US20230278991A1 - Glp-1r agonists and uses thereof - Google Patents

Glp-1r agonists and uses thereof Download PDF

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US20230278991A1
US20230278991A1 US18/113,859 US202318113859A US2023278991A1 US 20230278991 A1 US20230278991 A1 US 20230278991A1 US 202318113859 A US202318113859 A US 202318113859A US 2023278991 A1 US2023278991 A1 US 2023278991A1
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Wenge Zhong
Wei Guo
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Qilu Regor Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • Type 1 diabetes 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.
  • Insulin secretogogues including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells.
  • sulphonyl-ureas e.g., glipizide, glimepiride, glyburide
  • Sulphonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia.
  • DPP-IV inhibitors have limited efficacy.
  • Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity.
  • Biguanides e.g., metformin
  • Biguanides are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use.
  • Inhibitors of alpha-glucosidase decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances.
  • Thiazolidinediones e.g., pioglitazone, rosiglitazone
  • a specific receptor peroxisome proliferator-activated receptor-gamma
  • 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.
  • Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin
  • SGLT2 inhibitors 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.
  • the drugs have limited efficacy and do not address the most important problems, the declining 0-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.
  • 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 nonalcoholic fatty liver disease (NAFLD).
  • NAFLD nonalcoholic fatty liver disease
  • NAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma.
  • NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids.
  • the severity of NAFLD/NASH 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 NASH, 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. 17(2): 93-102, 2013).
  • 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 post-prandial rise in GLP-1 is absent or reduced (Vilsboll et al., Diabetes. 50:609-613, 2001).
  • GLP-1 receptor agonists such as GLP-1, liraglutide and exendin-4
  • FPG and PPG fasting and postprandial glucose
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, in a mixture with at least one pharmaceutically acceptable excipient.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisomer, solvate
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use as a medicament.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the prevention and/or treatment of cardiometabolic and associated diseases discussed herein, including T2DM, pre-diabetes, NASH, and cardiovascular disease.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a
  • the present disclosure provides a method of treating a disease for which an agonist of GLP-1R is indicated, in a subject in need of such prevention and/or treatment, comprising administering to the subject a therapeutically effective amount of a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.
  • a compound of any one of the formulae described herein e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (
  • the present disclosure provides a use of a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for the manufacture of a medicament for treating a disease or condition for which an agonist of the GLP-1R is indicated.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisome
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the treatment of a disease or condition for which an agonist of GLP-1R is indicated.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisomer, solvate, or
  • the present disclosure provides a pharmaceutical composition for the treatment of a disease or condition for which an agonist of the GLP-1R is indicated, comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.
  • Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisomer,
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the treatment and/or prevention of cardiometabolic and associated diseases discussed herein, including T2DM, pre-diabetes, NASH, and cardiovascular disease.
  • a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the treatment and/or treatment for cardiometabolic and associated diseases including diabetes (T1D and/or T2DM, including pre-diabetes), idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance,
  • 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, Parkinson's Disease, left ventricular hypertrophy, peripheral arterial disease, 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, prevention or treatment
  • the present disclosure provides a method of enhancing or stimulating GLP-1R-mediated cAMP signaling with reduced ⁇ -arrestin/arrestin-2 recruitment, comprising administering a compound of any one of the formulae described herein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.
  • a compound of any one of the formulae described herein e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′
  • the compounds of the present disclosure while being full agonists of GLP-1R-mediated cAMP signaling, are partial agonists of D-arrestin recruitment to activated GLP-1R, compared to the natural GLP-1R ligand GLP-1, in that maximal ⁇ -arrestin recruitment to activated GLP-1R by the compounds of the present disclosure is lower than maximal ⁇ -arrestin recruitment by GLP-1.
  • Such partial and/or biased agonists of GLP-1R for cAMP signaling may provide a more sustained cAMP signaling activity for better efficacy and lowered side effects.
  • the method of the present disclosure may be advantageously used for the treatment of any of the diseases or conditions described herein, such as type II diabetes (T2D) and related diseases.
  • T2D type II diabetes
  • the treatment elicits a glycemic benefit without concomitant increase, or at least reduced increase, in a GI side effect such as nausea, vomiting, or diarrhea.
  • the treatment has greater tolerability compared to a control treatment that has normal or enhanced ⁇ -arrestin recruitment (such as ⁇ -arrestin recruitment by GLP-1).
  • FIG. 1 shows dose-response curves for the GLP-1R/ ⁇ -Arrestin recruitment assay using certain compounds of the present disclosure and GLP-1 (7-37) as control.
