Oral complement factor d inhibitors

Abstract

To provide further complement inhibitors with therapeutic potential in the treatment of many disorders.SOLUTION: Disclosed are compounds of formula (I)-(IV), and pharmaceutically acceptable salts thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 913,021, filed October 9, 2019. [Background technology]

[0002] The complement system is part of the body's immune system and enhances the ability of antibodies and phagocytes to destroy and eliminate foreign substances (e.g., pathogens) within the body. The complement system comprises a series of plasma proteins that work together to attack extracellular forms of pathogens and induce a series of inflammatory responses to help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur in response to a specific pathogen or spontaneously upon antibody binding to the pathogen. Activation of complement proteins triggers a cascade in which one complement protein sequentially induces activation of the next. The activation of a few complement proteins at the beginning of the pathway is greatly amplified by each successive enzymatic reaction, rapidly generating a disproportionately large complement response (Non-Patent Document 1). Healthy organisms have regulatory mechanisms to prevent uncontrolled complement activation.

[0003] Once activated, complement proteins can bind to pathogens and opsonize them for engulfment by phagocytes that have complement receptors. Small fragments of some complement proteins then function as chemotactic factors, recruiting more phagocytes to the site of complement activation and activating these phagocytes. Complement proteins then form holes or pores in the invading organism, leading to its destruction. Complement plays an important role in protecting the body from foreign substances but can also destroy healthy cells and tissues. Inappropriate activation of complement has been implicated in the pathology of many diseases affecting the immune, renal, cardiovascular, and nervous systems (Non-Patent Document 2). Therefore, there is a need for the development of additional complement inhibitors with therapeutic potential in the treatment of many disorders. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Marrides, S.Pharmacological Reviews 1998,Vol.50,pages 59-88 [Non-patent document 2] Morgan,B.Eur J Clin Invest 1994,Vol.24,pages 219-228 Summary of the Invention [Means for solving the problem]

[0005] In certain embodiments, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0006] In a further embodiment, the present invention provides a compound of formula (II): [ka] and pharmaceutically acceptable salts thereof, wherein [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0007] In a further embodiment, the present invention provides a compound of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0008] In a further embodiment, the present invention provides a compound of formula (IV): [ka] and pharmaceutically acceptable salts thereof, wherein [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0009] In a still further aspect, the present invention provides a compound selected from the table below, or a pharmaceutically acceptable salt thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0010] In certain aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In certain aspects, the present invention provides methods of treating a disease or condition characterized by abnormal complement system activity, comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immune disorder. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome. In certain other aspects, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis. In further aspects, the disease or condition characterized by abnormal complement system activity is a blood disorder. In further aspects, the disease or condition characterized by abnormal complement system activity is a visual or eye disorder. In still further aspects, the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's disease uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or postoperative inflammation. DETAILED DESCRIPTION OF THE INVENTION

[0012] Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in treating disorders of the immune, renal, cardiovascular, and nervous systems. Provided herein are compounds of Formulas (I)-(IV) and pharmaceutically acceptable salts thereof that are useful for treating or preventing diseases or conditions characterized by abnormal activity of the complement system.

[0013] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0014] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention contemplates that all such compounds are within the scope of the present invention, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0015] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0016] The term "protecting group," as used herein, refers to temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals of aldehydes and ketals of ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2004). nd ed.; Wiley: New York, 1991) Protected forms of the compounds of the invention are included within the scope of the invention.

[0017] For purposes of this invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0018] Other chemical terms herein are used in accordance with conventional usage in the art as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0019] The term "pharmaceutically acceptable salt," as used herein, includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of salt-containing molecules is not 1:1. For example, a salt may contain two or more inorganic or organic acid molecules per base molecule, such as two hydrochloric acid molecules per compound of Formula I molecule. As another example, a salt may contain less than one inorganic or organic acid molecule per base molecule, for example, two molecules of the compound of Formula I per tartaric acid molecule.

[0020] The term "prodrug" as used herein refers to a compound that can be metabolized in vivo to yield a compound of the present invention. Thus, prodrugs include compounds that can be prepared by modifying one or more functional groups in the compound of the present invention to provide a corresponding compound that can be metabolized in vivo to yield a compound of the present invention. Such modifications are known in the art. For example, one or more hydroxyl or amine groups in the compound of the present invention can be acylated with an alkyl-C(=O)- group or a residue derived from an amino acid to yield a prodrug.

[0021] Prodrug forms of compounds with various nitrogen-containing functional groups (amino, hydroxyamino, amide, etc.) can include the following types of derivatives, where each R p The groups can independently be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, arylalkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl. (a)-NHC(O)R p Carboxamide represented as (b)-NHC(O)ORp Carbamates represented as (c)NHC(O)OROC(O)R p (Acyloxy)alkylcarbamates represented by the formula: (d)-NHCR(=CHCO2R p ) or -NHCR(=CHCONR p R p ) enamines (e)-N=CR p R p Schiff base represented as (f)RCONHCH2NR p R p Mannich base (derived from carboximide compound) represented as:

[0022] The preparation of such prodrug derivatives is discussed in various publications (eg Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO0041531, p. 30).

[0023] Prodrug forms of carboxyl-containing compounds are esters (-COR m ), wherein R m The group corresponds to any alcohol, and the alcohol released into the body via an enzymatic or hydrolytic process is at a pharmaceutically acceptable level. Another prodrug derived from the carboxylic acid form of the present disclosure can be a quaternary salt type structure as described by Bodor et al., J. Med. Chem. 1980, 23, 469.

[0024] The terms "carrier" and "pharmaceutically acceptable carrier," as used herein, refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils, and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, and urea. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may also be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, the entire contents of which are incorporated herein by reference.

[0025] The term "treating," as used herein, means preventing, halting, or slowing the progression of, or eliminating, a disease or condition in a subject. In one embodiment, "treating" means halting or slowing the progression of, or eliminating, a disease or condition in a subject. In one embodiment, "treating" means reducing at least one objective symptom of a disease or condition in a subject.

[0026] The term "effective amount," as used herein, refers to an amount sufficient to produce a desired biological effect.

[0027] The term "therapeutically effective amount," as used herein, refers to an amount sufficient to produce a desired therapeutic effect.

[0028] The term "inhibit," as used herein, refers to a reduction in an objectively measurable amount or extent. In various embodiments, "inhibit" refers to a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, "inhibit" refers to a 100 percent reduction, i.e., cessation or elimination.

[0029] The term "subject," as used herein, refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0030] compound The present invention relates to a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0031] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0032] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] is.

[0033] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] is.

[0034] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] In a preferred embodiment, [ka] teeth, [ka] is.

[0035] The present invention relates to a compound of formula (II): [ka] and pharmaceutically acceptable salts thereof, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0036] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to)

[0037] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] is.

[0038] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] is.

[0039] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] In a preferred embodiment, [ka] teeth, [ka] is.

[0040] The present invention relates to a compound of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0041] In some embodiments of the compound of Formula (III), [ka] teeth, [ka] is.

[0042] In some embodiments of the compound of Formula (III), [ka] teeth, [ka] is.

[0043] In some embodiments of the compound of Formula (III), [ka] teeth, [ka] is.

[0044] The present invention relates to a compound of formula (IV): [ka] and pharmaceutically acceptable salts thereof, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] (In the formula, the asterisk (*) represents [ka] (indicating the point of attachment to [ka] teeth, [ka] is selected from the group consisting of [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0045] In some embodiments of the compound of formula (IV), [ka] teeth, [ka] is.

[0046] In some embodiments of the compound of formula (IV), [ka] teeth, [ka] is.

[0047] In some embodiments of the compound of formula (IV), [ka] teeth, [ka] In a preferred embodiment, [ka] teeth, [ka] is.

[0048] In certain embodiments, the compound of the present invention is selected from the following table of compounds, and pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka]

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[0049] Medical ingredients The present invention provides pharmaceutical compositions, each comprising one or more compounds of the present invention or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.In certain embodiments, the pharmaceutical composition comprises one compound of the present invention or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention (which may comprise their pharmaceutically acceptable salts) and a pharmaceutically acceptable carrier.

[0050] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compound of the present invention. The at least one additional pharmaceutically active agent may be an agent useful in the treatment of a disease or condition characterized by abnormal complement system activity.

[0051] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0052] How to use The present invention provides compounds, and pharmaceutically acceptable salts thereof, that are useful for treating or preventing diseases or conditions characterized by abnormal complement system activity.

[0053] In certain aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0054] In certain aspects, the present invention provides a method for treating or preventing a disease or condition characterized by abnormal complement system activity. The method comprises administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, thereby treating or preventing the disease or condition characterized by abnormal complement system activity. By reducing the subject's complement system activity, the disease or condition characterized by abnormal complement system activity is treated.

[0055] Alternatively, in certain aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for treating a disease or condition characterized by abnormal complement system activity.

[0056] Alternatively, in certain aspects, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of a disease or condition characterized by abnormal complement system activity.

[0057] As used herein, a "disease or condition characterized by abnormal complement system activity" refers to any disease or condition in which it is desirable to reduce complement system activity. For example, it may be desirable to reduce complement system activity in situations of inappropriate or over-activation of the complement system.

[0058] In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immune disorder.

[0059] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

[0060] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a renal disease.

[0061] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

[0062] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

[0063] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

[0064] In certain embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

[0065] In certain embodiments, the disease or condition is atypical hemolytic uremic syndrome.

[0066] In certain embodiments, the disease or condition is organ transplant rejection.

[0067] In certain embodiments, the disease or condition is myasthenia gravis.

[0068] In certain embodiments, the disease or condition is neuromyelitis optica.

[0069] In certain embodiments, the disease or condition is membranoproliferative glomerulonephritis.

[0070] In certain embodiments, the disease or condition is dense deposit disease.

[0071] In certain embodiments, the disease or condition is cold agglutinin disease.

[0072] In certain embodiments, the disease or condition is fulminant antiphospholipid syndrome.

[0073] In other embodiments, the disease or condition characterized by abnormal complement system activity is adult respiratory distress syndrome, myocardial infarction, pulmonary inflammation, hyperacute rejection (transplant rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barré syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, organ rejection (transplant), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis.

[0074] In other embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

[0075] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a hematological disorder.

[0076] In another embodiment, the disease or condition characterized by abnormal complement system activity is a visual or ocular disorder.

[0077] In certain embodiments, the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's disease uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

[0078] Formulation, route of administration, and dosage The compounds of the present invention, and pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms compatible with the selected route of administration, for example, oral or parenteral, intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the present invention.

[0079] Thus, the compounds of the present invention can be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentage of the compositions and preparations may vary and may conveniently be about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0080] Tablets, troches, pills, capsules, etc. may also contain the following diluents and carriers: binders such as gum tragacanth, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring. If the unit dosage form is a capsule, it may contain, in addition to the above-mentioned materials, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, or the like. Syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavor.Of course, any material used to prepare any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amount used.In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0081] Active compound can also be administered intravenously or intraperitoneally by infusion or injection.The solution of active compound or its salt can be prepared in water or physiologically acceptable aqueous solution, and optionally can be mixed with non-toxic surfactant.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and their mixture, and in oil.These preparations contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0082] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient (optionally encapsulated in liposomes) suitable for the extemporaneous preparation of sterile solutions or dispersions for injection or infusion. In all cases, the ultimate dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage. Liquid carriers or vehicles can be solvents or liquid dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0083] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients listed above, and then optionally sterilizing by filtration. In the case of sterile powders for preparing sterile injectable solutions, the preparation method can include vacuum drying and freeze-drying techniques, which yields a powder of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0084] For topical administration, the compounds of the present invention can be applied in pure form (i.e., when they are liquids). However, it is generally desirable to administer the compounds of the present invention to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which can be solid or liquid.

[0085] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol, or glycol, or water-alcohol / glycol blends, in which the compounds of the present invention can be dissolved or dispersed at effective concentrations, optionally with the use of non-toxic surfactants. Adjuvants such as fragrances and additional antibacterial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-action or aerosol sprayer.

[0086] Thickening agents such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified cellulose, or modified inorganic materials may also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like for direct application to the user's skin.

[0087] Examples of useful dermatological compositions that can be used to deliver the compounds of the present invention to the skin are known in the art; see, e.g., Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; ​​incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

[0088] Useful dosages of the compounds of the invention can be determined, at least initially, by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated herein by reference.

[0089] The amount of the compound, or pharmaceutically acceptable salt thereof, required for therapeutic use will vary depending not only on the particular compound or salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.

[0090] However, in general, suitable dosages are in the range of about 0.5 to about 100 mg / kg body weight of the recipient per day, e.g., about 3 to about 90 mg / kg body weight per day, about 6 to about 75 mg / kg body weight per day, about 10 to about 60 mg / kg body weight per day, or about 15 to about 50 mg / kg body weight per day.

[0091] The compounds of the invention, or pharmaceutically acceptable salts thereof, can be conveniently formulated into unit dosage form, for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, formulated into such a unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, two, three, four or more sub-doses per day. The sub-dose itself may be further divided, for example, into a number of discrete loosely spaced administrations.

[0092] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may also be administered in combination with other therapeutic agents, such as other agents useful for the treatment or prevention of ischemia, blood loss, or reperfusion injury. In certain embodiments, the compounds of the present invention, and pharmaceutically acceptable salts thereof, may also be administered in combination with one or more other therapeutic agents useful for the treatment or prevention of visual or ocular disorders.

[0093] Other delivery systems may include sustained-release, delayed-release, or sustained-release delivery systems, as are well known in the art. Such systems can avoid repeated administration of active compounds, improving the convenience of patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. It may be desirable to use long-term sustained-release implants. Long-term release, as used herein, means that the delivery system or implant is configured or arranged to deliver therapeutic concentrations of active ingredients for at least 30 days, preferably 60 days.

[0094] In certain embodiments, the compounds of the present invention are formulated for intraocular administration, for example, by direct injection or by insertion into or associated with insertion into a medical device in the eye.In certain embodiments, the compounds of the present invention are formulated as eye drops.In certain embodiments, the compounds of the present invention can be administered by local administration to the eye, including, for example, topical administration, intravitreal administration, periocular administration, transscleral administration, retrobulbar administration, juxtascleral administration, suprachoroidal administration, or subtenon administration, via ocular delivery.The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents via ocular delivery.

[0095] The compounds of the present invention can be formulated for attachment within a medical device, which can include a variety of conventional grafts, stents, including stent-grafts, catheters, balloons, baskets, or any other device that can be placed or permanently implanted within a body lumen. As a particular example, it would be desirable to have devices and methods that can deliver the compounds of the present invention to a body area being treated by an interventional technique.

[0096] In an exemplary embodiment, the compounds of the invention can be deposited within a medical device, such as a stent, and delivered to a treatment site for treatment of a body part.

[0097] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral vessels. Stent designs include those described in U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor). Such designs include both metallic and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver drugs to sites of contact with the vascular system, as disclosed, for example, in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and International Patent Applications WO 91 / 12779 (Medtronic, Inc.), and WO 90 / 13332 (Cedars-Sanai Medical Center).

[0098] The term "attached" means that the compound is coated, adsorbed, disposed, or otherwise incorporated into the device by methods known in the art. For example, the compound can be embedded in and released from a polymeric material that coats or permeates the medical device ("matrix-type"), or can be surrounded by and released through a polymeric material ("reservoir-type"). In the latter example, the compound can be encapsulated within or bound to the polymeric material using one or more techniques for producing such polymeric materials known in the art. In other formulations, the compound can be linked to the surface of the medical device without the need for a coating, for example, by a detachable bond, and released over time, or can be removed by an active mechanical or chemical process. In other formulations, the compound can be in a permanently immobilized form, providing the compound at the implantation site.

[0099] In certain embodiments, the compounds can be incorporated with polymer compositions in forming biocompatible coatings for medical devices such as stents. The coatings produced from these components are typically homogeneous and useful for coating many devices designed for implantation.

[0100] The polymer can be either a biostable or a bioabsorbable polymer, depending on the desired release rate or the degree of polymer stability desired, although bioabsorbable polymers are often preferred for this embodiment because, unlike biostable polymers, they do not persist long after implantation and do not cause any adverse chronic local reactions. Bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoesters, polyphosphoelastomers, and polyisopropylmethylcellulose (POE). These include, but are not limited to, sterurethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), copoly(ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, hydrogel crosslinkable or amphiphilic block copolymers, and other suitable bioabsorbable polymers known in the art.Biostable polymers that have relatively low chronic tissue reactions, such as polyurethane, silicone, and polyester, can also be used, as well as other polymers such as polyolefins, polyisobutylene, and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; ethylene-methyl methacrylate copolymer, acrylonitrile-styrene copolymer, ABS resin, and ethylene-vinyl acetate copolymer. Copolymers of vinyl monomers with each other and with olefins, such as pyran copolymers; polyhydroxypropylmethacrylamidephenol; polyhydroxyethylaspartamidephenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose can also be used when dissolved and allowed to harden or polymerize on the medical device.

[0101] The polymers and semipermeable polymer matrices can be formed into shaped articles such as valves, stents, tubing, prostheses, and the like.

[0102] In certain embodiments of the invention, the compounds of the invention are bound to a polymer or semi-permeable polymer matrix formed as a stent or stent-graft device.

[0103] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be used for this purpose. Spraying methods include traditional methods as well as microdeposition techniques using inkjet-type dispensers. Additionally, photopatterning can be used to deposit the polymer onto the implantable device, placing the polymer only in specific areas of the device. This coating of the device provides a uniform layer around the device, which allows for improved diffusion of various analytes through the device coating.

[0104] In certain embodiments of the present invention, the compound is formulated to be released from the polymer coating into the environment in which the medical device is placed. Preferably, the compound is released in a controlled manner over an extended time frame (e.g., several months) using at least one of several well-known techniques for polymeric carriers or layers that control elution. Some of these techniques are described in U.S. Patent Application Publication No. 2004 / 0243225A1, the entire disclosure of which is incorporated herein in its entirety.

[0105] Furthermore, the release of a compound from a polymer coating can be controlled by manipulating the reagents and reaction conditions of the polymer composition, as described, for example, in U.S. Pat. No. 6,770,729 (incorporated herein in its entirety). For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of a compound from a polymer coating. In a variation of this topic, the diffusion coefficient of one or more polymer coatings can be controlled to adjust the accessibility of an analyte present in the environment in which the medical device is placed (e.g., an analyte that promotes the breakdown or hydrolysis of a portion of the polymer) to one or more components within the polymer composition (and thereby, for example, adjust the release of a compound from the polymer coating). Yet another embodiment of the present invention includes a device having multiple polymer coatings, each with multiple diffusion coefficients. In such an embodiment of the present invention, the release of a compound from the polymer coating can be adjusted by the multiple polymer coatings.

[0106] In yet another embodiment of the present invention, the release of the compound from the polymer coating is controlled by the presence of one or more endogenous or exogenous compounds, or alternatively by adjusting one or more properties of the polymer composition, such as the pH of the polymer composition. For example, certain polymer compositions can be designed to release the compound in response to a decrease in the pH of the polymer composition.

[0107] kit The present invention also provides a kit comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the present invention, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) to a mammal to treat or prevent a disease or condition characterized by abnormal complement activity. In one embodiment, the mammal is a human.

[0108] It will be appreciated by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and may be made without departing from the scope of the invention or any embodiment thereof. [Example]

[0109] Having now described the invention in detail, the same will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0110] Scheme 1 [ka] Preparation of 2-(2-((7-(5-(1-aminopropyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (1j) Step-1: Preparation of (7-bromobenzofuran-5-yl)methanol (1b) To a stirred solution of 7-bromobenzofuran-5-carboxylic acid (1a) (10 g, 41.5 mmol; CAS#286836-25-7) and N-methylmorpholine (5.47 mL, 49.8 mmol) in THF (200 mL) was added isobutyl chloroformate (6.54 mL, 49.8 mmol) at −5° C. The reaction mixture was stirred for 15 min, filtered through a Celite pad, and the precipitate was washed with THF (3×20 mL). The filtrate was cooled to 0° C., and a solution of NaBH (4.71 g, 124 mmol) in water (10 mL) was carefully added (gas evolved rapidly) to the filtrate. The reaction mixture was stirred for 30 min, diluted with water (20 mL), and washed with ethyl acetate (3×). The organic layers were combined, dried, filtered and concentrated in vacuo to give (7-bromobenzofuran-5-yl)methanol (1b) (9 g, 96% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 5.34 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H).

[0111] Step-2: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (1d) To a solution of (7-bromobenzofuran-5-yl)methanol (1b) (9 g, 39.6 mmol), triphenylphosphine (11.44 g, 43.6 mmol), and ethyl 2-(2-hydroxyphenyl)acetate (1c) (7.86 g, 43.6 mmol; CAS# 41873-65-8) in DCM (180 mL) was added dropwise a solution of bis(4-chlorobenzyl)azodicarboxylate (DCAD) (16.01 g, 43.6 mmol; CAS#: 916320-82-6) in DCM (40 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes and filtered to remove solids. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography [silica (80 g), elution with 0-50% EtOAc in hexanes] to afford ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (1d) (11.5 g, 75% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.30 - 7.19 (m, 2H), 7.11 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H).

[0112] Step-3: Preparation of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) To a degassed solution of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (1d) (8.9 g, 22.87 mmol), bis(pinacolato)diboron (8.71 g, 34.3 mmol, CAS#: 73183-34-3), and potassium acetate (6.73 g, 68.6 mmol) in anhydrous dioxane (150 mL) was added Pd(dppf)Cl-CHCl (1.87 g, 2.29 mmol). The resulting mixture was degassed, charged with Ar, and stirred at 90 °C overnight. The reaction mixture was then diluted with EtOAc (400 mL) and washed with water (100 mL). The aqueous layer was re-extracted with EtOAc (100 mL × 2). The organic layers were combined, washed with water (100 mL), brine (100 mL), dried, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (80 g), elution with 0-40% EtOAc in hexanes] to give ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (9 g, 90% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.34 - 7.17 (m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.98 - 6.87 (m, 2H), 5.17 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.59 (s, 2H), 1.34 (s, 12H), 1.05 (t, J = 7.1 Hz, 3H).

[0113] Step-4: Preparation of ethyl 2-(2-((7-(5-formylthiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1f) To a degassed solution of ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (2 g, 4.58 mmol) in dioxane (24 mL), 4-bromothiophene-2-carbaldehyde (0.876 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.527 g, 0.751 mmol), and a solution of KCO (2.076 g, 15.02 mmol) in water (8 mL) was added and heated at 90 °C in an oil bath under a nitrogen atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL) and water (15 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried, filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM] to afford ethyl 2-(2-((7-(5-formylthiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1f) (2.022 g, 100% yield) as a yellow syrup. 1 H NMR (300 MHz, DMSO-d6) δ 10.11 - 10.02 (m, 1H), 8.70 (s, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.25 - 7.21 (m, 2H), 7.14 - 7.09 (m, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.24 (s, 2H), 3.98 - 3.92 (m, 2H), 3.65 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H).

[0114] Step-5: Preparation of ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1g) To a solution of ethyl 2-(2-((7-(5-formylthiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1f) (2.02 g, 9.32 mmol) and (R)-2-methylpropane-2-sulfinamide (2.258 g, 18.63 mmol) in tetrahydrofuran (30 mL) was added tetraethoxytitanium (3.91 mL, 18.63 mmol) and stirred at room temperature overnight. The reaction was quenched with brine (40 mL) and stirred for 20 minutes. The separated solid was filtered off and the cake was washed with ethyl acetate (400 mL). The organic layer was separated, washed with brine (2 x 50 mL), dried and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, 40 g, elution with ethyl acetate (0 to 20%) in hexanes] to give ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1g) (1.596 g, 54% yield) as a brown syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.52 (d, J = 1.3 Hz, 2H), 8.14 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.25 - 7.20 (m, 1H), 7.14 - 7.09 (m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 5.24 (s, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.19 (s, 9H), 1.00 (t, J = 7.1 Hz, 3H).

[0115] Step-6: Preparation of ethyl 2-(2-((7-(5-(1-(1,1-dimethylethylsulfinamido)propyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1h) To a solution of ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1g) (0.3 g, 0.573 mmol) in THF (10 mL) was carefully added ethylmagnesium bromide (0.430 mL, 0.859 mmol) at −78° C. and stirred at −78° C. for 3 hours. The reaction was carefully quenched with saturated ammonium chloride and the aqueous phase was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluting with 0 to 100% EtOAc in hexanes] to give ethyl 2-(2-((7-(5-(1-(1,1-dimethylethylsulfinamido)propyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1h) (0.318 g, 100% yield). 1 H NMR (300 MHz, DMSO-d6) δ 8.14 - 8.11 (m, 1H), 8.09 - 8.01 (m, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.25 - 7.21 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 2.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 4.00 - 3.92 (m, 3H), 3.64 (s, 2H), 1.95 - 1.75 (m, 2H), 1.15 (s, 9H), 1.05 - 0.98 (m, 3H), 0.95 - 0.88 (m, 3H).

[0116] Step-7: Preparation of ethyl 2-(2-((7-(5-(1-aminopropyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1i) To a solution of ethyl 2-(2-((7-(5-(1-(1,1-dimethylethylsulfinamido)propyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1h) (318 mg, 0.574 mmol) in tetrahydrofuran (3 mL) was added 2 N aqueous HCl (0.861 mL, 1.723 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 3H), 8.22 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.27 (s, 1H), 7.24 (d, J = 6.0 Hz, 1H), 7.13 (s, 1H), 7.11 - 7.07 (m, 2H), 6.93 (s, 1H), 5.23 (s, 2H), 4.02 - 3.89 (m, 3H), 3.64 (s, 2H), 2.04 - 1.79 (m, 2H), 1.00 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H).

[0117] Step-8: Preparation of 2-(2-((7-(5-(1-aminopropyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (1j) To a stirred solution of ethyl 2-(2-((7-(5-(1-aminopropyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1i) (255 mg, 0.510 mmol, from the above step) in tetrahydrofuran (5 mL), methanol (1 mL), and water (1 mL) was added lithium hydroxide monohydrate (48.9 mg, 2.042 mmol) and stirred at room temperature for 10 hours. The reaction was concentrated in vacuo, diluted with 5 mL of water, and acidified to pH 5 using 1 M HCl. The separated solid was decanted, dissolved in DMSO, and purified by reverse-phase column chromatography [C-18 column, 40 g, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%] to give the hydrochloride salt of 2-(2-((7-(5-(1-aminopropyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (1j) (61 mg, 28.4% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.53 (s, 3H, D2O exchangeable), 8.22 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.29 - 7.19 (m, 2H), 7.09 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.26 (s, 2H), 4.65 - 4.54 (m, 1H), 3.61 (s, 2H), 2.14 - 1.85 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H);C 24 H 23 Analysis calculated for NO₄S.HCl.1.5H₂O: C, 59.44; H, 5.61; Cl, ​​7.31; N, 2.89; Found: C, 59.56; H, 5.26; Cl, ​​7.52; N, 3.09.

[0118] Scheme 2 [ka] Preparation of 2-(2-((7-(3-(1-aminopropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (2f) Step-1: Preparation of N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide (2b) Compound 2b was prepared from 3-bromobenzaldehyde 2a (2 g, 10.81 mmol) in THF (30 mL) using (R)-2-methylpropane-2-sulfinamide (2.62 g, 21.62 mmol), tetraethoxytitanium (4.53 mL, 21.62 mmol), and stirring at room temperature for 18 hours according to the procedure described in step 5 of Scheme 1. This afforded N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide 2b (2.157 g, 69.2% yield) as a brown syrup after workup and purification by flash column chromatography [silica gel (40 g), elution with ethyl acetate (0 to 20%) in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.11 (t, J = 1.8 Hz, 1H), 7.94 (dt, J = 7.7, 1.3 Hz, 1H), 7.76 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 1.17 (d, J = 3.1 Hz, 9H).

