WO2022031994A1 - Glp-1r agonists and uses thereof - Google Patents

Glp-1r agonists and uses thereof Download PDF

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Publication number
WO2022031994A1
WO2022031994A1 PCT/US2021/044785 US2021044785W WO2022031994A1 WO 2022031994 A1 WO2022031994 A1 WO 2022031994A1 US 2021044785 W US2021044785 W US 2021044785W WO 2022031994 A1 WO2022031994 A1 WO 2022031994A1
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saturated
halogen
optionally substituted
alkyl
groups selected
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PCT/US2021/044785
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French (fr)
Inventor
Wenge Zhong
Wei Guo
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Qilu Regor Therapeutics Inc.
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Publication of WO2022031994A1 publication Critical patent/WO2022031994A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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

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 P-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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
  • Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C) e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)
  • a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof e.g., Structural Formula (I), (II), (II-
  • 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C) e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C) e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)
  • a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof as defined
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C) e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-
  • 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), (II), (II- A), (II-B), (II-C), (III- A), (III-B), (III-B’), or (III-C)), 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), (II), (II- A), (II-B), (II-C), (III- A), (III-B), (III-B’), or (III-C)
  • the present disclosure provides a use of a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II- A), (II-B), (II-C), (III- A), (III-B), (IH-B’), or (III-C)), 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.
  • a compound of any one of the formulae described herein e.g., Structural Formula (I), (II), (II- A), (II-B), (II-C), (III- A), (III-B), (IH-B’), or (III-C)
  • 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C) e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)
  • 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.
  • 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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, prediabetes, NASH, and cardiovascular disease.
  • a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer,
  • the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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 prediabetes), idiopathic T1D (Type lb), 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
  • 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-lR-mediated cAMP signaling with reduced P-arrestin / arrestin-2 recruitment, comprising administering a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)
  • a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof as defined in any one of the embodiments described
  • the compounds of the present disclosure while being full agonists of GLP-lR-mediated cAMP signaling, are partial agonists of P-arrestin recruitment to activated GLP-1R, compared to the natural GLP-1R ligand GLP-1, in that maximal P-arrestin recruitment to activated GLP-1 R by the compounds of the present disclosure is lower than maximal P-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 P-arrestin recruitment (such as P-arrestin recruitment by GLP-1).
  • the present disclosure provides a compound represented by structural formula (I): or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: - indicates a single bond or a double bond;
  • X 1 , X 2 , X 3 , X 4 , and X 5 of ring A are each independently selected from N and CH;
  • W is selected from O, S, CR 5 R 6 , and NR 5 ’; ring wherein represents a portion of ring B bonded to ring C and “**” represents a portion of ring B bonded to W; or ring B, W, together with -CH(R a )-, form a bicyclic structure wherein represents a portion of the bicyclic structure bonded to ring C and “***” represents a portion of the bicyclic structure bonded to ring A;
  • Y 1 is N or CH
  • Y 3 and Y 5 are each independently selected from N, CH, O, and S; Y 2 are each independently N or CH;
  • Y 3 and Y 5 are each independently selected from N, CH, O, and S;
  • Y 4 is absent, N or CH; wherein there are no more than 3 hetero ring atoms in ring B and wherein ring B does not contain 3 hetero ring atoms at 3 contiguous positions; ring C is phenyl;
  • L is CHR d , O, S, or NR 5 ;
  • ring D is bicyclic heteroaryl;
  • each R a and R b are independently selected from hydrogen, deuterium, -CN, Ci-Ce alkyl, Ci-C 6 alkoxy, NR 5 R 6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R7R b is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R a /R b or in the group represented by R a /R b is optionally substituted with
  • each R 2 is independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR 5 R 6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy represented by R 2 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R 2 or in the
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, NR 5 R 6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R 5 or R 6 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R 5 or R 6 or in the group
  • R 5 and R 6 are each independently selected from hydrogen and Ci-Ce alkyl; wherein optionally two R 1 ; two R 2 ; two R 3 ; two R 4 ; R 1 and R 2 ; R 2 and R 3 ; R a and R 1 ; R a and R 2 ; R 1 and any of R 5 , R 5 (in the group represented by W), or R 6 ; R a and any of R 5 , R 5 (in the group represented by W), or R 6 ; R 2 and any of R 5 , R 5 (in the group represented by W), or R 6 ; R 5 and R 6 ; any of two groups selected from R c , R d , or R 4 and any one of R c or R d ; taken together with their respective intervening carbon or hetero atom(s), form phenyl, 5-6 membered heteroaryl, 4-8 membered saturated or partially saturated cycloalkyl or 4-8 membered saturated or partially saturated heterocyclyl, and each of which is optionally substitute
  • the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by structural formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
  • X 1 , X 2 , X 3 , X 4 , and X 5 of ring A are each independently selected from N and CH; wherein no more than three of X 1 , X 2 , X 3 , X 4 , and X 5 are N and wherein ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;
  • W is O, NH, or CH 2 ; ring wherein represents a portion of ring B bonded to ring C and “**” represents a portion of ring B bonded to W; or ring B, W, together with -C(R a )-, form a bicyclic structure , wherein represents a portion of the bicyclic structure bonded to ring C and “***” represents a portion of the bicyclic structure bonded to ring A;
  • T 2 is selected from N and C;
  • T 4 is selected from N, NR 4 , O, S, and CR 4 ;
  • T 6 , T 7 , and T 8 are each independently selected from N and CR 4 ; wherein no more than 4 of T 2 , T 4 , T 6 , T 7 , and T 8 are selected from N, O, and S;
  • R a is H, CH 3 , or CF 3 ;
  • R b is selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, NR 5 R 6 , 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl and 3-7 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R b is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C 3 -C 6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R b or in the group represented by R b is optionally substituted with one or more groups selected from halogen, oxo (when R b is non-aromatic), CN, OH, Ci-C 3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH
  • R c is selected from hydrogen, and C1-C4 alkyl optionally substituted with one or more groups selected from halogen and hydroxyl;
  • R d is H, F, CH3, or CF3; and each R 1 is independently selected from H, deuterium, halogen, -CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR 5 R 6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by R 1 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3,
  • each R 2 and R 3 are independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR 5 R 6 , wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R 2 and/or R 3 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); each R 4 is independently selected from H, deuterium, halogen, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and NR 5 R 6 , wherein the Ci-Ce alkyl and Ci-Ce alkoxy represented by R 4 is optionally substituted with one or more
  • 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 compound is represented by formula (II- A), (II-B), or (II-C):
  • the present disclosure provides a compound according to the first, second, or third embodiment, wherein the compound is represented by formula (III-A), (III-B), (III-B’), or (III-C):
  • the present disclosure provides a compound according to the first, second, third, or fourth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein Y 4 is N or CH.
  • ring A is each R 1 is independently selected from halogen, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxy alkoxy, C2-C4 alkenyl,
  • 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
  • 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 each R 3 is independently selected from halogen, CN, OH,
  • the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula each R 2 is independently selected from
  • H deuterium and halogen (e.g., F).
  • the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R 2 is deuterium, ring B is fully substituted with deuterium.
  • the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-B’), each R 2 is independently selected from H, deuterium and halogen (e.g., F).
  • the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-C); each R 2 is independently selected from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R 2 is deuterium, ring B is fully substituted with deuterium.
  • formula (III-C) each R 2 is independently selected from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R 2 is deuterium, ring B is fully substituted with deuterium.
  • 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 each R 1 is independently selected from halogen, OH, CN, C1-C2 alkyl, C1-C2 haloalkyl,
  • the present disclosure provides a compound according to the first, second, third, 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 first, 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 each R 3 is independently selected from F, Cl and CH3; and o is 0, 1, 2, 3 or 4.
  • the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula
  • the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, the compound is represented by
  • the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, herein the compound is represented by formula (III-B ’), and
  • 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 provides a compound according to the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 3 is F; and o is 0, 1, or 2.
  • 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+i). Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e. (Ci-C4)alkyl. As used herein, a “(Ci-C4)alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, Ao-propyl, and the like.
  • alkylene as used herein, means a straight or branched chain divalent hydrocarbon group of formula -C n H2 n -- 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.
  • (Ci-C4)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., C3, C4, C5, Ce, C7, Cs, or C3-8 or Cs e)-
  • 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-i).
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • heterocyclyl refers to a radical of a 3- to 12-membered nonaromatic 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, opotionally, 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 Cs 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., NH2, NHalkyl, N(alkyl)2), optionally, the alkyl may be further substituted.
  • substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH2, 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-l,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-l,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 of Pharmaceutical 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 may have a well-defined stoichiometry independent of humidity.
  • 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 n C, 13 C and 14 C, chlorine, such as 36 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 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., H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • positron emitting isotopes such as n C, 18 F, 15 O and 13 N
  • PET Positron Emission Topography
  • 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., D2O, de-acetone, de-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 antiobesity 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 antiobesity 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 lipa
  • 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/5 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
  • an emulsion formed upon mixing with a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
  • other ingredients may be added, for example glycerol or glucose, to adjust
  • 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 pm, particularly 0.1 and 0.5 pm, 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-fluorenyImethyIenoxycarbonyI (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.
  • 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 P-Arrestin, and/or the subsequent internalization of the GPCR (i.e., GLP-1 R) - P- 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-1 R stimulates the adenylyl cyclase pathway thus increases the intracellular concentration of cAMP, which results in increased insulin synthesis and release of insulin. Consequently GLP-1 R has been suggested as a potential target for the treatment of diabetes.
  • GLP-1 R activation following agonist / ligand binding also leads to P-arrestin recruitment to the GLP-1 receptor, which blocks GLP-1R signaling by, for example, occluding the binding site on GLP-1 R 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-1 R agonist activity with respect to P-arrestin recruitment can be determined with a cellbased functional assay using PathHunter eXpress GLP1R CHO-K1 P-Arrestin GPCR Assay kit (DiscoverX Cat#93-0300E2CP0M).
  • the PathHunter P- Arrestin GPCR assay technology utilizes a P-galactosidase (P-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-P- Arrestin and ED-GLP-1R.
  • the fusions can be stably expressed in a test cell line, such as the PathHunter CHO-K1 GLP1R P- Arrestin cells described below.
  • these fragment fusions have no P-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 P-gal substrate.
  • PathHunter CHO-K1 GLP1R P-Arrestin cells from the assay kit were plated at a density of 1000 or 2000 cclls/20pl/wcll 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% CO2 and kept for approximately 48 hours until ready to run the assay.
  • Reference and test compounds were dissolved in 100% DMSO. 5x concentration of an agonist was prepared in serum free DMEM (Thermo Cat#l 1965). 5 pL of this solution was added to 20 pL cell medium in assay plate for a final top concentration of 10 pM. Plates were then incubated at 37 °C under 5% CO2 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 pl 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.
  • EC50 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/20pL/well. Frozen cells were quickly thawed and added to 10 mL of cell plating medium. Cells were stored in a 37 °C incubator under 5% CO2 and left for approximately 48 hours until ready to run the assay
  • Test compounds came solubilized in 100% DMSO. Prepare lOx concentration of an agonist in serum free DMEM, and add all solutions into the compound plate. 2.5 pL of this solution was added to 20 p L cell medium in assay plate for a final top concentration of 10 pM. Plates were incubated at 37 °C under 5% CO2 for 30 min. An additional 2.5 pL of Buffer was added to the entire plate for agonist mode and incubated at 37 °C for another 90 min.
  • the partial maximum relative effect Bmax (at the highest concentration tested in the assays) for the majority of the tested compound generally approaches about 10-50% of the Bmax for the natural ligand GLP-1 (7-37), with just a couple of outliers on either side of the general range.
  • 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 P-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/20pL/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. 5x concentration of an agonist was prepared in serum free DMEM (Thermo Cat#l 1965). 5 pL of this solution was added to 20 pL cell medium in assay plate for a final top concentration of 10 pM. 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 pL 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.
  • EC50 determinations were made from agonist dose -response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
  • GLP-lR-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-1736 (Perkin Elmer) shows that plasma membranes derived from this cell line express a high GLP-1R density (Ka: ⁇ 1 nM, Bma X : > 800 fmol/mg protein).
  • Varying concentrations of each compound to be tested were diluted in DMSO to obtain 200x 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 900xg for 5 min at 22 ° C. The cell pellet was then re-suspended in 1 mL of assay buffer [DPBS with 500 pM IB MX (Sigma # 15879) and 0.1% BSA (Sigma # A1933). IB MX and BSA were freshly added on the day of assay. A 10 pL 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 pL 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% CO2 for 30 minutes. Following the 30 minute incubation, 5 pL of labeled d2 cAMP and 5 pL of anti-cAMP antibody (both diluted 1:20 in cell lysis buffer; as described in the manufacturer's assay protocol) were added to each well of the assay plate.
