EP4476212A1 - 2-((4-((s)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((s)-oxetan-2-yl)methyl)-1h-imidazole derivatives as activators of the glp1 receptor for the treatment of obesity - Google Patents

2-((4-((s)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((s)-oxetan-2-yl)methyl)-1h-imidazole derivatives as activators of the glp1 receptor for the treatment of obesity

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Publication number
EP4476212A1
EP4476212A1 EP23705679.1A EP23705679A EP4476212A1 EP 4476212 A1 EP4476212 A1 EP 4476212A1 EP 23705679 A EP23705679 A EP 23705679A EP 4476212 A1 EP4476212 A1 EP 4476212A1
Authority
EP
European Patent Office
Prior art keywords
methyl
alkyl
halo
oxetan
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23705679.1A
Other languages
German (de)
English (en)
French (fr)
Inventor
Martin Allan
Matthew Carson
Thomas CAYA
Tanzina Fazal
Troy Smith
Liansheng Su
Lihua Yang
Ping Zhang
Ming Qian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/IB2022/053367 external-priority patent/WO2022219495A1/en
Application filed by Novartis AG filed Critical Novartis AG
Publication of EP4476212A1 publication Critical patent/EP4476212A1/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to 1 ,3-benzodioxole derivatives, to their preparation, to pharmaceutical compositions comprising them and to their use in the treatment of conditions, diseases and disorders treatable by activating Glucagon-like Peptide 1 Receptor (GLP1 R).
  • GLP1 R Glucagon-like Peptide 1 Receptor
  • GLP1 R Glucagon-like Peptide 1 receptor belongs to family B1 of the G protein-coupled receptors (GPCRs) and is expressed in many tissues including pancreas, heart, gut and brain (Kieffer T. J. and Habener, J. F. Endocrin. Rev. 20:876-913 (1999); Drucker, D. J., Endocrinology 142:521-7 (2001); Hoist, J. J., Diabetes Metab. Res. Rev. 18:430-41 (2002); Regard J.B., Cell 135:561-71 (2008)).
  • GPCRs G protein-coupled receptors
  • GLP1 R natural agonist ligands are GLP-1 (7-36, 30 aa) and oxyntomodulin (OXM, 37 aa), both derived from pro-glucagon.
  • GLPI Rs couple to Gas-protein with subsequent activation of adenylate cyclase and intracellular increase of cAMP levels, thereby potentiating glucose-stimulated insulin secretion acting on the pancreatic beta-cells. Therefore, GLP1 R is an attractive therapeutic target for lowering blood glucose in diabetic patients.
  • GLP1 R agonist peptides e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide
  • GLP1 R agonist peptides are being developed for the treatment for patients suffering from diabetes, NASH and/or obesity.
  • Obesity is a chronic disease that is highly prevalent in modern society and is associated with a number of co-morbidities including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with type 2 diabetes mellitus (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 four-fold increased risk of coronary artery disease. Currently, the most effective obesity treatment is bariatric surgery, which is, however, both costly and risky for patients. Pharmacological replacement of bariatric surgery is therefore an attractive alternative.
  • type 2 diabetes mellitus T2DM
  • insulin resistance the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both.
  • T2DM is associated with a two- to four-fold increased risk of coronary artery disease.
  • bariatric surgery which is, however, both costly and risky for patients. Pharmacological replacement of bariatric
  • a GLP1 R agonist may be an effective therapy for T2DM remission.
  • a GLP1 R receptor agonist may reduce the risk of cardiovascular death and hospitalization for patients with chronic HFpEF. Metabolic disorders are therefore potentially treatable with small molecule agonists of GLP1R.
  • the present invention provides, inter alia, compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein constituent members are as defined herein.
  • the compounds of formula (I), and pharmaceutically acceptable salts thereof, as herein defined, are GLP1R agonists. Accordingly, these compounds may be useful in the treatment of metabolic diseases, disorders and conditions, such as obesity, type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including but not limited to chronic kidney disease), diabetic nephropathy, dyslipidemia and cardiovascular disease. The compounds may also be useful in the treatment of progressive liver disease and neuropathies.
  • compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • GLP1R Glucagon-like Peptide 1 Receptor
  • kits for treating, preventing, or ameliorating a condition, disease, or disorder treatable by activating or agonizing GLP1 R in a patient comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof (in, e.g., a therapeutically effective amount).
  • a disease, disorder, or condition selected from metabolic and related disorders including obesity and type 2 diabetes mellitus, cardiovascular disease such as heart failure (for example heart failure with preserved ejection fraction (HFpEF)), and non-alcoholic steatohepatitis (NASH) in a patient
  • cardiovascular disease such as heart failure (for example heart failure with preserved ejection fraction (HFpEF)), and non-alcoholic steatohepatitis (NASH)
  • HFpEF heart failure with preserved ejection fraction
  • NASH non-alcoholic steatohepatitis
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in any of the methods described herein. Also provided herein is a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
  • the compounds of the present invention may exhibit advantageous ADME (absorption, distribution, metabolism and excretion) properties, for example, in vivo exposure (in particular, when dosed orally), for example, as demonstrated by measurement of certain pharmacokinetic parameters such as maximum concentration in plasma (Cmax) and/or total exposure (area under the curve (AUC)) values.
  • ADME absorption, distribution, metabolism and excretion
  • substituents applies to compounds of any formulae provided herein, e.g., formulae (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), as appropriate.
  • the definition of the substituents applies to the end-products as well as to the corresponding intermediates as appropriate.
  • ⁇ is a single or double bond; indicates the point of attachment to the rest of the molecule;
  • W is O or CH 2 ;
  • X is O or CH 2 ;
  • R 1 and R 2 are each independently selected from H, Ci-3-alkyl, halo and CN;
  • R 3 is selected from H and Ci-3-alkyl
  • R 4 is (a) selected from H, Ci-e-alkyl, C2-6 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl-, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO2, OR 4a , SR 4a , C(O)R 4b , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ), wherein the Ci- 6 -alkyl, C 2-6 alkenyl, C 2.6 alkynyl, C 3 -e- cycloalkyl, 4-10 membered heterocycloalkyl, phenyl,
  • R 4 is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 4A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO2, OR 4A , SR 4A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O) 2 R 4B ), C(O)NR 4C (S(O) 2 NR 4C R 4D ), NR 4C OR 4A , NR 4C R 4D , NR 4C (C(O)R 4B
  • R 5 is (a) selected from H, Ci-e-alkyl, C2-6 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO2, OR 5a , SR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O) 2 R 5b ), C(O)NR 5c (S(O) 2 NR 5c R 5d ), NR 5c OR 5a , NR 5c R 5d , NR 5c (C(O)R 5b ), NR 5c (C(O)OR 5
  • R 5 is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 5A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO 2 , OR 5A , SR 5A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O) 2 R 5B ), C(O)NR 5C (S(O) 2 NR 5C R 5D ), NR 5C OR 5A , NR 5C R 5D , NR 5C (C(O)R 5
  • R 6 is selected from (4-10 membered heterocycloalkyl)-Ci-3-alkyl- and (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the (4-10 membered heterocycloalkyl)-Ci-3-alkyl- and (5-10 membered heteroaryl)-Ci-3-alkyl- of R 6 are each optionally substituted with 1 , 2, or 3 groups independently selected from Ci-e-alkyl, -OH, and halo;
  • R 4a , R 4b , R 4c , and R 4d are each independently selected from H, Ci-e-alkyl, C 2 .6 alkenyl, C 2 . 6 alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl, wherein the Ci-e-alkyl, C 2 -6 alkenyl, and C 2 -6 alkynyl of R 4a , R 4b , R 4c , and R 4d are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH and halo; and the Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl of R 4a , R 4b , R 4c , and R 4d are each optionally substituted with 1 , 2, or 3 groups independently selected from Ci-6-alkyl, -OH,
  • R 4e , R 4f , and R 49 are each independently selected from H and Ci-6-alkyl;
  • R 4A , R 4B , R 4C , and R 4D are each independently selected from H, Ci-ealkyl, C 2 -6 alkenyl, C 2 . 6 alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-Ci- 3-alkyl-, 5-10 membered heteroaryl, and phenyl, wherein the Ci-6-alkyl, C 2 -6 alkenyl, and C 2 -6 alkynyl of R 4A , R 4B , R 4C , and R 4D are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH, halo and -OC(O)-Ci-i5-alkyl; and the Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-Ci-3-alkyl-, 5-10 membered hetero
  • R 4E , R 4F , and R 4G are each independently selected from H and Ci-e-alkyl;
  • R 5a , R 5b , R 5c , and R 5d are each independently selected from H, Ci-e-alkyl, C2-6 alkenyl, C2- e alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl, wherein the Ci-e-alkyl, C2-6 alkenyl, and C ⁇ alkynyl of R 5a , R 5b , R 5c , and R 5d are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH and halo; and the Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl of R 5a , R 5b , R 5c , and R 5d are each optionally substituted with 1 , 2, or 3 groups independently selected from Ci-6-alkyl, -OH, and halo;
  • R 5e , R 5f , and R 5g are each independently selected from H and Ci-6-alkyl;
  • R 5A , R 5B , R 5C , and R 5D are each independently selected from H, Ci-6-alkyl, C2-6 alkenyl, C2-e alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloal kyl- Ci-3-alkyl-, 5-10 membered heteroaryl, and phenyl, wherein the Ci-6-alkyl, C2-6 alkenyl, and C2-6 alkynyl of R 5A , R 5B , R 5C , and R 5D are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH, halo and -OC(O)-Ci-i5-alkyl; and the Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-Ci-3-alkyl-, 5-10 membered heteroaryl, and
  • R 5E , R 5F , and R 5G are each independently selected from H and Ci-6-alkyl.