[0119] Step-2: Preparation of ethyl 2-(2-((7-(3-(((tert-butylsulfinyl)imino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2c) Compound 2c was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate 1e (1.665 g, 3.82 mmol) in dioxane (24 mL) using a solution of N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide 2b (1.1 g, 3.82 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.402 g, 0.573 mmol), and KCO (1.583 g, 11.45 mmol) in water (8 mL) by heating at 90 °C in an oil bath for 3 hours. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(((tert-butylsulfinyl)imino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2c) (1.64 g, 3.17 mmol, 83% yield) as a yellow syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.44 (t, J = 1.7 Hz, 1H), 8.14 (dd, J = 5.5, 2.2 Hz, 2H), 8.06 - 8.01 (m, 1H), 7.71 - 7.66 (m, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.14 (s, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 2H), 5.27 (d, J = 1.9 Hz, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 2.6 Hz, 2H), 1.21 (s, 9H), 1.00 - 0.94 (m, 3H).

[0120] Step-3: Preparation of ethyl 2-(2-((7-(3-(1-(1,1-dimethylethylsulfinamido)propyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2d) Compound 2d was prepared from ethyl 2-(2-((7-(3-(((tert-butylsulfinyl)imino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2c) (0.3 g, 0.580 mmol) in THF (10 mL) using ethylmagnesium bromide (0.435 mL, 0.869 mmol) at −78 °C and stirring at −78 °C for 3 h according to the procedure described in step 6 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 100% EtOAc in hexanes], ethyl 2-(2-((7-(3-(1-(1,1-dimethylethylsulfinamido)propyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2d) (279 mg, 88% yield). MS (ES+) 548.2 (M+1).

[0121] Step-4: Preparation of ethyl 2-(2-((7-(3-(1-aminopropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2e) To a solution of ethyl 2-(2-((7-(3-(1-(1,1-dimethylethylsulfinamido)propyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2d) (279 mg, 0.509 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous HCl (0.764 mL, 1.528 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and used in the next step without further purification. MS (ES+) 444.2 (M+1).

[0122] Step-5: Preparation of 2-(2-((7-(3-(1-aminopropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (2f) Compound 2f was prepared from ethyl 2-(2-((7-(3-(1-aminopropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2e) (226 mg, 0.510 mmol) in THF (5 mL), methanol (1 mL), and water (1 mL) using lithium hydroxide monohydrate (86 mg, 2.038 mmol) and stirring at room temperature for 10 hours according to the procedure described in step-8 of Scheme 1. This afforded the hydrochloride salt of 2-(2-((7-(3-(1-aminopropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (2f) (46 mg, 21.73% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H, D2O exchangeable), 8.45 (s, 3H, D2O exchangeable), 8.12 (d, J = 2.2 Hz, 1H), 8.01 - 7.98 (m, 1H), 7.96 - 7.92 (m, 1H), 7.81 - 7.74 (m, 1H), 7.68 - 7.64 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.31 - 7.19 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 2.2 Hz, MS (ES+): 416.1 (M+1);C 26 H 25 Analysis calculated for NO4.HCl.1.25H2O: C, 65.82; H, 6.05; Cl, ​​7.47; N, 2.95; Found: C, 65.89; H, 5.83; Cl, ​​7.61; N, 3.17.

[0123] Scheme 3 [ka] Preparation of 2-(2-((7-(3-(1-amino-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (3c) Step-1: Preparation of ethyl 2-(2-((7-(3-(1-(1,1-dimethylethylsulfinamido)-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (3a) Compound 3a was prepared from ethyl 2-(2-((7-(3-(((tert-butylsulfinyl)imino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (2c) (0.400 g, 0.773 mmol) in THF (10 mL) using isopropylmagnesium bromide (2.318 mL, 4.64 mmol) at −78° C. and stirring at −78° C. for 3 hours according to the procedure described in step 6 of Scheme 1. This gave ethyl 2-(2-((7-(3-(1-(1,1-dimethylethylsulfinamido)-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (3a) (360 mg, 83% yield) after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 100% EtOAc in hexanes]. MS (ES+): 562.3 (M+1).

[0124] Step-2: Preparation of ethyl 2-(2-((7-(3-(1-amino-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (3b) To a solution of ethyl 2-(2-((7-(3-(1-(1,1-dimethylethylsulfinamido)-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (3a) (360 mg, 0.641 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous HCl (0.764 mL, 1.528 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(3-(1-amino-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (3b), which was used in the next step without further purification. MS (ES+): 458.2 (M+1).

[0125] Step-3: Preparation of 2-(2-((7-(3-(1-amino-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (3c) Compound 3c was prepared from ethyl 2-(2-((7-(3-(1-amino-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (3b) (297 mg, 0.649 mmol) in THF (5 mL), methanol (1 mL), and water (1 mL) using lithium hydroxide monohydrate (62.2 mg, 2.60 mmol) and stirring at room temperature for 10 hours, according to the procedure described in step 8 of Scheme 1. This afforded the hydrochloride salt of 2-(2-((7-(3-(1-amino-2-methylpropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (3c) (16 mg, 6% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H, D2O exchangeable), 8.49 - 8.43 (m, 3H, D2O exchangeable), 8.12 (d, J = 2.2 Hz, 1H), 8.00 - 7.89 (m, 2H), 7.79 - 7.76 (m, 1H), 7.68 - 7.58 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.23 (m, J = 7.5 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.28 (s, 2H), 4.17 - 4.00 (m, 1H), 3.60 (s, 2H), 2.31 - 2.15 (m, 1H), 1.07 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H);MS (ES+): 430.2 (M+1).

[0126] Scheme 4 [ka] Preparation of 2-(2-((7-(5-(1-aminoethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (4c) Step-1: Preparation of ethyl 2-(2-((7-(5-(1-(1,1-dimethylethylsulfinamido)ethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (4a) Compound 4a was prepared from ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1g) (0.4 g, 0.773 mmol) in THF (10 mL) using methylmagnesium chloride (1.528 mL, 4.58 mmol) at −78° C. and stirring at −78° C. for 3 hours according to the procedure described in step-6 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 100% EtOAc in hexanes], ethyl 2-(2-((7-(5-(1-(1,1-dimethylethylsulfinamido)ethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (4a) (301 mg, 0.530 mmol, 69.4% yield). MS (ES+): 540.2 (M+1).

[0127] Step-2: Preparation of ethyl 2-(2-((7-(5-(1-aminoethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (4b) To a solution of ethyl 2-(2-((7-(5-(1-(1,1-dimethylethylsulfinamido)ethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (4a) (301 mg, 0.558 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous HCl (0.837 mL, 1.673 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(5-(1-aminoethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (4b), which was used in the next step without further purification. MS (ES+): 437.0 (M+1)

[0128] Step-3: Preparation of 2-(2-((7-(5-(1-aminoethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (4c) Compound 4c was prepared from ethyl 2-(2-((7-(5-(1-aminoethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (4b) (243 mg, 0.558 mmol) in THF (5 mL), methanol (1 mL), and water (1 mL) using lithium hydroxide monohydrate (53.4 mg, 2.232 mmol) and stirring at room temperature for 10 hours, according to the procedure described in step 8 of Scheme 1. This afforded the hydrochloride salt of 2-(2-((7-(5-(1-aminoethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (4c) (28 mg, 12% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 3H), 8.22 - 8.17 (m, 1H), 8.17 - 8.13 (m, 1H), 7.95 (d, J = 11.0 Hz, 1H), 7.75 (d, J = 10.5 Hz, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.31 - 7.13 (m, 2H), 7.11 - 7.07 (m, 2H), 6.96 - 6.88 (m, 1H), 5.27 - 5.15 (m, 2H), 4.82 (s, 1H), 3.73 (s, 2H), 1.66 (dd, J = 6.9, 2.3 Hz, 3H).MS (ES-): 405.1 (M-1);C 23 H 21 Analysis calculated for NO₄S.HCl.0.5H₂O: C, 60.99; H, 5.12; Cl, ​​7.83; N, 3.09; Found: C, 61.10; H, 5.45; Cl, ​​7.47; N, 2.98.

[0129] Scheme 5 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (5e) Step-1: Preparation of ethyl 2-(2-((7-(2-formylthiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5a) Compound 5a was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (1 g, 2.292 mmol) in dioxane (12 mL) according to the procedure described in step-4 of Scheme 1, using a solution of 2-bromothiazole-4-carbaldehyde (0.440 g, 2.292 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.241 g, 0.344 mmol), and KCO (0.950 g, 6.88 mmol) in water (4 mL) heated at 90 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(2-formylthiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5a) (664 mg, 1.575 mmol, 68.7% yield) as a yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (d, J = 1.3 Hz, 1H), 8.84 (d, J = 1.3 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.80 (t, J = 2.5 Hz, 1H), 7.57 - 7.47 (m, 1H), 7.40 (dd, J = 14.1, 7.0 Hz, 1H), 7.23 (dt, J = 7.6, 2.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.96 - 6.88 (m, 1H), 5.28 (d, J = 2.4 Hz, 2H), 4.03 - 3.93 (m, 2H), 3.63 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 422.0 (M+1).

[0130] Step-2: Preparation of ethyl 2-(2-((7-(2-(((tert-butylsulfinyl)imino)methyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5b) Compound 5b was prepared from 3-ethyl 2-(2-((7-(2-formylthiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5a) (950 mg, 2.254 mmol) in THF (15 mL) using (R)-2-methylpropane-2-sulfinamide (546 mg, 4.51 mmol), tetraethoxytitanium (0.945 mL, 4.51 mmol) and stirring at room temperature for 18 hours according to the procedure described in step 5 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with ethyl acetate (0 to 20%) in hexanes], ethyl 2-(2-((7-(2-(((tert-butylsulfinyl)imino)methyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5b) (1.142 g, 2.177 mmol, 97% yield) as a brown syrup. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 1.0 Hz, 1H), 8.68 (d, J = 1.0 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 7.13 (d, J = 2.2 Hz, 1H), 6.92 (td, J = 7.4, 1.2 Hz, 1H), 5.32 (s, 2H), 4.03 - 3.95 (m, 2H), 3.63 (s, 2H), 1.08 (s, 9H), 1.01 (t, J = 7.1 Hz, 3H);MS (ES+): 525.1 (M+1).

[0131] Step-3: Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5c) To a solution of ethyl 2-(2-((7-(2-(((tert-butylsulfinyl)imino)methyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5b) (862 mg, 1.643 mmol) in THF (10 mL) and water (1 mL) was added sodium borohydride (186 mg, 4.93 mmol) in portions over 2 minutes at below −56° C. The reaction was then stirred at the same temperature for 30 minutes and warmed to −12° C. over 30 minutes. The reaction was quenched by adding acetone (1 mL), stirred for 10 minutes, diluted with water (10 mL), and concentrated to remove acetone and tetrahydrofuran. The residue was dissolved in ethyl acetate (100 mL), washed with water (2×20 mL), brine (20 mL), dried, and concentrated to give a clear oil. The crude residue was purified by flash column chromatography [silica gel (25 g), elution with ethyl acetate (0 to 100%) in hexanes] to give ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5c) (236 mg, 0.448 mmol, 27.3% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.25 - 7.21 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 6.42 (t, J = 6.2 Hz, 1H), 5.25 (s, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.02 - 3.95 (m, 2H), 3.62 (s, 2H), 1.23 (s, 9H), 1.02 (t, J = 7.1 Hz, 3H);MS (ES+): 527.1 (M+1).

[0132] Step-4: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5d) To a solution of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5c) (234 mg, 0.444 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous HCl (0.666 mL, 1.333 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(2-(aminomethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5d), which was used directly in the next step without further purification. (ES+): 423.1 (M+1).

[0133] Step-5: Preparation of 2-(2-((7-(2-(aminomethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (5e) Compound 5e was prepared from ethyl 2-(2-((7-(2-(aminomethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (5d) (188 mg, 0.445 mmol) in THF (5 mL), methanol (1 mL), and water (1 mL) using lithium hydroxide monohydrate (42.6 mg, 1.780 mmol) and stirring at room temperature for 10 hours according to the procedure described in step 8 of Scheme 1. This afforded the hydrochloride salt of 2-(2-((7-(2-(aminomethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (5e) (83 mg, 47% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 8.74 - 8.63 (m, 3H, D2O exchangeable), 8.41 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 1.7 MS (ES+): 395.1 (M+1);C 21 H 18 Analysis calculated for N2O4S.1.3HCl.1.5H2O: C, 53.79; H, 4.79; Cl, ​​9.83; N, 5.97; Found: C, 53.83; H, 4.69; Cl, ​​9.93; N, 5.88.

[0134] Scheme 6 [ka] Preparation of 2-(2-((7-(4-(aminomethyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (6e) Step-1: Preparation of ethyl 2-(2-((7-(4-formylthiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6a) Compound 6a was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (1 g, 2.292 mmol) in dioxane (12 mL) according to the procedure described in step-4 of Scheme 1, using a solution of 2-bromothiazole-4-carbaldehyde (0.440 g, 2.292 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.241 g, 0.344 mmol), and KCO (0.950 g, 6.88 mmol) in water (4 mL) heated at 90 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(4-formylthiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6a) (664 mg, 68.7% yield) as a yellow syrup. 1 H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.94 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.27 (s, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.96 - 6.89 (m, 1H), 5.30 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.63 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 422.1 (M+1).

[0135] Step-2: Preparation of ethyl 2-(2-((7-(4-(((tert-butylsulfinyl)imino)methyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6b) Compound 6b was prepared from ethyl 2-(2-((7-(4-formylthiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6a) (664 mg, 1.575 mmol) in THF (15 mL) using (R)-2-methylpropane-2-sulfinamide (382 mg, 3.15 mmol), tetraethoxytitanium (0.661 mL, 3.15 mmol) and stirring at room temperature for 18 hours according to the procedure described in step 5 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with ethyl acetate (0 to 20%) in hexanes], ethyl 2-(2-((7-(4-(((tert-butylsulfinyl)imino)methyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6b) (528 mg, 63.9% yield) as a brown syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.66 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 5.30 (s, 2H), 4.02 - 3.95 (m, 2H), 3.62 (s, 2H), 1.22 (s, 9H), 0.98 (t, J = 7.1 Hz, 3H); MS (ES+): 525.1 (M+1).

[0136] Step-3: Preparation of ethyl 2-(2-((7-(4-((1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6c) Compound 6c was prepared from ethyl 2-(2-((7-(4-(((tert-butylsulfinyl)imino)methyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6b) (528 mg, 1.006 mmol) in THF (10 mL) and water (1 mL) using sodium borohydride (114 mg, 3.02 mmol). This afforded ethyl 2-(2-((7-(4-((1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6c) (484 mg, 91% yield) as a white solid after workup and purification by flash column chromatography [silica gel (25 g), elution with ethyl acetate (0 to 100%) in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.71 (s, 1H), 7.28 (dd, J = 7.9, 1.8 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.15 (d, J = 2.2 Hz, 2H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.94 (t, J = 6.0 Hz, 1H), 5.27 (s, 2H), 4.40 (dd, J = 6.2, 3.5 Hz, 2H), 4.01 - 3.94 (m, 2H), 3.62 (s, 2H), 1.19 (s, 9H), 1.01 (t, J = 7.1 Hz, 3H);MS (ES+): 527.2 (M+1).

[0137] Step-4: Preparation of ethyl 2-(2-((7-(4-(aminomethyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6d) To a solution of ethyl 2-(2-((7-(4-((1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6c) (484 mg, 0.919 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous HCl (1.378 mL, 2.76 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(4-(aminomethyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6d), which was used directly in the next step without further purification. (ES+): 423.1 (M+1).

[0138] Step-5: Preparation of 2-(2-((7-(4-(aminomethyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (6e) Compound 6e was prepared from ethyl 2-(2-((7-(4-(aminomethyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (6d) (388 mg, 0.918 mmol) in THF (5 mL), methanol (1 mL), and water (1 mL) using lithium hydroxide monohydrate (154 mg, 3.67 mmol) and stirring at room temperature for 10 hours, according to the procedure described in step 8 of Scheme 1. This afforded the white hydrochloride salt of 2-(2-((7-(4-(aminomethyl)thiazol-2-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (6e) (41 mg, 11.32% yield) after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 3H, D2O exchangeable), 8.28 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.98 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.16 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.92 (t, J = 7.1 Hz, 1H), 5.30 (s, 2H), 4.37 - 4.22 (m, 2H), 3.61 (s, 2H).MS (ES+): 395.1 (M+1);C 21 H 18 Analysis calculated for N2O4S.1.25HCl.2H2O: C, 52.98; H, 4.92; Cl, ​​9.31; N, 5.88; Found: C, 52.80; H, 4.98; Cl, ​​9.79; N, 5.93.

[0139] Scheme 7 [ka] Preparation of 2-(2-((7-(2-(1-aminoethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (7e) Step-1: Preparation of ethyl 2-(2-((7-(2-acetylthiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7a) Compound 7a was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (1 g, 2.292 mmol) in dioxane (12 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 1-(4-bromothiazol-2-yl)ethanone (0.472 g, 2.292 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.241 g, 0.344 mmol), and KCO (0.950 g, 6.88 mmol) in water (4 mL) heated at 90 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(2-acetylthiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7a) (950 mg, 98% yield) as a yellow syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.20 (t, J = 2.0 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.16 (s, 1H), 7.12 (t, J = 2.2 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 2.78 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H);MS (ES+): 436.0 (M+1).

[0140] Step-2: Preparation of ethyl 2-(2-((7-(2-(1-((tert-butylsulfinyl)imino)ethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7b) Compound 7b was prepared from ethyl 2-(2-((7-(2-acetylthiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7a) (950 mg, 2.181 mmol) in THF (10 mL) using (R)-2-methylpropane-2-sulfinamide (529 mg, 4.36 mmol), tetraethoxytitanium (0.915 mL, 4.36 mmol) and stirring at room temperature for 18 hours according to the procedure described in step 5 of scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with ethyl acetate (0 to 20%) in hexanes], ethyl 2-(2-((7-(2-(1-((tert-butylsulfinyl)imino)ethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7b) (714 mg, 61% yield) as a brown syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.21 - 8.18 (m, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.28 (dd, J = 7.8, 1.8 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.14 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.01 - 3.91 (m, 2H), 3.64 (s, 2H), 2.90 (s, 3H), 1.28 (s, 9H), 0.98 (t, J = 7.1 Hz, 3H);MS (ES+): 539.1 (M+1).

[0141] Step-3: Preparation of ethyl 2-(2-((7-(2-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7c) Compound 7c was prepared from ethyl 2-(2-((7-(2-(1-((tert-butylsulfinyl)imino)ethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7b) (714 mg, 1.325 mmol) in THF (10 mL) and water (1 mL) using sodium borohydride (150 mg, 3.98 mmol). This afforded ethyl 2-(2-((7-(2-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7c) (712 mg, 99% yield) as a white solid after workup and purification by flash column chromatography [silica gel (25 g), elution with 0 to 100% ethyl acetate in hexanes]. MS (ES+): 541.2 (M+1)

[0142] Step-4: Preparation of ethyl 2-(2-((7-(2-(1-aminoethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7d) To a solution of ethyl 2-(2-((7-(2-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7c) (715 mg, 1.322 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous HCl (1.984 mL, 3.97 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(2-(1-aminoethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7d), which was used directly in the next step without further purification. MS (ES+): 437.1 (M+1).

[0143] Step-5: Preparation of 2-(2-((7-(2-(1-aminoethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (7e) Compound 7e was prepared from ethyl 2-(2-((7-(2-(1-aminoethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (7d) (554 mg, 1.269 mmol) in THF (5 mL), methanol (1 mL), and water (1 mL) using lithium hydroxide monohydrate (213 mg, 5.08 mmol) and stirring at room temperature for 10 hours, according to the procedure described in step 8 of Scheme 1. This afforded the hydrochloride salt of 2-(2-((7-(2-(1-aminoethyl)thiazol-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (7e) (193 mg, 37% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.77 (s, 3H), 8.35 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.23 - 7.12 (m, 2H), 7.06 - 6.98 (m, 2H), 6.84 (t, J = 7.4, 1.1 Hz, 1H), 5.20 (s, 2H), 4.96 - 4.80 (m, 1H), 3.54 (s, 2H), 1.64 (d, J = 6.8 Hz, 3H).MS (ES+): 409.1 (M+1);C 22 H 20 Analysis calculated for N2O4S.HCl.H2O: C, 57.08; H, 5.01; Cl, ​​7.66; N, 6.05; Found: C, 56.88; H, 5.02; Cl, ​​7.56; N, 6.00.

[0144] Scheme 8 [ka] Preparation of 2-(2-((7-(5-(aminomethyl)-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (8 g) Step-1: Preparation of N-((4-bromo-1H-pyrrol-2-yl)methylene)-2-methylpropane-2-sulfinamide (8b) Compound 8b was prepared from 4-bromo-1H-pyrrole-2-carbaldehyde 8a (1 g, 5.75 mmol) in THF (30 mL) using (R)-2-methylpropane-2-sulfinamide (1.393 g, 11.49 mmol), tetraethoxytitanium (2.410 mL, 11.49 mmol), and stirring at room temperature for 18 h according to the procedure described in step 5 of Scheme 1. This afforded N-((4-bromo-1H-pyrrol-2-yl)methylene)-2-methylpropane-2-sulfinamide 8b (1.37 g, 4.94 mmol, 86% yield) as a brown syrup after workup and purification by flash column chromatography [silica gel (40 g), elution with ethyl acetate (0 to 20%) in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.22 (s, 1H), 7.30 (d, J = 1.6 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 1.15 (s, 9H);MS (ES+): 278.9 (M+1).

[0145] Step-2: Preparation of N-((4-bromo-1-tosyl-1H-pyrrol-2-yl)methylene)-2-methylpropane-2-sulfinamide (8c) To a solution of N-((4-bromo-1H-pyrrol-2-yl)methylene)-2-methylpropane-2-sulfinamide (8b) (650 mg, 2.345 mmol) in DMF (5 mL) was added sodium hydride (281 mg, 7.04 mmol) at 0° C. and stirred for 15 minutes, followed by the addition of 4-methylbenzene-1-sulfonyl chloride (1341 mg, 7.04 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature overnight and poured into EtOAc. The reaction mixture was acidified with 3 M HCl, washed with water, brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (80 g), elution with 0 to 100% EtOAc:MeOH (9:1) in hexanes] to give N-((4-bromo-1-tosyl-1H-pyrrol-2-yl)methylene)-2-methylpropane-2-sulfinamide (8c) (222 mg, 22% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 1.8 Hz, 1H), 2.39 (s, 3H), 1.10 (s, 9H);MS (ES+): 432.9 (M+1).

[0146] Step-3: Preparation of N-((4-bromo-1-tosyl-1H-pyrrol-2-yl)methyl)-2-methylpropane-2-sulfinamide (8d) Compound 8d was prepared from N-((4-bromo-1-tosyl-1H-pyrrol-2-yl)methylene)-2-methylpropane-2-sulfinamide (8c) (222 mg, 0.515 mmol) in THF (3 mL) and water (0.3 mL) using sodium borohydride (58.4 mg, 1.544 mmol) according to the procedure described in Scheme 5, Step 3. This afforded N-((4-bromo-1-tosyl-1H-pyrrol-2-yl)methyl)-2-methylpropane-2-sulfinamide (8d) (200 mg, 90% yield) as a white solid after workup and purification by flash column chromatography [silica gel (25 g), elution with ethyl acetate (0 to 100%) in hexanes]. MS(ES+): 434.9 (M+1).

[0147] Step-4: Preparation of ethyl 2-(2-((7-(5-((1,1-dimethylethylsulfinamido)methyl)-1-tosyl-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (8e) Compound 8e was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate 1e (224 mg, 0.512 mmol) in dioxane (12 mL) using a solution of N-((4-bromo-1-tosyl-1H-pyrrol-2-yl)methyl)-2-methylpropane-2-sulfinamide 8d (222 mg, 0.512 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (53.9 mg, 0.077 mmol), and KCO (212 mg, 1.537 mmol) in water (4 mL) by heating in an oil bath at 90 °C for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(5-((1,1-dimethylethylsulfinamido)methyl)-1-tosyl-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (8e) (208 mg, 61% yield) as a yellow syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.91 - 7.87 (m, 2H), 7.86 (s, 1H), 7.67 - 7.65 (m, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.23 (dd, J = 7.6, 3.8 Hz, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 5.21 MS (ES+): 663.0 (M+1).

[0148] Step-5: Preparation of ethyl 2-(2-((7-(5-(aminomethyl)-1-tosyl-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (8f) To a solution of ethyl 2-(2-((7-(5-((1,1-dimethylethylsulfinamido)methyl)-1-tosyl-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (8e) (208 mg, 0.314 mmol) in tetrahydrofuran (0.5 mL) was added 2N aqueous HCl (0.471 mL, 0.941 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(5-(aminomethyl)-1-tosyl-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (8f), which was used directly in the next step without further purification. (ES+): 559.2 (M+1).

[0149] Step-6: Preparation of 2-(2-((7-(5-(aminomethyl)-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (8 g) Compound 8g was prepared according to the procedure described in step-8 of Scheme 1 from ethyl 2-(2-((7-(5-(aminomethyl)-1-tosyl-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (8f) (166 mg, 0.297 mmol) in THF (1 mL), methanol (0.1 mL), and water (0.1 mL) using lithium hydroxide monohydrate (28.5 mg, 1.189 mmol) and stirring at room temperature for 10 hours. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(2-((7-(5-(aminomethyl)-1H-pyrrol-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (8 g) (25 mg, 22%) as a pale pink solid. 1H NMR (300 MHz, DMSO-d6) δ 12.21 (bs, 1H), 11.20 (bs, 1H), 8.17 (s, 3H), 8.07 (d, J = 2.2 Hz, 1H), 7.59 (s, 2H), 7.51 (s, 1H), 7.22 (d, J = 7.4 Hz, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.87 (s, 1H), 5.22 (s, 2H), 4.05 (s, 2H), 3.60 (s, 2H).MS (ES+): 377.1 (M+1);C 22 H 20 Analysis calculated for N2O4.1.1HCl.2.25H2O: C, 57.81; H, 5.65; Cl, ​​8.53; N, 6.13; Found: C, 57.77; H, 5.29; Cl, ​​8.97; N, 6.01.

[0150] Scheme 9 [ka] Preparation of 3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(carboxymethyl)benzoic acid (9d) Step-1: Preparation of ethyl 3-((7-bromobenzofuran-5-yl)methoxy)-4-(2-ethoxy-2-oxoethyl)benzoate (9b) Compound 9b was prepared from (7-bromobenzofuran-5-yl)methanol (1b) (191 mg, 0.842 mmol) in DCM (10 mL) according to the procedure described in step 2 of scheme 1 using triphenylphosphine (265 mg, 1.011 mmol) and ethyl 4-(2-ethoxy-2-oxoethyl)-3-hydroxybenzoate (9a) (170 mg, 0.674 mmol), a solution of bis(4-chlorobenzyl)azodicarboxylate (DCAD) (371 mg, 1.011 mmol) in DCM (10 mL). This gave, after work-up and purification by flash column chromatography [silica gel, elution with hexane / ethyl acetate (1:0 to 3:1)], ethyl 3-((7-bromobenzofuran-5-yl)methoxy)-4-(2-ethoxy-2-oxoethyl)benzoate (9b) (217 mg, 70%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 5.26(s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H);MS (ES+): 483.00 & 485.00 (M+Na).