  • the vertical axis represents relative effects of the test compounds normalized to percentage of effect by the natural ligand GLP-1 (7-37).
  • FIG. 1 compares Compounds 74-91, 93-95, 100, and 101 to GLP-1 (7-37).
  • FIG. 2 shows dose-response curves for the GLP-1R/ ⁇ -Arrestin internalization assay using certain compounds of the present disclosure and GLP-1 (7-37) as control.
  • the vertical axis represents relative effects of the test compounds normalized to percentage of effect by the natural ligand GLP-1 (7-37).
  • the two panels in FIG. 2 compare Compounds 74-80, 93-95, 100, and 101 (left panel), and Compounds 81-91 (right panel), respectively, to GLP-1 (7-37).
  • FIG. 3 shows NanoBit assay time course responses for both GLP-1 (7-37) and Compound 94 at different compound concentrations.
  • FIG. 4 shows dose-response curves for the GLP-1R/ ⁇ -Arrestin NanoBit assay using certain compounds of the present disclosure and GLP-1 (7-37) as control.
  • the vertical axis represents relative effects of the test compounds normalized to percentage of effect by the natural ligand GLP-1 (7-37).
  • the two panels in FIG. 4 compare Compounds 74-91, 93-95, 100, and 101 to GLP-1 (7-37), at 3 min. and 5 min. readouts, respectively.
  • FIG. 5 shows cAMP assay results using a monkey GLP-1R, for selected compounds of the present disclosure (i.e., Compounds 75, 84, 93, and 94) and GLP-1(7-37) as control.
  • the present disclosure provides a compound represented by structural formula (I):
  • the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by structural formula (II):
  • the present disclosure provides a compound according to the first or second embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to the first, second, or third embodiment, wherein the compound is represented by the structural formula (III):
  • the present disclosure provides a compound according to the second, third, or fourth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to the first, second, third, fourth, or fifth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, or sixth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein EE is COOH.
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R b is
  • the present disclosure provides a compound according to the second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 2 is independently selected from deuterium, halogen, —CN, OH, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 alkoxy; and n is an integer selected from 0, 1, 2, 3, and 4.
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
  • the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 2 is independently selected from halogen (e.g., F) or deuterium; and n is an integer selected from 0, 1, and 2, provided that when R 2 is deuterium, ring B is fully substituted with deuterium.
  • halogen e.g., F
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 3 is F, Cl or CH 3 ; and o is 0, 1, or 2.
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
  • the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
  • the present disclosure provides a compound according to the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure also provides a compound represented by structural formula (I-1) or (I-2):
  • halogen —CN, —OH, CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , oxo, and saturated or partially saturated C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , and saturated or partially saturated C 3 -C 6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the present disclosure also provides a compound represented by structural formula (I-A), (I-B), (I-C), or (I-D).
  • the present disclosure provides a compound according to structural formula (I-1), (I-2), (I-A), (I-B), (I-C), or (I-D), wherein the compound is represented by structural formula (II-A), (II-B), (II-B′), (II-C) or (II-D):
  • the present disclosure provides a compound according to structural formula (I-1), (I-2), (I-A), (I-B), (I-C), (II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
  • the present disclosure provides a compound according to structural formula (I-1), (I-2), (I-A), (I-B), (I-C), (II-A), (II-B), (II-B′), (II-C), or (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
  • the present disclosure provides a compound according to structural formula (I-1), (I-2), (I-A), (I-B), (I-C), (II-A), (II-B), (II-B′), (II-C), or (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to structural formula (I-1), (I-2), (I-A), (I-B), (I-C), (II-A), (II-B), (II-B′), or (II-C), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • R 3 is halogen, CN, OH, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or NR 5′ R 6′ ; and o is an integer selected from 0, 1, 2, and 3; and the remainder of the variables are as defined in the previous embodiments.
  • R 3 is halogen, CN, OH, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or NR 5′ R 6′ ; and o is an integer selected from 0, 1, 2, and 3; and the remainder of the variables are as defined in the previous embodiments.
  • R 3 is independently halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and o is 0, 1, or 2.
  • the present disclosure provides a compound according to structural formula (II-A) or (II-B′), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the present disclosure provides a compound according to structural formula (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof is selected from the compounds disclosed in examples and Table 1.
  • halogen refers to fluoride, chloride, bromide, or iodide.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy” or “haloalkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of formula —C n H (2n+1) .
  • an alkyl group typically has 1-4 carbon atoms, i.e. (C 1 -C 4 )alkyl.
  • a “(C 1 -C 4 )alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.
  • alkylene as used herein, means a straight or branched chain divalent hydrocarbon group of formula —C n H 2n —.
