EP4619098A1 - Glucagon-like peptide 1 receptor agonists - Google Patents

Glucagon-like peptide 1 receptor agonists

Info

Publication number
EP4619098A1
EP4619098A1 EP23828849.2A EP23828849A EP4619098A1 EP 4619098 A1 EP4619098 A1 EP 4619098A1 EP 23828849 A EP23828849 A EP 23828849A EP 4619098 A1 EP4619098 A1 EP 4619098A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
acceptable salt
methoxy
methyl
compound
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
EP23828849.2A
Other languages
German (de)
French (fr)
Inventor
Qi Chen
Todd Fields
Pushkar Gajendra GHANEKAR
Jared Thomas HAMMILL
Eric Michael Woerly
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP4619098A1 publication Critical patent/EP4619098A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • 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
    • A61P3/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to glucagon-like peptide-1 receptor agonists and therapeutic uses of the compounds to treat type II diabetes mellitus.
  • Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose dependent manner. However, GLP-1 is rapidly metabolized so that only a small percentage of the GLP-1 can be utilized to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes mellitus.
  • GLP-1R GLP-1 receptor
  • GLP-1R agonists that have been approved to treat type II diabetes mellitus are injectable agents. Patients often prefer orally administered drugs because of the drawbacks associated with injection such as inconvenience, pain, and the potential for injection site irritation.
  • W02018/109607 discloses certain benzimidazole derivatives, which are described as GLP-1R agonists. Further GLP-1 agonist compounds are disclosed in WO20 19/239371, WO2019/239319, W02020/103815, W02020/207474, WO2020/263695, W02021/018023, W02021/081207, WO2021/096284, W02021/096304, WO2021/112538, WO2021/154796, W02021/160127, WO2021/187886, WO2021/197464, CN113480534, CN113493447, W02021/219019, WO202 1/244645, WO2021/249492, CN113801136, CN113816948, WO2021/254470, WO2021/259309, W02022/007979, WO2022/031994, WO2022/028572, W02022/040600, WO2022/042691, WO2022/
  • GLP-1R agonists there is a need for alternative GLP-1R agonists.
  • GLP-1R agonists which can be administered orally.
  • GLP-1R agonists which can be administered orally.
  • GLP-1R agonists which are more potent small molecule GLP-1R agonists.
  • GLP-1R agonists which are more potent and may be effective at a lower dose.
  • Compounds disclosed herein have GLP-1R agonist activity. Certain compounds of the present invention have comparable in-vitro potency at the GLP-1 receptor to native GLP-1(7-36)NH 2 .
  • the present invention provides a compound of the formula: wherein is phenyl, a 5 or 6-membered heteroaryl or pyridone, which phenyl, heteroaryl or pyridone is optionally substituted with one or two R 1 ;
  • R 1 at each occurrence is independently CN; halo; Ci-C 3 alkyl optionally substituted with OH; Ci-C 3 haloalkyl; Ci-C 3 alkoxy; C 3 -C 5 cycloalkyl; -SO 2 Ci-C 3 alkyl; -C(O)NH 2 ; wherein each X 9 is independently CH or N and no more than one X 9 in the ring is N, each R e is independently selected from: H, Ci-C 3 haloalkyl, halo, C 3 -Cscycloalkyl and Ci-C 3 alkyl optionally substituted with OH, R h is H, Ci-C 3 haloalkyl, halo, C 3 -Cscycloalkyl, OH, -NR c R d or Ci-C 3 alkyl optionally substituted with OH;
  • heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from: Ci-C 3 alkoxy, C 3 - Cscycloalkyl, -CH 2 -C 3 -C5cycloalkyl, -SO 2 Ci-C 3 alkyl, C ⁇ Csheterocyclyl, -CH 2 -C4- Csheterocyclyl, halo, Ci-C 3 haloalkyl, Ci-C 3 haloalkoxy, CN, -CONR c R d , -NR c R d or Ci- C 3 alkyl optionally substituted with OH; -A- is -CH2O-, -OCH2- or -CH2NH-;
  • Y 1 , Y 2 , Y 7 and Y 8 are independently N, CH or CR 2 , wherein no more than one of Y 1 , Y 2 , Y 7 and Y 8 is N and no more than two of Y 1 , Y 2 , Y 7 and Y 8 is CR 2 ;
  • Y 3 , Y 4 , Y 5 and Y 6 are independently N, CH or CR 2 , wherein no more than two of Y 3 , Y 4 , Y 5 and Y 6 are N and no more than two of Y 3 , Y 4 , Y 5 and Y 6 are CR 2 ;
  • R 2 at each occurrence is independently halo or methyl
  • R 3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy, hydroxy or Ci-Cshaloalkyl;
  • R c and R d are each independently H or Ci-Csalkyl; or a pharmaceutically acceptable salt thereof.
  • Formula I includes all individual enantiomers, and mixtures thereof, as well as racemates.
  • is pyridine optionally substituted with one is pyridine substituted with one or two R 1 independently selected from CN, Ci-Csalkyl, halo, or -C(O)NH2.
  • R 1 selected from: CN and Ci-Csalkyl.
  • membered heteroaryl selected from: pyrazole, isoxazole, tetrazole, triazole or thiophene optionally substituted with one R 1 selected from: CN and CH3.
  • -A- is -CH2O-.
  • Y 3 is N.
  • Y 4 is CH.
  • Y 5 is CH.
  • Y 6 is CH.
  • Y 3 is N; and Y 4 , Y 5 and Y 6 are CH.
  • Y 1 is CR 2 .
  • Y 2 is CH.
  • Y 7 is CR 2 .
  • Y 8 is CH.
  • R 2 is F or methyl.
  • Y 1 and Y 7 are CR 2 and Y 2 and Y 8 are CH. In a further embodiment, Y 1 and Y 7 are CR 2 ; Y 2 and Y 8 are CH; and R 2 is independently F or methyl.
  • Y 1 is CHs) or C(F); Y 7 is C(F); Y 2 and Y 8 are CH.
  • Y 1 is CHs).
  • R 3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy.
  • R 3 is -OCH3, or -OCH2CH2OCH3.
  • R 3 is -OCH3.
  • R 5 is -CO2H.
  • R 1 is CN, halo, Ci-Csalkyl, Ci-Csalkoxy, -C(0)NH2 or 5-membered heteroaryl;
  • R 2 at each occurrence is independently halo or methyl
  • R 3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 2 is F or CH3
  • R 3 is -OCH3, or -OCH2CH2OCH3, or a pharmaceutically acceptable salt thereof.
  • R 3 is -OCH3.
  • linker A the left hand terminal group as written is attached to the X ring and the right hand terminal group is attached to the Y 3 containing ring.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • Ci-C n alkyl refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms.
  • Examples of a Ci-C4alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl.
  • Examples of a Ci-Csalkyl group include, but are not limited to, methyl, ethyl and propyl.
  • a Ci-C2alkyl group is methyl or ethyl.
  • Ci-C n haloalkyl refers to a Ci-C n alkyl group, as defined herein, which is substituted with one, or more halogen.
  • Ci-Cshaloalkyl groups include, but are not limited to, trifluorom ethyl, difluorom ethyl and pentafluoroethyl.
  • Ci-C n alkoxy refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms linked through an oxygen atom, i.e., - O(alkyl).
  • Examples of Ci-C4alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
  • Ci-C n haloalkoxy refers to a Ci-C n alkoxy group, as defined herein, which is substituted with one, or more halogen.
  • Ci-Cshaloalkoxy groups include, but are not limited to, trifluoromethoxy, difluorom ethoxy and pentafluoroethoxy.
  • Cs-Cscycloalkyl refers to a monocyclic saturated carbon ring containing between 3 and 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl or cyclopentyl.
  • heteroaryl refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from: N, S and O. Examples of 5-membered heteroaryls include, but are not limited to, pyrazole, triazole and thiazole. Examples of 6- membered heteroaryls include, but are not limited to, pyridine and pyridazine.
  • C ⁇ Csheterocyclyl refers to a 4 or 5 membered monocyclic saturated ring containing one or more heteroatoms, for example, oxetane.
  • Formula I encompasses Formulae II, Ila, lib, III, Illa, Illb, IV, IVa and IVb reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to each and all of these sub-formulae.
  • a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutically acceptable composition is formulated for oral administration.
  • a method of treating a patient for type II diabetes mellitus comprises administering to the patient in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutically acceptable composition is formulated for oral administration.
  • the patient is a human.
  • a method of treating a patient for type II diabetes mellitus comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of lowering blood glucose levels in a patient comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of treating hyperglycemia in a patient comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of treating obesity in a mammal comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of treating nonalcoholic steatohepatitis (NASH) in a patient comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a compound of Formula I for use in the treatment of type II diabetes mellitus.
  • a compound of Formula I for use in lowering blood glucose levels.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes mellitus.
  • a compound of Formula I for the manufacture of a medicament for the treatment of hyperglycemia.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of obesity.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes mellitus.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating hyperglycemia.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating obesity.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating NASH.
  • the compounds of Formula I may be used in simultaneous, separate, or sequential combination with one or more therapeutic agents.
  • additional therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, and ketohexokinase inhibitors.
  • the compound of Formula I is administered orally. In a preferred embodiment, the compound of Formula I is administered once daily. In another preferred embodiment, the therapeutic use is in a human.
  • pharmaceutically acceptable salt refers a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use.
  • pharmaceutically acceptable salts and common methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts” , Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
  • the term “effective amount” refers to the amount or dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.