  • W is O or CH 2 ;
  • X is O or CH2;
  • R 1 and R 2 are each independently selected from H, Ci-3-alkyl, halo and CN;
  • R 3 is selected from H and Ci-3-alkyl
  • R 4 and R 5 are selected from:
  • R 4 is selected from H, Ci-e-alkyl, C2-6 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl-, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO2, OR 4a , SR 4a , C(O)R 4b , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ), wherein the Ci- 6 -alkyl, C 2-6 alkenyl, C 2.6 alkynyl, C3-6- cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl,
  • R 5 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 5A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO2, OR 5A , SR 5A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O) 2 R 5B ), C(O)NR 5C (S(O) 2 NR 5C R 5D ), NR 5C OR 5A , NR 5C R 5D , NR 5C (C(O)R 5B ), NR
  • R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 4A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO2, OR 4A , SR 4A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O) 2 R 4B ), C(O)NR 4C (S(O) 2 NR 4C R 4D ), NR 4C OR 4A , NR 4C R 4D , NR 4C (C(O)R 4B
  • R 5 is selected from H, Ci-e-alkyl, C 2 .6 alkenyl, C 2 .6 alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO 2 , OR 5a , SR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), wherein the Ci-e-alkyl, C 2 .6 alkenyl, C 2 -e alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl-
  • R 6 is selected from (4-10 membered heterocycloalkyl)-Ci-3-alkyl- and (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the (4-10 membered heterocycloalkyl)-Ci-3-alkyl- and (5-10 membered heteroaryl)-Ci-3-alkyl- of R 6 are each optionally substituted with 1 , 2, or 3 groups independently selected from Ci-e-alkyl, -OH, and halo;
  • R 4a , R 4b , R 4c , and R 4d are each independently selected from H, Ci-6-alkyl, C 2 -6 alkenyl, C 2 . 6 alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl, wherein the Ci-6-alkyl, C 2 -6 alkenyl, and C 2 -e alkynyl of R 4a , R 4b , R 4c , and R 4d are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH and halo; and the Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl of R 4a , R 4b , R 4c , and R 4d are each optionally substituted with 1 , 2, or 3 groups independently selected from Ci-6-alkyl, -OH, and
  • R 4e , R 4f , and R 49 are each independently selected from H and Ci-6-alkyl;
  • R 4A , R 4B , R 4C , and R 4D are each independently selected from H, Ci-ealkyl, C 2 -6 alkenyl, C 2 . 6 alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-Ci- 3-alkyl-, 5-10 membered heteroaryl, and phenyl, wherein the Ci-6-alkyl, C 2 -6 alkenyl, and C 2 -6 alkynyl of R 4A , R 4B , R 4C , and R 4D are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH, halo and -OC(O)-Ci-i5-alkyl; and the Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-Ci-3-alkyl-, 5-10 membered hetero
  • R 4E , R 4F , and R 4G are each independently selected from H and Ci-e-alkyl;
  • R 5a , R 5b , R 5c , and R 5d are each independently selected from H, Ci-e-alkyl, C2-6 alkenyl, C2- 6 alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl, wherein the Ci-e-alkyl, C2-6 alkenyl, and C2-6 alkynyl of R 5a , R 5b , R 5c , and R 5d are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH and halo; and the Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl of R 5a , R 5b , R 5c , and R 5d are each optionally substituted with 1 , 2, or 3 groups independently selected from Ci-e-alkyl, -OH, and halo;
  • R 5e , R 5f , and R 59 are each independently selected from H and Ci-6-alkyl;
  • R 5A , R 5B , R 5C , and R 5D are each independently selected from H, Ci-e-alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloal kyl- Ci-3-alkyl-, 5-10 membered heteroaryl, and phenyl, wherein the Ci-e-alkyl, C2-6 alkenyl, and C2-6 alkynyl of R 5A , R 5B , R 5C , and R 5D are each optionally substituted with 1 , 2, or 3 groups independently selected from -OH, halo and -OC(O)-Ci-i5-alkyl; and the Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-Ci-3-alkyl-, 5-10 membered heteroaryl,
  • R 5E , R 5F , and R 5G are each independently selected from H and Ci-e-alkyl.
  • R 1 is halo
  • R 1 is CN
  • R 2 is halo
  • R 1 is chloro, fluoro or CN; and R 2 is chloro or fluoro.
  • R 1 is chloro; and R 2 is fluoro.
  • R 1 is CN; and R 2 is chloro or fluoro.
  • R 1 is CN; and R 2 is fluoro.
  • R 3 is H or -CH3.
  • R 3 is -CH3.
  • R 4 is (a) selected from Ci-e-alkyl, C2-6 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl-, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO2, OR 4a , SR 4a , C(O)R 4b , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ), wherein the Ci- 6 -alkyl, C 2-6 alkenyl, C 2.6 alkynyl, C3-6- cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C
  • R 4 is (a) selected from Ci-3-alkyl, C2-4 alkenyl, C ⁇ alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and halo, wherein the Ci-3-alkyl, C2-4 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl of R 4 are each optionally substituted with 1 , 2, or 3 groups independently selected from halo and Ci-3-alkyl, or R 4 is (b) 5- 10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 4A or with a carboxylic acid isostere
  • R 4 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl.
  • R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 4A or with a carboxylic acid isostere, and optionally with 1 , 2 or 3 groups independently selected from halo, CN, NO2, OR 4A , SR 4A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O) 2 R 4B ), C(O)NR 4C (S(O) 2 NR 4C R 4D ), NR 4C OR 4A , NR 4C R 4
  • R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 4A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, Ci-3-alkyl and Ci-3-alkyl substituted with 1 , 2 or 3 halo; wherein R 4A is selected from H and Ci-3-alkyl.
  • R 4 has the structure of Formula H1 or H2:
  • W is C(O)OR 4A or a carboxylic acid isostere; each is a single or a double bond; each R 4h is independently selected from H, Ci-e-alkyl, C2-6 alkenyl, C ⁇ alkynyl, C3-6- cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, Cs-e-cycloalkyl- Ci-3-alkyl-, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, (5-10 membered heteroaryl)-Ci-3- alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO 2 , OR 4a , SR 4a , C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e
  • R 4h and R 4i can be taken together to form a Cs-6-cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl which may be further substituted with groups independently selected from Ci-e-alkyl, -OH, and halo, wherein R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4 s, R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G are as defined herein.
  • R 4 has the structure of Formula H1a or H2a:
  • R 4A is selected from H and Ci-3-alkyl; and if present, R 4h is halo, Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, and R 4i is Ci- 3-alkyl.
  • R 4 is selected from the group consisting of:
  • Ra, Rb and Rc are independently selected from H, Ci-3-alkyl and Ci-3-alkyl substituted with 1 , 2 or 3 halo, and R 4A is selected from H and Ci-3-alkyl.
  • R 5 is (a) selected from Ci-e-alkyl, C2-6 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, Cs-e-cycloalkyl-Ci-s-alkyl, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO2, OR 5a , SR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O) 2 R 5b ), C(O)NR 5c (S(O) 2 NR 5c R 5d ), NR 5c OR 5a , NR 5c R 5d , NR 5c (C(O) (C(O)
  • R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5 s, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G are as defined herein.
