EA040011B1 - ANTIBACTERIAL COMPOUNDS AND THEIR USE - Google Patents

Description

including any stereochemically isomeric forms thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing said compounds, for the treatment of tuberculosis. Also proposed is a method for the treatment of tuberculosis using these compounds.

Technical field

The invention generally relates to diarylquinoline compounds having antibacterial activity, and in particular having antituberculous properties. All documents cited in this application or referenced below are expressly incorporated into this application by reference.

State of the art

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a debilitating infectious disease. It is estimated that about 2 million patients die from tuberculosis every year in the world. The lack of proper treatment of tuberculosis has caused global drug resistance in mycobacterium tuberculosis, as a result of which some drugs have been ineffective.

There is a need in the art to provide pharmaceutical compounds that provide advantages over currently used compounds.

The essence of the invention

The present invention relates to a compound of formula (I)

CH ₃ including any of its stereochemically isomeric forms, where

R ₁ is -5- or 6-membered heteroaryl, optionally mono-, bi- or tri-substituted independently with O _1-6 alkyl, halogen, O _1-10 alkoxy, -SCH ₃ , SCH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ or -N(CH ₃ ) ₂ , benzofuranil,

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

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

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

R ₂ and R ₃ are independently hydrogen or C _1-6 alkyl;

R4 is -5- or 6-membered heteroaryl mono-, bi- or tri-substituted independently with C _1-10 alkoxy, -O-C _3-8 cycloalkyl, -SC _1-6 alkyl, difluoromethoxy, or -N(CH ₃ ) ₂ , benzofuranyl, benzo[b]thiophenyl or

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

R5 is halo or cyano, where heteroaryl is heteroaryl containing 1-4 heteroatoms selected from

N, O or S, or

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

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;

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

2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2ol;

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

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

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

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

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

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

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

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

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

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

1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpi- 1040011 ridin-4-yl)butane -2-ol;

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

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

2-(2,6-bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro3-methoxyphenyl)butane -2-ol;

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

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

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

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

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

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

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

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

3-(2-(benzofuran-2-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybugyl)-2-methoxyquinolin-6carbonitrile;

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

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

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

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

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

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

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

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

3-(2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile; or or to its pharmaceutically acceptable salt.

The present invention also relates to a pharmaceutical composition for the treatment of tuberculosis, containing a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier.

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

Detailed description of the invention

It should be understood that the description of the present invention has been simplified to illustrate elements that are important for a clear understanding of the present invention, while in order to provide greater clarity, many other elements inherent in typical pharmaceutical compositions are not mentioned. Those skilled in the art will appreciate that other elements and/or steps are desirable and/or necessary to implement the present invention. However, since such elements and steps are well known in the art and because they do not contribute to a better understanding of the present invention, the present application does not provide a discussion of these elements and steps. The disclosure of the invention in this application refers to all such changes and modifications of these elements and methods, which are known to experts in this field of technology. In addition, the embodiments of the invention indicated and illustrated herein are for illustrative purposes only and are not meant to be exhaustive or limiting of the present invention.

Used in this application, technical and scientific terms have the meanings usually understood by a person skilled in the art for which the present invention is intended, unless otherwise indicated. References to various techniques and materials provided in this application are known to those skilled in the art. A standard set of reference literature concerning general principles of pharmacology includes Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 ^th Ed., McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to those skilled in the art may be used in the practice of the present invention. However, only preferred materials and methods are described. Materials, reagents, and the like referred to in the description and examples below may be obtained from commercial sources, unless otherwise indicated.

The compound of the present invention inherently includes all its stereochemically isomeric forms. The term stereochemically isomeric forms, as used above or hereinafter in this application, defines all possible stereoisomeric forms that the compounds of formula (I) and their N-oxides, pharmaceutically acceptable salts, or physiologically functional derivatives may have. Unless otherwise noted or indicated, the chemical designation of compounds refers to the mixture of all possible stereochemically isomeric forms. In particular, stereogenic centers may have an R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have the cis- or trans-configuration. Compounds having double bonds may have E-(entgegen) or Z-(zusammen) stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are known to the person skilled in the art.