  • Non-limiting examples include ethylene, and propylene.
  • alkenyl means an alkyl group in which one or more carbon/carbon single bond is replaced by a double bond.
  • alkynyl means an alkyl group in which one or more carbon/carbon single bond is replaced by a triple bond.
  • alkoxy means an alkyl radical attached through an oxygen linking atom, represented by —O-alkyl.
  • (C 1 -C 4 )alkoxy includes methoxy, ethoxy, propoxy, and butoxy.
  • haloalkyl and “haloalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • hydroxyalkyl and “hydroxyalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups.
  • cycloalkyl means a cyclic, hydrocarbon group containing at least three carbon atoms (e.g., C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , or C 3-8 or C 3-6 ).
  • the cycloalkyl may be (fully) saturated or partially saturated (i.e., not aromatic), and may contain one or more carbon-carbon double bond(s).
  • a fully saturated cycloalkyl has the formula C n H (2n-1) .
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • heterocyclyl refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyl”).
  • a heterocyclyl group is a 3-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-8 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”); polycyclic ring systems include fused, bridged, or spiro ring systems).
  • Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.
  • Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.
  • the cycloalkyl or the heterocyclyl may be unsubstituted, or be substituted with one or more substituents as valency allows, wherein the substituents can be independently selected from a number of groups such as oxo, —CN, halogen, alkyl and alkoxyl, optionally, the alkyl substitution may be further substituted.
  • heteroaryl refers to a monocyclic or multicyclic aromatic hydrocarbon in which at least one of the ring carbon atoms has been replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur.
  • the heteroaryl is based on a C 5 _s aryl with one or more of its ring carbon atoms replaced by the heteroatom.
  • a heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring nitrogen atom.
  • the heteroaryl may be unsubstituted, or be substituted with one or more substituents as valency allows with the substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH 2 , NHalkyl, N(alkyl) 2 ), optionally, the alkyl may be further substituted.
  • a wavy line denotes a point of attachment of a substituent to another group.
  • compositions of any one of the formulae described above include acid addition and base salts.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-Amino-2-(hydroxymethyl)propane-1,3-diol (tris or tromethamine) and zinc salts.
  • bases include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-Amino-2-(hydroxymethyl)propane-1,3-diol (tris or tromethamine) and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see Handbook ofPharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Incorporated herein by reference.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • solvate is used herein to describe a molecular complex comprising the compound of any one of the formulae described above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • hydrate is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of any one of the formulae described above may exhibit one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism).
  • the compounds of any one of the formulae described above may also be isotopically labelled. Such variation is implicit to the compounds of any one of the formulae described above defined as they are by reference to their structural features and therefore within the scope of the present disclosure.
  • tautomeric isomerism can occur. This can take the form of proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.
  • the term “geometric isomer” refers to compounds having at least one double bond, wherein the double bond(s) may exist in cis (also referred to as syn or Delta (E)) or trans (also referred to as anti or sixteen (Z)) forms as well as mixtures thereof.
  • geometric isomer When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • a compound When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • the pharmaceutically acceptable salts of compounds of any one of the formulae described above may also contain a counterion which is optically active (e.g. d-lactate or 1-lysine) or racemic (e.g. dl-tartrate or dl-arginine).
  • a counterion which is optically active (e.g. d-lactate or 1-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 crystallisation.
  • racemate or the racemate of a salt or derivative
  • HPLC high pressure liquid chromatography
  • the racemate or a racemic precursor
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of any one of the formulae described above 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 and/or fractional crystallization 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 any one of the formulae described above (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • the present disclosure also includes all pharmaceutically acceptable isotopically-labeled compounds of any one of the formulae described above 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 which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the present disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 3 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 15 S.
  • isotopically-labelled compounds of any one of the formulae described above for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Isotopically-labeled compounds of any one of the formulae described above 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-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D 2 O, d 6 -acetone, d 6 -DMSO.
  • One way of carrying out the present disclosure is to administer a compound of any one of the formulae described above in the form of a prodrug.
  • certain derivatives of a compound of any one of the formulae described above which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into a compound of any one of the formulae described above having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme.
  • Such derivatives are referred to as “prodrugs.” Further information on the use of prodrugs may be found in Pro - drugs as Novel Delivery Systems , Vol. 14, ACS Symposium Series (T. Higuchi and W.
  • Prodrugs in accordance with the present disclosure can, for example, be produced by replacing appropriate functionalities present in the compounds of any one of the formulae described above with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985) and Y. M. Choi-Sledeski and C. G. Wermuth, Designing Prodrugs and Bioprecursors in Practice of Medicinal Chemistry, (Fourth Edition), Chapter 28, 657-696 (Elsevier, 2015).