  • R 5 is (a) selected from Ci-3-alkyl, C2-4 alkenyl, C ⁇ alkynyl, Cs-6-cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and halo, wherein the Ci-3-alkyl, C2-4 alkenyl, C ⁇ alkynyl, Cs-e-cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 , 2, or 3 groups independently selected from halo and Ci-3-alkyl, or R 5 is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 5A or with a carboxylic acid isostere, and optional
  • R 5 is selected from halo, Ci-3-alkyl, and phenyl, wherein the Ci-3-alkyl and phenyl are each optionally substituted with 1 , 2, or 3 halo.
  • R 5 is selected from Ci-3-alkyl, C2-4 alkenyl, and Cs-e-cycloalkyl, wherein the Ci-3-alkyl, C2- 4 alkenyl, and Cs-6-cycloalkyl of R 5 are each optionally substituted with 1 , 2, or 3 halo.
  • R 5 is selected from -CH3, -CF3, F, -CH2CH3, and
  • R 5 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl.
  • R 5 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the R 5 is 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 5A or with a carboxylic acid isostere, optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO2, OR 5A , SR 5A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O) 2 R 5B ), C(O)NR 5C (S(O) 2 NR 5C R 5D ), NR 5C OR 5A , NR 5C
  • R 5 has the structure of Formula H1 1 or H12:
  • W is C(O)OR 5A or a carboxylic acid isostere; each is a single or a double bond; each R 5h is independently selected from H, Ci-e-alkyl, C 2 .6 alkenyl, C 2 .6 alkynyl, C3-6- cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, Cs-6-cycloalkyl- Ci-3-alkyl, (4-10 membered heterocycloalkyl)-Ci-3-alkyl-, (5-10 membered heteroaryl)-Ci-3-alkyl-, phenyl-Ci-3-alkyl-, halo, CN, NO 2 , OR 5a , SR 5a , C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR
  • 3-alkyl- are each optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, NO 2 , OR 5A , SR 5A , C(O)OR 5A , C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O) 2 R 5B ), C(O)NR 5C (S(O) 2 NR 5C R 5D ), NR 5C OR 5A , NR 5C R 5D , NR 5C (C(O)R 5B ), NR 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), NR 5C (C(O)NR 5C R 5D ), NR 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O) 2 R 5B ), NR 5C (S(O)
  • R 5 has the structure of Formula H1 1a or H12a:
  • R 5A is selected from H and Ci -3-alkyl; and if present, R 5h is halo, Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, and R 5i is Cis-alkyl.
  • R 5 has the structure of Formula H11a, for example wherein R 5 is selected from the group consisting of: wherein Ra, Rb and Rc are independently selected from H, Ci-3-alkyl and Ci-3-alkyl substituted with 1, 2 or 3 halo, and R 5A is selected from H and Ci-3-alkyl.
  • R 6 is selected from (4-6 membered heterocycloalkyl)-CH2- and (5-6 membered heteroaryl)-CH2-, wherein the (4-6 membered heterocycloalkyl)-CH2- and (5-6 membered heteroaryl)-CH2- of R 6 are each optionally substituted with 1, 2, or 3 groups independently selected from Ci-e-alkyl, -OH, and halo.
  • R 6 is selected from the group consisting of: wherein indicates the point of attachment to the rest of the molecule. In an embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 6 is of formula: wherein indicates the point of attachment to the rest of the molecule.
  • R 6 is of formula: wherein indicates the point of attachment to the rest of the molecule.
  • X is O.
  • W is O.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (la): wherein A, W, X, R 1 , R 2 and R 3 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (II):
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (Ila): wherein A, R 1 , R 2 and R 3 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (III): wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (Illa): wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (111 b) : wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (IV): wherein R 1 is chloro or CN, and R 3 , R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (I a): wherein R 1 is chloro or CN, and R 3 , R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (I b): wherein R 1 is chloro or CN, and R 3 , R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (V): wherein R 1 is chloro or CN, and R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (Va): wherein R 1 is chloro or CN, and R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is a compound of formula (Vb): wherein R 1 is chloro or CN, and R 4 and R 5 are as defined herein, or a pharmaceutically acceptable salt thereof.
  • R 4 is as defined herein.
  • R 5 is as defined herein.
  • R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 4A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, Ci-3-alkyl and Ci-3-alkyl substituted with 1 , 2 or 3 halo; wherein R 4A is selected from H and Ci-3-alkyl; and
  • R 5 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl.
  • R 4 has the structure of Formula H1 or H2 as defined herein;
  • R 5 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl.
  • R 4 has the structure of Formula H1a or H2a as defined herein;
  • R 5 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl.
  • R 4 is selected from the group consisting of:
  • Ra, Rb and Rc are independently selected from H, Ci-3-alkyl and Ci-3-alkyl substituted with 1 , 2 or 3 halo, and R 4A is selected from H and Ci-3-alkyl, and
  • R 5 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl.
  • R 4 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl, and
  • R 5 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with C(O)OR 5A or with a carboxylic acid isostere, and optionally with 1 , 2, or 3 groups independently selected from halo, Ci-3-alkyl and Ci-3-alkyl substituted with 1 , 2 or 3 halo; wherein R 5A is selected from H and Ci-3-alkyl.
  • R 4 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl, and
  • R 5 has the structure of Formula H11 or H12 as defined herein.
  • R 4 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl, and R 5 has the structure of Formula H11a or H12a as defined herein.
  • R 4 is Ci-3-alkyl or Ci-3-alkyl substituted with 1 , 2 or 3 halo, for example methyl, ethyl or trifluoromethyl
  • R 5 is selected from the group consisting of: wherein Ra, Rb and Rc are independently selected from H, Ci-3-alkyl and Ci-3-alkyl substituted with 1 , 2 or 3 halo, and R 5A is selected from H and Ci-3-alkyl.
  • the compound of formula (I) is selected from the group consisting of:
  • the compound of formula (I) is selected from the group consisting of:
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is selected from Table A:
  • R 4 and R 5 comprise a carboxylic acid, a carboxylic acid derivative (e.g., carboxylic acid ester derivative such as carboxylic acid methyl ester or carboxylic acid ethyl ester) or a carboxylic acid isostere (see, e.g., J. Med. Chem. 2016, 59, 3183-3203).
  • R 4 and R 5 are not the same.
  • only one of R 4 and R 5 comprises a carboxylic acid, a carboxylic acid derivative (e.g., carboxylic acid ester derivative such as carboxylic acid methyl ester or carboxylic acid ethyl ester) or a carboxylic acid isostere.
  • a carboxylic acid derivative e.g., carboxylic acid ester derivative such as carboxylic acid methyl ester or carboxylic acid ethyl ester
  • a carboxylic acid isostere e.g., A non-limiting list of example non-cyclic carboxylic acid isosteres is as follows:
  • the terms “compounds of the present invention”, “compound of the present invention”, “compound of the invention”, or “compounds of the invention” refer to a compound of formula (I), subformulae thereof (e.g., formulae (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb)) and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties.
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • the present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
  • Optically active (/?)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • substitution means unsubstituted or substituted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.
  • C n -m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.
  • C n -m alkenyl refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons.
  • the alkenyl group contains from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, or from 2 to 3 carbon atoms.
  • C n -m alkynyl refers to an alkyl group having one or more triple carboncarbon bonds and having n to m carbons.
  • the alkynyl group contains from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, or from 2 to 3 carbon atoms.
  • aryl refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings).
  • C n -m aryl refers to an aryl group having from n to m ring carbon atoms. In some embodiments, the aryl group has from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having two fused rings) groups, spirocycles, and bridged rings. Ring-forming carbon atoms of a cycloalkyl can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)).
  • the cycloalkyl groups have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (i.e., C3-10 cycloalkyl).
  • the cycloalkyl groups have 3, 4, 5, or 6 ringforming carbon atoms (j.e., C3-6 cycloalkyl).
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, and S.
  • a ring-forming N in a heteroayl group can be an N-oxide.
  • the heteroaryl is a 5-10 membered monocylic or bicyclic heteroaryl having 1 , 2, 3, or 4 heteroatom ring members independently selected from N, O, and S.
  • the heteroaryl is a 5-10 membered monocylic or bicyclic heteroaryl having 1 , 2, 3, or 4 heteroatom ring members independently selected from N, O, and S.
  • heterocycloalkyl refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein a ring-forming carbon or heteroatom of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), S(O)2), etc.).
  • the heterocycloalkyl group contains 4 to 10 ring-forming atoms (/.e., 4-10 membered), wherein 1 to 4 atoms are heteroatoms independently selected from N, O, and S.
  • C o -p-cycloalkyl-C n -m-alkyl refers to a group of formula cycloalkylalkylene, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.