It should be understood that the stereochemically isomeric forms of the compound of formula (I) are obviously within the scope of the present invention. Of particular interest are compounds of formula (I) which are stereochemically pure.

According to the CAS nomenclature convention, when two stereogenic centers of known absolute configuration are present in a molecule, the R or S descriptor is assigned (based on the Cahn-Ingold-Prelog precedence rule) to the lowest numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using the appropriate descriptors [R*,R*] or [R*,S*], where R* is always indicated as the reference center, and [R*,R*] means centers with the same chirality, a [R*,S*] means centers with different chirality. For example, if the lowest numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be S-[R*,S*]. When using α and β: the position of the substituent with the highest priority on the asymmetric carbon atom in the ring system having the lowest ring number is always randomly located in the α position from the center plane defined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the base atom is called α if it is on the same side of the center plane defined by the ring system, or β if it is on the other side of midplane defined by the ring system.

An indication of a specific stereoisomeric form, this means that said form is essentially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, even more preferably less than 2% and most preferably less than 1% of the other isomer(s). Thus, when a compound of formula (I), for example, is defined as (R,S), this means that the compound essentially does not contain the (S,R) isomer.

Compounds of formula (I) and certain intermediates invariably have at least two stereogenic centers in their structure, which can lead to at least 4 stereochemically distinct structures.

The compounds of formula (I) can be synthesized in the form of mixtures, in particular racemic mixtures, in the form of enantiomers which can be separated from each other using resolution techniques known in the art. The racemic compounds of formula (I) may be converted to the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. Said diastereomeric salt forms are then separated, for example by selective or fractional crystallization, and the enantiomers are liberated from the mixture with alkali. An alternative method for separating the enantiomeric forms of compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a particular stereoisomer is desired, said compound is synthesized by stereospecific preparation methods. These methods preferably use enantiomerically pure starting materials.

- 3 040011

Tautomeric forms of the compounds of formula (I) are intended to include compounds of formula (I) where, for example, an enol group is converted to a keto group (keto-enol tautomerism). The tautomeric forms of the compounds of formula (I) or intermediates of the present invention are intended to be included within the scope of the present invention.

Used in this application, the term alkyl means a saturated monovalent hydrocarbon group with a straight or branched chain containing from 1 to 10 carbon atoms. The term lower alkyl means a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms. Used in this application C ₁ . ₁₀ alkyl refers to alkyl consisting of 1-10 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, n-butyl, m-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

Where the term alkyl is used as a suffix to another term, such as in phenylalkyl or hydroxyalkyl, this refers to an alkyl group as defined above having one to two substituents selected from other groups specifically named. Thus, for example, phenylalkyl means the radical R'R-, where R' is a phenyl radical, and R is an alkylene radical, as defined in this application, and it should be understood that the point of attachment of the phenylalkyl group is on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms arylalkyl or aralkyl are treated similarly, except that R' is an aryl radical. The terms (het)arylalkyl or (het)aralkyl are interpreted similarly, except that R' is optionally an aryl or heteroaryl radical.

The terms haloalkyl or halogen lower alkyl or lower haloalkyl refer to a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms, where one or more carbon atoms are replaced by one or more halogen atoms.

As used herein, the term alkoxy means a -O-alkyl group, where alkyl is as defined above, such as methoxy, ethoxy, n-propyloxy, m-propoxy, n-butyloxy, mbutyloxy, t-butyloxy, pentyloxy, hexyloxy, including their isomers. As used herein, lower alkoxy means an alkoxy group with a lower alkyl group as defined above. C _1-10 alkoxy, as used herein, refers to -O-alkyl, where alkyl is C _1-10 .

The terms haloalkoxy or halogen-lower-alkoxy or lower-haloalkoxy refer to the group lower-alkoxy wherein one or more carbon atoms have been replaced by one or more halogen atoms.

Used in this application, the term hydroxyalkyl means an alkyl radical, as defined in this application, where from one to three hydrogen atoms on different carbon atoms replaced/replaced by hydroxyl groups.

As used herein, the term sulfonyl means a -SO2- group.