  • This assay demonstrates that the compounds of the present disclosure activates GLP-l R 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.
  • DMSO was removed from the media by carefully transferring thawed cells to a sterile 15/50 mL tube, filling a tube with 10-50 mL of complete media pre-warmed to 37 °C, and allowing the cells to sit 5 min before centrifuging at 900 rpm for 5 minutes for cell collection.
  • the optimized cell density is 1000 cells/well. Caution was taken because cell density optimization was crucial and needed to be optimized in different labotatories. The level of cAMP produced by the cells must fall within the linear range of the standard curve.
  • Test compounds were dissolved with DMSO to make stock solutions, aliquoted and stored at -80 °C. Serial dilutions of compound solutions were made using DMSO to obtain a 200x compound working solution first and then 50 nL of the working solution to 384-well plate with ECHO. The final DMSO concentration is 0.5%. The compound concentration range may be adjusted at any time.
  • Cell preparation cell suspensions were prepared according to procedures described above before running the assay.
  • Compound preparation prepare compound addition plates in advance of assay. Prepare 200x concentration of compound working solutions according to procedures described above.
  • Cell preparation cell suspensions are prepared according to procedures described above before running the assay.
  • Exendin (9-39) Antagonist addition Add 5 pL of 2x Exendin (9-39) to each well of the assay plate which already contains compound and cells. The final concentration of Exendin (9-39) is ICso- Seal the plate and incubate at 37 °C with 5% CO2 for 30 minutes.
  • EC50 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.
  • Table 1. Compound EC50 Values in HEK293T Cells
  • Example 3 Compound Synthesis
  • Step 1
  • reaction mixture was stirred at 100 °C for 2 h and upon completion of the reaction, as judged by TLC, the mixture was diluted with EtOAc (100 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
  • reaction mixture was stirred at rt for 8 h and upon completion of the reaction, as judged by TLC, the mixture was diluted with DCM (50 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous NazSCL, filtered and concentrated in vacuo.
  • reaction mixture was stirred at rt for 8 h and upon completion of the reaction, as judged by TLC, the mixture was diluted with EtOAc (50 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo.

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Abstract

Provided herewith are compounds of Formula (I) and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre- diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.

Description

GLP-1R AGONISTS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to International Patent Application No. PCT/CN2020/107368, filed on August 6, 2020. The entire contents of the aforementioned application are incorporated herein by reference.
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 (T1D) develops when the body’s immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump. Type 2 diabetes mellitus (referred to generally as T2DM) usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.
Currently, various pharmacological approaches are available for treating hyperglycemia and subsequently, T2DM (Hampp et al., Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 37:1367-1374, 2014). These may be grouped into six major classes, each acting through a different primary mechanism.
Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Sulphonyl- ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity.
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.
Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances.
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.
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) 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-1R agonists and SGLT2 inhibitors, the drugs have limited efficacy and do not address the most important problems, the declining P-cell function and the associated obesity.
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 a 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 nonalcoholic fatty liver disease (NAFLD).
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).
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 post-prandial rise in GLP-1 is absent or reduced (Vilsboll et al., Diabetes. 50:609-613, 2001).
Hoist Physiol. Rev. 87:1409, 2007) and Meier (Nat. Rev. Endocrinol. 8:728, 2012) 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 aspect, the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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.
In another aspect, the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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.
In another aspect, the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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.
In another aspect, 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), (II), (II- A), (II-B), (II-C), (III- A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.
In another aspect, the present disclosure provides a use of a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II- A), (II-B), (II-C), (III- A), (III-B), (IH-B’), or (III-C)), 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.
In another aspect, the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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.
In another aspect, 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), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.
Every Example or pharmaceutically acceptable salt thereof may be claimed individually or grouped together in any combination with any number of each and every embodiment described herein.
The present disclosure also provides a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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, prediabetes, NASH, and cardiovascular disease.
In another aspect, the present disclosure provides a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), 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 prediabetes), idiopathic T1D (Type lb), 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), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, 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 from use of other agents (e.g., from use of steroids and antipsychotics), excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, 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, 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 of Polycystic Ovary Syndrome and treatment of addiction (e.g., alcohol and/or drug abuse).
In another aspect, the present disclosure provides a method of enhancing or stimulating GLP-lR-mediated cAMP signaling with reduced P-arrestin / arrestin-2 recruitment, comprising administering a compound of any one of the formulae described herein (e.g., Structural Formula (I), (II), (II-A), (II-B), (II-C), (III-A), (III-B), (III-B’), or (III-C)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein. This is partly based on the surprising finding that the compounds of the present disclosure, while being full agonists of GLP-lR-mediated cAMP signaling, are partial agonists of P-arrestin recruitment to activated GLP-1R, compared to the natural GLP-1R ligand GLP-1, in that maximal P-arrestin recruitment to activated GLP-1 R by the compounds of the present disclosure is lower than maximal P-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.
Thus, 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.
In certain embodiments, 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. In certain embodiments, the treatment has greater tolerability compared to a control treatment that has normal or enhanced P-arrestin recruitment (such as P-arrestin recruitment by GLP-1).
DETAILED DESCRIPTION OF THE INVENTION
1. Compounds
In a first embodiment, the present disclosure provides a compound represented by structural formula (I):
Figure imgf000007_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: - indicates a single bond or a double bond;
X1, X2, X3, X4, and X5 of ring A are each independently selected from N and CH;
W is selected from O, S, CR5R6, and NR5’; ring
Figure imgf000007_0002
wherein represents a portion of ring B bonded to ring C and “**” represents a portion of ring B bonded to W; or ring B, W, together with -CH(Ra)-, form a bicyclic structure
Figure imgf000007_0003
wherein represents a portion of the bicyclic structure bonded to ring C and “***” represents a portion of the bicyclic structure bonded to ring A;
Y1 is N or CH;
Y3 and Y5 are each independently selected from N, CH, O, and S; Y2 are each independently N or CH;
Y3 and Y5 are each independently selected from N, CH, O, and S; and
Y4 is absent, N or CH; wherein there are no more than 3 hetero ring atoms in ring B and wherein ring B does not contain 3 hetero ring atoms at 3 contiguous positions; ring C is phenyl;
L is CHRd, O, S, or NR5 ; ring D is bicyclic heteroaryl;
EE is -COOH or a carboxylic group surrogate, optionally, the carboxylic group surrogate is:
Figure imgf000008_0001
each Ra and Rb are independently selected from hydrogen, deuterium, -CN, Ci-Ce alkyl, Ci-C6 alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R7Rb is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Ra/Rb or in the group represented by Ra/Rb is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 ; each Rc and Rd are independently selected from hydrogen, deuterium, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R7Rd is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R7Rd or in the group represented by R7Rd is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, and NR5 R6 ; each R1 is independently selected from H, deuterium, halogen, -CN, OH, Ci-Ce alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by R1 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R1 or in the group represented by R1 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 . each R2 is independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy represented by R2 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R2 or in the group represented by R2 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 ; each R3 is independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R3 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R3 or in the group represented by R3 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 ; each R4 is independently selected from H, deuterium, halogen, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and NR5 R6 , wherein the Ci-Ce alkyl and Ci-Ce alkoxy represented by R4 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
R5 and R6 are each independently selected from hydrogen, deuterium, CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R5 or R6 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R5 or R6 or in the group represented by R5 or R6 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5’R6’.
R5 and R6 are each independently selected from hydrogen and Ci-Ce alkyl; wherein optionally two R1; two R2; two R3; two R4; R1 and R2; R2 and R3; Ra and R1; Ra and R2; R1 and any of R5, R5 (in the group represented by W), or R6; Ra and any of R5, R5 (in the group represented by W), or R6; R2 and any of R5, R5 (in the group represented by W), or R6; R5 and R6; any of two groups selected from Rc, Rd, or R4 and any one of Rc or Rd; taken together with their respective intervening carbon or hetero atom(s), form phenyl, 5-6 membered heteroaryl, 4-8 membered saturated or partially saturated cycloalkyl or 4-8 membered saturated or partially saturated heterocyclyl, and each of which is optionally substituted with one or more groups selected from halogen, -CN, -OH, CF3, Ci-Ce alkyl, Ci-Ce alkoxy, -NH2, -NHC i-Cr, alkyl, -N(Ci-Ce alkyl)2, oxo, and saturated or partially saturated C3-C6 cycloalkyl, wherein the Ci-Ce alkyl and Ci-Ce alkoxy is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3; m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; o is an integer selected from 0, 1, 2, 3, and 4; and p is an integer selected from 0, 1, 2, 3, and 4.
In a second embodiment, the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by structural formula (II):
Figure imgf000011_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
X1, X2, X3, X4, and X5 of ring A are each independently selected from N and CH; wherein no more than three of X1, X2, X3, X4, and X5 are N and wherein ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;
W is O, NH, or CH2; ring
Figure imgf000011_0002
wherein represents a portion of ring B bonded to ring C and “**” represents a portion of ring B bonded to W; or ring B, W, together with -C(Ra)-, form a bicyclic structure
Figure imgf000011_0003
, wherein represents a portion of the bicyclic structure bonded to ring C and “***” represents a portion of the bicyclic structure bonded to ring A;
T2 is selected from N and C;
T4 is selected from N, NR4, O, S, and CR4;
T6, T7, and T8 are each independently selected from N and CR4; wherein no more than 4 of T2, T4, T6, T7, and T8 are selected from N, O, and S;
Ra is H, CH3, or CF3;
Rb is selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl and 3-7 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by Rb is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Rb or in the group represented by Rb is optionally substituted with one or more groups selected from halogen, oxo (when Rb is non-aromatic), CN, OH, Ci-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and 0CH3), and Ci-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 ;
Rc is selected from hydrogen, and C1-C4 alkyl optionally substituted with one or more groups selected from halogen and hydroxyl;
Rd is H, F, CH3, or CF3; and each R1 is independently selected from H, deuterium, halogen, -CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by R1 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R1 or in the group represented by R1 is optionally substituted with one or more groups selected from halogen, oxo (when R1 is non-aromatic), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 . each R2 and R3 are independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R2 and/or R3 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); each R4 is independently selected from H, deuterium, halogen, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and NR5 R6 , wherein the Ci-Ce alkyl and Ci-Ce alkoxy represented by R4 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3).
In a third embodiment, 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 compound is represented by formula (II- A), (II-B), or (II-C):
Figure imgf000012_0001
Figure imgf000013_0001
In a fourth embodiment, the present disclosure provides a compound according to the first, second, or third embodiment, wherein the compound is represented by formula (III-A), (III-B), (III-B’), or (III-C):
Figure imgf000013_0002
Figure imgf000014_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein Y4 is N or CH. In a fifth embodiment, the present disclosure provides a compound according to the first, second, third, or fourth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, ring A is
Figure imgf000014_0002
each R1 is independently selected from halogen, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxy alkoxy, C2-C4 alkenyl,
C2-C4 alkynyl, -NH2, -NHC1-C4 alkyl, and -N(CI-C4 alkylh; and m is an integer selected from 0, 1, and 2.
In a sixth embodiment, 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
Figure imgf000014_0003
Figure imgf000015_0001
In a seventh embodiment, 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 each R3 is independently selected from halogen, CN, OH,
C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and NR5 R6 ; and o is an integer selected from 0, 1, 2, 3, and 4.
In an eighth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula
Figure imgf000015_0002
Figure imgf000015_0003
each R2 is independently selected from
H, deuterium and halogen (e.g., F).
In a ninth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or
Figure imgf000015_0004
from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R2 is deuterium, ring B is fully substituted with deuterium. In a tenth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-B’),
Figure imgf000016_0001
Figure imgf000016_0002
each R2 is independently selected from H, deuterium and halogen (e.g., F).
In an eleventh embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-C); each R2 is independently selected from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R2 is deuterium, ring B is fully substituted with deuterium.
In a twelfth embodiment, 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
Figure imgf000016_0003
each R1 is independently selected from halogen, OH, CN, C1-C2 alkyl, C1-C2 haloalkyl,
C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 hydroxy alkoxy, C2-C4 alkenyl, and
C2-C4 alkynyl; and m is an integer selected from 0, 1, and 2.
In a thirteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
Figure imgf000016_0004
Figure imgf000016_0005
In a fourteenth embodiment, the present disclosure provides a compound according to the first, 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 each R3 is independently selected from F, Cl and CH3; and o is 0, 1, 2, 3 or 4.
In a fifteenth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula
Figure imgf000017_0001
In a sixteenth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, the compound is represented by
Figure imgf000017_0002
In a seventeenth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, herein the compound is represented by formula (III-B ’), and
Figure imgf000017_0003
In an eighteenth embodiment, 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
Figure imgf000017_0004
Figure imgf000018_0001
In a nineteenth embodiment, 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
Figure imgf000018_0002
In a twentieth embodiment, 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, eighteenth, or nineteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R3 is F; and o is 0, 1, or 2.