[0151] Step-2: Preparation of ethyl 3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-ethoxy-2-oxoethyl)benzoate (9c) Compound 9c was prepared from ethyl 3-((7-bromobenzofuran-5-yl)methoxy)-4-(2-ethoxy-2-oxoethyl)benzoate 9b (202 mg, 0.438 mmol) in dioxane (12 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride 9e (123 mg, 0.657 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (61.5 mg, 0.088 mmol), and KCO (182 mg, 1.314 mmol) in water (1.5 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel with dichloromethane / methanol (1:0 to 19:1)], ethyl 3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-ethoxy-2-oxoethyl)benzoate (9c) (126 mg, 59% yield) as a colorless gum. 1 H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.76 - 7.69 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 7.7, 1.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.06 (d, J = 2.2 Hz, 1H), 5.33 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.94 (q, J = 7.1 MS (ES+): 488.20 (M+1).

[0152] Step-3: Preparation of 3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(carboxymethyl)benzoic acid (9d) Compound 9d was prepared from ethyl 3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-ethoxy-2-oxoethyl)benzoate (9c) (120 mg, 0.246 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (105 mg, 2.461 mmol) in water (5 mL) and stirred at room temperature for 18 hours according to the procedure described in step 8 of Scheme 1. This gave, after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(carboxymethyl)benzoic acid (9d) (65 mg, 61%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J = 2.2 Hz, 1H), 8.01 (s, 1H), 7.94 (dt, J = 7.3, 1.8 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.68 (d, J = MS (ES+): 432.05 (M+1);C 25 H 21 Analysis calculated for NO6.HCl.1.75H2O: C, 60.12; H, 5.15; N, 2.80; Cl, ​​7.10; Found: C, 60.23; H, 5.17; N, 2.96; Cl, ​​7.14.

[0153] Scheme 10 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetic acid (10d) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetate (10b) Compound 10b was prepared from (7-bromobenzofuran-5-yl)methanol 1b (173 mg, 0.762 mmol) in DCM (10 mL) according to the procedure described in step 2 of Scheme 1 using triphenylphosphine (240 mg, 0.914 mmol) and ethyl 2-(2-hydroxy-4-(trifluoromethoxy)phenyl)acetate 10a (161 mg, 0.609 mmol; CAS#1261673-71-5), a solution of bis(4-chlorobenzyl)azodicarboxylate (DCAD) (336 mg, 0.914 mmol) in DCM (10 mL). This gave, after work-up and purification by flash column chromatography [silica gel, elution with hexane / ethyl acetate (1:0 to 4:1)], ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetate (10b) (180 mg, 62%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.15 - 7.10 (m, 2H), 6.96 - 6.90 (m, 1H), 5.22 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.64 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -56.67;MS (ES+): 494.90 & 496.90 (M+Na).

[0154] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetate (10c) Compound 10c was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetate 10b (170 mg, 0.359 mmol) in dioxane (12 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride 9e (101 mg, 0.539 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (50.4 mg, 0.072 mmol), and KCO (149 mg, 1.078 mmol) in water (1.5 mL) at 100 °C for 11 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel with dichloromethane / methanol (1:0 to 9:1)], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetate (10c) (115 mg, 64% yield) as a colorless gum. 1 H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 2.2 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.75 - 7.67 (m, 2H), 7.58 (d, J = 1.7 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.96 - 6.89 (m, 1H), 5.28 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.65 (s, 2H), 0.96 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -56.64;MS (ES+): 500.00 (M+1).

[0155] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetic acid (10d) Compound 10d was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetate (10c) (110 mg, 0.220 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (56.6 mg, 1.321 mmol) in water (5 mL) and stirring at room temperature for 18 hours according to the procedure described in step 8 of Scheme 1. This gave, after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethoxy)phenyl)acetic acid (10d) (68 mg, 66%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J = 2.2 Hz, 1H), 8.02 - 7.99 (m, 1H), 7.92 (dt, J = 7.4, 1.7 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.96 - 6.87 (m, 1H), 5.30 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -56.65;MS (ES+): 472.00 (M+1);MS (ES-): 470.00 (M-1);C 25 H 20Analysis calculated for F3NO5.HCl.0.75H2O: C, 57.59; H, 4.35; Cl, ​​6.80; N, 2.69; Found: C, 57.69; H, 4.25; Cl, ​​6.68; N, 2.70.

[0156] Scheme 11 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (11m) Step-1: Preparation of (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (11b) To a solution of 4-chloro-3-fluoropicolinaldehyde (11a) (6.73 g, 42.2 mmol; CAS# 1260788-78-1) and CsCO (27.5 g, 84 mmol) in DCM (350 mL) was added (S)-2-methylpropane-2-sulfinamide (5.88 g, 48.5 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with brine (3 × 200 mL). The organic layer was dried, filtered, and concentrated in vacuo to give (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (11b) (11.08 g, 100% yield), which was used in the next reaction without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 5.1 Hz, 1H), 8.56 (s, 1H), 7.97 (dd, J = 5.6, 5.0 Hz, 1H), 1.21 (s, 9H).

[0157] Step-2: Preparation of (+)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (11c) To a solution of (S)—N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (11b) (11.08 g, 42.2 mmol) in methanol (211 mL) was added NaBH (1.595 g, 42.2 mmol) at 0° C. and stirred for 0.5 h. The reaction was quenched with acetone (20 mL) and concentrated in vacuo. The residue was taken up in EtOAc and saturated aqueous NH Cl. The organic layer was separated, washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (120 g), eluting with a 9:1 mixture of ethyl acetate and methanol in hexane] to give (+)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (11c) (9.34 g, 84% yield) as a thick, clear syrup. 1 H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J = 5.2 Hz, 1H), 7.72 - 7.62 (m, 1H), 5.86 (t, J = 5.9 Hz, 1H), 4.34 (dd, J = 5.9, 2.2 Hz, 2H), 1.09 (s, 9H); Optical rotation [α]D = +53.88 (c = 0.49, MeOH).

[0158] Step-3: Preparation of methyl 7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate (11e) To a solution of 2,2,2-trifluoroethanamine HCl (1.71 g, 17.26 mmol; CAS#373-88-6) in DCM (15 mL) was added a solution of sodium nitrite (1.27 g, 18.41 mmol) in water (1.5 mL) at 0 °C. The mixture was kept in an ice bath for 1 h, cooled to −78 °C, and methyl 3-bromo-5-formyl-4-hydroxybenzoate (11d) (0.522 g, 2.015 mmol; CAS#706820-79-3) and boron trifluoride etherate (1.2 mL, 9.47 mmol) were added. The mixture was stirred at −78 °C for 12 h and allowed to warm to room temperature over 12 h. The reaction was quenched with methanol (8 mL), diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (24 g), eluting with 0 to 30% ethyl acetate / hexanes] to afford methyl 7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate (11e) (503 mg, 73% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 6.0 Hz, 1H), 8.11 (dd, J = 1.7, 0.6 Hz, 1H), 7.91 (dt, J = 1.8, 0.9 Hz, 1H), 6.28 (dd, J = 5.9, 2.4 Hz, 1H), 4.67 - 4.46 (m, 1H), 3.85 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -69.45.

[0159] Step-4: Preparation of methyl 7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (11f) A solution of methyl 7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate (11e) (495 mg, 1.451 mmol) in sulfuric acid (5 mL, 94 mmol) was stirred at room temperature for 30 minutes. The mixture was poured into ice water, and the resulting white solid was collected by filtration and dried in vacuo to give methyl 7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (11f) (462 mg, 99% yield). 1 H NMR (300 MHz, DMSO-d6) δ 9.11 (t, J = 1.7 Hz, 1H), 8.23 ​​(d, J = 1.5 Hz, 1H), 8.20 (dt, J = 1.5, 0.9 Hz, 1H), 3.92 (s, 3H).

[0160] Step-5: Preparation of (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (11 g) To a solution of methyl 7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (11f) (927 mg, 2.87 mmol) in THF (12 mL) was added LiBH (2.20 mL, 8.80 mmol, 2 M solution in THF) and MeOH (385 μL, 9.52 mmol) at −78° C. The reaction mixture was stirred at room temperature for 24 h, quenched with saturated aqueous NH Cl, and extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated in vacuo to give (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (11g) (836 mg, 99% yield) as a white solid. 1 H NMR (300 MHz, methanol-d4) δ 8.41 (d, J = 1.7 Hz, 1H), 7.61 (q, J = 1.6 Hz, 2H), 4.69 (s, 2H).

[0161] Step-6: Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11i) Compound 11i was prepared from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (11g) (1 g, 3.39 mmol) in DCM (35 mL) according to the procedure described in step-2 of Scheme 1 using a solution of triphenylphosphine (0.978 g, 3.73 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (11h) (0.806 g, 4.07 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.369 g, 3.73 mmol) in DCM (35 mL) and stirred at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography (silica gel (40 g), elution with 0 to 20% ethyl acetate in hexanes), ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11i) (1.16 g, 72.0% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.97 (q, J = 1.6 Hz, 1H), 7.79 (s, 2H), 7.23 - 6.98 (m, 3H), 5.23 (s, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -58.23, -123.71.

[0162] Step-7: Preparation of ethyl 2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (11j) Compound 11j was prepared from ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11i) (1.8 g, 3.79 mmol) in anhydrous dioxane (30 mL) using bis(pinacolato)diboron (1.443 g, 5.68 mmol), potassium acetate (1.115 g, 11.36 mmol), Pd(dppf)Cl-CHCl (0.309 g, 0.379 mmol) and heating at 90 °C under argon atmosphere for 18 hours. This gave, after work-up and purification by flash column chromatography [silica (80 g), elution with 0 to 15% EtOAc in hexanes], ethyl 2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (11j) (1.87 g, 95% yield) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.87 - 8.82 (m, 1H), 7.90 (s, 1H), 7.81 - 7.79 (m, 1H), 7.18 - 7.04 (m, 3H), 5.21 (s, 2H), 4.10 - 3.89 (m, 2H), 3.61 (s, 2H), 1.35 (s, 12H), 1.06 - 1.00 (m, 3H).

[0163] Step-8: Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11k) Compound 11k was prepared from ethyl 2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (11j) (1.00 g, 1.915 mmol) in dioxane (30 mL) according to the procedure described in step-4 of Scheme 1. (11c) (0.507 g, 1.915 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2Cl2] (0.269 g, 0.383 mmol), and a solution of K2CO3 (0.794 g, 5.74 mmol) in water (3.6 mL) heated at 100 °C in an oil bath for 14 h. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), elution with 0 to 50% MeOH in ethyl acetate (10%) in hexanes], ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11k) (245 mg, 21% yield) as a colorless oil. MS (ES+): 625.20 (M+1).

[0164] Step-9: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (111) To a solution of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11k) (220 mg, 0.352 mmol) in tetrahydrofuran (15 mL) was added 2N aqueous HCl (0.352 mL, 1.057 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11l), which was used directly in the next step without further purification.

[0165] Step-10: Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (11m) Compound 11m was prepared from ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (11l) (183 mg, 0.352 mmol) in THF (7 mL), methanol (7 mL) using a solution of lithium hydroxide monohydrate (121 mg, 2.82 mmol) in water (7 mL) and stirring at room temperature for 16 hours according to the procedure described in step-8 of scheme 1. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (11m) (97 mg, 56.0% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H, D2O exchangeable), 8.96 - 8.92 (m, 1H), 8.66 (d, J = 4.9 Hz, 1H), 8.51 (s, 3H, D2O exchangeable), 7.99 (s, 1H), 7.82 (t, J = 5.3 Hz, 1H), 7.77 (s, 1H), 7.17 - 7.04 (m, 3H), 5.32 (s, 2H), 4.39 (s, 2H), 3.60 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -58.01, -123.77, -128.49;MS (ES+): 493.1 (M+1);(ES-): 491.1 (M-1);C 24 H 17 Analysis calculated for F5N2O4·HCl·0.25H2O: C, 54.05; H, 3.50; Cl, ​​6.65; N, 5.25; Found: C, 54.08; H, 3.50; Cl, ​​6.61; N, 5.22.

[0166] Scheme 12 [ka] Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (12j) Step-1: Preparation of methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (12b) To a solution of methyl 4-hydroxy-3,5-diiodobenzoate (12a) (7 g, 17.33 mmol, CAS#3337-66-4) in pyridine (15 mL) was added methyl propargyl ether (1.22 g, 17.33 mmol) and copper(I) oxide (1.24 g, 8.66 mmol). The mixture was degassed, backfilled with Ar, stirred at room temperature for 10 min, and heated to 125 °C in a sealed flask for 3 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with 1 N aqueous HCl (4 x 100 mL), water, and brine. The organic layer was dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (24 g), elution with 0 to 70% EtOAc in hexanes] to give methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (12b) (3.45 g, 58% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 4.60 (s, 2H), 3.88 (s, 3H), 3.36 (s, 3H).

[0167] Step-2: Preparation of methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate (12d) Compound 12d was prepared from methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (12b) (500 mg, 1.44 mmol) in 1,4-dioxane (10.0 mL) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (12c) (625 mg, 1.87 mmol), Pd(PPh)Cl (0.15 g, 0.216 mmol), and KPO (919 mg, 4.33 mmol) in an oil bath at 90 °C under nitrogen atmosphere for 12 h. This gave, after work-up and purification by flash column chromatography (silica gel, elution with 0 to 30% EtOAc in n-heptane), methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate (12d) (200 mg, 32%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.67 (s, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.13 (s, 1H), 4.59 (s, 2H), 4.23 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.33 (s, 3H), 1.40 (s, 9H).

[0168] Step-3: Preparation of 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylic acid (12e) Compound 12e was prepared from methyl 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate (12d) (1.3 g, 3.05 mmol) in THF (13 mL), MeOH (39 mL) using aqueous sodium hydroxide (13.0 mL, 0.36 g, 9.16 mmol), following the procedure described in step 8 of Scheme 1. This gave, after workup, 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylic acid (12e) (1.2 g, 95.45%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.68 (s, 1H), 7.50 (dd, J = 8.7, 6.7 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 4.59 (s, 2H), 4.23 (d, J = 6.2 Hz, 2H), 3.33 (s, 3H), 1.40 (s, 9H).

[0169] Step-4: Preparation of tert-butyl 3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (12f) Compound 12f was prepared from 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylic acid (12e) (1.2 g, 2.91 mmol) using N-methylmorpholine (0.35 g, 3.49 mmol), isobutyl chloroformate (0.47 g, 3.49 mmol) in THF (24 mL), and NaBH (0.33 g, 8.74 mmol) in water (10 mL) according to the procedure described in step 1 of Scheme 1. This gave tert-butyl 3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (12f) (1.0 g, 86%) as an oil after workup and purification by flash column chromatography (silica gel, elution with 0 to 30% EtOAc in n-heptane). 1 H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H), 7.59 - 7.53 (m, 1H), 7.53 - 7.39 (m, 3H), 7.28 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 5.28 (t, J = 5.7 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 4.55 (s, 2H), 4.31 - 4.18 (m, 2H), 3.32 (s, 3H), 1.40 (s, 9H).

[0170] Step-5: Preparation of ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12g) Compound 12g was prepared from tert-butyl 3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate (12f) (1.2 g, 3.02 mmol) in DCM (30 mL) according to the procedure described in step-2 of Scheme 1 using a solution of triphenylphosphine (1.029 g, 3.92 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (12k) (0.782 g, 3.02 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.441 g, 3.92 mmol) in DCM (30 mL) and stirred at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography (silica gel (80 g), elution with 0 to 30% ethyl acetate in hexanes), ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12 g) (890 mg, 46% yield). 1 H NMR (300 MHz, DMSO-d6) δ 7.76 - 7.68 (m, 2H), 7.66 (s, 1H), 7.55 - 7.28 (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 5.25 (s, 2H), 4.57 (s, 2H), 4.23 (d, J = 6.2 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 3.33 (s, 3H), 1.39 (s, 9H), 0.95 (t, J = 7.1 Hz, 3H).

[0171] Step-6: Preparation of ethyl 2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12h) To a solution of ethyl 2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12g) (800 mg, 1.253 mmol) in toluene (15 mL) were added tributyl(1-ethoxyvinyl)stannane (0.558 mL, 1.566 mmol) and Pd(PhP) (145 mg, 0.125 mmol), and the resulting mixture was stirred at 120 °C under nitrogen for 20 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 mL) and water (100 mL), quenched with 3 N aqueous HCl (1.253 mL, 3.76 mmol), stirred for 10 min, and filtered through a Celite pad. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (100 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and evaporated to dryness. The residue was purified by flash column chromatography [silica gel (40 g), eluting with 0 to 35% ethyl acetate in hexanes] to afford ethyl 2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12h) (285 mg, 38% yield) as a clear oil. 1 H NMR (300 MHz, DMSO-d6) δ 7.76 - 7.67 (m, 3H), 7.62 (s, 1H), 7.60 - 7.55 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 5.9 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 5.32 (s, 2H), 4.57 (s, 2H), 4.22 (d, J = 6.1 Hz, 2H), 3.92 (q, J = 7.1Hz, 2H), 3.71 (s, 2H), 3.32 (s, 3H), 2.58 (s, 3H), 1.38 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H).

[0172] Step-7: Preparation of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12i) To a solution of ethyl 2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12h) (250 mg, 0.415 mmol) in DCM (10 mL) was added TFA (0.617 mL, 8.31 mmol) and stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12i), which was used directly in the next step without further purification. MS (ES+): 502.20 (M+1).

[0173] Step-8: Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (12j) Compound 12j was prepared from ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (12i) (208 mg, 415 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (142 mg, 3.32 mmol) in water (5 mL) and stirring at room temperature for 16 hours, according to the procedure described in step-8 of Scheme 1. This afforded the HCl salt of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (12j) (11 mg, 51% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H, D2O exchangeable), 8.42 (s, 3H, D2O exchangeable), 7.97 - 7.95 (m, 1H), 7.92 (dt, J = 7.7, 1.6 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.64 - 7.53 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.01 (s, 1H), 5.35 (s, 2H), 4.58 (s, 2H), 4.19 - 4.09 (m, 2H), 3.69 (s, 2H), 3.33 (s, 3H), 2.57 (s, 3H);MS (ES+): 474.1 (M+1);C 28 H 27 Analytical calculation for NO₆·HCl·H₂O: C, 63.69; H, 5.73; Cl, ​​6.71; N, 2.65; Found: C, 63.79; H, 5.60; Cl, ​​6.42; N, 2.79.

[0174] Scheme 13 [ka] Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (13f) Step-1: Preparation of (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methanol (13a) Compound 13a was prepared according to the procedure described in step-3 of Scheme 1 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (11g) (3 g, 10.17 mmol) in anhydrous dioxane (60 mL) using bis(pinacolato)diboron (3.87 g, 15.25 mmol), potassium acetate (2.99 g, 30.5 mmol), Pd(dppf)Cl-CHCl (0.830 g, 1.017 mmol) and heating at 90 °C under argon atmosphere for 18 h. This gave, after work-up and purification by flash column chromatography [silica (120 g), elution with 0 to 40% EtOAc in hexanes], (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methanol (13a) (2.4 g, 69% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.81 - 8.76 (m, 1H), 7.76 (s, 1H), 7.73 (d, J = 1.7 Hz, 1H), 5.40 - 5.31 (m, 1H), 4.63 (d, J = 5.9 Hz, 2H), 1.34 (s, 12H); 19 F NMR (282 MHz, DMSO-d6) δ -58.01.

[0175] Step-2: Preparation of N-((3-fluoro-4-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (13b) Compound 13b was prepared from (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methanol (13a) (1.8 g, 5.26 mmol) in dioxane (75 mL) using a solution of (+)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (11c) (1.393 g, 5.26 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.739 g, 1.052 mmol), and KCO (2.181 g, 15.78 mmol) in water (9 mL) at 100 °C in an oil bath for 14 hours. This gave, after work-up and purification by flash column chromatography [silica gel (120 g), elution with ethyl acetate / methanol (9:1) in hexanes from 0 to 75%], N-((3-fluoro-4-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (13b) (1.45 g, 62% yield). 1 H NMR (300 MHz, DMSO-d6) δ 8.88 - 8.83 (m, 1H), 8.53 (d, J = 4.9 Hz, 1H), 7.79 (s, 1H), 7.67 (t, J = 5.2 Hz, 1H), 7.59 (s, 1H), 5.85 (t, J = 5.9 Hz, 1H), 5.47 (t, J = 5.7 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.44 - 4.39 (m, 2H), 1.11 (s, 9H); 19 F NMR (282 MHz, DMSO-d6) δ -58.11, -128.31;MS (ES+): 445.10 (M+1).

[0176] Step-3: Preparation of ethyl 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13c) Compound 13c was prepared from N-((3-fluoro-4-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (13b) (1.4 g, 3.15 mmol) in DCM (40 mL) using triphenylphosphine (1.074 g, 4.10 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (12k) (0.816 g, 3.15 mmol), and a solution of (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.504 g, 4.10 mmol) in DCM (40 mL) by stirring at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography (silica gel (120 g), elution with ethyl acetate / methanol (9:1) in hexanes from 0 to 50%), 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13c) (1.91 g, 88% yield) as a white semi-solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (d, J = 1.8 Hz, 1H), 8.56 (d, J = 4.9 Hz, 1H), 7.94 (s, 1H), 7.74 - 7.52 (m, 2H), 7.36 (d, J = 1.8 Hz, 1H), 7.24 - 7.09 (m, 2H), 5.86 (t, J = 5.9 Hz, 1H), 5.35 (s, 2H), 4.46 - 4.38 (m, 2H), 3.89 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.11 (s, 9H), 0.95 (t, J = 7.1 Hz, 3H);19 F NMR (282 MHz, DMSO-d6) δ -58.08, -128.19.

[0177] Step-4: Preparation of ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13d) Compound 13d was prepared according to the procedure described in step-6 of Scheme 12 from 2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13c) (1.2 g, 1.750 mmol) in toluene (40 mL) using tributyl(1-ethoxyvinyl)stannane (0.780 mL, 2.188 mmol), Pd(PhP) (0.202 g, 0.175 mmol) and heating at 120 °C under nitrogen for 16 hours. This gave, after work-up and purification by flash column chromatography (silica gel, elution with 0 to 35% ethyl acetate in hexanes), ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13d) (154 mg, 14% yield) as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 8.94 - 8.88 (m, 1H), 8.56 (d, J = 4.9 Hz, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.70 (t, J = 5.2 Hz, 1H), 7.65 - 7.63 (m, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 5.86 (t, J = 5.8 Hz, 1H), 5.42 (s, 2H), 4.45 - 4.40 (m, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 2.59 (s, 3H), 1.11 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -58.09, -128.13;MS (ES+): 649.20 (M+1).

[0178] Step-5: Preparation of ethyl 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13e) To a solution of ethyl 2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13d) (140 mg, 0.216 mmol) in tetrahydrofuran (15 mL) was added 2N aqueous HCl (0.216 mL, 0.647 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13e), which was used directly in the next step without further purification. MS (ES+): 545.20 (M+1).

[0179] Step-6: Preparation of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (13f) Compound 13f was prepared from ethyl 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (13e) (118 mg, 0.216 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (74.0 mg, 1.728 mmol) in water (5 mL) and stirring at room temperature for 16 hours according to the procedure described in step-8 of scheme 1. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (13f) (5.5 mg, 5% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H, D2O exchangeable), 8.96 - 8.93 (m, 1H), 8.67 (d, J = 5.0 Hz, 1H), 8.45 (s, 3H, D2O exchangeable), 8.05 (s, 1H), 7.86 - 7.80 (m, 2H), 7.64 - 7.57 (m, 2H), 7.40 (d, J = 7.7 Hz, 1H), 5.45 (s, 2H), 4.45 - 4.36 (m, 2H), 3.68 (s, 2H), 2.58 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -58.04, -128.43;MS (ES+): 517.1 (M+1).

[0180] Scheme 14 [ka] Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (14k) Step-1: Preparation of (+)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (14b) Compound 14b was prepared from 1-(3-bromophenyl)-2-fluoroethanone (14a) (3 g, 13.82 mmol; CAS#1219632-64-0) and (R)-2-methylpropane-2-sulfinamide (3.35 g, 27.6 mmol) in tetrahydrofuran (50 mL) using tetraethoxytitanium (6.31 g, 27.6 mmol) according to the procedure described in step 5 of Scheme 1. This gave (+)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (14b) (2.08 g, 47% yield) as a brown syrup after workup and purification by flash column chromatography [silica gel (40 g), elution with ethyl acetate (0 to 20%) in hexanes]. MS (ES+): 320.0, 322.0 (M+1);Optical rotation [α] D = +2.76 (c = 1.02, MeOH)

[0181] Step-2: Preparation of (-)-N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (14c) Compound 14c was prepared from (+)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (14b) (2.0 g, 6.25 mmol) in tetrahydrofuran (40 mL) and water (1 mL) using sodium borohydride (0.709 g, 18.74 mmol) according to the procedure described in step 3 of Scheme 5. This gave (−)-N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (14c) (1.5 g, 75% yield) as a white solid after workup and purification by flash column chromatography [silica gel (80 g), elution with ethyl acetate (0 to 100%) in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 7.71 (t, J = 1.9 Hz, 1H), 7.56 - 7.41 (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), 6.05 (d, J = 8.9 Hz, 1H), 4.65 - 4.50 (m, 2H), 4.42 (d, J = 6.3 Hz, 1H), 1.13 (s, 9H); 19 F NMR (282 MHz, DMSO-d6) δ -217.83; optical rotation [α]D = -7.16 (c = 1.01, MeOH).

[0182] Step-3: Preparation of 7-bromo-5-(bromomethyl)benzofuran (14e) To a solution of (7-bromobenzofuran-5-yl)methanol (1b) (3.00 g, 13.21 mmol) and CBr (8.76 g, 26.4 mmol) in DCM (100 mL) was added a solution of triphenylphosphine (6.93 g, 26.4 mmol) in DCM (50 mL) over 15 min at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (2 × 150 mL). The combined organic layers were dried, filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluting with 0 to 100% ethyl acetate in hexane] to give 7-bromo-5-(bromomethyl)benzofuran (14e) (2.38 g, 62% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 4.84 (s, 2H).

[0183] Step-4: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14 g) To a stirred solution of 7-bromo-5-(bromomethyl)benzofuran (14e) (1.379 g, 4.76 mmol) in DMF (10 mL) was added KCO (1.972 g, 14.27 mmol), followed by ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (14f) (1 g, 4.76 mmol; CAS# 76322-29-7) and KCO (1.972 g, 14.27 mmol). The resulting mixture was stirred at room temperature for 12 h and diluted with EtOAc (100 mL) and brine (100 mL). The organic layer was dried, filtered, and evaporated to dryness to give ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14g) (1.95 g, 98% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.17 - 7.04 (m, 2H), 6.66 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.3, 2.4 Hz, 1H), 5.17 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.53 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H).

