HK1261374B - Antibacterial compounds and uses thereof - Google Patents

Description

Antimicrobial compounds and their uses

Invention Field

This invention generally relates to diarylquinoline compounds with antibacterial activity, and more specifically to diarylquinoline compounds with antituberculosis properties. All references or dependencies cited below are expressly incorporated herein by reference.

Background of the Invention

Mycobacterium tuberculosis is the causative agent of tuberculosis (“TB”), a devastating infectious disease. It is estimated that approximately 2 million people die from TB each year worldwide. Failure to properly treat TB has led to global drug resistance to Mycobacterium tuberculosis, rendering some medications ineffective.

There is a need in the art for pharmaceutical compounds that can provide superiority over compounds currently used in the art.

Invention Overview

This invention relates to compounds of formula (I):

Including any of its stereochemical isomers,

in:

_R1 is a -phenyl group, which may optionally be mono- or di-substituted independently by a lower alkyl group, halogen, or alkoxy group.

-5 or 6-membered heteroaryl groups, optionally and independently monosubstituted, disubstituted, or trisubstituted by lower alkyl groups, halogens, alkoxy _groups , _-SCH3 , _-SCH2CH3 , -N(CH2CH3) ₂ , or -N(CH3) ₂ .

-benzofuranyl,

-2,3-Dihydrobenzo[b][1,4]dioxin-5-yl,

-2,3-dihydro-1H-inden-4-yl or

-5,6,7,8-Tetrahydronaphth-1-yl;

_R2 and _R3 are independently hydrogen or lower alkyl groups;

_R4 is a phenyl group, which may optionally be independently mono- or di-substituted with a halogen or a lower alkyl group.

-5 or 6-membered heteroaryl groups, optionally and independently substituted with alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy, or -N(CH3) ₂ monosubstituted, disubstituted, or trisubstituted.

-benzofuranyl,

-benzo[b]thiophene or

-2,3-dihydro-1H-indenyl; and

_R5 is a halogen or cyano group.

Or its pharmaceutically acceptable salt.

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention further relates to a method for treating tuberculosis, comprising the step of administering to a patient in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Invention Details

It should be understood that the description of this invention has been simplified to illustrate the elements relevant to a clear understanding of the invention, while many other elements found in typical pharmaceutical compositions have been omitted for clarity. Those skilled in the art will recognize that other elements and/or steps are desired and/or necessary to achieve this invention. However, because such elements and steps are well known in the art, and because they do not necessarily contribute to a better understanding of the invention, discussion of such elements and steps is not provided in this application. The disclosure of this application relates to all such variations and modifications of such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and illustrated in this application are for illustrative purposes only and are not intended to be exclusive or limiting to the description of the invention.

Unless otherwise defined, the technical and scientific terms used in this application have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. This application references various methods and materials known to those skilled in the art. Standard references elucidating general principles of pharmacology include Goodman and Gilman's *The Pharmacological Basis of Therapeutics*, 10th edition, McGraw Hill Companies Inc., New York (2001). This invention can be practiced using any suitable materials and/or methods known to those skilled in the art. However, preferred materials and methods are described. Unless otherwise stated, the materials, reagents, etc., referenced in the following description and examples are commercially available.

The compounds described in this invention are inherently intended to include all their stereochemical isomers. The term "stereochemical isomer" as used above or below defines all possible stereoisomers that a compound of formula (I) and its N-oxide, pharmaceutically acceptable salt, or physiologically functional derivative may have. Unless otherwise stated or indicated, the chemical name of a compound represents a mixture of all possible stereochemical isomers. In particular, the stereocenter may have an R- or S-configuration; substituents on a divalent cyclic (partially) saturated group may have a cis or trans configuration. Compounds containing a double bond may have an E (entgegen) or Z (zusammen) stereochemistry at the double bond. The terms cis, trans, R, S, E, and Z are well known to those skilled in the art.

The stereochemical isomers of the compounds of formula (I) are obviously intended to be included within the scope of this invention. Of particular interest are those compounds of formula (I) that are stereochemically pure.

Following CAS nomenclature conventions, when two stereocenters with known absolute configurations exist in a molecule, the R or S descriptor (based on the Cahn-Ingold-Prelog sequence rule) is assigned to the smallest-numbered chiral center, i.e., the reference center. The configuration of the second stereocenter is represented by the relative descriptors [R*, R*] or [R*, S*], where R* is always designated as the reference center, [R*, R*] indicates centers with the same chirality, and [R*, S*] indicates centers with different chirality. For example, if the smallest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereodescriptor will be S--[R*, S*]. When using "α" and "β": in the ring system with the lowest ring number, the position of the highest-preferred substituent on the asymmetric carbon atom is always assigned to the "α" position in the mean plane determined by the ring system. The position of the highest preferred substituent on another asymmetric carbon atom in the ring system relative to the position of the highest preferred substituent on the reference atom is called "α" if it is on the same side of the mean plane defined by the ring system, or "β" if it is on the other side of the mean plane defined by the ring system.

When a specific stereoisomer is specified, it means that the form is substantially free of other isomers, i.e., less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2%, and most preferably less than 1% of other isomers. Therefore, when a compound of formula (I) is specified, for example, as (R, S), it means that the compound is substantially free of the (S, R) isomer.

The compounds of formula (I) and some intermediate compounds always have at least two stereocenters in their structure, which may result in at least four stereochemically different structures.

Compounds of formula (I) can be synthesized as mixtures of enantiomers, particularly racemic mixtures, which can be separated from each other using resolution methods known in the art. Racemic compounds of formula (I) can be converted to corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or stepwise crystallization, and the enantiomers are released from them by a base. An alternative method for separating the enantiomers of compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of suitable starting materials, provided the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods will preferably use enantiomerically pure starting materials.

The tautomerism of compounds of formula (I) refers to those compounds of formula (I) in which, for example, the enol group is converted to a keto group (keto-enol tautomerism). The tautomerism of compounds of formula (I) or intermediates of the present invention is intended to be included within the scope of the present invention.

The term "alkyl" as used in this application refers to a saturated monovalent hydrocarbon residue containing 1 to 10 carbon atoms, whether unbranched or branched. The term "lower alkyl" refers to a straight-chain or branched hydrocarbon residue containing 1 to 6 carbon atoms. " _C1-10 alkyl" as used in this application refers to an alkyl group consisting of 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term "alkyl" is used as a suffix after another term, such as in "phenylalkyl" or "hydroxyalkyl," it means that the alkyl group as defined above is substituted with one or two substituents selected from another specifically named group. Thus, for example, "phenylalkyl" represents a group R'R"-, where R' is phenyl and R" is an alkylene group as defined in this application, and it should be understood that the phenylalkyl moiety will be connected at the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, and 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly except that R' is aryl. The terms "(hetero)arylalkyl" or "(hetero)arylalkyl" are interpreted similarly except that R' is optionally aryl or heteroaryl.

The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refer to straight-chain or branched hydrocarbon residues containing 1 to 6 carbon atoms, wherein one or more carbon atoms are replaced by one or more halogen atoms.

The term "alkoxy" used in this application refers to -O-alkyl, wherein the alkyl group is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, including their isomers. The term "lower alkoxy" used in this application refers to an alkoxy group having a "lower alkyl" group as defined above. The term " _C1-10 alkoxy" used in this application refers to -O-alkyl, wherein the alkyl group is _C1-10 .

The term “haloalkoxy” or “halolower alkoxy” or “lower haloalkoxy” refers to a lower alkoxy group in which one or more carbon atoms are replaced by one or more halogen atoms.

The term “hydroxyalkyl” used in this application means an alkyl group as defined in this application, wherein one to three hydrogen atoms on different carbon atoms are replaced by hydroxyl groups.

The term “sulfonyl” used in this application means _-SO₂- group.

The terms “alkylsulfonyl” and “arylsulfonyl” used in this application refer to a group of the formula -S(=O) _₂R , wherein R is either alkyl or aryl, and alkyl and aryl are as defined in this application. The term “heteroalkylsulfonyl” used in this application denotes a group of the formula -S(=O) _₂R , wherein R is a “heteroalkyl” as defined in this application.

The term “lower alkyl sulfonamide group” used in this application refers to a group of _the formula -S(=O) _2NR2 , wherein each R is independently hydrogen or _C1-3 alkyl, and lower alkyl is as defined in this application.

The term “carboxyl” used in this application refers to a group of the formula -C(=O) _R2 , wherein each R is independently hydrogen or a _C1-3 alkyl group, and the lower alkyl group is as defined in this application.

The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms. In a particular embodiment, cycloalkyl refers to a monovalent saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. Specific cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclic [2.2.1]heptyl or bicyclic [2.2.2]octyl.

The term "amino" used in this application denotes a group of the formula -NR'R" where R' and R" are independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Alternatively, R' and R" may form a heterocycloalkyl group together with the nitrogen to which they are attached. The term "primary amino" indicates a group in which both R' and R" are hydrogen. The term "secondary amino" indicates a group in which R' is hydrogen and R" is not hydrogen. The term "tertiary amino" indicates a group in which neither R' nor R" is hydrogen. Specific secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, aniline, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine.

The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic system having 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azirzolyl, diazirzolyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiopheneyl, indolyl, isindolyl, isobenzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxolinyl.

The term "heterocyclic alkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic cyclic system having 3 to 9 ring atoms, comprising 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In a particular embodiment, a heterocyclic alkyl is a monovalent saturated monocyclic cyclic system having 4 to 7 ring atoms, comprising 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclic alkyl groups are aziridinyl, ethylene oxide, aziridine, oxadiazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine heptyl, diaziridine heptyl, homopiperazinyl, or oxadiazinyl heptyl. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, or dihydropyranyl.

"Patient" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey, and the terms "patient" and "subject" are used interchangeably in this application.

The term “carrier” used in this disclosure includes carriers, excipients and diluents, and refers to a material, composition or medium, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which participates in carrying or transporting a pharmaceutical agent from one part of an organ or body to another part of an organ or body.

The term "treatment" for a subject refers to the improvement of at least one symptom of the subject's condition. Treatment can be curative, improvement, or at least partial relief of the condition.

Unless otherwise stated, the term “symptom” is used in this disclosure to mean the term disease, condition or illness, and is used interchangeably with it.

The terms “administer,” “administering,” or “administration” used in this disclosure mean the direct administration of a compound or a pharmaceutically acceptable salt or composition thereof to a subject, or the administration of a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition thereof to a subject, which may form an equivalent amount of the active compound in the subject’s body.

The term “optionally substituted” as used in this disclosure means that a suitable substituent can replace a hydrogen atom bonded to carbon, nitrogen, or oxygen. When the substituent is oxo (i.e., =O), the two hydrogen atoms on the atom are replaced by a single O atom. Those skilled in the art will understand that for any group containing one or more substituents, such a group is not intended to introduce any sterically impractical, synthetically infeasible, and/or inherently unstable substitution or substitution pattern. Furthermore, such combinations are permitted only if the combination of substituents and/or variables in any formula presented in this application yields a stable compound or a useful synthetic intermediate, where stability means a reasonably pharmacologically relevant half-life under physiological conditions.

Dosage and administration:

The compounds of the present invention can be formulated into various oral dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, sugar-coated pills, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. The compounds of the present invention are effective when administered via other routes of administration, including continuous (intravenous infusion), local parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), oral, nasal, inhalation, and suppository administration, as well as other routes of administration. Preferred administration is generally oral, using a convenient daily dosing regimen that can be adjusted according to the degree of discomfort and the patient's response to the active ingredient.

One or more compounds of the present invention and their pharmaceutically available salts may be placed together with one or more conventional excipients, carriers, or diluents in the form of pharmaceutical compositions and unit dosage forms. Pharmaceutical compositions and unit dosage forms may consist of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and unit dosage forms may contain any suitable effective amount of active ingredient commensurate with the intended daily dose range. Pharmaceutical compositions may be used as solids, such as tablets or filled capsules, semi-solids, powders, sustained-release formulations, or as liquids, such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration; or as suppositories for rectal or vaginal administration; or as sterile injectable solutions for parenteral use. Typical formulations will contain about 5% to about 95% (w/w) of one or more active compounds. The terms “formulation” or “dosage form” are intended to include solid and liquid formulations of active compounds, and those skilled in the art will understand that, depending on the target organ or tissue and depending on the desired dose and pharmacokinetic parameters, the active ingredient may be present in different formulations.

The term "excipient" as used herein refers to a compound that can be used to prepare a pharmaceutical composition, is generally safe and non-toxic, is not biologically or otherwise undesirable, and includes veterinary and human pharmaceutically acceptable excipients. The compounds of the present invention can be administered alone, but are generally administered in combination with one or more suitable pharmaceutical excipients, diluents, or carriers selected according to the intended route of administration and standard pharmaceutical practice.

"Pharmaceutical acceptable" refers to substances that can be used to prepare pharmaceutical compositions, which are generally safe and non-toxic, neither biologically nor otherwise undesirable, and include substances that are acceptable for veterinary and human pharmaceutical use.

The "pharmaceutically acceptable salt" form of an active ingredient can also initially impart pharmacokinetic properties to the active ingredient that are not present in its non-salt form, and can even positively influence the pharmacodynamics of the active ingredient in terms of its therapeutic activity in vivo. The term "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts that form with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, The salt is formed by camphor sulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions or aluminum ions); or when it coordinates with organic bases (e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.).

Solid dosage forms include powders, tablets, pills, capsules, suppositories, and dispersible granules. Solid carriers can be one or more substances and can also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is typically a finely ground solid, a mixture with the finely ground active ingredient. In tablets, the active ingredient is typically mixed with a carrier in a suitable proportion with the necessary binding capacity and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. In addition to the active ingredient, solid dosage forms may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

Liquid formulations are also suitable for oral administration and include emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid formulations intended to be converted into liquid form shortly before use. Emulsions can be prepared in solution, such as in an aqueous solution of propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing finely crushed active ingredients in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspensions.

The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus or continuous infusion) and can be present in unit doses in ampoules, pre-filled syringes, small-volume infusions, or in multi-dose containers with added preservatives. The composition can take the form of suspensions, solutions, or emulsions in oily or aqueous media, such as solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents, or media include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulations such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers, and/or dispersants. Alternatively, the active ingredient can be in powder form, obtained by aseptic separation of sterile solids or by freeze-drying from a solution, for use prior to preparation with a suitable media (e.g., sterile pyrogen-free water).

The compounds of the present invention can be formulated as ointments, creams, or lotions, or as transdermal patches, for topical application to the epidermis. Ointments and creams can be formulated, for example, with an aqueous or oil-based matrix and with the addition of suitable thickeners and/or gelling agents. Lotions can be formulated with an aqueous or oil-based matrix and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Formulations suitable for topical application in the oral cavity include lozenges containing an active agent in a flavored matrix, typically sucrose and gum arabic or tragacanth; lozenges containing the active ingredient in an inert matrix (such as gelatin and glycerin or sucrose and gum arabic); and mouthwashes containing the active ingredient in a suitable liquid carrier.

The compounds of this invention can be formulated as suppositories for application. First, a low-melting-point wax, such as a mixture of fatty acid glycerides or cocoa butter, is melted and the active ingredient is dispersed uniformly, for example, by stirring. The molten, homogeneous mixture is then poured into a conveniently sized mold, allowing it to cool and solidify.

The compounds of the present invention can be formulated for vaginal application. Carriers, such as vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays, which are also contained in addition to the active ingredients, are known in the art to be suitable.

The compounds of the present invention can be formulated for nasal use. The solution or suspension is applied directly into the nasal cavity by conventional means, such as using a dropper, pipette, or nebulizer. The formulation can be provided in single-dose or multi-dose form. In the case of a dropper or pipette, this can be achieved by the patient administering an appropriate predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by a metering nebulizer pump.

The compounds of the present invention can be formulated for aerosol administration, particularly for respiratory administration, including intranasal administration. The compounds will generally have a small particle size, for example, five (5) micrometers or smaller. Such particle size can be obtained by means known in the art, such as by micronization. The active ingredient is provided in a pressurized package having a suitable propellant, such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant, such as lecithin. The dosage can be controlled by a metering valve. Alternatively, the active ingredient can be provided in dry powder form, for example, a powder mixture of the compound in a suitable powder matrix, such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be present in unit dose form, for example in capsules or chambers packaged in gelatin or blister packs from which the powder can be administered via an inhaler.

Formulations with enteric coatings can be prepared when needed, the enteric coating being suitable for sustained or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient adherence to the treatment regimen is critical. Compounds in transdermal delivery systems are often attached to a skin-adhesive solid support. Compounds of interest can also be combined with a penetration enhancer, such as azone (1-dodecylazacycloheptan-2-one). Sustained-release delivery systems are inserted subcutaneously into the subcutaneous layer via surgery or injection. The subcutaneous implant encapsulates the compound in a lipid-soluble membrane, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.

Suitable formulations, together with drug carriers, diluents, and excipients, are described in Remington: The Science and Practice of Pharmacy 1995, ed. E.W. Martin, Mack Publishing Company, 19th ed., Easton, Pennsylvania. Formulation scientists and technicians can modify the formulations within the teachings of the specification to provide multiple formulations for a particular route of administration without destabilizing the compositions of the present invention or impairing their therapeutic activity.

For example, modifying the compounds of the present invention to make them more soluble in water or other media can be easily accomplished through minor alterations (salt formulation, esterification, etc.), all of which are within the realm of common techniques skilled in the art. Modifying the route of administration and dosing regimen of a particular compound to control its pharmacokinetics in order to obtain the maximum beneficial effect in the patient is also within the realm of common techniques skilled in the art.

The term "therapeuticly effective amount" used in this application refers to the amount required to alleviate the symptoms of an individual's disease. The dosage will be adjusted according to the individual requirements of each specific situation. This dosage can vary over a wide range depending on many factors, such as the severity of the disease being treated, the patient's age and general health, other medications the patient is receiving, the route and form of administration, and the preferences and experience of the physician involved. For oral administration, a daily dose between about 0.01 and about 1000 mg/kg body weight should be appropriate in monotherapy and/or combination therapy. Preferred daily doses are between about 0.1 and about 500 mg/kg body weight, more preferably between 0.1 and about 100 mg/kg body weight, and most preferably between 1.0 and about 15 mg/kg body weight. Therefore, for administration to a 70 kg person, in one embodiment, the dosage range would be from about 70 mg to 0.7 g per day. The daily dose can be administered as a single dose or divided into multiple doses, typically 1 to 5 doses per day. Generally, treatment is started with a smaller dose, which is less than the optimal dose of the compound. Subsequently, the dosage is increased in small increments until the optimal effect for the individual patient is achieved. Those skilled in the art of treating the diseases described in this application can determine the therapeutically effective amount of the compounds described herein for a given disease and patient without excessive experimentation, relying solely on personal knowledge, experience, and the disclosure of this application.

Pharmaceutical formulations are preferably unit dosage forms. In such a form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. A unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, a unit dosage form can be a capsule, tablet, sachets, or lozenge itself, or it can be any of the above dosage forms in appropriate quantities within a packaged format.

Example

The following examples further describe and illustrate specific embodiments within the scope of this invention. The techniques and formulations are generally available in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). This disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of this disclosure to the specific processes described in this application. It should be understood that the examples are provided to illustrate certain implementations and are not intended to limit the scope of this disclosure. It should be further understood that various other implementations, modifications, and equivalents that may be conceived by those skilled in the art can be taken without departing from the spirit of this disclosure and/or the scope of the appended claims.

Melting points were determined using an Electrothermal 2300 melting point apparatus. NMR spectra at 400 MHz (for ^1H ) and 100 MHz (for ^13C ) were obtained using a Bruker Avance 400 spectrometer, referenced to _Me₄Si . Chemical shifts and coupling constants were recorded in ppm and Hz, respectively. Low-resolution atmospheric pressure chemical ionization mass spectra ([M+H]) of the methanol solution intermediates were measured using a ThermoFinnigan Surveyor MSQ mass spectrometer. Thin-layer chromatography was performed on aluminum-backed silica gel plates (Merck 60F ₂₅₄ ), with components visualized by UV light (254 nm) and/or exposure to _I₂ . Column chromatography was performed on silica gel (Merck 230-400 mesh) unless otherwise specified. The alumina used for column chromatography was Merck Alumina 90 (normalized). The final analysis of the tested compounds was performed on an Agilent 1200-6110 LC-MS system under the following conditions: column: Sunfrie C-18, 4.6 × 50 mm; mobile phase: ACN (0.05% TFA) - water (0.05% TFA); gradient: 5% ACN to 95% ACN in 1.0 min, hold for 1.0 min, total 2.5 min; flow rate: 1.8 mL/min; LC detector: UV 214 nm, 254 nm; MS ([M+H]): atmospheric piezoelectric ionization; MS cone voltage: (V) +4000, -3000. All tested compounds were determined to have a purity >95%.

abbreviation

ACN Acetonitrile

aq. Water-based

bd Wide double peak

bs Broad single peak

n-BuLi n-Butyllithium

d Double peaks

DCM (Dichloromethane)

dd Double peaks

ddd Double peaks

dist. (distilled)

DMAP 4-(dimethylamino)pyridine

DMF (Dimethylformamide)

DMSO (Dimethyl sulfoxide)

DPPP 1,3-Bis(diphenylphosphine)propane

dq Double Quadruple Peak

dt Double triple peak

Et ₂ O Diethyl ether

EtOAc (ethyl acetate)

h hours

HPLC (High-Performance Liquid Chromatography)

HOAc Acetic acid

m.p. Melting point

MeOH Methanol

mesyl (methanesulfonyl group)

min

p Five Peaks

pd Five Twin Peaks

q Four Peaks

qt Four or three peaks

r.t. Room temperature

s Single peak

sat. Saturated

sp Seven Peaks

t triple peak

TFA (Trifluoroacetic acid)

TFAA (Trifluoroacetic anhydride)

THF (Tetrahydrofuran)

I. Preparation of representative intermediates of the present invention (6-bromo-2-methoxyquinoline-3-yl)boronic acid (1)

A solution of 2,2,6,6-tetramethylpiperidine (14.4 mL, 84.8 mmol) in THF (100 mL, Na distillation) at -78 °C was treated with n-BuLi (33 mL, 2.5 M, hexane, 82.5 mmol), and the solution was then heated to -20 °C for 20 minutes and cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline (10.0 g, 42.0 mmol) and triisopropyl borate (20.0 mL, 87.2 mmol) in THF (100 mL, Na distillation) was added dropwise, and the solution was stirred at -78 °C for 3 hours to form an orange solution. The solution was then heated to -40 °C and quenched with a saturated aqueous solution of _NH₄Cl (500 mL). The reaction mixture was diluted with water (1 L) and the white precipitate was filtered off, ground with hexane, and dried to give 1 (11.17 g, 94%) as a white solid. ^¹H NMR (DMSO- _d₆ ) δ 8.44 (s, ¹H), 8.15–8.18 (m, ³H), 7.76 (dd, J = 8.8, 2.3 Hz, ¹H), 7.68 (d, J = 8.9 Hz, ¹H), 3.99 (s, ³H). Measured value: [M-OH+OMe] = 296.2

2,6-Diethoxyisonicotinic acid (2)

Sodium (4.08 g, 177 mmol) was added to anhydrous ethanol (75 mL), and after the sodium had completely reacted, the resulting solution was added to 2,6-dichloroisonicotinic acid (5.00 g, 29.6 mmol) in a steel reactor. The mixture was heated to 130 °C for 18 hours, cooled, and evaporated. The residue was dissolved in a minimal amount of water and acidified to pH 3 with 2 M HCl. The solid was filtered and dried to give a white solid, 2 (4.12 g, 66%). ^¹H NMR ( _CDCl₃ ) δ 6.80 (s, 2H), 4.28 (q, J = 6.8 Hz, 2H), 3.85 (br, 1H), 1.36 (s, 3H). Found: [M+H] = 212.2

2,6-Diethoxy-N-methoxy-N-methylisonicotinamide (3)

Oxaloyl chloride (0.73 mL, 8.6 mmol) was added to a suspension of 2 (1.52 g, 7.20 mmol) in DCM (50 mL, anhydrous) and DMF (0.20 mL, 2.6 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (0.77 g, 17.89 mmol) and pyridine (1.92 mL, 23.7 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and a saturated aqueous solution of _NaHCO3 . Column chromatography using a 3:1 hexane:EtOAc solution yielded 3 (1.26 g, 69%). ^¹H NMR ( _CDCl₃ ) δ 6.43 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.59 (br s, 3H), 3.32 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). Measured value: [M+H] = 255.1

1-(2,6-diethoxypyridin-4-yl)-3-(dimethylamino)prop-1-one (4)

    

Vinyl magnesium bromide (14.6 mL 1N THF solution, 14.6 mmol) was added to a solution of 3 (1.23 g, 4.85 mmol) in dry THF (50 mL) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then a solution of 2N dimethylamine in THF (14.6 mL, 29.2 mmol) and water (10 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give a brown oily 4 (1.24 g, 96%). ^¹H NMR ( _CDCl₃ ) δ 6.71 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.26 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H). Measured value: [M+H]＝267.2

N,2,6-Trimethoxy-N-methylisonicotinamide (5)

Oxaloyl chloride (1.34 mL, 15.8 mmol) was added to a suspension of 2,6-dimethoxyisonicotinic acid (2.41 g, 13.2 mmol) and DMF (0.20 mL, 2.6 mmol) in DCM (70 mL) at room temperature. The mixture was stirred for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.6 mmol) and pyridine (3.51 mL, 28.9 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and a saturated aqueous solution of _NaHCO3 . Column chromatography with hexane:EtOAc (2:1) yielded 5 (2.49 g, 83%). ^¹H NMR ( _CDCl3 ) δ 6.47 (s, 2H), 3.93 (s, 6H), 3.58 (br s, 3H), 3.32 (s, 3H). Measured value: [M+H]＝227.2

1-(2,6-Dimethoxypyridin-4-yl)-3-(dimethylamino)prop-1-one (6)

Vinyl magnesium bromide (32 mL 1N THF solution, 32 mmol) was added to a solution of 5 (2.45 g, 10.8 mmol) in dry THF (100 mL) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine (32 mL 2N THF solution, 64 mmol) and water (30 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated, and column chromatography was performed, with impurities eluted with DCM:MeOH (95:5) and DCM:MeOH (9:1) to give an oily solution of 6 (0.81 g, 31%). ^¹H NMR ( _CDCl₃ ) δ 6.74 (s, 2H), 3.95 (s, 6H), 3.06 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.27 (s, 6H). Measured value: [M+H]＝239.1

3-((2,4-dimethoxybenzyl)(methyl)amino)-1-(2,6-dimethoxypyridin-4-yl)prop-1-one (7)

Vinyl magnesium bromide (17.7 mL 1N THF solution, 17.7 mmol) was added to a solution of 5 (2.00 g, 8.84 mmol) in dry THF (30 mL) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then a solution of N-methyl-2,4-dimethoxybenzylamine (4.00 g, 22.0 mmol) in THF (10 mL) and water (10 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give a brown oil, which was subjected to chromatography. The fore fraction was eluted with EtOAc/hexane, and then eluted with EtOAc to give a pale yellow oil 7 (2.27 g, 68%). ^¹H NMR ( _CDCl₃ ) δ 7.13 (d, J = 8.9 Hz, 1H), 6.73 (s, 2H), 6.44–6.41 (m, 2H), 3.59 (s, 6H), 3.88 (s, 3H), 3.53 (s, 3H), 3.50 (s, 2H), 3.12 (t, J = 7.0 Hz, 1H), 2.84 (t, J = 7.0 Hz, 2H), 2.26 (s, 3H). Measured value: [M+H] = 375.3

6-Bromo-3-(2-fluoro-3-methoxybenzyl)-2-methoxyquinoline (8)

To a mixture of 1 (1.50 g, 5.32 mmol) and 2-fluoro-3-methoxybenzyl bromide (5.59 mmol) in 1,2-dimethoxyethane (25 mL), 2 M _Na₂CO₃ solution ( ₅ mL) was added, and the mixture was degassed under _N₂ for 15 min. Then, Pd( _PPh₃ ) _₄ (0.307 g, 0.27 mmol) was added, and the mixture was heated at 90 °C for 4 h. The reaction mixture was cooled to room temperature, water (100 mL) was added, and then extracted with EtOAc (2 × 125 _mL ). The organic layer was washed with brine, dried ( _Na₂SO₄ ), and concentrated to give a yellow residue. Purification by rapid column chromatography using hexane-EtOAc (100:0 to 95:5) yielded a colorless oily residue, which was solidified to give a white powder (1.16 g, 58%). ^¹H NMR ( _CDCl₃ ) δ 7.75 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.01 (dt, J = 8.1, 1.5 Hz, 1H), 6.88 (dt, J = 8.1, 1.5 Hz, 1H), 6.78 (dt, J = 8.1, 1.5 Hz, 1H), 4.09 (s, 3H), 4.05 (s, 2H), 3.90 (s, 3H). Measured value: [M+H] = 376.2

6-Bromo-3-(3-fluorobenzyl)-2-methoxyquinoline (9)