  • a prodrug in accordance with the present disclosure is (a) an ester or amide derivative of a carboxylic acid in a compound of any one of the formulae described above; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group in a compound of any one of the formulae described above; (c) an amide, imine, carbamate or amine derivative of an amino group in a compound form any one of the formulae described above; (d) an oxime or imine derivative of a carbonyl group in a compound of any one of the formulae described above; or (e) a methyl, primary alcohol or aldehyde group that can be metabolically oxidized to a carboxylic acid in a compound of any one of the formulae described above.
  • prodrugs in accordance with the present disclosure include:
  • Certain compounds of any one of the formulae described above may themselves act as prodrugs of other compounds of any one of the formulae described above. It is also possible for two compounds of any one of the formulae described above to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of any one of the formulae described above may be created by internally linking two functional groups in a compound of any one of the formulae described above, for instance by forming a lactone.
  • references to compounds of any one of the formulae described above are taken to include the compounds themselves and prodrugs thereof.
  • the present disclosure includes such compounds of any one of the formulae described above as well as pharmaceutically acceptable salts of such compounds and pharmaceutically acceptable solvates of said compounds and salts.
  • a compound of the present disclosure is administered in an amount effective to treat a condition as described herein.
  • the compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.
  • the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the present disclosure.
  • the compounds of the present disclosure 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 present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.
  • the compounds of the present disclosure 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.
  • the compounds of the present disclosure 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.
  • the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the present disclosure can also be administered intranasally or by inhalation.
  • the compounds of the present disclosure may be administered rectally or vaginally.
  • the compounds of the present disclosure may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds of the present disclosure 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.
  • the total daily dose of a compound of the present disclosure is typically from about 0.001 to about 100 mg/kg (i.e., mg compound of the present disclosure per kg body weight) for the treatment of the indicated conditions discussed herein.
  • total daily dose of the compound of the present disclosure 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 present disclosure 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.
  • 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.
  • doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammal such as primates, rodents (mice, rats, hamsters, rabbits etc). In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the present disclosure comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the present disclosure presented with a pharmaceutically acceptable carrier.
  • Other pharmacologically active substances can also be present.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers 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.
  • 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 antibody or antibody portion.
  • compositions of present disclosure 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, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the form depends on the intended mode of administration and therapeutic application.
  • 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).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • Oral administration of a solid dose 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 present disclosure.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of any one of the formulae described above are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose 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 wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the present disclosure comprises a parenteral dose form.
  • Parenter administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations i.e., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • the present disclosure comprises a topical dose form.
  • Topical administration includes, for example, 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.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated—see, for example, Finnin and Morgan, J Pharm. Sci., 88:955-958, 1999.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of present disclosure is dissolved or suspended in a suitable carrier.
  • 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.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the present disclosure 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.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present disclosure comprises a rectal dose form.
  • rectal dose 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.
  • compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • the compounds of the present disclosure can be used alone, or in combination with other therapeutic agents.
  • the present disclosure provides any of the uses, methods or compositions as defined herein wherein the compound of any embodiment of any one of the formulae described above herein, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, 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 that each may generate a biological effect in the same time frame.
  • the presence of one agent may alter the biological effects of the other compound(s).
  • the two or more compounds may be administered simultaneously, concurrently or sequentially. 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.
  • the present disclosure provides methods of treatment that include administering compounds of the present disclosure in combination with one or more other pharmaceutical agents, wherein the one or more other pharmaceutical agents may be selected from the agents discussed herein.
  • the compounds of present disclosure are administered with an antidiabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vildaglipt
  • glucose-dependent insulinotropic peptide GIP
  • an alpha glucosidase inhibitor e.g. voglibose, acarbose, or miglitol
  • an insulin or an insulin analogue including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.
  • the compounds of present disclosure are administered with an anti-obesity agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g.
  • an anti-obesity agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist, a
  • obeticholic acid zonisamide
  • phentermine alone or in combination with topiramate
  • a norepinephrine/dopamine reuptake inhibitor e.g., buproprion
  • an opioid receptor antagonist e.g., naltrexone
  • a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist e.g., a combination of bupropion and naltrexone
  • a GDF-15 analog sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin)
  • a serotonergic agent e.g., lorcaserin
  • a methionine aminopeptidase 2 (MetAP2) inhibitor e.g., beloranib or ZGN-1061
  • the compounds of present disclosure are administered with an agent to treat NASH including but not limited to PF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR a/6 agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., sizumab), a galectin 3 inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS-4997), a dual antagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor 21 (FGF21) agonist (e.g., BMS-986036), a leu
  • agents and compounds of the present disclosure can be combined with pharmaceutically acceptable vehicles such as saline, Ringer's solution, dextrose solution, and the like.