In one embodiment, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, is selected from the compounds disclosed in examples and Table 1.
2. Definitions
The term “halogen,” as used herein, refers to fluoride, chloride, bromide, or iodide.
The term “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 -CnH(2n+i). Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e. (Ci-C4)alkyl. As used herein, a “(Ci-C4)alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, Ao-propyl, and the like.
The term “alkylene” as used herein, means a straight or branched chain divalent hydrocarbon group of formula -CnH2n-- Non-limiting examples include ethylene, and propylene.
The term “alkenyl” means an alkyl group in which one or more carbon/carbon single bond is replaced by a double bond.
The term “alkynyl” means an alkyl group in which one or more carbon/carbon single bond is replaced by a triple bond.
The term “alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.
The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
The terms “hydroxyalkyl” and “hydroxyalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups.
The term “cycloalkyl,” as used herein, means a cyclic, hydrocarbon group containing at least three carbon atoms (e.g., C3, C4, C5, Ce, C7, Cs, or C3-8 or Cs e)- 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 CnH(2n-i). Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 12-membered nonaromatic 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”). In some embodiments, 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”). In 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.
Generally, 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, opotionally, the alkyl substitution may be further substituted.
The term “heteroaryl,” as used herein, 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. Preferably, the heteroaryl is based on a Cs 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. Generally, 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., NH2, NHalkyl, N(alkyl)2), optionally, the alkyl may be further substituted.
Certain abbreviations used herein include: Room temperature: RT; Methanol: MeOH.; Ethanol: EtOH; Isopropanol: iPrOH; Ethyl acetate: EtOAc; Tetrahydrofuran: THF; Toluene: PhCHs; Cesium carbonate: CS2CO3; Lithium bis(trimethylsilyl)amide: LiHMDS; Sodium t-butoxide: NaOtBu; Potassium t-butoxide: KotBu; Lithium diisopropylamide: LDA; Triethylamine: Et ;N; N,N- diisopropylethyl amine: DIPEA; Potassium carbonate: K2CO3; Dimethyl formamide: DMF; Dimethyl acetamide: DMAc; Dimethyl sulfoxide: DMSO; N-Methyl-2-pyrrolidinone: NMP; Sodium hydride: NaH; Trifluoroacetic acid: TFA; Trifluoroacetic anhydride: TFAA; Acetic anhydride: AC2O; Dichloromethane: DCM; 1,2-Dichloroethane: DCE; Hydrochloric acid: HC1; 1,8- Diazabicyclo[5.4.0]undec -7-ene: DBU; Borane-dimethylsulfide complex: BH3-DMS; Boranetetrahydrofuran complex: BH3-THF; Lithium aluminum hydride: LAH; Acetic acid: AcOH; Acetonitrile: MeCN; p-Toluenesulfonic acid: pTSA; Dibenzylidine acetone: DBA; 2,2'- Bis(diphenylphosphino)- 1 , 1 '-binaphthalene: BINAP; 1 , 1 '-Ferrocenediyl-bis(diphenylphosphine) : dppf; 1,3-Bis(diphenylphosphino)propane: DPPP; 3 -Chloroperbenzoic acid: m-CPBA; Tert-Butyl methyl ether: MTBE; Methanesulfonyl: Ms; N-Methylpyrrolidinone: NMP; Thin layer chromatography: TLC; Supercritical fluid chromatography: SFC; 4-(Dimethylamino)pyridine: DMAP; Tert-Butyloxycarbonyl: Boc; l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate: HATU; Petroleum ether: PE; 2-(lH-Benzotriazole-l-yl)-
1.1.3.3-tetramethyluronium hexafluorophosphate: HBTU; and 2-Amino-2-(hydroxymethyl)propane-
1.3-diol: tris; tris(dibenzylideneacetone)dipalladium: Pd2(dba)3
1 H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (5) are given in parts-per-million relative to the residual proton signal in the deuterated solvent (CHCL at 7.27 ppm; CD2HOD at 3.31 ppm; MeCN at 1.94 ppm; DMSO at 2.50 ppm) and are reported using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. ’H NMR spectra were obtained with field strengths of 400 or 600 MHz if not stated.
As used herein, a wavy line denotes a point of attachment of a substituent to another group.
Pharmaceutically Acceptable Salts
Pharmaceutically acceptable salts of the compounds 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, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acid and xinafoate salts.
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-l,3-diol (tris or 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 Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Incorporated herein by reference.
Pharmaceutically acceptable salts of compounds of any one of the formulae described above may be prepared by one or more of three methods:
(i) by reacting the compound of any one of the formulae described above with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of any one of the formulae described above 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 the compound of any one of the formulae described above to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions 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. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of any one of the formulae described above, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms.
Solvates and Hydrates
The term “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.
The term “hydrate” is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. 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.
Stereoisomers and Other Variations
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.
Compounds of any one of the formulae described above containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of any one of the formulae described above contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (“tautomerism”) 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.
Compounds having one or more chiral centers can exist in various stereoisomeric forms. 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 entgegen (E)) or trans (also referred to as anti or zusammen (Z)) forms as well as mixtures thereof. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.
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. When 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. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) 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.
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.
When the 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).
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
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 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. 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 disclosure 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). Columns can be obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.
It must be emphasized that the compounds of any one of the formulae described above have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the present disclosure.
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.
Examples of isotopes suitable for inclusion in the compounds of the present disclosure include isotopes of hydrogen, such as 2H and 3H, carbon, such as nC, 13C and 14C, chlorine, such as 36C1, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S.
Certain 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. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e., H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
Substitution with positron emitting isotopes, such as nC, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
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.
Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, de-DMSO.
Prodrugs
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. Thus, 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. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). Reference can also be made to Nature Reviews/Drug Discovery, 7:355, 2008, and Current Opinion in Drug Discovery and Development, 10:550, 2007.
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).
Thus, 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.
Some specific examples of prodrugs in accordance with the present disclosure include:
(i) where the compound of any one of the formulae described above contains a carboxylic acid functionality (-COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid functionality of the compound of any one of the formulae described above is replaced by Ci-C8 alkyl (e.g. ethyl) or (Ci-C8 alkyl)C(=O)OCH2- (e.g. tBuC(=O)OCH2-);
(ii) where the compound of any one of the formulae described above contains an alcohol functionality (-OH), an ester thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound of any one of the formulae described above is replaced by -CO(Ci-Cs alkyl) (e.g. methylcarbonyl) or the alcohol is esterified with an amino acid;
(iii) where the compound of any one of the formulae described above contains an alcohol functionality (-OH), an ether thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound of any one of the formulae described above is replaced by (Ci-Cs alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2;
(iv) where the compound of any one of the formulae described above contains an alcohol functionality (-OH), a phosphate thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound of any one of the formulae described above is replaced by - P(=O)(OH)2or -P(=O)(ONa)2or -P(=O)(Q-)2Ca2+;
(v) where the compound of any one of the formulae described above contains a primary or secondary amino functionality (-NH2or -NHR where R^H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of any one of the formulae described above is/are replaced by (Ci-Cw)alkanoyl, - COCH2NH2 or the amino group is derivatised with an amino acid;
(vi) where the compound of any one of the formulae described above contains a primary or secondary amino functionality (-NH2or -NHR where R^H), an amine thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of any one of the formulae described above is/are replaced by -CH2OP(=O)(OH)2;
(vii) where the carboxylic acid group within compound of any one of the formulae described above is replaced by a methyl group, a -CH2OH group or an aldehyde group.
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.
3. Administration and Dosing
Typically, 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. For administration and dosing purposes, 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.
In another embodiment, 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.
In another embodiment, the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, 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. In one embodiment, 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. In another embodiment, 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.
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 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.
4. Pharmaceutical Compositions
In another embodiment, 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.
As used herein, “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. Examples of 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.
The 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. The form depends on the intended mode of administration and therapeutic application.
Typical 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 antibody is administered by intravenous infusion or injection. In yet another embodiment, 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. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, 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. 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 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.
In another embodiment, the present disclosure comprises a parenteral dose form.
“Parenteral 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) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
In another embodiment, 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. When the compounds of present disclosure 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, 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. Such formulations may also be delivered by iontophoresis.
For intranasal administration or administration by inhalation, 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. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
In another embodiment, the present disclosure comprises a rectal dose form. Such 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.
Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical 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 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, Hoover, John E., Remington’ s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
5. Co-Administration
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 phrases “concurrent administration,” “co-administration,” “simultaneous administration,” and “administered simultaneously” mean that the compounds are administered in combination.
In another embodiment, 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.
In one embodiment, 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, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), a sodiumglucose linked transporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a GPR40 agonist (FFAR1/FFA1 agonist, e.g. fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogues thereof, an alpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol), or 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.
In another embodiment, the compounds of present disclosure are administered with an antiobesity 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. 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), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or in combination with another GLP-1R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.
In another embodiment, 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/5 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., simtuzumab), 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 leukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacin analogue (e.g., ARI 3037MO), an ASBT inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI 010976), a ketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1 receptor antagonist, an anti-CBlR antibody, or an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.
These 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. 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, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn- protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). 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.
These 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. 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 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. 3,773,919), 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 DEPOT™ (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 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 Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. 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 can 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.
The emulsion compositions can be those prepared by mixing a compound of the present disclosure with Intralipid™ 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 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.
6. Kits
Another aspect of the present disclosure provides 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. In some embodiments, the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof.
In yet another embodiment, the present disclosure comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, 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. In another embodiment, 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.
7. Preparation
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.
In the preparation of the compounds of any one of the formulae described above, it is noted that some of the preparation methods described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in any one of the formulae described above precursors). 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 Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
For example, 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-fluorenyImethyIenoxycarbonyI (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.
The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present disclosure. The compounds of the present disclosure including intermediates can also be prepared by the same or similar methods disclosed in International Application No. PCT/CN2020/084203 and International Application No. PCT/CN2019/119373, both of which are incorporated herein in its entireties by reference. Some of the compounds of the present present disclosure may contain single or multiple chiral centers with the stereochemical designation (R) or (S). It will be apparent to one skilled in the art that all of the synthetic transformations can be conducted in a 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.
EXAMPLES
Activation of a G protein-coupled receptor (GPCR) GLP-1R by its natural ligand GLP-1 causes recruitment of multiple intracellular proteins, each of which can activate distinct signaling pathways, most prominently the activation of downstream G proteins (which can be measured by cAMP production), the recruitment of P-Arrestin, and/or the subsequent internalization of the GPCR (i.e., GLP-1R) - P-Arrestin complex. Unlike the natural ligand GLP-1, certain 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 P-Arrestin, and/or the subsequent internalization of the GPCR (i.e., GLP-1 R) - P- Arrestin complex. The assays below provide means to measure the various downstream signaling pathways upon activation by the subject compounds.
Biological Example 1: GLP-lR/p-Arrestin Assay and Internalization Assay for Demonstrating Small Molecule Compound-Mediated GLP-1R/ P-Arrestin Interaction Activation
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-1 R stimulates the adenylyl cyclase pathway thus increases the intracellular concentration of cAMP, which results in increased insulin synthesis and release of insulin. Consequently GLP-1 R has been suggested as a potential target for the treatment of diabetes.
GLP-1 R activation following agonist / ligand binding also leads to P-arrestin recruitment to the GLP-1 receptor, which blocks GLP-1R signaling by, for example, occluding the binding site on GLP-1 R 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. The strength of arrestin-receptor interaction is believed to play a role in this choice: tighter complexes tend to increase the probability of receptor degradation (Class B), whereas more transient complexes favor recycling (Class A), although this “rule” is far from being absolute.
GLP-1 R agonist activity with respect to P-arrestin recruitment can be determined with a cellbased functional assay using PathHunter eXpress GLP1R CHO-K1 P-Arrestin GPCR Assay kit (DiscoverX Cat#93-0300E2CP0M).
The PathHunter P- Arrestin GPCR assay technology utilizes a P-galactosidase (P-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-P- Arrestin and ED-GLP-1R. The fusions can be stably expressed in a test cell line, such as the PathHunter CHO-K1 GLP1R P- Arrestin cells described below.
Independently, these fragment fusions have no P-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 P-gal substrate.
In this experiment, PathHunter CHO-K1 GLP1R P-Arrestin cells from the assay kit were plated at a density of 1000 or 2000 cclls/20pl/wcll 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% CO2 and kept for approximately 48 hours until ready to run the assay.
