is a compound of Formula II: or a pharmaceutically acceptable salt thereof.

E3 A compound of embodiment E1 or E2, wherein the compound is a compound of Formula III: or a pharmaceutically acceptable salt thereof.

E4 A compound of embodiment E1 , wherein the compound is a compound of Formula IV:

IV or a pharmaceutically acceptable salt thereof.

E5 A compound of any one of embodiments E1 to E4, or a pharmaceutically acceptable salt thereof, wherein R³ is — Ci _₃alkyl.

E6 A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

E7 A compound of any one of embodiments E1 to E6, or a pharmaceutically acceptable salt thereof, wherein Z³ is N or CH.

E8 A compound of embodiment E1 or E2, wherein the compound is a compound of or a pharmaceutically acceptable salt thereof.

E9 A compound of embodiment E8, or a pharmaceutically acceptable salt thereof, wherein R² is -Cl.

E10 A compound of embodiment E8, or a pharmaceutically acceptable salt thereof, wherein R² is -CN.

E11 A compound of any one of embodiments E8 to E10, or a pharmaceutically acceptable salt thereof, wherein Y is -CH2- or absent. E12 A compound of any one of embodiments E8 to E11 , or a pharmaceutically acceptable salt thereof, wherein R⁴ is 4- to 6-membered heterocycloalkyl, and the 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1 or 2 — Ci_₃alkyl substituents.

E13 A compound of embodiment E12, or a pharmaceutically acceptable salt thereof, wherein

R⁴ is selected from

E14 A compound of any one of embodiments E9 to E1 1 , or a pharmaceutically acceptable salt thereof, wherein R⁴ is 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 — Ci_₃alkyl substituents, and wherein the alkyl of the Ci-₃alkyl is unsubstituted or substituted with 1 , 2, or 3 -F substituents.

E15 A compound of embodiment E14, or a pharmaceutically acceptable salt thereof, R⁴ is selected from

E16 A compound of any one of embodiments E1 to E15, selected from the group consisting of:

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1 -

((tetrahydrofuran-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 1);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1 -(oxetan- 2-ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 2);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1 -(oxazol-

5-ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 3);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(oxetan-

2-ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 5);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(pyridin-

3-ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 6);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-

((tetrahydrofuran-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 7);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(oxazol- 5-ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 8); 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 9);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(pyridin- 3-ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 10); and 2-(6-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)spiro[2.5]octan-1 -y I) - 1 -((1 -

(2,2,2-trifluoroethyl)-1 H-imidazol-5-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 11), or a pharmaceutically acceptable salt thereof.

E17 A compound of any one of embodiments E1 to E15, selected from Table 1 : or a pharmaceutically acceptable salt thereof.

E18 A compound of any one of embodiments E1 to E15, selected from the group consisting of: 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1 -y I) - 1 -(((S)- oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 2a); 2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-((S)-4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4a);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(((S)- oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 5a); and

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1 -((S)-4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 9a), or a pharmaceutically acceptable salt thereof.

E19 A compound of any one of embodiments E1 to E15, selected from Table 2: or a pharmaceutically acceptable salt thereof.

In some embodiments, Compound 4a is a diastereomer selected from the group consisting of:

2-((1 S,3r,6S)-6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1 -yl)-1 -(((S)- oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4aa);

2-((1 S,3s,6R)-6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1 -yl)-1 - (((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4ab);

2-((1 R,3r,6R)-6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1 -yl)-1 -(((S)- oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4ac); and

2-((1 R,3s,6S)-6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1 -yl)-1 - (((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4ad); or a mixture of two or more diastereomers, or a pharmaceutically acceptable salt thereof.

In some embodiments, Compound 4a is a diastereomer selected from Table 3: or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt thereof.

Any of the compounds described in embodiments E16 to E19, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of embodiments E1 to E15, or pharmaceutically acceptable salts thereof.

E20 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

E21 A method for treating a condition, disease, or disorder in a subject comprising administering to the subject any one of embodiments E1 to E19, or a pharmaceutically acceptable salt thereof, or a method for weight management of a subject comprising administering to the subject any one of embodiments E1 to E19, 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 (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), 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).