[0184] Step-5: Preparation of ethyl 2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (14h) Compound 14h was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14g) (4.00 g, 9.54 mmol) in anhydrous dioxane (100 mL) according to the procedure described in step-3 of Scheme 1 using bis(pinacolato)diboron (3.63 g, 14.31 mmol), potassium acetate (2.81 g, 28.6 mmol), Pd(dppf)Cl-CHCl (0.779 g, 0.954 mmol) and heating at 90 °C under argon atmosphere for 12 hours. This gave, after work-up and purification by flash column chromatography [silica (120 g), elution with 0 to 15% EtOAc in hexanes], ethyl 2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (14h) (3.61 g, 81% yield) as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.3, 2.4 Hz, 1H), 5.16 (s, 2H), 3.99 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.50 (s, 2H), 1.34 (s, 12H), 1.10 - 1.00 (m, 3H);MS (ES+): 489.20 (M+Na).

[0185] Step-6: Preparation of ethyl 2-(2-((7-(3-(-1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14i) Compound 14i was prepared from ethyl 2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (14h) (1.20 g, 2.57 mmol) in dioxane (25 mL) according to the procedure described in step 4 of scheme 1. 1,1-Dimethylethylsulfinamide (14c) (0.995 g, 3.09 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.271 g, 0.386 mmol), and a solution of KCO (1.067 g, 7.72 mmol) in water (3 mL) were heated in an oil bath at 100 °C for 4 h. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluting with 0 to 50% ethyl acetate in hexanes], ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14i) (1.06 g, 71% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J = 2.2 Hz, 1H), 7.92 (s, 1H), 7.85 - 7.79 (m, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 4.7 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.3, 2.4 Hz, 1H), 6.03 (d, J = 8.2 Hz, 1H), 5.23 (s, 2H), 4.73 - 4.62 (m, 2H), 4.52 (d, J = 6.3 Hz, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.14 (s, 9H), 0.97 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -217.05;MS (ES+): 582.20 (M+1).

[0186] Step-7: Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14j) To a solution of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14i) (1.00 g, 1.719 mmol) in tetrahydrofuran (40 mL) was added 3N aqueous HCl (1.719 mL, 5.16 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14j), which was used directly in the next step without further purification. MS (ES+): 478.20 (M+1).

[0187] Step-8: Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (14k) Compound 14k was prepared from ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (14j) (821 mg, 1.719 mmol) in THF (10 mL), methanol (10 mL) using a solution of lithium hydroxide monohydrate (589 mg, 13.75 mmol) in water (10 mL) and stirring at room temperature for 16 hours according to the procedure described in step-8 of Scheme 1. This gave the HCl salt of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (14k) (450 mg, 58% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 3H, D2O exchangeable), 8.10 (d, J = 2.2 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.98 (dt, J = 7.2, 1.7 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.70 - 7.59 (m, 3H), 7.12 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.3, 2.3 Hz, 1H), 5.26 (s, 2H), 5.01 - 4.73 (m, 3H), 3.73 (s, 3H), 3.52 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -222.90;MS (ES+): 450.1 (M+1);(ES-): 448.15 (M-1);C 26 H24 Analysis calculated for FNO5·HCl·HO: C, 61.97; H, 5.40; Cl, ​​7.04; N, 2.78; Found: C, 62.08; H, 5.50; Cl, ​​6.85; N, 2.81; Optical rotation [α] D = +17.692 (c = 0.26, MeOH).

[0188] Scheme 15 [ka] Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (15f) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15b) Compound 15b was prepared from 7-bromo-5-(bromomethyl)benzofuran 14e (2.63 g, 9.08 mmol) using ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate 15a (1.8 g, 9.08 mmol; CAS#1261751-44-3), KCO (3.77 g, 27.2 mmol) in DMF (10 mL) and stirring at room temperature for 12 h according to the procedure described in step 4 of Scheme 14. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate 15b (3.224 g, 87% yield) as a white solid after workup and purification by flash column chromatography (SiO (40 g), elution with 0 to 50% EtOAc in hexanes). 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.25 (dd, J = 8.3, 6.9 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 11.3, 2.5 Hz, 1H), 6.75 (td, J = 8.5, 2.5 Hz, 1H), 5.20 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -112.61.

[0189] Step-2: Preparation of ethyl 2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (15c) Compound 15c was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15b) (1.5 g, 3.68 mmol) according to the procedure described in step-3 of Scheme 1 using bis(pinacolato)diboron (1.403 g, 5.53 mmol), potassium acetate (1.084 g, 11.05 mmol), and PdCl(dppf)-CHCl (0.301 g, 0.368 mmol) in anhydrous dioxane (50 mL) by heating at 90 °C under argon atmosphere overnight. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with 0 to 40% EtOAc in hexanes], ethyl 2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (15c) (1.44 g, 86% yield) as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 8.4, 6.9 Hz, 1H), 7.03 (dd, J = 11.4, 2.5 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.74 (td, J = 8.5, 2.5 Hz, 1H), 5.19 (s, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.57 (d, J = 1.7 Hz, 2H), 1.34 (s, 12H), 1.04 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -112.67.

[0190] Step-3: Preparation of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15d) Compound 15d was prepared from ethyl 2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (15c) (680 mg, 1.497 mmol) in dioxane (25 mL) using a solution of (−)-N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide (14c) (579 mg, 1.796 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (158 mg, 0.225 mmol), and KCO (621 mg, 4.49 mmol) in water (3 mL) at 100° C. in an oil bath for 4 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g)], ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15d) (553 mg, 65% yield). 1 H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 2.2 Hz, 1H), 7.92 (s, 1H), 7.85 - 7.80 (m, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.29 - 7.21 (m, 1H), 7.10 - 7.02 (m, 2H), 6.79 - 6.70 (m, 1H), 6.03 (d, J = 8.3 Hz, 1H), 5.25 (s, 2H), 4.77 - 4.48 (m, 3H), 3.90 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.13 (s, 9H), 0.95 (t, J = 7.1 Hz, 3H);MS (ES+): 570.20 (M+1).

[0191] Step-4: Preparation of ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15e) To a solution of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15d) (520 mg, 0.913 mmol) in tetrahydrofuran (20 mL) was added 3N aqueous HCl (0.913 mL, 2.74 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15e), which was used directly in the next step without further purification. MS (ES+): 466.15 (M+1).

[0192] Step-5: Preparation of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (15f) Compound 15f was prepared from ethyl 2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (15e) (425 mg, 0.913 mmol) in THF (8 mL), methanol (8 mL) using a solution of lithium hydroxide monohydrate (313 mg, 7.30 mmol) in water (8 mL) and stirred at room temperature for 16 hours according to the procedure described in step-8 of Scheme 1. This gave the HCl salt of (+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetic acid (15f) (216 mg, 54% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.09 - 8.05 (m, 1H), 7.97 (dt, J = 6.8, 1.9 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.25 (dd, J = 8.4, 6.9 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 11.3, 2.5 Hz, 1H), 6.74 (td, J = 8.5, 2.5 Hz, 1H), 5.28 (s, 2H), 5.00 - 4.71 (m, 3H), 3.57 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -112.95, -222.84;MS (ES+): 438.1 (M+1);(ES-): 436.1 (M-1);C 25 H 21 Analysis calculated for F2NO4·HCl·H2O: C, 61.04; H, 4.92; Cl, ​​7.21; N, 2.85. Found: C, 60.93; H, 4.77; Cl, ​​7.21; N, 2.94; optical rotation [α] D = +13.89 (c = 0.36, MeOH).

[0193] Scheme 16 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (16f) Step-1: Preparation of methyl 7-bromo-2-fluorobenzofuran-5-carboxylate (16b) To a stirred solution of methyl 7-bromobenzofuran-5-carboxylate (16a) (5 g, 19.60 mmol; CAS#286836-79-1) in dry THF (90 mL) was added LDA (19.6 mL, 1.5 M, 29.4 mmol) dropwise under N at −78° C. The mixture was maintained at −78° C. for 1.5 h, followed by the addition of a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (12.5 g, 39.6 mmol) in THF (60 mL). The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography [silica (40 g), elution with ethyl acetate / hexanes from 0 to 40%] to give methyl 7-bromo-2-fluorobenzofuran-5-carboxylate (16b) (453 mg, 9% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 6.64 (d, J = 6.5 Hz, 1H), 3.89 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -109.09.

[0194] Step-2: Preparation of (7-bromo-2-fluorobenzofuran-5-yl)methanol (16c) Compound 16c was prepared from methyl 7-bromo-2-fluorobenzofuran-5-carboxylate (16b) (495 mg, 1.813 mmol) in THF (15 mL) using LiBH (1.45 mL, 5.80 mmol) and MeOH (0.225 mL, 5.56 mmol) according to the procedure described in step 5 of Scheme 11. This afforded (7-bromo-2-fluorobenzofuran-5-yl)methanol (16c) (90 mg, 20% yield) as a white solid after workup and purification by flash column chromatography [silica (12 g), eluting with 0 to 50% EtOAc in hexanes] followed by reverse-phase column chromatography [C18 (50 g), eluting with 0 to 100% ACN in water (containing 0.1% HCl)]. 1 H NMR (300 MHz, chloroform-d) δ 7.46 - 7.25 (m, 2H), 5.89 (d, J = 6.6 Hz, 1H), 4.65 (s, 2H), 2.84 (s, 1H); 19 F NMR (282 MHz, chloroform-d) δ −109.55.

[0195] Step-3: Preparation of ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16d) Compound 16d was prepared from (7-bromo-2-fluorobenzofuran-5-yl)methanol (16c) (1.5 g, 6.12 mmol) in DCM (60 mL) according to the procedure described in step 2 of scheme 1 using triphenylphosphine (1.897 g, 7.23 mmol) and ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (11h) (1.103 g, 5.56 mmol), a solution of bis(4-chlorobenzyl)azodicarboxylate (DCAD) (2.66 g, 7.23 mmol) in DCM (60 mL). This gave, after work-up and purification by flash column chromatography (silica gel (80 g), elution with hexane / ethyl acetate from 0 to 20%), ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16d) (1.50 g, 63.4% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.14 (dd, J = 8.9, 2.6 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.54 (d, J = 6.4 Hz, 1H), 5.15 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H), 1.09 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -110.41, -123.85;MS (ES+): 446.90 (M+Na).

[0196] Step-4: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16e) Compound 16e was prepared from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16d) (200 mg, 0.470 mmol) in dioxane (20 mL) according to the procedure described in step 4 of Scheme 1 using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (132 mg, 0.706 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (49.5 mg, 0.071 mmol), and KCO (195 mg, 1.411 mmol) in water (4 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 5% MeOH in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16e) (158 mg, 74.4% yield). 1 H NMR (300 MHz, DMSO-d6) δ 7.78 - 7.73 (m, 1H), 7.65 (dt, J = 7.5, 1.7 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.17 - 7.06 (m, 3H), 6.44 (d, J = 6.4 Hz, 1H), 5.20 (s, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.65 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES+): 452.10 (M+1).

[0197] Step-5: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (16f) Compound 16f was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16e) (150 mg, 0.332 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (47.7 mg, 1.994 mmol) in water (5 mL) and stirred at room temperature for 16 hours according to the procedure described in step 8 of Scheme 1. This gave, after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (16f) (104 mg, 74%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.96 - 7.93 (m, 1H), 7.89 - 7.77 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.17 - 6.98 (m, 3H), 6.44 (d, J = 6.4 Hz, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -111.52, -124.07;MS (ES+): 424.1 (M+1);C 24 H 19 Analysis calculated for F2NO4·HCl·H2O: C, 60.32; H, 4.64; Cl, ​​7.42; N, 2.93; Found: C, 60.46; H, 4.80; Cl, ​​7.17; N, 2.96.

[0198] Scheme 17 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (17d) Step-1: Preparation of ethyl 2-(5-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (17a) Compound 17a was prepared from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (16d) (1.04 g, 2.446 mmol) according to the procedure described in step-3 of Scheme 1 using bis(pinacolato)diboron (0.932 g, 3.67 mmol), potassium acetate (0.720 g, 7.34 mmol), PdCl(dppf)-CHCl (0.200 g, 0.245 mmol) in anhydrous dioxane (30 mL) and heated at 90 °C under argon atmosphere for 18 h. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with 0 to 20% EtOAc in hexanes], ethyl 2-(5-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (17a) (954 mg, 83% yield). 1 H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.20 - 7.00 (m, 3H), 6.35 (d, J = 6.4 Hz, 1H), 5.13 (s, 2H), 4.10 - 3.96 (m, 2H), 3.61 (s, 2H), 1.33 (s, 12H), 1.06 (t, J = 7.1 Hz, 3H);MS (ES+): 495.15 (M+Na).

[0199] Step-2: Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (17b) Compound 17b was prepared from ethyl 2-(5-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (17a) (450 mg, 0.953 mmol) in dioxane (25 mL) according to the procedure described in step-4 of scheme 1. (11c) (303 mg, 1.143 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2Cl2] (100 mg, 0.143 mmol), and a solution of K2CO3 (395 mg, 2.86 mmol) in water (3 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with 0 to 2.5% methanol in DCM], ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (17b) (239 mg, 0.416 mmol, 43.7% yield). MS (ES+): 575.1 (M+1).

[0200] Step-3: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (17c) To a solution of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (17b) (220 mg, 0.383 mmol) in tetrahydrofuran (20 mL) was added 3N aqueous HCl (0.383 mL, 1.149 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (17c), which was used directly in the next step without further purification. MS (ES+): 471.15 (M+1).

[0201] Step-4: Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (17d) Compound 17d was prepared according to the procedure described in step-8 of Scheme 1 from ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (17c) (180 mg, 0.383 mmol) in THF (2 mL), acetonitrile (1 mL) using a 1N solution of lithium hydroxide monohydrate (1.149 mL, 1.149 mmol) and stirring at room temperature for 24 hours. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (17d) (7 mg, 4% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H, D2O exchangeable), 8.64 (d, J = 5.0 Hz, 1H), 8.48 - 8.38 (m, 3H, D2O exchangeable), 7.82 (d, J = 1.6 Hz, 1H), 7.80 (t, J = 5.4 Hz, 1H), 7.57 (s, 1H), 7.17 - 7.03 (m, 3H), 6.51 (d, J = 6.4 Hz, 1H), 5.25 (s, 2H), 4.49 - 4.29 (m, 2H), 3.60 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -111.15, -123.93, -128.48;MS (ES+): 443.1 (M+1).

[0202] Scheme 18 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (18c) Step-1: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (18b) Compound 18b was prepared from ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate 16d (200 mg, 0.470 mmol) in dioxane (20 mL) using a solution of (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride 18a (119 mg, 0.706 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (49.5 mg, 0.071 mmol), and KCO (195 mg, 1.411 mmol) in water (4 mL) at 100 °C for 3 h in an oil bath. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 5% MeOH in DCM], ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (18b) (152 mg, 69% yield). 1 H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J = 1.6 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.49 - 7.42 (m, 1H), 7.39 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.18 - 7.05 (m, 3H), 6.45 (d, J = 6.4 Hz, 1H), 5.19 (s, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 3.63 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H);MS (ES+): 470.1 (M+1).

[0203] Step-2: Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (18c) Compound 18c was prepared from ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (18b) (140 mg, 0.298 mmol) in THF (2 mL), acetonitrile (2 mL) using a solution of lithium hydroxide monohydrate (21.43 mg, 0.895 mmol) in water (1 mL) and stirring at room temperature for 14 hours according to the procedure described in step 8 of Scheme 1. This gave, after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the hydrochloride salt of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetic acid (18c) (54 mg, 41%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 3H), 7.75 - 7.62 (m, 3H), 7.50 - 7.38 (m, 2H), 7.16 - 7.02 (m, 3H), 6.45 (d, J = 6.4 Hz, 1H), 5.22 (s, 2H), 4.18 (s, 2H), 3.59 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -111.54, -118.50, -124.00;MS (ES+): 442.1 (M+1);C 24 H 18 Analysis calculated for F3NO4·HCl·H2O: C, 58.13; H, 4.27; Cl, ​​7.15; N, 2.82; Found: C, 57.76; H, 4.22; Cl, ​​6.95; N, 2.99.

[0204] Scheme 19 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetic acid (19i) Step-1: Preparation of ethyl 2-(2-methoxy-4-(methoxycarbonylamino)phenyl)acetate (19b) To a degassed solution of ethyl 2-(4-bromo-2-methoxyphenyl)acetate (19a) (750 mg, 2.75 mmol; CAS# 1261570-38-0) in toluene (30 mL), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (131 mg, 0.275 mmol), methyl carbamate (309 mg, 4.12 mmol), Pd(dba) (126 mg, 0.137 mmol), and cesium carbonate (895 mg, 2.75 mmol) were added and heated at 90 °C under nitrogen for 19 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (60 mL), brine (60 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel (24 g), eluting with 0 to 25% ethyl acetate in hexane) to give ethyl 2-(2-methoxy-4-(methoxycarbonylamino)phenyl)acetate (19b) (452 ​​mg, 61.6% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.20 - 7.17 (m, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.1, 2.0 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.66 (s, 3H), 3.49 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H);MS (ES+): 268.1 (M+1)

[0205] Step-2: Preparation of ethyl 2-(2-hydroxy-4-((methoxycarbonyl)amino)phenyl)acetate (19c) A solution of ethyl 2-(2-methoxy-4-(methoxycarbonylamino)phenyl)acetate (19b) (200 mg, 0.748 mmol) in DCM (15 mL) was cooled to −78° C., boron tribromide (0.283 mL, 2.99 mmol) was added, and the mixture was allowed to warm slowly to room temperature over 14 h. The reaction mixture was cooled to 0° C., quenched with ethanol (10 mL), and concentrated to dryness. The mixture was reconstituted with ethanol (10 mL) and concentrated to dryness. The residue was taken up in ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel (40 g), eluting with 0 to 25% ethyl acetate in hexanes) to give ethyl 2-(2-hydroxy-4-((methoxycarbonyl)amino)phenyl)acetate (19c) (47 mg, 24.80% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.51 - 9.47 (m, 2H), 7.07 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.77 (dd, J = 8.1, 2.0 Hz, 1H), 4.04 (q, MS (ES+): 254.00 (M+1)

[0206] Step-3: Preparation of 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (19e) Compound 19e was prepared from 7-bromobenzofuran-5-carboxylic acid 1a (3 g, 12.45 mmol) in dioxane (100 mL) using a solution of (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid 19d (4.38 g, 17.42 mmol), potassium bicarbonate (5.16 g, 37.3 mmol) in water (10 mL), and bis(triphenylphosphine)palladium(II) chloride (1.310 g, 1.867 mmol) in an oil bath at 100° C. under nitrogen atmosphere for 3 hours, according to the procedure described in step-4 of scheme 1. This gave, after workup and purification by flash column chromatography [silica (40 g), elution with 0 to 50% DMA80 in DCM], 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (19e) (2.7 g, 7.35 mmol, 59.0% yield) as a clear oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 1.5 Hz, 1H), 8.12 - 8.05 (m, 2H), 7.76 - 7.68 (m, 2H), 7.56 - 7.43 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 1.39 (s, 9H);MS (ES-) 366.3 (M-1).

[0207] Step-4: Preparation of tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (19f) Compound 19f was prepared from 7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylic acid (19e) (1.7 g, 4.63 mmol) according to the procedure described in step 1 of Scheme 1 using N-methylmorpholine (0.610 mL, 5.55 mmol), isobutyl chloroformate (0.729 mL, 5.55 mmol), and NaBH (0.525 g, 13.88 mmol) in THF (40 mL). This gave, after workup, tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (19f) (1.1 g, 67.3% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J = 2.2 Hz, 1H), 7.73 (m, 2H), 7.59 (d, J = 1.6 Hz, 1H), 7.52 - 7.38 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 4.22 (d, J = 6.2 Hz, 2H), 1.40 (s, 9H).

[0208] Step-5: Preparation of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetate (19g) Compound 19g was prepared from tert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (19f) (55.8 mg, 0.158 mmol) in DCM (5 mL) according to the procedure described in step 2 of Scheme 1 using a solution of triphenylphosphine (49.7 mg, 0.190 mmol) and ethyl 2-(2-hydroxy-4-((methoxycarbonyl)amino)phenyl)acetate (19c) (40 mg, 0.158 mmol), bis(4-chlorobenzyl)azodicarboxylate (DCAD) (69.6 mg, 0.190 mmol) in DCM (5 mL). This gave, after workup and purification by flash column chromatography (silica gel (4 g)), ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetate (19 g) (88 mg, 95% yield). MS (ES+): 611.10 (M+Na).

[0209] Step-6: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetate (19h) To a solution of ethyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetate (19g) (80 mg, 0.136 mmol) in DCM (10 mL) was added TFA (0.209 mL, 2.72 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetate (19h), which was used directly in the next step without further purification. MS (ES+): 489.1 (M+1).

[0210] Step-7: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetic acid (19i) Compound 19i was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetate (19h) (66.4 mg, 0.136 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (34.9 mg, 0.816 mmol) in water (5 mL) and stirring at room temperature for 16 hours, according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((methoxycarbonyl)amino)phenyl)acetic acid (19i) (3 mg, 5% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H, D2O exchangeable), 8.21 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.97 - 7.92 (m, 1H), 7.77 (s, 1H), 7.67 - 7.49 (m, 3H), 7.41 - 7.30 (m, 2H), 7.13 - 7.03 (m, 2H), 5.20 (s, 2H), 4.23 - 4.05 (m, 2H), 3.65 (s, 3H), 3.51 (s, 2H);MS (ES+): 461.1 (M+1);(ES-): 459.05 (M-1).

[0211] Scheme 20 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetic acid (20h) Step-1: Preparation of ethyl 2-(2-(benzyloxy)-4-bromophenyl)acetate (20b) To a solution of ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (12k) (8.8 g, 34 mmol; CAS# 1261585-89-0) and (bromomethyl)benzene (5.81 g, 34.0 mmol) in DMF (100 mL) was added potassium carbonate (14.08 g, 102 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (100 mL), brine (100 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel (220 g), eluting with 0 to 8% ethyl acetate in hexane) to give ethyl 2-(2-(benzyloxy)-4-bromophenyl)acetate (20b) (10.92 g, 92% yield). 1 H NMR (300 MHz, DMSO-d6) δ 7.43 - 7.29 (m, 5H), 7.27 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 8.0, 1.8 Hz, 1H), 5.13 (s, MS (ES+): 348.95 (M+1).

[0212] Step-2: Preparation of ethyl 2-(2-(benzyloxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20c) Compound 20c was prepared from ethyl 2-(2-(benzyloxy)-4-bromophenyl)acetate (20b) (750 mg, 2.148 mmol) in toluene (50 mL) according to the procedure described in step 1 of Scheme 19, using dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (102 mg, 0.215 mmol), isopropyl carbamate (339 mg, 3.22 mmol), Pd(dba) (98 mg, 0.107 mmol), cesium carbonate (700 mg, 2.148 mmol) and heating at 90 °C for 19 hours under nitrogen. This gave, after work-up and purification by flash column chromatography [silica (40 g), elution with 0 to 15% ethyl acetate in hexane], ethyl 2-(2-(benzyloxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20c) (428 mg, 54% yield). 1 H NMR (300 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.46 - 7.25 (m, 6H), 7.08 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.1, 1.9 Hz, 1H), 5.01 (s, 2H), 4.95 - 4.79 (m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 1.24 (d, J = 6.2 Hz, 6H), 1.10 (t, J = 7.1 Hz, 3H);MS (ES+): 372.10 (M+1).

[0213] Step-3: Preparation of ethyl 2-(2-hydroxy-4-((isopropoxycarbonyl)amino)phenyl)acetate (20d) To a solution of ethyl 2-(2-(benzyloxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20c) (400 mg, 1.077 mmol) in ethyl acetate (20 mL) was added Pd / C (92 mg, 0.086 mmol) and hydrogenated using a balloon at room temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel (12 g), eluting with 0 to 25% ethyl acetate in hexane) to give ethyl 2-(2-hydroxy-4-((isopropoxycarbonyl)amino)phenyl)acetate (20d) (245 mg, 81% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.40 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 4.96 - 4.74 (m, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.43 (s, 2H), 1.24 (d, J = 6.2 Hz, 6H), 1.16 (t, J = 7.1 Hz, 3H);MS (ES-): 280.00 (M-1).

[0214] Step-4: Preparation of 7-bromo-5-(chloromethyl)benzofuran (20e) To a solution of (7-bromobenzofuran-5-yl)methanol (1b) (5.00 g, 22.02 mmol) in DCM (100 mL) was added SOCl (3.21 mL, 44.0 mmol) and 1 drop of DMF (0.3 mL), and the reaction was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo to give 7-bromo-5-(chloromethyl)benzofuran (20e) (4.88 g, 90% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 4.88 (s, 2H).

[0215] Step-5: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20f) Compound 20f was prepared from 7-bromo-5-(chloromethyl)benzofuran 20e (201 mg, 0.818 mmol) using ethyl 2-(2-hydroxy-4-((isopropoxycarbonyl)amino)phenyl)acetate 20d (230 mg, 0.818 mmol), KCO (339 mg, 2.453 mmol) in DMF (10 mL) and stirring at room temperature for 16 h according to the procedure described in step 4 of Scheme 14. This gave ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate 20f (311 mg, 78%) after workup and purification by flash column chromatography (SiO (24 g), elution with 0 to 20% EtOAc in hexanes). 1 H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.4 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.13 - 7.05 (m, 2H), 6.99 - 6.94 (m, 1H), 5.10 (s, 2H), 4.96 - 4.77 (m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 1.24 (d, J = 6.2 Hz, 6H), 1.07 (t, J = 7.1 Hz, 3H);MS (ES+): 489.90 (M+1).

[0216] Step-6: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20 g) Compound 20g was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20f) (300 mg, 0.612 mmol) in dioxane (10 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (139 mg, 0.918 mmol), potassium bicarbonate (254 mg, 1.835 mmol) in water (1 mL), and bis(triphenylphosphine)palladium(II) chloride (64.4 mg, 0.092 mmol) in an oil bath at 100° C. under nitrogen atmosphere for 4 hours according to the procedure described in step-4 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20g) (181 mg, 57%). MS (ES+): 517.10 (M+1).

[0217] Step-7: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetic acid (20h) Compound 20h was prepared according to the procedure described in step-8 of Scheme 1 from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetate (20g) (160 mg, 0.310 mmol) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (80 mg, 1.858 mmol) in water (5 mL) and stirring at room temperature for 16 hours. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonyl)amino)phenyl)acetic acid (20h) (84 mg, 55.5% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H, D2O exchangeable), 9.55 (s, 1H), 8.36 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.02 - 7.98 (m, 1H), 7.95 (dt, J = 7.4, 1.6 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.39 (s, 1H), 7.11 - 7.04 (m, 2H), 6.94 (dd, J = 8.1, 1.9 Hz, MS (ES+): 489.2 (M+1); (ES-): 487.2 (M-1);C 28 H 28 Analysis calculated for N2O6 HCl 1.5H2O: C, 60.92; H, 5.84; Cl, ​​6.42; N, 5.07; Found: C, 61.09; H, 5.69; Cl, ​​6.55; N, 5.16.

[0218] Scheme 21 [ka] Preparation of 2-(2-((7-(3-((ethylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (21c) Step-1: Preparation of ethyl 2-(2-((7-(3-((ethylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (21b) Compound 21b was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (300 mg, 0.688 mmol) in dioxane (5 mL) using a solution of N-(3-bromobenzyl)ethanamine (21a) (221 mg, 1.031 mmol; CAS#90389-91-6), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (72.4 mg, 0.103 mmol), and KCO (285 mg, 2.063 mmol) in water (3 mL) by microwave heating at 135 °C for 30 minutes. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-((ethylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (21b) (122 mg, 40% yield) as a yellow oil. MS (ES+): 444.2 (M+1).