  • heterocycloalkyl-C n -m-alkyl refers to a group of formula heterocycloalkyl-alkylene, wherein the alkylene linking group has n to m carbon atoms.
  • heteroaryl-C n -m-alkyl refers to a group of formula heteroaryl-alkylene, wherein the alkylene linking group has n to m carbon atoms.
  • aryl-C n -m-alkyl refers to a group of formula aryl-alkylene, wherein the alkylene linking group has n to m carbon atoms.
  • salt refers to an acid addition or base addition salt of a compound provided herein.
  • Salts include in particular “pharmaceutically acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which typically are not biologically or otherwise undesirable.
  • the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of basic nitrogen atoms, for example as found in amino and pyridine groups or other groups similar thereto and/or acidic protons, for example as found in carboxylic acid or other groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • compounds provided herein are in sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt form.
  • compounds provided herein are in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphat
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen.
  • isotopes particularly deuterium (i.e. , 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability.
  • deuterium in this context is regarded as a substituent of a compound of the present invention.
  • concentration of deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopic enrichment factor can be applied to any isotope in the same manner as described for deuterium.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and sulfur, such as 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 35 S respectively. Accordingly, it should be understood that the invention includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • composition refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
  • the term "pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).
  • a therapeutically effective amount of a compound of the present invention refers to an amount of a compound of the present invention that will elicit the biological or medical response of a subject, for example, agonize GLP1 R activity, ameliorate symptoms, alleviate conditions, slow or delay the progression of a disease, disorder or condition, or prevent a disease, disorder or condition.
  • the term “a therapeutically effective amount” refers to the amount of a compound of the present invention that, when administered to a subject, is effective to at least partially alleviate, prevent and/or ameliorate a condition, or a disorder or a disease responsive to increasing or agonizing the activity of GLP1 R.
  • a therapeutically effective amount refers to the amount of a compound of the present invention that, when administered to a subject, cell, or a tissue, or a non-cellular biological material, or a medium, is effective to partially or fully agonize the activity of GLP1 R.
  • the term “a therapeutically effective amount” refers to the amount of a compound of the present invention that, when administered to a subject, is effective to cause an observable level of one or more desired biological or medicinal responses, for example selected from: lowering glucose levels (or improving glucose homeostasis), increasing insulin sensitivity, lowering triglyceride or cholesterol levels, reducing body weight, reducing food intake and reducing body fat mass (such as peripheral fat and/or visceral fat).
  • the term “subject” refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats and mice.
  • the subject is a primate. In yet other embodiments, the subject is a human.
  • the terms “agonize”, “agonism” and “agonizing” refer to an increase of signaling and/or activity of GLP1 R, for example, as measured by an increase in intracellular cyclic adenosine mono-phosphate (cAMP).
  • cAMP cyclic adenosine mono-phosphate
  • the term “treat”, “treating” or “treatment” of any disease, disorder or condition refers to alleviating or ameliorating the disease, disorder or condition (i.e. , slowing or arresting the development or progression of the disease, disorder or condition, or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease, disorder or condition, including those which may not be discernible to the patient.
  • the term “prevent”, “preventing” or “prevention” of any disease, disorder or condition refers to the prophylactic treatment of the disease, disorder or condition; or delaying the onset or progression of the disease, disorder or condition.
  • a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (/?)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (/?)- or (S)- configuration.
  • a compound of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of compounds of the present invention or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid.
  • Racemic compounds of the present invention or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • the compounds provided herein can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds provided herein can be synthesized using the methods described in the Examples, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis as described for example in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004.
  • Protective groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the compounds of formula (I) according to the invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds provided herein can be synthesized using the methods described in any of general synthetic Schemes A and B or in the Examples, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • intermediate II.A wherein R 1 , R 2 and R 3 are as defined herein
  • intermediate III.A wherein Y is Br or I
  • R 4 is as defined herein
  • the intermediate I.A wherein Y is Br or I, and R 1 , R 2 , R 3 and R 4 are as defined herein, is then reacted with a carboxylic acid ester derivative B1 in the presence of a Pd catalyst (e.g., Xphos Pd G2) and a base in a solvent (e.g., toluene) to afford a compound of formula (I).
  • a Pd catalyst e.g., Xphos Pd G2
  • solvent e.g., toluene
  • R is Ci .3-alkyl and H A is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, NO2, OR 5A , SR 5A , C1.3- alkyl, Ci.3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O) 2 R 5B ), C(O)NR 5C (S(O) 2 NR 5C R 5D ), NR 5C OR 5A , NR 5C R 5D , NR 5C (C(O)R 5B
  • intermediate I.A wherein Y is Br or I, and R 1 , R 2 , R 3 and R 4 are as defined herein, is reacted with a carboxylic acid ester derivative B1 , wherein R is Ci-3-alkyl and H A is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5- 10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with boronic acid or a dioxaborolan protecting group (e.g., 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl), and optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO 2 , OR 5A , SR 5A , Ci.3-alkyl, Ci- 3 -alkyl substituted with 1 , 2 or 3 halo, C(O)R 5B ,
  • R
  • the compound of formula (I) so obtained is a carboxylic acid ester derivative, wherein R 1 , R 2 , R 3 and R 4 are as defined herein, and H A ’ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkylene-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkylene- are each optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, NO 2 , OR 5A , SR 5A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O) 2 R 5B ), C(O)NR 5C (S(O) 2 NR 5C R 5D ), NR 5C OR 5A ), C
  • intermediate II.A wherein R 1 , R 2 and R 3 are as defined herein
  • intermediate III.B wherein Y is Br or I
  • R 5 is as defined herein
  • the intermediate I.B wherein R 1 , R 2 , R 3 and R 5 are as defined herein and Y is Br or I
  • a carboxylic acid ester derivative B2 is then reacted with a Pd catalyst (e.g., Xphos Pd G2) and a base in a solvent (e.g., toluene) to afford a compound of formula (I).
  • Pd catalyst e.g., Xphos Pd G2
  • solvent e.g., toluene
  • R is Ci -3-alkyl and H B is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, NO2, OR 4A , SR 4A , C1.3- alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O) 2 R 4B ), C(O)NR 4C (S(O) 2 NR 4C R 4D ), NR 4C OR 4A , NR 4C R 4D , NR 4C (C(O)R 4B ),
  • intermediate I.B wherein R 1 , R 2 , R 3 and R 5 are as defined herein and Y is Br or I, is reacted with a carboxylic acid ester derivative B2, wherein R is C1.3- alkyl and H B is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkyl- are each substituted with boronic acid or a dioxaborolan protecting group (e.g., 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl), and optionally with 1 , 2, or 3 groups independently selected from halo, CN, NO 2 , OR 4A , SR 4A , Ci-3-alkyl, Ci- 3 -alkyl substituted with 1 , 2 or 3 halo, C(O)R 4B , C(O)NR 4
  • R
  • the compound of formula (I) so obtained is a carboxylic acid ester derivative, wherein R 1 , R 2 , R 3 and R 5 are as defined herein, and H B ’ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-Ci-3-alkylene-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-Ci-3-alkylene- are each optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, NO 2 , OR 4A , SR 4A , Ci-3-alkyl, Ci-3-alkyl substituted with 1 , 2 or 3 halo, C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O) 2 R 4B ), C(O)NR 4C (S(O) 2 NR 4C R 4D ), NR 4C OR 4A ), C
  • Intermediate II.A is either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art.
  • intermediate II.A can be prepared as described below in Scheme C.
  • intermediate 11.1 is reacted with 3-bromobenzene-1 ,2-diol in the presence of p-TsOH in a solvent (e.g., toluene) to afford intermediate II.2.
  • a solvent e.g., toluene
  • Intermediate II.4 wherein R 1 , R 2 and R 3 are as defined herein, is then purified by SFC into intermediates II.5a and II.5b.
  • Intermediates II.5a and II.5b wherein R 1 , R 2 and R 3 are as defined herein, are converted into intermediates II.Aa and II.Ab, respectively, wherein R 1 , R 2 and R 3 are as defined herein, in the presence of HCI in a solvent (e.g., dioxane).
  • Intermediates III.A and III.B are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. For example, intermediates III.A and III.B can be prepared as described below in Scheme D.
  • intermediate III. a wherein Z is R 4 or R 5 as defined herein and Y is Br or I, is reacted with oxetan-2-ylmethyl 4-methylbenzenesulfonate in the presence of cesium carbonate in a solvent (e.g., acetonitrile).
