WO2024102625A1 - Glucagon-like peptide 1 receptor agonists - Google Patents

Glucagon-like peptide 1 receptor agonists Download PDF

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Publication number
WO2024102625A1
WO2024102625A1 PCT/US2023/078764 US2023078764W WO2024102625A1 WO 2024102625 A1 WO2024102625 A1 WO 2024102625A1 US 2023078764 W US2023078764 W US 2023078764W WO 2024102625 A1 WO2024102625 A1 WO 2024102625A1
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mmol
methyl
pharmaceutically acceptable
mixture
acceptable salt
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PCT/US2023/078764
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French (fr)
Inventor
Renato Alejandro BAUER
Travis Lamonte BUCHANAN
Qi Chen
Graham Robert Cumming
Antonio Rodriguez HERGUETA
Eric Michael Woerly
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Eli Lilly And Company
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Publication of WO2024102625A1 publication Critical patent/WO2024102625A1/en

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    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

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, WO2021/018023, 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, WO2021/254470, WO2021/259309, W02022/007979, WO2022/031994, WO2022/028572, W02022/040600, WO2022/042691, WO2022/068772, W02022/
  • the present invention provides a compound of the formula: wherein -A- is C 3 -C 4 alkylene optionally substituted with OH, halo or oxo, or C 3 -C 4 alkenylene; wherein a is the point of attachment to linker A; b is the point of attachment of linker B;
  • X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein no more than two of X 1 , X 2 , X 3 and X 4 are N and no more than two of X 1 , X 2 , X 3 and X 4 are CR 1 ;
  • X 5 is N, CH or CR la
  • X 6 , X 7 and X 8 are independently N, CH or CR 1 , wherein no more than two of X 5 , X 6 , X 7 and X 8 are N and no more than two of X 5 , X 6 , X 7 and X 8 are CR la or CR 1 ;
  • R 1 at each occurrence is independently CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; C 1 -C 3 alkoxy; C 3 -C 5 cycloalkyl; -SO 2 C 1 -C 3 alkyl; Q wherein each X 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, C 1 - C 3 haloalkyl, halo, C 3 -C 5 cycloalkyl and C 1 -C 3 alkyl optionally substituted with OH, R h is H, C 1 -C 3 haloalkyl, halo, C 3 -C 5 cycloalkyl, OH, -NR c R d or C 1 -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: C 1 -C 3 alkoxy, C3- C 5 cycloalkyl, -C ⁇ -C 3 -C 5 cycloalkyl, -SO2C 1 -C3alkyl, C ⁇ C 5 heterocyclyl, -CH2-C 4 - C 5 heterocyclyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, CN, -CONR c R d , -NR c R d or C 1 - Qalkyl optionally substituted with OH;
  • R la is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; or C 1 - C 3 alkoxy;
  • -B- is -CH2O-, -OCH2- or -CH2NH-;
  • Y 1 , Y 2 and Y 7 are independently N, CH or CR 2 , wherein no more than one of Y 1 , Y 2 and Y 7 is N and no more than two of Y 1 , Y 2 and Y 7 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
  • Z 1 , Z 2 and Z 3 are independently N, CH or CR 3 , wherein no more than two of Z 1 , Z 2 and Z 3 are N and no more than two of Z 1 , Z 2 and Z 3 are CR 3 ;
  • R 3 at each occurrence is independently halo; C 1 -C4alkyl; -OC 4 -C 6 cycloalkyl optionally substituted with C 1 -C2alkoxy, OH, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; -OC 4 -C 6 heterocyclyl optionally substituted with C 1 -C2alkoxy, OH, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; or C 1 - C4alkoxy optionally substituted with one or two substituents selected from: C 1 -C2alkoxy, OH, -NR f R g , -CONR c R d , CN, halo or 5- or 6- membered heteroaryl optionally substituted with C 1 -C 3 alkyl; R g and R d are each independently H or C 1 -C 3 alkyl;
  • R f is H or C 1 -C 3 alkyl
  • R s is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 5 cycloalkyl, C(O)C 1 -C 3 alkyl, or C 1 -C 3 alkylC 3 - C 5 cycloalkyl; or a pharmaceutically acceptable salt thereof.
  • Formula I includes all individual enantiomers, diastereomers, and mixtures thereof, as well as racemates.
  • a compound of the formula: or a pharmaceutically acceptable salt thereof are CH; X 2 is CR 1 ; and X 4 is N.
  • X 1 , X 2 , X 3 and X 4 are N. In an alternate embodiment, one embodiment, are CH.
  • only one of X 5 , X 6 , X 7 and X 8 is N.
  • R 1 is CN or halo.
  • X 2 is CR 1 ;
  • R 1 is CN or Cl.
  • X 1 is N
  • X 2 is CR 1
  • X 3 and X 4 are CH
  • R 1 is CN
  • X 1 and X 4 are CH; X 2 is CR 1 ;
  • X 3 is N; and R 1 is CN.
  • X 1 and X 3 are CH; X 2 is CR 1 ;
  • X 4 is N; and R 1 is Cl.
  • X 8 are CH; and R 1 is CN or Cl.
  • -B- 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 CH or CR 2 .
  • Y 2 is CH.
  • Y 7 is CH.
  • R 2 is methyl
  • Y 1 , Y 2 and Y 7 are all CH. In an alternate embodiment, Y 1 is CR 2 ; Y 2 is CH; Y 7 is CH; and R 2 is methyl.
  • Y 4 , Y 5 , Y 6 and Y 7 are all CH.
  • Z 1 is CH or CR 3 .
  • Z 2 is CH.
  • Z 3 is CH.
  • Z 2 and Z 3 are both CH.
  • R 3 is halo or C 1 -C4alkoxy, preferably, R 3 is F, -OCH 3 or - OCH 2 CH 3 .
  • Z 1 is CR 3 and R 3 is halo or C 1 -C4alkoxy, preferably, R 3 is F, - OCH 3 or -OCH2CH 3 .
  • R 5 is -CO2H.
  • X 1 , X 3 and X 4 are independently N or CH, wherein no more than one of X 1 , X 3 and X 4 is N;
  • R 1 is CN or halo
  • Y 1 is CH or CR 2 ;
  • R 2 is methyl
  • R 3 is halo or C1-C4 alkoxy; or a pharmaceutically acceptable salt thereof.
  • 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 1 , Y 2 and Y 7 containing ring.
  • the carbon substituted with the hydroxy group is attached to the X ring.
  • linker B the left hand terminal group is attached to the X ring and the right hand terminal group is attached the Y 3 containing ring.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • C 1 -C n alkyl refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms.
  • Examples of a C 1 -C4alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl.
  • Examples of a C 1 -C 3 alkyl group include, but are not limited to, methyl, ethyl and propyl.
  • a C 1 -C 2 alkyl group is methyl or ethyl.
  • C 3 -C 4 alkylene refers to a 3 or 4 carbon alkyl chain which is bonded at each end.
  • C 3 -C 4 alkenylene refers to a 3 or 4 carbon alkenyl chain which is bonded at each end.
  • C 1 -C n haloalkyl refers to a C 1 -C n alkyl group, as defined herein, which is substituted with one, or more halogen.
  • Examples of C 1 -C 3 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl.
  • C 1 -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 C 1 -C4alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
  • C 1 -C n haloalkoxy refers to a C 1 -C n alkoxy group, as defined herein, which is substituted with one, or more halogen.
  • Examples of C 1 -C 3 haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy and pentafluoroethoxy.
  • C 3 -C 5 cycloalkyl refers to a monocyclic saturated carbon ring containing between 3 and 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl or cyclopentyl.
  • C 4 -C 6 cycloalkyl refers to a monocyclic saturated carbon ring containing between 4 and 6 carbon atoms. Specifically, it refers to cyclobutyl, cyclopentyl or cyclohexyl.
  • heteroaryl refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from: N, S and O.
  • heteroatoms preferably selected from: N, S and O.
  • 5-membered heteroaryls include, but are not limited to, pyrazole, triazole and thiazole.
  • 6- membered heteroaryls include, but are not limited to, pyridine and pyridazine.
  • C 4 -C 6 heterocyclyl refers to a 4, 5 or 6 membered monocyclic saturated ring containing one or more heteroatoms, for example, pyrrolidine.
  • C 4 -C 5 heterocyclyl 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, and Illb 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, or a pharmaceutically acceptable salt thereof, for use in therapy is provided.
  • 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.
  • 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: Formula Illb, or pharmaceutically acceptable salts thereof.
  • 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!..
  • R is -CH 3 or -CH 2 CH 3
  • Y 1 , Y 2 , and Y 7 are as defined in Formula I Scheme 1 shows two routes to prepare intermediate 5, which is used to prepare compounds of the present invention.
  • alkyl bromide 1 is reacted with trimethysilylcyanide and TBAF to give intermediate 2, which undergoes acidic hydrolysis in the presence of an alcohol (R-OH) at elevated temperature to give intermediate 5.
  • acid intermediate 3 is iodinated with iodobenzene diacetate, palladium acetate, and iodine at elevated temperature to give intermediate 4, which undergoes Fischer esterification in the presence of alcohol R-OH to give intermediate 5.
  • W is -Br, -CO 2 CH 3 , or -CO 2 CH 2 CH 3
  • R 4 , Z 1 , Z 2 , and Z 3 are as defined in Formula I
  • Scheme 2 shows the preparation of intermediate 9, which is used to prepare compounds of the present invention.
  • Aryl fluoride 6 undergoes nucleophilic aromatic substitution (S N Ar) with amine 7 and a carbonate base at elevated temperature to give intermediate 8, which is then reduced to diamine intermediate 9 using a palladium catalyst and hydrogen gas.
  • W is -Br, -CO 2 CH 3 , or -CO 2 CH 2 CH 3
  • R is C 1 C 4 alkyl, optionally substituted as defined in Formula I
  • aryl difluoride 10 undergoes SxAr with amine 7 using a carbonate base at elevated temperature to give intermediate 12, which then undergoes a second SxAr with the sodium alkoxide of alcohol 11 to give intermediate 14.
  • these two steps are performed in the opposite order.
  • Scheme 4 shows the preparation of intermediates 19 and 20, which are used to prepare compounds of the present invention.
  • Intermediate 15 is brominated with N- bromosuccinimide and AIBN at elevated temperature to give intermediate 16, which is then alkylated with intermediate 25 using a carbonate base to give halogenated intermediate 17.
  • Intermediate 17 undergoes a Suzuki coupling with allylboronic acid pinacol ester using a palladium catalyst and carbonate base at elevated temperature to give allyl intermediate 18, which then undergoes a cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst and organic base at elevated temperature to give olefin intermediate 19.
  • the alkene can be reduced under hydrogen gas using platinum oxide and acetic acid or a rhodium catalyst to give alkane intermediate
  • Scheme 5 shows the preparation of intermediates 23 and 24, which are used to prepare compounds of the present invention.
  • Alkyl halide 41 is alkylated with intermediate 25 using a carbonate base to give intermediate 42, which is reduced to give alcohol 43 using NaBH 4 .
  • Alcohol 43 is then oxidized using manganese dioxide to give aldehyde 21, which is then reacted with vinylmagnesium bromide to give alkene intermediate 22.
  • Intermediate 22 undergoes a cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst and organic base at elevated temperature to give ketone intermediate 23. The ketone may then be reduced to give alcohol intermediate 24 using NaBH 4 .
  • Scheme 6 shows the preparation of intermediates 23 and 24, which are used to prepare compounds of the present invention.
  • Scheme 6 shows the preparation of intermediates 29, 30, and 33, which are used to prepare compounds of the present invention.
  • Intermediate 17 (see Scheme 4) first undergoes a cross-coupling with olefin 31 using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 32, then another cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst, carbonate base, and silver oxide at elevated temperature gives intermediate 33.
  • intermediate 17 is coupled with 2-[(E)-2-ethoxyvinyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 26, which is then converted to aldehyde intermediate 27 under acidic conditions.
  • Intermediate 27 is reacted with vinylmagnesium bromide to give alkene intermediate 28, which is then cross-coupled with aryl halide 5 (see Scheme 1) using a palladium catalyst and an organic base at elevated temperature to give intermediate 29.
  • the ketone then is optionally reduced using NaBEU to give intermediate 30.
  • Scheme 7 shows the preparation of compounds of the present invention starting with dihalo intermediate 34.
  • Intermediate 34 is cyclized to intermediate 36 via boronic ester intermediate 35, either in one pot or in two discrete steps, coupling first with bis(pinacolato)diboron using a palladium catalyst and a potassium carboxylate base and then undergoing an intramolecular cross-coupling reaction using a palladium catalyst and a phosphate base.
  • Acid intermediate 36 is then hydrolyzed in an aqueous/organic solvent mix with an organic base to give intermediate 37.
  • Amide coupling with diamino intermediate 9 and acid intermediate 37 using e.g. HATU and an organic base gives intermediate 38, which is cyclized using acetic acid at elevated temperature to give intermediate 39.
  • 6-Bromopyridin-2-ol (2.8 g, 16 mmol) and silver carbonate (8.6 g, 31 mmol) was added to a solution of 5-(bromomethyl)-2-chloro-4-iodopyridine (5.0 g, 14 mmol) in toluene (73 mL). The mixture was stirred at 80 °C overnight. The crude suspension was concentrated and the residue was purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give 750 mg of the title compound (10%). ESMS m/z 426 (M+H).
  • the output was directly added to a stirring suspension of 6-chloropyridin-2-ol (21.8 g, 168 mmol) and potassium carbonate (44.1 g, 319 mmol) in ACN (400 mL). The mixture was stirred at RT for 1 h.
  • the reaction vessel was purged with nitrogen, sealed, and stirred at ambient temperature for 10 min.
  • the mixture was diluted with water to 13 mL final volume, shaken for 5 min, then centrifuged. The supernatant was pipetted off, and the solid reslurried/centrifuged twice from water (each 12 mL). Material from a test reaction (0.112 mmol scale) was added.
  • the damp solid was suspended in THF (25 mL) and concentrated under reduced pressure at 50 °C, then the process was repeated twice more to afford the crude amide intermediate.
  • ES-MS m/z 619 (M+H) + .
  • a distereomeric mixture of the title compound was prepared essentially as described in Preparation 52 using and methyl (S)-4-amino-3-ethoxy-5-((oxetan-2- ylmethyl)amino)benzoate, purifying twice by silica gel chromatography (0-10% EtOH in DCM, then with 20-100% EtOAc in cyclohexane), then the diastereomeric mixture was separated using supercritical fluid chromatography under the conditions described in Preparation 52 to give Isomer 1 (first-eluting isomer, 86 mg, 42%) and Isomer 2 (second- eluting isomer, 91 mg, 44%).
  • Bromotrimethylsilane (35.0 mL, 265 mmol) was added to a solution of methyl 5,6-dichloropyridine-2-carboxylate (27.0 g, 131 mmol) in propionitrile (250 mL). The mixture was heated to 100 °C for 17 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with half-saturated aqueous sodium bicarbonate solution (200 mL). The aqueous layer was extracted with EtOAc (100 mL), then the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 42.0 g of the title compound (>100%), which was used without further purification. ES-MS m/z 250 and 252 (M+H).
  • sodium borohydride (4.08 g, 108 mmol) was added portionwise to a solution of methyl 2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-benzoate (10.77 g, 35.58 mmol) in THF (90 mL) and MeOH (45 mL). The resulting solution was stirred for 10 min at 0 °C before warming to RT and stirring for 3 h. More sodium borohydride (2 g, 50 mmol) was added and stirring was continued for 2 h. A final quantity was added of sodium borohydride (2 g, 50 mmol) and stirring was continued for 30 min before quenching with water (50 mL).
  • Citric acid (15% aq, 10 mL) was added dropwise forming a white solid.
  • the suspension was partitioned between DCM (200 mL) and water (50 mL).
  • the aqueous layer was separated and extracted with DCM (5 * 100 mL).
  • the combined organic layers were dried (MgSCL), filtered, and concentrated to afford the title compound (430 mg, 77% purity, 71% yield) which was used without further purification.
  • ES-MS m/z 415 (M+H).
  • the resulting yellow solution was separated from brown oil in the flask by decanting.
  • the yellow solution was extracted with EtOAc (100 mL), diluted with more EtOAc (400 mL), and was used to dissolve the brown oil in the reaction flask.
  • the resulting solution was washed with water (200 mL), half-saturated aq NaHCOs (3 /
  • a mixture of the title compounds was obtained as a brown foam (15 g) which was carried forward without further purification.
  • the mixture was allowed to cool to RT and was filtered through a pad of silica gel.
  • the silica gel and reaction flask were rinsed with dioxane (160 mL) and the filtrate was treated with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'- biphenyl)[2-(2'-amino-l,T-biphenyl)]palladium(II) (1.0 g, 1.2 mmol), water (40 mL), and tribasic potassium phosphate (5.4 g, 25 mmol).
  • the solution was heated at 55 °C for 1 h 20 min.
  • the mixture was allowed to cool to RT, adsorbed onto diatomaceous earth ( ⁇ 10 g), and dried in a vacuum over at 45 °C for 2 h.
  • the product was purified by first by reversed-phase flash chromatography using a Cl 8 column, which was eluted with a gradient of ACN in aqueous mobile phase containing ammonium bicarbonate, followed by SCF chromatography over a Chiralpak® AD-H column (4.6 x 150 mm), which was eluted with 40% isopropanol in CO2 at a rate of 5mL/min to give the title compound was as a white solid (7.8 mg, 54%).
  • Example 12 2-((5 4 -Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l 4 -yl)methyl)-l-(((5)-oxetan-2-yl)methyl)-17/-imidazo[4,5-b]pyridine-6-carboxylic acid (mixture of diastereomers)
  • a reaction vessel was charged with l 4 -((6-bromo-l-(((5 -oxetan-2-yl)methyl)-17T- imidazo[4,5-Z>]pyridin-2-yl)methyl)-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-5 4 -carbonitrile (81 mg, 0.13 mmol), bis(benzonitrile)palladium chloride (5.4 mg, 0.013 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.013 mmol).
  • the vessel was purged with nitrogen and anhydrous DMF (2.5 mL) was added.
  • the mixture was stirred at ambient temperature while purging with nitrogen for 5 min, then phenyl formate (75 pL, 0.64 mmol) and TEA (110 pL, 0.78 mmol) were added, and the vessel was sealed.
  • the mixture was stirred at ambient temperature for 10 min and then at 60 °C in a preheated bath for 7 h.
  • the mixture was cooled to ambient temperature, and aqueous citric acid (5% w/v) was added.
  • the solid was collected by filtration and washed with water.
  • reaction solution was adsorbed onto C18 (25 g) and dried in a vacuum oven for 1 h at 50 °C, then purified via reversed phase flash chromatography on a Cl 8 column using a gradient of 5 to 80% ACN in aqueous 10 mM ammonium carbonate to afford the title compound as a white solid (mixture of diastereomers, 93 mg, 95%).
  • the mixture was stirred at 40 °C for 18 h and then allowed to cool to RT and adsorbed onto diatomaceous earth (20 g).
  • the diatomaceous earth was dried in a vacuum oven for 2 h at 50 °C and then loaded directly onto a silica gel chromatography column for purification.
  • the product mixture co-eluted using a gradient of 0 to 10% MeOH in DCM containing acetic acid (1%) to give a product mixture as a yellow solid (1.35 g).
  • Example 21a The des-hydroxy product (Example 21a) was obtained as a white solid after subsequent purification by HPLC using a gradient of 25 to 40% ACN in 10 mM aqueous ammonium carbonate containing 5% MeOH (39 mg, 3%).