Reference and test compounds were dissolved in 100% DMSO. 5x concentration of an agonist was prepared in serum free DMEM (Thermo Cat#l 1965). 5 pL of this solution was added to 20 pL cell medium in assay plate for a final top concentration of 10 pM. Plates were then incubated at 37 °C under 5% CO2 for 90 min.
Following 90 min incubation, 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 pl 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.
EC50 determinations were made from agonist dose -response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
The effect of a small molecule compound, such as one of the instant present disclosure, on the GLP-1R / P-Arrestin interaction activation, or P-Arrestin recruitment, can be demonstrated and measured using the assay and commercial reagents described herein below.
Preparations
Reagents and Consumables:
Reagent Vendor Catalog No.
PathHunter eXpress GLP1R Discover X 93-0300E2CP0M
CHO-K1 P-Arrestin GPCR
Assay kit
384 well white/clear bottom Greiner 781098 plates
Instruments:
Instrument Vendor Internal Code
EnVision PerkinElmer HD-4HYSG2330
Media and Solutions
Prepare detection Working Solution by combining 1 part Galacton Star® Substrate with 5 parts Emerald IITM Solution, and 19 parts of PathHunter Cell Assay Buffer, respectively.
Once prepared, 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.
Procedures
1. Plating Cells
Cells were plated at a density of 1000 or 2000 cells/20pL/well. Frozen cells were quickly thawed and added to 10 mL of cell plating medium. Cells were stored in a 37 °C incubator under 5% CO2 and left for approximately 48 hours until ready to run the assay
2. Compound Preparation
1) Reference agonist compound GLP1 (7-37): dissolved with DMSO to make 1 mM stock solutions, aliquoted and stored at -80°C.
2) Test compounds (such as the compounds of the present disclosure) came solubilized in 100% DMSO. Prepare lOx concentration of an agonist in serum free DMEM, and add all solutions into the compound plate. 2.5 pL of this solution was added to 20 p L cell medium in assay plate for a final top concentration of 10 pM. Plates were incubated at 37 °C under 5% CO2 for 30 min. An additional 2.5 pL of Buffer was added to the entire plate for agonist mode and incubated at 37 °C for another 90 min.
3. Detection Reagents
Following 90 min incubation, detection reagents were made up as described. 12.5 pL was added to all wells. The plates were then incubated at room temperature in dark for 60 min. Plates were then read on Envision for 0.1 sec/well.
4. P-Arrestin Assay Data Processing
Data analysis: GraphPad Prism 6 was used for establishment of progression curve. EC50S or IC50S were determined by 4-parameter logistic dose response equation.
Note that the partial maximum relative effect Bmax (at the highest concentration tested in the assays) for the majority of the tested compound generally approaches about 10-50% of the Bmax for the natural ligand GLP-1 (7-37), with just a couple of outliers on either side of the general range.
P-Arrestin Recruitment as Measured by PathHunter CHO-K1 -based Assay
Figure imgf000038_0001
Figure imgf000039_0001
A similar assay can also be used to assess the extent of signal attenuation due to GLP-1R internalization (the Internalization Assay). In this assay, activated GLP1R Internalization cells were engineered to co-express an untagged GLP1R, Enzyme Acceptor (EA) tagged P-Arrestin, and a ProLink™ (PK) tag localized to the endosomes. Activation of the GLP1R induces P-Arrestin recruitment, which leads to internalization of the Receptor/ Arrestin-EA complex in PK-tagged endosomes. This forces complementation of the two P-galactosidase enzyme fragments (EA and PK) to form a functional enzyme that hydrolyzes substrate to generate a chemiluminescent signal. These cells have been modified to prevent long term propagation and expansion using a proprietary compound that has no apparent effect on assay performance.
Specifically, PathHunter engineered U2OS cells from the assay kit (Cat#93-0724E3CP0L) were plated at a density of 2000 cells/20pL/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. 5x concentration of an agonist was prepared in serum free DMEM (Thermo Cat#l 1965). 5 pL of this solution was added to 20 pL cell medium in assay plate for a final top concentration of 10 pM. Plates were incubated at 37 °C for 180 min.
Following 180 min incubation, 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 pL 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.
EC50 determinations were made from agonist dose -response curves analyzed with a curve fitting program using a 4-parameter logistic dose response equation.
The GLP-1R internalization dose-response curves for selected compounds of the present disclosure, as compared to GLP-1 (7-37) as a control, were created. Again, the partial maximum relative effect Bmax (at the highest concentration tested in the assays) for the tested compound generally approaches about 20-50% of the Bmax for the natural ligand GLP-1 (7-37). P-Arrestin Internalization as Measured by PathHunter U2OS Cell-based Assay
Figure imgf000040_0001
*This value stands for averaged Bmax where applicable (POC, or Percentage of Control).
Biological Example 2 GLP1R cAMP Assay for Demonstrating Small Molecule Compounds- Mediated GLP-1R Activation
HEK293/GLP-1R/CRE/Luc, Clone 4 - cAMP Assay
GLP-lR-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) is inversely proportional to the concentration of cAMP in either standard or experimental sample.
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 125I-GLP-1736 (Perkin Elmer) shows that plasma membranes derived from this cell line express a high GLP-1R density (Ka: < 1 nM, BmaX: > 800 fmol/mg protein).
Varying concentrations of each compound to be tested (in DMSO) were diluted in DMSO to obtain 200x 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 900xg for 5 min at 22 ° C. The cell pellet was then re-suspended in 1 mL of assay buffer [DPBS with 500 pM IB MX (Sigma # 15879) and 0.1% BSA (Sigma # A1933). IB MX and BSA were freshly added on the day of assay. A 10 pL 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 pL 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% CO2 for 30 minutes. Following the 30 minute incubation, 5 pL of labeled d2 cAMP and 5 pL of anti-cAMP antibody (both diluted 1:20 in cell lysis buffer; as described in the manufacturer's assay protocol) were added to each well of the assay plate. The plates were then incubated at room temperature and after 60 minutes, changes in the HTRF signal were read with an Envision multi-label plate reader using excitation of 330 nm and emissions of 615 and 665 nm. 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-l? 37 (10 nM) included on each plate. EC50 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-l R 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.
Preparations
Reagents and Consumables:
Reagent Vendor Catalog No.
HEK/GLPIR/CRE/Luc cell line HDB
DMEM Gibco 12100
Exendin (9-39) MCE HY-P0264
Human GLP-l-(7-37)-amide MCE HY-P0055
384 well plates, white Greiner 784075 cAMP dynamic 2 Cisbio 62AM4PEC
Fetal Bovine Serum Biosera FB-10581/500
IBMX Sigma 15879
BSA Sigma A1933-5G
DPBS Sigma D8537
Instruments:
Instrument Vendor Internal Code
EnVision PerkinElmer HD-4HYSG2330
Media and Solutions:
1) Assay buffer
DPBS with 500 pM IB MX and 0.1% BSA. IB MX and BSA are freshly added on the day of assay.
2) cAMP-d2 working solution preparation a) The lyophilisate was reconstituted with an appropriate amount of distilled water according to manufacturer’s instructions to make working stock which can be aliquoted and frozen (-20 °C). b) The working stock solution was diluted 1:20 in the conjugate and lysis buffer before use.
3) Anti-cAMP antibody-cryptate working solution preparation c) The lyophilisate was reconstituted with appropriate amount of distilled water according to manufacturer’s instruction to make working stock which can be aliquoted and frozen (-20 °C). d) The working stock solution was diluted 1:20 in the conjugate and lysis buffer before use.
Procedures
Procedures for Cell Suspension Preparation
1. Frozen cells were thawed very briefly in a 37 °C water bath under sterile conditions until just before ice completely melt (for about 1 minute) with a continuous agitation. Caution was taken because a longer incubation could result in cell death.
2. DMSO was removed from the media by carefully transferring thawed cells to a sterile 15/50 mL tube, filling a tube with 10-50 mL of complete media pre-warmed to 37 °C, and allowing the cells to sit 5 min before centrifuging at 900 rpm for 5 minutes for cell collection.
3. The cells were resuspended with assay buffer.
4. For stable GLP1-R assay, the optimized cell density is 1000 cells/well. Caution was taken because cell density optimization was crucial and needed to be optimized in different labotatories. The level of cAMP produced by the cells must fall within the linear range of the standard curve.
Procedures for Compound Preparation
1) Reference agonist compound GLP1 (7-37) was dissolved with DMSO to make a 1 rnM stock solution, which was then aliquoted and stored at -80 °C.
2) Reference antagonist compound Exendin (9-39) was dissolved with DMSO to make a 2 mM stock solution, which was then aliquoted and stored at -80 °C.
3) Test compounds were dissolved with DMSO to make stock solutions, aliquoted and stored at -80 °C. Serial dilutions of compound solutions were made using DMSO to obtain a 200x compound working solution first and then 50 nL of the working solution to 384-well plate with ECHO. The final DMSO concentration is 0.5%. The compound concentration range may be adjusted at any time.
4) IBMX: 500 mM stock solution dissolved in DMSO, aliquot and stored at -20 °C. Procedures for Agonist Assay
1) Compound preparation: compound addition plates were prepared in advance of the assay. 200x compound working solutions were prepared according to procedures described above.
2) Cell preparation: cell suspensions were prepared according to procedures described above before running the assay.
3) Compound addition: 50 nL/well of 200x compound working solutions were added to low-volume 384 white assay plate with Echo.
4) Cell addition: 10 pL cell suspensions were added to each well of the assay plate which already contained the compound working solution. The plate was sealed and incubated at 37 °C with 5% CO2 for 30 minutes.
5) 5 pL of a cAMP-d2 working solution was added to each well of the assay plate.
6) 5 pL of an anti-cAMP antibody-cryptate working solution was added to each well of the assay plate. The plate was covered with a lid. Incubate at room temperature for 1 hours.
7) The fluorescence was read at 665 and 615 nm with an EnVision plate reader with TRF LASER using the specified settings and the data was saved.
Procedures for Antagonist blocking Assay
1) Compound preparation: prepare compound addition plates in advance of assay. Prepare 200x concentration of compound working solutions according to procedures described above.
2) Cell preparation: cell suspensions are prepared according to procedures described above before running the assay.
3) Compound addition: add 50 nL/well of working concentration of 200x compound to low-volume 384 white assay plate.
4) Cell addition: Add 5 pL of 2X cell suspensions to each well of the assay plate which already contains compound.
5) Exendin (9-39) Antagonist addition: Add 5 pL of 2x Exendin (9-39) to each well of the assay plate which already contains compound and cells. The final concentration of Exendin (9-39) is ICso- Seal the plate and incubate at 37 °C with 5% CO2 for 30 minutes.
6) Add 5 pL cAMP-d2 working solution to each well of the assay plate.
7) Add 5 pL Anti-cAMP antibody-cryptate working solution to each well of the assay plate. Cover the plate with lid. Incubate at room temperature for 1-4 hours.
8) Read the fluorescence at 665 and 615 nm with EnVision plate reader with TRF LASER using the specified settings and save data.
Setting up EnVision for HTRF cAMP Measurements
Required filters and mirrors
• Excitation: TRF LASER
• Emission#!: 665 nm (CWL 665nm BW 7.5 nm)
• Emission#2: 615 nm (CWL 615 nm BW 8.5nm)
• Dichroic mirror: DELFIA/LANCE Dual Enh D400/D630
Required settings:
• Delay: 50 pis
• Window Time: 300 ps (also called “integration time”)
• Number of sequence windows: 1
• Cycle: Default 2000 ps (also called “time between flashes”)
• Time between flashes: 2000 ps
• number of flashes: 20
• number of flashes for 2nd detector: 10
• measurement height(mm):6.5
• Z height: Must be optimized (use optimization Wizard, optimize on a well with maximum FRET)
• Excitation and Emissions are done on the top of the well cAMP Assay Data Processing
Data analysis: GraphPad Prism 5 or IDBS XLfit software is used for establishment of progression curve. ECsos or IC50S were determined by 4-parameter logistic dose response equation.
Using the assay substantially as described above, dose-response curve for each compound tested below were obtained, and their respective EC50 values calculated and tabulated. Here, EC50 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.