  • a solvent e.g., acetonitrile
  • the residue is purified via chromatography to separate the isomers to afford intermediates 111.1a and 111.1b, wherein R 4 or R 5 is as defined herein and Y is Br or I.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose
  • the compounds of the present invention e.g., compounds of formulae (la), (II), (Ila), (III), (Illa), (II lb), (IV), (IVa), (IVb), (V), (Va) and (Vb), and pharmaceutically acceptable salts thereof) in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example as agonists of GLP1 R, e.g., as indicated in in vitro and in vivo tests as provided in the next sections, and are therefore indicated for therapy or for use as research chemicals, e.g., as tool compounds.
  • the compounds of the present invention may be useful in the treatment of metabolic and related diseases, disorders and conditions.
  • the compounds of the present invention may be useful in the treatment of metabolic and related diseases, disorders and conditions selected from: obesity, type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including but not limited to chronic kidney disease), diabetic nephropathy, dyslipidemia, metabolic syndrome, progressive liver disease, cardiovascular diseases and neuropathy (in particular, peripheral neuropathy, e.g., associated with diabetes).
  • metabolic and related diseases, disorders and conditions selected from: obesity, type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including but not limited to chronic kidney disease), diabetic nephropathy, dyslipidemia, metabolic syndrome, progressive liver disease, cardiovascular diseases and neuropathy (in particular, peripheral neuropathy, e.g., associated with diabetes).
  • the progressive liver disease may be, for example, non-alcoholic fatty liver disease (NAFLD), or, for example, non-alcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • the cardiovascular disease may be selected, for example, from: hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (for example heart failure with reduced ejection fraction (HFrEF), heart failure with midrange ejection fraction (HFmrEF)) and heart failure with preserved ejection fraction (HFpEF), coronary heart disease and arrhythmias (for example atrial arrhythmias and ventricular arrhythmias)).
  • heart failure for example heart failure with reduced ejection fraction (HFrEF), heart failure with midrange ejection fraction (HFmrEF)
  • HFpEF heart failure with preserved ejection fraction
  • coronary heart disease and arrhythmias for example atrial arrhythmias and ventricular arrhythmias
  • the compounds of the present invention may be useful in the treatment of several diseases, disorders or conditions co-occurring in a subject (termed ‘co-morbidities’).
  • Co-morbidities may be those in subjects which are type 2 diabetic and are additionally obese and/or additionally exhibit heart failure and/or NASH.
  • an obese subject may also exhibit type 2 diabetes and/or exhibit cardiovascular disease (for example heart failure).
  • Such subject may also exhibit a progressive liver disease (for example NASH).
  • an obese subject may also exhibit type 2 diabetes and/or exhibit cardiovascular disease (for example heart failure) and/or exhibit a progressive liver disease (for example NASH).
  • the subject may also have high blood pressure and/or high blood cholesterol level.
  • the subject may also suffer from peripheral neuropathy.
  • a compound provided herein may be useful in the treatment of a disease, disorder or condition selected from: obesity, type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including but not limited to chronic kidney disease), diabetic nephropathy, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (in particular, heart failure with reduced ejection fraction (HFrEF), heart failure with midrange ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF)), coronary heart disease, arrhythmias (in particular, atrial arrhythmias and ventricular arrhythmias) and neuropathy (in particular, peripheral neuropathy).
  • a disease, disorder or condition selected from: obesity, type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance
  • the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis, heart failure (in particular, HFpEF) and NASH.
  • the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, HFpEF).
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof
  • the therapy is treatment of a disease, disorder or condition which may be treated by agonism of GLP1R.
  • the therapy is treatment of a disease, disorder or condition selected from the afore-mentioned lists, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, and/or a subject with type 2 diabetes who also has heart failure and/or a subject with type 2 diabetes who also has NASH.
  • a disease, disorder or condition selected from the afore-mentioned lists suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, and/or a subject with type 2 diabetes who also has heart failure and/or a subject with type 2 diabetes who also has NASH.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof
  • the therapy is treatment of a disease, disorder or condition which may be treated by agonism of GLP1 R.
  • the therapy is treatment of a disease, disorder or condition selected from the afore-mentioned lists, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, and/or a subject with type 2 diabetes who also has heart failure and/or a subject with type 2 diabetes who also has NASH.
  • a disease, disorder or condition selected from the afore-mentioned lists suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, and/or a subject with type 2 diabetes who also has heart failure and/or a subject with type 2 diabetes who also has NASH.
  • the provided herein is a method of treating a disease, disorder or condition which is treatable by agonism of GLP1R comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (Iva), (Ivb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof).
  • the invention provides a method of treating a disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from the afore-mentioned lists, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, and/or a subject with type 2 diabetes who also has heart failure and/or a subject with type 2 diabetes who also has NASH.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof wherein the disease, disorder or condition is selected from the afore-mentioned lists, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type
  • the provided herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof), for the manufacture of a medicament.
  • the medicament is for treatment of a disease which may be treated by agonism of GLP1 R.
  • the disease is selected from the afore-mentioned lists, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, and/or a subject with type 2 diabetes who also has heart failure and/or a subject with type 2 diabetes who also has NASH.
  • metabolic disorders or diseases refers to an associated cluster of traits that includes, but is not limited to, glucose intolerance, insulin resistance, hyperinsulinemia, obesity, excess visceral adiposity, hypertension, dyslipidemia characterized by high triglycerides, low high-density lipoprotein (HDL)-cholesterol, and high low-density lipoprotein (LDL) cholesterol.
  • Subjects having metabolic disease or disorder are at risk of developing of type 2 diabetes mellitus and, for example, atherosclerosis.
  • type 2 diabetes mellitus is a condition characterized by persistently high glucose levels both in the fasted and fed state which results from a combination of impaired glucose utilization and excess glucose production. This may result from either inadequate production of insulin from the pancreas or peripheral insulin resistance.
  • insulin resistance refers to a condition where a normal quantity of insulin cannot induce the expected physiological response and cannot activate downstream pathways. In many examples insulin beyond the physiologic range either endogenously produced or exogenously administered, is sufficient to induce a complete or partial biologic response to induce the expected physiological response.
  • hyperinsulinemia refers to a condition where excess insulin can be detected in the blood.
  • glucose intolerance encompasses any disorder characterized by a clinical symptom or a combination of clinical symptoms that is associated with an elevated level of basal or post-prandial glucose and/or an elevated level of insulin or abnormal glucose stimulated insulin release or HOMA-IR (homeostatic model assessment of insulin resistance) in a subject relative to a healthy individual. Elevated levels of glucose and/or insulin may be manifested in the following diseases, disorders and conditions: obesity, metabolic syndrome, impaired glucose tolerance, type II diabetes, gestational diabetes, type I diabetes, insulin resistance, hyperinsulinemia, lipodystrophy, lipoatrophy and various MODY (maturity onset diabetes of the young) mutations.
  • the GLP1 R agonists provided herein, and compositions thereof, can be used, for example, to achieve and/or maintain glucose homeostasis, e.g., to reduce glucose level in the bloodstream and/or to reduce insulin level to a range found in a healthy subject.
  • hyperglycemia refers to a condition in which an elevated amount of glucose circulates in the blood plasma of a subject relative to a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measurement of fasting blood glucose levels as described herein.
  • diabetes complications are problems caused by persistently high blood glucose levels that damage other organs including kidneys, peripheral limbs, and eyes (e.g., retinopathies) or induce vascular disease and neuropathy. Impaired vascular function contributes to erectile dysfunction and can lead to increased risk of skin infections. Diabetes also increases the risk for heart disease and bone and joint disorders. Other long-term complications of diabetes include excess risk of cancer including hepatocellular carcinoma, endometrial cancer, breast cancer, and pancreatic cancer.
  • diabetes nephropathy is a condition resulting from diabetes and caused by damage to blood vessels and other cells in the kidney that reduces kidney function
  • the term “obesity” in human adults refers to a Body Mass Index (BMI) of 30 or greater (Centers for Disease Control and Prevention). Such subject may also be referred to as obese. This is referred to as Class I obesity. Class II obesity includes individuals with a BMI of 35-39.9 and Class III obesity refers to individuals with a BMI of greater than 40.
  • the human subject suffering from obesity has a BMI of >30 or >35 or a BMI in the range >35 to ⁇ 40 or >30 to ⁇ 40.
  • the amount ⁇ 40 can, for example, be 39.9.
  • the obesity is severe obesity or morbid obesity, wherein the human subject has a BMI of >40.