  • the hydroxy product diastereomeric mixture was obtained as a white solid after further purification of the mixture by preparative HPLC using a gradient of 5 to 100% ACN in 0.1% aqueous formic acid (190 mg, 14%).
  • a 150 mg portion of the diastereomeric mixture was dissolved in a mixture of DCM (1.5 mL) and MeOH (8 mL).
  • Example 22 -2-((5 4 -Chloro-6-oxo-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l 4 -yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
  • reaction mixture was adsorbed onto diatomaceous earth (10 g), dried in a vacuum oven at 50 C for 1.5 h, and purified by reversed phase flash chromatography on a C18 column using a gradient of 10 to 80% ACN in 10 mM aqueous ammonium bicarbonate to afford the title compound as a white solid (21 mg, 84%).
  • Example 23 2-((5 4 -Cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclononaphane- l 4 -yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (Isomer 1 - Example 23a, and Isomer 2 - Example 23b)
  • 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 EC 50 value and percent top (E max ) 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 EC 50 and Emax data when the compounds of Examples 1 to 23 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 23 are agonists of the human GLP-1 receptor.

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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, WO2021/018023, 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, 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, CN114763352, WO2022/165076, CN114907351, WO2022/184849, WO2022/192428, WO2022/192430, WO2022/202864, WO2022/199458, WO2022/199661, WO2022/216094, WO2022/219495, WO2022/225914 and WO2022/225941.
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 especially a need for potent GLP-1R agonists which have a favorable toxicology profile and/or a pharmacokinetic profile which supports once daily dosing. Accordingly, the present invention provides a compound of the formula:
Figure imgf000003_0001
wherein -A- is C3-C4alkylene optionally substituted with OH, halo or oxo, or C3-C4 alkenylene;
Figure imgf000003_0002
wherein a is the point of attachment to linker A; b is the point of attachment of linker B;
X1, X2, X3 and X4 are independently N, CH or CR1, wherein no more than two of X1, X2, X3 and X4 are N and no more than two of X1, X2, X3 and X4 are CR1;
X5 is N, CH or CRla, X6, X7 and X8 are independently N, CH or CR1, wherein no more than two of X5, X6, X7 and X8 are N and no more than two of X5, X6, X7 and X8 are CRla or CR1;
R1 at each occurrence is independently CN; halo; C1-C3alkyl optionally substituted with OH; C1-C3haloalkyl; C1-C3alkoxy; C3-C5cycloalkyl; -SO2C1-C3alkyl; Q
Figure imgf000003_0003
wherein each X is independently CH or N and no more than one X9 in the ring is N, each Re is independently selected from: H, C1- C3haloalkyl, halo, C3-C5cycloalkyl and C1-C3alkyl optionally substituted with OH, Rh is H, C1-C3haloalkyl, halo, C3-C5cycloalkyl, OH, -NRcRd or C1-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: C1-C3alkoxy, C3- C5cycloalkyl, -C^-C3-C5cycloalkyl, -SO2C1-C3alkyl, C^C5heterocyclyl, -CH2-C4- C5heterocyclyl, halo, C1-C3haloalkyl, C1-C3haloalkoxy, CN, -CONRcRd, -NRcRd or C1- Qalkyl optionally substituted with OH;
Rla is CN; halo; C1-C3alkyl optionally substituted with OH; C1-C3haloalkyl; or C1- C 3 alkoxy;
-B- is -CH2O-, -OCH2- or -CH2NH-;
Y1, Y2 and Y7 are independently N, CH or CR2, wherein no more than one of Y1, Y2 and Y7 is N and no more than two of Y1, Y2 and Y7 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;
Z1, Z2 and Z3 are independently N, CH or CR3, wherein no more than two of Z1, Z2 and Z3 are N and no more than two of Z1, Z2 and Z3 are CR3;
R3 at each occurrence is independently halo; C1-C4alkyl; -OC4-C6cycloalkyl optionally substituted with C1-C2alkoxy, OH, C1-C3alkyl or C1-C3haloalkyl; -OC4-C6heterocyclyl optionally substituted with C1-C2alkoxy, OH, C1-C3alkyl or C1-C3haloalkyl; or C1- C4alkoxy optionally substituted with one or two substituents selected from: C1-C2alkoxy, OH, -NRfRg, -CONRcRd, CN, halo or 5- or 6- membered heteroaryl optionally substituted with C1-C3alkyl;
Figure imgf000004_0001
Rg and Rd are each independently H or C1-C3alkyl;
Rf is H or C1-C3alkyl; and
Rs is H, C1-C3alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, C(O)C1-C3alkyl, or C1-C3alkylC3- C5cycloalkyl; or a pharmaceutically acceptable salt thereof.
Formula I includes all individual enantiomers, diastereomers, and mixtures thereof, as well as racemates.
In an embodiment, there is provided a compound of the formula:
Figure imgf000005_0001
Formula II or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
Figure imgf000005_0002
or a pharmaceutically acceptable salt thereof.
Figure imgf000005_0004
, ,
Figure imgf000005_0005
embodiment,
Figure imgf000005_0003
are CH; X2 is CR1; and X4 is N.
In an embodiment, only one of X1, X2, X3 and X4 is N. In an alternate embodiment,
Figure imgf000006_0001
one embodiment,
Figure imgf000006_0002
Figure imgf000006_0003
are CH.
In an embodiment, only one of X5, X6, X7 and X8 is N.
In an embodiment, R1 is CN or halo.
In one embodiment,
Figure imgf000006_0004
are CH; X2 is CR1; and
R1 is CN or Cl.
In an alternate embodiment,
Figure imgf000006_0005
; X1 is N; X2 is CR1; X3 and X4 are CH; and R1 is CN.
In an alternate embodiment,
Figure imgf000006_0006
X1 and X4 are CH; X2 is CR1;
X3 is N; and R1 is CN.
In an alternate embodiment,
Figure imgf000006_0007
X1 and X3 are CH; X2 is CR1;
X4 is N; and R1 is Cl.
In an alternate embodiment,
Figure imgf000006_0008
X8 are CH; and R1 is CN or Cl.
In an embodiment, -A- is - CH2CH(OH)CH2CH2-, -CH(OH)CH2CH2-, - CH2CH2CH2-, CH2CH2CH2CH2-, -C(O)CH2CH2- or -CH=CHCH2-. In an embodiment, -B- 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 CH or CR2.
In an embodiment, Y2 is CH.
In an embodiment, Y7 is CH.
In an embodiment, R2 is methyl.
In an embodiment, Y1, Y2 and Y7 are all CH. In an alternate embodiment, Y1 is CR2; Y2 is CH; Y7 is CH; and R2 is methyl.
In an embodiment, Y4, Y5, Y6 and Y7 are all CH.
In an embodiment, Z1 is CH or CR3.
In an embodiment, Z2 is CH.
In an embodiment, Z3 is CH.
In a particular embodiment, Z2 and Z3 are both CH.
In an embodiment, R3 is halo or C1-C4alkoxy, preferably, R3 is F, -OCH3 or - OCH2CH3.
In an embodiment, Z1 is CR3 and R3 is halo or C1-C4alkoxy, preferably, R3 is F, - OCH3 or -OCH2CH3.
In an embodiment, R5 is -CO2H.
In an embodiment, there is provided a compound of the formula:
Figure imgf000007_0001
X1, X3 and X4 are independently N or CH, wherein no more than one of X1, X3 and X4 is N;
R1 is CN or halo;
Y1 is CH or CR2;
R2 is methyl;
Z1 N, CH or CR3;
R3 is halo or C1-C4 alkoxy; or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound selected from: 2-((56-Cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-((56-Cyano-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-((oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-l-((oxetan-2-yl)m ethyl)- 1H-benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-ethoxy-l-((oxetan-2-yl)methyl)- 1H-benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-fluoro-l-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-l-((oxetan-2-yl)methyl)-l/7-imidazo[4,5-Z>]pyridine-6-carboxylic acid;
2-((55-Chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)-benzenacyclononaphane-l4-yl)methyl)-4- m ethoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid;
2-((55-Cyano-3-oxa-2,5(2,6)-dipyridina-l(l,3)-benzenacyclononaphane-l4-yl)methyl)-4- m ethoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylic acid; 2-((55-Cyano-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1H-bbenzo[ ]imidazole-6-carboxylic acid; 2-((55-Chl oro-3 -oxa-2(2, 6), 5(2,3 )-dipyridina- 1(1,3 )-benzenacy clooctaphane- 14- yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1H-bbenzo[ ]imidazole-6-carboxylic acid; 2-((54-chl oro-3 -oxa-2(2,6)-pyridina- 1(1, 3), 5(1 ,2)-dibenzenacyclooctaphan-6-en- 14- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)methyl)-4-fluoro- 1 -((oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylic acid;
2-((54-Cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-l-((oxetan-2-yl)methyl)-lH-benzo[d]imidazole- 6-carboxylic acid;
2-((54-Chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; 2-((54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- 14-yl)methyl)-4-methoxy- l -((oxetan-2-yl (methyl )- l/7-benzo[d]imidazole-6-carboxylic acid;
2-((54-Chloro-6-oxo-3 -oxa-2(2, 6)-pyridina- 1(1, 3), 5(1 ,2)-dibenzenacy clooctaphane- 14- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; and
2-((54-Cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclononaphane- l4-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-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 Y1, Y2 and Y7 containing ring. For example, in the group -CH(OH)CH2CH2- the carbon substituted with the hydroxy group is attached to the X ring. In linker B, the left hand terminal group is attached to the X ring and the right hand terminal group is attached the Y3 containing ring.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.
The term “C1-Cnalkyl” refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of a C1-C4alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of a C1-C3alkyl group include, but are not limited to, methyl, ethyl and propyl. A C1-C2alkyl group is methyl or ethyl.
The term “C3-C4alkylene” refers to a 3 or 4 carbon alkyl chain which is bonded at each end. The term “C3-C4alkenylene” refers to a 3 or 4 carbon alkenyl chain which is bonded at each end.
The term “C1-Cnhaloalkyl” refers to a C1-Cnalkyl group, as defined herein, which is substituted with one, or more halogen. Examples of C1-C3haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl.
The term “C1-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 C1-C4alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
The term “C1-Cnhaloalkoxy” refers to a C1-Cnalkoxy group, as defined herein, which is substituted with one, or more halogen. Examples of C1-C3haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy and pentafluoroethoxy.
The term “C3-C5cycloalkyl” refers to a monocyclic saturated carbon ring containing between 3 and 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl or cyclopentyl.
The term “C4-C6cycloalkyl” refers to a monocyclic saturated carbon ring containing between 4 and 6 carbon atoms. Specifically, it refers to cyclobutyl, cyclopentyl or cyclohexyl.
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 “C4-C6heterocyclyl” refers to a 4, 5 or 6 membered monocyclic saturated ring containing one or more heteroatoms, for example, pyrrolidine.
The term “C4-C5heterocyclyl” 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, and Illb 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.
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:
Figure imgf000014_0001
Formula Illb, or pharmaceutically acceptable salts thereof.
Although the present invention contemplates all individual enantiomers, mixtures thereof, and racemates, compounds of Formula Ila and Illa, 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; “AIBN” refers to azobisisobutyronitrile; “BHT” refers to butylated hydroxytoluene; “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; “EC50” refers to the concentration of an agent which produces 50% response of the target activity compared to a predefined positive control compound (absolute EC50); “ES/MS” refers to electrospray mass spectrometry; “EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol or ethyl alcohol; “HATU” refers to l- [bis(dimethylamino)methylene]-U/-l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate; “HEK” refers to human embryonic kidney; “HEPES” refers to 4- (2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid; “h” refers to hours or hour; “MeOH” refers to methanol or methyl alcohol; “min” refers to minute or minutes; “MTBE” refers to methyl tert-butyl ether; “RT” refers to room temperature; “SNAr” refers to nucleophilic aromatic substitution; “TBAF” refers to tetrabutyl ammonium fluoride; “TEA” refers triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; and “TMSCN” refers to trimethyl silyl cyanide.
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.
Figure imgf000016_0001
R is -CH3 or -CH2CH3
Y1, Y2, and Y7 are as defined in Formula I Scheme 1 shows two routes to prepare intermediate 5, which is used to prepare compounds of the present invention. In the first route, alkyl bromide 1 is reacted with trimethysilylcyanide and TBAF to give intermediate 2, which undergoes acidic hydrolysis in the presence of an alcohol (R-OH) at elevated temperature to give intermediate 5. In the second route, acid intermediate 3 is iodinated with iodobenzene diacetate, palladium acetate, and iodine at elevated temperature to give intermediate 4, which undergoes Fischer esterification in the presence of alcohol R-OH to give intermediate 5.
Scheme 2
Figure imgf000017_0001
W is -Br, -CO2CH3, or -CO2CH2CH3
R4, Z1, Z2, and Z3 are as defined in Formula I
Scheme 2 shows the preparation of intermediate 9, which is used to prepare compounds of the present invention. Aryl fluoride 6 undergoes nucleophilic aromatic substitution (SNAr) with amine 7 and a carbonate base at elevated temperature to give intermediate 8, which is then reduced to diamine intermediate 9 using a palladium catalyst and hydrogen gas.
Figure imgf000017_0002
W is -Br, -CO2CH3, or -CO2CH2CH3
R is C1C4 alkyl, optionally substituted as defined in Formula I R4, Z2, and Z3 are as defined in Formula I Scheme 3 shows the preparation of intermediate 14 via two routes. In the first route, aryl difluoride 10 undergoes SxAr with amine 7 using a carbonate base at elevated temperature to give intermediate 12, which then undergoes a second SxAr with the sodium alkoxide of alcohol 11 to give intermediate 14. In the second route, these two steps are performed in the opposite order.
Scheme 4
Figure imgf000018_0001
Scheme 4 shows the preparation of intermediates 19 and 20, which are used to prepare compounds of the present invention. Intermediate 15 is brominated with N- bromosuccinimide and AIBN at elevated temperature to give intermediate 16, which is then alkylated with intermediate 25 using a carbonate base to give halogenated intermediate 17. Intermediate 17 undergoes a Suzuki coupling with allylboronic acid pinacol ester using a palladium catalyst and carbonate base at elevated temperature to give allyl intermediate 18, which then undergoes a cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst and organic base at elevated temperature to give olefin intermediate 19. The alkene can be reduced under hydrogen gas using platinum oxide and acetic acid or a rhodium catalyst to give alkane intermediate
20.
Figure imgf000019_0001
Scheme 5 shows the preparation of intermediates 23 and 24, which are used to prepare compounds of the present invention. Alkyl halide 41 is alkylated with intermediate 25 using a carbonate base to give intermediate 42, which is reduced to give alcohol 43 using NaBH4. Alcohol 43 is then oxidized using manganese dioxide to give aldehyde 21, which is then reacted with vinylmagnesium bromide to give alkene intermediate 22. Intermediate 22 undergoes a cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst and organic base at elevated temperature to give ketone intermediate 23. The ketone may then be reduced to give alcohol intermediate 24 using NaBH4. Scheme 6
Figure imgf000020_0001
Scheme 6 shows the preparation of intermediates 29, 30, and 33, which are used to prepare compounds of the present invention. Intermediate 17 (see Scheme 4) first undergoes a cross-coupling with olefin 31 using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 32, then another cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst, carbonate base, and silver oxide at elevated temperature gives intermediate 33.
Alternatively, intermediate 17 is coupled with 2-[(E)-2-ethoxyvinyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 26, which is then converted to aldehyde intermediate 27 under acidic conditions. Intermediate 27 is reacted with vinylmagnesium bromide to give alkene intermediate 28, which is then cross-coupled with aryl halide 5 (see Scheme 1) using a palladium catalyst and an organic base at elevated temperature to give intermediate 29. The ketone then is optionally reduced using NaBEU to give intermediate 30. Scheme 7
Figure imgf000021_0001
Scheme 7 shows the preparation of compounds of the present invention starting with dihalo intermediate 34. Intermediate 34 is cyclized to intermediate 36 via boronic ester intermediate 35, either in one pot or in two discrete steps, coupling first with bis(pinacolato)diboron using a palladium catalyst and a potassium carboxylate base and then undergoing an intramolecular cross-coupling reaction using a palladium catalyst and a phosphate base. Acid intermediate 36 is then hydrolyzed in an aqueous/organic solvent mix with an organic base to give intermediate 37. Amide coupling with diamino intermediate 9 and acid intermediate 37 using e.g. HATU and an organic base gives intermediate 38, which is cyclized using acetic acid at elevated temperature to give intermediate 39. For examples where “W” represents a methyl or ethyl ester, hydrolysis using a guanidine base gives compound 40; for examples where “W” represents a bromine, compound 40 is obtained via carbonylation using a palladium catalyst, phenyl formate, and an organic base at elevated temperature.
Preparation 1
Methyl 3 , 5 -difluoro-4-nitro-benzoate
Figure imgf000022_0001
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, CDCl3) δ 7.78 (d, 2H), 4.0 (s, 3H).
Preparation 2
Methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate
Figure imgf000022_0002
A mixture of [(2S)-oxetan-2-yl]methanamine (545 mg, 6.13 mmol), methyl 3,5- difluoro-4-nitro-benzoate (1.4 g, 6.1 mmol), and potassium carbonate (1.7 g, 12 mmol) in ACN (14 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (3 x 14 mL). The combined organic layers were washed with saturated aqueous NaCl (14 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to give 1.68 g of the title compound (79%). ES-MS m/z 285 (M+H).
Preparation 3
Methyl (5)-3-ethoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate
Figure imgf000023_0001
Methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (0.50 g, 1.7 mmol) was dissolved in THF (5 mL) and EtOH (1 mL). The reaction vessel was flushed with nitrogen and the mixture was cooled in an ice bath before addition of sodium ethoxide in EtOH (2.68 M, 1.0 mL, 2.7 mmol) over approximately 10 min. After a further 30 min, 1 M aqueous dipotassium phosphate (25 mL) was added, and the mixture stood overnight at ambient temperature. EtOAc (50 mL) was added, and the phases separated. The organics were concentrated under reduced pressure and the residue coevaporated twice with THF (50 mL). The resulting residue was treated with sodium methoxide in MeOH (0.5 M, 5.0 mL, 2.5 mmol). After 75 min, 1 M aqueous monopotassium phosphate (25 mL) was added, followed by EtOAc (50 mL). The phases were separated, and the organics concentrated under reduced pressure to afford the crude product. The crude product was taken up in DCM and purified by chromatography on silica (0-10% EtOAc in DCM) to afford the title compound (0.29 g, 51%) as an orange- red oil. ES-MS m/z 311 (M+H)+.
Preparation 4
Methyl fS')-4-amino-3-ethoxy-5-((ox etan-2 -ylmethyl)amino)benzoate
Figure imgf000024_0001
A solution of methyl fS')-3-ethoxy-4-nitro-5 -((oxetan-2-yl methyl )amino)benzoate (0.29 g, 0.88 mmol) in EtOAc (5 mL) was charged to a glass tube along with followed by a slurry of palladium on charcoal (10 wt% dry basis, 57.5% water, 0.05 g, 0.02 mmol) in a little further EtOAc. The tube was mounted inside a glass pressure vessel, which was purged twice to 50 psi hydrogen, then refilled to 50 psi hydrogen. The mixture was stirred at ambient temperature for 24 h, then vented. The tube contents were filtered through a plug of diatomaceous earth, rinsing with further EtOAc (15 mL). The filtrate was concentrated under a stream of nitrogen at 40 °C to afford the title compound (258 mg, quantitative yield) as an off-white solid. ES-MS m/z 281 (M+H)+.