  • pharmaceutically acceptable vehicles such as saline, Ringer's solution, dextrose solution, and the like.
  • the particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual's medical history.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspara
  • Liposomes containing these agents and/or compounds of the present disclosure are prepared by methods known in the art, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomes can 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.
  • PEG-PE PEG-derivatized phosphatidylethanolamine
  • agents and/or the compounds of the present disclosure 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.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the compound of any one of the formulae described above, 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 (U.S. Pat. No.
  • copolymers of L-glutamic acid and 7 ethyl-L-glutamate 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 LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-( ⁇ )-3-hydroxybutyric acid.
  • LUPRON DEPOTTM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • sucrose acetate isobutyrate sucrose acetate isobutyrate
  • poly-D-( ⁇ )-3-hydroxybutyric acid 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 present disclosure 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 IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and LipiphysanTM.
  • 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.
  • an oil e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
  • other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emul
  • Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion can comprise fat droplets between 0.1 and 1.0 m, particularly 0.1 and 0.5 m, and have a pH in the range of 5.5 to 8.0.
  • the emulsion compositions can be those prepared by mixing a compound of the present disclosure with IntralipidTM 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.
  • 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 nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising 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.
  • kits comprising the compound of any one of the formulae described above or pharmaceutical compositions comprising the compound of any one of the formulae described above of the present disclosure.
  • a kit may include, in addition to the compound of any one of the formulae described above, of the present disclosure or pharmaceutical composition thereof, diagnostic or therapeutic agents.
  • a kit may also include instructions for use in a diagnostic or therapeutic method.
  • the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof and a diagnostic agent.
  • the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof.
  • the present disclosure comprises kits that are suitable for use in performing the methods of treatment described herein.
  • the kit contains a first dosage form comprising one or more of the compounds of the present disclosure in quantities sufficient to carry out the methods of the present disclosure.
  • the kit comprises one or more compounds of the present disclosure in quantities sufficient to carry out the methods of the present disclosure and a container for the dosage and a container for the dosage.
  • the compounds of any one of the formulae described above may be prepared by the general and specific methods described below, using the common general knowledge of one skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry , Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations , Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods , Vol. I-XII (published by Wiley-Interscience).
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art.
  • certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group 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 N-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 can typically be removed without chemically altering other functionality in the any one of the formulae described above compounds.
  • Amine compounds prepared via methods described herein can be alkylated with a protected 2-bromoacetate in the presence of a suitable base such as K 2 CO 3 , Et 3 N, NaH or LiHMDS in a polar aprotic solvent such as but not limited to DMF, DMAc, DMSO or NMP to deliver compounds.
  • a suitable base such as K 2 CO 3 , Et 3 N, NaH or LiHMDS
  • a polar aprotic solvent such as but not limited to DMF, DMAc, DMSO or NMP to deliver compounds.
  • Standard ester hydrolysis can be performed to provide acids.
  • Pg 2 is t-butyl
  • standard acidic deprotection methods such as TFA/DCM, HCl/1,4-dioxane, HCl/EtOAc or other suitable conditions may be used to deliver acids.
  • GPCR G protein-coupled receptor
  • GLP-1R agonists are so-called “biased agonists,” in that they preferentially stimulate subsets among the natural signaling pathways, such as the G protein activation/cAMP production pathway, as compared to the recruitment of D-Arrestin, and/or the subsequent internalization of the GPCR (i.e., GLP-1R)— ⁇ -Arrestin complex.
  • the assays below provide means to measure the various downstream signaling pathways upon activation by the subject compounds.
  • GLP1 plays an important physiological role in maintaining blood glucose homeostasis.
  • GLP-1R is known to be expressed in pancreatic beta cells. GLP-1 mediates its effects via a Gas-coupled pathway. Activated GLP-1R stimulates the adenylyl cyclase pathway thus increases the intracellular concentration of cAMP, which results in increased insulin synthesis and release of insulin. Consequently GLP-1R has been suggested as a potential target for the treatment of diabetes.
  • GLP-1R activation following agonist/ligand binding also leads to ⁇ -arrestin recruitment to the GLP-1 receptor, which blocks GLP-1R signaling by, for example, occluding the binding site on GLP-1R for heterotrimeric G-protein to prevent its activation (desensitization), and by linking the GLP-1R to elements of the internalization machinery, such as clathrin and clathrin adaptor AP2, which promotes receptor internalization via coated pits and subsequent transport to internal compartments endosomes. Subsequently, the receptor could be either directed to degradation compartments (lysosomes) or recycled back to the plasma membrane where it can again signal.