  • Dyslipidemia refers to complex disorders of lipoprotein metabolism, including lipoprotein overproduction or abnormal metabolism. Dyslipidemias may be manifested by elevation of the total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, and a decrease in high-density lipoprotein (HDL) cholesterol concentration in the blood.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • atherosclerosis refers to vascular disease characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries, sometimes causing narrowing of arterial lumens and proceeding eventually to fibrosis and calcification. Lesions are usually focal and progress slowly and intermittently. Limitation of blood flow accounts for most clinical manifestations, which vary with the distribution and severity of lesions.
  • progressive liver disease refers to the progression from a benign state of hepatosteatosis evidenced by fibrosis and cirrhosis, which predispose to hepatocellular carcinoma.
  • NASH non-alcoholic fatty liver
  • non-alcoholic fatty liver disease FLD
  • NAFLD non-alcoholic fatty liver disease
  • NAFLD non-alcoholic fatty liver disease
  • fatty liver hepatosteatosis
  • fibrosis or cirrhosis.
  • the most common cause of NAFLD is obesity, although NAFLD can also be seen in lean individuals.
  • NASH non-alcoholic steatohepatitis
  • fibrosis with interlobular bridging fibrosis or cirrhosis.
  • the term NASH may encompass steatohepatitis, hepatocellular ballooning and lobular inflammation.
  • metabolic syndrome refers to a cluster of risk factors that raises the risk for cardiovascular disease including coronary artery disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, cerebrovascular disease and peripheral vascular disease.
  • risk factors include: abdominal fat, high blood sugar (at least 110 milligrams per deciliter (mg/dl)) after fasting; high triglycerides (at least 150 mg/dL) in the bloodstream; low HDL (less than 40 mg/dl); and, blood pressure of 130/85 mmHg or higher (World Health Organization).
  • cardiovascular diseases refers to diseases related to the heart or blood vessels.
  • peripheral arterial disease refers to when a build-up of fatty deposits in the arteries restricts blood supply to leg muscles.
  • stroke refers to when the blood supply to part of the brain is cut off.
  • heart failure refers to when the heart has reduced ability to pump blood and can include heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF) and heart failure with mid-range ejection fraction (HFmrEF).
  • HFpEF preserved ejection fraction
  • HFrEF heart failure with reduced ejection fraction
  • HFmrEF heart failure with mid-range ejection fraction
  • coronary heart disease also called coronary artery disease, is a narrowing of the arteries that supply blood to the heart.
  • arrhythmias refers to abnormal heart rhythm and can include atrial arrhythmias, atrial fibrillation, and ventricular arrhythmias
  • neuropathy refers to when nerves are damaged.
  • the term includes peripheral neuropathy, which develops when nerves in the extremities such as hands, feet, and arms are damaged. Diabetes is a common cause of peripheral neuropathy.
  • cardiomyopathies is defined as acquired or congenital structural abnormalities of the atrial or ventricular myocardium that may affect cardiac function, or physiology, and conduction.
  • the pharmaceutical composition or combination provided for herein can be in a unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
  • a compound of the present invention may be administered either simultaneously with, or before, or after one or more other therapeutic agent.
  • a compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • a therapeutic agent is, for example, a chemical compound, peptide, peptide conjugates and fusions, antibody, antibody fragment, or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a subject in combination with a compound of the present invention.
  • a combination in particular a pharmaceutical combination, comprising (e.g., a therapeutically effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof), and one or more other therapeutically active agents.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa
  • a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof), and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof
  • at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease, disorder or condition selected from the afore-mentioned lists, suitably type 2 diabetes, obesity, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure.
  • a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure.
  • Products provided as a combined preparation include a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (Iva), (Ivb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof), and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present invention and the other therapeutic agent(s) in separate form, e.g., in the form of a kit.
  • a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (Iva), (Ivb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof)
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., a compound of any of formula (la), (II), (lia), (III), (Illa), (lllb), (IV), (Iva), (Ivb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof) and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.
  • kits comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit provided for herein typically comprises directions for administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (lia), (III), (Illa), (lllb), (IV), (Iva), (Ivb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof), and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g.
  • kits comprising the compound of compound of formula (I) or a pharmaceutically acceptable salt thereof, and the other therapeutic agent; (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other therapeutic agent.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (lia), (III), (Illa), (lllb), (IV), (Iva), (Ivb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof) in the preparation of medicament for treating a disease, disorder, or condition selected from the afore-mentioned lists, suitably type 2 diabetes, obesity, atherosclerosis, and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the medicament is prepared for administration with another therapeutic agent.
  • a disease, disorder, or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis, and heart failure (in particular, heart failure with preserved ejection fraction), including
  • Another therapeutic agent for treating a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the medicament is administered with a compound of the present invention.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof
  • a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis, and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the compound of formula (I) or a pharmaceutically acceptable slat thereof, is prepared for administration with another therapeutic agent.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Ill
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof), for use in a method of treating a disease, disorder or condition selected from the afore-mentioned lists, suitably type 2 diabetes, obesity, atherosclerosis and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered with another therapeutic agent.
  • a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis and heart failure (in particular, heart failure with
  • Another therapeutic agent for use in a method of treating a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis, and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the other therapeutic agent is administered with a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof
  • a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis, and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the patient has previously (e.g.
  • Another therapeutic agent for treating a disease, disorder or condition selected from the afore-mentioned lists suitably type 2 diabetes, obesity, atherosclerosis, and heart failure (in particular, heart failure with preserved ejection fraction), including where these present as co-morbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the patient has previously (e.g.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof including, e.g., a compound of any of formula (la), (II), (Ila), (III), (Illa), (lllb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmaceutically acceptable salt thereof).
  • the other therapeutic agent is selected from:
  • Antidiabetic agents such as insulin, insulin derivatives and mimetics
  • insulin secretagogues such as the sulfonylureas (e.g., chlorpropamide, tolazamide, acetohexamide, tolbutamide, glyburide, glimepiride, glipizide); glyburide and Amaryl
  • insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide
  • thiazolidinediones e.g., rosiglitazone (A ANDIA), troglitazone (REZULIN), pioglitazone (ACTOS), balaglitazone, rivoglitazone, netoglitazone, troglitazone, englitazone, ciglitazone, adaglitazone, darglitazone that enhance insulin action (e.g., by insulin
  • Hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; bile acid sequenstrants, such as cholestyramine and colesevelam; fibrates; nicotinic acid and aspirin; 3.
  • Anti-obesity agents such as orlistat, rimonabant, phentermine, topiramate, qunexa, and locaserin; GDF15 (such as variants, conjugates, fusions, analogs, mutants and fragments thereof, including other GFRAL modulators, such as NGM386, NGM395); the molecules described in PCT Publications WO2013/148117, W02014/120619 and all related patent family members (including but not limited to US Patent 9,161, 966B1), WO2012/138919,
  • GDF15 conjugates with fatty acids such as the conjugates described in PCT Publications WO2015/200078 and WO2017/109706
  • GDF15 fusions including for example GDF15 fusions with human serum albumin (HSA)
  • HSA human serum albumin
  • Anti-hypertensive agents e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; angiotensin receptor
  • Agonists of peroxisome proliferator-activator receptors such as fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585, L-796449, the compounds specifically described in the patent application WO 2004/103995 i.e. compounds of examples 1 to 35 or compounds specifically listed in claim 21, or the compounds specifically described in the patent application WO 03/043985 i.e.
  • the present invention provides combination therapy with agents and methods for promoting weight loss, such as agents that stimulate metabolism or decrease appetite, and modified diets and/or exercise regimens to promote weight loss.
  • All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
  • Emax efficacy maximum response achievable from a dosed agent
  • GLP1 R glucagon-like peptide 1 receptor
  • HATU (1-[bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate)
  • hGLPIR human glucagon-like peptide 1 receptor
  • MS mass spectrometry m multiplet mg milligram min minutes mL milliliter mM millimolar mmol millimol nM nanomolar m/z mass to charge ratio
  • solvent A 5 mM ammonium hydroxide in water
  • solvent B 5 mM ammonium hydroxide in acetonitrile.
  • solvent A 5 mM ammonium hydroxide in water
  • solvent B 5 mM ammonium hydroxide in acetonitrile
  • UV spectra were recorded at 276.0 nm Lambdamax.
  • Example 1-1 Synthesis of (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1 ,3]dioxol-2- yl)benzonitrile 4-methylbenzenesulfonate (II. B1).
  • the vial was opened and poured into a mixture of 1 N sodium hydroxide (30 mL) and ethyl acetate (75 mL). The mixture was strongly stirred for 10 minutes and then the phases was separated. The organic phase was dried with sodium sulfate and evaporated to dryness under reduced pressure. Purification using the ISCO (5-60% ethyl acetate in heptane gradient) gave the desired 11.1 b (445 mg, 1.02 mmol, 91% yield) as a white solid.