[0219] Step-2: Preparation of 2-(2-((7-(3-((ethylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (21c) Compound 21c was prepared from ethyl 2-(2-((7-(3-((ethylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (21b) (122 mg, 0.275 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (87 mg, 2.063 mmol) in water (1 mL) and heating at 50° C. overnight according to the procedure described in step-8 of Scheme 1. This gave 2-(2-((7-(3-((ethylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (21c) (22 mg, 6.81% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (40 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H, D2O exchangeable), 9.12 (s, 2H, D2O exchangeable), 8.05 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.93 - 7.83 (m, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.21 - 7.12 (m, 2H), 7.06 - 6.97 (m, 2H), 6.84 (td, J = 7.4, 1.1Hz, 1H), 5.21 (s, 2H), 4.16 (s, 2H), 3.54 (s, 2H), 2.93 (q, J = 7.3 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H);MS (ES+): 416.1 (M+1).

[0220] Scheme 22 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (22h) Step-1: Preparation of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (22b) Compound 22b was prepared from 4-chloropicolinaldehyde 22a (15 g, 106 mmol) in DCM (100 mL) using CsCO (51.8 g, 159 mmol), (S)-2-methylpropane-2-sulfinamide (14.77 g, 122 mmol) and stirring at room temperature for 1 h according to the procedure described in step 1 of Scheme 11. This gave, after workup, N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide 22b (25.9 g, 106 mmol, 100% yield), which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (dd, J = 5.3, 0.6 Hz, 1H), 8.48 (s, 1H), 8.13 (dd, J = 2.1, 0.6 Hz, 1H), 7.76 (dd, J = 5.3, 2.1 Hz, 1H), 1.22 (s, 9H).

[0221] Step-2: Preparation of (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22c) Compound 22c was prepared from N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (22b) (18.5 g, 76 mmol) in methanol (300 mL) using NaBH (2.86 g, 76 mmol) according to the procedure described in step-2 of Scheme 11. This gave (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22c) (15.7 g, 84%) as a white solid after workup and purification by flash column chromatography [silica gel (120 g), elution with a 9:1 mixture of ethyl acetate and methanol in hexane]. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (dd, J = 5.3, 0.6 Hz, 1H), 7.58 (dd, J = 2.1, 0.7 Hz, 1H), 7.43 (dd, J = 5.4, 2.1 Hz, 1H), 5.97 (t, J = 6.3 Hz, 1H), 4.29 (dd, J = 6.3, 3.3 Hz, 2H), 1.16 (s, 9H); optical rotation [α] D = +45.4 (0.81, MeOH).

[0222] Step-3: Preparation of (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (22i) Compound 22i was prepared from (7-bromobenzofuran-5-yl)methanol 1b (6.5 g, 28.6 mmol) according to the procedure described in step 3 of Scheme 1 using bis(pinacolato)diboron (10.9 g, 42.9 mmol), potassium acetate (8.43 g, 86 mmol), and PdCl(dppf)-CHCl (2.34 g, 2.86 mmol) in anhydrous dioxane (200 mL) heated at 90 °C for 18 h under an argon atmosphere. This afforded (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol 22i (6.81 g, 87% yield) as an off-white solid after workup and purification by flash column chromatography [silica (120 g), elution with 0 to 60% EtOAc in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 1.8, 0.9 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 5.22 (t, J = 5.8 Hz, 1H), 4.58 (dt, J = 5.8, 0.7 Hz, 2H), 1.34 (s, 12H).

[0223] Step-4: Preparation of (+)-N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22d) Compound 22d was prepared from (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (22i) (1.5 g, 5.47 mmol) in dioxane (60 mL) using a solution of (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22c) (1.620 g, 6.57 mmol), PdCl(PPh) (0.576 g, 0.821 mmol), and potassium carbonate (2.269 g, 16.42 mmol) in water (7 mL) by heating at 100 °C in an oil bath under nitrogen atmosphere for 16 hours. This gave, after work-up and purification by flash column chromatography [silica gel (80 g), elution with 0 to 7% methanol in DCM], (+)-N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22d) (875 mg, 45% yield) as an off-white gummy solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (dd, J = 5.2, 0.8 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 8.04 - 8.03 (m, 1H), 7.78 (dd, J = 5.2, 1.8 Hz, 1H), 7.72 - 7.69 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 5.98 (t, J = 6.1 Hz, 1H), 5.31 (t, J = 5.7 Hz, 1H), 4.65 (dt, J = 5.7, 0.7 Hz, 2H), 4.45 - 4.28 (m, 2H), 1.19 (s, 9H);MS (ES+): 359.10 (M+1);Optical rotation [α] D = +32.77 (c = 0.47, MeOH).

[0224] Step-5: Preparation of (+)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (22f) Compound 22f was prepared from (+)-N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22d) (0.861 g, 2.401 mmol) in DCM (40 mL) according to the procedure described in step-2 of Scheme 1 using triphenylphosphine (0.945 g, 3.60 mmol), ethyl 2-(2-hydroxy-3,4-dimethylphenyl)acetate (22e) (CAS#: 1806292-81-8, 0.5 g, 2.401 mmol), and a solution of (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.322 g, 3.60 mmol) in DCM (40 mL) and stirred at room temperature for 22 hours. This gave, after work-up and purification by flash column chromatography (silica gel (40 g), elution with ethyl acetate in hexanes from 0 to 100%), (+)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (22f) (145 mg, 11.01% yield) as a clear oil. MS (ES+): 549.2 (M+1); optical rotation [α] D = +15.238 (c = 0.105, MeOH).

[0225] Step-6: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (22 g) A solution of (+)-ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (22f) (140 mg, 0.255 mmol) in THF (150 mL) was treated with HCl (3N) (0.255 mL, 0.765 mmol) at room temperature and stirred for 6 hours. The reaction mixture was concentrated to give ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (22g) (140 mg, 0.315 mmol, 123% yield) as a clear oil, which was used in the next step without further purification. MS (ES+) 445.2 (M+1).

[0226] Step-7: Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (22h) Compound 22h was prepared from ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (22g) (140 mg, 0.315 mmol) in THF (6 mL), methanol (1 mL) using a solution of lithium hydroxide monohydrate (108 mg, 2.52 mmol) in water (1 mL) and stirring at room temperature for 19 hours according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetic acid (22h) (50 mg, 38% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 5.2 Hz, 1H), 8.38 (s, 3H, D2O exchangeable), 8.19 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 7.98 (dd, J = 5.3, 1.7 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 4.91 (s, 2H), 4.37 - 4.27 (m, 2H), 3.60 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H);MS (ES+): 417.2 (M+1);(ES-): 415.2 (M-1);C 25 H 24 Analysis calculated for N2O4.1.5HCl.2H2O: C, 59.20; H, 5.86; Cl, ​​10.49; N, 5.52; Found: C, 59.05; H, 5.59; Cl, ​​10.21; N, 5.44.

[0227] Scheme 23 [ka] Preparation of 2-(2-((2-(acetoxymethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23h) Step-1: Preparation of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) Compound 23a was prepared from methyl 4-hydroxy-3,5-diiodobenzoate (12a) (5 g, 12.38 mmol) in pyridine (10 mL) using tert-butyldimethyl(prop-2-ynyloxy)silane (2.11 g, 12.38 mmol; CAS#76782-82-6) and copper(I) oxide (0.89 g, 6.19 mmol) according to the procedure described in step 1 of Scheme 12. This gave methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) (3.2 g, 58% yield) as a clear oil after workup and purification by flash column chromatography [silica (80 g), elution with 0 to 70% EtOAc in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 6.95 (s, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 0.76 (s, 9H), -0.00 (s, 6H);MS (ES+): 469.1 (M+Na).

[0228] Step-2: Preparation of (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (23b) Compound 23b was prepared from methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) (12 g, 26.9 mmol) in THF (150 mL) using LiBH (26.9 mL, 53.8 mmol, 2 M solution in THF) and MeOH (2.2 mL, 53.8 mmol) according to the procedure described in step 5 of Scheme 11. This afforded (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (23b) (10.4 g, 92% yield) as a clear oil after workup and purification by flash column chromatography [silica (80 g), elution with 0 to 60% EtOAc in hexanes].1 H NMR (300 MHz, DMSO-d6) δ 7.62 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 5.25 (t, J = 5.8, 1.2 Hz, 1H, D2O exchangeable), 4.81 (s, 2H), 4.53 (d, J = 5.8 Hz, 2H), 0.89 (s, 9H), 0.12 (s, 6H);MS (ES+): 441.2 (M+Na);(ES-): 417.2 (M-1).

[0229] Step-3: Preparation of tert-butyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (23d) Compound 23d was prepared from (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (23b) (5 g, 11.95 mmol) in DCM (20 mL) according to the procedure described in step-2 of Scheme 1 using a solution of triphenylphosphine (3.45 g, 13.15 mmol), tert-butyl 2-(2-hydroxyphenyl)acetate (23c) (2.74 g, 13.15 mmol), (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (4.83 g, 13.15 mmol) in DCM (20 mL) and stirred at room temperature for 1 hour. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with 0 to 50% ethyl acetate in hexanes], tert-butyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (23d) (3.58 g, 49% yield) as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J = 1.5 Hz, 1H), 7.67 (s, 1H), 7.26 - 7.15 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.96 - 6.86 (m, 2H), 5.14 (s, 2H), 4.83 (s, 2H), 3.53 (s, 2H), 1.29 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H).

[0230] Step-4: Preparation of tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (23e) Compound 23c was prepared from tert-butyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (23d) (3.25 g, 5.34 mmol) in dioxane (35 mL) using a solution of 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (19d) (2.011 g, 8.01 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.562 g, 0.801 mmol), KCO (1.476 g, 10.68 mmol) in water (3 mL) and heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (23e) (3.4 g, 93% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.80 - 7.70 (m, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.09 (dd, J = 8.3, 1.2 Hz, 1H), 6.91 (dd, J = 7.4, 1.1 Hz, 1H), 6.89 - 6.85 (m, 1H), 5.22 (s, 2H), 4.83 (s, 2H), 4.22 (d, J = 6.2 Hz, 2H), 3.54 (s, 2H), 1.39 (s, 9H), 1.23 (s, 9H), 0.89 (s, 9H), 0.10 (s, 6H).

[0231] Step-5: Preparation of tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (23f) To a solution of tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (23e) (3.4 g, 4.94 mmol) in THF (35 mL) was added TBAF (1 M in THF) (4.94 mL, 4.94 mmol). The mixture was stirred at room temperature for 3 h. This gave, after workup and purification by flash column chromatography (silica gel, elution with 0 to 100% EtOAc in hexanes), tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (23f) (2.6 g, 92% yield) as a clear oil. MS (ES+): 596.3 (M +Na).

[0232] Step-6: Preparation of tert-butyl 2-(2-((2-(acetoxymethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23g) To a solution of tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (23f) (650 mg, 1.133 mmol) in DCM (5 mL) was added pyridine (0.137 mL, 1.700 mmol), acetic anhydride (0.107 mL, 1.133 mmol) and stirred at room temperature overnight. The reaction was quenched with KHSO4 (1 N) solution, extracted with EtOAc, dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (40 g), elution with 0 to 80% EtOAc / MeOH (9:1) in hexanes] followed by reverse-phase column chromatography [C18 column, elution with 0 to 100% ACN in water] to give tert-butyl 2-(2-((2-(acetoxymethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23g) (352 mg, 0.572 mmol, 50.5% yield) as a clear oil. MS (ES+): 516.1 (M-Boc+1)

[0233] Step-7: Preparation of 2-(2-((2-(acetoxymethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23h) To a solution of tert-butyl 2-(2-((2-(acetoxymethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (23g) (352 mg, 0.572 mmol) in DCM (10 mL) was added TFA (0.087 mL, 1.133 mmol). The resulting mixture was stirred at room temperature for 3 hours and concentrated to dryness in vacuo. The residue was purified by reverse-phase column chromatography [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)] to afford the HCl salt of 2-(2-((2-(acetoxymethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (23h) (157 mg, 30.2% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 2H, D2O exchangeable), 8.05 - 7.99 (m, 1H), 7.97 - 7.89 (m, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.23 (dd, J = 8.1, 6.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 5.27 (d, J = 2.7 Hz, 4H), 4.13 (s, 2H), 3.60 (s, 2H), 2.08 (s, 3H);MS (ES+): 460.1 (M+1);(ES-): 458.1 (M-1);C 27 H 25 Analysis calculated for NO6.HCl.1.25H2O: C, 62.55; H, 5.54; Cl, ​​6.84; N, 2.70; Found: C, 62.43; H, 5.56; Cl, ​​7.00; N, 2.80.

[0234] Scheme 24 [ka] Preparation of 2-(2-((2-(((2-amino-3-methylbutanoyl)oxy)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24b) Step-1, Preparation of 2-(2-((2-(((2-amino-3-methylbutanoyl)oxy)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24a) To a solution of tert-butyl 2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate (23f) (700 mg, 1.220 mmol) and Boc-L-Val-OH (318 mg, 1.464 mmol) in DCM (10 mL) was added DCC (302 mg, 1.464 mmol), DMAP (22.36 mg, 0.183 mmol). The reaction mixture was stirred at room temperature overnight, filtered through Celite, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica (40 g), elution with 0 to 80% EtOAc / MeOH (9:1) in hexanes] to give 2-(2-((2-(((2-amino-3-methylbutanoyl)oxy)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24a) (544 mg, 0.704 mmol, 57.7% yield) as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 7.77 - 7.67 (m, 3H), 7.59 (d, J = 1.7 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.34 - 7.26 (m, 1H), 7.26 - 7.15 (m, 3H), 7.12 - 7.02 (m, 2H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 5.41 - 5.26 (m, 2H), 5.23 (s, 2H), 4.23 (d, J = 6.1 Hz, 2H), 3.88 (t, J = 7.2 Hz, 1H), 3.54 (s, 2H), 2.04 - 1.98 (m, 1H), 1.39 (s, 9H), 1.33 (s, 9H), 1.23 (s, 9H), 0.87 - 0.80 (m, 6H).

[0235] Step-2, Preparation of 2-(2-((2-(((2-amino-3-methylbutanoyl)oxy)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24b) To a solution of 2-(2-((2-(((2-amino-3-methylbutanoyl)oxy)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24a) (544 mg, 0.704 mmol) in DCM (10 mL) was added TFA (0.940 mL, 12.20 mmol). The resulting mixture was stirred at room temperature for 3 hours, concentrated in vacuo, and purified by reverse-phase column chromatography [C18 column (30 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)] to give the HCl salt of 2-(2-((2-(((2-amino-3-methylbutanoyl)oxy)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24b) (240 mg, 38.1% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 5H, D2O exchangeable), 8.02 (d, J = 2.0 Hz, 1H), 7.97 - 7.89 (m, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.26 - 7.14 (m, 3H), 7.09 (d, J = 8.2 Hz, 1H), 6.94 - 6.84 (m, 1H), 5.47 (q, J = 13.4 Hz, 2H), 5.27 (s, 2H), 4.12 (s, 2H), 3.95 (d, J = 4.6 Hz, 1H), 3.60 (s, 2H), 2.29 - 2.09 (m, 1H), 0.93 (dd, J = 16.9, 6.9 Hz, 6H);MS (ES+): 517.2 (M+1);(ES-) 515.6 (M-1);C 30 H 32 Analysis calculated for N2O6.2HCl2.25H2O: C, 57.19; H, 6.16; Cl, ​​11.25; N, 4.45; Found: C, 57.48; H, 6.01; Cl, ​​11.08; N, 4.48.

[0236] Scheme 25 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((ethoxycarbonyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (25h) Step-1: Preparation of ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25i) Compound 25i was prepared from (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (23b) (2.6 g, 6.22 mmol) in DCM (50 mL) according to the procedure described in step-2 of Scheme 1 using triphenylphosphine (1.79 g, 6.84 mmol), ethyl 2-(2-hydroxyphenyl)acetate (1c) (1.23 g, 6.84 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.51 g, 6.84 mmol) in DCM (20 mL). This gave, after work-up and purification by flash column chromatography [silica (40 g), elution with 0 to 50% EtOAc in hexanes], ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25i) (2.86 g, 79% yield) as a clear oil. 1 H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.95 - 6.87 (m, 1H), 5.13 (s, 2H), 4.82 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.12 (s, 6H).

[0237] Step-2: Preparation of ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25a) Compound 25a was prepared from ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25i) (4 g, 6.89 mmol) in THF (60 mL) using TBAF (2.25 g, 8.61 mmol) according to the procedure described in step-5 of Scheme 23. This gave, after workup and purification by flash column chromatography [silica (24 g), elution with 0 to 70% EtOAc in hexanes], ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25a) (2.5 g, 78% yield) as a clear oil. 1 H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.29 - 7.18 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.95 - 6.87 (m, 2H), 5.54 (t, J = 5.9 Hz, 1H), 5.14 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.09 (t, J = 7.1 Hz, 3H);MS (ES+): 489.1 (M+Na).

[0238] Step-3: Preparation of ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25b) To a solution of ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25a) (500 mg, 1.07 mmol) in DCM (20 mL) was added Dess-Martin periodinane (546 mg, 1.29 mmol). The resulting mixture was stirred at room temperature for 3 h, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried, filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography [silica gel (24 g)] to give ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25b) (410 mg, 82% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 7.4, 1.1 Hz, 1H), 5.20 (s, 2H), 4.03 (q, J = 7.1, 1.7 Hz, 2H), 3.63 (s, 2H), 1.09 (t, J = 7.1, 1.7 Hz, 3H).

[0239] Step-4: Preparation of (+)-ethyl 2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25c) Compound 25c was prepared according to the procedure described in step-1 of Scheme 258 from ethyl 2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25b) (1.2 g, 2.58 mmol) and (+)-2-methylpropane-2-sulfinamide (0.394 g, 3.23 mmol) in tetrahydrofuran (15 mL) using tetraethoxytitanium (1.084 mL, 5.17 mmol) and heating at reflux for 14 hours. This gave, after work-up and purification by flash column chromatography [silica gel, elution with ethyl acetate in hexanes (1:0 to 2:1)], (+)-ethyl 2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25c) (965 mg, 66%) as a yellow gum. 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.96 (s, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.30 - 7.18 (m, 2H), 7.07 (dd, J = 8.3, 1.1 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.15 - 3.94 (m, 2H), 3.63 (s, 2H), 1.21 (s, 9H), 1.09 (t, J = 7.1 Hz, 3H); optical rotation [α] D = +61.76 (c = 0.34, MeOH)

[0240] Step-5: Preparation of (-)-ethyl 2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25d) Compound 25d was prepared from (+)-ethyl 2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25c) (0.92 g, 1.621 mmol) in tetrahydrofuran (25 mL) using sodium borohydride (0.125 g, 3.24 mmol) according to the procedure described in step 3 of Scheme 5. This afforded (−)-ethyl 2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25d) (722 mg, 78%) as a colorless gum after workup and purification by flash column chromatography [silica gel, eluting with 10% methanol in hexane / ethyl acetate (1:0 to 1:1)]. 1 H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.30 - 7.17 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.97 - 6.86 (m, 2H), 5.99 (t, J = 5.7 Hz, 1H), 5.13 (s, 2H), 4.48 - 4.23 (m, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.15 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H);MS (ES+): 570.00 (M+1);Optical rotation [α] D = -10.34 (c = 0.29, MeOH)

[0241] Step-6: Preparation of ethyl 2-(2-((2-(aminomethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25e) To a solution of (-)-ethyl 2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25d) (2.68 g, 4.71 mmol, 95% yield) in DCM (30 mL) was added HCl (4 N in dioxane) (4 mL). The resulting mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel (40 g), eluting with 0 to 100% EtOAc in hexanes) to give ethyl 2-(2-((2-(aminomethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25e) (2.01 g, 88% yield) as a clear oil. MS (ES+): 488.0 (M+Na).

[0242] Step-7: Preparation of ethyl 2-(2-((2-((ethoxycarbonylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25f) To a solution of ethyl 2-(2-((2-(aminomethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25e) (1 g, 2.149 mmol) in THF / HO (1:1, 8 mL) was added sodium bicarbonate (0.271 g, 3.22 mmol) and ethyl chloroformate (0.308 mL, 3.22 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. Then, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by flash column chromatography [silica gel (12 g), elution with 0 to 80% EtOAc in hexanes] to give ethyl 2-(2-((2-((ethoxycarbonylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25f) (521 mg, 45.1% yield) as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.86 - 7.78 (m, 1H), 7.70 (q, J = 1.9, 1.1 Hz, 1H), 7.62 (t, J = 1.8 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 6.84 (d, J = 4.3 Hz, 1H), 5.14 (d, J = 2.7 Hz, 2H), 4.36 (d, J = 5.9 Hz, 2H), 4.07 - 3.98 (m, 4H), 3.63 (d, J = 7.8 Hz, 2H), 1.18 (td, J = 7.1, 1.2 Hz, 4H), 1.09 (t, J = 7.0 Hz, 2H).

[0243] Step-8: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((ethoxycarbonylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (25 g) To a degassed solution of ethyl 2-(2-((2-((ethoxycarbonylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (25f) (500 mg, 0.93 mmol) in dioxane (10 mL) was added 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (262 mg, 1.40 mmol), KPO (2 M) (0.79 mL, 1.58 mmol), tricyclohexylphosphine (78 mg, 0.28 mmol), and Pd(dba) (128 mg, 0.14 mmol). The mixture was degassed, charged with Ar, and then heated at 100 °C for 3 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel (12 g), elution with 0 to 70% DMA-80 in DCM] to give ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((ethoxycarbonylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (25 g) (166 mg, 35% yield) as a clear oil. MS (ES+): 517.2 (M+1).

[0244] Step-9: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((ethoxycarbonyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (25h) Compound 25h was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-((ethoxycarbonylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (25g) (166 mg, 0.321 mmol) in THF (3 mL) using a solution of lithium hydroxide monohydrate (78 mg, 1.86 mmol) in water (1 mL) and stirring overnight at room temperature according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(((ethoxycarbonyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (25h) (107 mg, 24% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H, D2O exchangeable), 8.52 (s, 2H, D2O exchangeable), 8.03 (s, 1H), 7.98 - 7.91 (m, 1H), 7.85 (t, J = 5.9 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.27 - 7.18 (m, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.95 - 6.86 (m, 1H), 6.77 (s, 1H), 5.25 (s, MS (ES) + ) 489.2 (M+1);C 28 H 28 Analysis calculated for N2O6.HCl.1.25H2O: C, 61.42; H, 5.80; Cl, ​​6.48; N, 5.12; Found: C, 61.58; H, 5.57; Cl, ​​6.40; N, 5.20.

[0245] Scheme 26 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetic acid (26f) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (26b) Compound 26b was prepared from 7-bromo-5-(bromomethyl)benzofuran 14e (0.79 g, 2.73 mmol) using ethyl 2-(4-cyano-2-hydroxyphenyl)acetate 26a (0.56 g, 2.73 mmol; CAS#1261647-89-5), KCO (1.13 g, 8.19 mmol) in DMF (10 mL) and stirring at room temperature for 2 h, according to the procedure described in step 4 of Scheme 14. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate 26b (1 g, 88% yield) as a white solid after workup and purification by flash column chromatography (silica gel (40 g), eluting with 0 to 60% EtOAc in hexanes). 1 H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), 7.62 - 7.57 (m, 2H), 7.49 - 7.39 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 5.26 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 1.11 - 1.00 (m, 3H);MS (ES+): 436.00 & 438.00 (M+Na);MS (ES-): 412.00 & 414.00 (M-1).

[0246] Step-2: Preparation of ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) To a stirred solution of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (26b) (1 g, 2.41 mmol) in anhydrous methanol (15 mL) cooled to 0 °C, nickel(II) chloride hexahydrate (0.14 g, 0.60 mmol) was added in portions over 10 minutes, followed by sodium borohydride (0.27 g, 7.24 mmol). The reaction mixture was stirred for 3 hours, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.522 mL, 4.83 mmol), stirred for 1 hour, and concentrated in vacuo. The residue was taken up in brine (100 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel (40 g), eluting with MeOH / DCM from 0 to 60%) to give ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (0.3 g, 30% yield) as a pale yellow wax. MS (ES+): 418.00 & 420.05 (M+1).

[0247] Step-3: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetate (26d) To a solution of ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (0.3 g, 0.72 mmol) in DCM (8 mL) was added heptanoyl chloride (0.13 g, 0.86 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel (12 g), eluting with 0 to 100% EtOAc / hexanes) to give ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetate (26d) (0.25 g, 66% yield) as a yellow solid. MS (ES+): 530.10 & 532.20 (M+1).

[0248] Step-4: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetate (26e) Compound 26e was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetate (26d) (0.25 g, 0.471 mmol) in dioxane (5 mL) according to the procedure described in step 4 of Scheme 1 using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (0.088 g, 0.471 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2C2] (0.050 g, 0.071 mmol), K2CO3 (0.195 g, 1.414 mmol) in water (1 mL) heated at 90 °C in an oil bath for 3 h. After work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA80 in DCM], this afforded ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetate (26e) (0.11 g, 42% yield) as a yellow oil, which was further purified by reverse column chromatography [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)] to afford the HCl salt of compound (26e) (0.11 g, 42% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 3H), 8.33 (t, J = 6.0 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.92 (dt, J = 7.1, 1.8 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.15 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.79 (dd, J = 7.5, 1.5 Hz, 1H), 5.20 (s, 2H), 4.24 (d, J = 5.9 Hz, 2H), 4.13 (q, J = 5.8 Hz, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.59 (s, 2H), 2.11 (t, J = 7.4 Hz, 2H), 1.49 (q, J = 7.1 Hz, 2H), 1.24 (q, J = 4.9, 4.0 Hz, 6H), 0.98 (t, J = 7.1 Hz, 3H), 0.87 - 0.77 (m, 3H);MS (ES+): 557.30 (M+1);MS (ES-): 591.30 (M+Cl).

[0249] Step-5: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetic acid (26f) Compound 26f was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetate (26e) (110 mg, 0.198 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (66.3 mg, 1.581 mmol) in water (1 mL) and stirring at room temperature for 16 hours according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(heptanamidomethyl)phenyl)acetic acid (26f) (78 mg, 75% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. δ 8.30 (t, J = 5.9 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.02 (t, J = 1.8 Hz, 1H), 7.94 (dt, J = 7.4, 1.7 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.78 (dd, J = 7.6, 1.5 Hz, 1H), 5.22 (s, 2H), 4.23 (d, J = 5.9 Hz, 2H), 4.13 (s, 2H), 3.55 (s, 2H), 2.10 (t, J = 7.4 Hz, 2H), 1.48 (q, J = 7.2 Hz, 2H), 1.24 (m, 6H), 0.88 - 0.76 (m, 3H);MS (ES+): 529.30 (M+1);MS (ES-): 527.25 (M-1);C 32 H 36Analysis calculated for N2O5, HCl, and H2O: C, 65.91; H, 6.74; Cl, ​​6.08; N, 4.80; Found: C, 66.12; H, 6.46; Cl, ​​5.83; N, 4.87.