As described above regarding the preparation of 8, 1 was reacted with 3-fluorobenzyl bromide, yielding 9 (88%) as a white solid after chromatography. ^¹H NMR ( _CDCl₃ ) δ 7.77 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 7.52 (br s, 1H), 7.30–7.24 (m, 1H), 7.01 (bd d, J = 7.7 Hz, 1H), 6.96–6.90 (m, 2H), 4.07 (s, 3H), 3.98 (s, 2H). Found value: [M+H] = 346.2

6-Bromo-2-methoxy-3-(3-methylbenzyl)quinoline (10)

As described above regarding the preparation of 8, 1 was reacted with 3-methylbenzyl bromide, yielding 10 (73%) as a white solid after chromatography. ^¹H NMR ( _CDCl₃ ) δ 7.76 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.48 (br s, 1H), 7.21 (dd, J = 7.7, 7.8 Hz, 1H), 7.09–7.02 (m, 3H), 4.08 (s, 3H), 3.99 (s, 2H). Found value: [M+H] = 342.1

6-Bromo-3-(2,3-dimethoxybenzyl)-2-methoxyquinoline (11)

Deoxygenation was achieved by bubbling nitrogen through a stirred mixture of toluene (20 mL) containing product 1 (1.63 g, 5.79 mmol), 2,3- _{dimethoxybenzyl} bromide (1.60 g, 6.95 mmol), and _Cs₂CO₃ (3.78 g, 11.50 mmol) with DMF (10 mL) for 10 minutes. Pd( _PPh₃ ) _₄ (0.33 g, 0.29 mmol) was then added, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 5 hours. The mixture was diluted with EtOAc and washed with water, then with brine. The extract was dried over _Na₂SO₄ and the solvent was removed under reduced pressure. The product was subjected to chromatographic treatment. Elution with 0–4% EtOAc/hexane gave product ₁₁ (1.26 g, 56%) as a white solid, which was crystallized from methanol as colorless microneedles at 93 °C. ^¹H NMR ( _CDCl₃ ) δ 7.72 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 7.44 (br s, 1H), 7.01 (t, J = 7.0 Hz, 1H), 6.86 (dd, J = 8.2, 1.4 Hz, 1H), 6.75 (dd, J = 7.7, 1.4 Hz, 1H), 4.10 (s, 3H), 4.04 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H). Measured value: [M+H] = 388.3

2,5-Dimethylthiophene-3-carboxaldehyde (12)

A solution of 2,5-dimethylthiophene (7.80 g, 69.5 mmol) in DCM (15 mL) and a solution of dichloromethoxymethane (10.40 g, 90.5 mmol) in DCM (15 mL) were simultaneously added to a solution of _TiCl₄ (19.1 mL, 174 mmol) in DCM (20 mL), keeping the solution temperature below 5 °C. The mixture was stirred at 0 °C for 2 hours, heated to room temperature over 30 minutes, and then poured onto ice acidified with concentrated HCl (20 mL). The mixture was partitioned between DCM and water, and the organic layer was washed with water, dried, and evaporated. Kugelrohr distillation (membrane pump, Kugelrohr set to approximately 175 °C) was performed to give a colorless liquid 12 (5.81 g, 60%). ^¹H NMR ( _CDCl₃ ) δ 9.93 (s, ¹H), 7.00 (d, J = 1.1 Hz, ¹H), 2.70 (s, ³H), 2.40 (d, J = 0.4 Hz, ³H). Measured value: [M+H] = 141.1

(6-bromo-2-methoxyquinoline-3-yl)(2,5-dimethylthiophen-3-yl)methanol(13)

A solution of 2,2,6,6-tetramethylpiperidine (1.89 mL, 11.1 mmol) in dry THF (12 mL) was cooled to -40 °C. n-BuLi (4.45 mL, 2.5 N hexane solution, 11.1 mmol) was added, and the solution was stirred at -40 °C for 15 minutes, then cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline (2.20 g, 9.28 mmol) in THF (10 mL) was added dropwise, and the solution was stirred at -78 °C to produce an orange solution for 1.5 hours. Then, a solution of 12 (1.30 g, 9.27 mmol) in THF (10 mL) was added. The mixture was stirred at -78 °C for 3 hours, then acetic acid (1.60 mL, 28.0 mmol) was added, and the solution was warmed to room temperature. The mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Chromatography was performed, and the starting material was eluted with DCM:hexane (1:3), followed by elution with DCM:hexane (1:1) to give a white solid, 13 (1.97 g, 56%). ^¹H NMR ( _CDCl₃ ) δ 7.93 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.4, 2.1 Hz, 1H), 6.51 (d, J = 1.0 Hz, 1H), 6.04 (dd, J = 3.3, 0.8 Hz, 1H), 4.07 (s, 3H), 2.67 (d, J = 3.4 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H). Measured value: [M+H] = 378.2

6-Bromo-3-((2,5-dimethylthiophen-3-yl)methyl)-2-methoxyquinoline (14)

Triethylsilane (6.8 mL, 42.1 mmol) was added to a solution of 13 (1.99 g, 5.26 mmol) and TFA (3.9 mL, 52.5 mmol) in DCM (50 mL) at 0 °C, and the solution was stirred at 0 °C for 0.5 h, followed by stirring at room temperature for 2 h. The solution was cooled to 0 °C, quenched with a saturated aqueous solution of _NaHCO3 , and partitioned between DCM and water. Column chromatography (1:3 DCM:hexane) gave 14 (1.70 g, 89%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.76 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.40 br (s, 1H), 6.42 (s, 1H), 4.10 (s, 3H), 3.83 (s, 2H), 2.39 (s, 3H), 2.31 (s, 3H). Measured value: [M+H] = 362.2

(6-bromo-2-methoxyquinoline-3-yl)(5-methylthiophen-2-yl)methanol(15)

A solution of 2,2,6,6-tetramethylpiperidine (3.5 mL, 20.6 mmol) in dry THF (20 mL) was cooled to -40 °C. n-BuLi (8.0 mL, 2.5 N hexane solution, 20 mmol) was added, and the solution was stirred at -40 °C for 15 minutes, then cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline (4.00 g, 16.8 mmol) in THF (20 mL) was added dropwise, and the orange solution was stirred at -78 °C for 1.5 hours. A solution of 5-methylthiophene-2-carboxaldehyde (1.12 g, 16.8 mmol) in THF (10 mL) was added. The mixture was stirred at -78 °C for 3 hours, then acetic acid (2.9 mL, 50.7 mmol) was added, and the solution was warmed to room temperature. The mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Chromatography was performed, and unreacted starting material was eluted with DCM:hexane (1:3), followed by elution with DCM:hexane (1:1) to give 15 (3.37 g, 55%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 8.00 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.1 Hz, 1H), 6.72 (d, J = 3.4 Hz, 1H), 6.59 (dd, J = 3.4, 1.0 Hz, 1H), 6.18 (s, 1H), 4.07 (s, 3H), 3.03 (bs, 1H), 2.44 (s, 3H). Analytical value: [M+H] = 364.1

6-Bromo-2-methoxy-3-((5-methylthiophen-2-yl)methyl)quinoline (16)

Triethylsilane (13.6 mL, 84 mmol) was added to a solution of 15 (3.75 g, 10.3 mmol) and TFA (7.70 mL, 104 mmol) in DCM (100 mL) at 0 °C. The solution was then stirred at room temperature for 0.5 h and ice water was added. The solution was partitioned between a saturated _NaHCO3 aqueous solution and DCM, and the aqueous fraction was extracted with DCM. The organic fractions were combined and evaporated. Chromatography (1:3 DCM:hexane to 1:1 DCM:hexane) gave 16 (2.83 g, 79%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.78 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.62 (br s, 1H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 6.65 (d, J = 3.3 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H), 4.13 (br s, 2H), 4.10 (s, 3H), 2.44 (s, 3H). Measured value: [M+H] = 348.2

6-Bromo-2-methoxy-3-((2-methoxypyridin-3-yl)methyl)quinolone (17)

A mixture of 1 (1.00 g, 3.55 mmol), 3-(chloromethyl)-2-methoxypyridine (0.68 _g , 4.31 mmol), and _Cs₂CO₃ (2.31 g, 7.09 mmol) in toluene:DMF (60 mL, 2:1) was _degassed under N₂, followed by the addition of Pd( _PPh₃ ) _₄ (0.082 g, 0.071 mmol), and the mixture was heated at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth stopper, and extracted with water (150 mL) and EtOAc (3 × 100 mL). The combined organic layers were washed with brine ( ₁₀₀ mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (9:1) yielded 17 (0.94 g, 74%) as a white solid. ¹ H NMR (CDCl ₃ )δ8.08 (dd, J=5.0, 1.9Hz, 1H), 7.77 (d, J=2.2Hz, 1H), 7.68 (d, J=8.9Hz, 1H), 7.61 (dd, J=8.9, 2.2Hz, 1H), 7. 53 (s, 1H), 7.38 (dd, J=7.2, 1.9Hz, 1H), 6.83 (dd, J=7.2, 5.0Hz, 1H), 4.07 (s, 3H), 3.96 (s, 2H), 3.95 (s, 3H). Actual measured value: [M+H]=359.6.

N-Methoxy-N-methyl-2,3-dihydro-1H-indene-4-carboxamide (18)

DMF (0.426 mL) was added to a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (4.40 g, 27.5 mmol) in DCM (250 mL), followed by dropwise addition of oxaloyl chloride (4.19 g, 33.0 mmol). The reaction mixture was stirred for 1 hour, cooled to 0 °C, and then N,O-dimethylhydroxylamine hydrochloride (2.95 g, 30.3 mmol) and pyridine (7.32 mL, 90.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured onto a saturated aqueous solution of _NaHCO3 (150 mL) and extracted with DCM ( ₃ × 100 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to obtain a pale yellow residue. Crude product 18 (5.64 g, 100%) was used directly for the next step without further purification. ^¹H NMR ( _CDCl₃ ) δ 7.21–7.13 (m, 3H), 3.56 (s, 3H), 3.31 (s, 3H), 2.98–2.91 (m, 4H), 2.11–2.04 (m, 2H). Measured value: [M+H] = 206.5.

1-(2,3-dihydro-1H-inden-4-yl)-3-(dimethylamino)prop-1-one (19)

Vinyl magnesium bromide (1 M THF solution, 57.7 mL, 57.7 mmol) was added to a solution of 18 (5.64 g, 27.5 mmol) in 150 mL THF at 0 °C, and the solution was stirred at 0 °C for 3.5 h. Dimethylamine (2 M THF solution, 57.7 mL, 115.5 mmol) was added to the reaction mixture, followed by water (60 mL). After stirring at room temperature for 30 min, the reaction mixture was concentrated under reduced pressure to obtain a pale brown residue. This residue was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine ₍ 100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a brown oily residue of 19 (5.66 g, 95%). ¹ H NMR (CDCl ₃ )δ7.66 (d, J=7.8Hz, 1H), 7.34 (d, J=7.4Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 3.24 (t, J=7.5Hz, 2H), 3.11 (t, J=7.3Hz, 2H), 2.88 (t, J=7.5Hz, 2H), 2.72 (t, J=7.3Hz, 2H), 2.27 (s, 6H), 2.04 (t, J=7.5Hz, 2H). Actual measured value: [M+H]=218.6.

(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)methanol(20)

A fraction of lithium aluminum hydride (2.13 g, 56.0 mmol) was added to a solution of 2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (5.00 g, 28.0 mmol) in THF (150 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then stirred further at room temperature for 18 h. Water (150 mL) was added to the reaction mixture, which was then extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow oil, 20 (3.22 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 6.87–6.79 (m, 3H), 4.66 (s, 2H), 4.32–4.30 (m, 2H), 4.28–4.25 (m, 2H), 2.19 (bs, 1H). Measured value: [M+H-18] = 149.5.

5-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxin(21)

A solution of 20 (3.75 g, 32.3 mmol) in ether (80 mL) was cooled to 0 °C and phosphorus tribromide (3.67 mL, 38.8 mmol) was added dropwise. The solution was stirred at 0 °C for 10 min, then at room temperature for 1 h. Water (10 mL) was carefully added to quench any excess reagent, and the mixture was diluted with ether and washed with water (3 × 50 mL). The combined organic layers were washed with brine (100 mL ₎ , dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain 21 (4.61 g, 62%) as a brown solid. ^¹H NMR ( _CDCl₃ ) δ 6.91–6.77 (m, 3H), 4.52 (s, 2H), 4.35–4.33 (m, 2H), 4.29–4.27 (m, 2H). Found: [M + H-Br] = 149.5.

6-Bromo-3-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-methoxyquinoline (22)

A mixture of 1 (4.42 g, 15.4 mmol), 21 (4.6 g, 20.0 mmol), and _Cs₂CO₃ (11.54 _g , 0.77 mmol) was degassed in toluene:DMF (60 mL, 2:1) under _N₂ conditions, followed by the addition of Pd( _PPh₃ ) _₄ (0.890 g, 0.77 mmol), and the mixture was heated at 110 °C for ₄ hours. The mixture was cooled to room temperature, filtered through a diatomaceous earth stopper, and extracted with water (150 mL) and EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (9:1) yielded 22 (3.1 g, 52%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.75 (d, J = 2.2 Hz, ¹H), 7.73–7.70 (m, ¹H), 7.61–7.59 (m, ¹H), 7.43 (s, ¹H), 6.84–6.78 (m, 2H), 6.72–6.70 (m, ¹H), 4.27–4.22 (m, 4H), 4.10 (s, 3H), 3.98 (s, 2H). Measured value: [M+H] = 386.6.

3-Benzyl-6-iodo-2-methoxyquinoline (23)

A solution of 3-benzyl-6-bromo-2-methoxyquinoline (3.00 g, 9.14 mmol) in THF (7 mL) was cooled to -78 °C, and then n-BuLi (2 M cyclohexane solution, 5.48 mL, 11.0 mmol) was added to give a deep purple solution. After 60 seconds, iodine (1.74 g, 7.31 mmol) in THF (23 mL) was added, and the red solution was stirred at -78 °C for 10 minutes. Water (20 mL) was added to the resulting solution, which was extracted with EtOAc (3 × 30 mL), dried over _MgSO4 , filtered, and the solvent was evaporated to give an orange oil. MeOH (10 mL) was added to the mixture, and it was sonicated until a white solid was formed. The solid was filtered to give a white solid 23 (1.77 g, 52%). ^¹H NMR ( _CDCl₃ ) δ 7.96 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.8, 2.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.34–7.22 (m, 5H), 4.08 (s, 3H), 4.02 (s, 2H). Measured value: [M+H] = 376.6.

2,6-Bis(ethio)isonicotinic acid (24)

Ethyl mercaptan (3.29 mL, 45.5 mmol) was added dropwise to a suspension of sodium hydride (1.82 g, 45.5 mmol) in DMF (20 mL) at 0 °C. The milky white, foamy solution was stirred at 0 °C for 10 minutes, and 2,6-dichloroisonicotinic acid (3.17 g, 13.0 mmol) from DMF (5 mL) was added dropwise to the solution. The mixture was heated to 50 °C and stirred for 18 hours. Water (40 mL) was added to the resulting solution, and the pH was adjusted to ~3 using 2 M HCl solution. The aqueous solution was extracted with EtOAc (3 × 30 mL), dried over _MgSO₄ , filtered, and the solvent was evaporated to give a yellow solid, 24, which was used in the next step without further purification (2.82 g, 89%). ^¹H NMR ( _CDCl₃ ) δ 7.40 (s, 2H), 3.19 (q, J = 7.3 Hz, 4H), 1.39 (t, J = 7.3 Hz, 6H). Measured value: [M+H] = 244.5.

2,6-Bis(ethylthio)-N-methoxy-N-methylisonicotinamide (25)

DMF (0.206 mL) was added to a solution of 24 (3.24 g, 13.3 mmol) in DCM (150 mL), followed by dropwise addition of oxalyl chloride (1.37 mL, 16.0 mmol). The mixture was stirred at room temperature for 2 hours, then cooled to 0 °C and N,O-dimethylhydroxylamine hydrochloride (1.43 g, 14.6 mmol) was added, followed by _pyridine (3.55 mL, 43.9 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was poured onto saturated _NaHCO3 (150 mL) and extracted with DCM (150 mL) and EtOAc (100 mL). The combined organic phases were dried over _Na2SO4 and concentrated to give a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (1:1) yielded a colorless oily 25 (3.65 g, 96%). ^¹H NMR ( _CDCl₃ ) δ 7.02 (s, 2H), 3.56 (s, 3H), 3.32 (s, 3H), 3.19 (q, J = 7.3 Hz, 4H), 1.37 (t, J = 7.3 Hz, 6H). Measured value: [M+H] = 287.5.

1-(2,6-bis(ethylthio)pyridin-4-yl)-3-(dimethylamino)prop-1-one (26)

Vinyl magnesium bromide (1 MTHF solution, 31.5 mL, 31.5 mmol) was added to a solution of 25 (3.65 g, 12.7 mmol) in 150 mL of THF at 0 °C, and the mixture was stirred at 0 °C for 4 hours. Dimethylamine (2 MTHF solution, 31.5 mL, 63.0 mmol) was added, followed by water (60 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced _pressure to obtain a brown residue. This residue was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give a brown oil. Purification by rapid column chromatography using EtOAc:MeOH (9:1) yielded a yellow oil, 26 (2.51 g, 66%). ^¹H NMR ( _CDCl₃ ) δ 7.24 (s, 2H), 3.20 (q, J = 7.4 Hz, 4H), 3.03 (t, J = 7.1 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 2.26 (s, 6H), 1.38 (t, J = 7.4 Hz, 6H). Measured value: [M+H] = 299.6.

2,6-Bis(methylthio)isonicotinic acid (27)

Sodium methanethiol (4.38 g, 65.5 mmol) was added to a solution of 2,6-dichloroisonicotinic acid (4.00 g, 20.8 mmol) in DMF (40 mL) at 0 °C. The reaction mixture was stirred at 150 °C for 18 hours. Water (40 mL) was added to the resulting solution, and the pH was adjusted to ~3 using 2 M HCl solution. The aqueous solution was extracted with EtOAc (3 × 40 mL), dried over _MgSO4 , filtered, and concentrated under reduced pressure to give 27 as an orange solid, which was recrystallized from methanol (4.01 g, 90%). ^¹H NMR ( _CDCl₃ ) δ 7.44 (s, 2H), 2.61 (s, 6H). Found: [M+H] = 216.5.

N-Methoxy-N-methyl-2,6-bis(methylthio)isonicotinamide (28)

DMF (0.362 mL) was added to a solution of 27 (5.03 g, 23.4 mmol) in DCM (200 mL), followed by dropwise addition of oxaloyl chloride (2.41 mL, 28.0 mmol). The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, and N,O-dimethylhydroxylamine hydrochloride (2.51 g, 25.7 mmol) was added, followed by pyridine (6.22 mL, 77.1 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was poured onto saturated _NaHCO3 (150 mL) and extracted with DCM (150 mL) and EtOAc ( ₁₀₀ mL). The organic phase was dried over _Na2SO4 and concentrated to give a yellow oily 28, which was used in the next step without further purification (4.96 g, 82%). ^¹H NMR ( _CDCl₃ ) δ 7.04 (s, 2H), 3.56 (s, 3H), 3.33 (s, 3H), 2.60 (s, 6H). Measured value: [M+H] = 259.5.

1-(2,6-bis(methylthio)pyridin-4-yl)-3-(dimethylamino)prop-1-one (29)

Vinyl magnesium bromide (1 MTHF solution, 40.3 mL, 40.3 mmol) was added to a solution of 28 (4.96 g, 19.2 mmol) in 90 mL of THF at 0 °C, and the solution was stirred at 0 °C for 1 hour. Dimethylamine (2 MTHF solution, 40.3 mL, 80.6 mmol) was added, followed by water (60 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure to obtain a brown residue. It was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give 29 (4.87 g, 94%) as a brown oil. ^¹H NMR ( _CDCl₃ ) δ 7.26 (s, 2H), 3.04 (t, J = 7.0 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.61 (s, 6H), 2.26 (s, 6H). Measured value: [M+H] = 271.6.

6-Bromo-3-(2-fluoro-3-methylbenzyl)-2-methoxyquinoline (30)

A mixture of 1 (3.00 _g , 10.5 mmol), 1-(bromomethyl)-2-fluoro-3-methylbenzene (4.24 g, 20.9 mmol), and _Cs₂CO₃ (7.87 g, 24.2 mmol) was degassed in _toluene :DMF (60 mL, 2:1) under N₂ conditions, followed by the addition of Pd( _PPh₃ ) _₄ (0.607 g, 0.525 mmol), and the mixture was heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth stopper, and water (150 mL) was added. The mixture was extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (9:1) yielded ₃₀ (2.87 g, 76%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.75 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 7.50 (s, 1H), 7.11–6.96 (m, 3H), 4.09 (s, 3H), 4.03 (s, 2H), 2.28 (d, J = 2.1 Hz, 3H). Measured value: [M+H] = 360.6.

2-Methoxy-6-(methylthio)isonicotinic acid (31)

Lithium hydroxide (0.697 g, 29.1 mmol) was added to a mixture of methyl 2-methoxy-6-(methylthio)isonicotinic acid (WO 2010/036632) (2.07 g, 9.71 mmol) in MeOH:THF: _H₂O (60 mL, 1:1:1). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was washed with EtOAc (50 mL), discarding the EtOAc. 2 M HCl (50 mL) was added to the aqueous layer, which was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 _mL ), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain 31 (1.70 g, 88%) as a white solid. ^¹H NMR (DMSO- _d₆ ) δ 13.67 (s, ¹H), 7.22 (d, J = 0.92 Hz, ¹H), 6.86 (d, J = 0.92 Hz, ¹H), 3.90 (s, ³H), 2.55 (s, ³H). Measured value: [M+H] = 200.5.

N,2-Dimethoxy-N-methyl-6-(methylthio)isonicotinamide (32)

DMF (0.13 mL) was added to a solution of 31 (1.70 g, 8.53 mmol) in DCM (200 mL), followed by dropwise addition of oxalyl chloride (0.88 mL, 10.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and N,O-dimethylhydroxylamine hydrochloride (0.915, 9.38 mmol) was added, followed by _pyridine (2.27 mL, 28.2 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was poured onto saturated _NaHCO3 (150 mL) and extracted with DCM (150 mL) and EtOAc (100 mL). The combined organic phases were dried over _Na2SO4 and concentrated to give a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (4:1) yielded a yellow oily 32 (2.07 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 6.93 (d, J = 0.72 Hz, ¹H), 6.59 (s, ¹H), 3.97 (s, ³H), 3.57 (s, ³H), 3.32 (s, ³H), 2.57 (s, ³H). Measured value: [M+H] = 243.5.

3-(dimethylamino)-1-(2-methoxy-6-(methylthio)pyridin-4-yl)prop-1-one (33)

Vinyl magnesium bromide (1 MTHF solution, 17.9 mL, 17.9 mmol) was added to a solution of 32 (2.07 g, 8.54 mmol) in 100 mL of THF at 0 °C, and the solution was stirred at 0 °C for 3 hours. Dimethylamine (2 MTHF solution, 17.9 mL, 35.9 mmol) was added, followed by water (40 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure to obtain a brown residue. This residue was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give a brown oily 33 (2.17 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 7.19 (d, J = 1.2 Hz, 1H), 6.82 (d, J = 1.1 Hz, 1H), 3.98 (s, 3H), 3.04 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.58 (s, 3H), 2.27 (s, 6H). Measured value: [M+H] = 255.6.

2-(difluoromethoxy)-6-methoxyisonicotinic acid methyl ester (34)

Sodium dichlorofluoroacetate (7.50 g, 49.2 mmol) and _K₂CO₃ (2.73 g, 21.3 mmol) were added to a solution of methyl 2-hydroxy- ₆ -methoxyisonicotinic acid (WO 2009/083553) (3.00 g, 16.4 mmol) in DMF (40 mL). The reaction mixture was stirred at 80 °C for 72 h, washed with water (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (1:1) gave 34 (2.02 g, 52%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.40 (t, J = 73.0, ¹H), 7.10 (d, J = 1.0 Hz, ¹H), 7.00 (d, J = 1.0 Hz, ¹H), 3.94 (s, ³H), 3.93 (s, ³H). Measured value: [M+H] = 234.5.

2-(difluoromethoxy)-6-methoxyisonicotinic acid (35)

Lithium hydroxide (0.62 g, 26.0 mmol) was added to a solution of 34 (2.02 g, 8.66 mmol) in MeOH:THF: _H₂O (60 mL, 1:1:1), and the reaction mixture was stirred at room temperature for 72 hours. The solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was washed with EtOAc (50 mL), discarding the EtOAc. 2 M HCl (50 mL) was added to the aqueous layer, which was then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine ( ₁₀₀ mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain 35 (1.90 g, 99%) as a white solid. ^¹H NMR (DMSO- _d₆ ) δ 13.85 (bs, ¹H), 7.76 (t, J = 72.5 Hz, ¹H), 7.03 (d, J = 0.96 Hz, ¹H), 6.95 (d, J = 0.92 Hz, ¹H), 3.91 (s, ³H). Measured value: [M+H] = 220.6.

2-(difluoromethoxy)-N,6-dimethoxy-N-methylisonicotinamide (36)

DMF (4.83 mL, 34.7 mmol) was added to a solution of 35 (1.70 g, 8.53 mmol), hydroxybenzotriazole (1.29 g, 9.54 mmol), N,O-dimethylhydroxylamine hydrochloride (1.27 g, 13.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.48 g, 9.54 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water (100 mL) and extracted with DCM (3 × 50 mL). The organic phase was dried over _Na₂SO₄ and concentrated to give a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (1:1) gave _a yellow oily residue 36 (1.85 g, 81%). ^¹H NMR ( _CDCl₃ ) δ 7.41 (t, J = 73.1 Hz, 1H), 6.73 (d, J = 0.68 Hz, 1H), 6.65 (d, J = 0.64 Hz, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.34 (s, 3H). Measured value: [M+H] = 263.5.

1-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-3-(dimethylamino)prop-1-one (37)

Vinyl magnesium bromide (1 MTHF solution, 14.8 mL, 14.8 mmol) was added to a solution of 36 (1.85 g, 7.06 mmol) in 100 mL of THF at 0 °C, and the solution was stirred at 0 °C for 3 hours. Dimethylamine (2 MTHF solution, 14.8 mL, 29.7 mmol) was added, followed by water (40 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure to obtain a brown residue. This residue was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give _a brown oily residue of 37 (1.92 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 7.40 (t, J = 73.0 Hz, 1H), 6.97 (d, J = 1.1 Hz, 1H), 6.89 (d, J = 1.1 Hz, 1H), 3.95 (s, 3H), 3.07 (t, J = 7.0 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.27 (s, 6H). Measured value: [M+H] = 275.6.

(2,6-bis(methylthio)pyridin-4-yl)methanol(38)

Borane dimethyl sulfide complex (8.09 mL, 85.3 mmol) was added to a solution of 27 (6.12 g, 28.4 mmol) in THF (100 mL, Na distillation) at 0 °C, followed by trimethyl borate (9.68 mL, 85.3 mmol). The reaction mixture was heated to room temperature and stirred for 21 hours. The reaction mixture was cooled to 0 °C, MeOH (50 mL) was added to quench the reaction _, and the solvent was removed under reduced pressure. The residue was washed with water (100 mL), extracted with EtOAc (3 × 50 mL), and the organic phase was dried over _Na₂SO₄ and concentrated to give a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (4:1) gave 38 (4.56 g, 80%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 6.87 (t, J = 0.7 Hz, 2H), 4.61 (s, 2H), 2.58 (s, 6H). Measured value: [M+H] = 202.5.

4-(bromomethyl)-2,6-bis(methylthio)pyridine (39)

Phosphorus tribromide (2.97 mL, 31.4 mmol) was added to a solution of 38 (5.26 g, 26.1 mmol) in DCM (300 mL) at 0 °C. The reaction mixture was stirred at room temperature for 18 hours and the solvent was removed under reduced pressure. The residue was diluted with DCM (100 mL) and quenched with ice water (100 mL). The organic phase was then washed with a saturated aqueous solution of _NaHCO3 , dried over _{Na2SO4 ,} and concentrated to give a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (6:1) yielded a white solid, 39 (3.44 g, 50%). ^¹H NMR ( _CDCl3 ) δ 6.86 (s, 2H), 4.23 (s, 2H), 2.58 (s, 6H). Analytical value: [M+H] = 264.4.

3-((2,6-bis(methylthio)pyridin-4-yl)methyl)-6-bromo-2-methoxyquinoline (40)

A mixture of 1 (4.31 g, 15.0 mmol), 39 (3.44 g, 15.0 mmol), and _Cs₂CO₃ (11.24 _g , 34.5 mmol) in toluene:DMF (60 mL, 2:1) was degassed under _N₂ , then Pd( _PPh₃ ) _₄ (0.867 g, 0.75 mmol) was added and the mixture was heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth stopper, water (150 mL) was added, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine ( ₁₀₀ mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (9:1) gave 40 (2.91 g, 46%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.80 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.72 (s, 2H), 4.05 (s, 3H), 3.87 (s, 2H), 2.57 (s, 6H). Measured value: [M+H] = 421.8.