  • the attending physician can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-admini strati on of other agents, if used; the size, age, and general health of the patient; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances.
  • the compounds of the present invention are effective at a dosage per day that falls within the range of about 0.01 to about 15 mg/kg of body weight.
  • treating refers to lowering, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, such as hyperglycemia, which can include increasing insulin secretion.
  • the term “patient” includes mammals.
  • the patient is preferably human.
  • the compounds of Formula I can be formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable.
  • such compositions are for oral administration.
  • the pharmaceutical compositions are formulated as a tablet, capsule, or a solution.
  • the tablet, capsule, or solution can include a compound of Formula I in an amount effective for treating a patient in need of treatment.
  • Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., “Remington: The Science and Practice of Pharmacy”, A. Adejare Editor, 23 rd Ed., 2020, Elsevier Science).
  • Compounds of the present invention include:
  • a pharmaceutically acceptable salt of the compounds of the invention can be formed, for example, by reaction of a compound of Formula I and an appropriate pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R.J., et aE, Org. Process. Res. Dev., 4, 427- 435, 2000 and Berge, S.M., et al., ' J. Pharm. Se , 66, 1-19, 1977).
  • the compounds of the present invention may be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof.
  • the product of each step below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers may be separated or resolved at any convenient point in the synthesis, by methods such as, selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et a!..
  • Scheme 1 shows two routes used to prepare intermediate 7, which is used to prepare compounds of the present invention.
  • aryl difluoride 1 undergoes SxAr with amine 2 using a carbonate base at elevated temperature to give intermediate 3, which then undergoes a second SxAr with the sodium alkoxide of alcohol 4 to give intermediate 5.
  • these two steps are performed in the opposite order to give intermediate 5.
  • the nitro group of intermediate 5 is then reduced to diamine intermediate 7 using a palladium catalyst and hydrogen gas.
  • Scheme 2 shows the preparation of compound 14 beginning with coupling of acid intermediate 8 and amino intermediate 7 using T3P and an organic base to give amide intermediate 9.
  • Intermediate 9 is cyclized using acetic acid at elevated temperature to give benzimidazole intermediate 10, which then undergoes Suzuki coupling with boronic ester 11 using a palladium catalyst and a carbonate base at elevated temperature to give intermediate 12.
  • Alkylation with alkyl bromide 13 and a carbonate base at elevated temperature then gives compound 14.
  • reaction of intermediate 12 and alcohol 16 under Mitsunobu conditions diisopropyl azodi carb oxy late and triphenylphosphine gives compound 14 (a compound of Formula I wherein A is -CH2O-).
  • Scheme 3 shows the preparation of compound 14 beginning with coupling of acid intermediate 8 and amino intermediate 7 using T3P and an organic base to give amide intermediate 9.
  • Intermediate 9 is cyclized using acetic acid at elevated temperature to give benzimidazole intermediate 10, which then undergoes Suzuki coupling with boronic
  • Scheme 3 shows the preparation of compound 19 beginning with conversion of aryl bromide 10 to boronic ester 15 using bis(pinacolato)diboron, potassium acetate, and a palladium catalyst at elevated temperature.
  • alcohol 16 undergoes a nucleophilic aromatic substitution (SxAr) reaction with 2-bromo-6-fluoropyridine 17 using an alkoxide base at elevated temperature to give intermediate 18.
  • SxAr nucleophilic aromatic substitution
  • Intermediates 15 and 18 are then coupled using a palladium catalyst, potassium acetate, and elevated temperature to give compound 19 (a compound of Formula I wherein A is -CH2O-; Y 3 is N and Y 4 , Y 5 and Y 6 are CH).
  • Scheme 4 shows the preparation of compounds of Formula I starting with acid intermediate 20, which is coupled with aniline intermediate 7 using amide coupling conditions e.g. HATU and an amine base to give amide 21. Amide 21 is then cyclized using acetic acid at elevated temperature to give the compound of Formula I.
  • amide coupling conditions e.g. HATU and an amine base
  • Amide 21 is then cyclized using acetic acid at elevated temperature to give the compound of Formula I.
  • the title compound was prepared essentially as described in Example 3 using 5- (bromomethyl)pyridine-2-carbonitrile and purifying by reversed phase chromatography on a C18 column using a gradient of 23 to 58% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH followed by SFC purification on a Chiralpak® AS-H column with 40% IPA in CO2. ES/MS m/z 598 (M+H).
  • Example 6 2-[[4-[6-[(6-Cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6a) and 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6b)
  • a mixture of ACN (0.6 mL), 1,4-dioxane (0.6 mL), water (0.2 mL), and 1,5,7- triazabicyclo[4.4.0]dec-5-ene (65 mg, 0.46 mmol) was sparged for 10 min and transferred to a reaction vessel containing methyl 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2- pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (47 mg, 0.08 mmol).
  • reaction mixture was stirred at 55 °C for 2 h. After 2 h, the reaction mixture was transferred to a separatory funnel containing EtOAc, washed with 10% aqueous citric acid solution, saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography on a C18 column using a gradient of 0-100% ACN: 10 mM aqueous formic acid. Fractions containing the title compound were concentrated under reduced pressure to remove volatile organic solvents, then the remaining aqueous layer was acidified with 0.1 N aqueous hydrochloric acid and extracted three times with EtOAc.
  • the reaction was stirred at RT for 16 h, then diluted with EtOAc and 0.1 M aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography on a C18 column using a gradient of 0-100% ACN with 0.1% formic acid:0.1% formic acid in water. Fractions containing the desired product were concentrated under reduced pressure to remove volatile organic solvents. The remaining aqueous layer was extracted three times with EtOAc.
  • the hGLP-lR receptor expressing cells are treated with compound (20 point concentration-response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384 well plate Corning Cat# 3570) in DMEM (Gibco Cat# 31053) supplemented with IX GlutaMAXTM (Gibco Cat# 35050), 0.1% bovine casein (Sigma C4765-10ML), 250 pM IB MX (3 -Isobutyl- 1 -methylxanthine, Acros Cat# 228420010) and 20 mM HEPES (Gibco Cat# 15630) in a 20 pL assay volume (final DMSO concentration is 0.5%).
  • cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 pL) followed by the antibody anti-cAMP-Eu 3+ -Cryptate, also in cell lysis buffer (10 pL).
  • the resulting competitive assay is incubated for at least 60 min at RT, then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm.
  • Envision units (emission at 665nm/620nm* 10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve.
  • the amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed with human GLP-1(7-36)NH2.
  • a relative ECso value and percent top (E ma x) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation.
  • the ECso and Emax data when the compounds of Examples 1 to 14 are tested in the cAMP assay described above using HEK293 cells expressing 581 and 104 fmol/mg GLP-1R are shown in Tables 1 and 2, respectively. These data indicate that the compounds of Examples 1 to 14 are agonists of the human GLP-1 receptor.
  • the compounds of Examples 1, 2, 5 and 13 show comparable potency in the 104 fmol/mg assay to the native GLP-1(7-36)NH2 peptide.
  • HEK293 cell line with 104 fmol/mg expression density of GLP-1R, intracellular cAMP response, relative ECso, % Stim Max and Emax EC50, nM geometric mean of the concentration producing one-half of the maximal stimulation (one-half of the Emax), followed by SEM (delta method) and the number of observations in parentheses.
  • % Stim Max arithmetic mean of the percent stimulation by the point giving maximal stimulation in the concentration-response curve relative to the maximal response produced by GLP-1(7-36)NH 2 , followed by the SEM and the number of observations in parentheses.
  • Emax, % arithmetic mean of the fitted top of the concentration-response curve relative to the percent of maximal response to GLP-1(7-36)NH2 ⁇ SEM.
  • mice expressing the human GLP-1R NCBI accession number NP 002053 from the mouse Glp-lr genetic locus (Jun, L.S., et al., PLoS One. 2014 9:e93746).
  • mice expressing the human GLP-1R NCBI accession number NP 002053 from the mouse Glp-lr genetic locus (Jun, L.S., et al., PLoS One. 2014 9:e93746).
  • Overnight fasted mice are orally administered the test compound solubilized inlO% Kolliphor® (HS15) in Polyetheylene Glycol 400 (PEG400).
  • the animals are administered glucose by intraperitoneal injection (2 g/kg), and blood glucose levels are measured intermittingly over the next two hours using glucometers.
  • a dose range of the test compound is delivered, and area under the curve calculations for each dose group are determined and fit to a four-parameter logistic model for calculating in vivo potency as an ED50 with a 95% confidence interval.
  • the compound of Example 1 exhibits potency to lower the concentration of blood glucose in mice expressing the human GLP-1R with the ED50 (and 95% confidence interval) value as shown in Table 3, which indicates that this compound is an orally available potent GLP- 1R agonist in mice.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