Preparation 5
Methyl 3-fluoro-5-methoxy-4-nitro-benzoate
Figure imgf000024_0002
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 x 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 6
Methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate
Figure imgf000025_0001
The title compound was prepareed essentially as described in Preparation 2 using methyl 3-fluoro-5-methoxy-4-nitro-benzoate. The residue was purified via silica gel chromatography using a gradient of 5 to 30% EtOAc in DCM to give the title compound. ES-MS m/z 296 (M+H).
Preparation 7
Methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate
Figure imgf000025_0002
To a solution of methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2- ylmethyl]amino]benzoate (1.68 g, 4.84 mmol) in MeOH (17 mL) was added Lindlar catalyst containing 5% palladium (600 mg, 0.28 mmol). The reaction mixture was stirred at RT for 16 h under an atmosphere of hydrogen gas. The reaction mixture was filtered and concentrated under reduced pressure to give 1.4 g of the title compound (100%), which was carried forward without further purification. ES-MS m/z 255 (M+H).
Preparation 8
Methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate
Figure imgf000025_0003
The title compound was prepared essentially as described in Preparation 7 using methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate. The title compound was carried forward without further purification. ES-MS m/z 267 (M+H).
Preparation 9
6-Bromo-5-(bromomethyl)picolinonitrile
Figure imgf000026_0001
A solution of 6-bromo-5-methyl-pyridine-2-carbonitrile (10 g, 51 mmol), N- bromosuccinimide (16 g, 91 mmol), and AIBN (1.1 g, 6.3 mmol) in 1,2-di chloroethane (170 mL) was stirred at 85 °C for 4 h. The solution was concentrated under vacuum. To the residue was added THF (100 mL), diethyl phosphite (3.4 mL, 26 mmol), and DIPEA (9.0 mL, 52 mmol). The mixture was stirred at RT for 1 h, then diluted with EtOAc (200 mL) and washed with water (100 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in hexanes to give 13.6 g of the title compound (97%). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J= 8 Hz, 1H), 7.70 (d, J= 8 Hz, 1H), 4.59 (s, 2H).
Preparation 10
6-Bromo-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile
Figure imgf000026_0002
A suspension of 6-bromo-5-(bromomethyl)picolinonitrile (13.6 g, 49.4 mmol), 6- chloropyridin-2-ol (7.5 g, 58 mmol), and potassium carbonate (13.7 g, 98.8 mmol) in ACN (300 mL) was stirred at RT for 3 h. The suspension was filtered and the solid was rinsed with ACN. The filtrate was concentrated and the residue was purified via silica gel chromatography using a gradient of 20 to 80% EtOAc in hexanes to give 8.8 g of the title compound (55%). ES-MS m/z 325 (M+H).
Preparation 11
6-Allyl-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile
Figure imgf000027_0001
To a mixture of 6-bromo-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile (5.9 g, 18 mmol), bis(triphenylphosphine)palladium(II) dichloride (640 mg, 0.91 mmol), and potassium carbonate (5.0 g, 36 mmol) was added a solution of allyl boronic acid pinacol ester (5.3 mL, 27 mmol) in 1,4-dioxane (60 mL). Water (1.6 mL, 89 mmol) was added and the mixture was stirred at 90 °C for 3 h. The mixture was diluted with EtOAc (150 mL) and washed with water (150 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 45% EtOAc in hexanes to give 2.4 g of the title compound (46%). ES-MS m/z 286 (M+H).
Preparation 12 2-(4-Bromo-2-iodo-5-methylphenyl)acetic acid
Figure imgf000027_0002
A mixture of 2-(4-bromo-3-methyl-phenyl)acetic acid (14.7 g, 64.0 mmol), iodobenzene diacetate (15.6 g, 48.5 mmol), palladium acetate (1.5 g, 6.9 mmol), iodine (12.2 g, 48.3 mmol) in DMF (275 mL) was stirred at 60 °C under protection from light, for 16 h. The mixture was diluted with EtOAc (200 mL) and washed with a half-saturated aqueous sodium thiosulfate solution (500 mL). The pH of the aqueous layer was adjusted to pH=l and then extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 75% of 1% AcOH in EtOAc in hexanes to give 19.8 g of the title compound (87%). ES-MS m/z 372 and 374 (M+water).
Preparation 13
Ethyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate
Figure imgf000028_0001
A mixture of 2-(4-bromo-2-iodo-5-methylphenyl)acetic acid (19.7 g, 55.5 mmol), EtOH (110 mL), and concentrated sulfuric acid (0.2 mL) was stirred at 75 °C for 7 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with a half- saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 75% EtOAc in hexanes to give 18.0 g of the title compound (85%). ES-MS m/z 400 and 402 (M+water).
Preparation 14
Ethyl 2-(4-bromo-2-(3-(3 -(((6-chloropyri din-2 -yl)oxy)methyl)-6-cyanopyri din-2 - yl)propyl)-5-methylphenyl)acetate
Figure imgf000029_0001
To a solution of 6-allyl-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile (1.85 g, 6.48 mmol) in THF (32 mL) was added 9-borabicyclo[3.3.1]nonane (14 mL, 7.0 mmol, 0.5 M in THF). The mixture was stirred at RT for 2 h. To the solution was added a solution of ethyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate (2.5 g, 6.5 mmol) in THF (30 mL), [l,l’-bis(diphenylphosphino)ferrocene]di chloropalladium (II) (276 mg, 0.373 mmol), potassium carbonate (2.69 g, 19.5 mmol), and water (1.2 mL, 67 mmol). The mixture was stirred at RT for 3 h. An additional portion of water (0.6 mL, 34 mmol) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (220 mg, 0.30 mmol) was added and the mixture was stirred at RT for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with 1 :2 saturated aqueous NaCkwater (30 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 60% EtOAc in hexanes to give 2.0 g of the title compound (58%). ES-MS m/z 542 and 544 (M+H).
Preparation 15
Ethyl 2-(2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6-cyanopyridin-2-yl)propyl)-5- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate
Figure imgf000030_0001
A solution of ethyl 2-(4-bromo-2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6- cyanopyridin-2-yl)propyl)-5-methylphenyl)acetate (1.9 g, 3.5 mmol), bis(pinacolato)diboron (1.4 g, 5.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (286 mg, 0.407 mmol), and potassium 2-ethylhexanoate (1.95 g, 10.7 mmol) in 1,4- dioxane (15 mL) was stirred at 40 °C for 15.5 h. The mixture was diluted with EtOAc (50 mL) and washed with water (10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via C18 reversed phase chromatography using a gradient of 0 to 100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 420 mg of the title compound (20%). ES-MS m/z 590 (M+H).
Preparation 16
Ethyl 2-(56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetate
Figure imgf000030_0002
To a mixture of ethyl 2-(2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6- cyanopyridin-2-yl)propyl)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)acetate (420 mg, 0.712 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,T-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) (XPhos Pd Gen2, 57 mg, 0.070 mmol) was added 1,4-dioxane (14 mL). A solution of potassium phosphate (450 mg, 2.12 mmol) in water (3.5 mL) was then added and the mixture was stirred at 50 °C for 45 min. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in hexanes to give 221 mg of the title compound (71%). ES-MS m/z 428 (M+H).
Preparation 17 2-(56-Cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)acetic acid
Figure imgf000031_0001
To a solution of ethyl 2-(56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina- l(l,3)-benzenacyclooctaphane-l4-yl)acetate (220 mg, 0.514 mmol) in ACN (2.6 mL), water (0.9 mL), and 1,4-dioxane (1.0 mL), was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (233 mg, 1.64 mmol). The mixture was stirred at 45 °C for 2 h, then quenched with aqueous citric acid solution (1 M, 4 mL) and diluted with EtOAc (10 mL). The aqueous layer was removed layer and extracted with EtOAc (2 ^ 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 238 mg of the title compound (>100%), which was carried forward without further purification. ES-MS m/z 400 (M+H).
Preparation 18
Methyl (S)-4-(2-(56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate
Figure imgf000031_0002
To a solution of 2-(56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetic acid (200 mg, 0.5 mmol) and methyl 4-amino-3- [[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695, 135 mg, 0.570 mmol) in DMF (5 mL) was added pyridine (0.40 mL, 4.9 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.7 M in THF, 0.75 mL, 1.3 mmol). The mixture was stirred at RT for 2 h then diluted with water (20 mL). The resulting white solid was collected by vacuum filtration. The solid was washed with water and dried under vacuum to give 247 mg of the title compound (80%). ES-MS m/z 618 (M+H).
Preparation 19
Methyl (S)-2-((56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-l(l,3)- benzenacyclooctaphane- 14-yl)methyl)- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6- carb oxy late
Figure imgf000032_0001
A solution of methyl (S)-4-(2-(56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina- l(l,3)-benzenacyclooctaphane-l4-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (247 mg, 0.399 mmol) in 1,2-di chloroethane (2.0 mL) and acetic acid (2.0 mL) was stirred at 50 °C for 16 h. The crude reaction solution was loaded onto silica and purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in DCM to give 186 mg of the title compound (78%). ES-MS m/z 600 (M+H).
Preparation 22
4-[(6-Bromo-2-pyridyl)oxymethyl]-3-iodo-benzonitrile
Figure imgf000032_0002
To a mixture of 4-(bromomethyl)-3-iodo-benzonitrile (2.88 g, 8.93 mmol), 6- bromopyridin-2-ol (1.10 g, 6.30 mmol), and silver carbonate (5.1 g, 18.0 mmol) was added 1,4-dioxane (50 mL). The reaction mixture was stirred at 60 °C for 15 h, then diluted with EtOAc (50 mL) and filter through diatomaceous earth. The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 5 to 30% EtOAc in hexanes to give 2.8 g of the title compound (76%). ES-MS m/z 415 and 417 (M+H).
Preparation 23
3-Allyl-4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile
Figure imgf000033_0001
To a solution 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (3 g, 7.2 mmol) in 1,4-dioxane (155 mL) under nitrogen was added potassium carbonate (12 g, 86.8 mmol), bis(triphenylphosphine)palladium(II) di chloride (507 mg, 0.7 mmol) and allyboronic acid pinacol ester (2.1 mL, 10.9 mmol). The mixture was stirred at 80 °C for 6 h, then diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 10% EtOAc in heptane to give 1.4 g of the title compound (59%). ES-MS m/z 330 (M+H).
Preparation 24
2-(4-Bromo-2-iodophenyl)acetonitrile
Figure imgf000033_0002
To a solution of 4-bromo-l-(bromomethyl)-2-iodobenzene (10 g, 25.5 mmol) and
TMSCN (4.5 mL, 3.36 g, 33 mmol) in ACN (220 mL) was slowly added tetrabutyl ammonium fluoride hydrate (1 M solution in THF, 33 mL, 33 mmol) at 0 °C. The mixture was stirred at 40 °C for 4 h and the solvent was removed under vacuum. The residue was dissolved in H2O and extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSCU, filtered and evaporated under vacuum. To the residue was added TMSCN (3 mL, 2.07 g, 22.0 mmol) in ACN (220 mL), then tetrabutyl ammonium fluoride hydrate (20 mL, 20 mmol, 1 M) was added slowly at 0 °C. The mixture was stirred at 40 °C for 7 h, then the solvent was removed under vacuum. The residue was dissolved in H2O and extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and evaporated under vacuum. The crude mixture was purified by silica gel chromatography using a gradient of 0 to 15% EtOAc in heptane to afford the title compound (6.13 g, 74%) as a white solid. ES-MS m/z 322 (M+H).
Preparation 25 Ethyl 2-(4-bromo-2-iodo-phenyl)acetate
Figure imgf000034_0001
Sulfuric acid (15 mL, 267 mmol) was slowly added to a suspension of 2-(4- bromo-2-iodophenyl)acetonitrile (6.13 g, 19.0 mmol) in EtOH (57 mL). The colorless solution was stirred at 80 °C for 24 h, then quenched with NaHCOs until pH= 7-8 and the product was extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in heptane to give the title compound (5.47 g, 78%) as a yellow oil. ES-MS m/z 369 (M+H).
Preparation 26
Ethyl 2-[4-bromo-2-[(E)-3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]prop-l- eny 1 ] phenyl ] acetate
Figure imgf000035_0001
To a solution of 3-allyl-4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (1.4 g, 4.3 mmol), ethyl 2-(4-bromo-2-iodo-phenyl)acetate (2 g, 5.4 mmol) and TEA (1.2 mL, 8.6 mmol) in DMF (15 mL) was added palladium(II) acetate (48 mg, 0.21 mmol) and (dicyclohexylphosphino)biphenyl (150 mg, 0.43 mmol). The solution was degassed with nitrogen and stirred at 90 °C for 18 h. The mixture was filtered through diatomaceous earth, then diluted with EtOAc and water. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 100% DCM in heptane to give 1.1 g of the title compound (45%). ES-MS m/z 572 (M+H).
Preparation 27
Ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano- phenyl ] propyl ] phenyl ] acetate
Figure imgf000035_0002
To a solution of ethyl 2-[4-bromo-2-[(E)-3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5- cyano-phenyl]prop-l-enyl]phenyl]acetate (1.1 g, 1.9 mmol) and acetic acid (0.011 mL, 0.2 mmol) in EtOAc (10 mL), was added platinum(IV) oxide (44 mg, 0.20 mmol) and the mixture was stirred under hydrogen balloon at RT for 16 h. The mixture was filtered through diatomaceous earth and the filtrate was diluted with EtOAc and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 100% DCM in heptane to give 0.49 g of the title compound (44%). ESMS m/z 573 (M+H).
Preparation 28
Ethyl 2-(54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-
Figure imgf000036_0001
To a degassed solution of ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2- pyridyl)oxymethyl]-5-cyano-phenyl]propyl]phenyl]acetate (0.48 g, 0.8 mmol) and potassium acetate (247 mg, 2.5 mmol) in 1,4-dioxane (33.5 mL) was added bis(pinacolato)diboron (234 mg, 0.9 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium(II)dichloride DCM complex (35 mg, 0.04 mmol). The mixture was stirred at 100 °C for 4 h, then filtered through diatomaceous earth. Diluted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 100% DCM in heptane to give 90 mg of the title compound (30%). ES-MS m/z 413 (M+H).
Preparation 29 2-(54-Cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetic
Figure imgf000036_0002
To a solution of ethyl 2-(54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)acetate (90 mg, 0.2 mmol) in ACN (6 mL) and water (4 mL) was added l,3,4,6,7,8-hexahydro-2h-pyrimido[l,2-a]pyrimidine (100 mg, 0.7 mmol). The mixture was stirred at 45 °C for 2 h, then quenched to pH 6-7 with formic acid and extracted with cloroform/isopropanol (3: 1). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 85 mg of the title compound (99%). ES-MS m/z 385 (M+H).
Preparation 30
Methyl (S)-4-(2-(54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate
Figure imgf000037_0001
To a solution of 2-(54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)acetic acid (85 mg, 0.22 mmol), methyl 4-amino-3- [[(2S)-oxetan-2-yl]methylamino]benzoate (55 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol) and DMF (2 mL) under nitrogen was added TEA (92 pL, 0.66 mmol). The mixture was stirred at RTfor 1.5 h then quenched with water and diluted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 127 mg of the title compound (97%). ES-MS m/z 603 (M+H).
Preparation 31
Methyl (S)-2-((54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- 14-yl)methyl)- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylate
Figure imgf000037_0002
A solution of methyl (S)-4-(2-(54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)acetamido)-3 -((oxetan-2-ylmethyl)amino)benzoate (127 mg, 0.21 mmol) in acetic acid (2 mL, 34.9 mmol) was stirred at 65 °C for 2 h, then concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in DCM to give 85 mg of the title compound (69%). ES-MS m/z 585 (M+H).
Preparation 32
Methyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate
Figure imgf000038_0001
To a solution of 2-(4-bromo-2-iodo-5-methylphenyl)acetic acid (0.20 g, 0.56 mmol) in MeOH (1.0 mL) was added concentrated sulfuric acid (0.09 mL) and the mixture was stirred at 80 °C for 1 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 220 mg of the title compound (100%).
Figure imgf000038_0002
(t/r>- DMSO) 5 8.00 (s, 1H), 7.37 (s, 1H), 3.77 (s, 2H), 3.63 (s, 3H), 2.28 (s, 3H).
Preparation 33 5-(Bromomethyl)-2-chloro-4-iodopyridine
Figure imgf000038_0003
A solution of 2-chloro-4-iodo-5-methyl-pyridine (25 g, 97 mmol) and N- bromosuccinimide (19.3 g, 106 mmol) in ACN (483 mL) was passed through a photochemical flow reactor equipped with 440-460 nM, 200W lamp, (reactor size = 15m, 15mL, flow=lmL/min, 25°C). The reaction solution was diluted with water (300 mL) and extracted with EtOAc (2 x 300 mL). The combined organics were washed with saturated aqueous NaCl (2 x 300 mL). Dried the organic layer over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give 26.2 g of the title compound (74%). ES-MS m/z 333 (M+H).
Preparation 34
5-(((6-Bromopyridin-2-yl)oxy)methyl)-2-chloro-4-iodopyridine
Figure imgf000039_0001
6-Bromopyridin-2-ol (2.8 g, 16 mmol) and silver carbonate (8.6 g, 31 mmol) was added to a solution of 5-(bromomethyl)-2-chloro-4-iodopyridine (5.0 g, 14 mmol) in toluene (73 mL). The mixture was stirred at 80 °C overnight. The crude suspension was concentrated and the residue was purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give 750 mg of the title compound (10%). ESMS m/z 426 (M+H).
Preparation 35
4-Allyl-5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridine
Figure imgf000039_0002
To a mixture of 5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloro-4-iodopyridine (11 g, 25 mmol) and lithium chloride (3.2 g, 76 mmol) in 1,4-dioxane (130 mL), was added allyltributyltin (10 g, 29 mmol) and tetrakis(triphenylphosphine)palladium (1.5 g, 1.3 mmol). The mixture was stirred at 100 °C for 30 min. The reaction was quenched with saturated aqueous KF solution (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 8% EtOAc in petroleum ether to give 7.2 g of the title compound (80%). ES-MS m/z 341 (M+H). Preparation 36
Methyl (E)-2-(4-bromo-2-(3-(5-(((6-bromopyri din-2 -yl)oxy)methyl)-2-chloropyridin-4- yl)prop- 1 -en- 1 -yl)-5-methylphenyl)acetate
Figure imgf000040_0001
A mixture of 4-allyl-5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridine (0.85 g, 2.4 mmol), methyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate (1.2 g, 3.1 mmol), palladium acetate (54 mg, 0.24 mmol), 2-(cyclohexylphosphino)biphenyl (170 mg, 0.47 mmol), and TEA (0.67 mL, 4.8 mmol) in DMF (24 mL) was stirred at 90 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried the over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 9% EtOAc in petroleum ether to give 519 mg of the title compound (33%). ES-MS m/z 581 (M+H).
Preparation 37
Methyl 2-(4-bromo-2-(3-(5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridin-4- yl)propyl)-5-methylphenyl)acetate
Figure imgf000040_0002
A mixture of methyl (E)-2-(4-bromo-2-(3-(5-(((6-bromopyridin-2-yl)oxy)methyl)- 2-chloropyridin-4-yl)prop-l-en-l-yl)-5-methylphenyl)acetate (0.41 g, 0.62 mmol) and chlorotris(triphyenylphosphine)rhodium (0.34 g, 0.36 mmol) in MeOH (3 mL) was stirred overnight at 60 °C under an atmosphere for hydrogen gas (15 psi). The mixture was concentrated and then diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 18% EtOAc in petroleum ether to give 196 mg of the title compound (49%). ES-MS m/z 583 (M+H).