(2,3-Dihydro-1H-inden-4-yl)methanol(41)

Aliquots of lithium aluminum hydride (8.09 mL, 85.3 mmol) were added to a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (6.12 g, 28.4 mmol) in THF (100 mL, Na distillation) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then stirred further at room temperature for 24 h. The reaction mixture was washed with water (100 mL) and extracted with EtOAc (3 × 50 mL). The organic phase was dried _{over Na₂SO₄} and concentrated under reduced pressure to obtain a yellow oil, 41 (2.45 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 7.22–7.12 (m, 3H), 4.67 (s, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.09 (p, J = 7.6 Hz, 2H). Measured value: [M+H-18]＝131.5.

4-(chloromethyl)-2,3-dihydro-1H-indene (42)

Thionyl chloride (2.45 g, 16.5 mmol) was added to a solution of 41 (4.33 g, 36.4 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 24 hours and the solvent was removed under reduced pressure. The residue was diluted with DCM (100 mL) and quenched with ice water (100 mL). The organic phase was washed with a saturated aqueous solution of _NaHCO3 , dried over _Na2SO4 , and concentrated to give a yellow residue. 42 (2.36 g, 86%) was purified by rapid column chromatography using hexane:EtOAc (1:1) to give _a colorless oil. ^¹H NMR ( _CDCl3 ) δ 7.22–7.13 (m, 3H), 4.59 (s, 2H), 2.99 (t, J = 7.5 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.11 (p, J = 7.6 Hz, 2H). Measured value: [M+H]＝167.5.

6-Bromo-3-((2,3-dihydro-1H-inden-4-yl)methyl)-2-methoxyquinoline (43)

A mixture of 1 (3.69 g, 12.9 mmol), 42 (2.36 g, 14.2 mmol), and _Cs₂CO₃ (9.67 _g , 29.7 mmol) in toluene:DMF (60 mL, 2:1) was degassed under _N₂ , then Pd( _PPh₃ ) _₄ (0.745 g, 0.645 mmol) was added and the mixture was heated at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth stopper, water (150 mL) was added, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (9:1) yielded _a yellow oily 43 (4.70 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 7.71 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 7.33 (s, 1H), 7.18–7.11 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 4.11 (s, 3H), 3.98 (s, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H). Measured value: [M+H] = 368.5.

(5,6,7,8-Tetrahydronaphth-1-yl)methanol(44)

Aliquots of lithium aluminum hydride (2.46 g, 64.7 mmol) were added to a solution of 1-tetrahydronaphthoic acid (5.70 g, 32.3 mmol) in THF (100 mL, Na distillation) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then stirred at room temperature for an additional 24 h. The reaction mixture was washed with water (100 mL) and extracted with EtOAc (3 × 50 mL). The organic phase was dried _{over Na₂SO₄} and concentrated under reduced pressure to obtain a colorless oil, 44 (5.23 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 7.18 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.67 (s, 2H), 2.80 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.88–1.77 (m, 4H). Measured value: [M + H - 18] = 145.5.

5-(chloromethyl)-1,2,3,4-tetrahydronaphthalene (45)

Thionyl chloride (8.45 g, 71.1 mmol) was added to a solution of 44 (5.24 g, 32.3 mmol) in DCM (200 mL) at 0 °C. The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed under reduced pressure. The residue was diluted with DCM (100 mL) and quenched with ice water (100 mL). The organic phase was washed with a saturated aqueous solution of _NaHCO3 , dried over _{Na2SO4 ,} and concentrated to give 45 (3.25 g, 56%) as a brown oil. ^¹H NMR ( _CDCl3 ) δ 7.16–7.05 (m, 3H), 4.59 (s, 2H), 2.86 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 1.88–1.77 (m, 4H). Found: [M+H] = 181.6.

6-Bromo-2-methoxy-3-((5,6,7,8-tetrahydronaphth-1-yl)methyl)quinolone (46)

A mixture of 1 (4.69 g, 16.4 mmol), 45 (3.25 g, 18.0 mmol), and _Cs₂CO₃ (12.29 _g , 37.7 mmol) in toluene:DMF (60 mL, 2:1) was degassed under _N₂ , then Pd( _PPh₃ ) _₄ (0.948 g, 0.82 mmol) was added and the mixture was heated at 90 °C for 3 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth stopper, water (150 mL) was added, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine ( ₁₀₀ mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Purification by rapid column chromatography using hexane:EtOAc (9:1) gave 46 (4.64 g, 74%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.71–7.69 (m, 2H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 7.23 (s, 1H), 7.12–7.04 (m, 2H), 6.92 (d, J = 6.9 Hz, 1H), 4.11 (s, 3H), 3.96 (s, 2H), 2.83 (bs, 2H), 2.57 (bs, 2H), 1.76 (p, J = 3.5 Hz, 4H). Measured value: [M+H] = 382.1.

6-Fluoro-N-methoxy-N-methylnicotinamide (47)

Eight drops of anhydrous DMF were added to a suspension of 6-fluoronicotinic acid (2.00 g, 14.20 mmol) in anhydrous DCM (56 mL) under a nitrogen stream. Oxaloyl chloride (1.4 mL, 17.0 mmol) was added slowly. Effervescence was observed throughout the addition. The resulting mixture was stirred at room temperature for 1.5 h until it became clear. The mixture was cooled to 2 °C, and N,O-dimethylhydroxylamine hydrochloride (1.52 g, 15.60 mmol) was added, followed by anhydrous pyridine (2.5 mL, 31.2 mmol). The mixture was stirred from 2 °C to room temperature overnight. The mixture was treated with a saturated aqueous solution _{of NaHCO3} until gas escaping ceased. The organic layer was collected. The aqueous phase was further extracted with EtOAc (2×). The organic extract was washed with brine, dried ( _MgSO4 ), and concentrated under vacuum to provide the crude product. Rapid chromatography of the crude product using 1–3% MeOH in DCM as eluent yielded a pale brown oily 47. Yield = 1.96 g, 75%. ^¹H NMR ( _CDCl₃ ) δ 8.66 (¹H, d, J = 2.4 Hz), 8.19 (¹H, ddd, J = 2.4, 3.6, 8.8 Hz), 7.0 (¹H, ddd, J = 0.4, 2.8, 8.8 Hz), 3.57 (³H, s), 3.40 (³H, s).

6-(diethylamino)nicotinaldehyde (48)

A solution of 47 (2.13 g, 11.60 mmol) and diethylamine (2.4 mL, 23.20 mmol) in anhydrous acetonitrile (12 mL) was loaded into a glass pressure tube. The mixture was sealed in the tube and refluxed for 3 hours. The solvent was removed, and the residue was treated with a saturated aqueous solution _{of NaHCO3} and extracted with DCM (5×). The combined extracts were washed with brine, dried ( _MgSO4 ), and concentrated to give a brown oily crude product. ^¹H NMR analysis of the crude product showed that the product and starting material were mixed in a 10:7 ratio. The mixture was subjected to the above reaction conditions again and allowed to react overnight. After the above procedure, a brown oily crude product (2.58 g) was obtained, which was used directly in the next step. ^¹H NMR analysis confirmed the production of the diethylaminopyridine intermediate and its purity. ^¹H NMR ( _CDCl₃ ) δ 8.70 (¹H, d, J = 2.4 Hz), 7.90 (¹H, dd, J = 2.4, 9.1 Hz), 6.44 (¹H, d, J = 9.1 Hz), 3.62 (³H, s), 3.56 (⁴H, q, J = 7.1 Hz), 3.35 (³H, s), 1.20 (⁶H, t, J = 7.1 Hz). The intermediate adduct (2.58 g) was dissolved in freshly distilled THF (40 mL). Lithium aluminum hydride (0.31 g, 8.15 mmol) was added to the solution in a single step under nitrogen atmosphere at -78 °C. The mixture was maintained at -78 °C for 30 min, then at 2 °C for 75 min. The mixture was quenched dropwise with water until gas escape stopped. 1 M sodium hydroxide solution (16 mL) was added, and the resulting yellow mixture was stirred for 30 min. The aqueous mixture was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried ( _MgSO4 ), and concentrated under vacuum to give a yellow oily crude product. Rapid chromatography was performed on the crude product using a 4:1, then 3:1 hexane/EtOAc mixture as eluent to give a colorless oily product 48. Yield = 1.42 g, 75%. ^¹H NMR ( _CDCl3 ) δ 9.74 (¹H, d, J = 0.3 Hz), 8.53 (¹H, dd, J = 0.04, 2.3 Hz), 7.88 (¹H, dd, J = 0.4, 2.3 Hz), 6.51 (¹H, d, J = 9.2 Hz), 3.60 (4H, q, J = 7.0 Hz), 1.23 (6H, t, J = 7.1 Hz). Found: [M+H] = 179.6

(6-Bromo-2-methoxyquinoline-3-yl)(6-(diethylamino)pyridin-3-yl)methanol(49)

n-BuLi (4.4 mL, 8.760 mmol) was added to a freshly distilled solution of 2,2,6,6-tetramethylpiperidine (1.6 mL, 9.557 mmol) in freshly distilled THF (13 mL) under nitrogen atmosphere at -30 °C. The mixture was maintained at approximately -30 °C for 15 minutes, then cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline (1.90 g, 7.964 mmol) in dry THF (15 mL) was added dropwise at -78 °C, and the mixture was stirred at this temperature for 75 minutes. A solution of 48 (1.42 g, 7.964 mmol) in dry THF (6 mL) was added dropwise at -78 °C, the reaction mixture was kept orange-brown and stirred at -78 °C for 2.5 hours. The mixture was quenched with acetic acid (0.68 mL) at -65 °C. Water was added, and the aqueous mixture was extracted with EtOAc (2×). The combined extracts were washed with brine, dried ( _MgSO₄ ), and concentrated under vacuum to give a crude product as a yellow solid. Rapid chromatography was performed on the product using 10-100% EtOAc in hexane as eluent to give product 49 as a creamy white solid. Yield = 1.90 g, 57%. ¹ H NMR (CDCl ₃ ) δ 8.15 (1H, d, J = 2.4Hz), 8.01 (1H, s), 7.88 (1H, d, J = 2.1Hz), 7.69 (1H, d, J = 8.9Hz), 7.65 (1H, dd, J = 2.1, 9.0Hz), 7.40 (1H, dd, J = 2.5, 9.0 Hz), 6.42 (1H, d, J = 8.9Hz), 5.94 (1H, d, J = 3.7Hz), 4.04 (3H, s), 3.50 (4H, dq, J = 1.7, 7.1Hz), 2.65 (1H, d, J = 3.9Hz), 1.17 (6H, t, J = 7.0Hz).

5-((6-bromo-2-methoxyquinoline-3-yl)methyl)-N,N-diethylpyridin-2-amine (50)

Sodium borohydride (0.86 g, 23.0 mmol) was added in three portions over 10 minutes to a solution of 49 (1.90 g, 4.56 mmol) in freshly distilled THF (19 mL). The mixture was stirred at 2–4 °C for 1 hour. The mixture was cooled again to 2 °C and aluminum trichloride (1.83 g, 13.70 mmol) was added in four batches over 15 minutes. The mixture was stirred at 2 °C for 10 minutes and then refluxed for 2 hours. The mixture was then carefully quenched with water at 2 °C until gas escape stopped. The white slurry was filtered through diatomaceous earth. The milky filtrate was diluted in water and the organic phase was collected. The aqueous phase was extracted with EtOAc (3×). The organic extract was washed with brine, dried ( _MgSO4 ), and concentrated under vacuum to provide a crude product as a brown residue. The crude product was subjected to rapid chromatography using 10% EtOAc in hexane as eluent to give product 50 as a white solid. Yield = 1.39 g, 76%. ^¹H NMR ( _CDCl₃ ) δ 8.06 (¹H, d, J = 2.1 Hz), 7.75 (¹H, d, J = 2.2 Hz), 7.68 (¹H, d, J = 8.8 Hz), 7.60 (¹H, dd, J = 2.2, 8.8 Hz), 7.52 (¹H, s), 7.27 (¹H, dd, J = 2.4, 8.7 Hz), 6.43 (¹H, dd, J = 0.3, 8.7 Hz), 4.09 (³H, s), 3.85 (²H, s), 3.50 (⁴H, q, 7.0 Hz), 1.18 (⁶H, t, J = 7.0 Hz). Measured value: [M+H] = 400.8

2,3-Difluoroisonicotinic acid (51)

N,N-diisopropylamine (7.30 mL, 52.09 mmol) and 2,3-difluoropyridine (5.00 g, 43.41 mmol) were added sequentially to a solution of n-BuLi (26.1 mL, 52.09 mmol) in THF (70 mL, Na distillation) at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour and then poured onto crushed dry ice (excess). The reaction was heated to room temperature for 1 hour, and after evaporation of excess dry ice and THF, the residue was added to water (100 mL) and washed with EtOAc (2 × 50 mL). The aqueous layer was then acidified to pH 1 and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried and evaporated to give product 51. Yield = 2.39 g, 35%. ^¹H NMR ( _CDCl₃ ) δ 15.3–13.2 (¹H, br s), 8.14 (¹H, dd, J = 1.2, 5.0 Hz), 7.70 (¹H, dd, J = 4.8, 4.8 Hz). Measured value: [MH] = 158.5.

3-Fluoro-2-methoxyisonicotinic acid (52)

Sodium (0.79 g, 33.09 mmol) was added fractionally to MeOH (60 mL) over 0.5 h. Then 51 (2.39 g, 15.04 mmol) was added and the reaction was refluxed for 2 h. The solution was cooled and the solvent was evaporated. The residue was added to water (100 mL) and washed with EtOAc (2 × 50 mL). The aqueous layer was then acidified to pH 1 and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried and evaporated to give product 52. Yield = 2.23 g, 87%. ^¹H NMR (DMSO- _d₆ ) δ 14.6–12.8 (¹H, brs), 8.05 (¹H, d, J = 5.2 Hz), 7.28 (¹H, dd, J = 4.7, 4.9 Hz), 3.97 (³H, s). Found: [MH] = 170.5.

(3-Fluoro-2-methoxypyridin-4-yl)methanol (53)

Borane-dimethyl sulfide complex (2.47 mL, 26.07 mmol) and trimethyl borate (2.96 mL, 26.07 mmol) were added to a solution of 52 (13.03 mmol) in THF (80 mL, Na distillation) at 0 °C, and the solution was heated to room temperature and stirred overnight. The mixture was then cooled to 0 °C and quenched with methanol (10 mL). The solvent was then evaporated and the residue was partitioned between EtOAc and water. The organic layer was then dried and evaporated to give product 53. Yield = 1.89 g, 92%. ^¹H NMR ( _CDCl₃ ) δ 7.92 (¹H, d, J = 5.2 Hz), 7.02 (¹H, dd, J = 4.5, 5.1 Hz), 4.81 (²H, s), 4.03 (³H, s). Found: [M+H] = 158.5.

4-(bromomethyl)-3-fluoro-2-methoxypyridine (54)

At room temperature, methanesulfonyl chloride (1.12 mL, 14.44 mmol) was added dropwise to a solution of 53 (1.89 g, 12.03 mmol) and triethylamine (2.52 mL, 18.05 mmol) in DCM (30 mL, anhydrous). After 15 minutes, the reaction was diluted with DCM (20 mL), and the organic layer was washed with saturated _NaHCO3 , dried, and evaporated. The residue was dissolved in acetone (60 mL, anhydrous), lithium bromide (excess) was added, and the mixture was heated under reflux for 30 minutes. The solution was then cooled and the solvent was evaporated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the organic layer was dried and evaporated to give product 54. Yield = 2.20 g, 83%. ^¹H NMR ( _CDCl₃ ) δ 7.90 (¹H, d, J = 5.2 Hz), 6.90 (¹H, dd, J = 4.8, 4.9 Hz), 4.43 (²H, s), 4.02 (³H, s). Measured value: [M+H] = 220.2

6-Bromo-3-((3-fluoro-2-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (55)

The mixture of 1 (2.56 g, 9.09 mmol), 54 (2.20 g, 10.00 mmol), and cesium carbonate (5.92 g, 18.18 mmol) in toluene (45 mL, anhydrous) and DMF (22.5 mL, anhydrous) was purged with nitrogen. Then, Pd( _PPh3 ) ₄ (0.42 g, 0.363 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 4 hours under nitrogen. The reaction was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (19:1 hexane/EtOAc) gave product 55. Yield = 1.76 g, 51%. ^¹H NMR ( _CDCl₃ ) δ 7.82 (¹H, d, J = 5.2 Hz), 7.79 (¹H, d, J = 2.1 Hz), 7.69 (¹H, d, J = 8.8 Hz), 7.64 (¹H, dd, J = 2.2, 8.9 Hz), 7.60 (¹H, s), 6.69 (¹H, dd, J = 4.8, 5.0 Hz), 4.07 (³H, s), 4.06 (²H, s), 4.03 (³H, s). Measured value: [M+H] = 377.2

(2,6-Dimethoxypyridin-3-yl)boronic acid (56)

n-BuLi (43.10 mL, 86.21 mmol) was added dropwise to a solution of 2,6-dimethoxypyridine (10 g, 71.84 mmol) and N,N-diisopropylamine (0.50 mL, 3.59 mmol) in THF (200 mL, Na distillation) at -40 °C under nitrogen atmosphere. The resulting solution was stirred at -40 °C for 5 min, then heated to 0 °C and stirred further at this temperature for 3 h. The solution was then cooled again to -40 °C, and triisopropyl borate (24.87 mL, 107.76 mmol) was added dropwise, and the mixture was stirred at room temperature for an additional 1 h. Water (50 mL) was added and the solvent was removed under vacuum. 1 M NaOH (100 mL) was added to the residue, and the aqueous layer was washed with EtOAc (2 × 100 mL). The aqueous layer was then acidified to pH 3, and a solid precipitated. The solid was filtered and dried to give product 56. Yield = 8.10 g, 61%. ^¹H NMR (DMSO- _d₆ ) δ 7.87 (¹H, d, J = 7.9 Hz), 6.36 (¹H, d, J = 7.9 Hz), 3.90 (³H, s), 3.87 (³H, s).

2,6-Dimethoxypyridine-3-ol (57)

32% peracetic acid (21.53 mL, 86.98 mmol) was added dropwise to a solution of 56 (8.00 g, 43.49 mmol) in THF (150 mL, Na distillation) at 0 °C for 10 minutes. The resulting solution was stirred at room temperature for 2 hours. Then, 75 mL of 10% sodium sulfite solution was added and the mixture was stirred at room temperature for 0.5 hours. The solvent was evaporated and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice and the organic layer was dried and evaporated. Column chromatography with 9:1 hexane/EtOAc gave product 57. Yield = 6.05 g, 90%. ^¹H NMR ( _CDCl₃ ) δ 7.12 (¹H, d, J = 8.3 Hz), 6.21 (¹H, d, J = 8.2 Hz), 4.90 (¹H, s), 7.00 (³H, s), 3.86 (³H, s). Measured value: [M+H]＝156.7.

3-(ethoxymethoxy)-2,6-dimethoxypyridine (58)

At 0 °C, 60% sodium hydride (41.97 g, 9.16 mmol) in mineral oil was added in portions to a solution of 57 (6.45 g, 40.97 mmol) in DMF (70 mL, anhydrous). The mixture was heated to room temperature and stirred for 1 hour. Then, 1-chloro-2-methoxyethane (4.37 mL, 47.11 mmol) was added, and the resulting mixture was stirred further at room temperature for 2 hours. The reaction mixture was diluted with brine (100 mL) and extracted three times with EtOAc. The organic layer was washed three times with brine, dried, and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 58. Yield: 8.14 g, 93%. ¹ H NMR (CDCl ₃ )δ7.41-7.33 (1H, m), 6.26-6.17 (1H, m), 5.15 (2H, d, J = 1.9Hz), 3.98 (3H, d, J = 1.8H z), 3.87 (3H, d, J=2.0Hz), 3.77 (2H, dq, J=1.8, 7.1Hz), 1.22 (3H, dt, J=2.9, 7.0Hz).

3-Hydroxy-2,6-dimethoxyisonicotinic acid (59)

n-BuLi (17.43 mL, 34.86 mmol) was added dropwise to a solution of 58 (4.95 g, 23.24 mmol) and N,N-diisopropylamine (0.16 mL, 1.16 mmol) in THF (80 mL, Na distillation) under nitrogen atmosphere at -40 °C. The resulting solution was stirred at -40 °C for 5 min, then heated to 0 °C and stirred further at this temperature for 3 h. The solution was then cooled again to -40 °C and dry ice (20 g, excess) was added, and the mixture was stirred at room temperature for another 1 h. Water (25 mL) was added and the solvent was removed under vacuum. 1 M NaOH (100 mL) was added to the residue and the aqueous layer was washed with EtOAc (2 × 100 mL). The aqueous layer was then acidified to pH 1 with concentrated hydrochloric acid and a solid was precipitated. This solid was filtered and dried to give product 59. Yield = 3.85 g, 83%. ^¹H NMR (DMSO- _d₆ ) δ 6.52 (¹H, s), 3.90 (³H, s), 3.79 (³H, s). Measured value: [M+H] = 200.5.

2,3,6-Trimethoxyisonicotinic acid methyl ester (60)

A mixture of 59 (3.85 g, 19.34 mmol) and potassium carbonate (10.70 g, 7.39 mmol) in DMF (100 mL, anhydrous) was heated at 50 °C for 15 min. Iodomethane (3.61 mL, 58.03 mmol) was then added, and the mixture was stirred at this temperature for 2 h. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated. Column chromatography with 9:1 hexane/EtOAc gave product 60. Yield = 3.63 g, 96%. ^¹H NMR ( _CDCl₃ ) δ 6.51 (¹H, s), 4.01 (³H, s), 3.92 (³H, s), 3.89 (³H, s), 3.83 (³H, s).

2,3,6-Trimethoxyisonicotinic acid (61)

A solution of 60 (3.60 g, 55.86 mmol) in 1 M NaOH (100 mL) was heated at 50 °C for 2 h. The reaction was cooled and washed with EtOAc (2 × 50 mL). The aqueous layer was then acidified to pH 1, and the solid was filtered and dried to give product 61. Yield = 3.04 g, 90%. ^¹H NMR (DMSO- _d₆ ) δ 14.3–12.2 (¹H, br s), 6.42 (¹H, s), 3.93 (³H, s), 3.83 (³H, s), 3.69 (³H, s). Found: [M+H] = 214.5

N,2,3,6-Tetramethoxy-N-methylisonicotinamide (62)

Oxaloyl chloride (1.46 mL, 16.90 mmol) was added to a solution of 61 (3.00 g, 14.08 mmol) in DCM (60 mL, anhydrous) and DMF (0.22 mL, 2.82 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated and the residue was washed with benzene (2 × 50 mL). The residue was redissolved in DMF (60 mL, anhydrous) and cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.49 mmol) and pyridine (3.75 mL, 46.46 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours, then partitioned between EtOAc and a saturated aqueous solution of _NaHCO3 . Column chromatography with 9:1 hexane/EtOAc gave product 62. Yield = 2.89 g, 80%. ^¹H NMR ( _CDCl₃ ) δ 6.18 (¹H, s), 4.01 (³H, s), 3.89 (³H, s), 3.80 (³H, s), 3.60–3.47 (³H, br s), 3.42–3.26 (³H, s). Measured value: [M+H] = 257.6.

3-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)prop-1-one (63)

Vinyl magnesium bromide in THF (1N, 22.13 mL, 22.13 mmol) was added to a solution of 62 (2.70 g, 10.54 mmol) in THF (80 mL, Na distillation) at 0 °C, and the yellow/orange solution was then heated to room temperature for 1 hour. Dimethylamine in THF (2N, 22.13 mL, 44.27 mmol) was added, followed by water (30 mL). The solution was stirred at room temperature for 1 hour, the solvent was removed under vacuum, and the resulting mixture was then partitioned between EtOAc and water. The solution was dried and evaporated to give product 63. Yield = 2.81 g, 99%. ^¹H NMR ( _CDCl₃ ) δ 6.32 (¹H, s), 4.01 (³H, s), 3.89 (³H, s), 3.81 (³H, s), 3.08 (²H, t, J = 7.2 Hz), 2.68 (²H, t, J = 7.2 Hz), 2.24 (⁶H, s). Measured value: [M- _Me₂N ] = 224.5.

(3-Fluoro-4-methoxyphenyl)methanol (64)

Borane-dimethyl sulfide complex (2.79 mL, 29.40 mmol) and trimethyl borate (3.34 mL, 29.40 mmol) were added to a solution of 3-fluoro-4-methoxybenzoic acid (2.50 g, 14.69 mmol) in THF (80 mL, Na distillation) at 0 °C, and the solution was heated to room temperature and stirred overnight. The mixture was then cooled to 0 °C and quenched with MeOH (10 mL). The solvent was then evaporated and the residue was partitioned between EtOAc and water. The organic layer was then dried and evaporated to give product 64. Yield = 2.35 g, 100%. ^¹H NMR ( _CDCl₃ ) δ 7.11 (¹H, dd, J = 2.0, 11.9 Hz), 7.06 (¹H, ddd, J = 0.9, 2.0, 9.1 Hz), 6.94 (¹H, dd, J = 8.4, 8.4 Hz), 4.61 (²H, s), 3.89 (³H, s), 1.73 (¹H, s). Measured value: [M-OH] = 139.7.

4-(bromomethyl)-2-fluoro-1-methoxybenzene (65)

At room temperature, methanesulfonyl chloride (1.41 mL, 18.06 mmol) was added dropwise to a solution of 64 (2.35 g, 15.05 mmol) and triethylamine (3.15 mL, 22.58 mmol) in DCM (50 mL, anhydrous). After 15 minutes, the reaction was diluted with DCM (50 mL), and the organic layer was washed with a saturated aqueous solution of _NaHCO3 , dried, and evaporated. The residue was dissolved in acetone (100 mL, anhydrous), lithium bromide (excess) was added, and the mixture was heated under reflux for 30 minutes. The solution was then cooled, the solvent was evaporated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the organic layer was dried and evaporated to give product 65. Yield = 3.00 g, 91%. ¹ H NMR (CDCl ₃ ) δ 7.16-7.07 (2H, m), 6.90 (1H, dd, J=8.3, 8.4Hz), 4.45 (2H, s), 3.89 (3H, s).

6-Bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline (66)

The mixture of 1 (3.51 g, 12.45 mmol), 65 (3.00 g, 13.69 mmol), and cesium carbonate (8.93 g, 27.40 mmol) in toluene (60 mL, anhydrous) and DMF (30 mL, anhydrous) was purged with nitrogen. Then, Pd( _PPh3 ) ₄ (0.58 g, 0.50 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 5 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (19:1 hexane/EtOAc) gave product 66. Yield = 2.10 g, 41%. ^¹H NMR ( _CDCl₃ ) δ 7.76 (¹H, d, J = 2.2 Hz), 7.69 (¹H, d, J = 12.3 Hz), 7.62 (¹H, dd, J = 2.2, 8.9 Hz), 7.49 (¹H, s), 7.00–6.86 (³H, m), 4.07 (³H, s), 3.95 (²H, s), 3.88 (³H, s). Measured value: [M+H] = 376.0

3-(ethoxymethoxy)-2,6-dimethoxyisononin formaldehyde (67)

n-BuLi (14.09 mL, 28.17 mmol) was added dropwise to a solution of 58 (4.00 g, 18.78 mmol) and N,N-diisopropylamine (0.13 mL, 0.94 mmol) in THF (60 mL, Na distillation) under nitrogen atmosphere at -40 °C. The resulting solution was stirred at -40 °C for 5 min, then heated to 0 °C and stirred further at this temperature for 3 h. The solution was then cooled back to -40 °C, 1-formylpiperidine (3.75 mL, 33.80 mmol) was added dropwise, and the mixture was stirred at room temperature for an additional 1 h. Acetic acid (7.5 mL) was added and the solvent was removed under vacuum. The resulting mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 67. Yield = 2.30 g, 51%. ¹ H NMR (CDCl ₃ ) δ 10.39 (1H, s), 6.61 (1H, s), 6.19 (2H, s), 4.02 (3H, s), 3.88 (3H, s), 3.78 (2H, q, J=10.1Hz), 1.21 (3H, t, J=7.1Hz).

3-Hydroxy-2,6-dimethoxyisocyanuric acid formaldehyde (68)

   

A solution of 67 (2.30 g, 9.54 mmol) and 3 M hydrochloric acid (60 mL) in THF (30 mL, Na distillation) was heated at 40 °C for 1.5 h. The solution was then cooled, diluted with water, and the pH was adjusted to 7 using _NaHCO3 . The aqueous layer was then extracted three times with EtOAc, and the organic layer was dried and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 68. Yield = 1.36 g, 78%. ^¹H NMR ( _CDCl3 ) δ 9.96 (¹H, s), 9.61 (¹H, s), 6.46 (¹H, s), 4.06 (³H, s), 3.91 (³H, s).