[0250] Scheme 27 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetic acid (27c) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetate (27a) Compound 27a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (400 mg, 0.96 mmol) in THF / HO (1:1, 8 mL) using NaHCO (121 mg, 1.43 mmol), a solution of isopropyl carbonochloridate (1.43 mL, 1.43 mmol) in toluene, and stirring at room temperature for 1 h, according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetate (27a) (375 mg, 78% yield) as a colorless oil after workup and purification by flash column chromatography [silica gel column (12 g), elution with 0 to 80% EtOAc / hexane]. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.55 (t, J = 6.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.02 - 6.95 (m, 1H), 6.80 (dd, J = 7.5, 1.5 Hz, 1H), 5.14 (s, 2H), 4.74 (h, J = 6.2 Hz, 1H), 4.15 (d, J = 6.2 Hz, 2H), 4.00 (d, J = 7.1 Hz, 2H), 3.58 (s, 2H), 1.16 (d, J = 6.6 Hz, 6H), 1.07 (t, J = 7.1 Hz, 3H).;MS (ES+): 526.10 & 528.10 (M+Na).

[0251] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetate (27b) Compound 27b was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetate (27a) (375 mg, 0.74 mmol) in dioxane (5 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (209 mg, 1.12 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (78 mg, 0.11 mmol), and KCO (308 mg, 2.23 mmol) in water (1 mL) by heating at 90 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetate (27b) (240 mg, 61% yield) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 3H), 8.11 (d, J = 2.2 Hz, 1H), 8.01 (t, J = 1.6 Hz, 1H), 7.92 (m, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.58 (td, J = 4.6, 4.1, 2.8 Hz, 3H), 7.16 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.80 (dd, J = 7.7, 1.4 Hz, 1H), 5.21 (s, 2H), 4.75 (septet, J = 6.2 Hz, 1H), 4.22 - 4.05 (m, 4H), 3.92 (q, J = 7.1 Hz, 2H), 3.59 (s, 2H), 1.16 (d, J = 6.2 Hz, 6H), 0.98 (t, J = 7.1 Hz, 3H); MS (ES+): 531.30 (M+1).

[0252] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetic acid (27c) Compound 27c was prepared according to the procedure described in step-8 of Scheme 1 from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetate (27b) (150 mg, 0.28 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (95 mg, 2.26 mmol) in water (1 mL) and stirring at room temperature for 5 hours. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((isopropoxycarbonylamino)methyl)phenyl)acetic acid (27c) (115 mg, 81% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 2H), 8.11 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.94 (dt, J = 7.5, 1.7 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.63 - 7.51 (m, 3H), 7.15 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.79 (dd, J = 7.7, 1.5 Hz, MS (ES+): 503.20 (M+1);MS (ES-): 501.20 (M-1);C 29 H30 Analysis calculated for N2O6.HCl.H2O: C, 62.53; H, 5.97; Cl, ​​6.36; N, 5.03; Found: C, 62.77; H, 6.18; Cl, ​​6.44; N, 5.16.

[0253] Scheme 28 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetic acid (28c) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetate (28a) Compound 28a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (300 mg, 0.72 mmol) in DCM (4 mL) using triethylamine (0.15 mL, 1.08 mmol), 3-methylbutanoyl chloride (130 mg, 1.076 mmol) and stirring at room temperature for 1 h according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetate (28a) (300 mg, 83% yield) as a white solid after workup and purification by flash column chromatography [silica gel column (12 g), elution with 0 to 80% EtOAc / hexane]. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 7.6, 2.9 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.80 (dd, J = 7.6, 1.5 Hz, 1H), 5.13 (d, J = 4.0 Hz, 2H), 4.24 (d, J = 5.9Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 2.04 - 1.96 (m, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.89 - 0.85 (m, 6H).;MS (ES+): 502.10 & 504.10 (M+1);524.10 & 526.10 (M+Na);MS (ES-): 536.10 & 538.10 (M+Cl).

[0254] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetate (28b) Compound 28b was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetate 28a (270 mg, 0.54 mmol) in dioxane (5 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride 9e (151 mg, 0.81 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (56.6 mg, 0.08 mmol), and KCO (223 mg, 1.61 mmol) in water (1 mL) by heating at 90 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetate (28b) (0.2 g, 70% yield) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 2H), 8.36 (m, 1H), 8.12 (d, J = 2.2 Hz, 1H), 8.01 (s, 1H), 7.92 (dt, J = 6.9, 2.0 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.16 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.80 (dd, J = 7.5, 1.5 Hz, 1H), 5.20 (s, 2H), 4.25 (d, J = 5.9 Hz, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 2.04 - 1.94 (m, 3H), 0.98 (t, J = 7.1 Hz, 3H), 0.91 - 0.81 (m, 6H);MS (ES+): 529.30 (M+1);MS (ES-): 563.30 (M+Cl).

[0255] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetic acid (28c) Compound 28c was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetate (28b) (100 mg, 0.19 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (63.5 mg, 1.51 mmol) in water (1 mL) and stirring at room temperature for 5 hours according to the procedure described in step-8 of Scheme 1. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((3-methylbutanamido)methyl)phenyl)acetic acid (28c) (75 mg, 79% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (br s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.94 (dt, J = 7.5, 1.6 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.63 (t, J = 1.7 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (dt, J = 7.6, 1.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 1.5 Hz, 1H), 6.79 (dd, J = 7.6, 1.5 Hz, 1H), 5.22 (s, 2H), 4.24 (d, J = 5.9 Hz, 2H), 4.14 (s, 2H), 3.56 (s, 2H), 2.05 - 1.91 (m, 3H), 0.90 - 0.82 (m, 6H);MS (ES+): 501.20 (M+1);MS (ES-): 999.20 (2M-1);C 30 H 32 Analysis calculated for N2O 5.1.05 HCl 1.25 H2O: C, 64.18; H, 6.38; Cl, ​​6.63; N, 4.99; C, 64.34; H, 6.31; Cl, ​​6.84; N, 5.08.

[0256] Scheme 29 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetic acid (29c) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetate (29a) Compound 29a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (400 mg, 0.96 mmol) in THF / HO (1:1, 8 mL) using a solution of NaHCO (121 mg, 1.43 mmol), ethyl carbonochloridate (156 mg, 1.43 mmol) and stirring at room temperature for 1 h according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetate (29a) (300 mg, 64% yield) as a colorless oil after workup and purification by flash column chromatography [silica gel column (12 g), elution with 0 to 80% EtOAc / hexane]. 1 H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.15 (dd, J = 7.6, 3.1 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 1.5 Hz, 1H), 6.80 (dd, J = 7.5, 1.4 Hz, 1H), 5.14 (s, 2H), 4.17 - 4.14 (m, 2H), 4.01 - 3.98 (m, 2H), 3.58 (d, J = 3.6 Hz, 2H), 3.17 (d, J = 5.2 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H);MS (ES+): 512.05 & 514.10 (M+Na).

[0257] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetate (29b) Compound 29b was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetate (29a) (300 mg, 0.612 mmol) in dioxane (5 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (172 mg, 0.918 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (64.4 mg, 0.092 mmol), and KCO (254 mg, 1.835 mmol) in water (1 mL) by heating at 90 °C in an oil bath for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetate (29b) (0.2 g, 63% yield) as a pale yellow oil. The sample was further purified by reverse column [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)] to give 55 mg of the desired compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 3H), 8.12 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.92 (dt, J = 7.6, 1.6 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 7.05 (s, 1H), 6.80 (dd, J = 7.6, 1.5 Hz, 1H), 5.21 (s, 2H), 4.23 - 4.09 (m, 4H), 4.06 - 3.84 (m, 4H), 3.59 (s, 2H), 1.15 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H);MS (ES+): 517.20 (M+1).

[0258] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetic acid (29c) Compound 29c was prepared according to the procedure described in step-8 of Scheme 1 from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetate (29b) (120 mg, 0.23 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (78 mg, 1.86 mmol) in water (1 mL) and stirring at room temperature for 5 hours. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((ethoxycarbonylamino)methyl)phenyl)acetic acid (29c) (95 mg, 84% yield) as a white solid.1 H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.94 (dt, J = 7.3, 1.8 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.60 - 7.52 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.79 (dd, J = 7.6, 1.5 Hz, MS (ES+): 489.20 (M+1);C 28 H 28 Analytical calculation for N2O6.HCl.H2O: C, 61.93; H, 5.75; Cl, ​​6.53; N, 5.16; Found; C, 61.52; H, 5.77; Cl, ​​6.87; N, 5.23.

[0259] Scheme 30 [ka] Preparation of 2-(4-(acetamidomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (30c) Step-1: Preparation of ethyl 2-(4-(acetamidomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (30a) Compound 30a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (300 mg, 0.72 mmol) in DCM (4 mL) using NEt (0.20 mL, 1.43 mmol), acetic anhydride (0.14 mL, 1.43 mmol), and stirring at room temperature for 1 h according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(4-(acetamidomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (30a) (280 mg, 85% yield) as a colorless oil after workup and purification by flash column chromatography [silica gel column (12 g), elution with 0 to 80% EtOAc / hexane]. 1 H NMR (300 MHz, DMSO-d6) δ 8.32 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 7.6, 2.9 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.98 (t, J = 1.8 Hz, 1H), 6.83 - 6.77 (m, 1H), 5.14 (d, J = 3.1 Hz, 2H), 4.22 (d, J = 5.9 Hz, 2H), 4.01 (q, J = 7.0 MS (ES+): 460.05 & 462.00 (M+1);482.05 & 484.00 (M+Na);MS (ES-): 494.00 & 496.00 (M+Cl).

[0260] Step-2: Preparation of ethyl 2-(4-(acetamidomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (30b) Compound 30b was prepared from ethyl 2-(4-(acetamidomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate 30a (280 mg, 0.608 mmol) in dioxane (5 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride 9e (171 mg, 0.912 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (64.0 mg, 0.091 mmol), and KCO (252 mg, 1.825 mmol) in water (1 mL) heated at 90 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(4-(acetamidomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (30b) (70 mg, 23% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 2H), 8.40 (t, J = 5.9 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.92 (dt, J = 7.0, 2.0 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.83 - 6.75 (m, 1H), 5.22 (s, 2H), 4.23 (d, J = 5.9 Hz, 2H), 4.13 (q, J = 5.8 Hz, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.59 (s, 2H), 1.85 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H);MS (ES+): 487.20 (M+1);MS (ES-): 521.50 (M+Cl);LC, 1.99 min, 99.80%.

[0261] Step-3: Preparation of 2-(4-(acetamidomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (30c) Compound 30c was prepared from ethyl 2-(4-(acetamidomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (30b) (120 mg, 0.25 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (83 mg, 1.97 mmol) in water (1 mL) and stirring at room temperature for 5 hours, according to the procedure described in step 8 of Scheme 1. This gave the HCl salt of 2-(4-(acetamidomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (30c) (95 mg, 84% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H, D2O exchangeable), 8.45 - 8.23 ​​(m, 4H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 1.7 Hz, 1H), 7.94 (dt, J = 7.5, 1.7 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.54 (dt, J = 7.7, 1.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.02 (d, J = 1.5 Hz, 1H), 6.79 (dd, J = 7.6, 1.5 Hz, 1H), 5.24 (s, 2H), 4.22 (d, J = 5.8 Hz, 2H), 4.14 (q, J = 5.8 Hz, 2H), 3.56 (s, 2H), 1.84 (s, 3H);MS (ES+): 459.10 (M+1);C 27 H 26Analysis calculated for N2O5.HCl.1.75H2O: C, 61.60; H, 5.84; Cl, ​​6.73; N, 5.32; Found: C, 61.56; H, 5.72; Cl, ​​6.95; N, 5.35.

[0262] Scheme 31 [ka] Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (31d) Step-1: Preparation of ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (31a) Compound 31a was prepared from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (11g) (0.8 g, 2.71 mmol) in DCM (30 mL) according to the procedure described in step-2 of Scheme 1 using a solution of triphenylphosphine (0.78 g, 2.98 mmol), ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (26a) (0.61 g, 2.98 mmol), (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.10 g, 2.98 mmol) in DCM (20 mL) and stirred at room temperature for 30 minutes. This gave, after work-up and purification by flash column chromatography (silica gel (40 g), elution with 0 to 50% ethyl acetate in hexanes), ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (31a) (0.4 g, 31% yield) as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (q, J = 1.7 Hz, 1H), 7.89 - 7.74 (m, 2H), 7.60 (d, J = 1.3 Hz, 1H), 7.49 - 7.39 (m, 2H), 5.33 (s, 2H), 4.04 - 3.96 (m, 2H), 3.70 (s, 2H), 1.05 (t, J = 7.1 Hz, 3H).;MS (ES-): 480.40 (M-1).

[0263] Step-2: Preparation of ethyl 2-(4-(aminomethyl)-2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (31b) Compound 31b was prepared from ethyl 2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate (31a) (0.38 g, 0.79 mmol) in anhydrous methanol (10 mL) according to the procedure described in step-2 of Scheme 26 using nickel(II) chloride hexahydrate (0.05 g, 0.20 mmol), sodium borohydride (0.089 g, 2.364 mmol), and N-(2-aminoethyl)ethane-1,2-diamine (0.17 mL, 1.58 mmol) for quenching. This gave, after work-up and purification by flash column chromatography [(silica gel (40 g), elution with MeOH / DCM from 0 to 60%)], ethyl 2-(4-(aminomethyl)-2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (31b) (50 mg, 13% yield) as a pale yellow wax. MS (ES+): 486.00 & 488.00 (M+1).

[0264] Step-3: Preparation of ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (31c) Compound 31c was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate 31b (50 mg, 0.103 mmol) in dioxane (3 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride 9e (38.5 mg, 0.206 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (10.83 mg, 0.015 mmol), and KCO (42.6 mg, 0.308 mmol) in water (1 mL) heated at 90 °C in an oil bath for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA80 in DCM], ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (31c) (30 mg, 57% yield) as a pale yellow oil. MS (ES+): 513.20 (M+1).

[0265] Step-4: Preparation of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (31d) Compound 31d was prepared from ethyl 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate (31c) (30 mg, 0.059 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (19.65 mg, 0.468 mmol) in water (1 mL) and stirring at room temperature for 16 hours according to the procedure described in step-8 of Scheme 1. This gave, after work-up and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the HCl salt of 2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (31d) (19 mg, 67% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H, D2O exchangeable), 8.93 (t, J = 1.8 Hz, 1H), 8.44 (s, 6H), 8.03 (d, J = 2.1 Hz, 1H), 7.92 (dt, J = 6.6, 2.2 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.64 - 7.57 (m, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.6, 1.5 Hz, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 4.00 (s, 2H), 3.61 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -57.96;MS (ES+): 485.10 (M+1).

[0266] Scheme 32 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetic acid (32c) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetate (32a) Compound 32a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (300 mg, 0.72 mmol) in DCM (4 mL) using N-ethyl-N-isopropylpropan-2-amine (0.25 mL, 1.43 mmol), diethyl phosphorochloridate (0.21 mL, 1.43 mmol) and stirring at room temperature for 1 h according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetate (32a) (35 mg, 9% yield) as a clear oil after workup and purification by flash column chromatography [silica gel column (24 g), elution with 0 to 50% EtOAc / hexanes]. MS (ES+): 554.10 & 556.05 (M+1).

[0267] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetate (32b) Compound 32b was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetate 32a (70 mg, 0.13 mmol) in dioxane (4 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride 9e (47.3 mg, 0.25 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (13.29 mg, 0.02 mmol), and KCO (52.4 mg, 0.38 mmol) in water (1 mL) by heating in an oil bath at 90 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetate (32b) (40 mg, 55% yield) as a pale yellow oil. MS (ES+): 581.20 (M+1).

[0268] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetic acid (32c) Compound 32c was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetate (32b) (40 mg, 0.07 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (23.13 mg, 0.55 mmol) in water (1 mL) and stirring at room temperature for 16 hours according to the procedure described in step-8 of Scheme 1. This gave, after workup and purification by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((diethoxyphosphorylamino)methyl)phenyl)acetic acid (32c) (22 mg, 58% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H, D2O exchangeable), 8.40 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.93 (dt, J = 7.4, 1.7 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.63 - 7.51 (m, 2H), 7.18 - 7.10 (m, 2H), 7.06 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 7.6, 1.5 Hz, 1H), 5.48 (dt, J = 11.9, 7.2 Hz, 1H), 5.26 (s, 2H), 4.14 (s, 2H), 3.93 (dd, J = 11.8, 7.2 Hz, 2H), 3.88 - 3.73 (m, 4H), 3.57 (s, 2H), 1.12 (t, J = 7.0 Hz, 6H);MS (ES+): 553.20 (M+1);C 29 H 33Analysis calculated for N2O7P.HCl.1.75H2O: C, 56.13; H, 6.09; N, 4.51; Found: C, 56.11; H, 5.82; N, 4.62.

[0269] Scheme 33 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetic acid (33c) Step-1: Preparation of ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetate (33a) Compound 33a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (300 mg, 0.72 mmol) in DCM (4 mL) using N-ethyl-N-isopropylpropan-2-amine (0.25 mL, 1.43 mmol), methanesulfonyl chloride (0.11 mL, 1.43 mmol) and stirring at room temperature for 1 h according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetate (33a) (0.26 g, 73% yield) as a clear oil after workup and purification by flash column chromatography [silica gel column (24 g), elution with 0 to 50% DMA80 in DCM]. MS (ES-): 494.40 (M-1).

[0270] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetate (33b) Compound 33b was prepared from ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetate (33a) (0.26 g, 0.524 mmol) in dioxane (4 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (0.196 g, 1.048 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.055 g, 0.079 mmol), KCO (0.217 g, 1.571 mmol) in water (1 mL) and heated at 90 °C in an oil bath for 2 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetate (33b) (0.11 g, 40% yield) as a pale yellow oil. The sample was further purified by reverse column chromatography [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)] to give the HCl salt of compound 33b (80 mg) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 3H), 8.11 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.92 (dt, J = 6.5, 2.2 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 - 7.54 (m, 4H), 7.20 (d, J = 7.6 Hz, 1H), 7.17 - 7.15 (m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.93 - 6.87 (m, 1H), 5.24 (s, 2H), 4.21 - 4.07 (m, MS (ES+): 523.20 (M+1).

[0271] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetic acid (33c) Compound 33c was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetate (33b) (0.11 g, 0.21 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (0.07 g, 1.68 mmol) in water (1 mL) and stirring at room temperature for 16 hours according to the procedure described in step 8 of Scheme 1. This gave, after workup, the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(methylsulfonamidomethyl)phenyl)acetic acid (33c) (0.10 g, 94% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H, D2O exchangeable), 8.33 (s, 3H, D2O exchangeable), 8.11 (d, J = 2.2 Hz, 1H), 8.00 (s, 1H), 7.94 (dt, J = 7.5, 1.7 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 1.5 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.90 (dd, J = 7.6, 1.5 Hz, 1H), 5.26 (s, 2H), 4.19 - 4.08 (m, 4H), 3.58 (s, 2H), 2.82 (s, 3H);MS (ES+): 495.10 (M+1);C 26 H 26 Analysis calculated for N2O6S.HCl.1.25H2O: C, 56.42; H, 5.37; Cl, ​​6.40; N, 5.06; Found: C, 56.25; H, 5.15; Cl, ​​6.48; N, 5.15.

[0272] Scheme 34 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((bis(benzyloxy)phosphorylamino)methyl)phenyl)acetic acid (34c) Step-1: Preparation of ethyl 2-(4-((bis(benzyloxy)phosphorylamino)methyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (34a) Compound 34a was prepared from ethyl 2-(4-(aminomethyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (26c) (0.4 g, 0.956 mmol) in DCM (4 mL) using N-ethyl-N-isopropylpropan-2-amine (0.25 mL, 1.43 mmol), tetrabenzyl diphosphate (0.618 g, 1.148 mmol) and stirring at room temperature for 1 h according to the procedure described in step 6 of Scheme 25. This afforded ethyl 2-(4-((bis(benzyloxy)phosphorylamino)methyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (34a) (0.45 g, 69% yield) as a white oil after workup and purification by flash column chromatography [silica gel column (24 g), elution with 0 to 100% EtOAc in hexanes]. MS (ES+): 678.10 (M+1);700.10 (M+Na).

[0273] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((bis(benzyloxy)phosphorylamino)methyl)phenyl)acetate (34b) Compound 34b was prepared from ethyl 2-(4-((bis(benzyloxy)phosphorylamino)methyl)-2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (34a) (0.45 g, 0.66 mmol) in dioxane (4 mL) using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (0.249 g, 1.33 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.07 g, 0.10 mmol), and KCO (0.28 g, 1.99 mmol) in water (1 mL) by heating in an oil bath at 90 °C for 2 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((bis(benzyloxy)phosphorylamino)methyl)phenyl)acetate (34b) (0.2 g, 43% yield) as a pale yellow oil. MS (ES+): 705.20 (M+1).

[0274] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((bis(benzyloxy)phosphorylamino)methyl)phenyl)acetic acid (34c) Compound 34c was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((bis(benzyloxy)phosphorylamino)methyl)phenyl)acetate (34b) (0.48 g, 0.68 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (0.11 g, 2.72 mmol) in water (1 mL) and stirring at room temperature for 16 hours according to the procedure described in step-8 of Scheme 1. This gave, after work-up and purification by reverse column chromatography [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-((bis(benzyloxy)phosphorylamino)methyl)phenyl)acetic acid (34c) (0.26 g, 56% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H, D2O exchangeable), 8.39 (s, 3H, D2O exchangeable), 8.09 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.90 (dt, J = 7.3, 1.8 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.38 - 7.24 (m, 10H), 7.18 - 7.11 (m, 2H), 7.03 (d, J = 2.2 Hz, 1H), 6.87 (dd, J = 7.6, 1.5 Hz, 1H), 5.82 (dt, J = 13.5, 7.2 Hz, 1H), 5.15 (s, 2H), 4.98 - 4.81 (m, 4H), 4.14 (s, 2H), 3.99 (dd, J = 12.4, 7.2 Hz, 2H), 3.56 (s, 2H);MS (ES+): 677.20 (M+1);C 39 H 37Analysis calculated for N2O7P.HCl.1.25H2O: C, 63.67; H, 5.55; Cl, ​​4.82; N, 3.81; Found: C, 63.99; H, 5.48; Cl, ​​5.02; N, 3.83.

[0275] Scheme 35 [ka] Preparation of 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-2-(2-(carboxymethyl)phenoxy)acetic acid (35e) Step-1: Preparation of ethyl 2-bromo-2-(7-bromobenzofuran-5-yl)acetate (35b) A solution of ethyl 2-(7-bromobenzofuran-5-yl)acetate (35a) (0.5 g, 1.77 mmol; CAS# 1260774-41-1), NBS (0.35 g, 1.94 mmol), and benzoic peroxyanhydride (0.06 g, 0.27 mmol) in CCl4 (10 mL) was heated at reflux for 4 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 2-bromo-2-(7-bromobenzofuran-5-yl)acetate (35b) (0.2 g, 31% yield) as a pale yellow oil, which was used in the next step without further purification. MS (ES+): 360.90 & 362.90 (M+1).

[0276] Step-2: Preparation of ethyl 2-(7-bromobenzofuran-5-yl)-2-(2-(2-ethoxy-2-oxoethyl)phenoxy)acetate (35c) Compound 35c was prepared from ethyl 2-bromo-2-(7-bromobenzofuran-5-yl)acetate (35b) (0.2 g, 0.55 mmol) in acetonitrile (5 mL) using ethyl 2-(2-hydroxyphenyl)acetate (1c) (0.11 g, 0.61 mmol), KCO (0.23 g, 1.66 mmol), and stirring at room temperature for 15 h according to the procedure described in step 4 of Scheme 14. This afforded ethyl 2-(7-bromobenzofuran-5-yl)-2-(2-(2-ethoxy-2-oxoethyl)phenoxy)acetate (35c) (0.14 g, 55% yield) as a white oil after workup and purification by flash column chromatography (silica gel (24 g), elution with 0 to 60% EtOAc in hexanes). MS (ES+): 483.90 & 485.90 (M+Na).

[0277] Step-3: Preparation of ethyl 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-2-(2-(2-ethoxy-2-oxoethyl)phenoxy)acetate (35d) Compound 35d was prepared from ethyl 2-(7-bromobenzofuran-5-yl)-2-(2-(2-ethoxy-2-oxoethyl)phenoxy)acetate (35c) (0.14 g, 0.30 mmol) in dioxane (4 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (0.11 g, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.03 g, 0.05 mmol), and KCO (0.13 g, 0.91 mmol) in water (1 mL) heated at 90 °C in an oil bath for 2 h. This gave, after workup and purification by flash column chromatography [silica gel (24 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-2-(2-(2-ethoxy-2-oxoethyl)phenoxy)acetate (35d) (0.06 g, 41% yield) as a yellow oil. MS (ES+): 488.10 (M+1).

[0278] Step-4: Preparation of 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-2-(2-(carboxymethyl)phenoxy)acetic acid (35e) Compound 35e was prepared from ethyl 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-2-(2-(2-ethoxy-2-oxoethyl)phenoxy)acetate (35d) (50 mg, 0.10 mmol) in THF (4 mL), methanol (4 mL) using a solution of lithium hydroxide monohydrate (34.4 mg, 0.82 mmol) in water (1 mL) and stirring at room temperature for 15 hours according to the procedure described in step 8 of Scheme 1. This gave the HCl salt of 2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-2-(2-(carboxymethyl)phenoxy)acetic acid (35e) (40 mg, 90% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 2H, D2O exchangeable), 8.37 (s, 2H, D2O exchangeable), 8.13 (d, J = 2.2 Hz, 1H), 7.97 (s, 1H), 7.95 - 7.87 (m, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.22 (m, 2H), 7.11 (d, J = 2.2 Hz, 1H), 7.04 - 6.87 (m, 2H), 6.02 (s, 1H), 4.15 (s, 2H), 3.85 - 3.56 (m, 2H);MS (ES+): 432.05 (M+1);MS (ES-): 430.10 (M-1);C 25 H 21 Analysis calculated for NO6.HCl.2H2O: C, 59.59; H, 5.20; Cl, ​​7.03; N, 2.78; Found: C, 59.85; H, 5.17; Cl, ​​7.33; N, 2.90.

[0279] Scheme 36 [ka] Preparation of 2-(2-((7-(3-fluoro-2-(formamidomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36f) Step-1: Preparation of tert-butyl ((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (36b) Compound 36b was prepared from 4-chloro-3-fluoropicolinonitrile (36a) (0.26 g, 1.661 mmol; CAS#1155847-43-0) in methanol (15 mL) according to the procedure described in step-2 of Scheme 26 using BOC-anhydride (0.54 g, 2.49 mmol), nickel(II) chloride hydrate (0.025 g, 0.17 mmol), sodium borohydride (0.19 g, 4.98 mmol), and N-(2-aminoethyl)ethane-1,2-diamine (0.9 mL, 8.30 mmol) for quenching. This gave, after work-up and purification by flash column chromatography [silica gel 12 g, elution with 0 to 60% EtOAc in hexanes], tert-butyl ((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (36b) (0.26 g, 60% yield) as a crystalline solid.

[0280] Step-2: Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36c) Compound 36c was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate 1e (243 mg, 0.56 mmol) in dioxane (6 mL) using tert-butyl ((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate 36b (145 mg, 0.56 mmol), potassium phosphate tripotassium (3 M in water, 0.32 mL, 0.95 mmol), tricyclohexylphosphine (47 mg, 0.17 mmol), and Pd(dba) (51 mg, 0.056 mmol) in a microwave oven under Ar atmosphere for 90 min at 120 °C. This gave, after workup and purification by flash column chromatography [silica (12 g), elution with 0 to 70% EtOAc in hexanes], ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36c) (185 mg, 62% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.63 (t, J = 5.3 Hz, 1H), 7.53 (s, 1H), 7.34 - 7.28 (m, 1H), 7.28 - 7.19 (m, 2H), 7.15 - 7.08 (m, 2H), 6.91 (td, J = 7.3, 1.3 Hz, 1H), 5.25 (s, 2H), 3.95 - 3.86 (m, 2H), 3.62 (s, 2H), 3.34 (s, 2H), 1.39 (s, 9H), 1.00 - 0.92 (m, 3H);MS (ES+): 535.4 (M+1);557.4 (M+Na);(ES-): 534.3 (M-1).