  • Example 1-2 Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4- yl)piperidine hydrochloride (II.A1) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1 , 3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (II. B2).
  • Step 2 Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4-yl)- 3,6-dihydropyridine-1 (2H)-carboxylate (II.3a).
  • Step 3 Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidine-1-carboxylate (II.4a).
  • Step 4 SFC separation of II.6a and II.6b.
  • Step 5a Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidine 4-methylbenzenesulfonate (II. B2).
  • Step 5b Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidine hydrochloride (II.A1).
  • Example 1-3 Synthesis of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-2- yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4-yl)piperidine (I.A1).
  • Step 3 Synthesis of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)- 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1).
  • Example 2 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-5-yl)-5-methyloxazole- 4-carboxylic acid (C-1).
  • Step 2 Synthesis of (S)-5-iodo-4-methyl-1-(oxetan-2-ylmethyl)-1/7-imidazole-2-carbaldehyde
  • Step 3 Synthesis of 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((5- iodo-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1/7-imidazol-2-yl)methyl)piperidine (I.B1).
  • Step 5 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-5-yl)-5-methyloxazole- 4-carboxylic acid (C-1).
  • Compound C-2 was synthesized using same procedures as set forth in Example 2 but using (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1, and ethyl oxazole- 5-carboxylate in step 4.
  • Example 2-2 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4- carboxylic acid (C-3).
  • Compound C-3 was synthesized using same procedures as set forth in Example 2 but using (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1, and ethyl oxazole-4-carboxylate in step 4.
  • Compound C-4 was synthesized using same procedures as set forth in Example 2 but using 5- iodo-4-(trifluoromethyl)-1 H-imidazole in step 1 , and ethyl oxazole-4-carboxylate in step 4.
  • Compound C-5 was synthesized using same procedures as set forth in Example 2 but using 4- ethyl-5-iodo-1 H-imidazole in step 1 , and ethyl oxazole-4-carboxylate in step 4.
  • Compound C-6 was synthesized using same procedures as set forth in Example 2 but using 4- ethyl-5-iodo-1 H-imidazole in step 1 , and ethyl oxazole- 5-carboxylate in step 4.
  • Example 2-6 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1 H- imidazol-5-yl)oxazole-4-carboxylic acid (C-7).
  • Compound C-7 was synthesized using same procedures as set forth in Example 2 but using 4- ethyl-5-iodo-1 H-imidazole and (R)-oxetan-2-yl methyl 4-methylbenzenesulfonate in step 1 , and ethyl oxazole-4-carboxylate in step 4.
  • Example 2-7 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1 H- imidazol-5-yl)oxazole-5-carboxylic acid (C-8).
  • Compound C-8 was synthesized using same procedures as set forth in Example 2 but using 4- ethyl-5-iodo-1 H-imidazole and (R)-oxetan-2-yl methyl 4-methylbenzenesulfonate in step 1 , and ethyl oxazole-5-carboxylate in step 4.
  • Example 2-8 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H- imidazol-5-yl)oxazole-4-carboxylic acid (C-9).
  • Example 2-9 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H- imidazol-5-yl)-5-ethyloxazole-4-carboxylic acid (C-10).
  • Compound C-10 was synthesized using same procedures as set forth in Example 2 but using ethyl 5-ethyloxazole-4-carboxylate in step 4.
  • Example 2-10 Synthesis of 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2- methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H- imidazol-5-yl)-5-methyloxazole-4-carboxylic acid (C-11).
  • Compound C-11 was synthesized using same procedures as set forth in Example 2 but using intermediate II. B1 instead of II.A1 in step 3.
  • Example 3 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5- methyloxazole-4-carboxylic acid (C-12).
  • Step 1 Synthesis of (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (III.5).
  • Intermediate III.5 was synthesized using same procedures as set forth in step 2 of
  • Step 2 Synthesis of 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4-yl)-1-((4- iodo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-2-yl)methyl)piperidine (I.A2).
  • Step 3 Synthesis of ethyl 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-4-yl)-5- m ethyl oxazo I e-4-ca rboxy I ate ( 1.2) .
  • Step 4 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4- yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-4-yl)-5-methyloxazole- 4-carboxylic acid (C-12).
  • Compound C-12 was synthesized using same procedures as set forth in step 5 of Example 2 but using 1.2 instead of 1.1.
  • Example 3-1 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H- imidazol-4-yl)oxazole-4-carboxylic acid (C-13).
  • Compound C-13 was synthesized using same procedures as set forth in Example 3 but using ethyl oxazole-4-carboxylate in step 3.
  • Example 3-2 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2- methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H- imidazol-4-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (C-14).
  • Compound C-15 was synthesized using same procedures as set forth in Example 3 but using ethyl 4-methyloxazole-5-carboxylate in step 3.
  • Example 4 Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-4-yl)oxazole-2- carboxylic acid (C-16).
  • Step 1 Synthesis of ethyl 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-
  • Step 2 Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4- yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-4-yl)oxazole-2-
  • Example 4-1 Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H- pyrazole-5-carboxylic acid
  • Compound C-17 was synthesized using same procedures as set forth in Example 4 but using methyl 1-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-5-carboxylate in step 1.
  • Example 4-2 Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-
  • Example 4-3 Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-3-methylfuran- 2-carboxylic acid (C-19).
  • Example 5 Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2- carboxylic acid (C-20).
  • Step 2 Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-5-yl)oxazole-2-
  • Example 5-1 Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1-methyl-1H- pyrazole-5-carboxylic acid (C-21).
  • Compound C-21 was synthesized using same procedures as set forth in Example 5 but using methyl 1-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-5-carboxylate in step 1.
  • Example 5-2 Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2- carboxylic acid (C-22).
  • Compound C-22 was synthesized using same procedures as set forth in Example 5 but using (5-(ethoxycarbonyl)furan-2-yl)boronic acid in step 1.
  • Example 5-3 Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-5-yl)thiazole-2- carboxylic acid (C-31).
  • Compound C-31 was synthesized using same procedures as set forth in Example 5 but using (2-(ethoxycarbonyl)thiazol-4-yl)boronic acid in step 1 .
  • Example 6 Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-4-yl)nicotinic acid (C-23).
  • Example 7 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin- 1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid (C- 24).
  • Biological Assays and Data Compounds of formula (I) according to the invention were tested in the following cellular assays that measure the intracellular cAMP concentration, beta-arrestin recruitment and receptor internalization.
  • the cAMP is generated by the activation of GLP1 R.
  • the cAMP data obtained is shown in Table 1.
  • Beta-arrestin is recruited upon activation of GLP1 R and the data obtained are shown in Table 2.
  • the extent to which the GLP1 R is internalized into the cell and away from the plasma membrane following activation is also shown in Table 2.
  • EC50 for each assay is defined as the concentration of the compound that leads to half of the maximum response (after baseline correction).
  • E m ax is defined as the maximum response observed for the test compound, normalized to the maximum response observed for the endogenous ligand (GLP1 (7-36)) to GLPI R.
  • the agonist activity of compounds was determined using the GloSensorTM cAMP Assay (Promega Corp.), which measures changes in the intracellular concentration of cAMP after ligand activation of GPCRs.
  • the assay uses a biosensor encoded by pGloSensorTM-22F cAMP plasmid (Promega, cat # E2301) with cAMP binding domains fused to a mutant form of Photinus pyralis luciferase. Binding to cAMP causes conformational changes that promote large increases in light output, which can be measured by a luminescence detector.
  • HEK293-SNAP- hGLPI R-GloSensor cells stably overexpressing the human GLP1 receptor (hGLPI R) and pGloSensorTM-22F were seeded in white 384-well poly-D-Lysine coated plates (Greiner Bio One, cat # 781945) in CO2-independent media (Gibco cat # 18045-088 with 1.0% FBS, 2 mM L- glutamine, penicillin and streptomycin) and incubated overnight at 37 °C, 5% CO2 with humidity.
  • the assay was started the following morning by adding an equal volume of CO2-independent media containing 4% v/v dilution of the GloSensor substrate (Promega, cat # E1291) to all wells.
  • the cell plate was incubated at rt for 2 h in the dark.
  • the Biomek i7 (Beckman Coulter) instrument was used for the liquid handling steps.
  • 3-fold serially diluted compounds were added in to the cell assay plate to a final volume of 60 pL with final concentrations ranging from 30 pM through 0.06 pM in CO2-independent media containing 0.1 % BSA, 0.5 mM IBMX and 0.4% DMSO.