E22 A method of embodiment E21 , further comprising administering an additional therapeutic agent.

E23 A method of embodiment E21 or E22, wherein the condition, disease, or disorder is obesity.

E24 A method of embodiment E21 or E22, wherein the method is for weight management.

In some embodiments, the weight management is chronic weight management.

In some embodiments, the subject to be treated is overweight [i.e. having a body mass index (BMI) of 27 kg/m² or 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/m² or greater in the presence of at least one weight-related comorbid condition (e.g., hypertension, T2DM, or dyslipidemia). In some embodiments, the subject to be treated is obese (i.e. having an BMI of 30 kg/m² or greater) when the weight management treatment is initiated. In some further embodiments, the subject to be treated is adult.

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

E25 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 E1 to E19, or a pharmaceutically acceptable salt thereof.

E26. The method of embodiment E25, wherein said modulating is agonizing.

Each of the embodiments described herein may be combined with any other embodiment(s) described herein 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.

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

Definitions

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.

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

“Compounds of the invention” include compounds of Formula I, II, III, IV, and V, 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.

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. 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.

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).

“Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

“Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -CEN.

"Hydroxy" refers to an -OH group.

“Oxo” refers to a double bonded oxygen (=0).

"Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-C12 alkyl”), 1 to 8 carbon atoms (“Ci-Cs alkyl”), 1 to 6 carbon atoms (“CI-CB alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

“Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (“Ci-C₈ alkoxy”), 1 to 6 carbon atoms (“Ci-C₆ alkoxy”), 1 to 4 carbon atoms (“C1-C4 alkoxy”), or 1 to 3 carbon atoms (“C1-C3 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

“Cycloalkyl” refers to a fully saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Cycloalkyl groups may contain, but are not limited to, 3 to 12 carbon atoms (“C3-C12 cycloalkyl”), 3 to 8 carbon atoms (“C₃-C₈ cycloalkyl”), 3 to 6 carbon atoms (“C₃-C₆ cycloalkyl”), 3 to 5 carbon atoms (“C3-C5 cycloalkyl”) or 3 to 4 carbon atoms (“C3-C4 cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. Heterocycloalkyl” refers to a fully saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)_q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)_q as ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms.

Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto.

Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-7 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein.

"Aryl" or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp² hybridization and in which the pi electrons are in conjugation. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms ("C₆-C₂o aryl"), 6 to 14 carbon atoms ("C₆- Cu aryl"), 6 to 12 carbon atoms ("Ce-C^ aryl"), or 6 to 10 carbon atoms ("Ce-C aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in a ring in which all carbon atoms in the ring are of sp² hybridization and in which the pi electrons are in conjugation. Heteroaryl groups may contain, but are not limited to, 5 to 20 ring atoms (“5-20 membered heteroaryl”), 5 to 14 ring atoms (“5-14 membered heteroaryl”), 5 to 12 ring atoms (“5-12 membered heteroaryl”), 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5- 9 membered heteroaryl”), or 5 to 6 ring atoms (“5-6 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6- membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl and carbazolyl. Examples of 5- or e- membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

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.

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.

"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. 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.

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.

The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

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.

The term "treating", "treat", or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, including reversing, relieving, alleviating, or slowing the progression of the disease (or disorder or condition) or any tissue damage associated with one or more symptoms of the disease (or disorder or condition).

Salts

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.

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.

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.

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.

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.

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

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

(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

(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.

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.

Stereoisomers

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 cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention.

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. 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).

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

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. 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).

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 homogeneous form 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).

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.

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.

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 (^wvww), a solid wedge ("^^ ), a bolded line (^^"), a dotted wedge ( ^Hl), 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 atoms is 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.

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 IUPAC 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.

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.

Isotopes

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.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l, ¹²⁴l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

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 forthis purpose in view of their ease of incorporation and ready means of detection.

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.

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. Substitution with positron-emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

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.

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.