2,3,6-Trimethoxyisocyanuric acid formaldehyde (69)

A mixture of 68 (1.35 g, 7.38 mmol) and potassium carbonate (1.53 g, 11.07 mmol) in DMF (40 mL, anhydrous) was heated at 50 °C for 10 min. Iodimethane (0.56 mL, 8.86 mmol) was then added, and the mixture was stirred at this temperature for 2 h. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated to give product 69. Yield = 1.40 g, 96%. ^¹H NMR ( _CDCl₃ ) δ 10.40 (¹H, s), 6.58 (¹H, s), 4.04 (³H, s), 3.93 (³H, s), 3.91 (³H, s).

(2,3,6-Trimethoxypyridin-4-yl)methanol(70)

A mixture of 69 (1.40 g, 7.11 mmol) and sodium borohydride (0.54 g, 14.21 mmol) in MeOH (30 mL, anhydrous) was stirred for 1 hour at room temperature. The solvent was then removed and the residue was partitioned between EtOAc and water. The organic layer was dried and evaporated to give product 70. Yield = 1.35 g, 95%. ^¹H NMR ( _CDCl₃ ) δ 6.30 (¹H, s), 4.68 (²H, d, J = 5.6 Hz), 3.99 (³H, s), 3.88 (³H, s), 3.79 (³H, s), 2.21 (¹H, t, J = 5.9 Hz).

4-(bromomethyl)-2,3,6-trimethoxypyridine (71)

Methanesulfonyl chloride (0.63 mL, 8.14 mmol) was added dropwise to a solution of 70 (1.35 g, 6.78 mmol) and triethylamine (1.42 mL, 10.78 mmol) in DCM (20 mL, anhydrous) at room temperature. After 15 minutes, the reactants were diluted with DCM (20 mL), and the organic layer was washed with a saturated aqueous solution of _NaHCO3 , dried, and evaporated. The residue was dissolved in acetone (40 mL, anhydrous), lithium bromide (excess) was added, and the mixture was heated under reflux for 30 minutes. The solution was then cooled, the solvent was evaporated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the organic layer was dried and evaporated to give product 71. Yield = 1.69 g, 95%. ^¹H NMR ( _CDCl₃ ) δ 6.27 (¹H, s), 4.40 (²H, s), 3.98 (³H, s), 3.87 (³H, s), 3.87 (³H, s). Measured value: [M+H] = 262.5

6-Bromo-2-methoxy-3-((2,3,6-trimethoxypyridin-4-yl)methyl)quinolone (72)

The mixture of 1 (1.89 g, 6.69 mmol), 71 (1.67 g, 6.37 mmol), and cesium carbonate (4.15 g, 12.74 mmol) in toluene (40 mL, anhydrous) and DMF (20 mL, anhydrous) was purged with nitrogen. Then, Pd( _PPh3 ) ₄ (0.29 g, 0.26 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 4 hours under nitrogen. The reaction was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (19:1 hexane/EtOAc) gave product 72. Yield = 1.44 g, 54%. ^¹H NMR ( _CDCl₃ ) δ 7.76 (¹H, d, J = 2.2 Hz), 7.68 (¹H, d, J = 8.9 Hz), 7.61 (¹H, dd, J = 2.2, 8.8 Hz), 7.54 (¹H, s), 6.04 (¹H, s), 4.07 (³H, s), 4.00 (³H, s), 4.39 (²H, s), 3.85 (³H, s), 3.72 (³H, s). Measured value: [M+H] = 420.0

2-(dimethylamino)-6-(ethio)isonicotinic acid methyl ester (73)

   

Methyl 2-chloro-6-(dimethylamino)isonicotinic acid (WO 2010/100475) (2.44 g, 11.40 mmol), rac-bis(diphenylphosphine)-1,1'-binaphthol (0.71 g, 1.140 mmol), and cesium carbonate (4.43 g, 13.60 mmol) were added to a glass tube under a continuous nitrogen flow. Anhydrous toluene (30 mL) was added. The mixture was purged with nitrogen for 5 minutes, palladium acetate (0.26 g, 1.158 mmol) was added, and the mixture was purged with nitrogen again. Ethyl mercaptan (1.0 mL, 13.60 mmol) was added, the mixture was sealed in the tube, and heated at 150 °C for 22 hours. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated in a fume hood by heating the solution while purging with air. An orange crude solid was obtained. Rapid chromatography of the product using 2-5% diethyl ether in hexane yielded a yellow crystalline solid, product 73. Yield: 2.42 g, 88%. ^¹H NMR ( _CDCl₃ ) δ 6.96 (¹H, d, J = 1.0 Hz), 6.73 (¹H, d, J = 1.0 Hz), 3.89 (³H, s), 3.15 (²H, q, 7.3 Hz), 3.12 (⁶H, s), 1.38 (³H, t, J = 7.3 Hz). Observed value: [M+H] = 241.5.

(2-(dimethylamino)-6-(ethio)pyridin-4-yl)methanol (74)

Lithium aluminum hydride (0.31 g, 8.189 mmol) was added in three portions to a solution of 73 (1.64 g, 6.824 mmol) in freshly distilled THF (66 mL) under nitrogen atmosphere at 2 °C. The mixture was stirred at 2 °C for 15 min, then at room temperature for 1 h. The mixture was carefully quenched with water at 2 °C until gas escape stopped. 1 M NaOH (20 mL) was added. The mixture was stirred for 5 min, then the aluminum salt was decanted and filtered through diatomaceous earth. The aqueous mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (3 _× ). The combined organic extracts were washed with brine, dried ( _Na₂SO₄ ), and concentrated to give a brown oily crude product. The crude product was purified by rapid chromatography using a 4:1 mixture of hexane/EtOAc to give a brown oily product 74. Yield = 1.30 g, 90%. ^¹H NMR ( _CDCl₃ ) δ 6.43 (¹H, s), 6.18 (¹H, d, J = 0.8 Hz), 4.56 (2H, d, J = 5.0 Hz), 3.14 (2H, q, 7.4 Hz), 3.08 (6H, s), 1.67 (¹H, br t, J = 5.8 Hz), 1.57 (3H, s), 1.37 (3H, t, J = 7.3 Hz). Measured value: [M+H] = 213.5.

4-(bromomethyl)-6-(ethylthio)-N,N-dimethylpyridin-2-amine (75)

Triethylamine (0.59 mL, 4.26 mmol), followed by methanesulfonyl chloride (0.26 mL, 3.41 mmol), was added dropwise to a solution of 74 (0.60 g, 2.84 mmol) in anhydrous DCM (10 mL) under nitrogen atmosphere at 2 °C. The mixture was stirred from 2 °C to 5 °C for 1 hour. The mixture was quenched with a saturated aqueous solution of _NaHCO3 . The aqueous mixture was extracted with DCM (3×). The combined extracts were washed with brine, dried ( _MgSO4 ), and concentrated to give a crude product as a pale brown oil. The crude intermediate was dissolved in acetone (20 mL). Lithium bromide (0.99 g, 11.36 mmol) was added, and the suspension was stirred at room temperature for 2.5 hours. Rapid chromatography using 98:2 hexane/ _Et2O gave product 75 as a brown solid. The reaction was repeated at a scale of 3.29 mmol, and the products were combined. Overall yield = 1.39 g, 82%. ^¹H NMR ( _CDCl₃ ) δ 6.46 (¹H, d, J = 1.2 Hz), 6.15 (¹H, d, J = 0.8 Hz), 4.24 (²H, s), 3.13 (²H, q, J = 7.2 Hz), 3.08 (⁶H, s), 1.37 (⁻¹H, t, J = 7.2 Hz). Measured value: [M+H] = 275.5

4-((6-bromo-2-methoxyquinoline-3-yl)methyl)-6-(ethylthio)-N,N-dimethylpyridin-2-amine (76)

The mixture of 1 (1.42 g, 5.05 mmol), 75 (1.39 g, 5.05 mmol), and cesium carbonate (3.29 g, 10.09 mmol) in a mixture of toluene (14 mL) and DMF (7 mL) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.29 g) was added. The mixture was purged again with nitrogen and heated at 85 °C under nitrogen for 2.5 h. The mixture was partitioned between water and EtOAc. The aqueous mixture was extracted with EtOAc (2×). The extract was washed with water and brine, dried (MgSO ₄ ), and concentrated to give an orange oily crude product, which was chromatographically treated with 2-5% Et ₂ O in hexane as eluent to give product 76 as a pale yellow solid. Recrystallization from DCM/MeOH gave a white solid. Yield = 1.25 g, 57%. ^¹H NMR ( _CDCl₃ ) δ 7.79 (¹H, d, J = 2.4 Hz), 7.70 (¹H, d, J = 8.8 Hz), 7.64 (¹H, dd, J = 2.4, 9.2 Hz), 7.56 (¹H, s), 6.34 (¹H, s), 6.06 (¹H, s), 4.09 (³H, s), 3.86 (²H, s), 6.15 (²H, q, J = 7.2 Hz), 3.07 (⁶H, s), 1.39 (³H, t, J = 7.2 Hz). Measured value [M+H] = 432.1

2,5-Dimethoxynicotinaldehyde (77)

A mixture of 5-hydroxy-2-methoxynicotinaldehyde (Organic & Biomolecular Chemistry, 6(8), 1364-1376; 2008) (3.20 g, 20.89 mmol) and potassium carbonate (4.33 g, 31.34 mmol) in DMF (100 mL, anhydrous) was heated at 50 °C for 10 min. Iodimethane (1.56 mL, 25.08 mmol) was then added, and the mixture was stirred at this temperature for 2 h. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated to give product 77, which was identical to the compound reported in Organic & Biomolecular Chemistry, 6(8), 1364-1376; 2008. Yield = 2.70 g, 77%.

(2,5-Dimethoxypyridin-3-yl)methanol (78)

A mixture of 77 (2.70 g, 16.15 mmol) and sodium borohydride (1.22 g, 32.30 mmol) in methanol (60 mL, anhydrous) was stirred for 1 hour at room temperature. The solvent was then removed and the residue was partitioned between EtOAc and water. The organic layer was dried and evaporated to give product 78. Yield: 2.74 g, 99%. ^¹H NMR ( _CDCl₃ ) δ 7.72 (¹H, d, J = 3.0 Hz), 7.26 (¹H, d, J = 3.0 Hz), 4.62 (²H, d, J = 6.3 Hz), 3.94 (³H, s), 3.81 (³H, s), 2.37 (¹H, t, J = 6.4 Hz).

3-(bromomethyl)-2,5-dimethoxypyridine (79)

Methanesulfonyl chloride (13.46 mL, 18.79 mmol) was added dropwise to a solution of 78 (2.65 g, 15.66 mmol) and triethylamine (3.27 mL, 23.49 mmol) in DCM (45 mL, anhydrous) at room temperature. After 15 minutes, the reactants were diluted with DCM (25 mL), and the organic layer was washed with saturated _NaHCO3 , dried, and evaporated. The residue was dissolved in acetone (90 mL, anhydrous), lithium bromide (excess) was added, and the mixture was heated under reflux for 30 minutes. The solution was then cooled and the solvent was evaporated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the organic layer was dried and evaporated to give product 79. Yield = 3.08 g, 85%. ¹ H NMR (CDCl ₃ ) δ 7.78 (1H, d, J = 3.0 Hz), 7.25 (1H, d, J = 3.6 Hz), 4.46 (2H, s), 3.97 (3H, s), 3.82 (3H, s).

6-Bromo-3-((2,5-dimethoxypyridin-3-yl)methyl)-2-methoxyquinoline (80)

The mixture of 1 (3.40 g, 12.06 mmol), 79 (3.08 g, 13.27 mmol), and cesium carbonate (7.86 g, 24.12 mmol) in toluene (60 mL, anhydrous) and DMF (30 mL, anhydrous) was purged with nitrogen. Then, Pd( _PPh3 ) ₄ (0.057 g, 0.48 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 4 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (19:1 hexane/EtOAc) was performed to give product 80. Yield = 3.60 g, 69%. ^¹H NMR ( _CDCl₃ ) δ 7.77 (¹H, d, J = 2.2 Hz), 7.71 (¹H, d, J = 3.0 Hz), 7.68 (¹H, d, J = 8.9 Hz), 7.61 (¹H, dd, J = 2.2, 8.9 Hz), 7.55 (¹H, s), 7.04 (¹H, d, J = 3.0 Hz), 4.07 (³H, s), 3.94 (²H, s), 3.90 (³H, s), 3.78 (³H, s). Measured value: [M+H] = 389.8

2,6-Dimethoxy-3-((triisopropylsilyl)oxy)pyridine (81)

Triisopropylchlorosilane (13.33 mL, 62.23 mmol) was added to a mixture of 57 (8.05 g, 51.9 mmol) and imidazole (7.42 g, 108.99 mmol) in DMF (130 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The solution was then partitioned between EtOAc and water, and the aqueous layer was extracted three times. The combined organic layers were washed three times with brine, dried, and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 81. Yield: 15.59 g, 96%. ^¹H NMR ( _CDCl₃ ) δ 7.07 (¹H, d, J = 8.2 Hz), 6.13 (¹H, d, J = 8.2 Hz), 3.92 (³H, s), 3.86 (³H, s), 1.27–1.18 (³H, m), 1.08 (¹⁸H, d, J = 7.1 Hz). Measured value: [M+H] = 312.8.

2,6-Dimethoxy-5-((triisopropylsilyl)oxy)nicotinaldehyde (82)

n-BuLi (15.41 mL, 30.83 mmol) was added dropwise to a solution of 81 (8.00 g, 25.69 mmol) and N,N-diisopropylamine (0.18 mL, 1.28 mmol) in THF (100 mL, Na distillation) under nitrogen atmosphere at -40 °C. The resulting solution was stirred at -40 °C for 5 min, then heated to 0 °C and stirred further at this temperature for 3 h. The solution was then cooled back to -40 °C, formylpiperidine (4.28 mL, 38.54 mmol) was added dropwise, and the mixture was stirred at room temperature for an additional 1 h. Acetic acid (8 mL) was added and the solvent was removed under vacuum. The resulting mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography with 49:1 hexane/EtOAc gave product 82. Yield = 7.55 g, 87%. ^¹H NMR ( _CDCl₃ ) δ 10.17 (¹H, s), 7.51 (¹H, s), 4.02 (³H, s), 4.01 (³H, s), 1.30–1.19 (³H, m), 1.08 (¹⁸H, d, J = 7.3 Hz). Measured value: [M-CHO] ^⁺ = 312.8.

5-Hydroxy-2,6-dimethoxynicotinaldehyde (83)

Tetrabutylammonium fluoride (1N, 33.36 mL, 33.36 mmol) in THF was added to a solution of 82 (7.55 g, 22.24 mmol) in THF (35 mL, Na distillation) at 0 °C. The reaction was then heated to room temperature and stirred for 4 hours. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc, and the organic layer was dried and evaporated. Column chromatography with DCM followed by a 3:1 DCM/EtOAc yielded product 83. Yield = 3.15 g, 77%. ^¹H NMR ( _CDCl₃ ) δ 10.20 (¹H, s), 7.59 (¹H, s), 5.15–4.80 (¹H, br s), 4.10 (³H, s), 4.01 (³H, s).

2,5,6-Trimethoxynicotinaldehyde (84)

A mixture of 83 (3.15 g, 17.20 mmol) and potassium carbonate (3.57 g, 25.80 mmol) in DMF (80 mL, anhydrous) was heated at 50 °C for 10 min. Iodomethane (1.29 mL, 20.64 mmol) was then added, and the mixture was stirred at this temperature for 2 h. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated to give product 84. Yield = 3.39 g, 100%. ^¹H NMR ( _CDCl₃ ) δ 10.21 (¹H, s), 7.53 (¹H, s), 4.10 (³H, s), 4.02 (³H, s), 3.87 (³H, s).

(6-Bromo-2-methoxyquinoline-3-yl)(2,5,6-trimethoxypyridin-3-yl)methanol(85)

A solution of 2,2,6,6-tetramethylpiperidine (3.59 mL, 21.03 mmol) in THF (40 mL, Na distillation) was cooled to -40 °C. n-BuLi (10.52 mL, 21.03 mmol) was added, and the solution was stirred at -40 °C for 15 minutes, then cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline (17.53 mmol) in THF (40 mL, Na distillation) was added dropwise, and the orange solution was stirred at -78 °C for 1.5 hours. Then, a solution of 84 (3.42 g, 17.53 mmol) in THF (40 mL, Na distillation) was added. The mixture was stirred at -78 °C for 2 hours, then acetic acid (2.5 mL) was added, and the solution was warmed to room temperature. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography with 9:1 hexane/EtOAc followed by 4:1 hexane/EtOAc yielded a white solid product. Yield: 5.50 g, 72%. ^¹H NMR ( _CDCl₃ ) δ 7.85 (¹H, d, J = 2.1 Hz), 7.79 (¹H, s), 7.70 (¹H, d, J = 8.9 Hz), 7.65 (¹H, dd, J = 2.1, 8.9 Hz), 7.15 (¹H, s), 6.14 (¹H, d, J = 5.2 Hz), 4.08 (³H, s), 4.02 (³H, s), 3.90 (³H, s), 3.78 (³H, s), 3.48 (¹H, d, J = 5.4 Hz). Analytical value: [M+H] = 436.1

6-Bromo-2-methoxy-3-((2,5,6-trimethoxypyridin-3-yl)methyl)quinolone (86)

Trifluoroacetic acid (11.30 mL, 148.2 mmol) and triethylsilane (17.76 mL, 111.2 mmol) were added sequentially to a solution of 85 (5.35 g, 12.35 mmol) in DCM (125 mL), and the solution was stirred at room temperature for 1 hour, followed by the addition of ice water. The solution was partitioned between a saturated _NaHCO3 aqueous solution and DCM, and the aqueous fraction was extracted with DCM. The organic fractions were combined, dried, and evaporated. Column chromatography with 9:1 hexane/EtOAc gave product 86 as a white solid. Yield: 4.45 g, 86%. ^¹H NMR ( _CDCl₃ ) δ 7.76 (¹H, d, J = 2.2 Hz), 7.68 (¹H, d, J = 8.9 Hz), 7.60 (¹H, dd, J = 2.2, 8.4 Hz), 7.49 (¹H, s), 7.05 (¹H, s), 4.09 (³H, s), 4.01 (³H, s), 3.89 (⁵H, s), 3.79 (³H, s). Measured value: [M+H] = 419.0

2-(dimethylamino)-6-methoxyisonicotinic acid ethyl ester (87)

Ethyl 2-chloro-6-methoxyisonicotinic acid (WO 2009/024905) (4.01 g, 18.60 mmol), diphenylphosphine-1,1'-binaphthol (1.85 g, 2.976 mmol), and cesium carbonate (8.49 g, 26.10 mmol) were added to a glass tube under a continuous nitrogen flow. Anhydrous toluene (72 mL) was added. The mixture was purged with nitrogen for 5 minutes. Palladium acetate (0.33 g, 1.488 mmol) was added, and the mixture was purged with nitrogen again. Dimethylamine in tetrahydrofuran (2N, 11.2 mL, 22.3 mmol) was added, and the mixture was sealed in the tube and heated at 80 °C for 19.5 hours. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated under vacuum to give a crude product as a dark red liquid. Rapid column chromatography of the crude product with 3-10% _Et₂O in hexane yielded product 87, a yellow crystalline solid. Yield: 3.36 g, 80%. ^¹H NMR ( _CDCl₃ ) δ 6.61 (¹H, d, J = 0.96 Hz), 6.52 (¹H, d, J = 0.88 Hz), 4.35 (²H, q, J = 7.1 Hz), 3.90 (³H, s), 3.1 (⁶H, s), 1.38 (³H, t, J = 7.2 Hz). Analytical value: [M+H] = 225.5.

(2-(dimethylamino)-6-methoxypyridin-4-yl)methanol (88)

Lithium aluminum hydride (0.73 g, 19.3 mmol) was added in three portions to a solution of 87 (3.31 g, 14.8 mmol) in freshly distilled THF (70 mL) under nitrogen atmosphere at 2 °C. The mixture was stirred at 2 °C for 10 min, then at room temperature for 1 h. The mixture was carefully quenched with water at 2 °C until gas escape stopped. 1 M NaOH (30 mL) was added and the mixture was stirred for 1 h. The aqueous mixture was then diluted in water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried ( _Na₂SO₄ ), and concentrated to give product 88, a pale yellow oil, which was used without further purification. Yield = 2.69 _g , >99%. ¹ H NMR (CDCl ₃ ) δ 6.05 (1H, d, J = 0.4Hz), 5.97 (1H, d, J = 0.4Hz), 4.59 (2H, d, J = 4.8Hz), 3.88 (3H, s), 3.06 (6H, s), 1.70 (1H, t, J = 5.6Hz).

4-(bromomethyl)-6-methoxy-N,N-dimethylpyridine-2-amine (89)

Triethylamine (3.8 mL, 27.2 mmol), followed by methanesulfonyl chloride (1.7 mL, 21.7 mmol), was added dropwise to a solution of 88 (3.30 g, 18.1 mmol) in anhydrous DCM (54 mL) at 2 °C under nitrogen atmosphere. The mixture was stirred at 2 °C for 10 min, then at room temperature for 2 h. The mixture was quenched with a saturated aqueous solution _{of NaHCO3} . The aqueous mixture was extracted with DCM (2×), and the combined extracts were washed with brine, dried ( _MgSO4 ), and concentrated to give a crude product as a beige solid. The crude intermediate was dissolved in acetone (60 mL). Lithium bromide (1.53 g, 36.2 mmol) was added, and the suspension was refluxed for 2 h. Rapid chromatography using a mixture of 3–5% _Et2O in hexane as eluent gave a yellow, flowing oily product 89. Yield = 3.78 g, 85%. ¹ H NMR (CDCl ₃ ) δ 6.02 (1H, d, J = 0.8Hz), 6.00 (1H, d, J = 0.4Hz), 4.27 (2H, s), 3.88 (3H, s), 3.06 (6H, s).

4-((6-bromo-2-methoxyquinoline-3-yl)methyl)-6-methoxy-N,N-dimethylpyridin-2-amine (90)

The mixture of 1 (4.34 g, 15.4 mmol), 89 (3.77 g, 115.4 mmol), and cesium carbonate (10.03 g, 30.8 mmol) in a mixture of toluene (40 mL) and DMF (20 mL) was purged with nitrogen. Pd( _PPh3 ) ₄ (0.890 g, 0.774 mmol) was added, and the mixture was purged again with nitrogen and heated at 85 °C under nitrogen for 3.5 h. The mixture was partitioned between water and EtOAc, and extracted with EtOAc (2×). The extract was washed with water (2×) and brine, dried ( _MgSO4 ), and concentrated to give a crude product as a brown solid. Chromatographic treatment was performed using 3–10% _Et2O in hexane as eluent to give product 90 as a pale yellow solid. Yield = 3.69 g, 60%. ^¹H NMR ( _CDCl₃ ) δ 7.76 (¹H, d, J = 2 Hz), 7.68 (¹H, d, J = 8.8 Hz), 7.61 (¹H, dd, J = 2, 8.8 Hz), 7.55 (¹H, s), 5.92 (¹H, s), 5.86 (¹H, s), 4.07 (³H, s), 3.87 (⁵H, s), 3.04 (⁶H, s). Measured value: [M+H] = 402.0

2-(dimethylamino)-6-methoxyisonicotinic acid (91)

To a solution of 87 (6.77 g, 30.2 mmol) in EtOH (150 mL) at room temperature, NaOH (30.2 mL, 60.4 mmol) was added. The mixture was stirred at room temperature for 2 hours, then concentrated under vacuum to a pale yellow solution, which was further diluted in water. The aqueous mixture was acidified to pH ~2 with 2 M HCl, at which point a bright yellow solid precipitated. This solid was collected by filtration, washed with water, and dried under ambient conditions to give 91 as a bright yellow powder. Yield = 5.60 g, 95%. ^¹H NMR (DMSO- _d₆ ) δ 13.25 (¹H, br s), 6.54 (¹H, d, J = 0.9 Hz), 6.33 (¹H, d, J = 0.8 Hz), 3.82 (³H, s), 3.04 (⁶H, s).

2-(Dimethylamino)-N,6-dimethoxy-N-methylisonicotinamide (92)

Triethylamine (1.6 mL, 11.4 mmol) was added to a suspension of 91 (0.75 g, 3.81 mmol) in anhydrous DMF (22 mL), and the mixture was cooled to 2 °C. Ethyl chloroformate (0.62 mL, 4.19 mmol) was added dropwise, and fumes were observed. The mixture was stirred from 2 °C to room temperature for 2.5 hours, and then treated with N,O-dimethylhydroxylamine hydrochloride (0.557 g, 5.71 mmol) at 2 °C under nitrogen. The mixture was stirred at room temperature overnight. The mixture was diluted in water, and the aqueous mixture was extracted with EtOAc (4×). The organic extract was washed with water and brine, dried ( _MgSO₄ ), and concentrated to give a crude product. This crude product was purified by repeated rapid chromatography, eluting with a 4:1 followed by a 2:1 mixture of hexane/EtOAc as eluent, to give a yellow oily product 92. Yield = 0.70 g, 77%. ¹ H NMR (CDCl ₃ ) δ 6.17 (1H, s), 6.11 (1H, s), 3.89 (3H, s), 3.62 (3H, br s), 3.31 (3H, s), 3.08 (6H, s).

3-(dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)prop-1-one (93)

Vinyl magnesium bromide (1N, 21.1mL, 21.10mmol) in THF was added dropwise to a solution of 92 (2.53g, 10.60mmol) in freshly distilled THF (96mL) under nitrogen atmosphere at 2°C. The mixture was stirred at 2°C for 20 minutes, then at room temperature for 75 minutes. Dimethylamine (2N, 21.1mL, 42.20mmol) in THF was added, followed by water (40mL). The mixture was stirred at room temperature for 1 hour. The aqueous mixture was partitioned between water and EtOAc, the organic phase was separated, and the aqueous phase was extracted with EtOAc (2×). The organic extract was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under vacuum to give a yellow-brown oily crude product. The product was subjected to rapid chromatography using 2-8% MeOH in DCM as eluent to give a yellow oily 93, which was crystallized at -20°C. Yield = 1.91g, 72%. ¹ H NMR (CDCl ₃ ) δ 6.47 (1H, d, J = 1.0Hz), 6.39 (1H, d, J = 1.0Hz), 3.91 (3H, s), 3.10 (6H, s), 3.06 (2H, t, J = 7.0Hz), 2.72 (2H, t, J = 7.1Hz), 2.27 (6H, s).

2-(dimethylamino)-6-ethoxyisonicotinic acid ethyl ester (94)

Ethyl 2-chloro-6-ethoxyisonicotinic acid (WO 2010/080864) (1.00 g, 4.37 mmol), diphenylphosphine-1,1'-binaphthol (0.44 g, 0.70 mmol), and cesium carbonate (1.99 g, 6.12 mmol) were added to a glass tube under a continuous nitrogen flow. Anhydrous toluene (24 mL) was added. The mixture was purged with nitrogen for 5 minutes. Palladium acetate (0.079 g, 0.35 mmol) was added, and the mixture was purged with nitrogen again. Dimethylamine in THF (2N, 2.6 mL, 5.246 mmol) was added, the mixture was sealed in the tube, and heated at 80 °C overnight. The mixture was filtered through diatomaceous earth, washed with EtOAc, and the filtrate was concentrated under vacuum to give a deep red liquid crude product. Rapid chromatography using 2–4% _Et₂O in hexane gave a pale yellow oily product 94. Yield = 0.85 g, 82%. ^¹H NMR ( _CDCl₃ ) δ 6.60 (¹H, d, J = 0.8 Hz), 6.51 (¹H, d, J = 0.8 Hz), 4.35 (²H, q, J = 7.0 Hz), 4.33 (²H, q, J = 7.1 Hz), 3.09 (⁶H, s), 1.38 (³H, t, J = 7.2 Hz), 1.37 (³H, t, J = 7.2 Hz).

4-(bromomethyl)-6-ethoxy-N,N-dimethylpyridine-2-amine (95)

Lithium aluminum hydride (0.91 g, 24.0 mmol) was added in three portions to a solution of 94 (4.40 g, 18.50 mmol) in freshly distilled THF (90 mL) under nitrogen atmosphere at -78 °C. The mixture was stirred at -78 °C for 15 min, then at room temperature for 1 h. The mixture was carefully quenched with water at 2 °C until gas escape ceased. 1 M NaOH (32 mL) was added and the mixture was stirred for 1 h. The aqueous mixture was then diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried _{( Na₂SO₄} ), and concentrated to give the product, which was purified by rapid chromatography elution with a 6:1 followed by a 4:1 mixture of hexane/EtOAc to give a pale yellow, oily alcohol intermediate. Yield = 3.27 g, 90%. This material was used directly in the next step without further characterization.