In an embodiment, the present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof, and methods of using this compound for treating type II diabetes mellitus.

Description

GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS
This invention relates to glucagon-like peptide-1 receptor agonists and therapeutic uses of the compounds to treat type II diabetes mellitus.
Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose dependent manner. However, GLP-1 is rapidly metabolized so that only a small percentage of the GLP-1 can be utilized to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes mellitus.
The majority of GLP-1R agonists that have been approved to treat type II diabetes mellitus are injectable agents. Patients often prefer orally administered drugs because of the drawbacks associated with injection such as inconvenience, pain, and the potential for injection site irritation.
W02018/109607 discloses certain benzimidazole derivatives, which are described as GLP-1R agonists. Further GLP-1 agonist compounds are disclosed in WO20 19/239371, WO2019/239319, W02020/103815, W02020/207474, WO2020/263695, W02021/018023, W02021/081207, WO2021/096284, W02021/096304, WO2021/112538, WO2021/154796, W02021/160127, WO2021/187886, WO2021/197464, CN113480534, CN113493447, W02021/219019, WO202 1/244645, WO2021/249492, CN113801136, CN113816948, WO2021/254470, WO2021/259309, W02022/007979, WO2022/031994, WO2022/028572, W02022/040600, WO2022/042691, WO2022/068772, W02022/078407, W02022/078380, WO2022/078152, CN114478497, WO2022/109182, WO2022/111624, CN114591296, WO2022/116693, WO2022/135572, CN114634510, CN114716423, CN114763352, CN114805336, WO2022/165076, CN114907351, WO2022/184849, WO2022/192428, WO2022/192430, WO2022/202864, WO2022/199458, WO2022/199661, WO2022/216094, WO2022/219495, WO2022/225914, WO2022/225941, WO2022/228490 and WO2022/235717.
However, there is a need for alternative GLP-1R agonists. In particular, there is a need for GLP-1R agonists which can be administered orally. There is furthermore a need for more potent small molecule GLP-1R agonists. There is especially a need for GLP-1R agonists which are more potent and may be effective at a lower dose.
Compounds disclosed herein have GLP-1R agonist activity. Certain compounds of the present invention have comparable in-vitro potency at the GLP-1 receptor to native GLP-1(7-36)NH2.
Accordingly, the present invention provides a compound of the formula: wherein is phenyl, a 5 or 6-membered heteroaryl or pyridone, which phenyl, heteroaryl or pyridone is optionally substituted with one or two R1;
R1 at each occurrence is independently CN; halo; Ci-C3alkyl optionally substituted with OH; Ci-C3haloalkyl; Ci-C3alkoxy; C3-C5cycloalkyl; -SO2Ci-C3alkyl; -C(O)NH2; wherein each X9 is independently CH or N and no more than one X9 in the ring is N, each Re is independently selected from: H, Ci-C3haloalkyl, halo, C3-Cscycloalkyl and Ci-C3alkyl optionally substituted with OH, Rh is H, Ci-C3haloalkyl, halo, C3-Cscycloalkyl, OH, -NRcRd or Ci-C3alkyl optionally substituted with OH;
5- or 6- membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from: Ci-C3alkoxy, C3- Cscycloalkyl, -CH2-C3-C5cycloalkyl, -SO2Ci-C3alkyl, C^Csheterocyclyl, -CH2-C4- Csheterocyclyl, halo, Ci-C3haloalkyl, Ci-C3haloalkoxy, CN, -CONRcRd, -NRcRd or Ci- C3alkyl optionally substituted with OH; -A- is -CH2O-, -OCH2- or -CH2NH-;
Y1, Y2, Y7 and Y8 are independently N, CH or CR2, wherein no more than one of Y1, Y2, Y7 and Y8 is N and no more than two of Y1, Y2, Y7 and Y8 is CR2;
Y3, Y4, Y5 and Y6 are independently N, CH or CR2, wherein no more than two of Y3, Y4, Y5 and Y6 are N and no more than two of Y3, Y4, Y5 and Y6 are CR2;
R2 at each occurrence is independently halo or methyl;
R3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy, hydroxy or Ci-Cshaloalkyl;
Rc and Rd are each independently H or Ci-Csalkyl; or a pharmaceutically acceptable salt thereof.
Formula I includes all individual enantiomers, and mixtures thereof, as well as racemates.
In an embodiment, there is provided a compound of the formula:
Formula II or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
Formula Ila or a pharmaceutically acceptable salt thereof.
In an embodiment, is phenyl optionally substituted with one or two R1.
In a particular embodiment, is phenyl substituted with one or two R1 independently selected from CN, halo, Ci-Csalkyl, Ci-Csalkoxy or 5-membered heteroaryl. In a particular embodiment, is phenyl substituted with one or two R1 independently selected from CN, F, CH3, OCH3 or triazole. In a further embodiment, is phenyl substituted with one or two R1 independently selected from CN, F or
OCH3. In yet a further embodiment, is phenyl substituted with CN and F or phenyl substituted with CN and OCH3, preferably phenyl substituted with CN and F.
In an alternate embodiment, is pyridine optionally substituted with one is pyridine substituted with one or two R1 independently selected from CN, Ci-Csalkyl, halo, or -C(O)NH2. In a particular embodiment, is pyridine substituted with one or two R1 independently selected from CN, CH3 or -C(O)NH2. In a further alternate embodiment, is pyridone optionally substituted with one or two R1. In a particular embodiment, is pyridone substituted with one R1 which is Ci-Csalkyl.
In a further alternate embodiment, is a 5-membered heteroaryl selected from: pyrazole, isoxazole, tetrazole, triazole or thiophene optionally substituted with one or two R1. In a particular embodiment, is a 5-membered heteroaryl selected from: pyrazole, isoxazole, tetrazole, triazole or thiophene optionally substituted with one
R1 selected from: CN and Ci-Csalkyl. In a particular embodiment, membered heteroaryl selected from: pyrazole, isoxazole, tetrazole, triazole or thiophene optionally substituted with one R1 selected from: CN and CH3.
In an embodiment, -A- is -CH2O-.
In an embodiment, Y3 is N.
In an embodiment, Y4 is CH.
In an embodiment, Y5 is CH.
In an embodiment, Y6 is CH.
In an embodiment, Y3 is N; and Y4, Y5 and Y6 are CH.
In an embodiment, Y1 is CR2.
In an embodiment, Y2 is CH.
In an embodiment, Y7 is CR2.
In an embodiment, Y8 is CH.
In an embodiment, R2 is F or methyl.
In an embodiment, Y1 and Y7 are CR2 and Y2 and Y8 are CH. In a further embodiment, Y1 and Y7 are CR2; Y2 and Y8 are CH; and R2 is independently F or methyl.
In yet a further embodiment, Y1 is CHs) or C(F); Y7 is C(F); Y2 and Y8 are CH. Preferably, Y1 is CHs). In an embodiment, R3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy. In a further embodiment, R3 is -OCH3, or -OCH2CH2OCH3. Preferably, R3 is -OCH3.
In an embodiment, R5 is -CO2H.
In an embodiment, there is provided a compound of the formula: wherein is phenyl, a 5 or 6-membered heteroaryl or pyridone, which phenyl, heteroaryl or pyridone is optionally substituted with one or two R1;
R1 is CN, halo, Ci-Csalkyl, Ci-Csalkoxy, -C(0)NH2 or 5-membered heteroaryl;
R2 at each occurrence is independently halo or methyl;
R3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy; or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula: wherein R1 is F or OCH3;
R2 is F or CH3; and
R3 is -OCH3, or -OCH2CH2OCH3, or a pharmaceutically acceptable salt thereof.
In an embodiment, in a compound of Formula IV R3 is -OCH3.
In an embodiment, there is provided a compound selected from: 2-[[4-[6-[(4-Cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l-
(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((5-Cyanopyridin-2-yl)methoxy )pyri din-2 -yl)-2, 5-difluorobenzyl)-4-methoxy-l -
(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((6-Cyanopyridin-3-yl)methoxy )pyri din-2 -yl)-2, 5-difluorobenzyl)-4-methoxy-l -
(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2- methoxyethoxy)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-[[4-[6-[(6-Cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-[[2,5-Difluoro-4-[6-[(l-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-
(2 -methoxy ethoxy)-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-(4-(6-((5-cy anothi ophen-2 -yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l-
(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-cyano-2-methylbenzyl)oxy)pyri din-2 -yl)-2, 5-difluorobenzyl)-4-methoxy-l -
(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-((2-methyl-2H-l,2,3-triazol-4-yl)methoxy)pyridin-2-yl)benzyl)-4- methoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-(lH-l,2,4-triazol-l-yl)benzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4- m ethoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-(isoxazol-3-ylmethoxy)pyri din-2 -yl)benzyl)-4-m ethoxy- 1 -(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l-
(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-((l -methyl- lH-pyrazol-3-yl)methoxy)pyridin-2-yl)benzyl)-4- methoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-((2-methyl-2H-tetrazol-5-yl)methoxy)pyridin-2-yl)benzyl)-4- m ethoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid; or a pharmaceutically acceptable salt thereof.
In a further embodiment, there is provided a compound selected from: 2-[[4-[6-[(4-Cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid; 2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2- methoxyethoxy)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; 2-(4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; or a pharmaceutically acceptable salt thereof.
In linker A, the left hand terminal group as written is attached to the X ring and the right hand terminal group is attached to the Y3 containing ring.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.
The term “Ci-Cnalkyl” refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of a Ci-C4alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of a Ci-Csalkyl group include, but are not limited to, methyl, ethyl and propyl. A Ci-C2alkyl group is methyl or ethyl.
The term “Ci-Cnhaloalkyl” refers to a Ci-Cnalkyl group, as defined herein, which is substituted with one, or more halogen. Examples of Ci-Cshaloalkyl groups include, but are not limited to, trifluorom ethyl, difluorom ethyl and pentafluoroethyl.
The term “Ci-Cnalkoxy” refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms linked through an oxygen atom, i.e., - O(alkyl). Examples of Ci-C4alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
The term “Ci-Cnhaloalkoxy” refers to a Ci-Cnalkoxy group, as defined herein, which is substituted with one, or more halogen. Examples of Ci-Cshaloalkoxy groups include, but are not limited to, trifluoromethoxy, difluorom ethoxy and pentafluoroethoxy.
The term “Cs-Cscycloalkyl” refers to a monocyclic saturated carbon ring containing between 3 and 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl or cyclopentyl. The term “heteroaryl” refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from: N, S and O. Examples of 5-membered heteroaryls include, but are not limited to, pyrazole, triazole and thiazole. Examples of 6- membered heteroaryls include, but are not limited to, pyridine and pyridazine.
The term “C^Csheterocyclyl” refers to a 4 or 5 membered monocyclic saturated ring containing one or more heteroatoms, for example, oxetane.
Formula I encompasses Formulae II, Ila, lib, III, Illa, Illb, IV, IVa and IVb reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to each and all of these sub-formulae.
In another embodiment, there is provided a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient. In a preferred embodiment, the pharmaceutically acceptable composition is formulated for oral administration.