Pharmaceutical Compositions

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, II, III, IV, or V, 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 one embodiment, the additional medicinal or pharmaceutical agent is anti-diabetic agent as described below.

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 , II, III, IV, or V, or a pharmaceutically acceptable salt, including any solvate, hydrate, solid form, stereoisomer, tautomer, or prodrug) and (2) at least one pharmaceutically acceptable excipient.

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.

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.

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.

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, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

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.

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.

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.

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. 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.

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, skin patches, 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. 955- 958, 1999.

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.

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.

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.

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.

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).

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.

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.

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).

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.

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.

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.

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).

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 breathed directly 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.

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.

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.

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.

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.

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

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 per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

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.

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.

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.

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.

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.

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.

Therapeutic Methods and Uses

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 -related condition, disease, or disorder, including administering to a mammal, such as a human, in need of such treatment. 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 -related condition, disease, or disorder, including administering to a mammal, such as a human, in need of such treatment.

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-related condition, disease, or disorder, including administering to a mammal, such as a human, in need of such treatment a therapeutically effective amount.

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 (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), 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, 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).

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 (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), 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, 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).

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 (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), 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, 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).

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

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.

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.

Co-administration

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”.

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.

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).

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 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-1 receptor/glucagon receptor agonists (e.g. DD-01 , PB-718, mazdutide, pemvidutide, pegapamodutide, survodutide, LM-008, IBI-362, AZD9550), GLP-1 receptor agonists, 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. DR10624), NPY2 receptor agonists (e.g. Bl 1820237), GIPR antagonists, activin receptor type- 26 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, AMPK activators [e.g., ETC-1002 (bempedoic acid)], SCD1 inhibitors or MPO inhibitors.

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, MDR-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).

Some exemplary GIPR antagonists include the following:

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

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

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

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

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;

4'-({1-[(4-cyclopropylphenyl)carbamoyl]-DL-prolyl}amino)[1 ,1'-biphenyl]-4-carboxylic acid;

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

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

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;

4'-[(1-{[4-(prop-1-en-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1 ,1'-biphenyl]-4-carboxylic acid;

4'-({1-[(4-chlorophenyl)carbamoyl]-DL-prolyl}amino)[1 ,1'-biphenyl]-4-carboxylic acid;

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

3',5'-difluoro-4'-[(1 -{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1 ,1 bi pheny l]-4- carboxylic acid;

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

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

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

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 ,1 '-biphenyl]-4- carboxylic acid;

4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1 ,1 '-biphenyl]-4-carboxylic acid;

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

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

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;

4'-[(1 -{[4-(prop-1-en-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1 ,1 '-biphenyl]-4-carboxylic acid;

4'-({1-[(4-chlorophenyl)carbamoyl]-D-prolyl}amino)[1 ,1 '-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;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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;

4'-[(1 -{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino][1 ,1 '-biphenyl]-4-carboxylic acid;

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

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;

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

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

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

4'-({1-[(4-cyclobutylphenyl)carbamoyl]-DL-prolyl}amino)[1 ,1 '-biphenyl]-4-carboxylic acid;

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

4'-[(1-{[4-cyclopropyl-3-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino][1 ,1'- biphenyl]-4-carboxylic acid;

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

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

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

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

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 ,1'- biphenyl]-4-carboxylic acid;

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

4'-{[3-methyl-1 -{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1 ,1 '-bipheny l]-4- carboxylic acid;

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

4'-{[3-methyl-1 -{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1 ,1 '-bipheny l]-4- carboxylic acid;

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

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

4'-{[(4-c/s)-4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1 ,1 biphenyl]-4-carboxylic acid;

4'-{[1 -({1 -[4-(propan-2-yl)phenyl]ethyl}carbamoyl)-DL-prolyl]amino}[1 , 1 b iph e ny l]-4- carboxylic acid;

3-[6-({1-[(4-cyclobutylphenyl)carbamoyl]-DL-prolyl}amino)pyridin-3-yl]benzoic acid;