Triethylamine (3.5 mL, 25.0 mmol), followed by methanesulfonyl chloride (1.6 mL, 20.0 mmol), was added dropwise to a solution of an alcohol intermediate (3.27 g, 16.7 mmol) in anhydrous DCM (50 mL) at 2 °C under nitrogen atmosphere. The mixture was stirred at 2 °C for 10 min, then at room temperature for 0.5 h. The mixture was quenched with a saturated aqueous solution of _NaHCO3 . The aqueous mixture was extracted with DCM (3×), and the combined extracts were washed with brine, dried, and concentrated to give a brown, oily crude product. This was diluted in acetone (60 mL), lithium bromide (1.42 g) was added, and the suspension was refluxed for 2 h. Rapid chromatography using a mixture of 2–3% _Et2O in hexane as eluent gave a yellow, flowing, oily product. Yield = 3.84 g, 89%. ¹ H NMR (CDCl ₃ ) δ 6.011 (1H, s), 5.99 (1H, s), 4.30 (2H, q, J = 6.8Hz), 4.27 (2H, s), 3.05 (6H, s), 1.37 (3H, t, J = 7.2Hz).

4-((6-bromo-2-methoxyquinoline-3-yl)methyl)-6-ethoxy-N,N-dimethylpyridin-2-amine (96)

       

The mixture of 1 (4.13 g, 14.7 mmol), 95 (3.80 g, 14.7 mmol), and cesium carbonate (9.58 g, 29.4 mmol) in a mixture of toluene (40 mL) and DMF (20 mL) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.68 g) was added. The mixture was purged again with nitrogen and heated at 85 °C under nitrogen for 3 hours. The mixture was partitioned between water and EtOAc, and the aqueous mixture was extracted with EtOAc (2×). The extract was washed with water (2×) and brine, dried, and concentrated to give a crude, brown, oily product. Chromatographic treatment was performed using 3–10% Et ₂ O in hexane as eluent to give product 96 (3.83 g) as a yellow solid, which was then ground in diethyl ether to give a clean, pale yellow solid. Yield = 3.51 g, 57%. ^1HNMR (CDCl ₃ ) δ7.76 (1H, d, J = 2.2Hz), 7.68 (1H, d, J = 8.8Hz), 7.61 (1H, dd, J = 2.2, 8.8Hz), 7.55 (1H, s), 5.91 (1H, s ), 5.84 (1H, s), 4.30 (2H, q, J = 7.1Hz), 4.07 (3H, s), 3.87 (2H, s), 3.03 (6H, s), 1.36 (3H, t, J = 7.1Hz).

5-Isopropoxy-2-methoxynicotinaldehyde (97)

A mixture of 5-hydroxy-2-methoxynicotinaldehyde (Organic & Biomolecular Chemistry, 6(8), 1364-1376; 2008) (1.00 g, 6.53 mmol) and potassium carbonate (1.35 g, 9.80 mmol) in DMF (30 mL, anhydrous) was heated at 50 °C for 10 min, followed by the addition of isopropyl iodine (0.78 mL, 7.84 mmol), and the mixture was stirred at this temperature for 2 h. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated to give product 97. Yield = 0.90 g, 71%. ¹ H NMR (CDCl ₃ ) δ 10.34 (1H, s), 8.07 (1H, d, J = 3.2Hz), 7.66 (1H, d, J = 3.2Hz), 4.48 (1H, sp, J = 6.1Hz), 4.03 (3H, s), 1.33 (6H, d, J = 4.8Hz).

(5-Isopropoxy-2-methoxypyridin-3-yl)methanol (98)

A mixture of 97 (0.90 g, 4.61 mmol) and sodium borohydride (0.35 g, 9.22 mmol) in MeOH (15 mL, anhydrous) was stirred at room temperature for 1 hour. The solvent was then removed and the residue was partitioned between EtOAc and water. The organic layer was dried and evaporated. Column chromatography with 9:1 hexane/EtOAc gave product 98. Yield = 0.68 g, 75%. ^¹H NMR ( _CDCl₃ ) δ 7.72 (¹H, s), 7.25 (¹H, d, J = 3 Hz), 4.61 (2H, s), 4.42 (¹H, sp), 3.93 (3H, s), 2.92–2.19 (¹H, brs), 1.32 (6H, d, J = 6.1 Hz).

3-(bromomethyl)-5-isopropoxy-2-methoxypyridine (99)

Methanesulfonyl chloride (0.32 mL, 4.14 mmol) was added dropwise to a solution of 98 (0.68 g, 3.45 mmol) and triethylamine (0.72 mL, 5.18 mmol) in DCM (10 mL, anhydrous) at room temperature. After 15 minutes, the reactants were diluted with DCM (10 mL), the organic layer was washed with saturated _NaHCO3 , dried, and evaporated. The residue was redissolved in acetone (20 mL, anhydrous), lithium bromide (excess) was added, and the mixture was heated under reflux for 30 minutes. The solution was then cooled and the solvent was evaporated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the organic layer was dried and evaporated to give product 99. Yield = 0.70 g, 78%. ¹ H NMR (CDCl ₃ ) δ7.76 (1H, dd, J = 2.6, 3.4Hz), 7.25 (1H, dd, J = 2.4, 2.4Hz), 4.5 (2H, d, J = 2.2Hz) , 4.42 (1H, sp, J=2.6, 6.0Hz), 3.96 (3H, d, J=2.9Hz), 1.32 (6H, dd, J=3.0, 6.1Hz).

6-Bromo-3-((5-isopropoxy-2-methoxypyridin-3-yl)methyl)-2-methoxyquinoline(100)

The mixture of 1 (0.80 g, 2.82 mmol), 99 (0.70 g, 2.69 mmol), and cesium carbonate (1.75 g, 5.38 mmol) in toluene (10 mL, anhydrous) and DMF (5 mL, anhydrous) was purged with nitrogen. Then, Pd( _PPh3 ) ₄ (0.12 g, 0.11 mmol) was added, and the mixture was subsequently heated to 80 °C under nitrogen for 4 hours. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (19:1 hexane/EtOAc) gave product 100. Yield: 0.57 g, 48%. ¹ H NMR (CDCl ₃ ) δ7.77 (1H, d, J = 2.2Hz), 7.71 (1H, d, J = 2.9Hz), 7.69 (1H, d, J = 8.9Hz), 7.62 (1H, dd, J = 2.2, 8.9Hz), 7.56 (1H, s ), 7.02 (1H, d, J = 2.9Hz), 4.38 (1H, sp, J = 6.0Hz), 4.08 (3H, s), 3.92 (2H, s), 3.90 (3H, s), 1.29 (6H, d, J = 6.1Hz).

1-(6-bromo-2-methoxyquinoline-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)but-2-ol (101)

The product was prepared from 9 and 7 (using the following generic coupling procedure). Rapid chromatography of the crude product using a hexane/EtOAc mixture with increased eluent strength provided a pale yellow, foamy 1:1 mixture of diastereomers, 101 (65%). ^1H NMR (CDCl3 ₎ ) δ 8.71 (1H, s), 8.69 (1H, s), 8.12 (1H, bs), 7.81 (2H, m), 7.65 (1H, d, J = 8.9Hz), 7.59 (1H, dd, J = 2.2, 8.9Hz), 7.53 (1H, dd, J = 2.0, 8.8H z), 7.50 (1H, d, J = 8.81Hz), 7.43 (1H, dt, J = 2.4, 10.5Hz), 7.39 (1H, d, J = 7.8Hz), 7.25-7.17 (2H, m), 7.07 (1H, d, J = 7.8Hz), 7.0 (1H, d, J = 7.8Hz) =8.0Hz), 6.98-6.92 (2H, m), 6.87 (1H, dt, J = 1.8, 8.4Hz), 6.67 (1H, dt, J = 1.8, 9.2Hz), 6.55-6.31 (8H, m), 4.82 (1H, s), 4.71 (1H, s), 4. 10(3H,s),3.89(3H,s),3.87(3H,s),3.85(6H,s),3.83(3H,s),3.82(3H,s),3.81(3H,s),3.79(6H,s),3.29-3.17(4H,m),2.46(2H,br t, J = 2.4 Hz), 2.16-2.02 (4H, m), 1.93 (3H, s), 1.91 (3H, s), 1.69 (1H, t, J = 4.7 Hz), 1.58-1.50 (1H, m, partially masked by the water peak). One OH group is not significant. Measured value: [M+H] = 720.1

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-4-(methylamino)but-2-ol (102)

      

Triethylamine (1.1 mL) and trifluoroacetic anhydride (0.97 mL) were added sequentially to a solution of 101 (2.50 g, 3.471 mmol) in anhydrous DCM (80 mL) at 2 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated _NaHCO3 aqueous solution (2×), dried ( _MgSO4 ), and concentrated under vacuum to give crude trifluoroacetamide intermediate, which was dissolved in MeOH (55 mL). A solution of cesium carbonate (2.83 g, 8.678 mmol) in water (5.5 mL) was added. The resulting brown solution was stirred at room temperature for 10 minutes and then stored overnight at 4 °C. The mixture was then diluted in water and extracted with EtOAc (3×). The combined extracts were washed with brine, dried ( _MgSO4 ), and concentrated under vacuum to provide crude product, which was purified by column chromatography using 0–5% MeOH in DCM as eluent. Elution yielded product 102 in the form of a 1:1 diastereomer mixture. ^¹H NMR ( _CDCl₃ ) δ 8.66 (¹H, s), 8.57 (¹H, s), 7.89 (¹H, d, J = 2.1 Hz), 7.82 (¹H, d, J = 1.9 Hz), 7.67 (¹H, d, J = 8.9 Hz), 7.61 (¹H, dd, J = 2.1, 8.8 Hz), 7.53 (¹H, dd, J = 2.0, 8.9 Hz), 7.50 (¹H, d, J = 8.8 Hz), 7.38–7.31 (²H, m), 7.26–7.20 (²H, m), 7.11 (¹H, d, J = 7.8 Hz), 7.0 3-6.95 (1H, m), 6.90 (1H, dt, J = 2.6, 8.5Hz), 6.69 (1H, dt, J = 2.6, 8.4Hz), 6.47 (4H, bs), 4.88 (1H, s), 4.72 (1H, s), 4.12 (3 H, s), 3.90 (3H, s), 3.87 (6H, s), 3.81 (6H, s), 2.67-2.58 (2H, m), 2.42-2.31 (2H, m), 2.25 (3H, s), 2.21 (3H, s), 1.89 (1H, br t, J = 12.1 Hz), 1.84-1.78 (2H, m), 1.67 (1H, br d, J = 14.8 Hz). Measured value: [M+H] = 569.9

2,4-Dichlorothiazol(103)

Pyridine (3.80 mL, 46.96 mmol) was added dropwise to a mixture of thiazolidin-2,4-dione (5.00 g, 42.69 mmol) and phosphorus oxychloride (25 mL) at 0 °C. The mixture was then stirred under reflux for 3 hours, cooled, and poured onto ice water. The aqueous layer was then extracted with DCM, and the combined organic layers were dried and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 103. Yield: 0.94 g, 14%. ^¹H NMR ( _CDCl₃ ) δ 7.02 (¹H, s). Analytical value: [M+H] = 133.3

6-Bromo-2-methoxyquinoline-3-carboxaldehyde (104)

A solution of 2,2,6,6-tetramethylpiperidine (4.28 mL, 25.2 mmol) in THF (50 mL, Na distillation) was cooled to -40 °C. n-BuLi (12.60 mL, 25.2 mmol) was added, and the solution was stirred at -40 °C for 15 minutes, then cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline (5.00 g, 21 mmol) in THF (50 mL, Na distillation) was added dropwise, and the orange solution was stirred at -78 °C for 1.5 hours. DMF (2.19 mL, 31.5 mmol) was then added, and the solution was warmed to room temperature. Acetic acid (3 mL) was added to remove the solvent. The residue was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography with 4:1 hexane/DCM followed by 1:1 hexane/DCM followed by 1:4 hexane/DCM yielded a white solid product 104. Yield = 3.00 g, 53%. ^¹H NMR ( _CDCl₃ ) δ 10.46 (¹H, s), 8.49 (¹H, s), 7.99 (¹H, d, J = 2.1 Hz), 7.79 (¹H, dd, J = 2.2, 8.9 Hz), 7.74 (¹H, d, J = 8.9 Hz), 4.18 (³H, s).

(6-Bromo-2-methoxyquinoline-3-yl)(2,4-dichlorothiazol-5-yl)methanol(105)

A solution of N,N-diisopropylamine (0.93 mL, 6.65 mmol) in THF (30 mL, Na distillation) was cooled to -40 °C. n-BuLi (3.33 mL, 6.65 mmol) was added, and the solution was stirred at -40 °C for 15 minutes, then cooled to -78 °C. A solution of 103 (0.98 g, 6.043 mmol) in THF (20 mL, Na distillation) was added dropwise, and the orange solution was stirred at -78 °C for 2 hours. Then, a solution of 104 (1.78 g, 6.043 mmol) in THF (20 mL, Na distillation) was added. The mixture was stirred at -78 °C for 2 hours, then water (20 mL) was added, and the solution was warmed to room temperature. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography with 9:1 hexane/EtOAc gave product 105 as a white solid. Yield = 1.98 g, 78%. ^¹H NMR ( _CDCl₃ ) δ 7.92–7.87 (2H, m), 7.74–7.68 (2H, m), 6.25 (¹H, dd, 0.8, 4.8 Hz), 4.11 (³H, s), 3.43 (¹H, d, J = 4.8 Hz). Measured value: [M+H] = 421.9.

5-((6-bromo-2-methoxyquinoline-3-yl)methyl)-2,4-dichlorothiazol(106)

Trifluoroacetic acid (3.35 mL, 43.80 mmol) and triethylsilane (5.74 mL, 39.92 mmol) were added sequentially to a solution of 105 (1.84 g, 4.38 mmol) in DCM (50 mL). The solution was stirred under reflux for 3 hours, then cooled and placed in ice water. The solution was partitioned between a saturated _NaHCO3 aqueous solution and DCM, and the aqueous fraction was extracted with DCM. The organic fractions were combined, dried, and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 106. Yield = 1.10 g, 62%. ¹ HNMR (CDCl ₃ ) δ 7.84 (1H, d, J = 2.0Hz), 7.75 (1H, s), 7.70 (1H, d, J = 8.9Hz), 7.66 (1H, dd, J = 2.1, 8.8Hz), 4.13 (2H, s), 4.12 (3H, s).

5-((6-bromo-2-methoxyquinoline-3-yl)methyl)-4-chloro-2-methoxythiazole (107)

Sodium methoxide (0.20 g, 3.71 mmol) was added to a suspension of 106 (1.00 g, 2.78 mmol) in MeOH (50 mL, anhydrous), and the mixture was stirred under reflux for 18 hours. The solution was then cooled and the solvent was removed, and the residue was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography with 19:1 hexane/EtOAc gave product 106. Yield = 0.50 g, 45%. ^¹H NMR ( _CDCl₃ ) δ 7.83 (¹H, d, J = 2.1 Hz), 7.70 (¹H, d, J = 3.6 Hz), 7.69 (¹H, s), 7.64 (¹H, dd, J = 2.2, 9.0 Hz), 4.11 (³H, s), 4.05 (³H, s), 4.03 (²H, d, J = 0.8 Hz). Measured value: [M+H]＝399.1

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)but-2-ol (108)

The products were prepared from 22 and 7 using the following general coupling procedure. Column chromatography with EtOAc:hexane (1:1) yielded a fore fraction, followed by 108 (66%) as a yellow, foamy mixture of isomers. ^1H NMR (CDCl3 ₎ , 400MHz) δ8.69 (s, 1H), 8.46 (s, 1H), 7.93 (bs, 2H), 7.79 (d, J = 2.0Hz, 2H), 7.64 (d, J = 8.9Hz, 1H), 7.59-7.50 (m, 4H), 7.16 (dd, J = 5 .9, 3.6Hz, 1H), 7.00 (d, J=8.6Hz, 1H), 6.89 (d, J=8.3Hz, 1H), 6.70-6.60 (m, 3H), 6.58-6.45 (m, 4H), 6.46-6.39 (m, 4H), 6.37-6.34 ( m, 1H), 5.37 (s, 1H), 5.35 (s, 1H), 4.41-4.29 (m, 4H), 4.12 (s, 3H), 4.02-3.91 (m, 4H), 3.85 (s, 6H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82- 3.80 (m, 12H), 3.79 (s, 3H), 3.25-3.19 (m, 4H), 2.49-2.41 (m, 2H), 2.15-1.95 (m, 4H), 1.90 (s, 3H), 1.88 (s, 3H), 1.77-1.66 (m, 2H). Actual measured value: [M+H]=760.2.

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(methylamino)but-2-ol (109)

Triethylamine (1.67 mL, 11.9 mmol) and trifluoroacetic anhydride (1.51 mL, 10.9 mmol) were added to a solution of 108 (4.13 g, 5.43 mmol) in DCM (100 mL) cooled to 0 °C. The reaction mixture was stirred for 1 hour, poured onto a saturated aqueous solution of _NaHCO3 (150 mL), and extracted with DCM ( ₃ × 100 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to obtain a pale yellow residue. The crude material was dissolved in MeOH (150 mL) and cooled to -78 °C. Cesium carbonate (4.42 g, 13.6 mmol) was added to water (3 mL), and the reaction mixture was stirred at -20 °C for 72 hours. Water (150 mL) was added to the reaction mixture, and it was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a yellow residue. Column chromatography with EtOAc yielded the fore fraction, followed by racemic _A (35%). Elution with EtOAc:MeOH (6:1) gave racemic B (28%).

Racemic compound A, white solid. ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.33 (s, ¹H), 7.84 (d, J = 2.2 Hz, ¹H), 7.67 (d, J = 8.9 Hz, ¹H), 7.62–7.58 (m, 2H), 6.63 (t, J = 8.0 Hz, ¹H), 6.58–6.51 (m, 3H), 5.40 (s, ¹H), 4.14 (s, 3H), 4.03–3.95 (m, 4H). 3.87 (s, 6H), 2.57 (dt, J = 12.5, 3.1 Hz, 1H), 2.31 (td, J = 12.6, 2.1 Hz, 1H), 2.16 (s, 3H), 1.85 (dt, J = 15.2, 3.3 Hz, 1H), 1.72 (td, J = 12.7, 2.9 Hz, 1H) (OH and NH were not observed) Measured value: [M+H] = 610.1.

Racemic compound B, white solid. ^¹H NMR ( _CDCl₃ , 400 MHz) δ 8.75 (s, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.52–7.48 (m, 2H), 7.04 (dd, J = 6.7, 2.7 Hz, 1H), 6.72–6.67 (m, 2H), 6.58 (bs, 2H), 5.37 (s, 1H), 4.42–4.28 (m, 4H), 3.84 (s, 3H), 3.83 (s, 6H), 2.59 (dt, J = 12.4, 3.3 Hz, 1H), 2.34–2.89 (m, 1H), 2.21 (s, 3H), 1.85–1.80 (m, 2H). Measured value: [M+H] = 610.1 (OH and NH were not observed).

1-(6-bromo-2-methoxyquinoline-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1-(5-methylthiophene-2-yl)but-2-ol (110)

Products from 16 and 7 were prepared using the following general coupling procedure. Unreacted quinolone 16 was eluted by column chromatography with 9:1 hexane:EtOAc, while column chromatography with 3:1 hexane:EtOAc yielded a white, foamy product 110 (67%), which was a mixture of diastereomers in a 1:0.95 ratio. ^1H NMR (CDCl3 ₎ )δ8.60 (s, 1H), 8.53 (s, 0.95H), 8.05–8.25 (bs, 1.7H), 7.81 (dd, J＝11.6, 2.2Hz, 2H), 7.66 (d, J＝8.9Hz, 1H), 7.59 (dd, J＝8.8, 2.2Hz, 1H ), 7.47-7.54 (m, 1.95H), 7.09 (d, J=8.4Hz, 1H), 6.90-6.95 (m, 1.95H), 6.48-6.55 (m, 3.8H), 6.38-6.40 (m, 4.1H), 6.35 (bs, 1.4H), 6.28 -6.31 (m, 1.4H), 5.15 (s, 1H), 5.08 (s, 0.95H), 4.09-4.15 (m, 3.5H), 3.88-3.92 (m, 8.6H), 3.75 (bs, 2.7H), 2.40-2.54 (m, 2.4H), 2.39 (d, J = 0.9Hz, 3H), 2.29 (d, J = 0.9Hz, 3H), 2.08-2.19 (m, 1.6H), 2.04-2.07 (m, 3.7H), 1.79-1.89 (m, 4.2H), 1.59-1.59 (m, 2H plus additional water-masked signal). Measured value: [M+H] = 722.4

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(methylamino)-1-(5-methylthiophen-2-yl)but-2-ol (111)

Triethylamine (0.63 mL, 4.5 mmol) and trifluoroacetic anhydride (0.54 mL, 4.1 mmol) were added sequentially to a solution of 110 (1.459 g, 2.02 mmol) in DMF (30 mL) at 0 °C. The solution was stirred at room temperature for 1 hour, then partitioned between DCM and a saturated aqueous solution of _NaHCO3 . The organic fraction was dried and evaporated to give an oily substance, which was dissolved in MeOH (50 mL) and cooled to 0 °C. _Cs2CO3 ( _1.64 g, 5.03 mmol) was added to water (10 mL) and the mixture was stirred at 4 °C for 16 hours. The mixture was diluted with water and then extracted with EtOAc. Column chromatography (EtOAc) yielded 111 (0.876 g, 76%) as a white, foamy mixture of diastereomers in a 1:0.7 ratio. ^1H NMR (CDCl3 ₎ )δ8.54 (s, 1H), 8.51 (s, 0.7H), 7.89 (d, J = 2.2Hz, 1H), 7.81 (d, J = 1.6Hz, 0.7H), 7.68 (d, J = 8.9Hz, 1H), 7.62 (dd, J = 8.8, 2.2Hz , 1H), 7.47-7.53 (m, 1.5H), 6.91 (d, J=3.4Hz, 0.7H), 6.51-6.56 (m, 3.6H), 6.38-6.43 (m, 1.4H), 6.29-6.33 (m, 1H), 5.18 (s, 1 5.09 (s, 0.7H), 4.13 (s, 3.8H), 3.92 (s, 2.1H), 3.91 (s, 5.6H), 3.78 (m, 4.2H), 2.67 (dt, J = 9.2, 3.3Hz, 1H), 2.55 (dt, J = 12.6, 3.0Hz, 1H), 2.34-2.45 (m, 3.1H), 2.18-2.33 (m, 6.7H), 2.16 (s, 3H), 1.67-1.82 (m, 2.6H), 1.42-1.62 (m, 4H plus additional water-masked signal). Measured value: [M+H] = 572.1

1-(benzofuran-7-yl)ethane-1-ol (112)

A solution of 7-bromobenzofuran (2.05 g, 10.4 mmol) in dry THF (20 mL) was prepared. Approximately 4 mL of this solution was added to a flask containing magnesium (0.75 g, 30.9 mmol) and the mixture was stirred until an exothermic reaction occurred. The remaining solution was added and the mixture was refluxed for 1 hour. After cooling, the mixture was transferred to a dry flask through a sleeve. The solution was cooled to 0 °C and acetaldehyde (0.70 mL, 12.3 mmol) was added. The mixture was stirred at 0 °C for 1 hour, then partitioned between EtOAc and water. The organic fraction was dried and evaporated. Nonpolar impurities were eluted by column chromatography with hexane:DCM (1:1), yielding 112 (1.21 g, 72%). ^¹H NMR ( _CDCl₃ ) δ 7.64 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 7.7, 1.2 Hz, 1H), 7.34 (bd, J = 7.3 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 5.38 (td, J = 6.5, 4.8 Hz, 1H), 2.16 (d, J = 4.8 Hz, 1H), 1.67 (d, J = 6.5 Hz, 3H). Measured value: [ _MH₂O ] = 145.

1-(benzofuran-7-yl)ethyl-1-one (113)

A mixture of 112 (1.16 g, 7.15 mmol) and _MnO2 (3.10 g, 35.6 mmol) in benzene (40 mL) was refluxed for 1 hour, filtered through diatomaceous earth, and the solvent was evaporated. Column chromatography with hexane:DCM (3:1 to 1:1) yielded 113 (0.98 g, 86%). ^¹H NMR ( _CDCl3 ) δ 7.92 (dd, J = 7.6, 1.2 Hz, 1H), 7.81 (dd, J = 7.7, 1.2 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 2.86 (s, 3H). Analytical value: [M+H] = 161.1.

1-(benzofuran-7-yl)-3-(dimethylamino)prop-1-one (114)

A mixture of 113 (4.95 g, 30.9 mmol), dimethylamine HCl (3.78 g, 46.4 mmol), and paraformaldehyde (1.39 g, 46.3 mmol) in EtOH (50 mL) and HCl (0.5 mL, 12 M, 6 mmol) was refluxed in a sealed tube for 18 hours. The solvent was evaporated, and the solid residue was milled with _Et₂O and filtered. The solid was washed with _Et₂O , dissolved in water and alkalized with 2 M NaOH, and then extracted with EtOAc (3 × 100 mL). The organic fraction was dried and evaporated to give 114 (4.63 g, 69%). ^¹H NMR ( _CDCl₃ ) δ 7.93 (dd, J = 7.6, 1.1 Hz, 1H), 7.81 (dd, J = 7.7, 1.3 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 3.46 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.32 (s, 6H). Measured value: [M+H] = 218.2.

(5,6-Dimethoxypyridin-3-yl)methanol(115)

n-BuLi (4.90 mL, 2.0 M cyclohexane solution, 35.2 mmol) was added to a solution of 5-bromo-2,3-dimethoxypyridine (7.00 g, 32.1 mmol) in dry THF (100 mL) at -35 °C. The milky precipitate was stirred at -35 °C for 0.5 h, and then DMF (4.90 mL, 63.7 mmol) was added. The mixture was stirred at -35 °C for 1 h, then quenched with water and partitioned between EtOAc and water. The organic fraction was dried and evaporated. Crude aldehyde was dissolved in MeOH (50 mL) and cooled to -40 °C. _NaBH₄ (1.20 g, 32 mmol) was added, and the mixture was stirred at -40 °C for 1 h, then quenched with water. The mixture was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography using hexane:EtOAc (2:1) yielded 115 (4.02 g, 74%). ^¹H NMR ( _CDCl₃ ) δ 7.67 (d, J = 1.9 Hz, 1H), 7.13 (d, J = 1.9 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 1.77 (t, J = 5.4 Hz, 1H). Measured value: [M+H] = 170.2.

(5-Bromomethyl)-2,3-Dimethoxypyridine (116)

A solution of 115 (3.98 g, 23.6 mmol) in DCM (anhydrous, 80 mL) was treated at 0 °C with triethylamine (6.6 mL, 47.4 mmol) followed by methanesulfonyl chloride (2.73 mL, 35.3 mmol). The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (100 mL), LiBr (117 mmol) was added, and the mixture was refluxed for 1 hour and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) yielded 116 (3.36 g, 61%), which was contaminated with the corresponding chlorine derivative (0.30 g, 7%). ^¹H NMR ( _CDCl₃ ) δ 7.73 (d, J = 2.0 Hz, ¹H), 7.07 (d, J = 2.0 Hz, ¹H), 4.47 (s, 2H), 4.02 (s, 3H), 3.90 (s, 3H). Measured value: [M+H] = 232.4

6-Bromo-3-((5,6-dimethoxypyridin-3-yl)methyl)-2-methoxyquinoline (117)

The mixture of 1 (4.02 _g , 14.3 mmol), 116 (3.34 g, 14.4 mmol), and _Cs₂CO₃ (9.3 g, 28.5 mmol) in toluene (80 mL, anhydrous) and DMF (40 mL, anhydrous) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.33 g, 0.3 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 4 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (95:5 DCM:EtOAc) yielded the product, which was recrystallized from MeOH to give 117 (3.85 g, 69%). ^¹H NMR ( _CDCl₃ ) δ 7.77 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 7.52 (s, 1H), 6.92 (d, J = 1.9 Hz, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 3.95 (s, 2H), 3.83 (s, 3H). Measured value: [M+H] = 389.1

(2,3-Dimethoxypyridin-4-yl)methanol(118)

A warm solution of 2,3-dimethoxyisocyanin formaldehyde (0.68 g, 4.10 mmol) in EtOH (5 mL) was added dropwise to a suspension of _NaBH₄ (0.08 g, 2.04 mmol) in EtOH (10 mL) at -40 °C, resulting in gas escaping. The mixture was stirred at -40 °C for 45 min. The mixture was quenched with brine (10 mL) and diluted with water (10 mL), then extracted with ether (3 × 50 mL). Column chromatography (1:1 hexane:EtOAc) yielded 118 (0.69 g, 98%). ^¹H NMR ( _CDCl₃ ) δ 7.89 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 5.1 Hz, 1H), 4.73 (d, J = 6.1 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 2.15 (t, J = 6.1 Hz, 1H). Measured value: [M+H] = 170.2.