In another embodiment, there is provided a method of treating a patient for type II diabetes mellitus, the method comprises administering to the patient in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutically acceptable composition is formulated for oral administration.
Preferably, the patient is a human.
In another embodiment, there is provided a method of treating a patient for type II diabetes mellitus, the method comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, there is provided a method of lowering blood glucose levels in a patient, the method comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, there is provided a method of treating hyperglycemia in a patient, the method comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, there is provided a method of treating obesity in a mammal, the method comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, there is provided a method of treating nonalcoholic steatohepatitis (NASH) in a patient, the method comprises administering to the patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.
In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes mellitus.
In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.
In another embodiment, there is also provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating hyperglycemia.
In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating obesity.
In another embodiment, there is also provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating NASH.
In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes mellitus.
In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for lowering blood glucose levels.
In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hyperglycemia. In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of obesity.
In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of NASH.
In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes mellitus.
In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.
In another embodiment, there is also provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating hyperglycemia.
In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating obesity.
In another embodiment, there is also provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating NASH.
The compounds of Formula I may be used in simultaneous, separate, or sequential combination with one or more therapeutic agents. Examples of additional therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, and ketohexokinase inhibitors.
In a preferred embodiment, the compound of Formula I is administered orally. In a preferred embodiment, the compound of Formula I is administered once daily. In another preferred embodiment, the therapeutic use is in a human.
The term “pharmaceutically acceptable salt” as used herein refers a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts" , Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
The term “effective amount” refers to the amount or dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. The attending physician, as one skilled in the art, can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-admini strati on of other agents, if used; the size, age, and general health of the patient; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances. The compounds of the present invention are effective at a dosage per day that falls within the range of about 0.01 to about 15 mg/kg of body weight.
As used herein, the terms “treating”, “to treat”, or “treatment”, refers to lowering, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, such as hyperglycemia, which can include increasing insulin secretion.
As used herein, the term “patient” includes mammals. The patient is preferably human.
The compounds of Formula I can be formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable. Preferably, such compositions are for oral administration. Preferably the pharmaceutical compositions are formulated as a tablet, capsule, or a solution. The tablet, capsule, or solution can include a compound of Formula I in an amount effective for treating a patient in need of treatment. Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., “Remington: The Science and Practice of Pharmacy”, A. Adejare Editor, 23rd Ed., 2020, Elsevier Science).
The compounds of Formula I and the pharmaceutically acceptable salts thereof are useful in the therapeutic uses of the invention, with certain configurations being preferred.
Compounds of the present invention include:
Formula Illa,
Formula IVa,
Formula IVb, or pharmaceutically acceptable salts thereof.
Although the present invention contemplates all individual enantiomers, mixtures thereof, and racemates, compounds of Formula Ila, Illa and IVa, and pharmaceutically acceptable salts thereof, are particularly preferred.
Individual enantiomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques, chiral chromatography (See for example, J. Jacques, et a!.. "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds’", Wiley-Interscience, 1994), or supercritical fluid chromatography (SFC) (See for example, T. A. Berger; “Supercritical Fluid Chromatography Primer ,” Agilent Technologies, July 2015).
A pharmaceutically acceptable salt of the compounds of the invention can be formed, for example, by reaction of a compound of Formula I and an appropriate pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R.J., et aE, Org. Process. Res. Dev., 4, 427- 435, 2000 and Berge, S.M., et al., ' J. Pharm. Se , 66, 1-19, 1977).
Certain abbreviations used herein are defined according to Daub G.H., et al., “The Use of Acronyms in Organic Chemistry” Aldrichimica Acta, 1984, 17(1), 6-23. Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “cAMP” refers to cyclic adenosine-3 ’,5 ’-monophosphate; “DCM” refers to dichloromethane or methylene chloride; “DIPEA” refers to N,N-diisopropylethylamine; “DMEA” refers to 2- dimethylaminoethanol; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “ECso” refers to the concentration of an agent which produces 50% response of the target activity compared to a predefined positive control compound (absolute ECso); “ES/MS” refers to electrospray mass spectrometry; “EtOAc” refers to ethyl acetate; “HATU” refers to l -[bis(dimethylamino)methylene]- l/7- l ,2,3-triazolo[4,5- Z>]pyridinium 3-oxid hexafluorophosphate; “HEK” refers to human embryonic kidney; “HEPES” refers to 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; “h” refers to hours or hour; “IP A” refers to isopropanol; “MeOH” refers to methanol or methyl alcohol; “min” refers to minute or minutes; “RT” refers to room temperature; “SNAr” refers to nucleophilic aromatic substitution; “T3P” refers to 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide;“TEA” refers triethylamine; and “THF” refers to tetrahydrofuran.
The compounds of the present invention may be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof. The product of each step below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers may be separated or resolved at any convenient point in the synthesis, by methods such as, selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et a!.. "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds’", Wiley-Interscience, 1994). Without limiting the scope of the invention, the following preparations, and examples are provided to further illustrate the invention.
Scheme 1
Scheme 1 shows two routes used to prepare intermediate 7, which is used to prepare compounds of the present invention. In the first route, aryl difluoride 1 undergoes SxAr with amine 2 using a carbonate base at elevated temperature to give intermediate 3, which then undergoes a second SxAr with the sodium alkoxide of alcohol 4 to give intermediate 5. In the second route, these two steps are performed in the opposite order to give intermediate 5. The nitro group of intermediate 5 is then reduced to diamine intermediate 7 using a palladium catalyst and hydrogen gas.
Scheme 2
Scheme 2 shows the preparation of compound 14 beginning with coupling of acid intermediate 8 and amino intermediate 7 using T3P and an organic base to give amide intermediate 9. Intermediate 9 is cyclized using acetic acid at elevated temperature to give benzimidazole intermediate 10, which then undergoes Suzuki coupling with boronic ester 11 using a palladium catalyst and a carbonate base at elevated temperature to give intermediate 12. Alkylation with alkyl bromide 13 and a carbonate base at elevated temperature then gives compound 14. Alternatively, reaction of intermediate 12 and alcohol 16 under Mitsunobu conditions (diisopropyl azodi carb oxy late and triphenylphosphine) gives compound 14 (a compound of Formula I wherein A is -CH2O-). Scheme 3
Scheme 3 shows the preparation of compound 19 beginning with conversion of aryl bromide 10 to boronic ester 15 using bis(pinacolato)diboron, potassium acetate, and a palladium catalyst at elevated temperature. Separately, alcohol 16 undergoes a nucleophilic aromatic substitution (SxAr) reaction with 2-bromo-6-fluoropyridine 17 using an alkoxide base at elevated temperature to give intermediate 18. Intermediates 15 and 18 are then coupled using a palladium catalyst, potassium acetate, and elevated temperature to give compound 19 (a compound of Formula I wherein A is -CH2O-; Y3 is N and Y4, Y5 and Y6 are CH).
Scheme 4
Scheme 4 shows the preparation of compounds of Formula I starting with acid intermediate 20, which is coupled with aniline intermediate 7 using amide coupling conditions e.g. HATU and an amine base to give amide 21. Amide 21 is then cyclized using acetic acid at elevated temperature to give the compound of Formula I.
In each of Schemes 1-4, to prepare compounds of the present invention in which R5 as defined in Formula I is -CO2H, the synthetic steps described in Schemes 1-4 are carried out with R5 protected as a methyl or ethyl ester (-CO2CH3 or -CO2CH2CH3). As a last step, the ester is hydrolyzed with a guanidine base at elevated temperature to give the compound in which R5 = -CO2H.
Preparation 1
Methyl 3 , 5 -difluoro-4-nitro-benzoate
A solution of thionyl chloride (37 mL, 74 mmol) in MeOH (110 mL) was cooled to -10 °C and 3,5-difluoro-4-nitro-benzonitrile (2.8 g, 15 mmol) was added. The reaction mixture was stirred at RT for 3 h then the temperature was gradually increased to 65 °C over 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL) and the organics were washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using 10% EtOAc in petroleum ether to give 2.24 g of the title compound (66%). 'H-NMR (400 MHz, CDCh) 8 7.78 (d, 2H), 4.0 (s, 3H).
Preparation 2
Methyl 3-fluoro-5-methoxy-4-nitro-benzoate
To a solution of methyl 3,5-difluoro-4-nitro-benzoate (0.3g, 1.38mmol) in MeOH (4 mL) was added a solution of sodium methylate (25% by mass in MeOH, 0.33 mL, 1.44 mmol), and the reaction mixture was heated at 65 °C for 2.5 h. The reaction mixture was cooled to RT, then water was added and the mixture was extracted with EtOAc (3 5 mL). The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, then filtered and concentrated in vacuo. The residue was purified via silica gel chromatography using a gradient of EtOAc in heptane (0 to 10%) to give 245 mg (76%) of the title compound as a yellow oil. ES/MS m/z 230 (M+H).
Preparation 3
Methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate
To a solution of methyl 3-fluoro-5-methoxy-4-nitro-benzoate (1.0 g, 4.4 mmol) in THF (20 mL) and DMF (10 mL) was added TEA (1.5 mL, 1.09 g, 11 mmol) at RT. To the slightly yellow solution was added [(2S)-oxetan-2-yl]methanamine (0.42 g, 4.8 mmol, 100 mass%) and the rust colored solution was stirred at RT under nitrogen overnight, then heated at 35 °C for 72 h. The reaction mixture was partially concentrated; then diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer back-extracted with EtOAc (2 x 50 mL). The combined organics were washed with saturated aqueous NaCl and dried over Na2SO4, filtered, concentrated and dried under high vacuum. The residue was purified by flash chromatography using a gradient of 5 to 30% EtOAc in DCM to give the title compound (0.99g, 73%) as a yellow oil. Sample analyzed via 1H NMR and LC/MS. ES/MS m/z 296 (M+H).
Preparation 4
Methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate
To a slurry of 5% sulfided platinum on carbon (211 mg, 1.08 mmol) in EtOAc (25 mL) in a 250 mL Parr bottle was added a solution of methyl (S)-3-methoxy-4-nitro-5- ((oxetan-2-ylmethyl)amino)benzoate (0.98 g, 3.3 mmol) in EtOAc (25 mL). The reaction vessel was sealed, purged with nitrogen, purged with hydrogen, then pressurized to 60 psig with hydrogen. The reaction was sealed at this pressure and shaken at RT for 4 h. The suspension was filtered over a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give the title compound (0.90 g, quantitative yield) as an oil which crystallized upon standing. ES/MS m/z 267 (M+H).
Preparation 5
Methyl 3-fluoro-5-(2 -methoxy ethoxy)-4-nitro-benzoate
To a suspension of sodium hydride (60% in mineral oil, 92 mg, 2.30 mmol) in THF (10 mL) was added 2-methoxy ethanol (0.18 mL, 2.31 mmol) and the mixture was stirred at RT for 30 mm. Next, methyl 3,5-dmuoro-4-mtro-benzoate (0.5g, 2.30 mmol) was added and the mixture was stirred at 60 °C for 16 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in heptane to give the title compound (225 mg, 40%) as a yellow oil. ES/MS m/z 274 (M+H).
Preparation 6
Methyl 3-(2-methoxyethoxy)-4-nitro-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate
To a solution of methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitro-benzoate (0.34 g, 1.23 mmol) in dry DMF (4 mL), was added TEA (428 pL, 3.07 mmol) and (S)-oxetan-2- ylmethanamine (109.3 mg, 1.229 mmol) and the reaction mixture was stirred at 35 °C overnight. Additional TEA (100 pL, 0.717 mmol) and (S)-oxetan-2-ylmethanamine (32.8 mg, 0.369 mmol) were added and the reaction mixture was stirred for 1 h at 35 °C. The reaction was diluted with water and extracted four times with EtOAc. The combined organic phases were dried over MgSCE, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 30% EtOAc in heptane to give the title compound (228 mg, 55%) as an orange oil. ES/MS m/z 341 (M+H).
Preparation 7
Methyl 4-amino-3-(2 -m ethoxy ethoxy)-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate
To a reaction vessel with iron (0.325 g, 5.82 mmol), ammonium chloride (0.015 g, 0.28 mmol) suspended in water (4.36 mL) was added acetic acid (0.073 mL, 1.3 mmol) and the reaction mixture was stirred at 50 °C for 15 min. Then, a solution of methyl 3-(2- methoxyethoxy)-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (0.198 g, 0.582 mmol) in DMF (1.45 mL) was added and the reaction mixture was stirred at 50 °C for 20 min. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc. Saturated aqueous NaHCOs was added to the filtrate, and the organic layer was, dried over MgSCL, filtered, and concentrated under reduced pressure to give the title compound (0.181 g, quantitative yield) as a yellow oil which was carried forward without further purification of reaction. ES/MS m/z 311 (M+H)
Preparation 8
Methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate
To a mixture of 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro- phenyl]acetic acid (prepared essentially as described in WO 2020/263695, 500 mg, 1.3 mmol) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (375 mg, 1.4 mmol) in DIPEA (0.73 mL, 4.2 mmol), and DMF (5 mL) was added HATU (800 mg, 2.1 mmol) at RT. After stirring at RT for 3.5 h, the reaction mixture was diluted with EtOAc (30 mL), washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was dissolved in acetic acid (5 mL) the mixture was stirred at 35 °C for 48 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (25 mL). The organic mixture was washed with saturated aqueous NaHCOs and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography using a gradient of 20-100% EtOAc in hexanes to give the title compound (500 mg, 57% yield). ES/MS (m/z): 625 (M+H).
Preparation 9
Methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate
A mixture of 2-(4-bromo-2,5-difluoro-phenyl)acetic acid (5.0 g, 20 mmol), methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (5.8 g, 22 mmol), DMF (40 mL), pyridine (8.0 mL, 99 mol), and T3P (50% in THF, 30 mL, 50 mmol) was stirred at RT for 1 h. The mixture was diluted with 100 mL water and the resulting solid was collected by vacuum filtration to give 9.9 g of the title compound (100%). ES/MS m/z 499 and 501 (M+H).
Preparation 10
Methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate A solution of methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3- methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (9.9 g, 20 mmol) in acetic acid (100 mL) was stirred at 55 °C for 18 h. The solution was concentrated and the residue was purified via silica gel chromatography using a gradient of 10 to 100% EtOAc in hexanes followed by 5% MeOH in DCM to give 8.3 g of the title compound (87%). ES/MS m/z 481 and 483 (M+H).
Preparation 11 Methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyri din-2 -yl)benzyl)-4-methoxy-l -(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylate
A mixture of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-methoxy-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (4.3 g, 8.9 mmol), 6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-ol (2.7 g, 12 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dicholoropalladium(II) (0.37 g, 0.50 mmol), and potassium carbonate (4.0 g, 29 mmol) in 1,4-di oxane (45 mL) and water (11 mL) was stirred at 70 °C for 6.5 h. The mixture was diluted with 100 mL water and stirred vigorously at RT for 5 min. The solid was collected the solid by vacuum filtration and washed with EtOAc (6 x 50 mL) to give 3.0 g of the title compound (68%). ES/MS m/z 496 (M+H).
Preparation 12 Methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-(2 -methoxy ethoxy)-5- ((oxetan-2-ylmethyl)amino)benzoate
A mixture of 2-(4-bromo-2,5-difluoro-phenyl)acetic acid (2.1 g, 8.3 mmol), methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (2.3 g, 7.4 mmol), DMF (15 mL), pyridine (3.2 mL, 40 mol), and T3P (50% in THF, 12 mL, 20 mmol) was stirred at RT for 1 h. The mixture was diluted with 100 mL water and the resulting solid was collected by vacuum filtration to give 4.3 g of the title compound (95%). ES/MS m/z 543 and 545 (M+H).
Preparation 13
Methyl (S)-2-(4-bromo-2, 5-difluorobenzyl)-4-(2-methoxy ethoxy)- l-(oxetan-2 -ylmethyl)- lH-benzo[d]imidazole-6-carboxylate
A solution of methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-(2- methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate (4.3 g, 7.9 mmol) in acetic acid (40 mL) was stirred at 55 °C for 18 h. The solution was concentrated and the residue was purified via silica gel chromatography using a gradient of 20 to 100% EtOAc in hexanes to give 3.2 g of the title compound (78%). ES/MS m/z 525 and 527 (M+H).
Preparation 14
Methyl (S)-2-(2, 5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-(2 -methoxy ethoxy)- 1- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate - l-
A mixture of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (975 mg, 1.86 mmol), 6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-ol (632 mg, 2.86 mmol), [1,1 - bis(diphenylphosphino)ferrocene]dicholoropalladium(II) (0.098 g, 0.13 mmol), and potassium carbonate (826 mg, 5.98 mmol) in 1,4-dioxane (9.3 mL) and water (2.3 mL) was stirred at 70 °C for 3 h. The mixture was diluted with 50 mL water and stirred vigorously at RT for 5 min. The solid was collected by vacuum filtration and washed with EtOAc (5 x 20 mL) to give 885 mg of the title compound (88%). ES/MS m/z 540 (M+H).
Preparation 15
Methyl 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate
To a stirred solution of 5-(hydroxymethyl)-6-methyl-pyridine-2-carbonitrile (112 mg, 0.718 mmol) in anhydrous THF (3.5 mL) at 0 °C was added triphenylphosphine (245 mg, 0.934 mmol), methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4- methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (300 mg, 0.605 mmol), and finally diisopropyl azodicarboxylate (0.19 mL, 0.96 mmol) dropwise. The reaction was warmed to RT and stirred overnight. After 16 h, the reaction was diluted with EtOAc and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by via silica gel chromatography using a gradient of 0- 20% MeOH in EtOAc and concentrated under reduced pressure to give 82 mg of the title compound (22%). ES/MS m/z 626 (M+H).
Preparation 16
Methyl 2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl]- 7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate
To a stirred solution of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-(2- methoxyethoxy)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (150 mg, 0.286 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (148 mg, 0.577 mmol), potassium acetate (86 mg, 0.88 mmol), and the resulting mixture was degassed and purged with nitrogen three times. Then l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride DCM complex (24 mg, 0.03 mmol) was added and the mixture was stirred at 80 °C for 16 h. The reaction was cooled to RT, diluted with EtOAc, and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 0-10% MeOH in EtOAc and concentrated under reduced pressure to give 168 mg of the title compound (72%). ES/MS m/z 491 (M+H of boronic acid).
Preparation 17
5-[(6-Bromo-2-pyridyl)oxymethyl]-l-methyl-pyridin-2-one
To a stirred solution of 5-(hydroxymethyl)-l-methyl-pyridin-2-one (367 mg, 2.64 mmol) and 2-bromo-6-fluoropyridine (565 mg, 3.15 mmol) in anhydrous THF (4 mL) at RT was added potassium /-butoxide (358 mg, 3.16 mmol). The reaction was stirred at 55 °C for 16 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, warmed to RT, diluted with EtOAc, and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 0-10% MeOH in EtOAc and concentrated under reduced pressure to give 213 mg of the title compound (26%). ES/MS m/z 294 & 296 (M+H).
Preparation 18
Methyl 2-[[2,5-difluoro-4-[6-[(l-methyl-6-oxo-3-pyridyl)methoxy]-2- pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate
To a stirred solution of 5-[(6-bromo-2-pyridyl)oxymethyl]-l-methyl-pyridin-2-one (108 mg, 0.366 mmol), and methyl 2-[[2,5-difhioro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]methyl]-7-(2 -methoxy ethoxy)-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (168 mg, 0.293 mmol), and potassium acetate (91 mg, 0.93 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex (25 mg, 0.030 mmol). The reaction mixture was stirred at 90 °C under nitrogen for 2 h. After 2 h, the reaction was cooled to RT, diluted with EtOAc, and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 0-10% MeOH in EtOAc and concentrated under reduced pressure to give 81 mg of the title compound (42%). ES/MS m/z 661 (M+H).