4'-[(1 -{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1 ,1 '-biphenyl]-4-carboxylic acid;

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

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;

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

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

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

4'-({1-[(4-cyclobutylphenyl)carbamoyl]-D-prolyl}amino)[1 ,1 '-biphenyl]-4-carboxylic acid;

4-{5-fluoro-6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridin-3- yljbenzoic acid;

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

4'-[(1-{[4-cyclopropyl-3-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1 ,1 '-biphenyl]- 4-carboxylic acid;

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

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

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

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

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

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

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

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

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

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

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

Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1 ,4,6,7-tetrahydro-1 '/7- spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid, gemcabene, and firsocostat (GS-0976) and phamaceutally acceptable salts thereof.

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.

Exemplary KHK inhibitors include [(1 R,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.

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.

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

11542270 and 11059833, including the following:

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

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

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

5-(5-chloro-3-methylthiophen-2-yl)-1 /-/-tetrazole;

5-(3,5-dichlorothiophen-2-yl)-1 /-/-tetrazole;

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

5-(4-bromo-3-ethylthiophen-2-yl)-1 /-/-tetrazole;

5-(4-chloro-3-ethylthiophen-2-yl)-1 /-/-tetrazole;

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

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

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

5,6-difluorothieno[3,2-b]thiophene-2-carboxylic acid; and 3,5-difluorothieno[3,2-b]thiophene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.

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

6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 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;

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

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 (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 tyrosine phosphatase-1 B (PTP-1 B) 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 WO2010103437, WO2010103438, WO2010013161 , WG2007122482, 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 WO2010140092, WO2010128425, WG2010128414, WO2010106457, 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 .

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., PKCoc, PKCp, 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 IL1 beta, and modulators of RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat., 2010, 20(12), 1627-51.

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), l_fchannel 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.

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); 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)]. 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. 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.

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

Examples of suitable cardiac glycosides include digitalis and ouabain.

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™).

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.

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.

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.

Examples of suitable mineralocorticoid receptor antagonists include sprionolactone and eplerenone.

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

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.

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.

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.

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.

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.

Synthetic Methods

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.

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.

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.

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.

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. 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-t-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.

General Experimental Details

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 4A 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. 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 l₂, 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 or XBridge 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 acid or 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.

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, 5) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD₂HOD, 3.31 ppm; acetonitrile-c/₂, 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.

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

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

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.

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

The compounds and intermediates described below were named using the naming convention provided with ACD/ChemSketch 2020.2.1.1 , File Version C15S41 , Build 119425 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming convention provided with ACD/ChemSketch 2020.2.1 .1 is well known by those skilled in the art and it is believed that the naming convention provided with ACD/ChemSketch 2020.2.1.1 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.

Abbreviations

AcOH is acetic acid; cAMP is cyclic adenosine monophosphate °C is degrees Celsius;

CDCI₃ is deutero-chloroform;

5 is chemical shift; d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets;

DCE is 1 ,2-dichloroethane; DCM is dichloromethane; methylene chloride;

DMA is N,N-dimethylacetamide;

DMF is N,N-dimethylformamide;

DMSO is dimethyl sulfoxide;

DMSO-de is deuterodimethylsulfoxide;

Et2O is diethyl ether;

EtOAc is ethyl acetate;

EtOH is ethanol;

EtsN is triethylamine;

HCI is hydrogen chloride;

HPLC is high pressure liquid chromatography;

HTRF is homogeneous time-resolved fluorescence; iPrOAc is isopropyl acetate;

[lr((ppy)₂(dtbpy)][PF₆] is [4,4'-Bis(1 ,1-dimethylethyl)-2,2'-bipyridine-N1 ,N1']bis[2-(2-pyridinyl-

N)phenyl-C]iridium(l II) hexafluorophosphate;

L is liter;

LCMS is liquid chromatography mass spectrometry;

LiOH is lithium hydroxide m is multiplet;

M is molar;

MeCN is acetonitrile;

MeNHOMe HCI is N.O-dimethylhydroxylamine hydrochloride;