  • cAMP activity was calculated as percent of the GLP1 (7-36) EC100 control wells: [(sample signal - mean ECo signal)/(mean EC100 of GLP1 (7-36) signal - mean ECo signal) ⁇ *100.
  • Curve fitting for EC50 determinations was performed in the Helios module of the software package DAVID.
  • E m ax is the maximal activity detected within the concentration range, derived from the fitted curve.
  • Opti-MEM medium Gabco, cat # 31985-062
  • FuGENE® HD Promega, cat # E2311
  • 8.2 pL (4 pg, 0.485 pg/pL solution) of pSNAP-hGLP1 R plasmid (Cisbio, cat # PSNAP-GLP1) encoding human GLP1 R (NCBI Reference Sequence: NM_002062.3) fused with Cisbio’s SNAP tag was added in to the Fugene HD/Opti-MEM mix, and incubated at rt for 20 min.
  • a suspension of HEK293 cells (ATCC® CRL-1573TM) was prepared at 800,000 cells/mL. Then, the plasmid/FuGene HD mixture was added to 8 mL of cells and mixed gently. 2 mL of the new mix were added to 4 wells in a 6-well plate and 2 mL of un-transfected cells were added to two wells as control. The plate was incubated at 37 °C until 100% confluence. The antibiotic selection [800 pg/mL G418 (Geneticin, Gibco, cat # 10131-035)] was done after cell trypsinization at a dilution of 2500 cells/mL.
  • the HEK293 cells stably overexpressing SNAP-hGLP1 R (described above) were plated at a density of 3 million cells in a 10 cm dish containing 17 mL of DMEM complete growth medium (Gibco, cat # 11965-092) + 10% Fetal Bovine Serum (FBS, Gibco, cat # 16140-071). The following day, cells were transfected as follows.
  • the DNA complex was prepared as 0.020 pg/pL pGloSensorTM-22F cAMP plasmid (Promega, cat # E2301 ; GenBank® accession is GU174434) by adding 37 pg of plasmid DNA in 1758 pL Opti-MEM solution.
  • DiscoverX The extent to which agonists recruited B-arrestin was measured using the PathHunter® B-arrestin assay (DiscoverX). This assay measures binding of B-arrestin to the receptor using an enzyme complementation approach. Two inactive portions of a B-galactosidase enzyme (termed Prolink and Enzyme Acceptor, or ‘EA’) are tagged so that the human GLP1 R (hGLP1 R) contains the Prolink portion and B-arrestin contains the EA portion. When B-arrestin is recruited to the receptor the enzyme becomes active and generates luminescence in the presence of a chemiluminescent substrate (PathHunter® Detection Kit, DiscoverX cat # 93-0001). Luminescence can be measured on a relevant detector.
  • a chemiluminescent substrate PathHunter® Detection Kit, DiscoverX cat # 93-0001
  • CHO-hGLP1 R- -arrestin cells stably overexpressing hGLPI R with Prolink tag and B-arrestin with EA tag were seeded at 20 pL per well in white 384-well poly-D-Lysine coated plates (Greiner Bio One, cat # 781945) in Plating Reagent 2 (DiscoverX, cat # 93-0563R2A), and incubated overnight at 37 °C, 5% CO2 with humidity. The following day, agonists were prepared at 5 times the final required concentration.
  • compounds were serially diluted 3-fold in assay buffer (HBSS, 10 mM Hepes and 0.1% BSA), then added to the cell assay plate to a final volume of 25 pL and final top concentrations starting at 30 pM.
  • assay buffer HBSS, 10 mM Hepes and 0.1% BSA
  • EC100 control wells containing GLP1 (7-36) peptide Bachem, cat # H-6795
  • the plate was incubated at 37 °C, 5% CO2 with humidity for 2 h after adding the compounds to the cells.
  • the detection reagent was prepared (19 parts cell assay buffer, 5 parts substrate reagent 1 and 1 part substrate reagent 2 as per manufacturers recommendations, DiscoverX cat # 93-0001), and 12 pL were added per well to the cell assay plate. The plate was incubated for an additional hour in the dark at RT. Luminescence was then measured with an Envision 2104 Multilabel reader with “TRF Light Unit, 337 nm” (Perkin Elmer) using the Ultra-Sensitive protocol setting “384-well US luminescence detector” with the 384-well luminescence aperture, 0.1 sec per well.
  • B-arrestin recruitment was calculated and expressed as percent of the GLP1 (7-36) EC100 control wells: [(sample signal - mean ECo signal)/(mean EC100 of GLP1 (7-36) signal - mean ECo signal)]*100 using Microsoft Excel. Curve fitting for EC50 determinations was performed using GraphPad Prism.
  • Y Bottom + (Top-Bottom)/(1+10 A ((Log ECso-X)*Hill Slope)), where Y is the functional response; X is the compound concentration; bottom is A o or the minimum value (at 0 dose); top is Amf orthe maximum value (at infinite dose); EC50 is the point of inflection (i.e. the point on the sigmoid shaped curve halfway between Ao and Amf). The EC50 value was calculated in pM. Emax is the maximal activity detected within the concentration range, derived from the fitted curve relative to GLP1(7-36).
  • the reference compound is 2-((4-((S)-2-(4-chloro-2- fluorophenyl)-2-methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)- 1 H-benzo[d]imidazole-6-carboxylic acid (WO 2019/239319, Example 7) Generation of CHO-hGLP1R-B-arrestin cell line
  • PathHunter CHO-K1-EA parental cells (DiscoverX, cat # 93-0164) were plated at a density of 2 X 10 6 cells per T75 cm 2 flask in 22 mL of complete medium (AssayComplete Cell Culture kit 107, DiscoverX, cat # 92-3107G). The following day, the medium was replaced with 22 mL of fresh medium with no antibiotics and cells were transfected as follows. Plasmid/Fugene® HD Transfection mix was prepared in Opti-MEM media (3:1 Ratio of Reagent:DNA).
  • the extent to which agonists internalize the human GLP1 R was determined based on an optimized version of a RealTime FRET-based ‘DERET’ (Dissociation Enhanced Resonance Energy Transfer) assay.
  • the technology relies on labeling of the SNAP-tagged GPCR with a SNAP-Lumi-Terbium (donor fluorophore, Cisbio, cat # SSNPTBD).
  • donor fluorophore Cisbio, cat # SSNPTBD
  • the compounds are incubated with the cells over-expressing the GPCR of interest in the presence of an excess of fluorescein (acceptor fluorophore).
  • acceptor fluorophore fluorescein
  • the donor signal is quenched by the acceptor and the donor/acceptor ratio is low.
  • the acceptor is no longer excited so the donor/acceptor ratio increases.
  • HEK293-SNAP-hGLP1 R-GloSensor cells (stably overexpressing SNAP-tagged hGLPIR) were seeded overnight in white 384-well poly-D-Lysine coated plates (Greiner Bio One, cat # 781945) in regular DMEM growth medium (Gibco, cat # 11965-092, 10% heat- inactivated FBS, 10 mM HEPES, 1x penicillin/streptomycin, 0.5 mg/mL geneticin (Gibco, cat # 10131-035) and 0.25 mg/mL hygromycin B (Invitrogen, cat # 10687010).
  • regular DMEM growth medium Gibco, cat # 11965-092, 10% heat- inactivated FBS, 10 mM HEPES, 1x penicillin/streptomycin, 0.5 mg/mL geneticin (Gibco, cat # 10131-035) and 0.25 mg/mL hygromycin B (Invitrogen
  • the plate FRET fluorescence was measured immediately using a Perkin Elmer Envision with LANCE/DELFIA D400 single mirror, excitation filter X320, and emission filters M615_203 (donor emission) and M515 (acceptor emission), and then measured every 30 min. Peak Internalization was reached at 120 min. Plates were kept at 37°C between reads. Data was expressed as the ratio of donor/acceptor emissions using Microsoft Excel and plotted in GraphPad Prism.
  • Y Bottom + (Top-Bottom)/(1+10 A ((Log EC 5 o-X)*Hill Slope)), where Y is the functional response; X is the compound concentration; bottom is A o or the minimum value (at 0 dose); top is A in fOrthe maximum value (at infinite dose); EC50 is the point of inflection (i.e. the point on the sigmoid shaped curve halfway between Ao and Amf). The EC50 value was calculated in pM.
  • E m ax is the maximal activity that was measured within the concentration range, derived from the fitted curve relative to GLP1 (7-36).

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EP23705679.1A 2022-02-10 2023-02-10 2-((4-((s)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((s)-oxetan-2-yl)methyl)-1h-imidazole derivatives as activators of the glp1 receptor for the treatment of obesity Pending EP4476212A1 (en)

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