Example 1 2-[[4-[6-[(4-Cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid
To a mixture of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]- 2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (500 mg, 0.80 mmol), THF (5 mL), ACN (10 mL) and water (1 mL) was added l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (340 mg , 2.4 mmol). The mixture was heated 60 °C for Ih, then stirred at RT overnight. The mixture was neutralized with aqueous citric acid and concentrated. The residue was purified by reversed phase flash chromatography on a Cl 8 column using a gradient from 10 to 100% ACN in 10 mM aqueous ammonium bicarbonate (pH 10) to obtain the title compound (398 mg, 81%). ES/MS (m/z)'. 611 (M+H).
Example 2 (S)-2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy- l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
A mixture of methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4- methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (0.15 g, 0.30 mmol), potassium carbonate (0.18 g, 1.3 mmol), and 4-(bromomethyl)-3 -fluorobenzonitrile (80 mg, 0.37 mmol) in ACN (3.0 mL) was stirred at 45 °C for 4.5 h. To the mixture was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (215 mg, 1.51 mmol) in water (0.5 mL) and the mixture was stirred at 55 °C for 2 h. The reaction mixture was concentrated onto diatomaceous earth and purified by reversed phase chromatography on a Cl 8 column using a gradient of 0 to 100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 27 mg of the title compound (15%). ES/MS m/z 615 (M+H).
Example 3 (S)-2-(4-(6-((5-Cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4- methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
A mixture of methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4- methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (0.20 g, 0.40 mmol), potassium carbonate (0.17 g, 1.3 mmol), and 6-(bromomethyl)pyridine-3- carbonitrile (99 mg, 0.50 mmol) in ACN (4.0 mL) was stirred at 45 °C for 5 h and at 50 °C for 2 h. The suspension was filtered through a pad of diatomaceous earth, and to the filtrate was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (300 mg, 2.11 mmol) in water (0.7 mL). The mixture was stirred at 55 °C for 35 min then quenched with 1 M aqueous citric acid solution (2 mL). The mixture was extracted with EtOAc (2 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on a C18 column using a gradient of 14 to 48% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 23 mg of the title compound (10%). ES/MS m/z 598 (M+H).
Example 4
(S)-2-(4-(6-((6-Cyanopyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4- methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
The title compound was prepared essentially as described in Example 3 using 5- (bromomethyl)pyridine-2-carbonitrile and purifying by reversed phase chromatography on a C18 column using a gradient of 23 to 58% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH followed by SFC purification on a Chiralpak® AS-H column with 40% IPA in CO2. ES/MS m/z 598 (M+H).
Example 5
(S)-2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2- methoxyethoxy)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
The title compound was prepared essentially as described in Example 3 using 4- (bromomethyl)-3-fluoro-benzonitrile and methyl (S)-2-(2,5-difluoro-4-(6- hydroxypyridin-2-yl)benzyl)-4-(2 -methoxy ethoxy)- 1 -(oxetan-2-ylmethyl)- 1H- benzo[d]imidazole-6-carboxylate, purifying by reversed phase chromatography on a C18 column using a gradient of 23 to 58% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH. ES/MS m/z 659 (M+H).
Example 6 2-[[4-[6-[(6-Cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6a) and 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6b)
A mixture of ACN (0.6 mL), 1,4-dioxane (0.6 mL), water (0.2 mL), and 1,5,7- triazabicyclo[4.4.0]dec-5-ene (65 mg, 0.46 mmol) was sparged for 10 min and transferred to a reaction vessel containing methyl 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2- pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (47 mg, 0.08 mmol). The reaction mixture was stirred at 55 °C for 2 h. After 2 h, the reaction mixture was transferred to a separatory funnel containing EtOAc, washed with 10% aqueous citric acid solution, saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography on a C18 column using a gradient of 0-100% ACN: 10 mM aqueous formic acid. Fractions containing the title compound were concentrated under reduced pressure to remove volatile organic solvents, then the remaining aqueous layer was acidified with 0.1 N aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was repurified by reversed-phase chromatography on a C18 column using a gradient of 0-100% ACN with 0.1% formic acid:0.1% formic acid in water, separating the two title compounds: the nitrile compound (Example 6a, 15 mg, 33%), ES/MS m/z 612 (M+H); and the amide compound (Example 6b, 11 mg, 23%), ES/MS m/z 630 (M+H).
Example 7
2-[[2,5-Difluoro-4-[6-[(l-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-
(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid
A mixture of ACN (0.8 mL), 1,4-dioxane (0.8 mL), water (0.3 mL), and 1,5,7- triazabicyclo[4.4.0]dec-5-ene (49 mg, 0.34 mmol) was sparged for 10 min then added to a reaction vessel containing methyl 2-[[2,5-difluoro-4-[6-[(l-methyl-6-oxo-3- pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (75 mg, 0.11 mmol). The reaction was stirred at RT for 16 h, then diluted with EtOAc and 0.1 M aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography on a C18 column using a gradient of 0-100% ACN with 0.1% formic acid:0.1% formic acid in water. Fractions containing the desired product were concentrated under reduced pressure to remove volatile organic solvents. The remaining aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried with MgSCU, filtered, and concentrated under reduced pressure. The residue was repurified by reversed-phase chromatography on a Cl 8 column using a gradient of 0-100% ACN with 0.1% formic acid:0.1% formic acid in water to give 18.7 mg of the title compound (26%). ES/MS m/z 647 (M+H).
General Procedure: O-alkylation followed by ester hydrolysis: A mixture of methyl (S)-2- (2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (75 mg, 0.15 mmol), halide (1.2 eq, 0.18 mmol), and potassium carbonate (62 mg, 0.45 mmol) in ACN (1.5 mL) is stirred at 50 °C for 5 h. Water (1 mL) is added and the mixture is extracted with DCM (1 mL). The organic layer is filtered through diatomaceous earth, washing with DCM. The organic layer is concentrated and to the residue is added 3,4,6,7,8,9-hexahydro-2H-pyrimido[l,2- a]pyrimidine (0.11 g, 0.76 mmol), ACN (1.5 mL) and water (0.25 mL). The mixture is stirred at 50 °C for 1 h, then water (1 mL) is added and the mixture is extracted with DCM (1 mL). The organic layer is filtered through diatomaceous earth, washing with DCM, concentrated, then subjected to the specified chromatography conditions.
The following examples were prepared following the above General Procedure for O- alkylation followed by ester hydrolysis, using the halides listed as starting materials and using the chromatography conditions as specified.
Biological Assays Human GLP-1 Receptor HEK293 Cell cAMP Assay
GLP-1 Receptor functional activity is determined using cAMP formation in an HEK293 clonal cell line expressing human GLP-1R (NCBI accession number NP_002053) at an expression density of 581 ± 94 (n=6) and 104 ± 12 (n=5) fmol/mg protein (determined using [125I] GLP-1 (7-36)NH2 homologous competition binding analysis). The hGLP-lR receptor expressing cells are treated with compound (20 point concentration-response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384 well plate Corning Cat# 3570) in DMEM (Gibco Cat# 31053) supplemented with IX GlutaMAX™ (Gibco Cat# 35050), 0.1% bovine casein (Sigma C4765-10ML), 250 pM IB MX (3 -Isobutyl- 1 -methylxanthine, Acros Cat# 228420010) and 20 mM HEPES (Gibco Cat# 15630) in a 20 pL assay volume (final DMSO concentration is 0.5%). After a 30 min incubation at 37 °C, the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). Briefly, cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 pL) followed by the antibody anti-cAMP-Eu3+-Cryptate, also in cell lysis buffer (10 pL). The resulting competitive assay is incubated for at least 60 min at RT, then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665nm/620nm* 10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed with human GLP-1(7-36)NH2. A relative ECso value and percent top (Emax) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation. The ECso and Emax data when the compounds of Examples 1 to 14 are tested in the cAMP assay described above using HEK293 cells expressing 581 and 104 fmol/mg GLP-1R are shown in Tables 1 and 2, respectively. These data indicate that the compounds of Examples 1 to 14 are agonists of the human GLP-1 receptor. The compounds of Examples 1, 2, 5 and 13 show comparable potency in the 104 fmol/mg assay to the native GLP-1(7-36)NH2 peptide.
Table 1. HEK293 cell line with 581 fmol/mg expression density of GLP-1R, intracellular cAMP response, relative ECso and % Stim Max
Table 2. HEK293 cell line with 104 fmol/mg expression density of GLP-1R, intracellular cAMP response, relative ECso, % Stim Max and Emax EC50, nM = geometric mean of the concentration producing one-half of the maximal stimulation (one-half of the Emax), followed by SEM (delta method) and the number of observations in parentheses.
% Stim Max = arithmetic mean of the percent stimulation by the point giving maximal stimulation in the concentration-response curve relative to the maximal response produced by GLP-1(7-36)NH2, followed by the SEM and the number of observations in parentheses.
Emax, % = arithmetic mean of the fitted top of the concentration-response curve relative to the percent of maximal response to GLP-1(7-36)NH2 ± SEM. In vivo Intraperitoneal Glucose Tolerance Test in Human GLP-1R Knock-In Mice
The potency of the exemplified compounds to lower the concentration of blood glucose in vivo is determined using mice expressing the human GLP-1R (NCBI accession number NP 002053) from the mouse Glp-lr genetic locus (Jun, L.S., et al., PLoS One. 2014 9:e93746). Overnight fasted mice are orally administered the test compound solubilized inlO% Kolliphor® (HS15) in Polyetheylene Glycol 400 (PEG400). One hour post-dose, the animals are administered glucose by intraperitoneal injection (2 g/kg), and blood glucose levels are measured intermittingly over the next two hours using glucometers. A dose range of the test compound is delivered, and area under the curve calculations for each dose group are determined and fit to a four-parameter logistic model for calculating in vivo potency as an ED50 with a 95% confidence interval. When tested in the in vivo intraperitoneal glucose tolerance test described above, the compound of Example 1 exhibits potency to lower the concentration of blood glucose in mice expressing the human GLP-1R with the ED50 (and 95% confidence interval) value as shown in Table 3, which indicates that this compound is an orally available potent GLP- 1R agonist in mice.
Table 3. Blood glucose lowering efficacy in mice expressing human GLP-1R