MeOD_d4 is deuterated methanol;

MeOH is methanol;

2-MeTHF is 2-methyl tetra hydrofuran; mg is milligram;

MgSO₄ is magnesium sulfate

MHz is mega Hertz; min(s) is minute(s); mL is milliliter; mmol is millimole; mol is mole;

MS (m/z) is mass spectrum peak;

MTBE is te/Y-butyl methyl ether;

NaBH₄ sodium borohydride

NaSO₄ is sodium sulfate

NH₄OH is ammonium hydroxide

Ni(dtbbpy)Br₂ is [4,4'-Bis(1 ,1-dimethylethyl)-2,2'-bipyridine] nickel (II) dibromide; NMI is N-methylimidazole

NMR is nuclear magnetic resonance; pH is power of hydrogen; q is quartet; rt is room temperature;

RT is retention time; s is singlet; t is triplet;

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

TCFH is chloro-/V,/V,/V',/V-tetramethylformamidinium hexafluorophosphate THF is tetrahydrofuran; pL is microliter; pmol is micromole; and

The Scheme described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention. In the following Schemes, the general methods for the preparation of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that all of the synthetic transformations may be conducted in a precisely similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature.

General Methods:

Unless stated otherwise, the variables in Schemes I have the same meanings as defined herein.

Scheme I:

Examples

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.

The compounds and intermediates described below were named using the naming convention provided with ChemDraw, Version 20.1.1.125. The naming convention provided with ChemDraw, Version 20.1 .1 .125is well known by those skilled in the art and it is believed that the naming convention provided with ChemDraw, Version 20.1.1.125 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.

Example 1 : Synthesis of 2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2- yl)spiro[2.5]octan-1-yl)-1 -(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4a).

A solution of methyl 6-oxospiro[2.5]octane-1-carboxylate (400 mg, 2.20 mmol) in methanol (4.39 mL) was treated with sodium borohydride (125 mg, 3.29 mmol) at 0 °C under a nitrogen atmosphere. After stirring at the same temperature for 2 hours, the reaction was warmed up to ambient temperature and stirred for 18 hours, at which point water (2 mL) was added. The mixture was extracted with EtOAc (3 x 2 mL). The combined organic extracts were washed with brine (6 mL), dried over MgSO₄, and concentrated to afford methyl 6- hydroxyspiro[2.5]octane-1-carboxylate as a mixture of diastereomers in 68.5% (277 mg, 1.5 mmol). GCMS m/z 166.1 [M-H₂O]⁺. ¹H NMR (400 MHz, CDCh) 5 ppm 3.64 - 3.82 (m, 4 H) 1 .75 - 1 .97 (m, 3 H) 1 .42 - 1 .75 (m, 6 H) 1 .27 - 1 .35 (m, 1 H) 1 .06 - 1 .22 (m, 2 H) 0.82 - 0.95 (m, 1 H).

Steps 2 and 3 - Synthesis of 6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2- yl)spiro[2.5]octane-1-carboxylic acid

A 20 mL vial (A) was charged with 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (539 mg, 1 .36 mmol) along with an X-shaped stir bar and evacuated/back- filled with nitrogen 3 times. A degassed solution of methyl 6-hydroxyspiro[2.5]octane-1- carboxylate (157 mg, 0.85 mmol) in cyclopentyl methyl ether (6.00 mL) was added and the solution was stirred vigorously at ambient temperature. After 5 minutes, pyridine (110 pL, 1 .36 mmol) was added.