Preparation 38
Methyl 2-(56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetate
Figure imgf000041_0001
A mixture of methyl 2-(4-bromo-2-(3-(5-(((6-bromopyri din-2 -yl)oxy)methyl)-2- chloropyridin-4-yl)propyl)-5-methylphenyl)acetate (0.14 g, 0.22 mmol), potassium acetate (72 mg, 0.73 mmol), bis(pinacolato)diboron (96 mg, 0.36 mmol), and dichlorobis(tricyclophosphine)palladium (20 mg, 0.026 mmol) in 1,4-dioxane (5.0 mL) was stirred at 90 °C for 5 h. The mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organics were washed with saturated aqueous NaCl (2 X 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 13% EtOAc in petroleum ether to give 38 mg of the title compound (33%). ES-MS m/z 423 (M+H).
Preparation 39
2-(56-Chloro- 16-methyl-3 -oxa-2(2, 6), 5 (3 ,4)-dipyridina- 1(1,3 )-benzenacy cl ooctaphane- 14- yl)acetic acid
Figure imgf000042_0001
To a solution of methyl 2-(56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina- l(l,3)-benzenacyclooctaphane-l4-yl)acetate (165 mg, 0.323 mmol) in ACN (3.5 mL), water (1.7 mL), and 1,4-dixoane (3.5 mL) was added aqueous lithium hydroxide (1 M, 0.7 mL, 0.7 mmol). The mixture was stirred at RT overnight, then quenched with 1 M citric acid solution to pH = 4. The solid was collected by vacuum filtration to give 95 mg of the title compound (68%). ES-MS m/z 409 (M+H).
Preparation 40
Methyl (S)-4-(2-(56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate
Figure imgf000042_0002
To a solution of 2-(56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetic acid (95 mg, 0.22 mmol) and methyl 4-amino-3- methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (80 mg, 0.29 mmol) in DMF (2.5 mL) was added HATU (150 mg, 0.39 mmol) and DIPEA (0.12 mL, 0.68 mmol). The mixture was stirred at RT overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 272 mg was carried forward without further purification (>100%). ES-MS m/z 657 (M+H). Preparation 41
Methyl (S)-2-((56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina-l(l,3)- benzenacy clooctaphane- 14-yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate
Figure imgf000043_0001
A mixture of methyl (S)-4-(2-(56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)- dipyridina-l(l,3)-benzenacyclooctaphane-l4-yl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate (272 mg, 0.25 mmol) in 1,2-di chloroethane (1.0 mL) and acetic acid (1.0 mL) was stirred at 55 °C overnight. The crude solution was concentrated under reduced pressure and azeotroped with 1 : 1 EtOAc:toluene (3 ^ 3 mL). The residue was purified via silica gel chromatography using a gradient of 0 to 3% MeOH in DCM to give 149 mg of the title compound (77%). ES-MS m/z 639 (M+H).
Preparation 42
Methyl (S)-2-((56-cyano-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina-l(l,3)- benzenacy clooctaphane- 14-yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate
Figure imgf000043_0002
To a mixture of methyl (S)-2-((56-chloro-l6-methyl-3-oxa-2(2,6),5(3,4)- dipyridina- 1(1 ,3)-benzenacy clooctaphane- 14-yl)methyl)-4-m ethoxy- 1 -(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (0.14 g, 0.18 mmol), zinc cyanide (0.11 g, 0.93 mmol), palladium trifluoroacetate (15 mg, 0.044 mmol), rac-2-(di-t- butylphosphino)-l,L -binaphthyl (30 mg, 0.074 mmol), zinc (40 mg, 0.60 mmol) was added N,N-dimethylacetamide (1.8 mL). The reaction was stirred at 80 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 33% EtOAc in petroleum ether to give 105 mg of the title compound (83%). ES-MS m/z 630 (M+H).
Preparation 43
2-Chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine
Figure imgf000044_0001
A solution of 4-chloro-2-iodo-l-methyl-benzene (40.0 g, 159 mmol) and N- bromosuccinimide (27.3 g, 153 mmol) in ACN (500 mL) was transferred through a photochemical flow reactor equipped with 4100K, 42W light bulb, (reactor size = 72 feet, of 1/8” outer diameter reaction tubing, flow=1.3 mL/min, 25 °C). The output was directly added to a stirring suspension of 6-chloropyridin-2-ol (21.8 g, 168 mmol) and potassium carbonate (44.1 g, 319 mmol) in ACN (400 mL). The mixture was stirred at RT for 1 h. The suspension was filtered and rinsed with ACN. The filtrate was concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient of 0 to 10% EtOAc in hexanes to give 45.8 g of the title compound (76%). ESMS m/z 380 and 382 (M+H).
Preparation 44
5-Chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzaldehyde
Figure imgf000044_0002
A mixture of 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine (25.0 g, 64.5 mmol) in THF (0.25 L) under nitrogen was added n-butyllithium in hexanes (36 mL, 90 mmol, 2.5 mol/L) by syringe pump over 30 min with cooling in a dry ice-acetone bath. After the addition was complete, the mixture was stirred for a further 10 min and then anhydrous DMF (10.0 mL, 129 mmol) was added. After 15 min, the flask was removed from the cooling bath and left to warm with stirring for 30 min. Saturated aqueous ammonium chloride (50 mL) and water (50 mL) were added and after 2.5 h, the mixture was transferred to a separating funnel and diluted with EtOAc (0.5 L). The aqueous phase was drained off, and the organics were washed with 10% aqueous lithium chloride (2 x 0.1 L) and saturated aqueous NaCl (0.1 L), then dried over MgSCU, filtered and partially concentrated under reduced pressure. When reduced to 0.1 L, the mixture was filtered, and the filtrate was diluted with heptane and then concentrated under reduced pressure at 50 °C to afford the crude title compound (81% purity, 18.51 g, 53.81 mmol) as a pale brown oil. ES-MS m/z 282 and 284 (M+H)+.
Preparation 45 l-[5-Chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-2-en-l-ol (racemic mixture)
Figure imgf000045_0001
5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzaldehyde (81% purity, 18.51 g, 53.15 mmol) was taken up in THF (0.20 L) in a round-bottomed flask with stir bar, septum and nitrogen inlet. The flask was cooled in an ice-water bath and then vinylmagnesium bromide solution in THF (60 mL, 60 mmol, 1.0 mol/L) was added using a syringe pump over 45 min. Stirring was continued for a further 30 min, then saturated aqueous ammonium chloride (0.10 L) and saturated aqueous NaCl (0.10 L) were added to the mixture. The mixture was transferred to a separating funnel and shaken with EtOAc (0.50 L). The aqueous phase was drained off, and the organics were washed with 2 M aqueous tripotassium phosphate (0.10 L) and then with saturated aqueous NaCl (0.10 L), then dried over MgSO4, filtered and concentrated under reduced pressure. When reduced to 0.10 L, the mixture was filtered, and the filtrate diluted with heptane (0.20 L) and concentrated under reduced pressure. The crude product was purified by chromatography on silica (0-10% EtOAc in cyclohexane) to afford the title compound (10.21 g. 62%) as a thick yellow oil. ES-MS m/z 292 and 294 (M-0H)+.
Preparation 46
Ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-oxo- propyl ] phenyl ] acetate
Figure imgf000046_0001
Ethyl 2-(4-bromo-2-iodo-phenyl)acetate (13.31 g, 36.07 mmol) and l-[5-chloro-2- [(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-2-en-l-ol (racemic mixture, 10.20 g, 31.24 mmol) were dissolved in ACN (0.10 L) in a round-bottomed flask with stir bar. TEA (11 mL, 79 mmol) was added and the resulting solution was purged with nitrogen (using a sub-surface needle) with stirring for 20 min. Palladium(II) acetate (0.14 g, 0.62 mmol) was added to the mixture and the nitrogen purge was maintained for a further 10 min. The mixture was heated at 82 °C for 22 h, then the mixture was partially cooled and filtered through paper, with further ACN (0.10 L) as rinse. The filtrate was stirred and diluted to 0.60 L with water. The mixture was seeded with purified product, and a dark solid formed. After 10 min, the solid was collected by filtration and washed with water (0.20 L). The damp solid was dissolved in EtOAc (0.20 L), dried over MgSO4, and eluted through a pad of EtOAc-washed silica (6 cm diameter - 4 cm depth) under suction. The pad was eluted with further EtOAc (0.40 L). The eluate was concentrated under reduced pressure to 0.10 L volume, then swapped into EtOH by put-and-take distillation under reduced pressure at 50 °C, with a final volume of 0.20 L. The flask was transferred to a 50 °C heating block, heating was stopped, and the mixture left to cool slowly with stirring. After 22 h, the solid was collected by filtration and rinsed with EtOH until the filtrate ran clear (70 mL). The filter cake was dried in a vacuum oven (10 mbar, 50 °C) for 26 h to afford the title compound (11.78 g, 68%) as a light grey solid. ES-MS m/z 550, 552 and 552 (M+H)+.
Preparation 47
Ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxy- propy 1 ]pheny 1 ] acetate(racemi c mixture)
Figure imgf000047_0001
Ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3- oxo-propyl]phenyl] acetate (4.99 g, 8.87 mmol) was dissolved in THF (25 mL) in a round- bottomed flask with stirring, and mounted in a water bath at ambient temperature. EtOH (50 mL) was added to the mixture, followed by sodium borohydride (0.17 g, 4.5 mmol). After 1.5 h, aqueous acetic acid (10% v/v, 25 mL) was added and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (0.20 L) and water (0.20 L), and the phases were separated. The organic phase was washed successively with water, 2 M aqueous tripotassium phosphate and then saturated aqueous NaCl (each 50 mL), then dried over MgSCU and filtered. The filtrate was concentrated under reduced pressure, with heptane (50 mL) added when near to completion, to afford the crude title compound (5.11 g, 96%) as a thick brown oil. ES-MS m/z 552, 554 and 556 (M+H)+.
Preparation 48
Ethyl 2-[2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxy-propyl]-4- (4, 4, 5 , 5 -tetramethyl - 1 , 3 , 2 -di oxab orol an-2 -y l)pheny 1 ] acetate (racemi c mixture)
Figure imgf000048_0001
Bis(pinacolato)diboron (3.41 g, 13.2 mmol) and potassium 2-ethylhexanoate (3.35 g, 17.5 mmol) were added to a stirred solution of ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6- chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxy-propyl]phenyl]acetate (racemic mixture, 5.02 g, 8.35 mmol) in 1,4-dioxane (0.10 L) in a round-bottomed flask. A septum with nitrogen needle was fitted to the flask, and the solution was purged with nitrogen for 20 min. Bis(triphenylphosphine)palladium(II) dichloride (0.33 g, 0.46 mmol) was added, and the mixture was heated to 50 °C for 3 h. The mixture was concentrated under reduced pressure, taken up in EtOAc (0.15 L) and washed successively with 2 M aqueous tripotassium phosphate, water and saturated aqueous NaCl (each 70 mL), and then concentrated under reduced pressure. The residue was taken up in DCM and chromatographed on silica (0-10% EtOAc in DCM) to afford the title compound (3.85 g, 69%) as a thick, pale yellow oil that contained 8 wt% residual solvent. ES-MS m/z 600 and 602 (M+H)+.
Preparation 49
Ethyl 2-(54-chl oro-6-hy droxy-3-oxa-2(2, 6)-pyridina-l (1,3), 5(1,2)- dibenzenacyclooctaphane-l4-yl)acetate (racemic mixture)
Figure imgf000048_0002
Ethyl 2-[2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxy- propyl]-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate (racemic mixture, 3.85 g, 5.77 mmol, 90 mass%) was dissolved in THF (0.60 L). Anisole (1.26 mL, 11.6 mmol, internal standard) was added and the mixture was heated to 50 °C. 1 M aqueous tribasic potassium phosphate (60 mL, 60 mmol) was added and the mixture was purged with argon using a sub-surface PTFE canula. After 20 min, [chloro(2- dicyclohexylphosphino-2',4',6'-tri-z-propyl- 1 , 1 '-biphenyl)(2'-amino- 1 , 1 '-biphenyl-2-yl) palladium(II) (0.23 g, 0.29 mmol) was added, and the argon purge continued for a further 5 min. After 3 h, the mixture was cooled, diluted with EtOAc (0.60 L) and the phases were separated. The organic phase was washed successively with 2 M aqueous tripotassium phosphate (50 mL), water (0.10 L) and saturated aqueous NaCl (2 x 50 mL), and then dried over MgSCU, filtered and concentrated under reduced pressure The residue was purified on silica gel (0-20% EtOAc in DCM) to afford the title compound (1.62 g, 62%) as an off-white foam. ES-MS m/z 438 and 440 (M+H)+.
Preparation 50 Ethyl 2-(54-cyano-6-hy droxy-3-oxa-2(2, 6)-pyridina-l (1,3), 5(1,2)- dibenzenacyclooctaphane-l4-yl)acetate (racemic mixture)
Figure imgf000049_0001
A mixture of ethyl 2-(54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)acetate (racemic mixture, 1.01 g, 2.24 mmol) potassium ferrocyanide trihydrate (0.41 g, 1.1 mmol), 1 M aqueous potassium acetate (0.66 mL, 0.66 mmol), 1,4-di oxane (40 mL) and water (20 mL) was purged with argon using a subsurface needle while stirring. After 5 min, chloro(2-dicyclohexylphosphino-2',4',6'-tri-z- propyl-l,l'-biphenyl)(2'-amino-l,l'-biphenyl-2-yl) palladium(II) (92 mg, 0.115 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl] (27 mg, 0.055 mmol) were added and the reaction mixture was heated to 90 °C for 5.5 h under a balloon of argon. The mixture was cooled and combined with material from a test reaction (0.22 mmol scale). The mixture was diluted with EtOAc (50 mL), filtered through diatomaceous earth, and the filter cake rinsed with further EtOAc (50 mL). The phases of the filtrate were separated, and the aqueous extracted with further EtOAc (2 x 25 mL). The organic portions were combined, washed with saturated aqueous NaCl (50 mL), dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (0-20% EtOAc in DCM). The purified product was taken up in DCM, diluted with cyclohexane, and concentrated to afford the title compound (1.04 g, 87%) as a white solid. ES-MS m/z 429 (M+H)+.
Preparation 51 2-(54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4- yl)acetic acid (racemic mixture)
Figure imgf000050_0001
Ethyl 2-(54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)acetate (1.0 g, 2.1 mmol, racemic mixture) was dissolved in ACN (20 mL), THF (7 mL) and water (7 mL) in a glass tube. Triazabicyclo[4.4.0]dec- 5-ene (0.88 g, 6.2 mmol) was added, and a septum with nitrogen inlet needle was fitted. The solution was purged with nitrogen for 5 min, then heated to 40 °C and stirred under a positive pressure of nitrogen. After 2 h, the reaction mixture was poured into water (50 mL). 5% aqueous citric acid (30 mL) was added and the mixture was extracted three times with DCM (60 mL, 30 mL, 30 mL), and the extracts combined, washed with saturated aqueous NaCl (30 mL), dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was taken up in DCM and filtered through a pad of diatomaceous earth. The filtrate was diluted with cyclohexane and then concentrated under reduced pressure to afford the title compound (0.947 g, quant, yield) as a white solid that contained 5 wt% residual solvent. ES-MS m/z 401 (M+H)+. Preparation 52
Methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((5)-oxetan-2-yl)m ethyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 1 and Isomer 2)
Figure imgf000051_0001
2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in EtOAc (1.68 M, 0.67 mL, 1.1 mmol) was added to a stirred solution of 2-(54-cyano-6-hydroxy-3-oxa- 2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetic acid (racemic mixture, 198 mg, 0.445 mmol) and methyl 4-amino-3-[[(25)-oxetan-2- yl]methylamino]benzoate (121 mg, 0.512 mmol) in anhydrous DMF (2 mL) and pyridine (0.4 mL, 5 mmol). The reaction vessel was purged with nitrogen, sealed, and stirred at ambient temperature for 10 min. The mixture was diluted with water to 13 mL final volume, shaken for 5 min, then centrifuged. The supernatant was pipetted off, and the solid reslurried/centrifuged twice from water (each 12 mL). Material from a test reaction (0.112 mmol scale) was added. The damp solid was suspended in THF (25 mL) and concentrated under reduced pressure at 50 °C, then the process was repeated twice more to afford the crude amide intermediate. ES-MS m/z 619 (M+H)+.
The crude amide intermediate was dissolved in acetic acid (7 mL) and 2- chlorotoluene (7 mL), stirred in a 60 °C heating block under nitrogen for 8 h and then concentrated under reduced pressure at 50 °C. The residue was purified by chromatography on silica (0-10% EtOH in DCM) to afford a diastereomeric mixture of the title compound (315 mg, 79%) as a white solid that contained 12 wt% residual solvent.
A portion of the diastereomeric mixture (270 mg, 84 wt% purity, 0.378 mmol) was separated using supercritical fluid chromatography [column: Chiralcel® OD (20 x 250 mm, 5 pm); mobile phase: carbon dioxide (A), (MeOH + 0.5% DMEA) (B), isocratic 40 % B; column temperature: 40 °C; flowrate: 80 mL/min] to give Isomer 1 (first-eluting isomer, 102 mg, 40%) and Isomer 2 (second-eluting isomer, 103 mg, 40%). Both Isomer 1 and Isomer 2: ES-MS m/z 601 (M+H)+.
Preparation 53
Methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-ethoxy-l-(((5)-ox etan-2 -yl)m ethyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 1 and Isomer 2)
Figure imgf000052_0001
A distereomeric mixture of the title compound was prepared essentially as described in Preparation 52 using and methyl (S)-4-amino-3-ethoxy-5-((oxetan-2- ylmethyl)amino)benzoate, purifying twice by silica gel chromatography (0-10% EtOH in DCM, then with 20-100% EtOAc in cyclohexane), then the diastereomeric mixture was separated using supercritical fluid chromatography under the conditions described in Preparation 52 to give Isomer 1 (first-eluting isomer, 86 mg, 42%) and Isomer 2 (second- eluting isomer, 91 mg, 44%). ES-MS m/z 645 (M+H)+.
Preparation 54
Methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)methyl)-4-fluoro- 1 -(((5 -oxetan-2-yl)methyl)- 1/7- benzo[ ]imidazole-6-carboxylate (Isomer 1 and Isomer 2)
Figure imgf000052_0002
A diastereomeric mixture of the title compound was prepared essentially as described in Preparation 52 using methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2- ylmethyl]amino]benzoate. The diastereomers were separated using supercritical fluid chromatography under the conditions described in Preparation 52 to give Isomer 1 (first- eluting isomer) and Isomer 2 (second-eluting isomer. ES-MS m/z 619 (M+H)+.
Preparation 55 (S)-5-Bromo-2-nitro-N-(oxetan-2-ylmethyl)pyridin-3-amine
Figure imgf000053_0001
TEA (2.5 mL, 18 mmol) was added to a solution of 5-bromo-3-fluoro-2- nitropyridine (2.5 g, 11 mmol) in DMF (5 mL). Then, [(2S)-oxetan-2-yl]methanamine (1.0 g, 10 mmol) was added and the mixture was stirred at RT for 2 h. The mixture was diluted with water (30 mL) and the resulting precipitate was collected by filtration to give the title compound (2.8 g, 86%). ES-MS m/z 288 and 290 (M+H)+.