Two different cell types were used for this assay. In one assay, each compound was tested in HEK293T cells. The results are shown below in Table 1. In another assay, 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. Table 1. Compound EC50 Values in HEK293T Cells
Figure imgf000045_0001
Table 2. Compound EC50 Values in CHO Cells Stably Expressing hGLP-lR
Figure imgf000045_0002
The data shows that, similar to GLP-1 (7-37), many tested compounds have nanomolar or sub-nanomolar (< 1 nM) EC50 values in the cAMP assay. This, coupled with the fact that many tested compounds also have Bmax values reaching essentially the same level as that for GLP-1 (7-37), suggests that many of the tested compounds of the present disclosure are full agonists of the GLP-1 R signaling leading to cAMP production. In contrast, as shown in Example 1 above, particularly the data for the compounds listed in the tables, the compounds of the present disclosure generally have Bmax approaching about 10-50% of that of GLP-1 (7-37) in the -Arrestin recruitment assay and GLP-1 R internalization assay, though a few exceptions exist. Example 3 Compound Synthesis
(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid (Compound 1)
Figure imgf000046_0001
Step 1 :
A mixture of (4-chloro-2-fluoro-phenyl)methanol 1 (2.4 g, 14.95 mmol), 2,4-dibromothiazole 2 (3.0 g, 12.35 mmol), sodium (567.8 mg, 24.70 mmol) in THF (15 mL) was stirred for 2 h at 0 °C under N2 until the reaction was completed as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organic layer was concentrated in vacuo, purified by silica gel chromatography (Hexanes/EtOAc = 4:1) to give the desired product 4-bromo-2-((4-chloro- 2-fluorobenzyl)oxy)thiazole 3 (3.8 g, 10.37 mmol, 83.9% yield) as pale transparent oily. Step 2
To a mixture of methyl 4-amino-3-[[(2S)-oxetan-2-yl] methylamino] benzoate 5 (100 mg, 423 pmol, the synthese of 5 is disclosed in international application WO2018/109607, which is incorporated herein by reference) in DCM (20 mL) was added slowly 2-(4-bromo-2, 5 -difluoro-phenyl) acetyl chloride 4 (228 mg, 847 pmol) in DCM (20 mL) at ice -bath, and stirred for 1 h at rt until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo, purified by silica gel chromatography (Hexanes/EtOAc = 1:2) to give the desired product methyl 4-[[2-(4- bromo-2, 5 -difluoro-phenyl) acetyl] amino]-3-[[(2S)-oxetan-2-yl] methylamino] benzoate 6 (71 mg, 151 pmol, 35.9% yield) as a pale yellow solid. LCMS: [M+H]+ = 469.0; HPLC retention time (0.01% TFA/H2O) = 1.57 min.
Step 3
A mixture of methyl 4-[[2-(4-bromo-2, 5 -difluoro-phenyl) acetyl] amino]-3-[[(2S)-oxetan-2-yl] methylamino] benzoate 6 (71 mg, 151 pmol) in AcOH (5 mL) was stirred for 30 min at 120 °C, until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo, purified by silica gel chromatography (Hexanes/EtOAc = 20:1) to give the desired product methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 7 (40 mg, 89 pmol, 58.6% yield) as pale yellow solid. LCMS: [M+H]+ = 451.1; HPLC retention time (0.01% TFA/H2O) =1.49 min.
Step 4:
A mixture of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate 7 (87.0 mg, 192.8 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane 8 (146.9 mg, 578.4 pmol), Pd(dppf)C12 (42.3 mg, 57.8 pmol), and potassium acetate (75.7 mg, 771.2 pmol) in dioxane (10 mL) was stirred for 16 h at 100 °C under N2until the reaction was complete as indicated by LCMS. The reaction mixture was used for next step. LCMS: [M+H]+ = 499.2; HPLC retention time (0.01% TFA/H2O) =1.69 min.
Step 5:
A mixture of methyl (S)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 9 (96.0 mg, 192.7 pmol), 4-bromo-2-[(4- chloro-2-fluoro-phenyl)methoxy]thiazole 3 (62.1 mg, 192.7 pmol), sodium bicarbonate (48.6 mg, 577.9 pmol) and palladium triphenylphosphane (44.5 mg, 38.5 pmol) in water (1 mL) and dioxane (5 mL) was stirred for 2 h at 90 °C under N2, until the reaction was complete as indicated by LCMS, the reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo, purified by silica gel chromatography (Hexanes/EtOAc = 20:1) to give the desired product methyl (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-2,5-difluorobenzyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 10 (54 mg, 72.10 pmol, 37.4% yield) as white solid. LCMS: [M+H] + = 615.9; HPLC retention time (0.01% TFA/H2O) =2.16 min.
Step 6:
A mixture of methyl (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-2,5-difluorobenzyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 10 (54.0 mg, 87.9 pmol), lithium hydroxide hydrate (29.5 mg, 703.5 pmol) in water (1 mL), methanol (1 mL), THF (1 mL) was stirred for 1.5 h at 25°C under N2, until the reaction was completed as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organic layer was concentrated in vacuo, purified by HPLC to give the desired product (S)-2-(4-(2-((4-chloro-2- fluorobenzyl)oxy)thiazol-4-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid Compound 1 (12.4 mg, 20.7 pmol, 23.5% yield) as white solid. LCMS: [M+H]+ = 600.0; HPLC retention time (0.01% TFA/H2O) = 1.62 min. ’H NMR (400 MHz, DMSO) 5 8.24 (s, 1H), 7.83 - 7.77 (m, 2H), 7.70 (t, J = 8.2 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 10.0, 2.1 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.39 - 7.31 (m, 2H), 5.60 (s, 2H), 5.05 (d, J = 6.8 Hz, 1H), 4.73 (dd, J = 15.7, 6.9 Hz, 1H), 4.60 (d, J = 12.7 Hz, 1H), 4.48 (dd, J = 20.6,10.9 Hz, 2H), 4.44 - 4.32 (m,2H), 2.75 - 2.65 (m, 1H), 2.41- 2.35 (m, 1H).
(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 2)
Figure imgf000048_0001
Prepared in analogous manner as for Compound 1
LCMS: [M+H] + = 601.2; HPLC retention time (0.01% TFA/H2O) = 1.46 min. ’H NMR (400 MHz, DMSO) 58.05 (d, J= 8.2 Hz, 1H), 7.96 (d, J= 8.2 Hz, 1H), 7.81 (dd, J= 10.4, 6.4 Hz, 1H), 7.70 (t, J = 8.2 Hz, 1H), 7.54 (dd, J= 9.9, 2.0 Hz, 1H), 7.48 (d, J= 2.2 Hz, 1H), 7.38 (dq, J= 12.8, 6.3 Hz, 2H), 5.60 (s, 2H), 5.15 (td, J= 10.0, 6.6 Hz, 1H), 4.73 (dd, J= 15.1, 6.3 Hz, 1H), 4.66 - 4.60 (m, 1H), 4.59 (d, J= 11.1 Hz, 1H), 4.50 (dd, J= 14.8, 7.7 Hz, 2H), 4.34 (dt, J= 9.0, 6.0 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.45 - 2.40 (m, 1H).
(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-2,5-difluorobenzyl)-7-fluoro-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (Compound 3)
Figure imgf000048_0002
Prepared in analogous manner as for Compound 1
LCMS: [M+H]+ = 617.8; HPLC retention time (0.01% TFA/H2O) = 1.70 min. ’H NMR (400 MHz, MeOD) 57.87 (dd, J = 10.7, 6.3 Hz, 1H), 7.76 (dd, J= 8.5, 6.8 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.41 (d, 7= 8.5 Hz, 1H), 7.33 (d, 7= 2.0 Hz, 1H), 7.27 (dd, 7= 14.2, 4.9 Hz, 2H), 7.14 (dd, 7= 11.5, 6.0 Hz, 1H), 5.59 (s, 2H), 5.21 (d, 7= 6.7 Hz, 1H), 4.82 - 4.76 (m, 1H), 4.65 (dd, 7= 14.3, 8.1 Hz, 2H), 4.56 (d, 7 = 16.7 Hz, 1H), 4.49 - 4.40 (m, 2H), 2.88 - 2.76 (m, 1H), 2.59 - 2.45 (m, 1H). 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][l,3]dioxol-4-yl)-2,5-difluorobenzyl)-l-(((S)- oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (Compound 4)
Figure imgf000049_0001
Step 1
To a suspension of 3-bromobenzene-l,2-diol 2 (1.2 g, 6.37 mmol) in toluene (100 mL) was added 1-
(4-chloro-2-fluoro-phenyl)ethenone 1 (1.0 g, 5.79 mmol) and 4-methylbenzenesulfonic acid hydrate
(1.1 g, 5.79 mmol). The reaction apparatus was fitted with a Dean-Stark trap, and the reaction mixture was heated at 140 °C for 60 h, whereupon the solution was concentrated in vacuo and purified by flash chromatography to afford 4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-l,3- benzodioxole 3 (280 mg, 774.2 pmol, 13.4% yield) as yellow oil. LCMS: [M+H]+ = 343.0; HPLC retention time (0.01% TFA/H2O) = 2.07 min.
Step 2
To a mixture of 4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-l,3-benzodioxole 3 (150 mg, 436.59 pmol) and methyl 2-[2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate 4 (1363 mg, 436 pmol) in water (1 mL) and 1,4-dioxane (5 mL) was added NazSCL (92.6 mg, 873 pmol) and Pd(dppf)C12 (31.9 mg, 43 pmol). Then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by silica gel chromatography (PE: EtOAc = 10:1) to give the methyl 2-[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl- l,3-benzodioxol-4-yl]-2,5-difluoro-phenyl]acetate 5 (150 mg, 334.2 pmol, 76.6% yield) as yellow oil. LCMS: [M+H]+ = 449.1; HPLC retention time (0.01% TFA/H2O) = 2.07 min Step 3
To a mixture of methyl 2-[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-l,3-benzodioxol-4-yl]-2,5- difluoro-phenyl] acetate 5 (150 mg, 334 pmol) in methanol (3 mL), water (3 mL) and THF (3 mL) was added LiOH (84.1 mg, 2.01 mmol). And then the mixture was stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was diluted with water and adjusted to pH 4 and extracted with DCM (20 mL><3). The organic layer was concentrated to yield 2-[4-[2-(4-chloro-2-fluoro-phenyl)-2- methyl-l,3-benzodioxol-4-yl]-2,5-difluoro-phenyl]acetic acid 6 (140 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 435.0; HPLC retention time (0.01% TFA/H2O) = 1.93 min.
Step 4
To a mixture of 2-[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-l,3-benzodioxol-4-yl]-2,5-difluoro- phenyl]acetic acid 6 (150 mg, 345.0 pmol) and methyl 4-amino-3-[[(2S)-oxetan-2- yl] methylamino] benzoate 7 (81.5 mg, 345.0 pmol) in DCM (10 mL) was added
Figure imgf000050_0001
tetramethyl-l-(3-oxido-2,3-dihydrotriazolo[4,5-b]pyridin-3-ium-l-yl)methanediamine hexafluorophosphate (171.4 mg, 448.5 pmol) and A-ethyl-A-isopropyl-propan-2-amine (133.8 mg, 1.03 mmol). Then the mixture was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with water and extracted with DCM (20 mLx3), the organic was concentrated to yield methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] [1 ,3]dioxol-4-yl)-2,5- difluorophenyl)acetamido)-3-((((>S')-oxetan-2-yl)methyl)amino)benzoate 8 (200 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 653.2; HPLC retention time (0.01% TFA/H2O) = 2.01 min.
Step 5
A mixture of methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][l,3]dioxol-4-yl)-2,5- difluorophenyl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate 8 (200 mg, 306.3 pmol) in toluene (6 mL) and AcOH (1.5 mL) was stirred at 60 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated to yield methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][l,3]dioxol-4-yl)-2,5-difluorobenzyl)-l-(((S)-oxetan-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate 9 (100 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 635.2; HPLC retention time (0.01% TFA/H2O) =1.86 min.
Step 6
To a mixture of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][l,3]dioxol-4-yl)-2,5- difluorobenzyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate 9 (100 mg, 157.5 pmol) in methanol (3 mL), water (3 mL) and THF (3 mL) was added LiOH (52.9 mg, 1.26 mmol). Then the mixture was stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was diluted with water and adjusted the pH to 4 and extracted with DCM (20 mLx3) the organic was concentrated to yield a residue which was purified by prep-HPLC to give 2-(4-(2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][l,3]dioxol-4-yl)-2,5-difluorobenzyl)-l-(((S)-oxetan-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid Compound 4 (43.3 mg, 69 pmol, 44.3% yield). LCMS: [M+H]+ = 621.0; HPLC retention time (10 mM NH4HCO3) = 1.70 min. ’H NMR (400 MHz, DMSO) 5 8.25 (s, 1H), 7.79 (dd, J = 8.4, 1.5 Hz, 1H), 7.67-7.53 (m, 3H), 7.46 - 7.33 (m, 3H), 7.05 (dd, J = 8.8, 4.4 Hz, 1H), 7.04 - 6.96 (m, 2H), 5.07 (dd, J = 9.6, 4.4 Hz, 1H), 4.76 (dd, J = 15.6, 7.0 Hz, 1H), 4.62 (d, J = 12.8 Hz, 1H), 4.56 - 4.30 (m, 4H), 2.77-2.65 (m, 1H), 2.46 - 2.35 (m, 1H), 2.05 (s, 3H).