[0281] Step-3: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36d) Compound 36d was prepared from ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36c) (182 mg, 0.34 mmol) in DCM (5 mL) using TFA (0.26 mL, 3.40 mmol) according to the procedure described in Scheme 23, Step-7. This gave the HCl salt of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36d) (136 mg, 92% yield) as a white solid after workup and purification by flash column chromatography [silica (12 g), elution with 0 to 50% DMA80 in DCM] followed by reverse-phase column purification [C18 (50 g), elution with 0 to 100% ACN in water (containing 0.1% HCl)]. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 5.0 Hz, 4H, partially D2O exchangeable), 8.12 (d, J = 2.2 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.80 (t, J = 5.3 Hz, 1H), 7.57 (s, 1H), 7.31 - 7.19 (m, 2H), 7.16 - 7.09 (m, 2H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.36 (s, 2H), 3.94 (q, J = 7.1, 1.3 Hz, 2H), 3.63 (s, 2H), 1.00 (t, J = 7.1, 1.3 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -128.52;MS (ES+): 435.3 (M+1);(ES-): 469.3 (M+Cl).

[0282] Step-4: Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36e) Compound 36e was prepared from ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36d) (61 mg, 0.14 mmol) in MeOH / THF (10 mL) using a solution of lithium hydroxide monohydrate (18 mg, 0.42 mmol) in water (1 mL) according to the procedure described in step 6 of Scheme 1. This gave the HCl salt of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36e) (32 mg, 56% yield) as a white solid after workup and purification on a reverse-phase column [C18 (50 g), elution with ACN in water (containing 0.1% HCl) from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 8.73 - 8.58 (m, 4H, partially D2O exchangeable), 8.11 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.80 (t, J = 5.3 Hz, 1H), 7.61 (s, 1H), 7.28 - 7.19 (m, 2H), 7.14 - 7.06 (m, 2H), 6.91 (t, J = 7.3 Hz, 1H), 5.29 (s, 2H), 4.39 - 4.33 (m, 2H), 3.59 (s, 2H); 19F NMR (282 MHz, DMSO-d) δ -128.34; MS (ES+): 407.2 (M+1); 429.2 (M+Na); (ES-): 405.3 (M-1); 441.3 (M+Cl). The HCl salt of compound 36e (3.0 g) was suspended in a saturated solution of NaHCO3 (60.0 mL) and stirred for 30 min. The suspension was filtered, washed with water, and dried to give 2.2 g. The chloride content was not determined by elemental analysis. A sample (1 g) was dissolved in methanol by adding a small amount of aqueous ammonium hydroxide and purified by flash column chromatography [silica gel 100 g, elution with 0 to 100% DMA-80 in DCM] to give the free base of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36e) (0.82 g, 82%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 5.0 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.69 - 7.55 (m, 2H), 7.28 - 7.14 MS (ES+): 407.3 (M+1).

[0283] Step-5: Preparation of 2-(2-((7-(3-fluoro-2-(formamidomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36f) To a stirred solution of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36e) (free base 0.200 g, 492 μmol) in a sealed tube was added DMF (2.5 mL) followed by cobalt acetate (24.5 mg, 98.4 μmol) under a positive nitrogen stream and heated at 150° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with a minimal amount of DMSO, and filtered. The resulting residue was purified by reverse-phase column chromatography [EZ-PREP, C-18 column, 50 g, elution with 0 to 100% acetonitrile in water (containing 0.1% HCl)] to give 2-(2-((7-(3-fluoro-2-(formamidomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (36f) (0.0150 g, 7.02%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 5.0 Hz, 1H), 8.53 (t, J = 5.3 Hz, 1H), 8.17 - 8.08 (m, 2H), 7.90 (dd, J = 7.6, 1.6 Hz, 1H), 7.74 (dt, J = 40.5, 5.2 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.23 (ddd, J = 9.1, 7.5, 1.6 Hz, 2H), 7.11 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.90 (td, J = 7.4, 1.2 Hz, 1H), 5.28 (d, J = 2.7 Hz, 2H), 4.59 (dd, J = 5.9, 2.0 Hz, 2H), 3.58 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -128.85, -128.87;MS (ES+): 435.3 (M+1), (ES-) 433.3 (M-1);C 24 H 19 Analysis calculated for FN2O5.0.5H2O: C, 65.01; H, 4.55; N, 6.32; Found: C, 64.80; H, 4.75; N, 6.27.

[0284] Scheme 37 [ka] Preparation of 2-(2-((7-(2-((ethylamino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (37d) Step-1: Preparation of ethyl 2-(2-((7-(3-fluoro-2-formylpyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (37b) Compound 37b was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (23.0 g, 52.71 mmol) in DME (345 mL) using a solution of 4-chloro-3-fluoropicolinaldehyde (37a) (CAS#1260878-78-1; 10.34 g, 64.82 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (5.5 g, 7.83 mmol), and KPO (24.17 g, 113.86 mmol) in water (46 mL) by heating at 70 °C in an oil bath for 2 h. This gave, after work-up and purification by flash column chromatography [silica gel, elution with 30% EtOAc in n-heptane], ethyl 2-(2-((7-(3-fluoro-2-formylpyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (37b) (8.5 g, 37% yield) as a yellow solid.

[0285] Step-2: Preparation of ethyl 2-(2-((7-(2-((ethylamino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (37c) To a stirred solution of ethyl 2-(2-((7-(3-fluoro-2-formylpyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (37b) (8.0 g, 18.45 mmol) in THF (160 mL) was added ethylamine (0.83 g, 18.45 mmol), triethylamine (0.56 g, 55.53 mmol) at room temperature and stirred for 1 hour. To this reaction mixture was added NaBH4 (1.04 g, 27.68 mmol) in portions at room temperature and stirred for 30 minutes. The reaction mixture was quenched with water (80 mL) and extracted with EtOAc (2 x 500 mL). The combined organics were washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, elution with 50% EtOAc in n-heptane] to give ethyl 2-(2-((7-(2-((ethylamino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (37c) (8.0 g, 94% yield) as a yellow liquid.

[0286] Step-3: 2-(2-((7-(2-((ethylamino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (37d) Compound 37d was prepared from ethyl 2-(2-((7-(2-((ethylamino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (37c) (4.5 g, 9.7 mmol) in THF (45 mL), methanol (45 mL) using a solution of lithium hydroxide monohydrate (1.22 g, 29.18 mmol) in water (45 mL) and heating at 40° C. for 1 hour according to the procedure described in step-8 of Scheme 1. This gave 2-(2-((7-(2-((ethylamino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (37d) (0.96 g, 23% yield) as a yellow solid after workup and purification by flash column chromatography [silica gel, elution with 10% MeOH in DCM]. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J = 4.9 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.67 (t, J = 5.3 Hz, 1H), 7.61 (s, 1H), 7.27 - 7.17 (m, 2H), 7.12 - 7.05 (m, 2H), 6.90 (t, J = 7.3 Hz, 1H), 5.28 (s, 2H), 4.05 (d, J = 2.3 Hz, 2H), 3.57 (s, 2H), 2.73 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -128.85;MS (ES+): 435.3 (M+1);(ES-) 433.3 (M-1);C 25 H 23 Analysis calculated for FN2O4.1.5H2O: C, 65.07; H, 5.68; N, 6.07; Found: C, 65.34; H, 5.75; N, 5.76.

[0287] Scheme 38 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoic acid (38c) Step-1: Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoate (38a) To a stirred solution of DMF (80.0 mL) and NaH (2.23 gm, 93.18 mmol) was added a solution of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (36c) (20.0 g, 37.41 mmol) in DMF (80.0 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1 hour, and bromoethane (3.26 gm, 29.93 mmol) was added dropwise at 0° C. and stirred at 0° C. for 1 hour under nitrogen. The reaction mixture was poured into water (2.0 L) with stirring, and the resulting precipitate was collected by filtration. The resulting residue was dissolved in EtOAc (200 mL), dried, filtered, and concentrated in vacuo to give ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoate (38a) (15.0 g, 71% yield) as a yellow viscous semi-solid. MS (ES+): 563.2 (M+1).

[0288] Step-2: Preparation of 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoic acid (38b) To a stirred solution of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoate (38a) (12.0 g, 21.32 mmol) in THF (120 mL) was added a solution of NaOH (2.55 gm, 63.98 mmol) in MeOH (96 mL) and water (96 mL) at room temperature and heated at 55° C. for 3 hours. The reaction mixture was cooled, concentrated in vacuo, and diluted with 100 mL of water. The reaction mixture was cooled to 0° C. and acidified to pH 2-3 using a solution of 10% KHSO4. The reaction mixture was stirred at 0° C. for 1 hour and the resulting solid was collected by filtration to give 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoic acid (38b) (9.1 gm, 80% yield) as a yellow solid. MS (ES+): 535.2 (M+1).

[0289] Step-3: 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoic acid (38c) To a stirred solution of 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoic acid (38b) (6.0 g, 11.22 mmol) in EtOAc (72 mL) was added 15% MTBE·HCl (60 mL) at room temperature and heated at 40° C. for 1 h. Excess solvent was decanted and the solid formed was isolated by trituration with EtOAc (30 mL) to give the HCl salt of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)butanoic acid (38c) (3.8 g, 68% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (t, J = 5.4 Hz, 4H), 8.20 - 8.05 (m, 1H), 7.94 (s, 1H), 7.81 (t, J = 5.3 Hz, 1H), 7.63 (s, 1H), 7.30 - 7.19 (m, 2H), 7.18 - 7.06 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 5.30 (s, 2H), 4.36 (q, J = 6.0 Hz, 2H), 3.84 (t, J = 7.4 Hz, 1H), 1.95 (dp, J = 14.6, 7.2 Hz, 1H), 1.67 (dt, J = 13.9, 7.3 Hz, 1H), 0.80 (t, J = 7.3 Hz, 3H);MS (ES+): 435.5 (M+1);C 25 H 23 Analysis calculated for FN2O4.1.35HCl.H2O: C, 59.85; H, 5.29; Cl, ​​9.54; N, 5.58; Found: C, 59.59; H, 5.33; Cl, ​​9.87; N, 5.57.

[0290] Scheme 39 [ka] Preparation of tert-butyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (39e) Step-1: Preparation of 3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)picolinonitrile (39b) Compound 39b was prepared from (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol (22i) in dioxane using 3-fluoro-4-iodopicolinonitrile (39a) (CAS#669066-35-7), PdCl(PPh), and aqueous potassium carbonate according to the procedure described in step 4 of Scheme 1. This gave 3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)picolinonitrile (39b) after workup and purification. 1 HNMR (300 MHz, DMSO) δ 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 4.9 Hz, 1H), 8.15 (ddd, J = 6.1, 4.8, 1.1 Hz, 1H), 8.11 - 8.06 (m, 1H), 7.80 (s, 1H), 7.52 (s, MS (ES+): 269.10 (M+1).

[0291] Step-2: Preparation of tert-butyl 2-(2-((7-(2-cyano-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (39d) Compound 39d was prepared from 3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)picolinonitrile (39b) (5.0 g, 18.64 mmol) in THF (75 mL) according to the procedure described in step 2 of Scheme 1 using a solution of triphenylphosphine (7.8 g, 29.73 mmol), tert-butyl 2-(2-hydroxyphenyl)acetate (39c) (CAS#: 258331-10-1; 4.0 g, 19.23 mmol), and DIAD (6.0 g, 29.67 mmol) in THF (10 mL) with stirring at room temperature for 30 minutes. This gave, after workup, tert-butyl 2-(2-((7-(2-cyano-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (39d) (5.6 g, 66% yield) as an off-white solid.

[0292] Step-3: Preparation of tert-butyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (39e) To a stirred solution of tert-butyl 2-(2-((7-(2-cyano-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (39d) (5.5 g, 11.32 mmol) in THF (75.0 mL) was added TEA (8.6 g, 7.5 mmol) and wet Raney nickel (16.5 g) at room temperature, and the reaction mixture was stirred under hydrogen (1.5 bar pressure) at room temperature overnight. The reaction mixture was filtered through a pad of Celite and washed with water (50 mL) and THF (50 mL). The filtrate was extracted with EtOAc (2 x 55 mL), and the combined organics were washed with brine (100 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (80 g), elution with 0 to 50% DCM in DMA-80] to give tert-butyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate (39e) (0.750 g, 17%) as a yellow syrup (Note: Before analyzing the sample, the column was saturated with 8 mL of aqueous ammonium hydroxide). 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 5.0 Hz, 1H), 8.52 (s, 3H), 8.06 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.73 (t, J = 5.3 Hz, 1H), 7.52 (s, 1H), 7.18 (td, J = 7.7, 1.7 Hz, 1H), 7.13 (dd, J = 7.4, 1.7 Hz, 1H), 7.07 - 7.00 (m, 2H), 6.84 (td, J = 7.4, 1.0 Hz, 1H), 5.20 (s, 2H), 4.30 (d, J = 5.4 Hz, 2H), 3.47 (s, 2H), 1.16 (s, 9H);MS (ES+): 463.10 (M+1).

[0293] Scheme 40 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (40 g) Step-1: Preparation of (7-bromo-2,3-dihydrobenzofuran-5-yl)methanol (40b) Compound 40b was prepared from 7-bromo-2,3-dihydrobenzofuran-5-carboxylic acid (40a) (500 g, 2057 mmol; CAS# 335671-77-7) and N-methylmorpholine (500 g, 2057 mmol) in THF (10 L) using isobutyl chloroformate (337.12 g, 2468.4 mmol), an aqueous solution of NaCO (981.0 g, 9256.46 mmol) in water (6.6 L), and NaBH (326.8 g, 8639.7 mmol) according to the procedure described in step 1 of Scheme 1. This gave (7-bromo-2,3-dihydrobenzofuran-5-yl)methanol (40b) (490 g) as a pale pink solid after workup. 1 H NMR (300 MHz, DMSO-d6) δ 7.22 - 7.20 (m, 1H), 7.16 - 7.13 (m, 1H), 5.15 (td, J = 5.8, 0.7 Hz, 1H), 4.59 (t, J = 8.8 Hz, 2H), 4.38 (d, J = 5.7 Hz, 2H), 3.27 (t, J = 8.8 Hz, 2H).

[0294] Step-2: Preparation of 3-fluoro-4-(5-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl)picolinonitrile (40c) To a stirred solution of (7-bromo-2,3-dihydrobenzofuran-5-yl)methanol (40b) (480 g, 2095.52 mmol) in toluene (3.36 L), BISPIN (643.8 g, 2535.5 mmol), TPP (3.07 g, 11.73 mmol), PdCl(PPh) (14.7 g, 20.95 mmol), and potassium acetate (343.4 g, 3499.51 mmol) were added under nitrogen at room temperature and heated to 110 °C for 4 h. The reaction mixture was cooled to room temperature, and a solution of 3-fluoro-4-iodopicolinonitrile (39a) (478.1 g, 1927.87 mmol), PdCl(PPh) (23.53 g, 33.52 mmol), and NaCO (1108 g, 10456.6 mmol) in water (3.6 L) was added at room temperature under nitrogen and stirred at 100 °C for 14 h, which gave, after workup, 3-fluoro-4-(5-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl)picolinonitrile (40c) (135.0 g, 24% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (dd, J = 4.9, 0.9 Hz, 1H), 7.96 (dd, J = 6.3, 4.9 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.24 (s, 1H), 5.19 (t, J = MS (ES+): 271.3 (M+1).

[0295] Step-3: Preparation of ethyl 2-(2-((7-(2-cyano-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (40d) Compound 40d was prepared from 3-fluoro-4-(5-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl)picolinonitrile (40c) (125.0 g, 462.53 mmol) in THF (1.87 L) according to the procedure described in step 2 of Scheme 1 using a solution of triphenylphosphine (194.10 g, 740.02 mmol), ethyl 2-(2-hydroxyphenyl)acetate (1c) (116.79 g, 648.11 mmol), and DIAD (150.15 g, 740.01 mmol) in THF (0.25 L). This gave, after workup, ethyl 2-(2-((7-(2-cyano-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (40d) (131.0 g, 66% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.67 (d, J = 4.9 Hz, 1H), 7.99 (dd, J = 6.2, 4.9 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.38 (s, 1H), 7.28 - 7.16 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.98 - 6.85 (m, 1H), 5.06 (s, 2H), 4.64 (t, J = 8.7 Hz, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 3.32 - 3.21 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H).

[0296] Step-4: Preparation of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (40e) To a solution of ethyl 2-(2-((7-(2-cyano-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (40d) (130.0 g, 300.61 mmol) in THF (2.6 L) was added Boc anhydride (180.0 g, 4824.74 mmol), TEA (190.0 g, 1877.6 mmol), and Raney nickel (200.0 g) at room temperature. The reaction mixture was heated at 38° C. and 7 Kg / cm 2 This gave, after workup, ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (40e).

[0297] Step-5: Preparation of 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (40f) To a stirred solution of ethyl 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (40e) (160.0 g, 298.18 mmol) in THF (2.4 L) was added a solution of NaOH (80.0 g, 2000 mmol) in water (0.800 L), MeOH (0.800 L) and stirred at 40° C. for 2 h. The reaction mixture was concentrated to remove volatile solvents, cooled to 0° C. and acidified with KHSO solution (480.0 g in 1.2 L). The resulting solid was collected by filtration to give 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (40f) (75.0 g, 46% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.36 (s, 1H), 7.29 - 7.21 (m, 3H), 7.11 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 5.11 (s, 2H), 4.64 (t, J = 8.7 Hz, 2H), 4.41 (s, 2H), 3.59 (s, 2H), 3.38 - 3.23 (m, 2H), 1.44 (s, 9H).

[0298] Step-6: Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (40 g) To a stirred solution of 2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (40f) (75.0 g, 147.48 mmol) in MTBE (1.5 L) was added 15% MTBE·HCl (375.0 mL) and heated at 40° C. for 5 hours. TEA (80.0 mL) was added to the reaction mixture at room temperature and stirred for 30 minutes. The resulting solid was collected by filtration to give the triethylamine hydrochloride salt of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetic acid (40g) (37.0 g) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 5.0 Hz, 1H), 7.54 (t, J = 5.3 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.34 (s, 1H), 7.26 - 7.15 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 7.3 Hz, 1H), 5.07 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.15 (s, 2H), 3.52 (s, 2H), 3.27 (t, J = 8.7 Hz, 2H), 2.77 (q, J = 7.2 Hz, 5H), 1.07 (t, J = 7.2 Hz, 8H);MS (ES+): 409.10, (ES-): 407.3 (M-1);C 23 H 21 Analytical calculation for FN2O4.1.25H2O.HCl.N(CH2CH3)3: C, 61.26; H, 7.00; Cl, ​​6.24; N, 7.39; Found: C, 61.07; H, 6.76; Cl, ​​6.55; N, 7.39.

[0299] Scheme 41 [ka] Preparation of 2-(2-((7-(3-(1-amino-3,3,3-trifluoropropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (41e) Step-1: Preparation of N-(1-(3-bromophenyl)-3,3,3-trifluoropropylidene)-2-methylpropane-2-sulfinamide (41b) Compound 41b was prepared from 1-(3-bromophenyl)-3,3,3-trifluoropropan-1-one (41a) (0.77 g, 2.88 mmol; CAS#13541-14-5) and (R)-2-methylpropane-2-sulfinamide (0.699 g, 5.77 mmol) in tetrahydrofuran (15 mL) using tetraethoxytitanium (1.973 g, 8.65 mmol), following the procedure described in step 5 of Scheme 1. This afforded N-(1-(3-bromophenyl)-3,3,3-trifluoropropylidene)-2-methylpropane-2-sulfinamide (41b) (0.33 g, 30.9% yield) as a thick yellow oil after workup and purification by flash column chromatography (silica gel, 0 to 30% EtOAc in hexanes). 1 H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.99 - 7.85 (m, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 4.92 - 4.67 (m, 1H), 4.68 - 4.39 (m, 1H), 1.28 (s, 9H). 19 F NMR (282 MHz, DMSO) δ -59.46.

[0300] Step-2: Preparation of (R)-N-(1-(3-bromophenyl)-3,3,3-trifluoropropyl)-2-methylpropane-2-sulfinamide (41c) Compound 41c was prepared from N-(1-(3-bromophenyl)-3,3,3-trifluoropropylidene)-2-methylpropane-2-sulfinamide (41b) (330 mg, 0.891 mmol) in tetrahydrofuran (10 mL) using sodium borohydride (169 mg, 4.46 mmol) according to the procedure described in step 3 of Scheme 5. This afforded (R)-N-(1-(3-bromophenyl)-3,3,3-trifluoropropyl)-2-methylpropane-2-sulfinamide (41c) (260 mg, 0.698 mmol, 78% yield) as a clear, colorless oil after workup and purification by flash column chromatography [silica gel, elution with ethyl acetate (0 to 30%) in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 7.76 (d, J = 1.8 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.31 (td, J = 7.7, 2.4 Hz, 1H), 5.92 (d, J = 10.1 Hz, 1H), 4.53 (td, J = 9.5, 4.7 Hz, 1H), 3.10 - 2.57 (m, 2H), 1.12 (s, 9H). 19 F NMR (282 MHz, DMSO) δ -61.36.

[0301] Step-3: Preparation of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-3,3,3-trifluoropropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (41d) Compound 41d was prepared from ethyl 2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (366 mg, 0.838 mmol) in dioxane (5 mL) using (R)—N-(1-(3-bromophenyl)-3,3,3-trifluoropropyl)-2-methylpropane-2-sulfinamide (41c) (260 mg, 0.698 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2Cl2] (49.0 mg, 0.070 mmol), and 3.3 M aqueous K2CO3 solution (0.635 mL, 2.095 mmol) in an oil bath at 100 °C for 16 h according to the procedure described in step 4 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), elution with 0 to 3% MeOH in DCM], ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-3,3,3-trifluoropropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (41d) (248 mg, 59.0% yield) as an orange oil, which was used directly in the next reaction. MS (ES+) 602 (M+1).

[0302] Step-4: Preparation of 2-(2-((7-(3-(1-amino-3,3,3-trifluoropropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (41e) To a solution of ethyl 2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-3,3,3-trifluoropropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (41d) (248 mg, 0.412 mmol) in EtOH (5 mL) was added 4 M HCl in dioxane (0.206 mL, 0.824 mmol) and stirred at room temperature for 1 h. The reaction was added 2 M aqueous LiOH (0.561 mL, 1.122 mmol), stirred at room temperature for 16 h, and neutralized to pH 7 with 3 M aqueous HCl. The neutral solution was purified by reverse-phase column chromatography [C-18 column (100 g), elution with 0.1% aqueous HCl and MeCN from 0 to 100%] to give the HCl salt of 2-(2-((7-(3-(1-amino-3,3,3-trifluoropropyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (41e) (135 mg, 77% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J = 2.2 Hz, 2H), 7.93 (dt, J = 7.2, 1.7 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.66 - 7.50 (m, 3H), 7.17 (t, J = 7.6 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 5.21 (s, 2H), 4.66 (dd, J = 8.9, 5.5 Hz, 1H), 3.53 (s, 2H), 3.14 (d, J = 10.0 Hz, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -61.80;MS (ES+): 470.0 (M+1), (ES-): 467.0 (M-1);C 26 H 22 Analysis calculated for F3NO4.HCl.1.25H2O: C, 59.10; H, 4.86; Cl, ​​6.71; N, 2.65; Found: C, 59.11; H, 4.67; Cl, ​​6.75; N, 2.78.

[0303] Scheme 42 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (42e) Step-1: Preparation of (7-bromo-4-fluorobenzofuran-5-yl)methanol (42b) Compound 42b was prepared from 7-bromo-4-fluorobenzofuran-5-carboxylic acid (42a) (900 mg, 3.47 mmol, purchased from PharmaBlock, PB95207) according to the procedure described in step 1 of Scheme 1 using N-methylmorpholine (0.44 mL, 3.97 mmol), isobutyl chloroformate (0.55 mL, 4.17 mmol), and NaBH (394 mg, 10.42 mmol) in water (5 mL) in THF (10 mL). This afforded (7-bromo-4-fluorobenzofuran-5-yl)methanol (42b) (760 mg, 89% yield) as a white solid after workup and purification by flash chromatography [silica (12 g), elution with 0 to 60% EtOAc in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 8.17 (dt, J = 2.2, 0.5 Hz, 1H), 7.60 (dt, J = 6.4, 0.6 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 5.39 (t, J = 5.8 Hz, 1H), 4.65 - 4.57 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -126.62.

[0304] Step-2: Preparation of ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (42c) Compound 42c was prepared from (7-bromo-4-fluorobenzofuran-5-yl)methanol (42b) (594 mg, 2.424 mmol) in DCM (75 mL) according to the procedure described in step 2 of scheme 1 using triphenylphosphine (699 mg, 2.67 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (14f) (612 mg, 2.91 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (979 mg, 2.67 mmol) in DCM (20 mL). This gave, after work-up and purification by flash column chromatography [silica (24 g), elution with 0 to 50% EtOAc in hexanes], ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (42c) (703 mg, 66% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 6.1 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 5.20 (d, J = 1.4 Hz, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 3.48 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -124.53.

[0305] Step-3: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (42d) Compound 42d was prepared from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate 42c (150 mg, 0.343 mmol) in dioxane (5 mL) according to the procedure described in step 4 of Scheme 1, using a solution of (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride 18a (87 mg, 0.515 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (36.1 mg, 0.051 mmol), and KCO (142 mg, 1.029 mmol) in water (0.5 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 70% DMA80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (42d) (165 mg, 100% yield) as a dark oil. MS (ES+): 482.2 (M+1).

[0306] Step-4: Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (42e) Compound 42e was prepared from ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (42d) (163 mg, 0.339 mmol) in THF (6 mL), acetonitrile (6 mL) using a solution of lithium hydroxide monohydrate (86 mg, 2.050 mmol) in water (2 mL) and stirring overnight at room temperature according to the procedure described in step-8 of Scheme 1. This gave the HCl salt of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (42e) (55 mg, 36% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.58 (d, J = 6.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H), 5.28 (s, 2H), 4.17 (s, 2H), 3.75 (s, 3H), 3.43 (s, 2H); 19 F NMR (282 MHz, DMSO) δ -118.46, -123.53;MS (ES+): 454.1 (M+1);MS (ES-): 452.1 (M-1);C 25 H 21 Analysis calculated for F₂NO₅55.0.95HCl.1.5H₂O: C, 58.29; H, 4.88; Cl, ​​6.54; N, 2.72; Found: C, 57.91; H, 4.82; Cl, ​​6.44; N, 2.61.

[0307] Scheme 43 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (43d) Step-1: Preparation of ethyl 2-(2-((7-(2-((tert-butoxycarbonylamino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (43b) Compound 43b was prepared from ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (42c) (137 mg, 0.313 mmol) in dioxane (5 mL) according to the procedure described in step 4 of scheme 1, by the addition of tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. A solution of (-2-yl)methylcarbamate (43a) (136 mg, 0.407 mmol; CAS# 1425334-54-8), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2Cl2] (33.0 mg, 0.047 mmol), and K2CO3 (130 mg, 0.940 mmol) in water (0.5 mL) was heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 70% DMA80 in DCM], ethyl 2-(2-((7-(2-((tert-butoxycarbonylamino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (43b) (177 mg, 0.313 mmol, 100% yield) as a dark oil. MS (ES+): 565.2 (M+1).