4-(bromomethyl)-2,3-dimethoxypyridine (119)

  

A solution of 118 (2.83 g, 16.8 mmol) and triethylamine (4.70 mL, 33.7 mmol) in DCM (50 mL, anhydrous) was cooled to 0 °C and then treated with methanesulfonyl chloride (1.95 mL, 25.2 mmol). The turbid suspension was stirred at 0 °C for 1 hour and partitioned between DCM and water. The organic fraction was dried and evaporated to give crude methanesulfonate. The crude methanesulfonate was dissolved in acetone (100 mL) and LiBr (14.5 g, 167 mmol) was added. The mixture was refluxed for 1 hour, evaporated, and the residue was partitioned between DCM and water. The organic fraction was dried and evaporated. Column chromatography (DCM) gave 119 (3.53 g, 91%). ^¹H NMR ( _CDCl₃ ) δ 7.85 (d, J = 5.2 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H), 4.45 (s, 2H), 4.01 (s, 3H), 3.95 (s, 3H). Measured value: [M+H] = 232.4

6-Bromo-3-((2,3-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (120)

The mixture of 1 (10.28 _g , 36.5 mmol), 119 (8.64 g, 36.5 mmol), and _Cs₂CO₃ (24.0 g, 73.7 mmol) in DMF:toluene (1:2, 200 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.84 g, 0.73 mmol) was added, and the mixture was heated to 80 °C for 3 hours under nitrogen. The mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic fraction was dried and evaporated, and column chromatography was performed using a gradient from 3:1 hexane:DCM to 95:5 DCM:EtOAc to give 120 (8.65 g, 61%). ^¹H NMR ( _CDCl₃ ) δ 7.80 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (s, 1H), 6.66 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H), 4.03 (s, 2H), 4.02 (s, 3H), 3.80 (s, 3H). Measured value: [M+H] = 389.1

N-Methoxy-N-methylbenzofuran-2-carboxamide (121)

Oxaloyl chloride (3.13 mL, 3.70 mmol) was added to a suspension of benzofuran-2-carboxylic acid (5.00 g, 3.08 mmol) in DCM (100 mL, anhydrous) and DMF (0.1 mL, 1.3 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (3.31 g, 3.39 mmol) and pyridine (7.5 mL, 9.27 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and a saturated aqueous solution of _NaHCO3 . Column chromatography (3:1 hexane:EtOAc) yielded 121 (6.32 g, 100%). ^¹H NMR ( _CDCl₃ ) δ 7.69 (ddd, 7.9, 1.2, 0.7 Hz, 1H), 7.61 (ddd, J = 8.4, 1.7, 0.9 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.48 (ddd, J = 7.9, 7.2, 1.3 Hz, 1H), 7.30 (ddd, J = 7.5, 7.3, 0.9 Hz, 1H), 3.84 (s, 3H), 3.43 (s, 3H). Measured value: [M+H] = 206.2.

1-(benzofuran-2-yl)-3-(dimethylamino)prop-1-one (122)

Vinyl magnesium bromide (58 mL, 58 mmol, 1 M in THF) was added to a solution of 121 (3.95 g, 19.2 mmol) in THF (200 mL, anhydrous) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine (58 mL, 116 mmol, 2 M in THF) and water (40 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give 122 (4.17 g, 100%). ^¹H NMR ( _CDCl₃ ) δ 7.72 (ddd, J = 7.9, 1.0, 0.8 Hz, 1H), 7.59 (dd, J = 8.4, 0.8 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.48 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 7.32 (ddd, J = 7.5, 7.2, 1.0 Hz, 1H), 3.14 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H). Measured value: [M+H] = 218.2.

Methyl benzofuran-5-carboxylate (123)

A mixture of 5-bromobenzofuran (4.00 g, 20.3 mmol), DPPP (0.42 g, 1 mmol), triethylamine (6.3 mL, 45 mmol), and Pd(OAc) _₂ (0.23 g, 1 mmol) in DMSO (30 mL) and MeOH (30 mL) from a Berghof pressure reactor was purged and then purged three times with carbon monoxide. The mixture was heated to 80 °C at 60 psi carbon monoxide pressure for 18 hours, cooled, and partitioned between EtOAc and water. Column chromatography was performed, eluting trace impurities with 3:1 hexane:DCM, while elution with DCM yielded 123 (2.77 g, 78%). ¹ H NMR (CDCl ₃ )δ8.35 (d, J=1.4Hz, 1H), 8.03 (dd, J=8.7, 1.7Hz, 1H), 7.69 (d, J=2.2Hz, 1H), 7.53 (dt, J=8.7, 0.8Hz, 1H), 6.84 (dd, J=2.2, 1.0Hz, 1H), 3.94 (s, 3H).

Benzofuran-5-carboxylic acid (124)

A solution of LiOH (1.13 g, 47.2 mmol) in water (20 mL) was added to a solution of 123 (2.77 g, 15.7 mmol) in THF (40 mL) and MeOH (40 mL). The solution was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in water (50 mL) and acidified to pH 2 with concentrated HCl. The precipitate was dissolved in EtOAc, and the organic fraction was dried and evaporated to give 124 (2.49 g, 98%). ¹ H NMR (DMSO-d ₆ ) δ12.86 (s, 1H), 8.30 (d, J=1.4Hz, 1H), 8.10 (d, J=2.2Hz, 1H), 7.92 (dd, J=8.6, 1.8Hz, 1H), 7.68 (dt, J=8.6, 0.7Hz, 1H), 7.08 (dd, J=2.2, 0.9Hz, 1H).

N-Methoxy-N-methylbenzofuran-5-carboxamide (125)

Oxaloyl chloride (1.55 mL, 18.3 mmol) was added to a suspension of 124 (2.48 g, 15.3 mmol) in DCM (100 mL, anhydrous) and DMF (0.05 mL, 0.64 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (1.64 g, 16.8 mmol) and pyridine (3.71 mL, 45.9 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and a saturated aqueous solution of _NaHCO3 . Column chromatography with a 95:5 DCM:EtOAc solution yielded a pale brown oily 125 (2.28 g, 73%). ^¹H NMR ( _CDCl₃ ) δ 7.99 (d, J = 1.4 Hz, 1H), 7.65–7.69 (m, 2H), 7.52 (dt, J = 8.6, 0.6 Hz, 1H), 6.82 (dd, J = 2.2, 0.9 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H). Measured value: [M+H] = 206.2.

1-(benzofuran-5-yl)-3-(dimethylamino)prop-1-one (126)

Vinyl magnesium bromide (33.2 mL, 1 M in THF, 33.2 mmol) was added to a solution of 125 (2.27 g, 11.1 mmol) in THF (100 mL, Na distillation) at 0 °C. The brown solution was stirred at 0 °C for 1 hour, and then dimethylamine (33.2 mL, 2 M in THF, 66.4 mmol) and water (20 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give 126 (2.33 g, 97%). ^¹H NMR ( _CDCl₃ ) δ 8.27 (d, J = 1.8 Hz, 1H), 7.98 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.84 (dd, J = 2.2, 0.8 Hz, 1H), 3.22 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.31 (s, 6H). Measured value: [M+H] = 218.2.

(2,6-Diethoxypyridin-4-yl)methanol(127)

Trimethyl borate (3.88 mL, 34.2 mmol) and borane-dimethyl sulfide (3.25 mL, 34.3 mmol) were added sequentially to a solution of 2,6-diethoxyisonicotinic acid (2) (2.41 g, 11.4 mmol) in THF (100 mL, Na distillation) at 0 °C, and the mixture was stirred at room temperature for 18 hours. The solution was cooled to 0 °C and methanol was carefully added to quench excess borane. The solvent was removed to give a solid, which was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography (3:1 hexane:EtOAc) gave 127 (2.13 g, 95%). ^¹H NMR (DMSO- _d₆ ) δ 6.27 (d, J = 0.6 Hz, 2H), 4.62 (d, J = 6.2 Hz, 2H), 4.31 (q, J = 7.1 Hz, 4H), 1.72 (t, J = 6.2 Hz, 1H), 1.38 (t, J = 7.1 Hz, 6H). Measured value: [M+H] = 198.1.

4-(bromomethyl)-2,6-diethoxypyridine (128)

A solution of 127 (2.07 g, 10.5 mmol) in DCM (100 mL, anhydrous) was treated sequentially with triethylamine (2.93 mL, 21.0 mmol) and methanesulfonyl chloride (1.22 mL, 15.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (100 mL), LiBr (9.15 g, 105 mmol) was added, and the mixture was refluxed for 1 hour, and then evaporated. The residue was partitioned between DCM and water, and the organic fraction was dried and evaporated. Column chromatography (DCM) yielded 128 (2.63 g, 92%). ^¹H NMR ( _CDCl₃ ) δ 6.28 (s, 2H), 4.31 (q, J = 7.1 Hz, 4H), 4.28 (s, 2H), 1.38 (t, J = 7.1 Hz, 6H). Measured value: [M+H] = 260.5

6-Bromo-3-((2,6-diethoxypyridin-4-yl)methyl)-2-methoxyquinoline (129)

The mixture of 1 (2.20 _g , 7.80 mmol), 128 (2.13 g, 8.20 mmol), and _Cs₂CO₃ (5.13 g, 15.6 mmol) in toluene (40 mL) and DMF (20 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.18 g, 0.156 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 3 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography was performed, eluting nonpolar impurities with 3:1 hexane:DCM and eluting with 1:1 hexane:DCM to give 129 (2.35 g, 72%). ^¹H NMR ( _CDCl₃ ) δ 7.77 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.58 (s, 1H), 6.13 (s, 2H), 4.29 (q, J = 7.1 Hz, 4H), 4.06 (s, 3H), 3.90 (s, 2H), 1.36 (t, J = 7.1 Hz, 6H). Measured value: [M+H] = 417.1

Benzofuran-4-yltrifluoromethanesulfonate (130)

A solution of benzofuran-4-ol (2.61 g, 19.5 mmol), DMAP (0.060 g, 0.49 mmol), and pyridine (2.37 mL, 29.3 mmol) in DCM (60 mL, anhydrous) was treated with TFAA (4.92 mL, 29.2 mmol) at 0 °C and stirred at 0 °C for 2 h. The mixture was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (hexane) yielded 130 (3.93 g, 76%). ^¹H NMR ( _CDCl₃ ) δ 7.70 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 1.9, 1.0 Hz, 1H). Measured value: [M+H]＝267.0.

Methyl benzofuran-4-carboxylate (131)

A mixture of 130 (3.88 g, 14.6 mmol), DPPP (0.180 g, 0.44 mmol), triethylamine (4.07 mL, 29.2 mmol), and Pd(OAc) _₂ (0.098 g, 0.44 mmol) in DMSO (50 mL) and MeOH (50 mL) from a Berghof pressure reactor was purged and then purged three times with carbon monoxide. The mixture was heated to 80 °C at 60 psi carbon monoxide pressure for 18 hours, cooled, and partitioned between EtOAc and water. Column chromatography was performed, eluting trace impurities with 3:1 hexane:DCM, while elution with DCM yielded 131 (2.08 g, 81%). ¹ H NMR (CDCl ₃ ) δ 7.99 (dd, J=7.7, 0.9Hz, 1H), 7.74 (d, J=2.2Hz, 1H), 7.70 (dt, J=8.2, 0.9Hz, 1H), 7.33-7.39 (m, 2H), 3.99 (s, 3H).

Benzofuran-4-carboxylic acid (132)

A solution of LiOH (1.44 g, 34.3 mmol) in water (20 mL) was added to a solution of 131 (2.02 g, 11.4 mmol) in THF (20 mL) and MeOH (20 mL), and the solution was stirred at room temperature for 16 hours, then evaporated. The residue was dissolved in water (50 mL) and acidified with concentrated HCl. The precipitate was filtered and dried to give 132 (1.83 g, 99%). ^¹H NMR (DMSO- _d₆ ) δ 13.10 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.85–7.91 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.33 (dd, J = 2.1, 1.0 Hz, 1H). Observed value: [MH] = 161.1.

N-Methoxy-N-methylbenzofuran-4-carboxamide (133)

Oxaloyl chloride (1.14 mL, 13.5 mmol) was added to a suspension of 132 (1.82 g, 11.2 mmol) in DCM (100 mL, anhydrous) and DMF (0.2 mL, 2.5 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (1.31 g, 13.5 mmol) and pyridine (2.72 mL, 33.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between DCM and water. Column chromatography with 95:5 DCM:EtOAc yielded 133 (2.13 g, 93%). ^¹H NMR ( _CDCl₃ ) δ 7.68 (d, J = 2.2 Hz, 1H), 7.59 (dt, J = 8.3, 0.8 Hz, 1H), 7.51 (dd, J = 7.5, 0.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.95 (dd, J = 2.2, 0.9 Hz, 1H), 3.56 (s, 3H), 3.40 (s, 3H). Measured value: [M+H] = 206.2.

1-(benzofuran-4-yl)-3-(dimethylamino)prop-1-one (134)

Vinyl magnesium bromide (20.5 mL, 20.5 mmol) was added to a solution of 133 (2.11 g, 10.3 mmol) in THF (100 mL, Na distillation) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine in THF (20.5 mL, 2 M, 41 mmol) and water (20 mL) was added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give 134 (1.83 g, 82%). ^¹H NMR ( _CDCl₃ ) δ 7.86 (dd, J = 7.6, 0.6 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.71 (dt, J = 8.2, 0.8 Hz, 1H), 7.55 (dd, J = 2.2, 1.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 3.27 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H), 2.32 (s, 6H). Measured value: [M+H] = 218.2.

Benzo[b]thiophene-7-carboxylate (135)

A suspension of 2-mercaptobenzoic acid (10.00 g, 6.49 mmol) in EtOH (50 mL) was treated with 2-bromo-1,1,-dimethoxyethane (10 mL, 8.5 mmol) and NaOH (5.70 g, 14.3 mmol), and the mixture was refluxed for 3 hours. The solvent was evaporated, and the residue was dissolved in DMF (100 mL), with MeI (6.0 mL, 9.6 mmol) and _K₂CO₃ (27.0 g, 19.5 mmol) added _. The mixture was stirred at room temperature for 1 hour, then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried, and evaporated. The residue was dissolved in chlorobenzene (50 mL), with polyphosphoric acid (33 g) added, and the mixture was heated to 130 °C for 2 hours. The viscous residue was poured onto ice and extracted with EtOAc. The organic fraction was washed with water and brine, dried, and evaporated. Column chromatography with 10:1 hexane:EtOAc yielded 135 (6.46 g, 52%). ^¹H NMR ( _CDCl₃ ) δ 8.12 (ddd, J = 6.9, 1.0, 0.4 Hz, 1H), 8.03 (dd, J = 7.9, 1.2 Hz, 1H), 7.58 (dd, J = 5.6, 0.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 5.6 Hz, 1H), 4.03 (s, 3H).

Benzo[b]thiophene-7-carboxylic acid (136)

A solution of LiOH (2.10 g, 87.7 mmol) in water (25 mL) was added to a solution of 135 (5.61 g, 29.2 mmol) in THF (50 mL) and MeOH (50 mL), and the solution was stirred at room temperature for 18 hours, then evaporated. The residue was dissolved in water (150 mL) and acidified to pH 2 with concentrated HCl. The precipitate was extracted into EtOAc, and the organic fraction was dried and evaporated to give 136 (4.69 g, 90%). ^¹H NMR (DMSO- _d₆ ) δ 13.42 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.50–7.56 (m, 2H). Observed value: [MH] = 177.1.

N-Methoxy-N-methylbenzo[b]thiophene-7-carboxamide (137)

Oxaloyl chloride (2.67 mL, 31.6 mmol) was added to a suspension of 136 (4.69 g, 26.3 mmol) in DCM (200 mL, anhydrous) and DMF (0.5 mL, 6.5 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour and then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (3.08 g, 31.6 mmol) and pyridine (6.38 mL, 78.9 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, then partitioned between EtOAc and saturated _NaHCO3 aqueous solution. Column chromatography with DCM yielded 137 (5.48 g, 94%). ^¹H NMR ( _CDCl₃ ) δ 7.92 (dd, J = 7.9, 1.0 Hz, 1H), 7.81 (dd, J = 7.5, 0.5 Hz, 1H), 7.53 (dd, J = 5.5, 0.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 5.5 Hz, 1H), 3.61 (s, 3H), 3.43 (s, 3H). Measured value: [M+H] = 222.1.

1-(benzo[b]thiophene-7-yl)-3-(dimethylamino)prop-1-one (138)

Vinyl magnesium bromide (49 mL, 1 M, 49 mmol) was added to a solution of 137 (5.38 g, 24.3 mmol) in THF (250 mL, Na distillation) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine in THF (49 mL, 2 M, 98 mmol) and water (25 mL) was added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give 138 (5.45 g, 96%). ^¹H NMR ( _CDCl₃ ) δ 8.07 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 5.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 3.34 (t, J = 7.7 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.33 (s, 6H). Measured value: [M+H] = 234.1.

2-Hydroxy-6-methoxyisonicotinic acid methyl ester (139)

A suspension of 2,6-dihydroxyisonicotinic acid (10.00 g, 64.5 mmol) in MeOH (60 mL) was treated dropwise _{with H₂SO₄} (10 mL, 18.4 M, 184 mmol). The solution was refluxed for 72 hours and then evaporated. The residue was treated with saturated _NaHCO₃ aqueous solution to pH 8 and extracted with EtOAc (3 × 200 mL). The organic extract was washed with saturated _NaHCO₃ aqueous solution and brine, then dried and evaporated to give 139 (3.55 g, 30%). ^¹H NMR (DMSO- _d₆ ) δ 11.2 (bs, 1H), 6.61 (bs, 2H), 3.84 (s, 3H), 3.83 (s, 3H). Found: [M+H] = 184.2.

2-Isopropoxy-6-methoxyisonicotinic acid methyl ester (140)

A solution of 139 (5.04 g, 27.5 mmol) in DMF (100 mL, anhydrous) was treated _{with K₂CO₃} (4.75 g, 34.4 mmol) followed by 2-iodopropane (3.43 mL, 34.4 mmol). The mixture was stirred at room temperature for 24 h, then more 2-iodopropane (3.43 mL, 34.3 mmol) was added and the mixture was stirred for another ⁷² h. The mixture was then partitioned between EtOAc and water, and the aqueous layer was further extracted with EtOAc. The organic fraction was washed with water, dried, and evaporated. Chromatography (DCM) yielded 140 (6.21 g, 100%). ¹H NMR ( _CDCl₃ ) δ 6.81 (s, 2H), 5.24 (sp, J = 6.2 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 1.36 (d, J = 6.2 Hz, 6H). Measured value: [M+H]＝226.2.

2-Isopropoxy-6-methoxyisonicotinic acid (141)

A solution of LiOH (1.98 g, 82.7 mmol) in water (60 mL) was added to a solution of 140 (6.20 g, 27.5 mmol) in MeOH (60 mL) and THF (60 mL), and the solution was stirred at room temperature for 18 hours, then evaporated. The residue was dissolved in water (150 mL) and acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 141 (5.33 g, 92%) as a white solid. ^¹H NMR (DMSO- _d₆ ) δ 13.50 (bs, 1H), 6.70 (d, J = 1.0 Hz, 1H), 6.66 (d, J = 1.0 Hz, 1H), 5.20 (sp, J = 6.2 Hz, 1H), 3.86 (s, 3H), 1.31 (d, J = 6.2 Hz, 6H). Measured value: [M+H]＝212.1.

2-Isopropoxy-N,6-Dimethoxy-N-methylisonicotinamide (142)

Oxaloyl chloride (1.75 mL, 20.7 mmol) was added to 141 (3.65 g, 17.3 mmol) in DCM (100 mL, anhydrous) and DMF (0.3 mL) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (2.03 g, 20.8 mmol) and pyridine (4.2 mL, 51.9 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and water. Column chromatography with a 3:1 hexane:EtOAc solution yielded 142 (4.58 g, 100%), which was used directly for the subsequent synthesis of 143. ^¹H NMR ( _CDCl₃ ) δ 6.42 (s, ¹H), 6.41 (s, ¹H), 5.24 (sp, J = 6.2 Hz, ¹H), 3.90 (s, ³H), 3.60 (bs, ³H), 3.32 (bs, ³H), 1.35 (d, J = 6.2 Hz, ⁶H). Measured value: [M+H] = 255.2.

3-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)prop-1-one (143)

Vinyl magnesium bromide (36 mL, 1 M, 36 mmol) was added to a solution of 142 (4.54 g, 17.9 mmol) in THF (200 mL, Na distillation) at 0 °C. The brown solution was heated to room temperature for 1 hour, followed by the addition of dimethylamine in THF (36 mL, 2 M, 72 mmol) and water (30 mL). The solution was stirred at room temperature for 1 hour and then partitioned between EtOAc and water. Column chromatography using a gradient from 97.5:2.5 DCM:MeOH to 95:5 DCM:MeOH yielded 143 (3.58 g, 75%). ^¹H NMR ( _CDCl₃ ) δ 6.70 (d, J = 1.0 Hz, 1H), 6.69 (d, J = 1.0 Hz, 1H), 5.25 (sp, J = 6.2 Hz, 1H), 3.92 (s, 3H), 3.05 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.26 (s, 6H), 1.36 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 267.2.

2-Ethoxy-6-methoxyisonicotinic acid methyl ester (144)

A solution of 139 (6.96 g, 38.0 mmol) in DMF (100 mL, anhydrous) was treated _{with K₂CO₃} (6.57 g, 47.6 mmol) followed by iodoethane (3.85 mL, 47.6 mmol). The mixture was stirred at room temperature for 24 h, partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic fraction was washed with water, dried, and evaporated, and subjected to DCM chromatography to give 144 (6.20 g, 77%). ^¹H NMR ( _CDCl₃ ) δ 6.84 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). Analytical value: [M+H] = 212.1.

2-Ethoxy-6-methoxyisonicotinic acid (145)

A solution of LiOH (2.10 g, 87.7 mmol) in water (60 mL) was added to a solution of 144 (6.20 g, 29.4 mmol) in MeOH (60 mL) and THF (60 mL). The solution was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in water (150 mL) and acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 145 (5.61 g, 97%) as a white solid. ^¹H NMR (DMSO- _d₆ ) δ 13.54 (bs, ¹H), 6.73 (d, J = 1.0 Hz, ¹H), 6.71 (d, J = 1.0 Hz, ¹H), 4.32 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). Measured value: [M+H]＝198.2.

2-Ethoxy-N,6-Dimethoxy-N-methylisonicotinamide (146)

Oxaloyl chloride (2.18 mL, 25.8 mmol) was added to a suspension of 145 (4.23 g, 21.5 mmol) in DCM (100 mL, anhydrous) and DMF (0.3 mL) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (2.51 g, 25.8 mmol) and pyridine (5.2 mL, 64.3 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between DCM and a saturated aqueous solution of _NaHCO3 . Column chromatography with 3:1 hexane:EtOAc yielded 146 (5.02 g, 97%). ^¹H NMR ( _CDCl₃ ) δ 6.46 (s, ¹H), 6.45 (s, ¹H), 4.35 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.59 (bs, 3H), 3.32 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). Measured value: [M+H] = 241.1.

3-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)prop-1-one (147)

Vinyl magnesium bromide (16.6 mL, 1 M, 16.6 mmol) was added to a solution of 146 (2.00 g, 8.30 mmol) in THF (100 mL, Na distillation) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine was added to THF (2 M, 16.6 mL, 33.2 mmol) and water (25 mL). The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated, and column chromatography of the residue (95:5 DCM:MeOH) gave 147 (1.40 g, 67%). ^¹H NMR ( _CDCl₃ ) δ 6.73 (s, ¹H), 6.72 (s, ¹H), 4.37 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.06 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.27 (s, 6H), 1.41 (t, J = 7.0 Hz, 3H). Measured value: [M+H] = 253.2.

(2-Isopropoxy-6-methoxypyridin-4-yl)methanol(148)

   

Trimethyl borate (6.81 mL, 59.6 mmol) and borane dimethyl sulfide complex (5.66 mL, 59.7 mmol) were added sequentially to a solution of 141 (6.30 g, 29.8 mmol) in THF (100 mL, Na distillation) at 0 °C. The mixture was stirred at room temperature for 18 hours. The solution was cooled to 0 °C and quenched with methanol. The solvent was removed to give a white solid, which was partitioned between EtOAc and water. The organic fraction was dried and evaporated to give 148 (5.86 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 6.26 (t, J = 0.8 Hz, 1H), 6.25 (t, J = 0.8 Hz, 1H), 5.23 (sp, J = 6.2 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 1.73 (t, J = 6.2 Hz, 1H), 1.34 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 212.2 (M-OH+MeO).

4-(bromomethyl)-2-isopropoxy-6-methoxypyridine (149)

A solution of 148 (5.86 g, 29.9 mmol) in DCM (100 mL, anhydrous) was treated with triethylamine (8.3 mL, 59.5 mmol) followed by methanesulfonyl chloride (3.47 mL, 44.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (200 mL), LiBr (25.9 g, 299 mmol) was added, and the mixture was refluxed for 1 hour and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) yielded 149 (6.98 g, 90%). ^¹H NMR ( _CDCl₃ ) δ 6.28 (s, ¹H), 6.27 (s, ¹H), 5.23 (sp, J = 6.2 Hz, ¹H), 4.27 (s, 2H), 3.88 (s, 3H), 1.35 (d, J = 6.3 Hz, 6H). Measured value: [M+H] = 260.1

6-Bromo-3-((2-isopropoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (150)

The mixture of 1 (7.45 _g , 26.4 mmol), 149 (6.84 g, 26.4 mmol), and _Cs₂CO₃ (17.3 g, 52.7 mmol) in toluene (100 mL) and DMF (50 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.61 g, 0.528 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 3 hours under nitrogen. The reaction mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography was performed, with impurities eluted with 3:1 hexane:DCM and eluted with 1:1 hexane:DCM to give 150 (8.59 g, 78%). ^¹H NMR ( _CDCl₃ ) δ 7.78 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.58 (s, 1H), 6.14 (d, J = 0.9 Hz, 1H), 6.10 (d, J = 0.9 Hz, 1H), 5.22 (sp, J = 6.2 Hz, 1H), 4.06 (s, 3H), 3.90 (s, 2H), 3.87 (s, 3H), 1.33 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 417.1

(2-Ethoxy-6-methoxypyridin-4-yl)methanol (151)

Trimethyl borate (6.06 mL, 53.1 mmol), followed by borane-dimethyl sulfide (5.04 mL, 53.1 mmol), was added to a solution of 145 (5.24 g, 26.6 mmol) in THF (100 mL, Na distillation) at 0 °C, and the mixture was stirred at room temperature for 18 hours. The solution was cooled to 0 °C and quenched with methanol. The solvent was removed to obtain a solid, which was partitioned between EtOAc and water. The organic fraction was dried and evaporated to give 151 (4.79 g, 98%). ^¹H NMR ( _CDCl₃ ) δ 6.29 (bd, J = 0.7 Hz, 1H), 6.28 (bd, J = 0.7 Hz, 1H), 4.63 (d, J = 6.2 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.76 (t, J = 6.2 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H). Measured value: [M+H] = 184.2.

4-(bromomethyl)-2-ethoxy-6-methoxypyridine (152)

A solution of 151 (4.72 g, 25.9 mmol) in DCM (100 mL, anhydrous) was treated sequentially with triethylamine (7.22 mL, 51.8 mmol) and methanesulfonyl chloride (3.00 mL, 38.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (200 mL). LiBr (22.5 g, 259 mmol) was added, and the mixture was refluxed for 1 hour and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) yielded 152 (5.78 g, 91%). ^¹H NMR ( _CDCl₃ ) δ 6.30 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4.28 (s, 2H), 3.90 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). Measured value: [M+H] = 246.0

6-Bromo-3-((2-ethoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (153)

The mixture of 1 (6.61 _g , 23.4 mmol), 152 (5.77 g, 23.4 mmol), and _Cs₂CO₃ (15.25 g, 46.5 mmol) in toluene (100 mL) and DMF (50 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.54 g, 0.465 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 3 hours under nitrogen. The reaction mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography was performed, eluting impurities with 3:1 hexane:DCM followed by elution with 1:1 hexane:DCM to give 153 (6.69 g, 71%). ^¹H NMR ( _CDCl₃ ) δ 7.78 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.15 (d, J = 8.0 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 3.91 (s, 2H), 3.88 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). Measured value: [M+H] = 403.1

2-Ethoxy-6-hydroxyisonicotinic acid ethyl ester (154)

A suspension of 2,6-dihydroxyisonicotinic acid (40.00 g, 258 mmol) in EtOH (300 mL) was treated dropwise _{with H₂SO₄} (40 mL, 18.4 M, 752 mmol). The solution was refluxed for 72 hours and then evaporated; the residue was treated with saturated _NaHCO₃ aqueous solution to pH 8 and then extracted with EtOAc (3 × 500 mL). The organic extract was washed with saturated _NaHCO₃ aqueous solution and brine, then dried and evaporated to give 154 (10.86 g, 20%). ^¹H NMR (DMSO- _d₆ ) δ 11.15 (bs, ¹H), 6.59 (d, J = 1.0 Hz, ¹H), 6.57 (bs, ¹H), 4.29 (q, J = 7.1 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.298 (t, J = 7.1 Hz, 3H), 1.296 (t, J = 7.1 Hz, 3H). Measured value: [M+H] = 212.2.