2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][l,3]dioxol-4-yl)-2-fluorobenzyl)-l-((S)-oxetan- 2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (Compound 5)
Figure imgf000051_0001
Prepared in analogous manner as for Compound 4
LCMS: [M+H]+ = 603.0, HPLC retention time (10 mM NH4HCO3) = 1.74 min. ’H NMR (400 MHz, MeOD) 5 8.27-8.26 (brs, 1H), 7.96 (dd, J= 8.5, 1.3 Hz, 1H), 7.69 - 7.52 (m, 4H), 7.40 - 7.28 (m, 2H), 7.21 (dd, 7 = 8.4, 1.8 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 6.98 - 6.82 (m, 2H), 5.13 (d, J= 7.0 Hz, 1H), 4.73 > 4.40 (m, 6H), 2.75 (dt, J= 15.3, 7.6 Hz, 1H), 2.51 - 2.40 (m, 1H), 2.09 (s, 3H).
2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][l,3]dioxol-4-yl)-3-fluorobenzyl)-l-(((S)- oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (Compound 6)
Figure imgf000051_0002
Prepared in analogous manner as for Compound 4
LCMS: [M+H]+ = 603.0; HPLC retention time (10 mM NH4HCO3) = 1.37 min. ’H NMR (400 MHz, DMSO) 5 8.22 (s, 1H), 7.80 (dd, J = 8.4, 1.5 Hz, 1H), 7.62 - 7.55 (m, 3H), 7.47 (t,J = 7.9 Hz, 1H), 7.32 (ddd, J = 30.3, 13.6, 3.8 Hz, 3H), 7.02 - 6.94 (m, 3H), 4.98 (d, J = 7.1 Hz, 1H),4.71 (dd, J = 15.5, 7.2 Hz, 1H), 4.57 (d, J = 13.0 Hz, 1H), 4.48 - 4.32 (m, 4H), 2.71 - 2.66 (m, 1H),2.4O - 2.34 (m, 1H), 2.02 (s, 3H). (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-5-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid (Compound 7)
Figure imgf000052_0001
Step 1
To a mixture of 4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole 1 (300 mg, 1.23 mmol) in THF (10 mL) was added 1 -bromopyrrolidine -2, 5-dione (328.7 mg, 1.85 mmol, 156.5 pL). The mixture was stirred at rt for 3 h under N2 atmosphere. The reaction mixture was diluted with water and extracted with DCM (40 mLx3) and then concentrated to yield a residue which was purified by silica gel chromatography (PE/EtOAc = 98:2) to give 5-bromo-4-[(4-chloro-2-fluoro- phenyl)methoxy] thiazole 2 (330 mg, 1.02 mmol, 83.1% yield). LCMS: [M+H]+ = 322.0; HPLC retention time (0.01% TFA/H2O) =1.97 min.
Step 2
To a mixture of 5-bromo-4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole 2 (100 mg, 310.0 pmol) and methyl 2-[2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate 3 (145.1 mg, 465.00 pmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(dppf)C12 (22.68 mg, 31.00 pmol) and sodium bicarbonate (65.71 mg, 620.0 pmol). And then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by silica gel chromatography (PE: EtOAc = 2: 3) to give the methyl 2-[4-[4-[(4-chloro-2- fluoro-phenyl)methoxy]thiazol-5-yl]-2,5-difluoro-phenyl]acetate 4 (50 mg, 116.87 pmol, 37.7% yield). LCMS: [M+H]+ = 428.0; HPLC retention time (0.01% TFA/H2O) = 2.01 min. Step 3
To a mixture of methyl 2-[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-2,5-difluoro- phenyl] acetate 4 (50 mg, 116.9 pmol) in THF (2 mL), water (2 mL) and methanol (2 mL) was added lithium hydroxide (29.4 mg, 701.2 pmol). And then the mixture was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with water and adjusted the pH to 3-4, extracted with DCM (20 mL>'3), then the organic phase was concentrated to yield the 2-[4-[4-[(4-chloro-2-fluoro- phenyl)methoxy]thiazol-5-yl] -2, 5 -difluoro-phenyl] acetic acid 5 (48 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 414.0; HPLC retention time (0.01% TFA/H2O) = 1.85 min.
Step 4
To a mixture of 2-[4-[4-[(4-chloro-2-fhroro-phenyl)methoxy]thiazol-5-yl]-2,5-difluoro-phenyl]acetic acid 5 (48 mg, 116.0 pmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 6 (27.4 mg, 116.0 pmol) in DCM (5 mL) was added N,N,N',N'-tetramethyl-l-(3-oxido-2,3- dihydrotriazolo[4,5-b]pyridin-3-ium-l-yl)methanediamine hexafluorophosphate (88.7 mg, 232.0 pmol) and N-ethyl-N-isopropyl-propan-2-amine (19.5 mg, 150.8 pmol). The mixture was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with water and extracted with DCM (20 mLx3), the organic phase was concentrated to yield the methyl 4-[[2-[4-[4- [(4-chloro-2-fluoro-phenyl)methoxy] thiazol-5-yl] -2,5 -difluoro-phenyl] acetyl] amino] -3 -[ [(2S')-oxetan- 2-yl]methylamino]benzoate 7 which was used into next step without further purification. LCMS: [M+H]+ = 632.0; HPLC retention time (0.01% TFA/H2O) = 1.93 min.
Step 5
To a mixture of methyl 4-[[2-[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-2,5-difluoro- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 7 (50.0 mg, 79.1 pmol) in Toluene (4 mL) was added AcOH (1 mL). The mixture was stirred at 60 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated to yield the methyl 2-[[4-[4-[(4-chloro-2-fluoro- phenyl)methoxy]thiazol-5-yl]-2,5-difluoro-phenyl]methyl]-3-[[(2lS')-oxetan-2- yl]methyl]benzimidazole-5-carboxylate 8 (48 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 614.1; HPLC retention time (0.01% TFA/H2O) = 1.82 min. Step 6
To a mixture of methyl 2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-2,5-difluoro- phenyl]methyl]-3-[[(2lS')-oxetan-2-yl]methyl]benzimidazole-5-carboxylate 8 (48.0 mg, 78.2 pmol) in water (3 mL), THF (3 mL) and methanol (3 mL) was added lithium hydroxide (32.8 mg, 781.7 pmol). And then the mixture was stirred at 20 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by prep-HPLC to provide (S)-2-(4-(4-((4-chloro-2- fluorobenzyl)oxy)thiazol-5-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid Compound 7 (8.4 mg, 14.0 pmol, 17.9% yield). LCMS: [M+H]+ = 599.8; HPLC retention time (10 mM NH4HCO3) = 1.36 min. ’H NMR (400 MHz, DMSO) 5 9.06 (s, 1H), 8.22 (s, 1H), 7.84 - 7.71 (m, 2H), 7.61 - 7.46 (m, 3H), 7.39 - 7.30 (m, 2H), 5.56 (brs, 2H), 5.05 (d, J = 4.8 Hz, 1H), 4.72 (dd, J = 15.6, 8.0 Hz, 1H), 4.58 (d, J = 12.8 Hz, 1H), 4.53 - 4.28 (m, 4H), 2.68 (m, 1H), 2.42 - 2.32 (m, 1H).
(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-5-yl)-3-fluorobenzyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid (Compound 8)
Figure imgf000054_0001
Prepared in analogous manner as for Compound 7
LCMS: [M+H]+ = 581.9; HPLC retention time (0.1%TFA/H2O) = 1.66 min. ’H NMR (400 MHz, DMSO) 59.00 (s, 1H), 8.21 (s, 1H), 7.83 - 7.77 (m, 2H), 7.62 - 7.46 (m, 3H), 7.31-7.20 (m, 3H), 5.50 (s, 2H), 4.96 - 4.94 (m, 1H), 4.66 - 4.52 (m, 2H), 4.46-4.32 (m, 4H), 2.67 - 2.66 (m, 1H), 2.34 - 2.33 (m, 1H).
(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-5-yl)-2-fluorobenzyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid (Compound 9)
Figure imgf000054_0002
Prepared in analogous manner as for Compound 7
LCMS: [M+H]+ = 582.1; HPLC retention time (10 mM NH4HCO3) = 1.38 min. ’H NMR (400 MHz, DMSO) 58.94 (s, 1H), 8.18 (s, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 25.5 Hz,3H), 7.44 - 7.27 (m, 4H), 5.55 (s, 2H), 5.01 (s, 1H), 4.61 (d, J = 39.4 Hz, 2H), 4.46 - 4.30 (m, 4H),2.67 (s, 1H), 2.36 - 2.31 (m, 1H)
(S)-2-(4-(3-(4-chloro-2-fluorobenzyloxy)isothiazol-4-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid (Compound 10)
Figure imgf000054_0003
Figure imgf000055_0001
Step 1
To a stirred solution of 3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole 1 (500.0 mg, 2.05 mmol) in HOAc (8 mL) solution was added Br2 (2.63 g, 16.41 mmol). The reaction mixture was stirred at rt for 8 h and upon completion of the reaction. The mixture was diluted with EtOAc (50 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with IM NaHCO; (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, hexanes/ethyl acetate 10:1) to afford 4-bromo-3-[(4-chloro-2-fluoro- phenyl)methoxy] isothiazole 2 (350 mg, 680.4 pmol, 33.2% yield) as a light-yellow liquid. LCMS: [M+H] += 321.9; HPLC retention time (0.05%TFA/H20) = 2.00 min.
Step 2
To a stirred solution of 4-bromo-3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole 2 (350 mg, 680.4 pmol) in 1,4-dioxane (10 mL) and water (2 mL) solution was added methyl 2-[2, 5-difluoro-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate 3 (233.6 mg, 748.4 pmol), Pd(dppf)C12 (49.7 mg, 68.04 pmol), K2CO3 (187.8 mg, 1.36 mmol). The reaction mixture was stirred at 100 °C for 2 h and upon completion of the reaction, as judged by TLC, the mixture was diluted with EtOAc (100 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, hexanes/ethyl acetate 5:1) to afford methyl 2-[4-[3-[(4-chloro-2- fluoro-phenyl)methoxy]isothiazol-4-yl]-2,5-difluoro-phenyl]acetate 4 (180 mg, 358.7 pmol, 52.7% yield) as a light-yellow liquid. LCMS: [M+H]+= 428.1; HPLC retention time (0.01%TFA/H20) = 2.08 min Step 3
To a stirred solution of methyl 2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-2,5- difluoro-phenyl] acetate 4 (180 mg, 358.7 pmol) in THF (3 mL) and MeOH (3 mL) water (3 mL) solution was added LiOH.PFO (75.3 mg, 1.79 mmol). The reaction mixture was stirred at rt for 2 h and upon completion of the reaction. The mixture was diluted with DCM (50 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with DCM (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous NazSCL, filtered and concentrated in vacuo. The crude product was afford 2-[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]isothiazol-4-yl]-2,5-difluoro-phenyl]acetic acid S (140 mg, 338.3 pmol, 94.3% yield) as a white solid. LCMS: [M+H]+= 413.8; HPLC retention time (0.1%TFA/H2O) = 2.10 min. Step 4
To a stirred solution of 2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-2,5-difluoro- phenyl]acetic acid 5 (140 mg, 338.3 pmol) in DCM (10 mL) solution was added methyl 4-amino-3- [[(2S)-oxetan-2-yl]methylamino]benzoate 6 (87.9 mg, 372.2 pmol) HATU (193.0 mg, 507.5 pmol) DIPEA (131.2 mg, 1.01 mmol). The reaction mixture was stirred at rt for 8 h and upon completion of the reaction, as judged by TLC, the mixture was diluted with DCM (50 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous NazSCL, filtered and concentrated in vacuo. The crude product was afford methyl 4-[[2-[4-[3-[(4-chloro-2- fluoro-phenyl)methoxy] isothiazol-4-yl] -2 ,5 -difluoro-phenyl] acetyl] amino] -3 - [ [ (2 S) -oxetan-2- yl] methylamino] benzoate 7 (200 mg, 193.5 pmol, 57.2% yield) as a brown liquid. LCMS: [M+H]+ = 632.0; HPLC retention time (10 mM NH4HCO3) =1.85 min.
Step 5
To a stirred solution of methyl 4-[[2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-2,5- difluoro-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 7 (200 mg, 193.5 pmol) in toluene (5 mL) solution was added CH3COOH (1.16 g, 19.35 mmol). The reaction mixture was stirred at 60°C for 1 h and upon completion of the reaction. T he mixture was concentrated in vacuo. The crude product was afford methyl (S)-2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)isothiazol-4-yl)-2,5- difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 8 (200 mg, 143.1 pmol, 74.0% yield) as a brown liquid. LCMS: [M+H]+= 614.0; HPLC retention time (10 mM NH4HCO3) = 1.90 min.