Claims

Claims
1. A compound of the formula: wherein is phenyl, a 5 or 6-membered heteroaryl or pyridone, which phenyl, heteroaryl or pyridone is optionally substituted with one or two R1;
R1 at each occurrence is independently CN; halo; Ci-C3alkyl optionally substituted with OH; Ci-C3haloalkyl; Ci-C3alkoxy; C3-C5cycloalkyl; -SO2Ci-C3alkyl; -C(O)NH2; wherein each X9 is independently CH or N and no more than one X9 in the ring is N, each Re is independently selected from: H, Ci-C3haloalkyl, halo, C3-Cscycloalkyl and Ci-C3alkyl optionally substituted with OH, Rh is H, Ci-C3haloalkyl, halo, C3-Cscycloalkyl, OH, -NRcRd or Ci-C3alkyl optionally substituted with OH;
5- or 6- membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from: Ci-C3alkoxy, C3- Cscycloalkyl, -CH2-C3-C5cycloalkyl, -SO2Ci-C3alkyl, C^Csheterocyclyl, -CH2-C4- Csheterocyclyl, halo, Ci-C3haloalkyl, Ci-C3haloalkoxy, CN, -CONRcRd, -NRcRd or Ci- C3alkyl optionally substituted with OH;
-A- is -CH2O-, -OCH2- or -CH2NH-; Y1, Y2, Y7 and Y8 are independently N, CH or CR2, wherein no more than one of Y1, Y2, Y7 and Y8 is N and no more than two of Y1, Y2, Y7 and Y8 is CR2;
Y3, Y4, Y5 and Y6 are independently N, CH or CR2, wherein no more than two of Y3, Y4, Y5 and Y6 are N and no more than two of Y3, Y4, Y5 and Y6 are CR2;
R2 at each occurrence is independently halo or methyl;
R3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy, hydroxy or Ci-Cshaloalkyl;
Rc and Rd are each independently H or Ci-Csalkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.
4. The compound according to any one of claims 1 to 3, wherein is phenyl optionally substituted with one or two R1, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4, wherein the phenyl is substituted with one or two R1 independently selected from CN, halo, Ci-Csalkyl, Ci-Csalkoxy or 5-membered heteroaryl, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5, wherein the one or two R1 are independently selected from CN, F, CH3, OCH3 or triazole, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6, wherein the one or two R1 are independently selected from CN, F, or OCH3, or a pharmaceutically acceptable salt thereof.
8. The compound according to any one of claims 1 to 7, wherein -A- is -CH2O-, or a pharmaceutically acceptable salt thereof.
9. The compound according to any one of claims 1 to 8, wherein Y1 and Y7 are CR2 and Y2 and Y8 are CH, or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9, wherein R2 is F or methyl, or a pharmaceutically acceptable salt thereof.
11. The compound according to any one of claims 1 to 10, wherein Y3 is N; and Y4, Y5 and Y6 are CH, or a pharmaceutically acceptable salt thereof.
12. The compound according to any one of claims 1 to 11, wherein R3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy, or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 12, wherein R3 is -OCH3, or -OCH2CH2OCH3, or a pharmaceutically acceptable salt thereof.
14. The compound according to any one of claims 1 to 13, wherein R5 is -CO2H, or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1, which is selected from: 2-[[4-[6-[(4-Cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((5-Cyanopyri din-2-yl)methoxy)pyri din-2 -yl)-2, 5-difluorobenzyl)-4-methoxy-l - (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((6-Cyanopyri din-3 -yl)methoxy)pyri din-2 -yl)-2, 5-difluorobenzyl)-4-methoxy-l - (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2- methoxyethoxy)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-[[4-[6-[(6-Cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro- phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-[[2,5-Difluoro-4-[6-[(l-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7- (2 -methoxy ethoxy)-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;
2-(4-(6-((5-cy anothi ophen-2 -yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-cyano-2-methylbenzyl)oxy)pyri din-2 -yl)-2, 5-difluorobenzyl)-4-methoxy-l - (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; 2-(2,5-difluoro-4-(6-((2-methyl-2H-l,2,3-triazol-4-yl)methoxy)pyridin-2-yl)benzyl)-4- methoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-(lH-l,2,4-triazol-l-yl)benzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4- m ethoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-(isoxazol-3-ylmethoxy)pyri din-2 -yl)benzyl)-4-m ethoxy- 1 -(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-((l -methyl- lH-pyrazol-3-yl)methoxy)pyri din-2-yl)benzyl)-4- m ethoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-(2,5-difluoro-4-(6-((2-methyl-2H-tetrazol-5-yl)methoxy)pyridin-2-yl)benzyl)-4- methoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid; or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1, which is of the formula: wherein is phenyl, a 5 or 6-membered heteroaryl or pyridone, which phenyl, heteroaryl or pyridone is optionally substituted with one or two R1;
R1 is CN, halo, Ci-Csalkyl, Ci-Csalkoxy, -C(0)NH2 or 5-membered heteroaryl;
R2 at each occurrence is independently halo or methyl;
R3 is Ci-C4alkoxy optionally substituted with Ci-C2alkoxy; or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1, which is of the formula: wherein
R2 is F or CH3; and
R3 is -OCH3, or -OCH2CH2OCH3, or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 and at least one pharmaceutically acceptable carrier, diluent, or excipient.
19. A method of treating type II diabetes mellitus in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.
20. A method of lowering blood glucose levels in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.
21. A method of treating hyperglycemia in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.
22. A method of treating obesity in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.
23. The method according to any one of claims 19 to 22 wherein the compound is administered orally.
24. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 for use in therapy.
25. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 for use in the treatment of type II diabetes mellitus.
26. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 for use in lowering blood glucose levels.
27. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 for use in the treatment of hyperglycemia.
28. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 for use in the treatment of obesity.
29. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 24 to 28, wherein the compound is administered orally.
30. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of type II diabetes mellitus.
31. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 in the manufacture of a medicament to lower blood glucose levels.
32. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of hyperglycemia. -SO-
33. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of obesity.
EP23828849.2A 2022-11-16 2023-11-15 Glucagon-like peptide 1 receptor agonists Pending EP4619098A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263425751P 2022-11-16 2022-11-16
PCT/US2023/079720 WO2024107781A1 (en) 2022-11-16 2023-11-15 Glucagon-like peptide 1 receptor agonists

Publications (1)

Publication Number Publication Date
EP4619098A1 true EP4619098A1 (en) 2025-09-24

Family

ID=89378473

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23828849.2A Pending EP4619098A1 (en) 2022-11-16 2023-11-15 Glucagon-like peptide 1 receptor agonists

Country Status (13)

Country Link
EP (1) EP4619098A1 (en)
JP (1) JP2025538389A (en)
KR (1) KR20250085816A (en)
CN (1) CN120344520A (en)
AU (1) AU2023379473A1 (en)
CL (1) CL2025001423A1 (en)
CO (1) CO2025005958A2 (en)
CR (1) CR20250178A (en)
DO (1) DOP2025000110A (en)
IL (1) IL320810A (en)
JO (1) JOP20250110A1 (en)
MX (1) MX2025005718A (en)
WO (1) WO2024107781A1 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT4408840T (en) 2021-09-27 2025-10-07 Terns Pharmaceuticals Inc Benzimidazole carboxylic acids as glp-1r agonists
CN118401519A (en) 2021-10-25 2024-07-26 拓臻制药公司 Compounds as GLP-1R agonists
CN119095843A (en) 2022-02-23 2024-12-06 拓臻制药公司 Compounds as GLP-1R agonists
EP4568664B1 (en) 2023-04-07 2026-04-01 Terns Pharmaceuticals, Inc. Combination comprising a thr-beta agonist and a glp-1r agonist for use in treating obesity
CN120981457A (en) 2023-09-14 2025-11-18 歌礼制药(中国)有限公司 GLP-1R agonists and their treatments
TW202521534A (en) 2023-11-24 2025-06-01 香港商歌禮製藥(中國)有限公司 Glp-1r agonist and therapeutic method thereof