  • GLP-1R agonist activity with respect to ⁇ -arrestin recruitment can be determined with a cell-based functional assay using PathHunter eXpress GLP1R CHO-K1 ⁇ -Arrestin GPCR Assay kit (DiscoverX Cat #93-0300E2CP0M).
  • the PathHunter ⁇ -Arrestin GPCR assay technology utilizes a ⁇ -galactosidase ( ⁇ -gal) enzyme that is split into two fragments, the smaller Enzyme Donor (ED) and the larger Enzyme Acceptor (EA). These fragments can be fused to two proteins that may interact with each other, such as EA- ⁇ -Arrestin and ED-GLP-1R.
  • the fusions can be stably expressed in a test cell line, such as the PathHunter CHO-K1 GLP1R ⁇ -Arrestin cells described below.
  • these fragment fusions have no ⁇ -gal activity; however, in solution or in a living cell, they can be brought together and complement to form an active p-gal enzyme due to the interaction between the fused proteins, thus generating a chemiluminescent signal in the presence of a suitable ⁇ -gal substrate.
  • PathHunter CHO-K1 GLP1R ⁇ -Arrestin cells from the assay kit were plated at a density of 1000 or 2000 cells/20 ⁇ l/well in a 384-well white/clear bottom plates (Greiner Cat #781098). Frozen cells were quickly thawed and 10 mL of cell plating medium (provided by the kit) was added to thawed cells. Cells were stored in a 37° C. incubator under 5% CO 2 and kept for approximately 48 hours until ready to run the assay.
  • Reference and test compounds were dissolved in 100% DMSO. 5 ⁇ concentration of an agonist was prepared in serum free DMEM (Thermo Cat #11965). 5 ⁇ L of this solution was added to 20 ⁇ L cell medium in assay plate for a final top concentration of 10 ⁇ M. Plates were then incubated at 37° C. under 5% CO 2 for 90 min.
  • detection reagents were made up by combining 1 part Galacton Star Substrate with 5 parts Emerald IITM Solution, and 19 parts of PathHunter Cell Assay Buffer, respectively. 12.5 ⁇ l detection reagent was added to each well. The plates were then incubated at room temperature in dark for 60 min. Plates were then read on Envision for 0.1 sec/well.
  • EC 50 determinations were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
  • the working solution is stable for at least 24 hours at room temperature with no impact on assay performance.
  • Sufficient reagents are provided in each kit to perform the indicated number of assays.
  • Cells were plated at a density of 1000 or 2000 cells/20 ⁇ L/well. Frozen cells were quickly thawed and added to 10 mL of cell plating medium. Cells were stored in a 37 degree incubator under 5% CO 2 and left for approximately 48 hours until ready to run the assay
  • the tested compounds include Compounds 74-91, 93-95, 100, 101, 257, 262, 263, 266, 267, 271, 276-278, 281, 284, 285, 289-293, 303, 305, 307, 308, 310-312, 323, and 331-334. Note that the partial maximum relative effect B (at the highest concentration tested in the assays) for the tested compound generally approaches about 20-40% of the B max for the natural ligand GLP-1 (7-37).
  • the partial maximum relative effect B max (at the highest concentration tested in the assays) for the tested compounds generally fall within about 10% to about 40% of the B max for the natural ligand GLP-1 (7-37). See B max values in the table above.
  • GLP-1R internalization A similar assay can also be used to assess the extent of signal attenuation due to GLP-1R internalization (the Internalization Assay).
  • activated GLP1R Internalization cells were engineered to co-express an untagged GLP1R, Enzyme Acceptor (EA) tagged ⁇ -Arrestin, and a ProLinkTM (PK) tag localized to the endosomes.
  • EA Enzyme Acceptor
  • PK ProLinkTM
  • PathHunter engineered U2OS cells from the assay kit (Cat #93-0724E3CP0L) were plated at a density of 2000 cells/20 L/well in a 384-well white/clear bottom plates (Greiner Cat #781098). Frozen cells were quickly thawed and 10 mL of cell plating medium (provided by the kit) was added to thawed cells. Cells were stored in a 37° C. incubator and kept for approximately 48 hours until ready for the assay.
  • Reference and test compounds were dissolved in 100% DMSO. 5 ⁇ concentration of an agonist was prepared in serum free DMEM (Thermo Cat #11965). 5 ⁇ L of this solution was added to L cell medium in assay plate for a final top concentration of 10 ⁇ M. Plates were incubated at 37° C. for 180 min.