2-Ethoxy-6-isopropoxyisonicotinic acid ethyl ester (155)

A solution of 154 (10.82 g, 51.2 mmol) in DMF (125 mL, anhydrous) was treated _{with K₂CO₃} (8.65 g, 62.5 mmol), followed by 2-iodopropane (6.4 mL, 64 mmol). The mixture was stirred at room temperature for 48 hours, then _K₂CO₃ (8.65 _g , 62.5 mmol) and 2-iodopropane (6.4 mL, 64 mmol) were added, and the mixture was stirred for an additional 24 hours. The mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic fraction was washed with water, dried, and evaporated. Chromatography (DCM) was performed to give 155 (11.56 g, 89%). ^¹H NMR (DMSO- _d₆ ) δ 6.81 (s, 2H), 5.23 (sp, J = 6.2 Hz, 1H), 4.20–4.38 (m, 4H), 1.35–1.42 (m, 12H). Measured value: [M+H] = 254.1.

2-Ethoxy-6-isopropoxyisonicotinic acid (156)

A solution of LiOH (3.25 g, 136 mmol) in water (60 mL) was added to a solution of 155 (11.42 g, 45.1 mmol) in THF (60 mL) and MeOH (60 mL). The solution was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in water (150 mL) and acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 156 (10.03 g, 99%). ^¹H NMR (DMSO- _d₆ ) δ 13.48 (bs, ¹H), 6.66 (d, J = 0.9 Hz, ¹H), 6.64 (d, J = 0.9 Hz, ¹H), 5.17 (sp, J = 6.2 Hz, ¹H), 4.29 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.30 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 226.1.

2-Ethoxy-6-isopropoxy-N-methoxy-N-methylisonicotinamide (157)

Oxaloyl chloride (3.13 mL, 37 mmol) was added to 156 (6.95 g, 30.8 mmol) in DCM (100 mL, anhydrous) and DMF (5.2 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (3.61 g, 37.0 mmol) and pyridine (7.5 mL, 92.7 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and water. The organic fraction was washed with water, dried, and evaporated. Column chromatography with 95:5 DCM:EtOAc yielded 157 (7.98 g, 97%). ^¹H NMR ( _CDCl₃ ) δ 6.40 (s, ¹H), 6.39 (s, ¹H), 5.22 (sp, J = 6.2 Hz, ¹H), 4.33 (q, J = 7.1 Hz, 2H), 3.60 (bs, 3H), 3.31 (s, 3H), 1.39 (t, J = 6.2 Hz, 3H), 1.34 (d, J = 7.1 Hz, 6H). Measured value: [M+H] = 269.2.

3-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)prop-1-one (158)

Vinyl magnesium bromide (40 mL, 1 M, 40 mmol in THF) was added to a solution of 157 (5.33 g, 19.9 mmol) in THF (100 mL, distilled Na) at 0 °C. The brown solution was stirred at 0 °C for 1 hour, and then dimethylamine (40 mL, 2 M, 80 mmol in THF) and water (40 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give a brown oily 158 (5.57 g, 100%). ^¹H NMR ( _CDCl₃ ) δ 6.68 (d, J = 1.0 Hz, 1H), 6.67 (d, J = 1.0 Hz, 1H), 5.22 (sp, J = 6.2 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.26 (s, 6H), 1.40 (t, J = 6.2 Hz, 3H), 1.36 (d, J = 7.0 Hz, 6H). Measured value: [M+H] = 281.7.

2-Methoxy-6-propoxyisonicotinic acid methyl ester (159)

A solution of 139 (6.00 g, 32.8 mmol) in DMF (100 mL, anhydrous) was treated _{with K₂CO₃} (6.80 g, 49.2 mmol), followed by 1-iodopropane (4.8 mL, 49.2 mmol). The mixture was stirred at room temperature for 48 hours, partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic fraction was washed with water, dried, and evaporated. Column chromatography (DCM) was performed to give 159 (6.59 g, 89%). ^¹H NMR ( _CDCl₃ ) δ 6.85 (d, J = 1.0 Hz, 1H), 6.83 (d, J = 1.0 Hz, 1H), 4.24 (t, J = 6.7 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.80 (qt, J = 7.4, 6.7 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). Measured value: [M+H] = 226.1.

2-Methoxy-6-propoxyisonicotinic acid (160)

A solution of LiOH (2.04 g, 85.2 mmol) in water (60 mL) was added to a solution of 159 (6.40 g, 28.4 mmol) in THF (60 mL) and MeOH (60 mL). The solution was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in water (200 mL) and acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 160 (5.39 g, 90%). ^¹H NMR (DMSO- _d₆ ) δ 13.53 (bs, ¹H), 6.73 (d, J = 1.0 Hz, ¹H), 6.72 (d, J = 1.0 Hz, ¹H), 4.23 (t, J = 6.6 Hz, 2H), 3.87 (s, 3H), 1.73 (qt, J = 7.4, 6.6 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). Measured value: [M+H] = 212.1.

(2-Methoxy-6-propoxypyridin-4-yl)methanol(161)

Trimethyl borate (5.8 mL, 50.8 mmol) and borane dimethyl sulfide complex (4.8 mL, 50.6 mmol) were added sequentially to a solution of 160 (5.39 g, 25.5 mmol) in THF (100 mL, Na distillation) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The solution was cooled to 0 °C and methanol was carefully added to quench the reaction. The solvent was removed to give a solid, which was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography (3:1 hexane:EtOAc) was performed to give 161 (5.04 g, 100%). ^¹H NMR ( _CDCl₃ ) δ 6.28 (d, J = 0.8 Hz, 1H), 6.26 (d, J = 0.8 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.20 (t, J = 6.8 Hz, 2H), 1.72–1.83 (m, 3H), 1.38 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). Measured value: [M+H] = 198.2.

4-(bromomethyl)-2-methoxy-6-propoxypyridine (162)

A solution of 161 (5.00 g, 25.4 mmol) in DCM (100 mL, anhydrous) was treated at 0 °C with triethylamine (7.07 mL, 50.7 mmol), followed by methanesulfonyl chloride (2.94 mL, 38.0 mmol). The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (150 mL), LiBr (22.0 g, 253 mmol) was added, and the mixture was refluxed for 1 hour and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) yielded a colorless oil of 162 (6.15 g, 93%). ^¹H NMR ( _CDCl₃ ) δ 6.31 (d, J = 1.0 Hz, ¹H), 6.30 (d, J = 1.0 Hz, ¹H), 4.28 (s, 2H), 4.22 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 1.79 (qt, J = 7.4, 6.7 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). Measured value: [M+H] = 260.5

6-Bromo-2-methoxy-3-((2-methoxy-6-propoxypyridin-4-yl)methyl)quinoline (163)

The mixture of 1 (6.62 _g , 23.5 mmol), 162 (6.11 g, 23.5 mmol), and _Cs₂CO₃ (15.3 g, 47.0 mmol) in toluene (66 mL) and DMF (33 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.54 g, 0.47 mmol) was added, and the mixture was purged with nitrogen. The mixture was then heated to 80 °C for 3 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography with 1:1 DCM:hexane yielded an impure product, which was re-chromatographically treated with a gradient from 2:1 hexane:DCM to 1:1 hexane:DCM to give 163 (6.63 g, 68%). ^¹H NMR ( _CDCl₃ ) δ 7.78 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 7.58 (s, 1H), 6.15 (s, 1H), 6.14 (s, 1H), 4.21 (t, J = 6.8 Hz, 2H), 4.06 (s, 3H), 3.91 (s, 2H), 3.88 (s, 3H), 1.79 (qt, J = 7.4, 6.8 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). Measured value: [M+H] = 417.1

6-Chloro-2-methoxyquinoline (164)

A mixture of 2,6-dichloroquinoline (12.92 g, 65.3 mmol) and sodium methoxide (17.63 g, 326 mmol) in MeOH (200 mL) was refluxed for 18 hours. The solvent was removed under vacuum, and the residue was partitioned between EtOAc and water. Recrystallization from MeOH gave 164 (11.63 g, 92%). ^¹H NMR ( _CDCl₃ ) δ 7.89 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.9, 2.4 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 4.06 (s, 3H). Found: [M+H] = 194.0

(6-Chloro-2-methoxyquinoline-3-yl)1(165)

A solution of anhydrous 2,2,6,6,-tetramethylpiperidine (6.7 mL, 39.7 mmol) in THF (70 mL, Na distillation) was treated with n-BuLi (19.8 mL, 2 M, 39.7 mmol in cyclohexane) at -40 °C, and then the solution was stirred at -40 °C for 5 min and then cooled to -78 °C. A solution of 164 (6.35 g, 32.9 mmol) and triisopropyl borate (9.1 mL, 39.7 mmol) in THF (50 mL, Na distillation) was added dropwise, and the orange solution was stirred at -78 °C for 3 h, then quenched with a saturated _NH4Cl aqueous solution and ice. The precipitate was filtered, ground with hexane, and dried to give 165 (5.84 g, 75%). ^¹H NMR (DMSO- _d₆ ) δ 8.35 (s, ¹H), 8.17 (s, 2H), 8.02 (d, J = 2.4 Hz, ¹H), 7.76 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.9, 2.5 Hz, 1H), 3.99 (s, 3H). Measured value: [M–OH+OMe] = 252.2

6-Chloro-3-(2-fluoro-3-methoxybenzyl)-2-methoxyquinoline (166)

A mixture of 165 (5.00 g, 21.1 mmol), 1-(bromomethyl)-2-fluoro-3-methoxybenzene (4.61 _g , 21.0 mmol), and _Cs₂CO₃ (13.7 g, 42.0 mmol) in toluene (100 mL) and DMF (50 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.49 g, 0.42 mmol) was added, and the mixture was purged with nitrogen and then heated to 80 °C for 3 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography was performed, eluting impurities with 3:1 hexane:DCM followed by elution with 1:1 hexane:DCM to give 166 (3.40 g, 57%). ^¹H NMR ( _CDCl₃ ) δ 7.74 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.52 (s, 1H), 7.48 (dd, J = 8.9, 2.4 Hz, 1H), 7.01 (td, J = 8.0, 1.5 Hz, 1H), 6.88 (td, J = 8.1, 1.5 Hz, 1H), 6.78 (td, J = 7.0, 1.5 Hz, 1H), 4.09 (s, 3H), 4.05 (s, 2H), 3.90 (s, 3H). Measured value: [M+H] = 332.1

N,2-Dimethoxy-N-methyl-6-propoxyisonicotinamide (167)

Oxaloyl chloride (2.76 mL, 32.6 mmol) was added to 160 (5.74 g, 27.2 mmol) in DCM (100 mL, anhydrous) and DMF (0.4 mL, 5.2 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (3.18 g, 32.6 mmol) and pyridine (6.6 mL, 81.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between DCM and water. Column chromatography on alumina with DCM yielded 167 (6.29 g, 91%). ^¹H NMR ( _CDCl₃ ) δ 6.42 (s, ¹H), 6.41 (s, ¹H), 5.24 (sp, J = 6.2 Hz, ¹H), 3.90 (s, ³H), 3.59 (bs, ³H), 3.32 (s, ³H), 1.35 (d, J = 6.2 Hz, ⁶H). Measured value: [M+H] = 255.1.

3-(dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)prop-1-one (168)

Vinyl magnesium bromide (43 mL, 1 M, 43 mmol in THF) was added to a solution of 167 (5.78 g, 21.7 mmol) in THF (100 mL, distilled Na) at 0 °C. The brown solution was stirred at 0 °C for 1 hour, and then dimethylamine (43 mL, 2 M, 86 mmol in THF) and water (40 mL) were added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give 168 (5.75 g, 100%). ^¹H NMR ( _CDCl₃ ) δ 6.73 (d, J = 1.1 Hz, 1H), 6.72 (d, J = 1.1 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 3.93 (s, 3H), 3.06 (t, J = 7.4 Hz, 2H), 2.72 (J = 7.4 Hz, 2H), 2.27 (s, 6H), 1.80 (qt, J = 7.4, 6.7 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). Measured value: [M+H] = 267.2.

Benzofuran-7-ylmethanol (169)

A solution of methyl benzofuran-7-carboxylate (3.59 g, 20.4 mmol) in _Et₂O (100 mL, Na distillation) was treated with _LiAlH₄ (1.54 g, 40.6 mmol) at 0 °C, then stirred at room temperature for 3 h and quenched with ice. The mixture was partitioned between _Et₂O and a saturated aqueous solution of sodium potassium tartrate, and then filtered through diatomaceous earth. The aqueous layer was extracted with _Et₂O , and the organic phases were combined and dried. Column chromatography (0–5% EtOAc:DCM) was performed to give 169 (2.60 g, 86%). ¹ H NMR (CDCl ₃ )δ7.65 (d, J=2.2Hz, 1H), 7.56 (dd, J=7.7, 1.2Hz, 1H), 7.31 (dd, J=7.3, 0.6Hz, 1H), 7.2 3(t, J=7.5Hz, 1H), 6.80 (d, J=2.2Hz, 1H), 5.02 (d, J=6.2Hz, 2H), 1.93 (t, J=6.2Hz, 1H).

7-(bromomethyl)benzofuran (170)

A solution of 169 (4.72 g, 31.8 mmol) in DCM (100 mL, anhydrous) was treated sequentially at 0 °C with triethylamine (8.9 mL, 63.9 mmol) followed by methanesulfonyl chloride (3.70 mL, 47.8 mmol). The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (200 mL), LiBr (27.6 g, 318 mmol) was added, and the mixture was refluxed for 0.5 hours and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) yielded 170 (6.08 g, 90%). ¹ H NMR (CDCl ₃ ) δ7.69 (d, J=2.2Hz, 1H), 7.57 (dd, J=7.7, 1.2Hz, 1H), 7.32 (dd, J=7.4, 0.7Hz, 1H), 7.22 (t, J=7.6Hz, 1H), 6.80 (d, J=2.2Hz, 1H), 4.81 (s, 2H).

3-(benzofuran-7-ylmethyl)-6-bromo-2-methoxyquinoline (171)

The mixture of 1 (8.00 _g , 28.4 mmol), 170 (5.99 g, 28.4 mmol), and _Cs₂CO₃ (18.5 g, 56.7 mmol) in toluene (100 mL) and DMF (50 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.66 g, 0.57 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 3 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography was performed, eluting impurities with 3:1 hexane:DCM, followed by elution with 1:1 hexane:DCM and then DCM to give 171 (6.95 g, 67%). ^¹H NMR ( _CDCl₃ ) δ 7.71 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.58–7.62 (m, 2H), 7.50–7.54 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.13 (dd, J = 7.4, 0.6 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 4.32 (s, 2H), 4.10 (s, 3H). Measured value: [M+H] = 368.8

2-Cyclobutoxy-6-methoxyisonicotinic acid methyl ester (172)

A solution of 139 (3.00 g, 16.4 mmol) in DMF (50 mL, anhydrous) was treated with _K₂CO₃ (4.52 g, 32.7 mmol), followed by bromocyclobutane (2.00 mL, 25.0 mmol). The mixture was stirred at room temperature for 48 hours, partitioned between EtOAc and water _, and the aqueous layer was extracted with EtOAc. The organic fraction was washed with water, dried, and evaporated. Column chromatography (DCM) was performed to give 172 (2.21 g, 57%). ^¹H NMR ( _CDCl₃ ) δ 6.84 (d, J = 1.0 Hz, ¹H), 6.79 (d, J = 1.0 Hz, ¹H), 5.08 (pd, J = 7.4, 0.8 Hz, ¹H), 3.91 (s, ³H), 3.90 (s, ³H), 2.42–2.52 (m, ²H), 2.12–2.24 (m, ²H), 1.80–1.90 (m, ¹H), 1.62–1.75 (m, ¹H). Measured value: [M+H] = 238.2.

2-Cyclobutoxy-6-methoxyisonicotinic acid (173)

A solution of LiOH (0.71 g, 29.6 mmol) in water (20 mL) was added to a solution of 172 (2.20 g, 9.29 mmol) in MeOH (20 mL) and THF (20 mL); the solution was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in water (80 mL) and acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 173 (2.02 g, 97%). ^¹H NMR (DMSO- _d₆ ) δ 13.56 (bs, ¹H), 6.74 (d, J = 1.0 Hz, ¹H), 6.67 (d, J = 1.0 Hz, ¹H), 5.07 (pd, J = 7.1, 0.7 Hz, ¹H), 3.85 (s, ³H), 2.37–2.46 (m, ²H), 2.14–2.22 (m, ²H), 1.74–1.83 (m, ¹H), 1.59–1.72 (m, ¹H). Measured value: [M+H] = 224.2.

2-Cyclobutoxy-N,6-Dimethoxy-N-methylisonicotinamide (174)

Oxaloyl chloride (0.45 mL, 5.32 mmol) was added to a suspension of 173 (1.00 g, 4.48 mmol) in DCM (50 mL, anhydrous) and DMF (0.2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.33 mmol) and pyridine (1.09 mL, 13.5 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between DCM and a saturated aqueous solution of _NaHCO3 . Column chromatography on alumina with DCM yielded 174 (1.01 g, 85%). ^¹H NMR ( _CDCl₃ ) δ 6.46 (s, ¹H), 6.40 (d, J = 0.6 Hz, ¹H), 5.08 (pd, J = 7.4, 0.9 Hz, ¹H), 3.90 (s, ³H), 3.58 (bs, ³H), 3.32 (s, ³H), 2.41–2.51 (m, ²H), 2.12–2.23 (m, ²H), 1.80–1.90 (m, ¹H), 1.62–1.74 (m, ¹H). Measured value: [M+H] = 267.2.

1-(2-Cyclobutoxy-6-methoxypyridin-4-yl)-3-(dimethylamino)prop-1-one (175)

Vinyl magnesium bromide (8.0 mL, 1 M, 8.0 mmol) was added to a solution of 175 (1.02 g, 3.84 mmol) in THF (50 mL, Na distillation) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine in THF (8.0 mL, 2 M, 16.0 mmol) and water (10 mL) was added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated, and column chromatography (95:5 DCM:MeOH) was performed to give 175 (1.05 g, 97%). ^¹H NMR ( _CDCl₃ ) δ 6.73 (d, J = 1.1 Hz, 1H), 6.68 (d, J = 1.2 Hz, 1H), 5.10 (pd, J = 7.4, 1.1 Hz, 1H), 3.91 (s, 3H), 3.05 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.42–2.50 (m, 2H), 2.27 (s, 6H), 2.13–2.23 (m, 2H), 1.80–1.90 (m, 1H), 1.62–1.74 (m, 1H). Measured value: [M+H] = 279.2.

(2-ethoxy-6-isopropoxypyridin-4-yl)methanol (176)

Trimethyl borate (3.03 mL, 26.7 mmol), followed by borane-dimethyl sulfide (2.53 mL, 26.7 mmol), was added to a solution of 156 (3.00 g, 13.3 mmol) in THF (50 mL, Na distillation) at 0 °C, and the mixture was stirred at room temperature for 18 hours. The solution was cooled to 0 °C and methanol was carefully added to quench the reaction. The solvent was removed to give a solid, which was partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography (3:1 hexane:EtOAc) was performed to give 176 (2.72 g, 97%). ^¹H NMR ( _CDCl₃ ) δ 6.24 (s, ¹H), 6.23 (s, ¹H), 5.21 (sp, J = 6.2 Hz, ¹H), 4.60 (d, J = 6.2 Hz, 2H), 4.30 (q, J = 7.0 Hz, 2H), 1.70 (t, J = 6.2 Hz, 1H), 1.38 (t, J = 7.0 Hz, 3H), 1.34 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 212.2.

4-(bromomethyl)-2-ethoxy-6-isopropoxypyridine (177)

A solution of 176 (2.60 g, 12.3 mmol) in DCM (50 mL, anhydrous) was treated sequentially at 0 °C with triethylamine (3.43 mL, 24.6 mmol), followed by methanesulfonyl chloride (1.43 mL, 18.5 mmol). The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (100 mL), LiBr (10.7 g, 123 mmol) was added, and the mixture was refluxed for 1 hour and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) was performed to give 177 (3.04 g, 100%). ^¹H NMR ( _CDCl₃ ) δ 6.26 (s, ¹H), 6.25 (s, ¹H), 5.20 (sp, J = 6.2 Hz, ¹H), 4.26–4.33 (m, 4H), 1.38 (t, J = 7.0 Hz, 3H), 1.34 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 274.1

6-Bromo-3-((2-ethoxy-6-isopropoxypyridin-4-yl)methyl)-2-methoxyquinoline (178)

The mixture of ₁ (11.6 mmol), 177 (3.18 g, 11.6 mmol), and _Cs₂CO₃ (7.56 g, 23.2 mmol) in toluene (66 mL) and DMF (33 mL) was purged with nitrogen. Pd( _PPh₃ ) _₄ (0.27 g, 0.23 mmol) was added, the mixture was purged with nitrogen, and then heated to 80 °C for 3 hours under nitrogen. The reactants were partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography was performed, eluting impurities with 3:1 hexane:DCM, followed by elution with DCM to give 178 (3.42 g, 68%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.77 (d, J = 2.1 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.58 (s, 1H), 6.11 (s, 1H), 6.10 (s, 1H), 5.20 (sp, J = 6.2 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.32 (d, J = 6.2 Hz, 6H). Measured value: [M+H] = 431.1

(6-Chloro-2-methoxyquinoline-3-yl)(m-tolyl)methanol (179)

At -40 °C, n-BuLi (12.4 mL, 2 M, 24.8 mmol in cyclohexane) was added to a solution of 2,2,6,6,-tetramethylpiperidine (4.18 mL, 24.8 mmol) in THF (50 mL, distilled Na), and the solution was stirred for 5 minutes, then cooled to -78 °C. A solution of 164 (4.00 g, 20.7 mmol) in THF (40 mL, distilled Na) was added, and the solution was stirred at -78 °C for 1.5 hours. Then, a solution of m-methylbenzaldehyde (2.49 g, 20.7 mmol) in THF (10 mL, distilled Na) was added. The solution was stirred at -78 °C for 3 hours, then acetic acid (3.55 mL, 62.0 mmol) was added. The mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The organic fractions were combined and evaporated. Column chromatography (3:1 hexane:DCM to 2:1 hexane:DCM to DCM, then 95:5 DCM:EtOAc) yielded 179 (3.39 g, 55%) as a white solid. ^¹H NMR ( _CDCl₃ ) δ 7.88 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.9, 2.4 Hz, 1H), 7.16–7.25 (m, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.03 (d, J = 3.8 Hz, 1H), 4.05 (s, 3H), 2.86 (d, J = 4.3 Hz, 1H), 2.34 (s, 3H). Measured value: [M+H]＝314.1

6-Chloro-2-methoxy-3-(3-methylbenzyl)quinoline (180)

A solution of 179 (3.36 g, 11.3 mmol) in DCM (60 mL) was treated with trifluoroacetic acid (8.4 mL, 113 mmol), followed by triethylsilane (14.5 mL, 89.9 mmol). The solution was refluxed for 18 hours, neutralized with a saturated aqueous solution _{of NaHCO3} , and partitioned with water. The organic phase was dried and evaporated, and column chromatography (3:1 hexane:DCM) was performed to give 180 (2.27 g, 67%). ^¹H NMR ( _CDCl₃ ) δ 7.75 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.46–7.50 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 7.01–7.08 (m, 3H), 4.08 (s, 3H), 3.99 (s, 2H), 2.33 (s, 3H). Measured value: [M+H] = 298.1

(2,6-Dimethoxypyridin-4-yl)methanol (279)

Borane-dimethyl sulfide (4.60 mL, 48.5 mmol) and trimethyl borate (5.58 mL, 49.1 mmol) were added to a solution of 2,6-dimethoxyisonicotinic acid (3.00 g, 16.4 mmol) in THF (100 mL, Na distillation) at 0 °C. The solution was then stirred at room temperature for 18 hours, cooled to 0 °C, quenched with MeOH, and evaporated. The residue was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (2:1 hexane:EtOAc) yielded 279 (2.72 g, 98%). ^¹H NMR ( _CDCl₃ ) δ 6.30 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 3.91 (s, 6H), 1.75 (t, J = 6.1 Hz, 1H). Analytical value: [M+H] = 170.1.

4-(bromomethyl)-2,6-dimethoxypyridine (280)

A solution of 279 (1.57 g, 9.30 mmol) in DCM (40 mL, anhydrous) was treated at 0 °C with triethylamine (2.60 mL, 18.6 mmol) followed by methanesulfonyl chloride (1.08 mL, 13.9 mmol). The mixture was stirred at 0 °C for 1 hour and then partitioned between DCM and water. The organic fraction was dried and evaporated, and the residue was dissolved in acetone (50 mL). LiBr (4.04 g, 46.5 mmol) was added, and the mixture was refluxed for 1 hour and then evaporated. The residue was partitioned between DCM and water, and the organic fraction was dried and evaporated. Column chromatography (DCM) yielded 280 (1.96 g, 91%). ^¹H NMR ( _CDCl₃ ) δ 6.32 (s, 2H), 4.29 (s, 2H), 3.91 (s, 6H). Analytical value: [M+H] = 232.0

6-Bromo-3-((2,6-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (281)

The mixture of 1 (2.20 g, 7.80 mmol), 280 (1.93 g, 8.30 mmol), _Cs₂CO₃ ( _5.10 g, 15.7 mmol), and Pd( _PPh₃ ) _₄ (0.45 g, 0.39 mmol) in DMF (10 mL) and toluene (20 mL) was purged with nitrogen and then heated to 80 °C for 4 hours under nitrogen. The mixture was partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography (3:1 hexane:DCM) was performed to elute nonpolar impurities, and elution with DCM yielded 281 (1.95 g, 64%). ^¹H NMR ( _CDCl₃ ) δ 7.78 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.17 (s, 2H), 4.06 (s, 3H), 3.92 (s, 2H), 3.89 (s, 6H). Measured value: [M+H] = 389.1

N-Methoxy-N,2,6-Trimethylisonicotinamide (282)

Oxaloyl chloride (1.46 mL, 17.3 mmol) was added to a suspension of 2,6-dimethylisonicotinic acid (2.38 g, 15.7 mmol) in DCM (100 mL, anhydrous) and DMF (1.3 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour to obtain a colorless solution, which was then cooled to 0 °C. N,O-dimethylhydroxylamine hydrochloride (1.46 mL, 17.3 mmol) and pyridine (3.82 mL, 47.2 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours, followed by partitioning between EtOAc and a saturated aqueous solution of _NaHCO3 . Column chromatography with hexane:EtOAc 1:1 yielded an oily 282 (1.50 g, 49%). ^¹H NMR ( _CDCl3 ) δ 7.15 (s, 2H), 3.56 (s, 3H), 3.35 (s, 3H), 2.57 (s, 6H). Measured value: [M+H]＝195.1

3-(dimethylamino)-1-(2,6-dimethylpyridin-4-yl)prop-1-one (283)

A solution of vinyl magnesium bromide in THF (1N, 22.0 mL, 22 mmol) was added to a solution of 282 (1.43 g, 7.37 mmol) in THF (100 mL, Na distillation) at 0 °C. The brown solution was heated to room temperature for 1 hour, and then dimethylamine in THF (2N, 22.0 mL, 44 mmol) and water (20 mL) was added. The solution was stirred at room temperature for 1 hour, and then partitioned between EtOAc and water. The solution was dried and evaporated to give a yellow oily 283 (1.54 g, 99%). ^¹H NMR ( _CDCl₃ ) δ 7.38 (s, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.61 (s, 6H), 2.28 (s, 6H). Observed value: [M+H] = 207.2

II. Preparation of representative embodiments of the present invention

Example 1

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)but-2-ol (181)

General coupling procedure:

n-BuLi (2.63 mL 2N cyclohexane solution, 5.26 mmol) was added to a solution of dry diisopropylamine (0.74 mL, 5.26 mmol) in dry THF (6 mL) under dry nitrogen atmosphere at -30 °C, and the solution was stirred at this temperature for 10 min, then cooled to -78 °C. 10 (1.50 g, 4.38 mmol) in dry THF (6 mL) was added dropwise, and the mixture was stirred at -78 °C for 90 min to obtain a deep wine-red solution. 6 (1.15 g, 4.82 mmol) in dry THF (7 mL) was added, and the reaction mixture was stirred at this temperature for 4 h. HOAc (0.90 mL) was added, and the reaction mixture was heated to room temperature. Water (100 mL) was added, and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with a saturated aqueous solution of _NaHCO3 and brine, then _dried ( _Na2SO4 ) and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography. Elution with 0–10% MeOH/DCM gave an unreacted fore fraction of 10, followed by product 181 (0.91 g, 36%) as a 1:1 mixture of diastereomers. Analytical value: [M+H] = 580.1

The following compounds were synthesized using a generic coupling procedure. Each coupling product was decomposed into its four optical isomers using preparative chiral HPLC.