Preparation 56 (S)-5-Bromo-N3-(oxetan-2-ylmethyl)pyridine-2,3-diamine
Figure imgf000053_0002
To a Parr shaker bottle was added 5% sulfided platinum on carbon(469 mg, 2.41 mmol) and EtOAc (60 mL) followed by (S)-5-bromo-2-nitro-N-(oxetan-2- ylmethyl)pyri din-3 -amine (2.4 g, 8.3 mmol) as a solution in EtOAc (60 mL). The reaction vessel was pressurized with 60 psi of hydrogen gas and shaken at RT for 4 h. The reaction mixture was filtered over diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give 2.3 g of the title compound (92%). ES-MS m/z 258 and 260 (M+H)+. Preparation 57 l4-((6-Bromo-l-(((5)-oxetan-2-yl)methyl)-17/-imidazo[4,5-Z>]pyridin-2-yl)methyl)-6- hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-54-carbonitrile (mixture of diastereomers)
Figure imgf000054_0001
A flask was charged with 2-(54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina- l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetic acid (racemic mixture, 290 mg, 0.652 mmol), (5)-5-bromo-N3-(oxetan-2-ylmethyl)pyridine-2,3-diamine (188 mg, 0.728 mmol), anhydrous DMF (3.3 mL) and pyridine (580 pL, 7.17 mmol). The mixture was purged with nitrogen, then 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in EtOAc (1.68 M, 0.97 mL, 1.63 mmol) was added and solution was stirred at ambient temperature. After 30 min, further 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide in EtOAc (1.68 M, 0.97 mL, 1.63 mmol) was added to the mixture. After 30 min, water was added, the mixture was stirred for 5 min, then the solid was collected by filtration and washed with water. The filter cake was dried under reduced pressure at 40 °C overnight. The solid was dissolved in acetic acid (6.5 mL) and stirred at 60°C overnight. The resulting mixture was concentrated to dryness, water was added, and the solid was filtered and washed with water. The solid was purified by chromatography on silica gel (25-100% EtOAc in DCM) to afford the title compound (82 mg, 20%) as a white solid. ES-MS m/z 622 and 624 (M+H)+.
Preparation 58
2-(But-3-en-l-yl)-6-methyl-l,3,6,2-dioxazaborocane-4,8-dione
Figure imgf000054_0002
A solution of but-3-enylboronic acid (19.1 g, 192 mmol) and 4- methylmorpholine-2,6-dione (49.5 g, 383 mmol) in 1,4-di oxane (500 mL) was stirred at 70 °C for 20 h. The suspension was filtered and the solid was rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The resulting solid was suspended in warm acetone (500 mL) and filtered through a pad of silica gel. The silica gel pad was eluted with acetone and the filtrate was concentrated to give 34 g of the title compound (84%). 1H NMR (d6 -DMSO) 5 5.89 (m, 1H), 4.99 (dd, J= 17 and 1.5 Hz, 1H), 4.88 (dd, J = 10.5 and 1.5 Hz, 1H), 4.18 (d, J= 17 Hz, 2 H), 3.98 (d, J= 17 Hz, 2 H), 2.84 (s, 3H), 2.00 (m, 2 H), 0.61 (m, 2H).
Preparation 59 Methyl 6-bromo-5-chloropicolinate
Figure imgf000055_0001
Bromotrimethylsilane (35.0 mL, 265 mmol) was added to a solution of methyl 5,6-dichloropyridine-2-carboxylate (27.0 g, 131 mmol) in propionitrile (250 mL). The mixture was heated to 100 °C for 17 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with half-saturated aqueous sodium bicarbonate solution (200 mL). The aqueous layer was extracted with EtOAc (100 mL), then the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 42.0 g of the title compound (>100%), which was used without further purification. ES-MS m/z 250 and 252 (M+H).
Preparation 60 (6-Bromo-5-chloropyri din-2 -yl)methanol
Figure imgf000055_0002
A solution of methyl 6-bromo-5-chloropicolinate (42.0 g crude) in THF (300 mL) and MeOH (100 mL) was cooled to 0 °C. Sodium borohydride (10.2 g, 270 mmol) was added portionwise and stirred at 0 °C for 30 min. An additional portion of sodium borohydride (2.0 g, 53 mmol) was added and the mixture stirred at RT for 20 min. The reaction was quenched with water (20 mL), diluted with EtOAc (300 mL) and washed with water (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to 27.8 g of the title compound (95%). ES-MS m/z 222 and 224 (M+H).
Preparation 61
2-Bromo-3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridine
Figure imgf000056_0001
A solution of (6-bromo-5-chloropyridin-2-yl)methanol (27.8 g, 125 mmol), 6- chloropyridin-2-ol (18.0 g, 139 mmol), and triphenylphosphine (49.9 g, 190 mmol) in THF (400 mL) was cooled to 0 °C. Diisopropyl azodicarboxylate (38.0 mL, 192 mmol) was added dropwise. The mixture was stirred at 0 °C for 10 min then at RT for 4 h, diluted with EtOAc (600 mL) and washed with 1 :2 saturated aqueous NaCl : water (300 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10 to 25% EtOAc in hexanes to give 25.2 g of the title compound (61%). ES-MS m/z 333, 335, and 337 (M+H).
Preparation 62 2-(4-(3-Chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyri din-2 -yl)butyl)-6-methyl- 1,3, 6, 2-dioxazaborocane-4, 8-dione
Figure imgf000057_0001
9-Borabicyclo[3.3.1]nonane (50 mL, 25 mmol, 0.5 M in THF) was added to a solution of 2-(but-3-en-l-yl)-6-m ethyl- 1, 3,6, 2-dioxazaborocane-4, 8-dione (5.05 g, 23.9 mmol) in THF (150 mL). The mixture was stirred at RT for 2 h. 2-Bromo-3-chloro-6- (((6-chloropyridin-2-yl)oxy)methyl)pyridine (7.91 g, 23.7 mmol), chloro(2- dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl)[2-(2'-amino- 1,1'- biphenyl)]palladium(II) (RuPhos Pd Gen2, 1.3 g, 1.6 mmol), and anhydrous potassium phosphate (15 g, 69 mmol) was added to the resulting white suspension. The mixture was stirred at 50 °C for 7 h. The reaction was diluted with EtOAc (300 mL) and washed with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with 1 : 1 water: saturated aqueous NaCl (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 30% EtOAc in hexanes followed by 0 to 50% acetone in diethyl ether to give 5.8 g of the title compound (53%). ES-MS m/z 466 and 468 (M+H).
Preparation 63
Ethyl 2-(4-bromo-2-(4-(3 -chi oro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyri din-2- yl)butyl)phenyl)acetate
Figure imgf000057_0002
An aqueous solution of sodium hydroxide (1 M, 13 mL, 13 mmol) was added to a solution of 2-(4-(3 -chi oro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyri din-2 -yl)butyl)-6- methyl-l,3,6,2-dioxazaborocane-4,8-dione (2.0 g, 4.3 mmol) in THF (21 mL). The mixture was stirred at RT for 1 h. The mixture was diluted with diethyl ether (25 mL) and washed with saturated aqueous ammonium chloride solution (40 mL). The aqueous layer was extracted with diethyl ether (2 x 25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.9 g of crude boronic acid, which was used immediately. Ethyl 2-(4-bromo-2-iodo- phenyl)acetate (1.6 g, 4.3 mmol) and 1,4-dioxane (42 mL) was added to the boronic acid. Potassium carbonate (3.5 g, 25 mmol), silver oxide (3.0 g, 13 mmol), and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (410 mg, 0.554 mmol) were added. The mixture was placed under a nitrogen atmosphere and heated to 60 °C for 4 h. Water (0.2 mL, 10 mmol) was added and the reaction mixture was heated at 60 °C for 14 h. The reaction was filtered through diatomaceous earth, rinsed with EtOAc, and concentrated. The residue was purified via silica gel chromatography using a gradient of 0 to 45% EtOAc in hexanes to give 1.3 g of the title compound (56%). ES-MS m/z 551 and 553 (M+H).
Preparation 64 Ethyl 2-(55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)-benzenacyclononaphane-l4-yl)acetate
Figure imgf000058_0001
To a mixture of ethyl 2-(4-bromo-2-(4-(3-chloro-6-(((6-chloropyridin-2- yl)oxy)methyl)pyridin-2-yl)butyl)phenyl)acetate (952 mg, 1.72 mmol), bis(pinacolato)diboron (550 mg, 2.17 mmol), potassium acetate (577 mg, 5.88 mmol), and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (130 mg, 0.175 mmol) was added 1,4-dioxane (8.5 mL). The mixture was stirred at 90 °C for 4.5 h. An additional portion of bis(pinacolato)diboron (560 mg, 2.21 mmol) was added and the mixture was stirred at 95 °C for 2 h. The suspension was cooled and filtered through a pad of silica. The solution was eluted with THF (60 mL). Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) (XPhos Pd Gen2, 150 mg, 0.186 mmol) and a solution of potassium phosphate (1.0 g, 4.7 mmol) in water (11 mL) was added to the solution. The mixture was stirred at 55 °C for 1 h. The solution was diluted with EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography using a gradient of 0 to 25% EtOAc in hexanes to give 227 mg of the title compound (30%). ESMS m/z 437 (M+H).
Preparation 65
2-(55-Chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)-benzenacyclononaphane-l4-yl)acetic acid
Figure imgf000059_0001
To a solution of ethyl 2-(55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)- benzenacyclononaphane-l4-yl)acetate (226 mg, 0.517 mmol) in ACN (2.6 mL) and water (0.9 mL), was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (227 mg, 1.60 mmol). The mixture was stirred at 45 °C for 4 h. The reaction was quenched with aqueous citric acid solution (1 M, 5 mL). The solution was diluted with EtOAc (10 mL). The aqueous layer was removed and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 202 mg of the title compound (96%), which was taken forward without further purification. ES-MS m/z 409 (M+H).
Preparation 66
Methyl (S)-4-(2-(55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)-benzenacyclononaphane-l4- yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate
Figure imgf000060_0001
To a solution of 2-(55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)- benzenacyclononaphane-l4-yl)acetic acid (202 mg, 0.494 mmol) and methyl 4-amino-3- methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (147 mg, 0.552 mmol) in DMF (5 mL) was added pyridine (0.40 mL, 4.9 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (1.7 M in EtOAc, 0.75 mL, 1.3 mmol). The mixture was stirred at RT for 2 h. The crude reaction mixture was diluted with water (20 mL). The resulting white solid was collected by vacuum filtration. The solid was washed with water and dried under vacuum to give 286 mg of the title compound (88%). ES-MS m/z 657 (M+H).
Preparation 67
Methyl (S)-2-((55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)-benzenacyclononaphane-l4- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate
Figure imgf000060_0002
A solution of methyl (S)-4-(2-(55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)- benzenacyclononaphane-l4-yl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate (286 mg, 0.434 mmol) in 1,2-di chloroethane (2.5 mL) and acetic acid (2.5 mL) was stirred at 45 °C for 14 h. The solution was heated at 55 °C for an additional hour. The reaction mixture was loaded onto silica gel, concentrated, and purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in hexanes to give 107 mg of the title compound (39%). ES-MS m/z 639 (M+H).
Preparation 68 Methyl 3-bromo-5-chloro-pyridine-2-carboxylate
Figure imgf000061_0001
To a solution of 3-bromo-5-chloro-pyridine-2-carboxylic acid (25.0 g, 100.4 mmol) in MeOH (200 mL) was added sulfuric acid (28.0 mL, 512 mmol) at 0 °C. The mixture was warmed to RT, then heated to 90 °C and stirred for 4 h. The mixture was concentrated under reduced pressure, then the residue was diluted with a saturated solution of NaHCOs (150 mL, 2 N). The aqueous material was transferred to a separatory funnel, then extracted with EtOAc (100 mL) three times. The combined organic extracts were washed with saturated aqueous NaCl (100 mL), dried over magnesium sulfate, filtered, then concentrated under reduced pressure to yield 24.9 g of the title compound as a yellow solid (95%). ES-MS m!z 251.8 (M+l).
Preparation 69
(3-Bromo-5-chloro-2-pyridyl)methanol
Figure imgf000061_0002
To a solution of methyl 3-bromo-5-chloro-pyridine-2-carboxylate (20.0 g, 76.7 mmol) in MeOH (50 mL) and cooled to 0 °C was added NaBH4 (8.79 g, 230 mmol) which had been pre-dissolved in THF (10.0 mL). The solution was stirred at ambient temperature for 5 h, then quenched via the addition of a saturated solution of NH4CI (100 mL). The mixture was transferred to a separatory funnel, further diluted with water (100 mL), then twice extracted with EtOAc (50 mL). The combined organics were washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-26% EtOAc in petroleum ether to afford 17.0 g of the title compound as a pale-yellow solid (98%). ES-MS m/z 224.1 (M+l).
Preparation 70 3-Bromo-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine
Figure imgf000062_0001
To a solution of (3-bromo-5-chloro-2-pyridyl)methanol (10.0 g, 44.1 mmol) and triphenylphosphine (14.0 g, 52.8 mmol) in THF (50 mL) was added 6-chloro-2- hydroxypyridine (6.40 g, 48.0 mmol) and diisopropyl azidodi carb oxy late (10.6 mL, 52.8 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was stirred at ambient temperature overnight and purified via silica gel chromatography using a gradient of 0-10% EtOAc in petroleum ether to afford 15.0 g of the title compound as a pale-yellow solid (83%). ES-MS m/z 334.8 (M+l).
Preparation 71
3-Allyl-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine
Figure imgf000062_0002
To a solution of 3-bromo-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine (12.5 g, 36.7 mmol), tetrakis(triphenylphosphine)palladium(0) (4.37 g, 3.67 mmol), and LiCl (4.66 g, 110 mmol) in 1,4-dioxane (60 mL) was added allyltributyl tin (15.9 g, 46.4 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was heated to 110 °C and stirred for 1 h. The reaction was quenched with a saturated solution of KF (50 mL), then the mixture was transferred to a separatory funnel and extracted with EtOAc (50 mL) three times. The combined organic extracts were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-10% EtOAc in petroleum ether to afford 11.6 g of the title compound as a pale-yellow oil (95%). ES-MS m/z 295.2 (M+l).
Preparation 72 Ethyl 2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-pyridyl]prop- l-enyl]phenyl]acetate
Figure imgf000063_0001
To a solution of 3-allyl-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine (5.0 g, 16 mmol) and ethyl 2-(4-bromo-2-iodo-phenyl)acetate (9.0 g, 22 mmol) in DMF (160 mL) was added Pd(OAc)2, 2-(dicylohexylphosphino)biphenyl (1.1 g, 3.0 mmol), and TEA(4.4 mL, 31 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was heated to 90 °C and stirred overnight. Volatiles were removed under reduced pressure, then the residue was diluted with water (60 mL), transferred to a separatory funnel, and extracted with EtOAc (20 mL) three times. The combined organics were washed with saturated aqueous NaCl (60 mL), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography using a gradient of 0-16% EtOAc in petroleum ether to afford 7.6 g of the title compound as a brown oil (81%). ES-MS m/z 537 (M+l).
Preparation 73
Ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3- py ri dy 1 ]propy 1 ]pheny 1 ] acetate
Figure imgf000063_0002
To a solution of ethyl 2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2- pyridyl)oxymethyl]-3-pyridyl]prop-l-enyl]phenyl]acetate (5.0 g, 8.4 mmol) in MeOH (10.0 mL) was added chlorotris(triphenylphosphine)rhodium(I) (3.2 g, 3.4 mmol) at ambient temperature under an atmosphere of hydrogen (15 PSI). The mixture was stirred overnight at ambient temperature, then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (10 mL) three times. The combined organics were washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography using a gradient of 0-20% EtOAc in petroleum ether to afford 3.71 g of the title compound as a brown oil (72%). ES-MS m/z 539 (M+l).
Preparation 74
Ethyl 2-(55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)acetate
Figure imgf000064_0001
To a solution of ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2- pyridyl)oxymethyl]-3-pyridyl]propyl]phenyl]acetate (2.5 g, 4.1 mmol) and CsF (1.0 g, 6.5 mmol) in 1,4-dioxane (290 mL) was added (2-dicyclohexylphosphino-2',4',6'- triisopropyl-1, l'-biphenyl)[2-(2'-amino-l, l'-biphenyl)]palladium(II) methanesulfonate (350 mg, 0.405 mmol) and hexamethylditin (1.76 g, 5.32 mmol) under a nitrogen atmosphere at ambient temperature. The mixture was heated to 110 °C and stirred overnight. The mixture was diluted with water (50 mL), then extracted with EtOAc (100 mL) three times. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via reverse-phase chromatography [column: YMC -Tri art Prep C18 250 mm x 50 mm, 10 pm; mobile phase: 0.225% aqueous formic acid (A), ACN (B), gradient: 55%-95% solvent B in solvent A], The combined aqueous fractions were lyophilized to afford 220 mg of the title compound as a yellow solid (11%). ES-MS m/z 423.2 (M+l). Preparation 75 2-(55-Chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane-l4-yl)acetic acid
Figure imgf000065_0001
A solution containing ethyl 2-(55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetate (210 mg, 0.447 mmol) in ACN (4.0 mL), water (1.5 mL), and THF (1.5 mL) was sparged with nitrogen. The flask was then charged with l,5,7-triazabicyclo[4.4.0]dec-5-ene (192 mg, 1.35 mmol), sealed with a septum, and flushed with nitrogen. The mixture was stirred at ambient temperature for two hours, then quenched with a 1 M solution of citric acid in water (5 mL, until pH = 4.5). The resultant colorless solid was filtered and dried under vacuum to afford 187.7 mg of the title compound as a colorless solid (99%). ES-MS m/z 395.2 (M+l).
Preparation 76
Methyl (S)-4-(2-(55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate
Figure imgf000065_0002
To a solution of 2-(55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetic acid (180 mg, 0.429 mmol), methyl 4-amino-3- methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (135 mg, 0.502 mmol), and HATU (250 mg, 0.644 mmol) in DMF (4.60 mL) was added DIPEA (0.205 mL, 1.15 mmol) at ambient temperature. The mixture was stirred at ambient temperature for two hours, then diluted with water (15 mL) and extracted with EtOAc (15 mL) three times. The combined organics were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 380 mg of the crude title compound as a pale-yellow solid (99%) that was used without purification. ES-MS m/z 643.3 (M+l).
Preparation 77
Methyl (S)-2-((55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane- 14-yl )methyl )-4-methoxy- l -(oxetan-2-yl methyl )- IH -benzo[d]i mi dazole-6-carboxyl ate
Figure imgf000066_0001
A solution of methyl (S)-4-(2-(55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)- benzenacyclooctaphane-l4-yl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate (370 mg, 0.414 mmol) in 1,2-di chloroethane (4.14 mL) and acetic acid (4.14 mL) was heated to 55 °C under nitrogen and stirred overnight. The volatiles were removed under reduced pressure, then the crude residue was dissolved in toluene (5 mL) and concentrated under reduced pressure (concentration with toluene repeated two additional times). The residue was purified via silica gel chromatography using a gradient of 0-7% MeOH in DCM to afford 281 mg of the title compound as a yellow solid (86%). ES-MS m/z 625.3 (M+l).
Preparation 78
Methyl (S)-2-((55-cyano-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate
Figure imgf000066_0002
A dry round bottom flask was charged with methyl (S)-2-((55-chloro-3-oxa- 2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (210 mg, 0.265 mmol), zinc cyanide (30.0 mg, 0.240 mmol), Pd(TFA)2 (9 mg, 0.03 mmol), rac-2-(di-tert- butylphosphino)-l,E -binaphthyl (22 mg, 0.054 mmol), and zinc (0.1 g, 2 mmol) under nitrogen. The flask was evacuated and refilled with nitrogen three times, then DMF (2.7 mL) was added via syringe. The mixture was heated to 80 °C and stirred overnight. The crude material was diluted with water (5 mL), then extracted with EtOAc (10 mL) two times. The combined organics were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography using a gradient of 0-4% MeOH in DCM to afford 143 mg of the title compound as a brown solid (62%). ES-MS m/z 616.3 (M+l).