[0308] Step-2: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (43c) To a solution of ethyl 2-(2-((7-(2-((tert-butoxycarbonylamino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (43b) (177 mg, 0.313 mmol) in ethanol (6 mL) was added 4 M HCl in dioxane (0.8 mL, 3.20 mmol) and stirred at room temperature for 48 hours. The solvent was removed in vacuo to give ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (43c) (146 mg, 100% yield) as a yellow solid. MS (ES+): 465.2 (M+1).

[0309] Step-3: Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (43d) Compound 43d was prepared from ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (43c) (146 mg, 0.314 mmol) in THF (6 mL), acetonitrile (6 mL) using a solution of lithium hydroxide monohydrate (135 mg, 3.22 mmol) in water (2 mL) and stirring at room temperature overnight, according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetic acid (43d) (105 mg, 77% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J = 5.3 Hz, 1H), 8.60 (s, 3H), 8.25 (d, J = 2.3 Hz, 1H), 8.10 (s, 1H), 8.04 - 7.87 (m, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.3 Hz, 1H), 5.31 (s, 2H), 4.31 (d, J = 5.3 Hz, 2H), 3.76 (s, 3H), 3.48 (s, 2H); 19 F NMR (282 MHz, DMSO) δ -121.51;MS (ES+): 437.1 (M+1);MS (ES-): 435.1 (M-1);C 24 H 21 Analysis calculated for FN2O5.1.35HCl.2.5H2O: C, 54.32; H, 5.19; Cl, ​​9.02; N, 5.28; Found: C, 54.18; H, 5.13; Cl, ​​9.24; N, 5.28.

[0310] Scheme 44 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (44d) Step-1: Preparation of ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44b) Compound 44b was prepared from (7-bromo-3-fluorobenzofuran-5-yl)methanol (44a) (PharmaBlock, Catalog No.: PB98116, 202 mg, 0.824 mmol) in DCM (6 mL) according to the procedure described in step 2 of Scheme 1 using triphenylphosphine (281 mg, 1.072 mmol), ethyl 2-(2-hydroxyphenyl)acetate (1c) (193 mg, 1.072 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 393 mg, 1.072 mmol) in DCM (2 mL). This gave, after work-up and purification by flash column chromatography [silica (12 g), elution with 0 to 50% EtOAc in hexanes], ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44b) (196 mg, 58% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 4.4 Hz, 1H), 7.75 (dd, J = 12.2, 1.5 Hz, 2H), 7.31 - 7.17 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.93 (td, J = 7.3, 1.1 Hz, 1H), 5.22 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H), 1.09 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -174.46.

[0311] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44c) Compound 44c was prepared from ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44b) (155 mg, 0.381 mmol) in dioxane (5 mL) according to the procedure described in step 4 of Scheme 1 using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (86 mg, 0.571 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2Cl2] (40.1 mg, 0.057 mmol), K2CO3 (158 mg, 1.142 mmol) in water (0.5 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 70% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44c) (146 mg, 88% yield) as a dark oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.37 (d, J = 4.4 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.75 - 7.65 (m, 3H), 7.51 - 7.38 (m, 2H), 7.31 - 7.19 (m, 2H), 7.15 - 7.07 (m, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 3.94 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.65 (s, 2H), 1.01 (t, J = 7.1Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -176.97;MS (ES+): 434.1 (M+1).

[0312] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (44d) Compound 44d was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44c) (143 mg, 0.330 mmol) in THF (6 mL), acetonitrile (6 mL) using a solution of lithium hydroxide monohydrate (72 mg, 1.716 mmol) in water (2 mL) and stirred at room temperature for 40 hours according to the procedure described in step 8 of Scheme 1. This gave 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (44d) (101 mg, 76% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.60 (s, 2H), 8.46 - 8.29 (m, 1H), 8.01 (s, 1H), 7.96 - 7.85 (m, 1H), 7.78 (d, J = 9.8 Hz, 2H), 7.69 - 7.48 (m, 2H), 7.33 - 7.17 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H), 3.62 (s, 2H); 19 F NMR (282 MHz, DMSO) δ -176.63.MS (ES+): 406.1 (M+1);MS(ES-): 404.1 (M-1);C 24 H 20 Analysis calculated for FNO4.HCl.H2O: C, 62.68; H, 5.04; Cl, ​​7.71; N, 3.05; Found: C, 63.03; H, 5.02; Cl, ​​7.59; N, 3.09.

[0313] Scheme 45 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (45b) Step-1: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (45a) Compound 45a was prepared from ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate 44b (146 mg, 0.359 mmol) in dioxane (5 mL) according to the procedure described in step 4 of Scheme 1 using a solution of (3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride 18a (91 mg, 0.538 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (37.7 mg, 0.054 mmol), and KCO (149 mg, 1.076 mmol) in water (0.5 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 70% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (45a) (149 mg, 92% yield) as a dark oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.33 (d, J = 4.4 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.67 - 7.50 (m, 4H), 7.45 (td, J = 7.3, 1.9 Hz, 1H), 7.38 - 7.17 (m, 3H), 7.12 (d, J = 8.1 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 3.92 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 3.63 (s, 2H), 1.00 (t, J = 7.1 Hz, 3H); 19F NMR (282 MHz, DMSO) δ -121.74, -176.64.MS (ES+): 452.1 (M+1).

[0314] Step-2: Preparation of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (45b) Compound 45b was prepared from ethyl 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (45a) (146 mg, 0.323 mmol) in THF (6 mL), acetonitrile (6 mL) using a solution of lithium hydroxide monohydrate (91 mg, 2.169 mmol) in water (2 mL) and stirring overnight at room temperature according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (45b) (102 mg, 75% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.64 (s, 3H), 8.36 (d, J = 4.4 Hz, 1H), 7.87 (s, 1H), 7.82 - 7.53 (m, 3H), 7.44 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 5.31 (s, 2H), 4.17 (s, 2H), 3.60 (s, 2H); 19 F NMR (282 MHz, DMSO) δ -118.38, -176.29.MS (ES+): 424.1 (M+1);MS (ES-): 422.1 (M-1);C 24 H 19Analysis calculated for F2NO4.HCl.0.75H2O: C, 60.89; H, 4.58; Cl, ​​7.49; N, 2.96; Found: C, 61.19; H, 4.64; Cl, ​​7.68; N, 3.06.

[0315] Scheme 46 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (46d) Step-1: Preparation of ethyl 2-(2-((3-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (46a) Compound 46a was prepared from ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (44b) (420 mg, 1.031 mmol) according to the procedure described in step-3 of Scheme 1 using bis(pinacolato)diboron (393 mg, 1.547 mmol), potassium acetate (304 mg, 3.09 mmol), and PdCl(dppf)-CHCl (126 mg, 0.155 mmol) in anhydrous dioxane (12 mL) heated at 95 °C under nitrogen atmosphere overnight. This gave, after work-up and purification by flash column chromatography [silica (12 g), elution with 0 to 40% EtOAc in hexanes], ethyl 2-(2-((3-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (46a) (436 mg, 93% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (d, J = 4.3 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.14 - 7.05 (m, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.34 (s, 12H), 1.07 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -177.50.

[0316] Step-2: Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (46b) Compound 46b was prepared from (+)-N-((4-chloro-3-fluoropyridine)-2-(2-((3-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (46a) (219 mg, 0.482 mmol) in dioxane (5 mL) according to the procedure described in step-4 of scheme 1. The crude product was prepared using a solution of 11c (191 mg, 0.723 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (50.8 mg, 0.072 mmol), and KCO (200 mg, 1.446 mmol) in water (0.5 mL) heated at 100 °C in an oil bath for 3 h. This afforded, after workup and purification by flash column chromatography [silica gel (12 g), elution with 0 to 15% methanol in DCM], ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (46b) (268 mg, 100% yield) as a dark oil. MS (ES+): 557.2 (M+1).

[0317] Step-3: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (46c) To a solution of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (46b) (268 mg, 0.481 mmol) in EtOH (6 mL) was added 4 M HCl in dioxane (1.5 mL, 6.00 mmol) at 0 °C and warmed to room temperature over 1 h. The reaction mixture was concentrated in vacuo to give ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (46c) (218 mg, 100% yield) as a yellow oil. MS (ES+): 453.1 (M+1).

[0318] Step-4: Preparation of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (46d) Compound 46d was prepared from ethyl 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (46c) (218 mg, 0.482 mmol) in THF / acetonitrile (6 mL each) using a solution of LiOH (150 mg, 3.57 mmol) in water (2 mL) and stirring at room temperature for 48 hours according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (46d) (40 mg, 19.56% yield) as a pale yellow solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.62 (q, J = 6.4, 5.7 Hz, 4H), 8.42 (d, J = 4.3 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.80 (t, J = 5.3 Hz, 1H), 7.71 (s, 1H), 7.25 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 5.32 (s, 2H), 4.38 (t, J = 5.9 Hz, 2H), 3.60 (s, 2H); 19 F NMR (282 MHz, DMSO) δ -128.26, -176.19.MS (ES+): 425.1 (M+1);MS (ES-): 423.1 (M-1);C 23 H 18 Analysis calculated for F2N2O4.1.1HCl.1.4H2O: C, 56.41; H, 4.51; Cl, ​​7.96; N, 5.72; Found: C, 56.44; H, 4.16; Cl, ​​7.73; N, 6.09.

[0319] Scheme 47 [ka] Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (47c) Step-1: Preparation of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (47a) Compound 47a was prepared from ethyl 2-(2-((3-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (46a) (199 mg, 0.438 mmol) in dioxane (5 mL) using a solution of (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (22c) (162 mg, 0.657 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (46.1 mg, 0.066 mmol), and KCO (182 mg, 1.314 mmol) in water (0.5 mL) by heating in an oil bath at 100 °C for 3 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with MeOH / DCM from 0 to 15%], ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (47a) (236 mg, 0.438 mmol, 100% yield) as a yellow oil. MS (ES+): 539.2 (M+1).

[0320] Step-2: Preparation of ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (47b) To a solution of ethyl 2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (47a) (236 mg, 0.438 mmol) in EtOH (6 mL) was added 4 M HCl in dioxane (1.5 mL, 6.00 mmol) at 0 °C and warmed to room temperature over 1 h. The reaction mixture was concentrated in vacuo to give ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (47b) (190 mg, 100% yield) as a yellow oil. MS (ES+): 435.1 (M+1).

[0321] Step-3: Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (47c) Compound 47c was prepared from ethyl 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (47b) (190 mg, 0.437 mmol) in THF (6 mL), acetonitrile (6 mL) using a solution of lithium hydroxide monohydrate (132 mg, 3.15 mmol) in water (2 mL) and stirring at room temperature for 48 hours according to the procedure described in step 8 of Scheme 1. This afforded the HCl salt of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (47c) (67 mg, 38% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 5.3 Hz, 1H), 8.57 (s, 3H), 8.47 (d, J = 4.3 Hz, 1H), 8.13 - 8.04 (m, 1H), 8.00 - 7.94 (m, 1H), 7.92 (s, 2H), 7.32 - 7.18 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 5.33 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 3.62 (s, 2H); 19 F NMR (282 MHz, DMSO) δ -176.55.MS (ES+): 407.1 (M+1);MS (ES-): 405.1 (M-1);C 23 H 19 Analysis calculated for FN2O4.1.5HCl.2H2O: C, 55.57; H, 4.97; Cl, ​​10.70; N, 5.64; Found: C, 55.52; H, 4.91; Cl, ​​10.82; N, 5.67.

[0322] Scheme 48 [ka] Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (48 g) Step-1: Preparation of tert-butyl 3-(4-fluoro-5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (48c) Compound 48c was prepared from (7-bromo-4-fluorobenzofuran-5-yl)methanol (42b) (413 mg, 1.685 mmol) in 1,4-dioxane (8 mL) according to the procedure described in step 4 of Scheme 1 using a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (12c) (674 mg, 2.022 mmol), Pd(PPh)Cl (177 mg, 0.253 mmol), KCO (699 mg, 5.06 mmol) in water (0.8 mL) heated at 100 °C in an oil bath for 3 h. This gave, after work-up and purification by flash column chromatography (silica gel (24 g), elution with 0 to 80% EtOAc in hexanes), tert-butyl 3-(4-fluoro-5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (48c) (454 mg, 72.5% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 2.2 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.57 (d, J = 6.9 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 5.32 (t, J = 5.7 Hz, 1H), 4.68 (dd, J = 5.7, 1.5 Hz, 2H), 4.22 (d, J = 6.2 Hz, 2H), 1.40 (s, 9H); 19 F NMR (282 MHz, DMSO) δ -127.07.

[0323] Step-2: Preparation of ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48d) Compound 48d was prepared from tert-butyl 3-(4-fluoro-5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (48c) (450 mg, 1.212 mmol) in DCM (6 mL) according to the procedure described in step-2 of Scheme 1 using a solution of triphenylphosphine (413 mg, 1.575 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (12k) (471 mg, 1.817 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (578 mg, 1.575 mmol) in DCM (2 mL) and stirred at room temperature for 3 hours. This gave, after work-up and purification by flash column chromatography [silica (12 g), elution with 0 to 50% EtOAc in hexanes], ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48d) (483 mg, 65.1% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 2.3 Hz, 1H), 7.73 - 7.62 (m, 3H), 7.52 - 7.42 (m, 3H), 7.30 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.20 - 7.11 (m, 2H), 5.30 (s, 2H), 4.22 (d, J = 6.1 Hz, 2H), 3.83 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 1.39 (s, 9H), 0.87 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -125.01.

[0324] Step-3: Preparation of ethyl 2-(4-acetyl-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48e) Compound 48e was prepared from ethyl 2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48d) (480 mg, 0.784 mmol) in toluene (20 mL) using tributyl(1-ethoxyvinyl)stannane (0.349 mL, 0.980 mmol), Pd(PhP) (91 mg, 0.078 mmol) and heating at 120 °C for 24 hours according to the procedure described in Scheme 12, Step-6. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), elution with 0 to 80% ethyl acetate in hexanes], ethyl 2-(4-acetyl-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48e) (240 mg, 53.2% yield) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 2.3 Hz, 1H), 7.75 - 7.63 (m, 4H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.53 - 7.41 (m, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 5.37 (s, 2H), 4.22 (d, J = 6.2 Hz, 2H), 3.85 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 2.61 (s, 3H), 1.39 (s, 9H), 0.89 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -125.07.

[0325] Step-4: Preparation of ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48f) To a solution of ethyl 2-(4-acetyl-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48e) (235 mg, 0.408 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (0.629 mL, 8.17 mmol) and stirred at room temperature for 70 minutes. The reaction mixture was concentrated to dryness in vacuo to give ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48f) (194 mg, 100% yield) as a pale yellow oil. MS (ES+): 476.2 (M+1).

[0326] Step-5: Preparation of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (48 g) Compound 48g was prepared from ethyl 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (48f) in THF (5 mL), methanol (5 mL) using a solution of lithium hydroxide monohydrate (109 mg, 2.60 mmol) in water (2 mL) and stirring overnight at room temperature according to the procedure described in step 8 of Scheme 1. This gave the HCl salt of 2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetic acid (48g) (116 mg, 0.259 mmol, 63.5% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1H NMR (300 MHz, DMSO-d6) δ 12.29 (s, 1H, D2O exchangeable), 8.51 (s, 3H, D2O exchangeable), 8.18 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.94 - 7.83 (m, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.63 - 7.51 (m, 3H), 7.44 - 7.30 (m, 1H), 7.23 (d, J = 2.3 Hz, 1H), 5.40 (s, 2H), 4.12 (s, 2H), 3.64 (s, 2H), 2.60 (s, 3H); 1 H NMR (300 MHz, DMSO-d6 / D2O) δ 8.05 (d, J = 2.2 Hz, 1H), 7.93 - 7.81 (m, 2H), 7.68 (d, J = 6.7 Hz, 1H), 7.58 (dd, J = 15.2, 7.4 Hz, 3H), 7.48 (d, J = 7.7 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.15 (d, J = 2.2 Hz, 1H), 5.35 (s, 2H), 4.10 (s, 2H), 3.60 (s, 2H), 2.55 (s, 3H); 19 F NMR (282 MHz, DMSO) δ -124.49.MS (ES+): 448.1 (M+1);C 26 H 22 Analysis calculated for FNO5.1.1HCl.1.25H2O: C, 61.22; H, 5.06; N, 2.75; Cl, ​​7.65; Found: C, 61.59; H, 5.04; N, 2.81; Cl, ​​7.72.

[0327] Scheme 49 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (49d) Step-1: Preparation of ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (49b) Compound 49b was prepared from (7-bromo-3-fluorobenzofuran-5-yl)methanol (44a) (PharmaBlock, Catalog Number: PB98116, 202 mg, 0.824 mmol) in DCM (10 mL) using triphenylphosphine (471 mg, 1.796 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (49a) (CAS#1261451-91-5, 380 mg, 1.959 mmol), and (£)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (659 mg, 1.796 mmol) in DCM (5 mL) according to the procedure described in Step-2 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with 0 to 50% EtOAc in hexanes], ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (49b) (510 mg, 74% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.20 (s, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.59 (s, 2H), 2.30 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -174.41.

[0328] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (49c) Compound 49c was prepared from ethyl 2-(2-((7-bromo-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (49b) (0.5 g, 1.187 mmol) in dioxane (15 mL) according to the procedure described in step 4 of Scheme 1, using a solution of 3-(aminomethyl)phenylboronic acid hydrochloride (9e) (0.267 g, 1.424 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (0.125 g, 0.178 mmol), KCO (0.492 g, 3.56 mmol) in water (1.5 mL) heated at 100 °C in an oil bath for 4 hours. This gave, after work-up and purification by flash column chromatography [silica gel (40 g), elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (49c) (430 mg, 81% yield) as a clear oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.39 (d, J = 4.3 Hz, 1H), 7.82 (s, 1H), 7.75 - 7.64 (m, 3H), 7.47 (dt, J = 13.8, 7.5 Hz, 2H), 7.10 (d, J = 7.5 Hz, 1H), 6.97 (s, 1H), 6.74 (d, J = 7.4 Hz, 1H), 5.26 (s, 2H), 3.93 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 3.59 (s, 2H), 2.31 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO) δ -176.93.MS (ES+): 448.2 (M+1).

[0329] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (49d) Compound 49d was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (49c) (181 mg, 0.404 mmol) in THF (6 mL), acetonitrile (6 mL) using a solution of lithium hydroxide monohydrate (118 mg, 2.81 mmol) in water (2 mL) and stirred at room temperature for 16 hours according to the procedure described in step 8 of Scheme 1. This gave the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-3-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetic acid (49d) (28 mg, 17% yield) as a white solid after workup and purification by reverse-phase column chromatography [C-18 column, elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%]. 1 H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.64 - 8.42 (m, 3H), 8.39 (d, J = 4.3 Hz, 1H), 7.99 (s, 1H), 7.95 - 7.84 (m, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.59 (d, J = 4.9 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.55 (s, 2H), 2.29 (s, 3H); 19 F NMR (282 MHz, DMSO) δ -176.58;MS (ES+): 420.1 (M+1);MS (ES-): 418.1 (M-1);C 25 H 22 Analysis calculated for FNO4.HCl.1.75H2O: C, 61.60; H, 5.48; N, 2.87; Cl, ​​7.27; Found: C, 61.47; H, 5.40; N, 3.14; Cl, ​​6.96.

[0330] Scheme 50 [ka] Preparation of 2-(2-((7-(5-(aminomethyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (50e) Step-1: Preparation of ethyl 2-(2-((7-(5-formylfuran-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50a) Compound 50a was prepared from ethyl 2-(2-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate (1e) (500 mg, 1.146 mmol) in dioxane (6 mL) by adding a solution of 4-bromofuran-2-carbaldehyde (CAS#21921-76-6; 201 mg, 1.146 mmol), bis(triphenylphosphine)palladium(II) chloride [Pd(PPh)Cl] (121 mg, 0.172 mmol), and KCO (475 mg, 3.44 mmol) in water (2 mL) and heating at 90 °C for 3 h according to the procedure described in step 4 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel 12 g, elution with 0 to 50% DMA-80 in DCM], ethyl 2-(2-((7-(5-formylfuran-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50a) (400 mg, 86% yield) as a yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (d, J = 0.8 Hz, 1H), 8.77 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 0.9 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.14 - 7.06 (m, 2H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.66 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H).

[0331] Step-2: Preparation of (S)-ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50b) Compound 50b was prepared from ethyl 2-(2-((7-(5-formylfuran-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50a) (390 mg, 0.964 mmol) in THF (10 mL) using (S)-2-methylpropane-2-sulfinamide (234 mg, 1.929 mmol), tetraethoxytitanium (0.404 mL, 1.929 mmol) and heating at 60° C. for 1 hour according to the procedure described in step 5 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), elution with ethyl acetate (0 to 50%) in hexanes], (S)-ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50b) (321 mg, 65.6% yield) as a yellow gum. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.42 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.31 - 7.19 (m, 2H), 7.14 - 7.05 (m, 2H), 6.91 (t, J = 7.3 Hz, 1H), 5.23 (s, 2H), 4.00 - 3.89 (m, 2H), 3.65 (s, 2H), 1.19 (s, 9H), 1.01 (t, J = 7.1 Hz, 3H).

[0332] Step-3: Preparation of (S)-ethyl 2-(2-((7-(5-((1,1-dimethylethylsulfinamido)methyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50c) Compound 50c was prepared from (S)-ethyl 2-(2-((7-(5-(((tert-butylsulfinyl)imino)methyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50b) (317 mg, 0.625 mmol) in MeOH (10 mL) using sodium borohydride (23.63 mg, 0.625 mmol). This afforded (S)-ethyl 2-(2-((7-(5-((1,1-dimethylethylsulfinamido)methyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50c) (226 mg, 0.443 mmol, 71.0% yield) as a clear gum after workup and purification by flash column chromatography [silica gel (24 g), elution with ethyl acetate (0 to 100%) in hexanes]. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 0.9 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.30 - 7.19 (m, 2H), 7.13 - 7.07 (m, 1H), 7.03 (d, J = 2.2 Hz, 1H), 7.00 (s, 1H), 6.91 (td, J = 7.3, 1.1 Hz, 1H), 5.86 (t, J = 5.7 Hz, 1H), 5.21 (s, 2H), 4.22 (dd, J = 5.6, 2.3 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.63 (s, 2H), 1.14 (s, 9H), 1.02 (t, J = 7.1 Hz, 3H).

[0333] Step-4: Preparation of ethyl 2-(2-((7-(5-(aminomethyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50d) To a solution of (S)-ethyl 2-(2-((7-(5-((1,1-dimethylethylsulfinamido)methyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50c) (220 mg, 0.432 mmol) in tetrahydrofuran (6 mL) was added 4 N aqueous HCl in dioxane (0.216 mL, 0.863 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness to give ethyl 2-(2-((7-(5-(aminomethyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate (50d), which was used in the next step without further purification.

[0334] Step-5: Preparation of 2-(2-((7-(5-(aminomethyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (50e) The residue from step 4 above was dissolved in tetrahydrofuran (4.00 mL) and acetonitrile (2 mL), and lithium hydroxide monohydrate (1N aqueous solution, 2.158 mL, 2.158 mmol) was added and stirred at room temperature for 18 hours. The reaction was concentrated in vacuo, diluted with water (2 mL), and acidified to pH 4 using 1 M HCl. The separated solid was purified by reverse-phase column chromatography [C-18 column (50 g), elution with 0.1% aqueous HCl and acetonitrile from 0 to 100%] to give the HCl salt of 2-(2-((7-(5-(aminomethyl)furan-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (50e) (55 mg, 26.5% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H, D2O exchangeable), 8.53 (s, 3H, D2O exchangeable), 8.44 (d, J = 0.9 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.68 (s, 2H), 7.28 - 7.18 (m, 3H), 7.10 - 7.01 (m, 2H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.18 (d, J = 5.3 Hz, 2H), 3.60 (s, 2H). 1 H NMR (300 MHz, DMSO-d6 / D2O) δ 8.45 (d, J = 0.9 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.68 (q, J = 1.7 Hz, 2H), 7.29 - 7.17 (m, 3H), 7.15 - 7.00 (m, 2H), 6.98 - 6.83 (m, 1H), 5.25 (s, 2H), 4.19 (s, 2H), 3.60 (d, J = 4.5 Hz, 18H).MS (ES+): 755.2 (2M+1);(ES-): 376.1 (M-1);C 22 H 19Analysis calculated for NO5.HCl.1.25H2O: C, 60.55; H, 5.20; Cl, ​​8.12; N, 3.21; Found: C, 60.57; H, 4.89; Cl, ​​7.99; N, 3.19.

[0335] Scheme 51 [ka] Preparation of (-)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetic acid (51f) Step-1: Preparation of (R)-2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetic acid (51b) To a solution of (R)-2-amino-2-(2-hydroxyphenyl)acetic acid (51a) (0.5 g, 2.456 mmol; CAS#185339-06-4) in water (10 mL) cooled to 0 °C was added sodium bicarbonate (0.825 g, 9.82 mmol) and a solution of cyclopropanecarbonyl chloride (0.337 mL, 3.68 mmol) in tetrahydrofuran (5 mL) and warmed to room temperature. The solution was acidified with 3 N HCl and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washe...

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, 【Chemistry 2】 The partial structure represented by the formula: 【Transformation 3】 【Chemistry 4】 is a group selected from the group consisting of 【Transformation 5】 The partial structure represented by the formula: 【Transformation 6】 (wherein the asterisk (*) represents 【Transformation 7】 (indicating the point of attachment to the substructure represented by is a group selected from the group consisting of 【Transformation 8】 The partial structure represented by the formula: 【Chemistry 9】 is a group selected from the group consisting of 【Chemistry 10】 The partial structure represented by the formula: 【Chemistry 11】 【Chemistry 12】 is a group selected from the group consisting of:

2. In formula (II), 【Chemistry 13】 The partial structure represented by the formula: 【Chemistry 14】 2. The compound of claim 1, wherein the group is

3. In formula (II), 【Chemistry 15】 The partial structure represented by the formula: 【Chemistry 16】 3. The compound according to claim 1 or 2, wherein the group is

4. In formula (II), 【Chemistry 17】 The partial structure represented by the formula: [Chemistry 18] The compound according to any one of claims 1 to 3, wherein the group is selected from the group consisting of:

5. In formula (II), 【Chemistry 19】 The partial structure represented by the formula: 【Chemistry 20】 5. The compound of claim 4, wherein the group is

6. A compound selected from the compounds shown in the table below, or a pharmaceutically acceptable salt thereof. 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A composition for treating or preventing a disease or condition characterized by abnormal complement system activity, comprising the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of immune disorders, diseases of the central nervous system, neurodegenerative or neurological diseases, renal diseases, cardiovascular diseases, blood disorders, or visual or ocular disorders, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, fulminant antiphospholipid syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, focal segmental glomerulosclerosis, macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neoplasia, and the like. The composition is selected from the group consisting of corneal neovascularization (CNV), uveitis, Behcet's disease uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, and postoperative inflammation.

9. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is an immune disorder.

10. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

11. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

12. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is a renal disease.

13. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

14. 9. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

15. 9. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

16. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is a blood disorder.

17. 9. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is a visual or eye disorder.

18. 9. The composition of claim 8, wherein the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's disease uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

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