Step 6
To a stirred solution ofmethyl (S)-2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)isothiazol-4-yl)-2,5- difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 8 (200 mg, 143.12 pmol) in THF (3 mL) MeOH (3 mL) water (3 mL) solution was added LiOH.HzO (30.06 mg, 715.60 pmol). The reaction mixture was stirred at rt for 8 h and upon completion of the reaction, as judged by TLC, the mixture was diluted with EtOAc (50 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Prep-HPLC (NH4HCO3) to afford (S)-2-(4-(3-(4-chloro-2- fhmrobenzyloxy)isothiazol-4-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid Compound 10 (64.6 mg, 107.7 pmol, 75.2% yield) as a white solid. LCMS: [M+H]+ = 599.8; HPLC retention time (lOmM NH4HCO3) =1.67 min. ’H NMR (400 MHz, DMSO) 59.15 (d, J = 1.5 Hz, 1H), 8.23 (s, 1H), 7.83 - 7.74 (m, 1H), 7.64 - 7.54 (m, 2H), 7.54 - 7.45 (m, 2H), 7.40 - 7.29 (m, 2H), 5.50 (s, 2H), 5.04 (d, J = 7.3 Hz, 1H), 4.73 (dd, J = 15.5, 6.9 Hz, 1H), 4.59 (d, J = 13.1 Hz, 1H), 4.52 - 4.28 (m, 4H), 2.76 - 2.63 (m, 1H), 2.37 (dd, J = 19.2, 8.0 Hz, 1H).
(S)-2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid (Compound 11)
Figure imgf000057_0001
Step 1
To a suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile 1 (1.0 g, 6.62 mmol) in THF (20 mL) was added slowly potassium tert-butylate (816.7 mg, 7.28 mmol) at 0°C and stirred for 0.5 h under N2, and then added 3-bromo-2-fluoro-pyridine 2 (1.28 g, 7.28 mmol) in THF (20 mL) stirred for 1 h under N2. After completion of the reaction as judged by LCMS, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mLx3). The organic phase was washed with brine (50 mL) and dried over anhydrous NazSCL, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 4-[(3-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile 3 (2.1 g, 5.95 mmol, 89.9% yield) as a red solid. LCMS: [M+H]+ = 307.0; HPLC retention time (10 mM NH4HCO3) = 1.67 min.
Step 2
To a mixture of 4-[(3-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile 3 (200 mg, 651.22 pmol) and methyl 2-[2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate 4 (243.91 mg, 781.46 pmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)C12 (47.65 mg, 65.12 pmol) and Na2CC>3(138.04 mg, 1.30 mmol). The mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by silica gel chromatography (PE/EtOAc = 10:1) to give methyl 2-[4-[2-[(4-cyano-2-fluoro-phenyl)methoxy]-3- pyridyl]-2,5-difluoro-phenyl]acetate 5 (80 mg, 194.00 pmol, 29.8% yield) as solid. LCMS: [M+H]+ = 413.1; HPLC retention time (0.01% TFA/H2O) = 1.86 min.
Step 3
To a mixture of methyl 2-[4-[2-[(4-cyano-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro- phenyl] acetate 5 (80 mg, 194.00 pmol) in MeCN (6 mL) and water (2 mL) was added 1, 1,3,3- tetramethylguanidine (111.72 mg, 970.0 pmol). And then the mixture was stirred at 60 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by silica gel chromatography (PE: EtOAc = 2:1) to give the 2-[4-[2-[(4-cyano-2-fluoro- phenyl)methoxy]-3-pyridyl]-2,5-difluoro-phenyl]acetic acid 6 (70 mg, crude). LCMS: [M+H]+ = 399.1; HPLC retention time (0.01% TFA/H2O) = 1.73 min.
Step 4
To a mixture of 2-[4-[2-[(4-cyano-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro-phenyl]acetic acid 6 (70 mg, 175.7 pmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 7 (41.5 mg, 175.7 pmol) in DCM (5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (68.1 mg, 527.2 pmol) and N,N,N',N'-tetramethyl-l-(3-oxido-2,3-dihydrotriazolo[4,5-b]pyridin-3-ium- lyl)methanediamine;hexafluorophosphate (87.3 mg, 228.5 pmol). And then the mixture was stirred at rt for 2 h under N2 atmosphere. The reaction mixture was diluted with water and extracted with DCM (20 mLx3) and then concentrated to yield the methyl 4-[[2-[4-[2-[(4-cyano-2-fluoro- phenyl)methoxy] -3 -pyridyl] -2 , 5 -difluoro-phenyl] acetyl] amino] -3 - [ [ (2 S) -oxetan-2- yl] methylamino] benzoate 8 (180 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 617.2; HPLC retention time (0.01% TFA/H2O) = 1.82 min.
Step 5
To a mixture of methyl 4-[[2-[4-[2-[(4-cyano-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 8 (180 mg, 291.9 pmol) in toluene (4 mL) was added AcOH (1 mL). And then the mixture was stirred at 60 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated to yield methyl (S)-2-(4-(2-((4-cyano-2- fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylate 9 (170 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 599.2; HPLC retention time (0.01% TFA/H2O) = 1.73 min.
Step 6
To a mixture of methyl (S)-2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)- l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 9 (150 mg, 250.6 pmol) in water (2 mL) and MeCN (6 mL) was added 1,1,3,3-tetramethylguanidine (288.6 mg, 2.51 mmol). And then the mixture was stirred at 60 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by Prep-HPLC to give (S)-2-(4-(2-((4-cyano-2- fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid Compound 11 (19.8 mg, 33.9 pmol, 13.5% yield). LCMS: [M+H]+ = 585.0; HPLC retention time (10 mM NH4HCO3) = 1.31 min. ’H NMR (400 MHz, DMSO) 5 8.24 (m, 2H), 7.89 (dd, J = 10.0, 1.4 Hz, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.70 - 7.66 (m, 1H), 7.60 - 7.54 (m, 2H), 7.40 (dd, J = 9.6, 6.1 Hz, 1H), 7.34 (dd, J = 10.0, 6.4 Hz, 1H), 7.18 (dd, J = 7.2, 4.8 Hz, 1H), 5.54 (brs, 2H), 5.06 (m,lH), 4.74 (dd, J = 15.6, 7.2 Hz, 1H), 4.61 (m, 1H), 4.55 - 4.27 (m, 4H), 2.73 - 2.66 (m, 1H), 2.33 (m, 1H).
(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid (Compound 12)
Figure imgf000059_0001
Step 1
To a mixture of 2-(4-bromo-2,5-difluoro-phenyl)acetic acid 1 (2.0 g, 7.97 mmol) in methanol (20 mL) was added thionyl chloride (1.90 g, 15.93 mmol, 1.16 mL). The mixture was stirred at 70 °C for 3 h under N2 atmosphere. The reaction mixture extracted with EtOAc (30 mLx3) and then concentrated to give methyl 2-(4-bromo-2,5-difluoro-phenyl)acetate 2 (2.0 g, 7.55 mmol, 94.7% yield) as colorless oil, which was used into next step without further purification. LCMS: [M+H]+ = 265.0; HPLC retention time (0.01% TFA/H2O) =1.91 min.
Step 2
To a mixture of methyl 2-(4-bromo-2,5-difluoro-phenyl)acetate 2 (1.0 g, 3.77 mmol) and 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.44 g, 5.66 mmol) in 1,4-dioxane (5 mL) was added K2CO3 (740.6 mg, 7.55 mmol) and Pd(dppf)C12 (276.1 mg, 377 pmol). Then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was used into next step without further purification. LCMS: [M-81]+ = 231.0; HPLC retention time (0.01% TFA/H2O) = 1.34 min.
Step 3
To a mixture of 3-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (300 mg, 947.7 pmol) 4 and methyl 2-[2,5-difluoro-4-(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl] acetate 3 (354.9 mg, 1.14 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)CL (69.3 mg, 94 pmol) and NazCOs (200.9 mg, 1.90 mmol). Then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated to yield a residue which was purified by silica gel chromatography (PE: EtOAc = 10:1) to give the methyl 2-[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]- 3-pyridyl]-2,5-difluoro-phenyl]acetate 5 (350 mg, 829.8 pmol) as colorless oil. LCMS: [M+H]+ = 422.0; HPLC retention time (0.01% TFA/H2O) = 2.27 min.
Step 4
To a mixture of methyl 2-[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro- phenyl] acetate 5 (350 mg, 829.8 pmol) in THF (3 mL), water (3 mL) and Methanol (3 mL) was added LiOH (174.1 mg, 4.15 mmol). Then the mixture was stirred at 20 °C for 2 h under N2 atmosphere. The reaction mixture was adjust to pH 3-4 by AcOH, extracted with EtOH (20 mLx3), the organics was concentrated to yield the 2-[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro- phenyl]acetic acid 6 (300 mg, 735.7 pmol, 88.7% yield) as a white solid, which was used into next step without further purification. LCMS: [M+H]+ = 407.9; HPLC retention time (0.01% TFA/H2O) = 2.06 min.
Step 5
To a mixture of 2-[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro-phenyl]acetic acid 6 (200 mg, 490.47 pmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 7 (115.9 mg, 490 pmol) in DCM (10 mL) was added N,N,N',N'-tetramethyl-l-(3-oxido-2,3- dihydrotriazolo[4,5-b]pyridin-3-ium-l-yl)methanediamine hexafluorophosphate (243.7 mg, 637 pmol) and /V-cthyl-/V-isopropyl-propan-2-aminc (190.2 mg, 1.47 mmol). Then the mixture was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with water and extracted with EtOAc (20 mLx3), the organics was concentrated to give the methyl 4-[[2-[4-[2-[(4-chloro-2-fluoro- phenyl)methoxy] -3 -pyridyl] -2 , 5 -difluoro-phenyl] acetyl] amino] -3 - [ [ (2 S) -oxetan-2- yl] methylamino] benzoate 8 (300 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 626.0; HPLC retention time (0.01% TFA/H2O) = 1.72 min. Step 6
A mixture of methyl 4-[[2-[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-2,5-difluoro- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 8 (300 mg, 479.2 pmol) in toluene (6 mL) and AcOH (1.5 mL) was stirred at 60 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated to yield methyl (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)-2,5- difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 9 (250 mg, crude) which was used into next step without further purification. LCMS: [M+H]+ = 607.9; HPLC retention time (0.01% TFA/H2O) = 1.80 min.
Step 7
To a mixture of methyl (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)- l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate 9 (250 mg, 411.2 pmol) in THF (3 mL), water (3 mL), and methanol (3 mL) was added LiOH (103.5 mg, 2.47 mmol). Then the mixture was stirred at 20 °C for 3 h under N2 atmosphere. The reaction mixture was diluted with water and then adjusted to pH 3-4 then extracted with DCM (20 mL x3), the organics was concentrated to yield a residue which was purified by prep-HPLC to give the (S)-2-(4-(2-((4-chloro-2- fluorobenzyl)oxy)pyridin-3-yl)-2,5-difluorobenzyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid Compund 12 (36.5 mg, 61.5 pmol, 14.9% yield) as a yellow solid. LCMS: [M+H]+ = 594.0; HPLC retention time (10 mM NH4HCO3) = 1.36 min. ’H NMR (400 MHz, DMSO) 5 8.25 (s, 1H), 7.79 (dd, J = 8.4, 1.5 Hz, 1H), 7.67-7.53 (m, 3H), 7.46 - 7.33 (m, 3H), 7.05 (dd, J = 8.8, 4.4 Hz, 1H), 7.04 - 6.96 (m, 2H), 5.07 (dd, J = 9.6, 4.4 Hz, 1H), 4.76 (dd, J = 15.6, 7.0 Hz, 1H), 4.62 (d, J = 12.8 Hz, 1H), 4.56 - 4.30 (m, 4H), 2.77-2.65 (m, 1H), 2.46 - 2.35 (m, 1H), 2.05 (s, 3H).
(S)-2-(4-(2-(4-chloro-2 acid-fluorobenzyloxy)pyridin-3-yl)-2-fluorobenzyl)-l-(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic (Compound 13)
Figure imgf000061_0001
Prepared in analogous manner as for Compound 12 LCMS: [M+H]+= 575.9; HPLC retention time (lOmM NH4HCO3) = 1.63 min. ’H NMR (400 MHz, MeOD) 58.25 - 8.15 (m, 2H), 7.96 (dd, J = 8.5, 1.3 Hz, 1H), 7.80 (dd, J = 7.4, 1.8 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.51 - 7.33 (m, 3H), 7.33 - 7.22 (m, 2H), 7.18 (dd, J = 8.2, 1.8 Hz, 1H), 7.10 (dd, J = 7.4, 5.0 Hz, 1H), 5.47 (s, 2H), 5.13 (dt, J = 7.1, 4.7 Hz, 1H), 2.72 (dd, J = 16.2, 12.9, 8.2 Hz, 1H), 2.44 (dq, J = 11.4, 7.3 Hz, 1H).