A 20 mL vial (B) was charged with 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (270 mg, 0.85 mmol), lr[ppy]₂(dtbbpy)PF₆ (11.7 mg, 12.8 pmol), and NiBr₂(dtbbpy) (20.8 mg, 42.6 pmol), and evacuated/back-filled with nitrogen 3 times. A degassed solution of quinuclidine (166 mg, 1 .49 mmol) in /V,/V-dimethylacetamide (6.00 mL) was added to vial B. Subsequently, the suspension that was formed in vial A was filtered into vial B via a syringe that was attached to a 0.45 pM acrodisc filter and needle, thereby transferring the cyclopentyl methyl ether solution of the NHC-complex to the rest of the reaction mixture. This mixture was split between two 2-dram vials. Both vials were further degassed with nitrogen for 15 min before they were placed in a PennPHD “Merck” photoreactor and irradiated with blue LEDs (450 nm), stirring at 900 rpm, fan cooling at 2500 rpm, LED power at 100 %, and on a timer for 12 hours. The reaction was diluted with water (5 mL) and saturated aqueous ammonium chloride (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (2 x 40 mL), brine (40 mL), dried over MgSC , and concentrated. LCMS m/z 404.2 [M+H]⁺.

The residue was suspended in 1 :1 :1 THF:MeOH:Water (10 mL) and treated with LiOH (123 mg, 5.12 mmol). The reaction was heated to in an aluminum heating block set to 70 °C. After 18 hours, the reaction was concentrated to remove volatile organics. The resulting basic aqueous solution was washed with diethyl ether (2 x 10 mL). The pH of the aqueous layer was adjusted to 3 with 1 .0 M aq. HCI and then extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated to give the crude product. Chromatography on silica gel (Gradient: 0% to 40% ethyl acetate in heptanes) provided a product mixture, containing the desired product 6-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octane-1 -carboxylic acid, and a co-eluting impurity as a white solid that was used without further purification. A total of 116 mg of purified residue containing the desired product was isolated . LCMS m/z 590.2 [M+H]+.

To a solution of 6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octane-1- carboxylic acid (60 mg, 0.15 mmol) in THF (0.77 mL) was treated with a solution of chloro- /V,/V,A/',/V-tetramethylformamidinium hexafluorophosphate (65 mg, 0.23 mmol) in DMF (0.77 mL). /V-Methylimidazole (37 L, 0.46 mmol) was then immediately added. The solution was stirred at ambient temperature for 30 min, at which point methyl 4-amino-3-[[(2S)-oxetan-2- yl]methylamino]benzoate (36 mg, 0.15 mmol) was then added. After an additional 18 hours water (3 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with water (2 x 20 mL), brine (20 mL), dried over MgSO4, and concentrated to give the desired crude product mixture.

The crude mixture was suspended in acetic acid (3 mL) and heated in an aluminum heating block at 100 °C. At 4 hours, the reaction was concentrated and diluted with sat. aq. NaHCO₃ (5 mL). The solution was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO₄, and concentrated.

Chromatography on silica gel (solvent gradient: 0% to 90% ethyl acetate in heptanes) provided the desired product methyl 2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1- yl)-1-(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylate as a mixture of diastereomers in 70% yield (64 mg, 0.11 mmol). LCMS m/z 590.2 [M+H]⁺.

A solution of methyl 2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1- yl)-1-(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylate (62 mg, 0.11 mmol) in MeCN (1.1 mL) was treated with 1 molar aq. TBD (1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene, 0.21 mL, 0.21 mmol) at ambient temperature. After 18 hours, the reaction was diluted with water (1 mL) and then acidified to pH 6 with 5% aq. citric acid. The solution was extracted with EtOAc (3 x 2 mL) and the combined organic extracts were dried over Na₂SO₄ and concentrated to give the crude product mixture, which was purified via reversed-phase HPLC (Column: C18, 19 x 100 mm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobile Phase B: 0.03% NH₄OH in Acetonitrile (v/v). Method: 75.0% H₂O/25.0% Acetonitrile linear to 55.0% H₂O/45.0% Acetonitrile in 8.5 min, 55.0% H₂O/45.0% 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.