Family Cites Families (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102314286B1 (en) 2016-12-16 2021-10-21 화이자 인코포레이티드 GLP-1 receptor agonists and uses thereof
US10934279B2 (en) 2018-06-13 2021-03-02 Pfizer Inc. GLP-1 receptor agonists and uses thereof
DK3806855T5 (en) 2018-06-15 2023-05-22 Pfizer GLP-1 receptor agonists and uses thereof
MA54555A (en) 2018-11-22 2021-09-29 Qilu Regor Therapeutics Inc GLP-1R AGONISTS AND THEIR USES
EP3953344A4 (en) 2019-04-12 2023-08-09 Qilu Regor Therapeutics Inc. Glp-ir agonists and uses thereof
TWI751585B (en) 2019-06-28 2022-01-01 美商美國禮來大藥廠 Glucagon-like peptide 1 receptor agonists
WO2021018023A1 (en) 2019-08-01 2021-02-04 济南泰达领创医药技术有限公司 Small molecule glp-1 receptor modulator
EP4048664A1 (en) 2019-10-25 2022-08-31 Gilead Sciences, Inc. Glp-1r modulating compounds
WO2021096284A1 (en) 2019-11-15 2021-05-20 일동제약(주) Glp-1 receptor agonist and use thereof
CN114761395B (en) 2019-12-02 2024-11-15 现代药品株式会社 GLP-1 receptor agonists
ES3016132T3 (en) 2020-01-29 2025-05-08 Gilead Sciences Inc Glp-1r modulating compounds
JP7836762B2 (en) 2020-02-13 2026-03-27 ガシャーブラム・バイオ・インコーポレイテッド Heterocyclic GLP-1 agonist
IL296336A (en) 2020-03-18 2022-11-01 Lg Chemical Ltd A agonist for the glp-1 receptor, a pharmaceutical preparation containing it and a method for its preparation
CN113493447B (en) 2020-04-03 2024-06-11 轩竹(北京)医药科技有限公司 GLP-1 receptor agonists
TW202144340A (en) 2020-04-03 2021-12-01 大陸商江蘇恆瑞醫藥股份有限公司 Fused imidazole derivatives, preparation method and medical use thereof
TW202206429A (en) 2020-04-29 2022-02-16 美商迦舒布魯姆生物有限公司 Heterocyclic glp-1 agonists
MX2022015026A (en) 2020-06-04 2023-01-04 Hangzhou Sciwind Biosciences Co Ltd FIVE-MEMBER HETEROAROMATIC IMIDAZOLE COMPOUND AND USE THEREOF.
CN115697338B (en) 2020-06-10 2024-08-09 东宝紫星(杭州)生物医药有限公司 Methyl substituted benzobisoxazole compound and application thereof
CN113801136B (en) 2020-06-16 2023-04-07 江苏恒瑞医药股份有限公司 Imidazo heteroaryl derivative, preparation method and application thereof in medicine
CN113816948B (en) 2020-06-19 2023-08-11 江苏恒瑞医药股份有限公司 Condensed imidazole derivative, preparation method and medical application thereof
CN115916772B (en) 2020-06-19 2025-01-14 江苏恒瑞医药股份有限公司 6-Oxo-3, 6-dihydropyridine derivative, preparation method and application thereof in medicines
CN113831337B (en) 2020-06-24 2023-03-24 广州市恒诺康医药科技有限公司 GLP-1 receptor agonist, and pharmaceutical composition and use thereof
JP2023537501A (en) 2020-08-06 2023-09-01 ガシャーブラム・バイオ・インコーポレイテッド heterocyclic GLP-1 agonists
WO2022031994A1 (en) 2020-08-06 2022-02-10 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
CA3192601A1 (en) 2020-08-21 2022-02-24 Terns Pharmaceuticals, Inc. Compounds as glp-1r agonists
EP4204415A4 (en) 2020-08-28 2025-03-26 Gasherbrum Bio, Inc. Heterocyclic glp-1 agonists
CA3188891A1 (en) 2020-09-01 2022-01-13 Fanglong Yang Fused imidazole derivative, preparation method therefor, and medical use thereof
WO2022068772A1 (en) 2020-09-29 2022-04-07 深圳信立泰药业股份有限公司 Benzimidazole derivative, and preparation method therefor, and medical use thereof
WO2022078152A1 (en) 2020-10-12 2022-04-21 杭州中美华东制药有限公司 Benzimidazolone glp-1 receptor agonist and use thereof
EP4229050A4 (en) 2020-10-13 2024-12-11 Gasherbrum Bio, Inc. HETEROCYCLIC GLP-1 AGONISTS
US20240083886A1 (en) 2020-10-13 2024-03-14 Gasherbrum Bio, Inc. Heterocyclic glp-1 agonists
CN114478497B (en) 2020-11-12 2023-10-20 杭州中美华东制药有限公司 Arylalkyl acid GLP-1 receptor agonists and uses thereof
EP4247804A1 (en) 2020-11-20 2023-09-27 Gilead Sciences, Inc. Polyheterocyclic glp-1 r modulating compounds
MX2023006186A (en) 2020-11-27 2023-08-07 Shenzhen Salubris Pharm Co Ltd Benzimidazole derivative and preparation method therefor and medical use thereof.
CN114591296A (en) 2020-12-02 2022-06-07 海思科医药集团股份有限公司 A kind of GLP-1R agonist and its application in medicine
CN114591308B (en) 2020-12-03 2024-03-08 苏州闻泰医药科技有限公司 A class of GLP-1R receptor agonist compounds and their uses
CN114634510B (en) 2020-12-16 2025-11-04 杭州中美华东制药有限公司 Imidazolidine derivatives and their uses
WO2022135572A1 (en) 2020-12-25 2022-06-30 四川海思科制药有限公司 Five-membered ring derivative and medical use thereof
CN114763352A (en) 2021-01-15 2022-07-19 海思科医药集团股份有限公司 GLP-1 receptor agonist and application thereof in medicine
CN114805336B (en) 2021-01-20 2026-04-14 江苏恒瑞医药股份有限公司 Condensed imidazole compound, preparation method and medical application thereof
CR20230330A (en) 2021-01-28 2023-11-15 Carmot Therapeutics Inc Gpcr receptor agonists, pharmaceutical compositions comprising the same, and methods for their use
CN114907351A (en) 2021-02-07 2022-08-16 杭州中美华东制药有限公司 Tricyclic GLP-1 receptor agonists and uses thereof
WO2022184849A1 (en) 2021-03-04 2022-09-09 Les Laboratoires Servier Glp-1r agonists, uses and pharmaceutical compositions thereof
WO2022192428A1 (en) 2021-03-11 2022-09-15 Gilead Sciences, Inc. Glp-1r modulating compounds
EP4304712A1 (en) 2021-03-11 2024-01-17 Gilead Sciences, Inc. Glp-1r modulating compounds
US20240208952A1 (en) 2021-03-22 2024-06-27 Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. Thiophene glp-1 receptor agonist and use thereof
CN117222631A (en) 2021-03-24 2023-12-12 诚益生物(美国)公司 Phenyl-[1,3]dioxolo[4,5-C]pyridyl-phenyl-, phenyl-[1,3]dioxolo[4,5-C ]pyridyl-heteroaryl-or phenyl-[1,3]dioxolo[4,5-C]pyridyl-piperidyl-methyl-oxetanylmethyl- 1H-benzo[D]imidazole-carboxylic acid derivatives and methods of use thereof
JP7772778B2 (en) 2021-03-24 2025-11-18 塩野義製薬株式会社 Pharmaceutical composition containing a GLP-1 receptor agonist having a fused ring
WO2022216094A1 (en) 2021-04-08 2022-10-13 주식회사 엘지화학 Glp-1 receptor agonist, pharmaceutical composition comprising same, and method for preparing same
WO2022219495A1 (en) 2021-04-12 2022-10-20 Novartis Ag 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
ES3025032T7 (en) 2021-04-21 2026-04-24 Gilead Sciences Inc Carboxy-benzimidazole glp-1r modulating compounds
IL306110A (en) 2021-04-21 2023-11-01 Gilead Sciences Inc Carboxybenzimidazole GLP-1R modulatory compounds
CN117177970A (en) 2021-04-30 2023-12-05 上海翰森生物医药科技有限公司 Polycyclic derivative regulators, preparation methods and applications thereof
EP4334304A1 (en) 2021-05-03 2024-03-13 Carmot Therapeutics, Inc. Benzimidazoyl glp-1 receptor agonists, pharmaceutical compositions comprising the same, and methods for their use
CN113480534B (en) 2021-07-23 2022-05-13 广州必贝特医药股份有限公司 Benzimidazole or azabenzimidazole-6-carboxylic acid compounds and application thereof
CN114716423A (en) 2022-05-20 2022-07-08 中国科学院上海药物研究所 5,6-Dihydro-1,2,4-triazine compounds and their pharmaceutical uses as GLP-1 receptor agonists

Also Published As

Publication number Publication date
CR20250178A (en) 2025-06-06
DOP2025000110A (en) 2025-06-15
JP2025538389A (en) 2025-11-28
MX2025005718A (en) 2025-06-02
CN120344520A (en) 2025-07-18
WO2024107781A1 (en) 2024-05-23
IL320810A (en) 2025-07-01
JOP20250110A1 (en) 2025-05-13
CL2025001423A1 (en) 2025-08-08
CO2025005958A2 (en) 2025-05-29
KR20250085816A (en) 2025-06-12
AU2023379473A1 (en) 2025-05-15

Similar Documents

Publication Publication Date Title
KR102738278B1 (en) Glucagon-like peptide 1 receptor agonist
AU2023379473A1 (en) Glucagon-like peptide 1 receptor agonists
JP7703691B2 (en) Macrocyclic glucagon-like peptide 1 receptor agonists
US10736883B2 (en) Triazole furan compounds as agonists of the APJ receptor
AU2023377707A1 (en) Glucagon-like peptide 1 receptor agonists
JP2014094886A (en) Gpr119 agonist
KR20250075662A (en) PCSK9 inhibitors and methods of use thereof
WO2022076503A1 (en) 6-methoxy-3,4-dihydro-1h-isoquinoline compounds useful in the treatment of diabetes
WO2010123018A1 (en) Diazaspiroalkane derivative
WO2025106780A1 (en) Rxfp1 receptor agonists
EA045067B1 (en) GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS
HK40063744A (en) Glucagon-like peptide 1 receptor agonists

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250616

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR

P01 Opt-out of the competence of the unified patent court (upc) registered

Free format text: CASE NUMBER: UPC_APP_8698_4619098/2025

Effective date: 20251001

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40124254

Country of ref document: HK

RAV Requested validation state of the european patent: fee paid

Extension state: MA

Effective date: 20250616

Extension state: MD

Effective date: 20250616

Extension state: TN

Effective date: 20250616