Preparation 79
Methyl 2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-benzoate
Figure imgf000067_0001
A mixture of 6-chloropyridin-2-ol (5.37 g, 41.5 mmol), potassium carbonate (10.87 g, 78.65 mmol), and methyl 2-(bromomethyl)-5-cyano-benzoate (10 g, 39 mmol) in ACN (130 mL) was stirred under nitrogen at RT for 4 h. More ACN (50 mL) was added and the mixture was stirred for an additional 15 min. The crude suspension was filtered through a pad of silica, rinsing with ACN. The filtrate was concentrated to afford the title compound (10.77 g, 90%) which was used without further purification. ES-MS m/z 303 (M+l).
Preparation 80
4-[(6-Chl oro-2 -pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile
Figure imgf000068_0001
At 0 °C, sodium borohydride (4.08 g, 108 mmol) was added portionwise to a solution of methyl 2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-benzoate (10.77 g, 35.58 mmol) in THF (90 mL) and MeOH (45 mL). The resulting solution was stirred for 10 min at 0 °C before warming to RT and stirring for 3 h. More sodium borohydride (2 g, 50 mmol) was added and stirring was continued for 2 h. A final quantity was added of sodium borohydride (2 g, 50 mmol) and stirring was continued for 30 min before quenching with water (50 mL). The quenched reaction was partitioned between EtOAc (100 mL) and saturated aqueous NaCl (50 mL). The saturated aqueous NaCl was separated and extracted with more EtOAc (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a crude white solid that was purified by silica gel chromatography to afford the title compound (7.75 g, 79%). ES-MS m/z 275 (M+l).
Preparation 81 4-[(6-Chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile
Figure imgf000068_0002
At RT, a suspension was stirred consisting of manganese dioxide (33 g, 380 mmol) and 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile (10.3 g, 37.5 mmol) in DCM (150 mL). After 3 h, additional manganese dioxide (30 g, 350 mmol) was added and stirring was continued. After 1.5 h, more manganese dioxide (15 g, 170 mmol) was added and stirring continued for 2 h. The reaction suspension was then filtered through diatomaceous earth, rinsing with EtOAc. The filtrate was concentrated to afford the title compound which was used without further purification (8.88 g, 87%). ESMS m/z 273 (M+l).
Preparation 82
4-(((6-Chloropyridin-2-yl)oxy)methyl)-3-(l-hydroxyallyl)benzonitrile (racemic mixture)
Figure imgf000069_0001
Vinylmagnesium bromide (1.0 M in THF, 34 mL, 34 mmol) was added at 0 °C over 15 min to a stirred solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl- benzonitrile (8.88 g, 32.6 mmol) in THF (160 mL). The reaction was stirred for 10 min before adding half-saturated aq NH4CI. The mixture was diluted with EtOAc (100 mL) and the aqueous phase was separated and extracted with additional EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified using silica gel chromatography using a gradient of EtOAc and hexanes to afford the title compound (5.4 g, 17 mmol). ES-MS m/z 283 (M-OH).
Preparation 83
Ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo- propyl ] -5 -methyl -phenyl ] acetate
Figure imgf000069_0002
A mixture of ethyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate (4.5 g, 12 mmol), 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-(l-hydroxyallyl)benzonitrile (racemic mixture, 3.2 g, 11 mmol), palladium(II) acetate (120 mg, 0.53 mmol), TEA (3.7 mL, 27 mmol), and ACN (20 mL) was sparged with nitrogen for 20 min and then heated at 80 °C for 20 h. More palladium(II) acetate (120 mg, 0.53 mmol) was added and heating was conitnued for 5 h. More palladium(II) acetate (120 mg, 0.53 mmol) and TEA (2.2 mL, 16 mmol) was added and heating was continued for 19 h. The mixture was cooled to RT and filtered over a pad of diatomaceous earth, rinsing the pad with EtOAc. The filtrate was concentrated to give a residue that was purified using silica gel chromatography using a gradient of EtOAc and hexanes. The product obtained from flash chromatography was combined with the previously isolated gray solid to give the title compound as an overall off-white solid (3.8 g, 63%). ES-MS m/z 555/557/559 (M+H).
Preparation 84
Ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy- propyl]-5-methyl-phenyl]acetate (racemic mixture)
Figure imgf000070_0001
At RT, sodium borohydride (130 mg, 3.44 mmol) was added to a suspension of ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo- propyl]-5-methyl-phenyl]acetate (3.8 g, 6.8 mmol) in a mixture of EtOH (40 mL) and THF (20 mL). The mixture was stirred for 15 min before quenching with saturated aqueous NaHCO3 (25 mL). The quenched mixture was partitioned between EtOAc (500 mL) and water (100 mL). The organic phase was separated, washed with saturated aqueous NaCl (75 mL), dried over MgSO4, filtered, and concentrated to give the title compound (3.8 g, 100%) which was carried forward without further purification. ES-MS m/z 557/559/561 (M+H).
Preparation 85 Ethyl 2-(54-cyano-6-hy droxy- l6-methyl-3-oxa-2(2, 6)-pyridina-l (1,3), 5(1,2)- dibenzenacyclooctaphane-l4-yl)acetate (racemic mixture)
Figure imgf000071_0001
A mixture of bis(tri-fert-butylphosphine)palladium(0) (420 mg, 0.805 mmol), cesium fluoride (2.50 g, 16.3 mmol), ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2- pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-propyl]-5-methyl-phenyl]acetate (racemic mixture, 3.00 g, 5.38 mmol), and bis(pinacolato)diboron (2.09 g, 8.07 mmol) in 9: 1 MeOH/water (100 mL) was sparged with nitrogen gas for 20 min at RT. The mixture was then warmed to 70 °C and stirred for 20 h. After cooling to RT the mixture was filtered over diatomaceous earth, washing with DCM (25 mL). The filtrate was concentrated and the product was purified via silica gel chromatography using a gradient of EtOAc in DCM. The title compound was obtained as a white solid (408 mg, 17%). ES-MS m/z 443 (M+H).
Preparation 86
2-(54-Cyano-6-hy droxy- l6-methyl-3-oxa-2(2, 6)-pyridina- 1(1, 3), 5(1,2)- dibenzenacyclooctaphane-l4-yl)acetic acid (racemic mixture)
Figure imgf000071_0002
A solution of ethyl 2-(54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetate (racemic mixture, 458 mg, 1.03 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (400 mg, 2.82 mmol) in water (2 mL), 1,4-di oxane (4 mL), and ACN (4 mL) was sparged with nitrogen for 10 min and stirred at RT for 16 h. Citric acid (15% aq, 10 mL) was added dropwise forming a white solid. The suspension was partitioned between DCM (200 mL) and water (50 mL). The aqueous layer was separated and extracted with DCM (5 * 100 mL). The combined organic layers were dried (MgSCL), filtered, and concentrated to afford the title compound (430 mg, 77% purity, 71% yield) which was used without further purification. ES-MS m/z 415 (M+H).
Preparation 87
Methyl 4-(2-(54-cyano-6-hy droxy-l6-methyl-3-oxa-2(2, 6)-pyridina-l (1,3), 5(1,2)- dibenzenacy clooctaphane- 14-yl)acetamido)-3 -fluoro-5-((((5)-oxetan-2- yl)methyl)amino)benzoate (mixture of diastereomers)
Figure imgf000072_0001
A mixture of 2-(54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetic acid (racemic mixture, 200 mg, 77% purity, 0.371 mmol), methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2- ylmethyl]amino]benzoate (104 mg, 0.409 mmol), pyridine (0.300 mL, 3.71 mmol), and 1- propanephosphonic anhydride (50% by mass in DMF, 0.550 mL, 0.933 mmol) were stirred in DMF (4 mL) for 21 h at RT. Water (8 mL) was added to give a white precipitate, and the entire mixture was partitioned between half saturated aq NaHCOs (75 mL) and methylene chloride (200 mL). The organic phase was separated and dried with magnesium sulfate, filtered and concentrated to afford the title compound (265 mg, 70% purity, 77% yield) which was carried forward without further purification. ES-MS m/z 651 (M+H).
Preparation 88
Methyl 2-((54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)methyl)-4-fluoro- 1 -(((5 -oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylate (mixture of diastereomers)
Figure imgf000073_0001
A solution of methyl 4-(2-(54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetamido)-3-fluoro-5-((((5)-oxetan-2- yl)methyl)amino)benzoate (mixture of diastereomers, 235 mg, 70% purity, 0.253 mmol) in a mixture of acetic acid (2 mL) and 1,2-di chloroethane (1 mL) was heated at 55 °C for 18 h. The mixture was warmed to 60 °C for 3 h, and at 65 °C for 48 h. The mixture was cooled to RT, concentrated, and purified by silica gel chromatography using a gradient of EtOAc in hexanes to afford the title compound as a brown oil (99 mg, 62%). ES-MS m/z 633 (M+H).
Preparation 89
Methyl 4-(2-(54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (mixture of diastereomers)
Figure imgf000073_0002
A mixture of 2-(54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetic acid (racemic mixture, 200 mg, 77% purity, 0.371 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (96 mg, 0.40 mmol), pyridine (0.300 mL, 3.71 mmol), and 1 -propan ephosphonic anhydride (50% by mass in DMF, 0.550 mL, 0.933 mmol) was stirred in DMF (4 mL) for 21 h at RT. Water (8 mL) was added to give a white precipitate which was filtered, rinsed with additional water (10 mL), and dried under vacuum to afford the title compound as a white solid (204 mg, 83% purity, 60% yield). ES-MS m/z 635 (M+H). Preparation 90
Methyl 2-((54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((S)-oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylate (Isomer 1 and Isomer 2)
Figure imgf000074_0001
A solution of methyl 4-(2-(54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- l(l,3),5(l,2)-dibenzenacyclooctaphane-l4-yl)acetamido)-3-((((S)-oxetan-2- yl)methyl)amino)benzoate (mixture of diastereomers, 204 mg, 83% purity, 0.267 mmol) in a mixture of acetic acid (2 mL) and 1,2-di chloroethane (1 mL) was heated at 55 °C for 18 h. The mixture was cooled to RT, concentrated, and purified by silica gel chromatography using a gradient of EtOAc in hexanes to afford the title compound as a white solid (mixture of diastereomers, 165 mg, 99%). ES-MS m/z 615 (M+H).
The diastereomeric mixture was dissolved in MeOH (3 mL) and DCM (3 mL), filtered, and eluted through a Chiralpak® AS-H column (30 x 250 mm) using 40% iPrOH (w/ 0.2% IP Am): 60% CO2 at a rate of 90 mL/min to afford Isomer 1 (first-eluting isomer) as a white solid (48.9 mg, >99% de) and Isomer 2 (second-eluting isomer) as a white sold (46.5 mg, >99% de). Both isomers: ES-MS m/z 615.2.0 (M+l).
Preparation 91
2-((2-Allyl-4-chlorobenzyl)oxy)-6-chloropyridine
Figure imgf000074_0002
A mixture of 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine (25.2 g, 66.3 mmol), bis(triphenylphosphine)palladium(II) di chloride (2.4 g, 3.4 mmol), potassium carbonate (18.6 g, 135 mmol), and allylboronic acid pinacol ester (19 mL, 98.3 mmol) were stirred in a mixture of 1,4-dioxane (150 mL) and water (6 mL) at 90 °C. After 5.5 h the reaction mixture was allowed to cool to RT and filtered over a pad of diatomaceous earth and magnesium sulfate. The filtrate was concentrated. The crude product was purified by silica gel chromatography using a gradient of EtOAc and hexanes to give 16.75 g of the title compound (86%). ES-MS m/z 294/296 (M+H).
Preparation 92 (£)-2-(4-Bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2- yl)oxy)methyl)phenyl)allyl)phenyl)acetic acid and
2-[4-Bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-l- enyl] phenyl] acetic acid (mixture of olefin regioisomers)
Figure imgf000075_0001
In DMF (60 mL), stirred 2-(4-bromo-2-iodo-phenyl)acetic acid (15.73 g, 30.45 mmol), 2-((2-allyl-4-chlorobenzyl)oxy)-6-chloropyridine (8.35 g, 28.4 mmol), TEA (7.7 mL, 55 mmol), palladium(II) acetate (320 mg, 1.42 mmol), and 2- (dicyclohexylphosphino)biphenyl (975 mg, 2.78 mmol) were stirred under nitrogen at 90 °C for 16 h. The reaction mixture was allowed to cool to RT and 15% aq citric acid was added (200 mL). The resulting yellow solution was separated from brown oil in the flask by decanting. The yellow solution was extracted with EtOAc (100 mL), diluted with more EtOAc (400 mL), and was used to dissolve the brown oil in the reaction flask. The resulting solution was washed with water (200 mL), half-saturated aq NaHCOs (3 / | 00 mL), and saturated aqueous NaCl (200 mL), before drying over magnesium sulfate, filtering, and concentrating. A mixture of the title compounds was obtained as a brown foam (15 g) which was carried forward without further purification. ES-MS m/z 508 (M+H).
Preparation 93
Methyl (£,£)-4-(2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2- yl)oxy)methyl)phenyl)allyl)phenyl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate and
Methyl 4-[[2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2- pyridyl)oxymethyl]phenyl]prop-l-enyl]phenyl]acetyl]amino]-3-methoxy-5-[[[(2S)- oxetan-2-yl]methyl]amino]benzoate (mixture of olefin regioisomers)
Figure imgf000076_0001
A solution of (£)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2- yl)oxy)methyl)phenyl)allyl)phenyl)acetic acid and 2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6- chloro-2-pyridyl)oxymethyl]phenyl]prop-l-enyl]phenyl]acetic acid (mixture of olefin regioisomers, 7.15 g, 14.1 mmol), methyl 4-amino-3-methoxy-5-[[(25)-oxetan-2- yl]methylamino]benzoate (4.03 g, 15.1 mmol), pyridine (5.6 mL, 69 mmol), and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% in DMF, 21 mL, 35 mmol) was stirred in DMF (28 mL) at RT for 5.25 h and water (150 mL) was added. The resulting paste was taken up in EtOAc. The aqueous layer was separated and extracted with additional EtOAc (100 mL). The organic layers were combined, washed with water (100 mL), dried over MgSO4, filtered, and concentrated to afford the title product (13 g) which was taken forward without purification. ES-MS m/z 756.2 (M+H). Preparation 94
Methyl (S, E)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyri din-2 - yl)oxy)methyl)phenyl)allyl)benzyl)-4-methoxy- 1 -(oxetan-2-ylmethyl)- 1H- benzo[d]imidazole-6-carboxylate and
Methyl 2-[[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-l- enyl]phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5- carboxylate (mixture of olefin regioisomers)
Figure imgf000077_0001
A solution of methyl (£,E)-4-(2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2- yl)oxy)methyl)phenyl)allyl)phenyl)acetamido)-3-methoxy-5-((oxetan-2- ylmethyl)amino)benzoate and methyl 4-[[2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2- pyridyl)oxymethyl]phenyl]prop-l-enyl]phenyl]acetyl]amino]-3-methoxy-5-[[[(2S)- oxetan-2-yl]methyl]amino]benzoate (mixture of olefin regioisomers, 13 g, 14 mmol) in a mixture of 1,2-di chloroethane (32 mL) and acetic acid (32 mL) was heated at 50 °C for 18 h. The temperature was increased to 60 °C for Ih before cooling to RT. The mixture was concentrated and the product was purified by silica gel chromatography using a gradient of EtOAc and hexanes to give the title compound (7.1 g, 73%, mixture of olefin regioisomers). ES-MS m/z 738 (M+H).
Preparation 95 Methyl (S,E)-2-((54-chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphan-
6-en-l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carb oxy late and
Methyl (S,E)-2-((54-chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphan-
7-en-l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylate (mixture of olefin regioisomers)
Figure imgf000078_0001
A mixture of [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (627 mg, 0.848 mmol), bis(pinacolato)diboron (2.48 g, 9.77 mmol), potassium acetate (2.21 g, 22.5 mmol), and methyl (S,E)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2- yl)oxy)methyl)phenyl)allyl)benzyl)-4-methoxy- 1 -(oxetan-2-ylmethyl)- 1H- benzo[d]imidazole-6-carboxylate and methyl 2-[[4-bromo-2-[(E)-3-[5-chloro-2-[(6- chloro-2-pyridyl)oxymethyl]phenyl]prop-l-enyl]phenyl]methyl]-7-methoxy-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate (6.0 g, 8.1 mmol, mixture of olefin regioisomers) in dioxane (40 mL) was heated at 90 °C for 3.5 h before adding additional bis(pinacolato)diboron (440 mg, 1.7 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (160 mg, 0.22 mmol) and heating for an additional 3.5 h. The mixture was allowed to cool to RT and was filtered through a pad of silica gel. The silica gel and reaction flask were rinsed with dioxane (160 mL) and the filtrate was treated with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'- biphenyl)[2-(2'-amino-l,T-biphenyl)]palladium(II) (1.0 g, 1.2 mmol), water (40 mL), and tribasic potassium phosphate (5.4 g, 25 mmol). The solution was heated at 55 °C for 1 h 20 min. After cooling to RT, the reaction mixture was partitioned between EtOAc (200 mL) and half-saturated saturated aqueous NaCl (100 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel chromatography using a gradient of EtOAc and hexanes to afford the title compound as an orange white solid (1.8 g, 36%, mixture of olefin regioisomers). ES-MS m/z 622 (M+H).
Preparation 96
Methyl 2-((54-chl oro-6-hy droxy-3-oxa-2(2, 6)-pyridina-l (1,3), 5(1,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l-(((5)-oxetan-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate and methyl (S)-2-((54-chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate
Figure imgf000079_0001
At RT a solution of borane dimethyl-sulfide complex in THF (1 M, 0.700 mL, 7.52 mmol) was added over 5 min to a solution of methyl (S,E)-2-((54-chloro-3-oxa- 2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphan-6-en-l4-yl)methyl)-4-methoxy-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate and methyl (S,E)-2-((54- chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphan-7-en-14-yl)methyl)- 4-methoxy-l -(ox etan-2 -ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (mixture of olefin isomers, 1.55 g, 2.49 mmol) in THF (30 mL). The reaction was stirred at RT for 4 h and then water (10 mL) and sodium perborate tetrahydrate (4.0 g, 26 mmol) were carefully added. After 2.5 h, the reaction mixture was filtered over diatomaceous earth and concentrated. The crude residue was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc was separated, washed with saturated aqueous NaCl (2 * 75 mL), dried over MgSO4, filtered, and concentrated to give the crude product as a yellow powder (1.55 g). The product mixture contained a 1 :3 ratio of des-hydroxy and hydroxy products and was used in the next step without further purification. Hydroxy product ES-MS m/z 640.0 (M+l). Des-hydroxy product: ES-MS m/z 624.0 (M+l).
Preparation 97
4-[(6-Chl oro-2 -pyridyl)oxymethyl]-3-iodo-benzonitrile
Figure imgf000080_0002
A mixture of 4-(bromomethyl)-3 -iodo-benzonitrile (20 g, 62 mmol), 6- chloropyridin-2-ol (8.5 g, 65 mmol), and silver carbonate (17.1 g, 62.0 mmol) in 1,4- dioxane (600 mL) was stirred at 70 °C for 24 h. The mixture was recharged with 6- chloropyridin-2-ol (1.6 g, 12 mmol) and silver carbonate (3.5 g, 13 mmol) and stirred at 70 °C for 5 h and at RT for 18 h. The mixture was filtered through a pad of silica, rinsed with DCM and concentrated to give 24.5 g of the title compound (107%). ES-MS m/z 371 (M+H)+.