Two mixtures containing the desired Compound 4a were isolated based on retention time, and each mixture contains two or more diastereomers, as analyzed by ¹H NMR spectroscopy, selected from the group consisting of:

Mixture A had a retention time of 2.85 min and an isolated yield of 18% (10.7 mg, 0.02 mmol). LCMS m/z 576.3 [M+H]⁺. ¹H NMR (600 MHz, DMSO-c/₆) 5 ppm 12.67 (br s, 1 H) 8.14 - 8.18 (m, 1 H) 7.71 - 7.83 (m, 1 H) 7.50 - 7.63 (m, 2H) 7.41 (s, 1 H) 7.17 - 7.22 (m, 1 H) 6.77 - 6.87 (m, 1H)6.65(s, 1 H) 5.35 - 5.45 (m, 2H) 5.09 - 5.19 (m, 1H) 4.75 - 4.87 (m, 1H) 4.64 -4.73 (m, 1 H) 4.38- 4.46 (m, 1H) 4.19 - 4.37 (m, H) 2.60 - 2.75 (m, 2H) 2.29 - 2.45 (m, 2H) 1.81 -2.09 (m, 3H) 1.54 - 1.73 (m, 3H) 1.43 - 1.54 (m, 1 H) 1.27 - 1.41 (m, 1 H) 1.11 - 1.19 (m, 1 H) 0.87 - 0.99 (m, 1H). One proton is not observed. Mixture B had a retention time of 2.88 min and an isolated yield of 18% (11.7 mg, 0.02 mmol). LCMS m/z 576.3 [M+H]⁺. ¹H NMR (600 MHz, DMSO-c/_e) 5 ppm 12.56- 12.90 (m, 1H) 8.18-8.25 (m, 1H) 7.75 - 7.82 (m, 1H) 7.55 - 7.66 (m, 2H) 7.45 - 7.51 (m, 1H) 7.28 -7.35 (m, 1 H) 6.83 - 6.90 (m, 1 H) 6.64 - 6.70 (m, 1 H) 5.35 - 5.43 (m, 2H) 5.02 - 5.15 (m, 1 H) 4.61 - 4.80 (m, 2H) 4.48 - 4.57 (m, 2H) 4.28 - 4.45 (m, 1H) 2.70 - 2.82 (m, 1H) 2.58 - 2.69 (m, 1H) 2.33 - 2.45 (m, 2H) 2.00 - 2.16 (m, H) 1.82 - 1.90 (m, 1 H) 1.55 - 1.82 (m, 3H) 1.45 - 1.53 (m, 1 H) 1.20

- 1.40 (m, 3H) 1.06- 1.14 (m, 1H)

Using the appropriate starting materials, the compounds shown below in Table 4 may be synthesized by methods similar to the method as described in Example 1.

Example 2: Biological assay

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; Rewity 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.

The human GLP-1 R 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) using ¹²⁵I-GLP-1 (Perkin Elmer) showed that plasma membranes derived from this cell line (designated clone C6) express a low GLP-1 R density (K_d: 0.3 nM, B_max: 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%.

Frozen assay-ready vials (at 1 E7 cells/vial) of CHO-TREX cells stably expressing the Gs-coupled human GLP-1 R 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% 02: 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 Rewity’s protocol (10 pL of d2 and then 10 pL cryptate, incubated for 1 hour at room temperature).

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 (IDBS 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- para meter logistic dose response equation, and the concentration required for 50% effect (EC₅o) was determined.

Results:

As described in Example 1 , Compound 4a was isolated in two mixtures, Mixture A and Mixture B respectively, wherein each mixture comprises two or more diastereomers selected from the group consisting of:

Mixture A had an EC50 of >10,000 nM, and Mixture B had an EC50 of 59.3 nM.

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.

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

CLAIMS We claim:

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

A is A1 or A2: and wherein each R¹ is independently halogen, -CN, - Ci-₃alkyl, or -OCi-₃alkyl, wherein the alkyl of Ci-salkyl and OCi-₃alkyl is unsubstituted or substituted with 1 , 2, or 3 F atoms; each R² is independently halogen, -CN, — Ci_₃alkyl, or -OCi.₃alkyl, wherein the alkyl of Ci-₃alkyl and OCi.₃alkyl is unsubstituted or substituted with 1 , 2, or 3 F atoms m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3;

Z^A1 is CH, CR^A1 , or N;