  • detection reagents were made up by combining 1 part Galacton Star Substrate with 5 parts Emerald IITM Solution, and 19 parts of PathHunter Cell Assay Buffer, respectively. 12.5 ⁇ L detection reagent was added to each well. The plates were then incubated at room temperature for 60 min. Plates were then read on Envision for 0.1 sec/well.
  • EC 50 determinations were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
  • the tested compounds include Compounds 74-80, 93-95, 100, and 101 (left panel), and Compounds 81-91 (right panel).
  • B max at the highest concentration tested in the assays
  • the partial maximum relative effect B max (at the highest concentration tested in the assays) for the tested compound generally approaches about 20-30% of the B max for the natural ligand GLP-1 (7-37).
  • the partial maximum relative effect B max (at the highest concentration tested in the assays) for the tested compounds generally fall within about 10% to about 40% of the B max for the natural ligand GLP-1 (7-37).
  • GLP-1R-mediated interaction with ⁇ -Arrestin by agonist activity is determined with a cell-based functional assay, utilizing a NanoLuc® Binary Technology (NanoBiT) (Promega N2015) designed to detect GLP-1R and ⁇ -Arrestin interaction in a living cell.
  • the method is a two-subunit system based on NanoLuc® luciferase that can be used for intracellular detection of protein: protein interactions (PPIs).
  • the two subunits are known as the Large BiT (LgBiT; 17.6 kDa) and the Small BiT (SmBiT; 11 amino acids). These two subunits are fused to two proteins of interest, respectively. When both are expressed, the PPI brings the subunits into close proximity to form a functional enzyme that generates a bright, luminescent signal.
  • the human GLP-1R coding sequence (NCBI Reference Sequence NM_002062) and ⁇ -Arrestin2 coding sequence (NCBI Reference Sequence NM_004313.3) were subcloned into transient expression vectors provided in the NanoBiT kit, such that GLP-1R-LgBiT and SmBiT- ⁇ -Arrestin2 fusions were generated.
  • a total of 8 combinations were selected using HEK293T-based transfection with activation by the natural ligand GLP-1 7-37 .
  • the combination showed the highest assay window (GLP-1R-LgBiT and SmBiT- ⁇ -Arrestin2) was selected for testing the compounds of the present disclosure.
  • HEK293T cells (7.5 k cells/well) were seeded in 96-well culture plate (Corning Cat #3917) in DMEM (Thermo Cat #11965) with 10% FBS (Biosera Cat #FB-10581) that was heat inactivated, and 25 mM glucose. After 48 hours, cells were transfected with the GLP-1R-LgBiT and SmBiT- ⁇ -Arrestin2 constructs using Lipofectamine2000 (Thermo Cat #11668019) following the manufacturer's assay protocol.
  • plasmids encoding the GLP-1R-LgBiT and SmBiT- ⁇ -Arrestin2 fusions, and transfection reagent were diluted with Opti-MEM (Thermo Cat #31985-070). Then about 50 ng of GLP-1R-LgBiT and 50 ng of SmBiT- ⁇ -Arrestin2 plasmid constructs were mixed, and the resulting plasmids mixture was added into diluted transfection reagent. The ratio of plasmid (g): Lipofectamine2000 ( ⁇ l) was 1:10. The mixtures were then added into cells after 5 minutes' incubation at room temperature. About 48 hours after transfection, medium was replaced by 65 l/well fresh Opti-MEM.
  • Nano-Glo® Live Cell Substrate was then diluted with Nano-Glo® LCS Dilution Buffer at 1:24 ratio. About 25 ⁇ l of Nano-Glo® Live Cell Reagent was added into each well. Varying concentrations of each subject compound to be tested (in DMSO) were diluted in Opti-MEM with 0.1% BSA (Sigma Cat #A7409) to make 10 ⁇ stocks. About 10 ⁇ l compound stocks were added into each well using pipette. Luminescence was measured immediately by EnVision for 40, 60, or 120 repeats, with 0.25 seconds per well.
  • EC 50 determinations were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
  • test compounds dilute 1 mM stock to 100 ⁇ M using Opti-MEM containing 1% BSA, final top concentration is 10 ⁇ M, 1 ⁇ 4 log (4-fold) dilution, 8-dilution points, duplicate samples for each dilution.
  • the layout is similar to GLP-1 above.
  • NanoBit assay time-course responses at different compound concentrations are plotted for GLP-1 (7-37) and Compound 94 ( FIG. 3 ).