Example 2

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-phenylbut-2-ol (182)

The coupling from 3-benzyl-6-bromo-2-methoxyquinoline and (114). The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 182. Analytical value: [M+H] = 544.9

Example 3

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)but-2-ol (183)

The coupling from 117 and 3-(dimethylamino)-1-(3-fluorophenyl)prop-1-one. Column chromatography of the crude product with 0-5% MeOH:DCM yielded the fore fraction, followed by 183. Analytical value: [M+H] = 583.9

Example 4

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(m-tolyl)but-2-ol (184)

The coupling from 120 and 3-(dimethylamino)-1-(m-tolyl)prop-1-one. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 184. Analytical value: [M+H] = 580.0

Example 5

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (185)

The coupling from 8 and 4. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 185. Analytical value: [M+H] = 642.1

Example 6

2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)but-2-ol (186)

Coupling from 9 and 122. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 186. Analytical value: [M+H] = 562.9

Example 7

2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (187)

Coupling from 120 and 122. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 187. Analytical value: [M+H] = 606.1

Example 8

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)but-2-ol (188)

Coupling from 9 and 114. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 188. Analytical value: [M+H] = 562.9

Example 9

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (189)

The coupling from 120 and 6. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 189. Analytical value: [M+H] = 627.1

Example 10

2-(benzofuran-5-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (190)

Coupling from 120 and 126. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 190. Analytical value: [M+H] = 606.1

Example 11

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-methylthiophen-2-yl)but-2-ol (191)

The coupling from 16 and 6. Column chromatography of the crude product with 0-5% MeOH:DCM yielded the fore fraction, followed by 191. Analytical value: [M+H] = 586.1

Example 12

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (192)

       

Coupled from 129 and 114. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 192. Analytical value: [M+H] = 634.2

Example 13

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (193)

Coupling from 8 and 6. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 193. Analytical value: [M+H] = 614.0

Example 14

2-(benzofuran-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-phenylbut-2-ol (194)

The coupling was derived from 3-benzyl-6-bromo-2-methoxyquinoline and 134. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 194. Analytical value: [M+H] = 544.5

Example 15

2-(benzo[b]thiophene-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-phenylbut-2-ol (195)

The coupling was derived from 3-benzyl-6-bromo-2-methoxyquinoline and 138. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 195. Analytical value: [M+H] = 561.0

Example 16

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol (196)

Coupling from 8 and 143. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 196. Analytical value: [M+H] = 642.1

Example 17

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (197)

Coupling from 8 and 147. Column chromatography of the crude product with 0-5% MeOH:DCM yielded the fore fraction, followed by 197. Analytical value: [M+H] = 627.7

Example 18

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol (198)

Coupling from 120 and 143. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 198. Analytical value: [M+H] = 655.1

Example 19

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol (199)

The coupling from 150 and 6. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 199. Analytical value: [M+H] = 655.0

Example 20

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)but-2-ol (200)

Coupling from 120 and 147. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 200. Analytical value: [M+H] = 641.2

Example 21

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol (201)

Coupling from 150 and 114. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 201. Analytical value: [M+H] = 634.1

Example 22

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)but-2-ol (202)

Coupling from 153 and 114. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 202. Analytical value: [M+H] = 620.1

Example 23

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol (203)

Coupling from 120 and 158. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 203. Analytical value: [M+H] = 669.0

Example 24

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol (204)

Coupling from 281 and 158. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 204. Analytical value: [M+H] = 669.0

Example 25

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)-1-(m-tolyl)but-2-ol (205)

Coupling from 10 and 143. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 205. Analytical value: [M+H] = 607.7

Example 26

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)but-2-ol (206)

The coupling from 163 and 6. Column chromatography of the crude product with 0-5% MeOH:DCM yielded the fore fraction, followed by 206. Analytical value: [M+H] = 654.7

Example 27

1-(6-chloro-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (207)

The coupling from 166 and 4. Column chromatography of the crude product with 0-3% MeOH:DCM yielded the fore fraction, followed by 207. Analytical value: [M+H] = 597.8

Example 28

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy-6-propoxypyridin-4-yl)but-2-ol (208)

Coupling from 120 and 168. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 208. Analytical value: [M+H] = 654.7

Example 29

1-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (209)

The coupling from 171 and 6. Column chromatography of the crude product with 0-5% MeOH:DCM yielded the fore fraction, followed by 209. Analytical value: [M+H] = 605.7

Example 30

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (210)

Coupling from 120 and 175. The crude product was subjected to column chromatography with 0-5% MeOH:DCM to obtain the fore fraction, followed by 210. Analytical value: [M+H] = 666.7

Example 31

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol (211)

The coupling from 178 and 6. Column chromatography of the crude product with 0-5% MeOH:DCM yielded the fore fraction, followed by 211. Analytical value: [M+H] = 669.0

Example 32

1-(6-chloro-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)but-2-ol (212)

The coupling from 180 and 4. The crude product was subjected to column chromatography with 0-3% MeOH:DCM to obtain the fore fraction, followed by 212. Analytical value: [M+H] = 564.0

Example 33

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5-dimethylthiophen-3-yl)but-2-ol (213)

The coupling from 14 and 6. Column chromatography was performed, eluting unreacted 14 with EtOAc:hexane (1:3), while hexane:EtOAc (1:1) yielded 213. Analytical value: [M+H] = 600.1

Example 34

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)but-2-ol (214)

The coupling from 10 and 4. Column chromatography was performed, with the fore fraction obtained by elution with EtOAc:hexane (1:9), followed by elution with EtOAc:hexane (1:4) to give 214. Analytical value: [M+H] = 608.2

Example 35

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)but-2-ol (215)

The coupling from 11 and 4. Column chromatography was performed, with the fore fraction obtained from EtOAc:hexane (1:9), followed by elution with EtOAc:hexane (1:1) to give 215. Analytical value: [M+H] = 654.1

Example 36

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (216)

Coupling from 120 and 4. Column chromatography was performed with EtOAc:hexane (1:4), followed by EtOAc to obtain the fore fraction, then 216. Analytical value: [M+H] = 655.1

Example 37

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)but-2-ol (217)

Coupling from 11 and 283. Column chromatography with MeOH:DCM (0-8%) yielded the fore-fraction, followed by 217. Analytical value: [M+H] = 594.1

Example 38

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxypyridin-3-yl)but-2-ol (218)

Coupling from 17 and 6. Column chromatography was performed using EtOAc:hexane (1:1), followed by EtOAc to obtain the fore fraction, then 218. Analytical value: [M+H] = 597.1

Example 39

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)but-2-ol (219)

Coupling from 9 and 6. Column chromatography with EtOAc:hexane (1:1), followed by EtOAc, yielded 219. Analytical value: [M+H] = 584.1

Example 40

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamino)-1-phenylbut-2-ol (220)

The coupling from 3-benzyl-6-bromo-2-methoxyquinoline and 19. Column chromatography with EtOAc:hexane (1:1) yielded the fore fraction, followed by 220. Analytical value: [M+H] = 545.3.

Example 41

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (221)

The coupling from 22 and 6. Column chromatography with EtOAc:hexane (1:1) yielded the fore fraction, followed by 221. Analytical value: [M+H] = 624.1

Example 42

2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinoline-3-yl)-1-phenylbut-2-ol (222)

Coupling from 23 and 6. Column chromatography with EtOAc:hexane (3:7) yielded the fore fraction, followed by 222. Analytical value: [M+H] = 614.1

Example 43

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)but-2-ol (223)

Coupling from 22 and 4. Column chromatography with EtOAc:hexane (1:1), followed by EtOAc, yielded 223. Analytical value: [M+H] = 652.2

Example 44

2-(2,6-bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (224)

Coupling from 8 and 26. Column chromatography with EtOAc:hexane (1:1), followed by EtOAc, yielded 224. Analytical value: [M+H] = 674.1

Example 45

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (225)

Coupling from 8 and 29. Column chromatography was performed with EtOAc:hexane (1:1), followed by EtOAc to obtain the fore fraction, then 225. Analytical value: [M+H] = 646.0

Example 46

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (226)

Coupling from 120 and 29. Column chromatography was performed with EtOAc:hexane (1:1), followed by EtOAc to obtain the fore fraction, then 226. Analytical value: [M+H] = 659.1

Example 47

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol (227)

The coupling from 30 and 4. Column chromatography with EtOAc:hexane (1:1) yielded the fore fraction, followed by 227. Analytical value: [M+H] = 626.1

Example 48

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-methoxy-6-(methylthio)pyridin-4-yl)but-2-ol (228)

Coupling from 8 and 33. Column chromatography was performed with EtOAc:hexane (1:1), followed by EtOAc to obtain the fore fraction, then 228. Analytical value: [M+H] = 630.0

Example 49

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol (229)

Coupling from 8 and 37. Column chromatography with EtOAc:hexane (1:1), followed by EtOAc, yielded 229. Analytical value: [M+H] = 650.0

Example 50

1-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (230)

The coupling from 40 and 6. Column chromatography with EtOAc:hexane (1:1) yielded the fore fraction, followed by 230. Analytical value: [M+H] = 658.9.

Example 51

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (231)

Coupling from 120 and 37. Column chromatography was performed with EtOAc:hexane (1:1), followed by EtOAc to obtain the fore fraction, then 231. Analytical value: [M+H] = 663.0

Example 52

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (232)

Coupling from 43 and 6. Column chromatography with EtOAc:hexane (1:1) yielded the fore fraction, followed by 232. Analytical value: [M+H] = 605.7

Example 53

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8-tetrahydronaphthyl-1-yl)but-2-ol (233)

The coupling from 46 and 6. Column chromatography with EtOAc:hexane (1:4) yielded the fore fraction, followed by the measured value of 233: [M+H] = 619.7.

Example 54

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol (234)

Coupling from 30 and 37. Column chromatography with EtOAc:hexane (1:4) yielded the fore fraction, followed by 234. Analytical value: [M+H] = 633.7

Example 55

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol (235)

Coupling from 30 and 29. Column chromatography with EtOAc:hexane (1:4) yielded the fore fraction, followed by 235. Analytical value: [M+H] = 629.6

Example 56

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)but-2-ol (236)

Coupling from 22 and 29. Column chromatography was performed with EtOAc:hexane (1:1), followed by EtOAc to obtain the fore fraction, then 236. Analytical value: [M+H] = 656.0

Example 57

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol (237)

Coupling from 30 and 6. Column chromatography with EtOAc:hexane (1:1) yielded the fore fraction, followed by 237. Analytical value: [M+H] = 598.0

Example 58

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)but-2-ol (238)

Coupling from 22 and 37. Column chromatography with EtOAc:hexane (1:1), followed by EtOAc, yielded 238. Analytical value: [M+H] = 659.9.

Example 59

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(6-(diethylamino)pyridin-3-yl)-4-(dimethylamino)but-2-ol (239)

The coupling from 50 and 4. Column chromatography of the crude product using a mixture of hexane and ethyl acetate yielded 239. Analytical value: [M+H] = 666.1

Example 60

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-2-methoxypyridin-4-yl)but-2-ol (240)

The coupling from 55 and 6. Column chromatography was performed, eluting unreacted starting material XX with 9:1 hexane/EtOAc, followed by chromatographic processing with 1:2 hexane/EtOAc to obtain 240. Measured value: [M+H] = 614.9

Example 61

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6-trimethoxypyridin-4-yl)but-2-ol (241)

Coupled from 120 and 63. Eluted by column chromatography with 1:1 DCM/EtOAc followed by EtOAc 241. Measured value: [M+H] = 656.6

Example 62

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-4-methoxyphenyl)but-2-ol (242)

The coupling from 66 and 6. Column chromatography was performed, eluting the unreacted starting material with 9:1 hexane/EtOAc, followed by elution with 1:1 hexane/EtOAc to elute 242. Analytical value: [M+H] = 613.7

Example 63

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)but-2-ol (243)

The coupling from 72 and 6. Column chromatography was performed, eluting unreacted starting material with 2:1 hexane/EtOAc, followed by chromatographic processing with 1:1 hexane/EtOAc to obtain 243. Analytical value: [M+H] = 656.7

Example 64

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-(ethylthio)pyridin-4-yl)but-2-ol (244)

The coupling from 76 and 6. Column chromatography of the crude product, eluted with 10-50% EtOAc/hexane, yielded a measured value of 244: [M+H] = 669.7.

Example 65

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (245)

Coupled from 80 and 6. Column chromatography was performed, eluting unreacted starting material with 1:1 hexane/EtOAc, followed by chromatography with 1:3 hexane/EtOAc, then eluting with 19:1 EtOAc/MeOH at 245. Analytical value: [M+H] = 627.0

Example 66

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6-trimethoxypyridin-3-yl)but-2-ol (246)

The coupling from 86 and 6. Column chromatography was performed, eluting unreacted starting material with 2:1 hexane/EtOAc, followed by chromatography with 1:1 hexane/EtOAc to obtain 246. Analytical value: [M+H] = 656.7

Example 67

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)but-2-ol (247)

The coupling from 90 and 6. The crude product was subjected to column chromatography, eluted with DCM to remove unreacted starting material, and then eluted with a hexane/EtOAc mixture with increased eluent strength to give 247. Analytical value: [M+H] = 639.7

Example 68

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)but-2-ol (248)

Coupling from 120 and 93. Repeated rapid chromatography was performed on the crude product, eluting with DCM to remove unreacted starting material, followed by elution with a hexane/EtOAc mixture at increased eluent strength to give 248. Analytical values:

[M+H]＝639.7

Example 69

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)but-2-ol (249)

Coupling from 96 and 6. Repeated rapid chromatography of the crude product with a hexane/EtOAc mixture at increased eluent strength yielded 249. Analytical value: [M+H] = 653.7

Example 70

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-isopropoxy-2-methoxypyridin-3-yl)but-2-ol (250)

       

The coupling from 100 and 6. Column chromatography of the crude product using 0-5% MeOH/DCM yielded 250. Analytical value: [M+H] = 654.7

Example 71

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(4-chloro-2-methoxythiazolyl-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol (251)

Coupling from 107 and 6. Column chromatography was performed, eluting unreacted starting material with 9:1 hexane/EtOAc, followed by chromatography with 4:1 hexane/EtOAc, then 2:1 hexane/EtOAc to elute 251. Analytical value: [M+H] = 636.6

Example 72

3-(1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (252)

General cyanide process

The solution of 245 (0.61 g, 0.969 mmol) in DMF (6 mL, anhydrous) was purged with nitrogen and heated to 55 °C for 10 min. Then, tris(o-methylphenyl)phosphine (0.044 g, 0.145 mmol), zinc powder (0.006 g, 0.097 mmol), and tris(dibenzylacetone)palladium(0) (0.067 g, 0.073 mmol) were added, and the reaction mixture was again purged with nitrogen and heated to 55 °C for an additional 10 min. Zinc cyanide (0.063 g, 0.533 mmol) was then added, and the reaction mixture was heated to 65 °C for 4 h. The reactants were diluted with water and extracted three times with EtOAc. The organic layer was washed three times with brine, dried, and evaporated. Column chromatography with 1:1 hexane/EtOAc followed by 1:3 hexane/EtOAc yielded a foamy solid, 252 (0.41 g, 74%). Measured value: [M+H]＝573.8

The following compounds were synthesized using a generic cyanidation procedure. Each coupling product was decomposed into its four optical isomers using preparative chiral HPLC.

Example 73

3-(2-(benzofuran-2-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (253)

186 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. 253 was obtained by elution with 0-6% MeOH:DCM. Analytical value: [M+H] = 510.1

Example 74

3-(2-(benzofuran-7-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (254)

188 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. 254 was obtained by elution with 0-6% MeOH:DCM. Analytical value: [M+H] = 510.2

Example 75

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (255)

191 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. 255 was obtained by elution with 0-6% MeOH:DCM. Analytical value: [M+H] = 533.2

Example 76

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (256)

199 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. 256 was obtained by elution with 0-6% MeOH:DCM. Analytical value: [M+H] = 602.2

Example 77

3-(2-(benzofuran-7-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (257)

201 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. 257 was obtained by elution with 0-6% MeOH:DCM. Analytical value: [M+H] = 581.0

Example 78

3-(2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (258)

Cyanide 111 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. Elution with 0-10% MeOH:DCM yielded 258. Measured value: [M+H] = 518.7

Example 79

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (259)

211 was cyanided using a universal cyanidation procedure. The crude product was purified by column chromatography. 259 was obtained by elution with 0-5% MeOH:DCM. Measured value: [M+H] = 615.8

Example 80

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (260)

219 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:1), followed by 260. Analytical value: [M+H] = 531.2

Example 81

3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (261)

221 was cyanided using a universal cyanidation procedure. 261 was obtained by column chromatography with EtOAc:hexane (1:1), followed by EtOAc. Analytical value: [M+H] = 571.0

Example 82

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (262)

229 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:2), followed by EtOAc, then 262. Analytical value: [M+H] = 597.1

Example 83

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (263)

231 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:2), followed by EtOAc, then 263. Analytical value: [M+H] = 610.2

Example 84

3-(2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (264)

223 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:1), followed by 264. Analytical value: [M+H] = 599.2

Example 85

3-(1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (265)

232 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:1), followed by 265. Measured value: [M+H] = 552.9.

Example 86

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (266)

237 was cyanided using a universal cyanidation program. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:1), followed by 266. Analytical value: [M+H] = 545.1

Example 87

3-(4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (267)

228 was cyanided using a universal cyanidation program. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:3), followed by 267. Analytical value: [M+H] = 576.8

Example 88

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (268)

234 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (2:1), followed by 268. Analytical value: [M+H] = 580.8

Example 89

3-(2-(2,6-bis(methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (269)

235 was cyanided using a universal cyanidation program. The fore fraction was obtained by column chromatography with EtOAc:hexane (2:1), followed by 269. Analytical value: [M+H] = 576.7

Example 90

3-(2-(2,6-bis(methylthio)pyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (270)

236 was cyanided using a universal cyanidation procedure. Column chromatography with EtOAc:hexane (1:1), followed by EtOAc, yielded 270. Analytical value: [M+H] = 602.7

Example 91

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (271)

238 was cyanided using a universal cyanidation procedure. The fore fraction was obtained by column chromatography with EtOAc:hexane (2:1), followed by EtOAc, then 271. Analytical value: [M+H] = 606.8

Example 92

3-(2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (272)

227 was cyanided using a universal cyanidation program. The fore fraction was obtained by column chromatography with EtOAc:hexane (1:1), followed by 272. Analytical value: [M+H] = 573.1

Example 93

3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carboxynitrile (273)

109 was cyanided using a universal cyanidation procedure. Column chromatography with EtOAc followed by EtOAc:MeOH (4:1) yielded 273. Analytical value: [M+H] = 557.0

Example 94

3-(1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (274)

248 was cyanided using a universal cyanidation procedure, except that the reaction mixture was heated overnight at 45°C. Rapid chromatography of the crude product using a hexane/EtOAc mixture with increased eluent strength yielded a bright yellow, foamy 274. Analytical value: [M+H] = 586.8

Example 95

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile (275)

249 was cyanided using a universal cyanidation procedure, except that the reaction mixture was heated overnight at 55°C. The crude product was then subjected to column chromatography with a mixture of hexane/EtOAc to increase the eluent strength, yielding 275. Analytical value: [M+H] = 600.8

Example 96

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (276)

Cyanide 250 was cyanided using a universal cyanidation procedure, except that the reaction mixture was heated at 60°C for 2 hours. Column chromatography of the crude product with a hexane/EtOAc mixture to increase eluent strength yielded 276. Analytical values:

[M+H]＝601.8

Example 97

3-(2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carboxynitrile (277)

       

Cyanide 102 was cyanided using a universal cyanidation procedure, except that the reaction mixture was heated overnight at 40°C. The crude product was subjected to column chromatography with a mixture of hexane/EtOAc with increased eluent strength and 5% MeOH in the final EtOAc, yielding 277. Analytical value: [M+H] = 516.8

Example 98

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trimethoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carboxynitrile (278)

246 was cyanided using a universal cyanidation procedure. The crude product was then subjected to column chromatography using a 1:1 hexane/EtOAc mixture to obtain 278. Analytical value: [M+H] = 603.8

Example 99

Activity against replicating Mycobacterium tuberculosis _H37 Rv

The minimum inhibitory concentration (MIC) of representative compounds against Mycobacterium tuberculosis _H37 Rv (ATCC 27294) was assessed using the microplate Alamar Blue assay (MABA) and 7H12 medium (Collins, L. and S.G. Ranzblau. 1997. Microplate Alamar Blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41:1004-9.).

The culture was incubated in 200 ml of medium in 96-well plates at 37°C for 7 days. Alamar Blue and Tween 80 were added, and the plates were incubated at 37°C for another 24 hours. Fluorescence was measured at excitation/emission wavelengths of 530/590 nm. The MIC was defined as the lowest concentration that produced a 90% reduction in fluorescence relative to the control.

Table 1 provides MIC data for representative compounds of the present invention:

Table 1

The invention is further described in the following numbered paragraphs:

1. Compounds of formula (I):

Including any of its stereochemical isomers,

in:

_R1 is a -phenyl group, which may optionally be mono- or di-substituted independently by a lower alkyl group, halogen, or alkoxy group.

-5 or 6-membered heteroaryl groups, optionally and independently monosubstituted, disubstituted, or trisubstituted by lower alkyl groups, halogens, alkoxy _groups , _-SCH3 , _-SCH2CH3 , -N(CH2CH3) ₂ , or -N(CH3) ₂ .

-benzofuranyl,

-2,3-Dihydrobenzo[b][1,4]dioxin-5-yl,

-2,3-dihydro-1H-inden-4-yl or

-5,6,7,8-Tetrahydronaphth-1-yl;

_R2 and _R3 are independently hydrogen or lower alkyl groups;

_R4 is a phenyl group, which may optionally be independently mono- or di-substituted with a halogen or a lower alkyl group.

-5 or 6-membered heteroaryl groups, optionally and independently substituted with alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy, or -N(CH3) ₂ monosubstituted, disubstituted, or trisubstituted.

-benzofuranyl,

-benzo[b]thiophene or

-2,3-dihydro-1H-indenyl; and

_R5 is a halogen or cyano group.

Or its pharmaceutically acceptable salt.

2. The compound according to paragraph 1, wherein _R1 is an unsubstituted phenyl group.

3. The compound according to paragraph 1, wherein _R1 is a phenyl group that is independently mono- or di-substituted by a lower alkyl, halogen, or alkoxy group.

4. The compound according to paragraph 1, wherein _R1 is an unsubstituted 5- or 6-membered heteroaryl group.

5. The compound according to paragraph 1, wherein _R1 is pyridyl.

6. The compound according to paragraph 1, wherein _R1 is a 5- or 6-membered heteroaryl group that is independently monosubstituted, _{disubstituted} , or trisubstituted by a lower alkyl group, halogen, alkoxy group, _-SCH3 , _-SCH2CH3 , -N(CH2CH3) ₂ , or -N(CH3) ₂ .

7. The compound according to paragraph 1, wherein _R1 is a pyridinyl group that is independently monosubstituted, disubstituted, or trisubstituted by a lower alkyl group, _halogen , alkoxy group, _-SCH3 , _-SCH2CH3 , -N(CH2CH3) ₂ , or -N(CH3) ₂ .

8. The compound according to paragraph 1, wherein _R1 is a pyridinyl group that is independently monosubstituted or disubstituted by a lower alkyl group, _halogen , alkoxy group, _-SCH3 , _-SCH2CH3 , -N(CH2CH3) ₂ or -N(CH3) ₂ .

9. The compound according to paragraph 1, wherein _R1 is benzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or 5,6,7,8-tetrahydronaphth-1-yl.

10. The compound according to paragraph 1, wherein _R2 and _R3 are independently hydrogen or methyl.

11. The compound according to paragraph 1, wherein both _R2 and _R3 are methyl groups.

12. The compound according to paragraph 1, wherein _R4 is an unsubstituted phenyl group.

13. The compound according to paragraph 1, wherein _R4 is a phenyl that is independently mono- or di-substituted with a halogen or a lower alkyl group.

14. The compound according to paragraph 1, wherein _R4 is an unsubstituted 5- or 6-membered heteroaryl group.

15. The compound according to paragraph 1, wherein _R4 is a pyridyl group.

16. The compound according to paragraph 1, wherein _R4 is a 5- or 6-membered heteroaryl group that is independently monosubstituted, disubstituted, or trisubstituted by an alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy, or -N(CH3) ₂ .

17. The compound according to paragraph 1, wherein _R4 is a pyridinyl group that is independently monosubstituted, disubstituted, or trisubstituted by an alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy, or -N(CH3) ₂ .

18. The compound according to paragraph 1, wherein _R4 is a pyridinyl group that is independently monosubstituted or disubstituted with an alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy or -N(CH3) ₂ .

19. The compound according to paragraph 1, wherein _R4 is benzofuranyl, benzo[b]thiophenylyl or 2,3-dihydro-1H-indenyl.

20. The compound according to paragraph 1, wherein _R5 is a halogen.

21. The compound according to paragraph 1, wherein _R5 is bromine, chlorine or iodine.

22. The compound according to paragraph 1, wherein _R5 is bromine.

23. The compound according to paragraph 1, wherein _R5 is a cyano group.

24. The compound according to paragraph 1, wherein the compound is:

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)but-2-ol;

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-phenylbut-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(m-tolyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)but-2-ol;

2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

2-(benzofuran-5-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-methylthiophen-2-yl)but-2-ol;

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

2-(benzofuran-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-phenylbut-2-ol;

2-(benzo[b]thiophen-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-phenylbut-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)but-2-ol;

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol;

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)-1-(m-tolyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)but-2-ol;

1-(6-chloro-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy-6-propoxypyridin-4-yl)but-2-ol;

1-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol;

1-(6-chloro-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5-dimethylthiophen-3-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxypyridin-3-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamino)-1-phenylbut-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinoline-3-yl)-1-phenylbut-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)but-2-ol;

2-(2,6-bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-methoxy-6-(methylthio)pyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol;

1-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8-tetrahydronaphthyl-1-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol;

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol;

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(6-(diethylamino)pyridin-3-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-2-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6-trimethoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-4-methoxyphenyl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-(ethylthio)pyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6-trimethoxypyridin-3-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-isopropoxy-2-methoxypyridin-3-yl)but-2-ol;

1-(6-bromo-2-methoxyquinoline-3-yl)-1-(4-chloro-2-methoxythiazolyl-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol;

3-(1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(benzofuran-2-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(benzofuran-7-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(benzofuran-7-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-bis(methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-bis(methylthio)pyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carboxynitrile;

3-(2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carboxynitrile; or

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trimethoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carboxynitrile.

25. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in paragraph 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in paragraph 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A method for treating tuberculosis, comprising the step of administering to a patient in need a therapeutically effective amount of the compound described in paragraph 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. A method for treating tuberculosis, comprising the steps of administering to a patient in need a therapeutically effective amount of the compound described in paragraph 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

***

It should be understood that the present invention is not limited to the specific embodiments described above, as variations may be made to the specific embodiments, and these variations still fall within the scope of the appended claims.

Claims (14)

1. Compounds of formula (I): Including any of its stereochemical isomers, in: _R1 is a pyridyl group, which is independently monosubstituted, disubstituted, or _{trisubstituted} by a _C1-6 alkyl group, halogen, _C1-6 alkoxy group, _-SCH3 or _-SCH2CH3 ; _R2 and _R3 are independently hydrogen or _C1-6 alkyl; _R4 is a pyridyl group, which is independently monosubstituted, disubstituted, or trisubstituted by a _C1-6 alkoxy, -O-cycloalkyl, _-SC1-6 alkyl, or difluoromethoxy group; and _R5 is a halogen or cyano group. Or its pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein _R1 is a pyridinyl group that is independently monosubstituted or _{disubstituted} by a _C1-6 alkyl, halogen, _C1-6 alkoxy, _-SCH3 or _-SCH2CH3 . 3. The compound according to claim 1, wherein _R2 and _R3 are independently hydrogen or methyl. 4. The compound according to claim 1, wherein _R2 and _R3 are both methyl groups. 5. The compound according to claim 1, wherein _R4 is a pyridyl group that is independently monosubstituted or disubstituted with a _C1-6 alkoxy, -O-cycloalkyl, _-SC1-6 alkyl, or difluoromethoxy group. 6. The compound according to claim 1, wherein _R5 is a halogen. 7. The compound according to claim 1, wherein _R5 is bromine, chlorine or iodine. 8. The compound according to claim 1, wherein _R5 is bromine. 9. The compound according to claim 1, wherein _R5 is a cyano group. 10. A compound, wherein the compound is: 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy-6-propoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxypyridin-3-yl)but-2-ol; 2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-2-methoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6-trimethoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6-trimethoxypyridin-3-yl)but-2-ol; 1-(6-bromo-2-methoxyquinoline-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-isopropoxy-2-methoxypyridin-3-yl)but-2-ol; 3-(1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2,6-bis(methylthio)pyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carboxynitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carboxynitrile; or 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trimethoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carboxynitrile, Or any stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating tuberculosis. 14. Use of the compound of claim 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating tuberculosis.