R^A1 is -F, -Cl, or -CN;

Z^A2 is CH, CR^A2, or N;

R^A2 is -F, -Cl, or -CN;

Z^A3 is CH, CR^A3, or N, provided that Z^A2 and Z^A3 are not simultaneously N;

R^A3 is -F, -Cl, or -CN; each R³ is independently -F, -OH, -CN, — Ci_₃alkyl, -OCi-₃alkyl, or -C_3.4cycloalkyl, wherein each of the — Ci_₃alkyl, -OCi-₃alkyl, and -C_3.4cycloalkyl is independently unsubstituted or substituted with 1 -OH or 1 , 2, or 3 F atoms; q is 0, 1 , or 2;

Y is -Ci-₃alkylene- or absent;

R⁴ is 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with

1 or 2 substituents selected from oxo (=O), -CN, -F, — Ci_₃alkyl, and -OCi-₃alkyl, and wherein each of the — Ci_₃alkyl and -OCi.₃alkyl are independently unsubstituted or substittued with 1 , 2, or 3 substituents each independently selected from -F, -CN, and -OR⁰; and the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from halogen, — Ci _₃alkyl , -OR⁰, and -N(R^N)₂ and wherein — Ci -₃alkyl is unsubstituted or substituted with 1 , 2, or 3 substituents each independently selected from -F, and -OR⁰; each R° is H or-Ci.₃alkyl, wherein Ci_₃alkyl is unsubstituted or substituted with 1 , 2, or 3 F atoms; each R^N is independently H or -Ci-₃alkyl;

Z¹ , Z², and Z³ are each independently -CR^Z, or one of Z¹, Z², and Z³ is N and each of the other two is independently -CR^Z; and each R^z is independently -H, -F, -Cl, or -CH₃.

2. The compound of claim 1 , wherein the compound is a compound of Formula II: or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is a compound of Formula III: or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is a compound of Formula IV:

IV or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1 to 4, wherein R³ is - Ci _₃alkyl, or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 to 5, wherein q is 1 or 2, or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1 to 6, wherein Z³ is N or CH, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 or 2, wherein the compound is a compound of Formula V: or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, wherein R² is -Cl, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein R² is -CN, or a pharmaceutically acceptable salt thereof.

11 . The compound of any one of claims 8 to 10, wherein Y is -CH₂- or absent, or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 8 to 11 , wherein R⁴ is 4- to 6-membered heterocycloalkyl, and the 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1 or 2 - Ci.₃alkyl substituents, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein R⁴ is selected from ' /'° , , or , or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 9 to 11 , wherein R⁴ is 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1 or 2 — Ci-salkyl substituents, and wherein the alkyl of the Ci.₃alkyl is unsubstituted or substituted with 1 , 2, or 3 -F substituents, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein R⁴ is selected from or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , selected from the group consisting of:

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-

((tetrahydrofuran-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 1);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(oxetan-2- ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 2);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(oxazol-5- ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 3);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(oxetan-2- ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 5);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(pyridin-3- ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 6);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1- ((tetrahydrofuran-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 7);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(oxazol-5- ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 8);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 9);

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(pyridin-3- ylmethyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 10); and

2-(6-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)spiro[2.5]octan-1-yl)-1-((1 -(2,2,2- trifluoroethyl)- 1 H-imidazol-5-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 11), or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , selected from the group consisting of:

2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(((S)- oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 2a);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-((S)-4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 4a);

2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-(((S)- oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 5a); and 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)spiro[2.5]octan-1-yl)-1-((S)-4,4- dimethyltetrahydrofuran-3-yl)-1 H-benzo[d]imidazole-6-carboxylic acid (Compound 9a), or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound according to any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

19. A method for treating a condition, disease, or disorder in a subject comprising administering to the subject any of claims 1 to 17, 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 17, 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 (T1 D), Type 2 diabetes mellitus (T2DM), including p re-diabetes], idiopathic T1 D (Type 1 b), 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).

20. The method of claim 19, further comprising administering an additional therapeutic agent.