(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)-3-fluorobenzyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid (Compound 14)
Figure imgf000062_0001
Prepared in analogous manner as for Compound 12
LCMS: [M+H]+ = 576.1; HPLC retention time (10 mM NH4HCO3) = 1.47 min.
’H NMR (400 MHz, DMSO) 5 8.23 - 8.21 (m, 2H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.74 (dd, J = 7.2, 1.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.46-7.37 (m, 3H), 7.28-7.20 (m, 3H), 7.14 (dd, J = 7.2, 4.8 Hz, 1H), 5.4 (s, 2H), 4.96-4.93 (m, 1H), 4.72-4.66 (m, 1H), 4.58-4.53 (m, 1H), 4.46-4.41 (m, 3H), 4.33- 4.31 (m, 1H), 2.67-2.60 (m, 1H), 2.34-2.31 (m, 1H).
(S)-2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)-3-fluorobenzyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid Compound 15)
Figure imgf000062_0002
Prepared in analogous manner as for Compound 12
LCMS: [M+H]+ = 566.9; HPLC retention time (0.01% TFA/H2O) = 1.59 min.
’H NMR (400 MHz, MeOD) 5 8.30 (s, 1H), 8.20 - 8.18 (m, 1H), 8.00 (dd, J = 8.8, 1.6 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.57 - 7.53 (m, 2H), 7.48 (dd, J = 8.0, 1.2 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.21 - 7.16 (m, 2H), 7.12 - 7.09 (m, 1H), 5.54 (s, 2H), 5.11 - 5.08 (m, 1H), 4.69 - 4.49 (m, 5H), 4.44 - 4.40 (m, 1H), 2.71 - 2.68 (m, 1H), 2.44 - 2.42 (m, 1H). (S)-2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)-2-fluorobenzyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid (Compound 16)
Figure imgf000063_0001
Prepared in analogous manner as for Compound 12 LCMS: [M+H]+ = 567.0; HPLC retention time (10 mM NH4HCO3) = 1.22 min. ’H NMR (400 MHz, DMSO) 5 8.22 (s, 2H), 7.92 (d, J= 9.5 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.72 -7.63 (m, 2H), 7.56 (d, J= 8.0 Hz, 1H), 7.53-7.47 (m, 1H), 7.41 (d, J= 13.6 Hz, 2H), 7.18(s, 1H), 5.56(s, 2H), 5.03 (s, 1H), 4.71 (s, 1H), 4.61 - 4.34 (m, 5H), 2.68 (s, 1H), 2.36 (s, 1H).

Claims

1. A compound represented by formula (I):
Figure imgf000064_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: - indicates a single bond or a double bond;
X1, X2, X3, X4, and X5 of ring A are each independently selected from N and CH;
W is selected from O, S, CR5R6, and NR5’; ring
Figure imgf000064_0002
wherein represents a portion of ring B bonded to ring C and “**” represents a portion of ring B bonded to W; or ring B, W, together with -CH(Ra)-, form a bicyclic structure
Figure imgf000064_0003
wherein represents a portion of the bicyclic structure bonded to ring C and “***” represents a portion of the bicyclic structure bonded to ring A;
Y1 is N or CH;
Y3 and Y5 are each independently selected from N, CH, O, and S;
Y2 are each independently N or CH;
Y3 and Y5 are each independently selected from N, CH, O, and S; and
Y4 is absent, N or CH; wherein there are no more than 3 hetero ring atoms in ring B and wherein ring B does not contain 3 hetero ring atoms at 3 contiguous positions; ring C is phenyl;
L is CHRd, O, S, or NR5 ; ring D is bicyclic heteroaryl;
EE is -COOH or a carboxylic group surrogate, optionally, the carboxylic group surrogate is:
Figure imgf000065_0001
each Ra and Rb are independently selected from hydrogen, deuterium, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by Ra/Rb is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Ra/Rb or in the group represented by Ra/Rb is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 ; each Rc and Rd are independently selected from hydrogen, deuterium, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R7Rd is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R7Rd or in the group represented by R7Rd is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, and NR5 R6 ; each R1 is independently selected from H, deuterium, halogen, -CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by R1 is optionally substituted with one or more
- 64 - groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R1 or in the group represented by R1 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 . each R2 is independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy represented by R2 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R2 or in the group represented by R2 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5’R6’; each R3 is independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R3 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R3 or in the group represented by R3 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5’R6’; each R4 is independently selected from H, deuterium, halogen, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and NR5 R6 , wherein the Ci-Ce alkyl and Ci-Ce alkoxy represented by R4 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, and
- 65 - saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
R5 and R6 are each independently selected from hydrogen, deuterium, CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl,
3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R5 or R6 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R5 or R6 or in the group represented by R5 or R6 is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 .
R5 and R6 are each independently selected from hydrogen and Ci-Ce alkyl; wherein optionally two R1; two R2; two R3; two R4; R1 and R2; R2 and R3; Ra and R1; Ra and R2; R1 and any of R5, R5 (in the group represented by W), or R6; Ra and any of R5, R5 (in the group represented by W), or R6; R2 and any of R5, R5 (in the group represented by W), or R6; R5 and R6; any of two groups selected from Rc, Rd, or R4 and any one of Rc or Rd; taken together with their respective intervening carbon or hetero atom(s), form phenyl, 5-6 membered heteroaryl, 4-8 membered saturated or partially saturated cycloalkyl or
4-8 membered saturated or partially saturated heterocyclyl, and each of which is optionally substituted with one or more groups selected from halogen, -CN, -OH, CF3, Ci-Ce alkyl, Ci-Ce alkoxy, -NH2, -NHCi-Cr, alkyl, -N(Ci-Ce alkyl)2, oxo, and saturated or partially saturated C3-C6 cycloalkyl, wherein the Ci-Ce alkyl and Ci-Ce alkoxy is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3; m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; o is an integer selected from 0, 1, 2, 3, and 4; and p is an integer selected from 0, 1, 2, 3, and 4.
- 66 - The compound according to claim 1, wherein the compound is represented by formula (II):
Figure imgf000068_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
X1, X2, X3, X4, and X5 of ring A are each independently selected from N and CH; wherein no more than three of X1, X2, X3, X4, and X5 are N and wherein ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;
W is O, NH, or CH2; ring
Figure imgf000068_0002
wherein represents a portion of ring B bonded to ring C and “**” represents a portion of ring B bonded to W; or ring B, W, together with -C(Ra)-, form a bicyclic structure
Figure imgf000068_0003
represents a portion of the bicyclic structure bonded to ring C and “***” represents a portion of the bicyclic structure bonded to ring A;
T2 is selected from N and C;
T4 is selected from N, NR4, O, S, and CR4;
T6, T7, and T8 are each independently selected from N and CR4; wherein no more than 4 of T2, T4, T6, T7, and T8 are selected from N, O, and S;
Ra is H, CH3, or CF3;
Rb is selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl and 3-7 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by Rb is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C(> saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Rb or in the group represented by Rb is optionally substituted with one or more groups selected from halogen, oxo (when Rb is non-aromatic), CN, OH,
- 67 - C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and
C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5’R6’;
Rc is selected from hydrogen, and C1-C4 alkyl optionally substituted with one or more groups selected from halogen and hydroxyl;
Rd is H, F, CH3, or CF3; and each R1 is independently selected from H, deuterium, halogen, -CN, OH, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR5 R6 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by R1 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R1 or in the group represented by R1 is optionally substituted with one or more groups selected from halogen, oxo (when R1 is non-aromatic), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5 R6 . each R2 and R3 are independently selected from H, deuterium, halogen, -CN, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR5 R6 , wherein the Ci-Ce alkyl or Ci-Ce alkoxy represented by R2 and/or R3 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3); each R4 is independently selected from H, deuterium, halogen, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and NR5 R6 , wherein the Ci-Ce alkyl and Ci-Ce alkoxy represented by R4 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3). The compound according to claim 1 or 2, wherein the compound is represented by formula
Figure imgf000070_0001
The compound according to any one of claims 1-3, wherein the compound is represented by formula (III- A), (III-B), (III-B’), or (III-C):
Figure imgf000070_0002
Figure imgf000071_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein Y4 is N or CH. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
Figure imgf000071_0002
each R1 is independently selected from halogen, OH, CN, C1-C4 alkyl,
C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy,
C2-C4 alkenyl, C2-C4 alkynyl, -NH2, -NHC1-C4 alkyl, and -N(CI-C4 alkylh; and m is an integer selected from 0, 1, and 2. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt,
Figure imgf000072_0001
The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R3 is independently selected from halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and NR5 R6 ; and o is an integer selected from 0, 1, 2, 3, and 4. The compound according to any one of claims 4-7, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula
Figure imgf000072_0002
each R2 is independently selected from H, deuterium and halogen (e.g., F).
- 71 - The compound according to any one of claims 4-7, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (
Figure imgf000073_0001
Figure imgf000073_0002
each R2 is independently selected from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R2 is deuterium, ring B is fully substituted with deuterium. The compound according to any one of claims 4-7, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-B’),
Figure imgf000073_0003
each R2 is independently selected from H, deuterium and halogen (e.g., F). The compound according to any one of claims 4-7, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-C); each R2 is independently selected from H, deuterium, and halogen (e.g., F); and n is an integer selected from 0, 1, 2, 3, and 4, provided that when R2 is deuterium, ring B is fully substituted with deuterium.
- 72 - The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
Figure imgf000074_0001
each R1 is independently selected from halogen, OH, CN, C1-C2 alkyl,
C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 hydroxyalkoxy,
C2-C4 alkenyl, and C2-C4 alkynyl; and m is an integer selected from 0, 1, and 2. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt,
Figure imgf000074_0002
The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R3 is independently selected from F, Cl and CH3; and o is 0, 1, 2, 3 or 4.
The compound according to any one of claims 4-7 and 12-14, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula
Figure imgf000074_0003
The compound according to any one of claims 4-7 and 12-14, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (
Figure imgf000074_0004
17. The compound according to any one of claims 4-7 and 12-14, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the compound is represented by formula (III-B ’), and
Figure imgf000075_0001
The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
Figure imgf000075_0002
19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
Figure imgf000075_0003
20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R3 is F; and o is 0, 1, or 2.
21. A compound selected from any one of the compounds listed in Table 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
22. A pharmaceutical composition comprising the compound of any of claims 1-21, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and a pharmaceutically acceptable excipient.
23. A method of treating cardiometabolic and associated diseases comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any of claims 1-21 or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the disease is T1D, T2DM, pre -diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity, eating disorders, weight gain from use of other agents,
- 74 - excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, 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 of Polycystic Ovary Syndrome and treatment of addiction. Use of a therapeutically effective amount of a compound of any of claims 1-21 or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, in the manufacture of a medicament for of treating a subject in need of with cardiometabolic and associated diseases, wherein the disease is T1D, T2DM, pre -diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity, eating disorders, weight gain from use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, 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
- 75 - bowel syndrome Crohn's disease, colitis, irritable bowel syndrome, prevention or treatment of Polycystic Ovary Syndrome and treatment of addiction.
PCT/US2021/044785 2020-08-06 2021-08-05 Glp-1r agonists and uses thereof WO2022031994A1 (en)

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CN114630823A (en) * 2019-10-25 2022-06-14 吉利德科学公司 GLP-1R modulating compounds
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US12121511B2 (en) 2021-01-27 2024-10-22 Gilead Sciences, Inc. GLP-1R modulating compounds
US12091404B2 (en) 2021-03-11 2024-09-17 Gilead Sciences, Inc. GLP-1R modulating compounds
WO2022202864A1 (en) 2021-03-24 2022-09-29 塩野義製薬株式会社 Pharmaceutical composition containing glp-1 receptor agonist having fused ring
WO2022246019A1 (en) 2021-05-20 2022-11-24 Eli Lilly And Company Macrocyclic glucagon-like peptide 1 receptor agonists
WO2023038039A1 (en) 2021-09-08 2023-03-16 塩野義製薬株式会社 Medicine for prevention and treatment of diseases linked to anti-obesity activity
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WO2023057429A1 (en) 2021-10-05 2023-04-13 Astrazeneca Ab Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators
WO2023057414A1 (en) 2021-10-05 2023-04-13 Astrazeneca Ab Certain octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators
WO2023057427A1 (en) 2021-10-05 2023-04-13 Astrazeneca Ab Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators
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