Preparation 98
4-[(6-Chl oro-2 -pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile
Figure imgf000080_0001
A solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (9.2 g, 25 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.5 mL, 31 mmol), bis(triphenylphosphine)palladium(II) dichloride (900 mg, 1.27 mmol), and potassium phosphate (2.0 M in water, 40 mL, 80 mmol) in THF (140 mL) was stirred at reflux for 4 h. The solution was diluted with water (150 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and saturated aqueous NaCl (100 mL) and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography using a gradient of 5 to 50% EtOAc in cyclohexane to give 5.9 g of the title compound (75%). ES-MS m/z 315 (M+H)+.
Preparation 99
4-[(6-Chl oro-2 -pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile
Figure imgf000081_0001
A mixture of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-[(E)-2- ethoxyvinyl]benzonitrile (3.84 g, 12.0 mmol) and hydrochloric acid (4 M in 1,4-dioxane) (18.0 mL, 72.0 mmol) in THF (40 mL) was stirred for 2 h at RT. Then, more hydrochloric acid (4 M in 1,4-dioxane, 40 mL, 40 mmol) was added and the mixture stirred for 2 h at RT and then for a further 2 h at 40 °C. On cooling to RT, the solvents were removed under reduced pressure to give a residue that was taken up in MTBE (100 mL). Water (100 mL) was added and the mixture stirred for 5 min at RT. The organic layer was separated and the aqueous was extracted with MTBE (3 x 100 mL). The combined organic layers were washed with 2 M sodium carbonate aqueous solution (2 x 100 mL), water (100 mL), saturated aqueous NaCl (100 mL) and dried over sodium sulphate. The organic mixture was filtered through a pad of silica gel and the solvents were removed under reduced pressure to give the title compound as a brown solid (5.46 g, 80%). ES-MS m/z 287 (M+H)+.
Preparation 100 4-[(6-Chloro-2-pyridyl)oxymethyl]-3-(2-hydroxybut-3-enyl)benzonitrile (racemic mixture)
Figure imgf000082_0001
A mixture of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (5.45 g, 19.0 mmol) in dry THF (100 mL) was cooled to -20°C. Then, vinylmagnesium bromide solution (1.0 M in THF, 57 mL, 57 mmol) was added dropwise and the mixture stirred for 30 min at RT. The mixture was cooled to -10°C, more vinylmagnesium bromide solution (1.0 M in THF, 20 mL, 20 mmol) was added and the mixture stirred for a further 30 min at RT. On cooling to -10°C, the reaction was quenched with 5% citric acid aqueous solution (100 mL) and EtOAc (100 mL) was added. The mixture was stirred for 10 min at RT, the organic phase separated and the aqueous extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), saturated aqueous NaCl (100 mL), dried over sodium sulphate and the solvents removed under reduced pressure to give a residue that was purified by column chromatography (5% to 50% EtOAc in cyclohexane) to give the title compound as a colourless oil that solidified upon standing (1.85 g, 31%). ES-MS m/z 315 (M+H)+.
Preparation 101
Ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo- buty 1 ]pheny 1 ] acetate
Figure imgf000082_0002
A mixture of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(2-hydroxybut-3- enyl)benzonitrile (racemic mixture, 1.8 g, 5.7 mmol), ethyl 2-(4-bromo-2-iodo- phenyl)acetate (2.50 g, 6.78 mmol) and TEA (2.0 mL, 14 mmol) in ACN (20 mL) was degassed for 10 min (N2 bubbling) at RT. Then, palladium(II) acetate (0.134 g, 0.597 mmo) was added portionwise and the mixture heated at 85 °C for 3 h. On cooling to RT, the solvents were removed under reduced pressure to give a brown residue that was purified by column chromatography (cyclohexane/EtOAc 5% to 70% mixtures as eluants) to give the title compound as a white solid (1.51 g, 47%). ES-MS m/z 555, 557 and 558 (M+H)+ .
Preparation 102
Ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy- butyl]phenyl]acetate (racemic mixture)
Figure imgf000083_0001
A solution of ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano- phenyl]-3-oxo-butyl]phenyl]acetate (1.0 g, 1.8 mmol) in EtOH (8.0 mL) and THF (BHT stabilised) (4.5 mL) was cooled to 0°C. Then, sodium borohydride (100 mg, 2.64 mmol) was added portionwise and the mixture stirred for 30 min at RT. On cooling to 0°C, the reaction was quenched with saturated aqueous sodium bicarbonate (10.0 mL) and EtOAc (20.0 mL) was added. The organic layer separated and the aqueous extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (25 mL), saturated aqueous NaCl (25 mL) and the solvents removed under reduced pressure to give a residue that was purified by silica gel chromatography (5 to 75% EtOAc in cyclohexane) to give the title compound (0.99 g, 99%) as a colorless oil that solidified upon standing. ES-MS m/z 557, 559 and 561 (M+H)+.
Preparation 103
Ethyl 2-[2-[(4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-butyl]-4- (4, 4, 5 , 5 -tetramethyl - 1 , 3 , 2 -di oxab orol an-2 -y l)pheny 1 ] acetate (racemi c mixture)
Figure imgf000084_0001
A mixture of ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano- phenyl]-3-hydroxy-butyl]phenyl]acetate (racemic mixture, 940 mg, 1.68 mmol), bis(pinacolato)diboron (1.31 g, 5.06 mmol) and potassium 2-ethylhexanoate (1.29 g, 6.72 mmol) in 1,4-dioxane (25 mL) was degassed by argon bubbling for 15 min at RT. Then, bis(triphenylphosphine)palladium(II) dichloride (120 mg, 0.167 mmol) was added and the mixture stirred at 60°C for 18 h. On cooling to RT, the solvents were removed under reduced pressure to give a black residue that was purified by filtration through a pad of silica gel using DCM as eluant to give the title compound as a pale brown solid (1.21 g, 1.845 mmol, 100%). ES-MS m/z 605 and 607 (M+H)+.
Preparation 104
Ethyl 2-(54-cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclononaphane-l4-yl)acetate (racemic mixture)
Figure imgf000084_0002
A mixture of ethyl 2-[2-[(4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]- 3-hydroxy-butyl]-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate (racemic mixture, 1.175 g, 1.942 mmol) in THF (BHT stabilized) (200 mL) was degassed with nitrogen bubbling for 15 min at RT. Then, degassed (N2 bubbling for 10 min) IM potassium phosphate tribasic in water (20 mL) was added and the mixture degassed (N2 bubbling) for a further 10 min at RT. Finally, X-Phos-Pd-G2 - [Chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-amino- 1 , 1 '-biphenyl-2-yl) palladium(II)] (160 mg, 0.1993 mmol) was added portionwise and the mixture was stirred for 45 min at 70 °C. On cooling to RT, EtOAc (100 mL) was added. The organic phase was separated and the aqueous extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), saturated aqueous NaCl (50 mL) and the solvents were removed under reduced pressure to give a brown oil that was purified by silica gel chromatography (10 to 100% EtOAc in cyclohexane) to give the title compound as a white solid (243 mg, 28%). ES-MS m/z 443 and 444 (M+H)+.
Preparation 105 2-(54-Cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclononaphane- l4-yl)acetic acid (racemic mixture)
Figure imgf000085_0001
A mixture of ethyl 2-(54-cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclononaphane-l4-yl)acetate (racemic mixture, 225 mg, 0.493 mmol) in ACN (5.0 mL), THF (1.7 mL) and water (1.7 mL) was degassed (N2 bubbling) for 10 min at RT. Then, l,5,7-triazabicyclo[4.4.0]dec-5-ene (210 mg, 1.47 mmol) was added portionwise and the resulting mixture stirred at 50 °C for 1.0 h. On cooling to RT, water (5 mL) was added and 5% aqueous citric acid solution was added dropwise up to pH~5 and the mixture stirred for 15 min at RT. Then, more water (10 mL) was added and the mixture was stirred for a further 30 min. The resulting solid was filtered, washed with water (5 mL) and dried at RT under reduced pressure to give the title compound (154 mg, 75.4%) as a white solid. ES-MS m/z 415 and 416 (M+H)+.
Preparation 106
Methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy cl onaphane-l4-yl)methyl)-l-(((5)-oxetan-2-yl)m ethyl)- 1H- benzo[d]imidazole-6-carboxylate (mixture of diastereomers)
Figure imgf000086_0001
A mixture of 2-(54-cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclononaphane-l4-yl)acetic acid (150 mg, 0.3620 mmol) and methyl 4-amino- 3-[[(2S)-oxetan-2-yl]methylamino]benzoate (121 mg, 0.51213 mmol) in pyridine (0.4 mL) and anhydrous DMF (2 mL) was stirred at RT. Then, 1.68 M 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in EtOAc (0.67 mL, 1.1 mmol) was added dropwise and the mixture stirred for 2 h at RT. The reaction was quenched with 2 M sodium carbonate aqueous solution (10 mL) and EtOAc (10 mL) was added. The organic layer was separated and the aqueous extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), saturated aqueous NaCl (10 mL), dried over sodium sulphate and the solvents removed under reduced pressure to give a brown oil that was taken up in acetic acid (7.5 mL) and 2-chlorotoluene (7.5 mL). The mixture was stirred for 18 h at 60 °C. On cooling to RT, the solvents were removed under reduced pressure to give a residue that was purified by column chromatography (0 to 50% EtOAc in DCM) to give the title compound as a colorless vitreous solid (101 mg, 45%). ES-MS m/z 615 and 616 (M+H)+.
Example 1
(S)-2-((56-Cy ano- 16-methyl-3 -oxa-2(2, 6), 5 (3 ,2)-dipyridina- 1(1,3)- benzenacyclooctaphane- 14-yl)methyl)- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6- carboxylic acid
Figure imgf000086_0002
To a solution of methyl (S)-2-((56-cyano-l6-methyl-3-oxa-2(2,6),5(3,2)- dipyridina-1 (1 ,3)-benzenacyclooctaphane- l4-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1H- benzo[d]imidazole-6-carboxylate (95 mg, 0.16 mmol) in ACN (0.8 mL), 1,4-dioxane (0.8 mL), and water (0.3 mL), was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (85 mg, 0.60 mmol). The mixture was stirred at 30 °C for 5 h. An additional portion of 1,5,7- triazabicyclo[4.4.0]dec-5-ene (10 mg, 0.07 mmol) was added and the mixture was stirred at 35 °C for 2 h. The crude reaction solution was loaded onto silica and the residue was purified via silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give 57 mg of the title compound (59%). ES-MS m/z 586 (M+H).
Example 2 (S)-2-((54-Cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
Figure imgf000087_0001
To a solution of methyl (S)-2-((54-cyano-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylate (85 mg, 0.15 mmol) in ACN (6 mL) and water (4 mL) was added 1, 3, 4, 6,7,8- hexahydro-2h-pyrimido[l,2-a]pyrimidine (81 mg, 0.6 mmol). The mixture was stirred at 45 °C for 2 h. The reaction was quenched to pH 6-7 with formic acid and extracted with cloroform/isopropanol (3: 1). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by Cl 8 reversed phase chromatography using a gradient of 55 to 80% ACN in aqueous ammonium acetate solution to give 29 mg of the title compound (35%). ES-MS m/z 571 (M+H).
Example 3
(S)-2-((56-Cy ano- 16-methyl-3 -oxa-2(2, 6), 5 (3 ,4)-dipyridina- 1(1,3)- benzenacy clooctaphane- 14-yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylic acid
Figure imgf000088_0001
A solution of methyl (S)-2-((56-cyano-l6-methyl-3-oxa-2(2,6),5(3,4)-dipyridina- l(l,3)-benzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (105 mg, 0.148 mmol) and 1,5,7- triazabicyclo[4.4.0]dec-5-ene (60 mg, 0.42 mmol) in ACN (1.5 mL), 1,4-dioxane (0.5 mL), and water (0.5 mL) was stirred overnight at RT. The pH was adjusted to pH = 5 with formic acid and then concentrated under reduced pressure. The residue was purified by Cl 8 reversed phase chromatography using a gradient of 28 to 68% ACN in water containing 0.225% formic acid to give 30 mg of the title compound (32%). ES-MS m/z 616 (M+H).
Example 4
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-
Figure imgf000088_0002
A mixture of 2-((54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l-(((5)-ox etan-2 -yl)m ethyl)- 1H- benzo[d]imidazole-6-carboxylic acid (Isomer 1, see Example 21; 35 mg, 0.056 mmol), potassium ferrocyanide trihydrate (40 mg, 0.11 mmol), chloro(crotyl)(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl) palladium(II) (9 mg, 0.01 mmol), potassium carbonate (8 mg, 0.06 mmol), water (0.75 mL), and 1,4-dioxane (2 mL) was heated at 75 °C for 1 h. The mixture was allowed to cool to RT, adsorbed onto diatomaceous earth (~10 g), and dried in a vacuum over at 30 °C for 16 h. The product was purified reversed phase flash chromatography on a C18 column which was eluted with a gradient of 10 to 90% ACN in aqueous mobile phase containing ammonium bicarbonate. The appropriate fractions were lyophilized to afford the title compound as a white solid (10.5 mg, 31%). ES-MS m/z 617.4 (M+l).
Example 5 2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6- carboxylic acid (Isomer 2)
Figure imgf000089_0001
A mixture of 2-((54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l-(((5)-ox etan-2 -yl)m ethyl)- 1H- benzo[d]imidazole-6-carboxylic acid (Isomer 2, see Example 21; 15 mg, 0.024 mmol), potassium ferrocyanide trihydrate (18 mg, 0.049 mmol), chloro(crotyl)(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl) palladium(II) (4 mg, 0.006 mmol), potassium carbonate (4 mg, 0.029 mmol), water (0.5 mL), and 1,4-dioxane (1 mL) was heated at 90 °C for 1.25 h. The mixture was allowed to cool to RT, adsorbed onto diatomaceous earth (~10 g), and dried in a vacuum over at 45 °C for 2 h. The product was purified by first by reversed-phase flash chromatography using a Cl 8 column, which was eluted with a gradient of ACN in aqueous mobile phase containing ammonium bicarbonate, followed by SCF chromatography over a Chiralpak® AD-H column (4.6 x 150 mm), which was eluted with 40% isopropanol in CO2 at a rate of 5mL/min to give the title compound was as a white solid (7.8 mg, 54%). ES-MS m/z 617.2 (M+l). Example 6 2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-l-(((5)-oxetan-2-yl)m ethyl)- 1H-benzo[d]imidazole-6-carboxylic acid (Isomer 1)
Figure imgf000090_0001
A solution of methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((5)-oxetan-2-yl)m ethyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 1, 102 mg, 0.170 mmol) in a mixture of ACN (3.5 mL), 1,4-di oxane (1.2 mL) and water (1.2 mL) was purged with nitrogen for 5 min, then l,5,7-triazabicyclo[4.4.0]dec-5-ene (74 mg, 0.52 mmol) was added. The mixture was stirred at 60 °C for 70 min, then cooled to ambient temperature. Aqueous citric acid (5% w/v) was added, and organic solvents were removed under a stream of nitrogen. The resulting solid was collected by filtration and washed with water. The filter cake was dried in a vacuum oven at 40 °C overnight to afford the title compound (84 mg, 81%) as a white solid. ES-MS m/z 587 (M+H)+.
Example 7 2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-l-(((5)-oxetan-2-yl)m ethyl)- 1H-benzo[d]imidazole-6-carboxylic acid (Isomer 2)
Figure imgf000090_0002
The title compound was prepared essentially as described in Example 6 using methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((5)-oxetan-2-yl)m ethyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 2). ES-MS m/z 587 (M+H)+.
Example 8
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-ethoxy-l-(((5)-oxetan-2-yl)methyl)- 1H-benzo[d]imidazole-6-carboxylic acid (Isomer 1)
Figure imgf000091_0001
The title compound was prepared essentially as described in Example 6 using methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-ethoxy-l-(((5)-ox etan-2 -yl)m ethyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 1). ES-MS m/z 631 (M+H)+.
Example 9
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-ethoxy-l-(((5)-oxetan-2-yl)methyl)-1H-bbenzo[d]imidazole-6-carboxylic acid (Isomer 2)
Figure imgf000091_0002
The title compound was prepared essentially as described in Example 6 using methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- l4-yl)methyl)-4-ethoxy-l-(((5)-ox etan-2 -yl)m ethyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 2). ES-MS m/z 631 (M+H)+. Example 10
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-fluoro-l-(((5)-oxetan-2-yl)methyl)-1H-bbenzo[d]imidazole-6-carboxylic acid (Isomer 1)
Figure imgf000092_0001
The title compound was prepared essentially as described in Example 6 using methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)methyl)-4-fluoro- 1 -(((5 -oxetan-2-yl)methyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 1). ES-MS m/z 605 (M+H)+.
Example 11
2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-fluoro-l-(((5)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Isomer 2)
Figure imgf000092_0002
The title compound was prepared essentially as described in Example 6 using methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)methyl)-4-fluoro- 1 -(((5 -oxetan-2-yl)methyl)- 1H- benzo[ ]imidazole-6-carboxylate (Isomer 2). ES-MS m/z 605 (M+H)+. Example 12 2-((54-Cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-l-(((5)-oxetan-2-yl)methyl)-17/-imidazo[4,5-b]pyridine-6-carboxylic acid (mixture of diastereomers)
Figure imgf000093_0001
A reaction vessel was charged with l4-((6-bromo-l-(((5 -oxetan-2-yl)methyl)-17T- imidazo[4,5-Z>]pyridin-2-yl)methyl)-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-54-carbonitrile (81 mg, 0.13 mmol), bis(benzonitrile)palladium chloride (5.4 mg, 0.013 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.013 mmol). The vessel was purged with nitrogen and anhydrous DMF (2.5 mL) was added. The mixture was stirred at ambient temperature while purging with nitrogen for 5 min, then phenyl formate (75 pL, 0.64 mmol) and TEA (110 pL, 0.78 mmol) were added, and the vessel was sealed. The mixture was stirred at ambient temperature for 10 min and then at 60 °C in a preheated bath for 7 h. The mixture was cooled to ambient temperature, and aqueous citric acid (5% w/v) was added. The solid was collected by filtration and washed with water. The filter cake was stirred in THF (1.3 mL) and treated with 1 M aqueous lithium hydroxide (0.30 mL, 0.30 mmol, added in 6 portions over 2 h). After 2.5 h, aqueous citric acid (5% w/v) was added. The crude solid was collected by filtration, washed with water, and dried under reduced pressure. The dried solid was taken up in DMSO and purified by reversed-phase flash chromatography (Cl 8 column, gradient of 10 to 100% ACN in aqueous NH4CO3) to afford the title compound (15 mg, 19%) as a pale brown solid. ES-MS m/z 588 (M+H)+.
Example 13
(S)-2-((55-Chl oro-3 -oxa-2, 5(2,6)-dipyridina- 1(1 ,3 )-benzenacyclononaphane- 14- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
Figure imgf000094_0001
To a solution of methyl (S)-2-((55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)- benzenacy clononaphane- 14-yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate (107 mg, 0.167 mmol) in ACN (1.0 mL), 1,4-dioxane (1.0 mL), and water (0.3 mL), was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (75 mg, 0.53 mmol). The mixture was stirred at 55 °C for 3.5 h. The crude reaction solution was loaded onto diatomaceous earth and the residue was purified via C18 reversed phased flash chromatography using a gradient of 0 to 100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 85 mg of the title compound (81%). ES-MS m/z 626 (M+H).