  • NanoBit assay dose response curves for the 3 min (180 sec) and 5 min (300 sec) time points were also generated for additional test compounds, including Compounds 74-91, 93-95, 100, and 101 ( FIG. 4 ).
  • the maximum relative effects for the tested compounds E, for the highest concentrations tested are generally no more than 40% (usually about 20-40%) of that of GLP-1 (7-37).
  • data analysis/report to obtain EC50 values can be done when compounds reach maximal signals—such as at 450-500 sec ( ⁇ 8 min).
  • GLP-1R-mediated agonist activity was determined with a cell-based functional assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP Dynamic 2 Assay Kit; CisBio cat #62AM4PEC) that measures cAMP levels in the cell.
  • the method is a competitive immunoassay between native cAMP produced by the cells and exogenous cAMP labeled with the dye d2.
  • the tracer binding is visualized by a mAb anti-cAMP labeled with Cryptate.
  • the specific signal i.e., energy transfer
  • the human GLP-1R coding sequence (NCBI Reference Sequence NM_002062) was subcloned into pcDNA3.1+/Hygro vector (Invitrogen) and transfected into HEK293/CRE/Luc parental cell line. A cell line stably expressing the receptor was isolated. Saturation binding analyses (filtration assay procedure) using 125 I-GLP-1 7-36 (Perkin Elmer) shows that plasma membranes derived from this cell line express a high GLP-1R density (K d : ⁇ 1 nM, B max : >800 fmol/mg protein).
  • Varying concentrations of each compound to be tested were diluted in DMSO to obtain 200 ⁇ compound working solution first and then 50 nl compounds were added to a white 384-well assay plate (Greiner 784075) with ECHO. The final DMSO concentration was 0.5%. The compound concentration range may be adjusted at any time.
  • Cells were removed from cryopreservation, re-suspended in 5 mL of Dulbecco's Phosphate Buffered Saline (DPBS-Sigma Cat #D8537) and centrifuged at 900 ⁇ g for 5 min at 22° C. The cell pellet was then re-suspended in 1 mL of assay buffer [DPBS with 500 ⁇ M IBMX (Sigma #15879) and 0.1% BSA (Sigma #A1933). IBMX and BSA were freshly added on the day of assay]. A 10 ⁇ L sample of the cell suspension was counted on an Invitrogen Countess II to determine cell viability and cell count per mL.
  • the remaining cell suspension was then adjusted with assay buffer to deliver 1000 viable cells per well using a Matrix Combi Multidrop reagent dispenser. 10 ⁇ L cell suspensions were added to each well of the assay plate which already contains compound. The plate was sealed and incubated at 37° C. with 5% CO 2 for 30 minutes.
  • Raw data were converted to nM cAMP by interpolation from a cAMP standard curve (as described in the manufacturer's assay protocol) and the percent effect was determined relative to a saturating concentration of the full agonist GLP-1 7-37 (10 nM) included on each plate.
  • EC 50 determinations were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
  • This assay demonstrates that the compounds of the present disclosure activates GLP-1R signaling through the cAMP pathway, thus behave as GLP-1R agonists.
  • the representive commercial reagents/kits that can be (were) used in such assays are described below.
  • EC 50 value for each compound is defined as the compound concentration that yielded 50% of the maximum cAMP level achieved with the same compound.
  • Final compound concentration is 10, 100, or 300 nM in 0.5% DMSO. A total of 11 data points were generated for each compound serial dilution.
  • each compound was tested in HEK293T cells. The results are shown below in Table 1.
  • selected compounds were also tested in CHO cells that have been stably transfected to express human GLP-1R. The results are shown below in Table 2.
  • the compounds of the present disclosure generally have B max approaching about 20-40% of that of GLP-1 (7-37) in the ⁇ -Arrestin recruitment assay and GLP-1R internalization assay, though a few exceptions exist. Further, the NanoBit time course profiles are different between the compounds of the present disclosure and those of GLP-1(7-37).
  • Step 7 Synthesis of methyl (S)-2-((6′-((4-chloro-2-fluorobenzyl)oxy)-[2,2′-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate
  • reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (3 ⁇ 20 mL). The organic phase was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • Trifluoromethylsulfonyl trifluoromethanesulfonate (2.39 g, 8.46 mmol, 1.42 mL) was added dropwise to a solution of 2,6-ditert-butyl-4-methyl-pyridine (2.17 g, 10.58 mmol) in Dichloromethane (16 mL) followed by the dropwise addition of a solution of methyl 2-(4-oxocyclohexyl)acetate (1.2 g, 7.05 mmol) in Dichloromethane (16 mL). The reaction mixture was allowed to stir at 25° C.

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