Example 14
(S)-2-((55-Cyano-3 -oxa-2, 5(2,6)-dipyridina- 1(1 ,3 )-benzenacy clononaphane- 14- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
Figure imgf000094_0002
A mixture of methyl (S)-2-((55-chloro-3-oxa-2,5(2,6)-dipyridina-l(l,3)- benzenacy clononaphane- 14-yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate (30 mg, 0.047 mmol), palladium(II) trifluoroacetate (11 mg, 0.031 mmol), zinc (2 mg, 0.03 mmol), zinc cyanide (15 mg, 0.13 mmol), and rac-2- (di-t-butylphosphino-l,L -binaphthyl (22 mg, 0.054 mmol) in N,N-dimethylacetamide (1 mL) was stirred at 80 °C for 16.5 h. The crude reaction mixture was loaded onto diatomaceous earth and the residue was purified via Cl 8 reversed phased chromatography using a gradient of 0 to 60% ACN in 0.1% formic acid in water to give 8.5 mg of the title compound (29%). ES-MS m/z 616 (M+H).
Example 15
(S)-2-((55-Cyano-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- lH -benzo[d]imidazole-6-carboxylic acid
Figure imgf000095_0001
A solution of methyl (S)-2-((55-cyano-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)- benzenacyclooctaphane- 14-yl)methyl)-4-m ethoxy- l-(oxetan-2-ylmethyl)- 1H- benzo[d]imidazole-6-carboxylate (137 mg, 0.158 mmol) in ACN (1.58 mL), water (0.527 mL), and 1,4-dioxane (0.527 mL) was sparged with nitrogen. The flask was then charged with l,5,7-triazabicyclo[4.4.0]-dec-5-ene (67 mg, 0.47 mmol), sealed with a septum, then flushed with nitrogen. The mixture was stirred overnight at ambient temperature, then quenched with an aqueous formic acid solution (0.5 mL) until pH = 4.5. The resultant solid was filtered and dried under vacuum. The residue was purified via reverse phase chromatography using a C18 column (100 mm x 30 mm x 10 μm) and a mobile phase gradient of 40%-70% solvent A in solvent B where solvent A is water containing 0.225% formic acid and solvent B is ACN. The combined fractions were concentrated under reduced pressure to remove organic volatiles, then the residual aqueous solvent was removed via lyophilization to afford 50.2 mg of the title compound as a colorless solid (52%). ES-MS m/z 602.5 (M+l).
Example 16
(S)-2-((55-Chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane-l4- yl)methyl)-4-m ethoxy- 1 -(oxetan-2-ylmethyl)- lH- benzo[d]imidazole-6-carboxylic acid
Figure imgf000096_0001
The title compound was prepared essentially as described in Example 15 using methyl (S)-2-((55-chloro-3-oxa-2(2,6),5(2,3)-dipyridina-l(l,3)-benzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate to give the title compound as a colorless solid. ES-MS m/z 611.5 (M+l).
Example 17
(S,E)-2-((54-chloro-3 -oxa-2(2,6)-pyridina- 1(1 ,3), 5 (1 ,2)-dibenzenacyclooctaphan-6-en- 14- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
Figure imgf000096_0002
A solution of methyl (S,E)-2-((54-chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphan-6-en- 14-yl)methyl)-4-methoxy- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate and methyl (S,E)-2-((54-chl oro-3 -oxa-2(2,6)-pyri dina- 1(1, 3), 5(1 ,2)-dibenzenacy clooctaphan-7 -en- 14-yl)methyl)-4-methoxy- 1 -(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (mixture of olefin regioisomers, 20 mg, 0.032 mmol) and l,5,7-triazabicyclo[4.4.0]dec-5-ene (10 mg, 0.070 mmol) in ACN (0.33 mL), water (0.33 mL), and THF (0.33 mL) was sparged with nitrogen. The mixture was then stirred at 45 °C (16 h), 50 °C (7 h), and 55 °C (14 h). Upon cooling to RT, the product was adsorbed onto diatomaceous earth (10 g) and dried under reduced pressure at 50 °C for 1 h. The diatomaceous earth was used to load the product onto a Cl 8 column which was purified using a gradient of 10 to 90% ACN in aqueous mobile phase containing 10 mM ammonium bicarbonate to give the title compound (12.5 mg, quantitative yield, single olefin regioisomer) as a white solid. ES-MS m/z 608.0 (M+l). Example 18
2-((54-Cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane- 14-yl)methyl)-4-fluoro- 1 -(((S)-oxetan-2-yl)m ethyl)- 1H- benzo[d]imidazole-6-carboxylic acid (Isomer 1 - Example 18a and Isomer 2 - Example 18b)
Figure imgf000097_0001
A solution of methyl 2-((54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- 1(1, 3), 5(1 ,2)-dibenzenacy clooctaphane- 14-yl)methyl)-4-fluoro- 1 -(((5)-oxetan-2- yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (99 mg, 0.16 mmol) in water (0.5 mL), 1,4-di oxane (1 mL), and ACN (1 mL) was sparged with nitrogen for 10 min and stirred at 50 °C for 2 h. The reaction solution was adsorbed onto C18 (25 g) and dried in a vacuum oven for 1 h at 50 °C, then purified via reversed phase flash chromatography on a Cl 8 column using a gradient of 5 to 80% ACN in aqueous 10 mM ammonium carbonate to afford the title compound as a white solid (mixture of diastereomers, 93 mg, 95%). The mixture of diastereomers was dissolved in MeOH (6 mL), filtered, and eluted through a Chiralpak® AS-H column (20 * 150 mm) using 35% EtOH : 65% CO2 at a rate of 80 mL/min to afford Isomer 1 (first-eluting isomer, 43 mg, >98% de) and Isomer 2 (second- eluting isomer, 41 mg, 91% de). Both Isomer 1 and Isomer 2: ES-MS m/z 619.0 (M+l).
Example 19 2-((54-Cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((S)-oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylic acid (Isomer 1)
Figure imgf000097_0002
A solution of methyl 2-((54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina- 1(1, 3), 5(1 ,2)-dibenzenacy clooctaphane- 14-yl)methyl)- 1 -(((S)-oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylate (Isomer 1, 48.9 mg, 0.0796 mmol) in water (0.5 mL), 1,4-di oxane (1 mL), and ACN (1 mL) was sparged with nitrogen for 10 min. 1,5,7- Triazabicyclo[4.4.0]dec-5-ene (30 mg, 0.21 mmol) was added and the mixture was stirred at 50 °C for 2 h. The reaction solution was adsorbed onto C18 (25g) and dried in a vacuum oven for 1 h at 50 °C, then purified by reversed phase flash chromatography on a C18 column using a gradient of 5 to 80% ACN in 10 mM aqueous ammonium carbonate to afford the title compound as a white solid (30 mg, 63%). ES-MS m/z 601.0 (M+H).
Example 20
2-((54-cy ano-6-hydroxy- l6-methyl-3-oxa-2(2, 6)-pyridina-l (1,3), 5(1,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((S)-oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylic acid (Isomer 2)
Figure imgf000098_0001
The title compound was prepared essentially as described in Example 19 using methyl 2- ((54-cyano-6-hydroxy-l6-methyl-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacy clooctaphane- 14-yl)m ethyl)- 1 -(((S)-oxetan-2-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylate (Isomer 2). ES-MS m/z 601.0 (M+H).
Example 21
(5)-2-((54-Chloro-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane-l4- yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
(Example 21a)
Figure imgf000099_0001
2-((54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-m ethoxy- l-(((5)-ox etan-2 -yl)m ethyl)- 1H-benzo[d]imidazole-6- carboxylic acid (Isomer 1 - Example 21b; Isomer 2 - Example 21c)
Figure imgf000099_0002
A mixture of methyl 2-((54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l-(((5)-oxetan-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate and methyl (5)-2-((54-chloro-3-oxa-2(2,6)-pyridina- 1(1, 3), 5(1 ,2)-dibenzenacy clooctaphane- 14-yl)methyl)-4-methoxy- 1 -(oxetan-2-ylmethyl)- lH-benzo[d]imidazole-6-carboxylate (1.35 g, 2.11 mmol) was stirred in a degassed solution of 1 : 1 : 1 ACN, THF, and water (10 mL) containing l,3,4,6,7,8-hexahydro-2h- pyrimido[l,2-a]pyrimidine (1 g, 7 mmol). The mixture was stirred at 40 °C for 18 h and then allowed to cool to RT and adsorbed onto diatomaceous earth (20 g). The diatomaceous earth was dried in a vacuum oven for 2 h at 50 °C and then loaded directly onto a silica gel chromatography column for purification. The product mixture co-eluted using a gradient of 0 to 10% MeOH in DCM containing acetic acid (1%) to give a product mixture as a yellow solid (1.35 g).
The des-hydroxy product (Example 21a) was obtained as a white solid after subsequent purification by HPLC using a gradient of 25 to 40% ACN in 10 mM aqueous ammonium carbonate containing 5% MeOH (39 mg, 3%). ES-MS m/z 610.0 (M+l)
The hydroxy product diastereomeric mixture was obtained as a white solid after further purification of the mixture by preparative HPLC using a gradient of 5 to 100% ACN in 0.1% aqueous formic acid (190 mg, 14%). ES-MS m/z 626.0 (M+l). A 150 mg portion of the diastereomeric mixture was dissolved in a mixture of DCM (1.5 mL) and MeOH (8 mL). The resulting solution was filtered and eluted through a Chiralpak® AS-H column (21 x 150 mm) using 20% MeOH (w/ 0.5% DMEA) : 80% CO2 at a rate of 80 mL/min to afford Isomer 1 (first-eluting isomer - Example 21b) as a white solid (66.2 mg, >99% de) and Isomer 2 (second-eluting isomer - Example 21c) as a white sold (71.9 mg, 94.2% de). Both Isomer 1 and Isomer 2: ES-MS m/z 626.0 (M+l).
Example 22 (5)-2-((54-Chloro-6-oxo-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclooctaphane- l4-yl)methyl)-4-methoxy-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid
Figure imgf000100_0001
A solution of 2-((54-chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclooctaphane-l4-yl)methyl)-4-methoxy-l-(((5)-ox etan-2 -yl)m ethyl)- 1H- benzo[d]imidazole-6-carboxylic acid (25 mg, 1 : 1 diastereomeric mixture, 0.040 mmol) and Dess-Martin periodinane (18 mg, 0.042 mmol) in DCM (0.5 mL) was stirred at rRT for 2.5 h. The reaction mixture was adsorbed onto diatomaceous earth (10 g), dried in a vacuum oven at 50 C for 1.5 h, and purified by reversed phase flash chromatography on a C18 column using a gradient of 10 to 80% ACN in 10 mM aqueous ammonium bicarbonate to afford the title compound as a white solid (21 mg, 84%). ES-MS m/z 624.0 (M+l).
Example 23 2-((54-Cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)-dibenzenacyclononaphane- l4-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (Isomer 1 - Example 23a, and Isomer 2 - Example 23b)
Figure imgf000101_0001
A mixture of methyl 2-((54-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-l(l,3),5(l,2)- dibenzenacyclonaphane- l4-yl)m ethyl)- l-(((5 -oxetan-2-yl)methyl)- 1H- benzo[ ]imidazole-6-carboxylate (mixture of diastereomers, 96 mg, 0.1562 mmol) in ACN (6.5 mL), water (2.0 mL) and 1,4-dioxane (2.0 mL) was degassed for 15 min by bubbling argon gently into the mixture at RT. Then, l,5,7-triazabicyclo[4.4.0]dec-5-ene (67 mg, 0.47 mmol) was added portionwise and the mixture heated at 65 °C for 3 h. On cooling to 0 °C, 5% aqueous citric acid was added up to pH=5, then water (5.0 mL) was carefully added and the mixture stirred for a further 30 min at RT. The resulting solid was filtered, washed with water (10 mL) and dried under vaccum at 40 °C for 72 h to give a mixture of diastereomers of the title compound as a pale pink solid (82 mg, 87%). A portion (65 mg, 0.108 mmol) of the diastereomeric mixture was purified by supercritical fluid chromatography [column: Chiralpack® IH (20 x 250 mm; 5 pm); mobile phase: Solvent A - CO2, Solvent B - MeOH + 0.5% DMEA, isocratic 30% Solvent B in Solvent A; column temperature: 40 °C; flow rate: 80 mL/min] to give Isomer 1 (Example 23a, first-eluting isomer, 18.7 mg, 39%) and Isomer 2 (Example 23b, second-eluting isomer, 18.7 mg, 39%). Both Isomer 1 and Isomer 2: ES-MS m/z 601 and 602 (M+H)+.
Biological Assays
Human GLP-l 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 EC50 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 EC50 and Emax data when the compounds of Examples 1 to 23 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 23 are agonists of the human GLP-1 receptor.
Table 1. HEK293 cell line with 581 fmol/mg expression density of GLP-1R, intracellular cAMP response, relative EC50 and Emax
Figure imgf000102_0001
Figure imgf000103_0001
Table 2. HEK293 cell line with 104 fmol/mg expression density of GLP-1R, intracellular cAMP response, relative EC50 and Emax
Figure imgf000103_0002
Figure imgf000104_0001

Claims

Claims
1. A compound of the formula:
Figure imgf000105_0001
wherein -A- is C3-C4alkylene optionally substituted with OH, halo or oxo, or C3-
C4alkenylene;
Figure imgf000105_0002
wherein a is the point of attachment to linker A; b is the point of attachment of linker B;
X1, X2, X3 and X4 are independently N, CH or CR1, wherein no more than two of X1, X2, X3 and X4 are N and no more than two of X1, X2, X3 and X4 are CR1;
X5 is N, CH or CRla, X6, X7 and X8 are independently N, CH or CR1, wherein no more than two of X5, X6, X7 and X8 are N and no more than two of X5, X6, X7 and X8 are CRla or CR1;
R1 at each occurrence is independently CN; halo; C1-C3alkyl optionally substituted with OH; C1-C3haloalkyl; C1-C3alkoxy; C3-C5cycloalkyl; -SO2C1-C3alkyl;
Figure imgf000105_0003
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, C1- C3haloalkyl, halo, C3-C5cycloalkyl and C1-C3alkyl optionally substituted with OH, Rh is H, C1-C3haloalkyl, halo, C3-C5cycloalkyl, OH, -NRcRd or C1-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: C1-C3alkoxy, C3- C5cycloalkyl, -CH2-C3-C5cycloalkyl, -SO2C1-C3alkyl, C4-C5heterocyclyl, -CH2-C4- C5heterocyclyl, halo, C1-C3haloalkyl, C1-C3haloalkoxy, CN, -CONRcRd, -NRcRd or C1- C3alkyl optionally substituted with OH;
Rla is CN; halo; C1-C3alkyl optionally substituted with OH; C1-C3haloalkyl; or C1- C 3 alkoxy;
-B- is -CH2O-, -OCH2- or -CH2NH-;
Y1, Y2 and Y7 are independently N, CH or CR2, wherein no more than one of Y1, Y2 and Y7 is N and no more than two of Y1, Y2 and Y7 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;
Z1, Z2 and Z3 are independently N, CH or CR3, wherein no more than two of Z1, Z2 and Z3 are N and no more than two of Z1, Z2 and Z3 are CR3;
R3 at each occurrence is independently halo; C1-C4alkyl; -OC4-C6cycloalkyl optionally substituted with C1-C2alkoxy, OH, C1-C3alkyl or C1-C3haloalkyl; -OC4-C6heterocyclyl optionally substituted with C1-C2alkoxy, OH, C1-C3alkyl or C1-C3haloalkyl; or C1- C4alkoxy optionally substituted with one or two substituents selected from: C1-C2alkoxy, OH, -NRfRs, -CONRcRd, CN, halo or 5- or 6- membered heteroaryl optionally substituted with C1-C3alkyl;
Figure imgf000107_0001
Rc and Rd are each independently H or C1-C3alkyl;
Rf is H or C1-C3alkyl; and
Rs is H, C1-C3alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, C(O)C1-C3alkyl, or C1-C3alkylC3- C5cycloalkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein the compound is of the formula:
Figure imgf000107_0002
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein the compound is of the formula:
Figure imgf000107_0003
or a pharmaceutically acceptable salt thereof.
4. The compound according to any one of claims 1 to 3, wherein
Figure imgf000108_0001
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4, wherein X1, X3 and X4 are CH and X2 is CR1, and R1 is CN or Cl, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 4, wherein X1 is N; X2 is CR1; X3 and X4 are CH; and R1 is CN, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 4, wherein X1 and X4 are CH; X2 is CR1; and X3 is N; and R1 is CN, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 4, wherein X1 and X3 are CH; X2 is CR1; X4 is N; and R1 is Cl, or a pharmaceutically acceptable salt thereof.
9. The compound according to any one of claims 1 to 3, wherein
Figure imgf000108_0002
pharmaceutically acceptable salt thereof.
10. The compound according to claim 9, wherein X5 is N; X6 is CR1; and X7 and X8 are CH; and R1 is CN or Cl, or a pharmaceutically acceptable salt thereof.
11. The compound according to any one of claims 1 to 10, wherein -A- is - CH2CH(OH)CH2CH2-, -CH(OH)CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - C(O)CH2CH2- or -CH=CHCH2-, or a pharmaceutically acceptable salt thereof.
12. The compound according to any one of claims 1 to 11, wherein -B- is -CH2O-, or a pharmaceutically acceptable salt thereof.
13. The compound according to any one of claims 1 to 12, wherein Y1, Y2 and Y7 are all CH, or a pharmaceutically acceptable salt thereof.
14. The compound according to any one of claims 1 to 13, wherein Y1 is CR2, Y2 is CH and Y7 is CH and R2 is methyl, or a pharmaceutically acceptable salt thereof.
15. The compound according to any one of claims 1 to 14, wherein Y3 is N; and Y4, Y5 and Y6 are CH, or a pharmaceutically acceptable salt thereof.
16. The compound according to any one of claims 1 to 15, wherein Z1 is CR3 and R3 is F, -OCH3, or -OCH2CH3, or a pharmaceutically acceptable salt thereof.
17. The compound according to any one of claims 1 to 16, wherein Z2 is CH, or a pharmaceutically acceptable salt thereof.
18. The compound according to any one of claims 1 to 17, wherein Z3 is CH, or a pharmaceutically acceptable salt thereof.
19. The compound according to any one of claims 1 to 18, wherein R5 is -CO2H, or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1, which is of the formula:
Figure imgf000109_0001
wherein X is
Figure imgf000109_0002
X1, X3 and X4 are independently N or CH, wherein no more than one of X1, X3 and X4 is
N;
R1 is CN or halo;
Y1 is CH or CR2;
R2 is methyl;
Z1is N, CH or CR3; R3 is halo or C1-C4 alkoxy; or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 and at least one pharmaceutically acceptable carrier, diluent, or excipient.
22. 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 20, or a pharmaceutically acceptable salt thereof.
23. 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 20, or a pharmaceutically acceptable salt thereof.
24. 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 20, or a pharmaceutically acceptable salt thereof.
25. 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 20, or a pharmaceutically acceptable salt thereof.
26. The method according to any one of claims 22 to 25 wherein the compound is administered orally.
27. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in therapy.
28. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in the treatment of type II diabetes mellitus.
29. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in lowering blood glucose levels.
30. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in the treatment of hyperglycemia.
31. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in the treatment of obesity.
32. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 27 to 31, wherein the compound is administered orally.
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