As used herein, the terms alkylsulfonyl and arylsulfonyl refer to a group of formula -S(=O)2R, where R is alkyl or aryl, respectively, where alkyl and aryl are as described herein. Used in this application, the term heteroalkylsulfonyl means a group of the formula -S(=O) 2 R, where R represents a heteroakyl, as described in this application.

As used herein, the term lower alkyl sulfonylamido refers to a group of formula -S(=O) ₂ NR ₂ where each R is independently hydrogen or C1.3 alkyl and lower alkyl is as described herein.

Used in this application, the term carboxyl refers to a group of formula -C(=O)R ₂ where each R is independently hydrogen or C1.3 alkyl, and lower alkyl is as described in this application.

The term cycloalkyl means a monovalent saturated monocyclic or bicyclic hydrocarbon group containing from 3 to 10 ring carbon atoms. According to specific variants of implementation of the present invention cycloalkyl means a monovalent saturated monocyclic hydrocarbon group containing from 3 to 8 carbon atoms. Bicyclic means consisting of two saturated carbon rings containing one or more common carbon atoms. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl.

Used in this application, the term amino means a group of formula -NR'R, where R' and R independently represent hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. Alternatively, R' and R, together with the hydrogen atom to which they are attached, may form a heterocycloalkyl. The term primary amino means a group in which both R' and R are hydrogen. The term secondary amino means a group in which R' is hydrogen and R is not hydrogen. The term tertiary amino means a group in which both R' and R are not hydrogen. Specific secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine and diisopropylamine.

The term heteroaryl means a monovalent aromatic heterocyclic mono- or bicyclic ring system consisting of 5-12 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl residues include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, indolylbenzothiene, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl.

The term heterocycloalkyl means a monovalent saturated or partially unsaturated mono- or bicyclic ring system consisting of 3-9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. According to specific embodiments of the invention, heterocycloalkyl is a monovalent saturated monocyclic ring system consisting of 4-7 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms representing carbon. Examples of monocyclic saturated heterocycloalkyls are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxolidinyl-1-thiomorpholinyl, il, azepanil, diazepanil, homopiperazinil or oxazepanil. Examples of bicyclic saturated heterocycloalkyls are 8-azabicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 9-azabicyclo[3.3.1]nonyl, 3- oxa-9-azabicyclo[3.3.1]nonyl or 3-thia-9-azabicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyls are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, or dihydropyranyl.

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

As used herein, the term carrier includes carriers, excipients, and diluents, and means a substance, composition, or excipient, such as a liquid or solid excipient, diluent, excipient, solvent, or encapsulating agent, involved in the transfer or transport of a pharmaceutical agent from one organ. or body part to another organ or body part.

The term treatment, referring to a subject, means the improvement of at least one symptom of the disease of the subject. The treatment may be complete recovery, amelioration, or at least partial alleviation of the disorder.

Used in the description of the present application, the term violation, unless otherwise indicated, means and is used interchangeably with the terms disease, condition or disease.

As used herein, the terms administer, administer, or use refer either to the direct administration of a compound or a pharmaceutically acceptable salt of said compound or composition to a subject, or to the administration of a prodrug, derivative or analog of said compound or a pharmaceutically acceptable salt of said compound or composition to a subject, in resulting in an equivalent amount of the active compound in the subject's body.

Used in the description of the present application, the term optionally substituted means that the hydrogen associated with carbon, nitrogen or oxygen can be replaced by a suitable substituent. In the case where the substituent is oxo (i.e. = O), the two hydrogens at the indicated atom are replaced by one O. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to be introducing any substitution or substitution structures which are sterically inapplicable and/or which cannot be synthesized and/or which are essentially unstable. Moreover, combinations of substituents and/or variables in any of the formulas presented in this application are only permissible if such combinations lead to the formation of stable compounds or suitable prepared intermediates, and stability implies a pharmacologically acceptable half-life in physiological conditions.

Dosages and Application

The compounds of the present invention may be presented in a wide variety of oral formulations and carriers. Oral administration may be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. Compounds of the present invention are effective when administered by other routes, including continuous (intravenous drip), topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), buccal, nasal, inhalation, and suppository administration, among others. routes of administration. The preferred route of administration is generally oral administration using a daily dosing regimen which may be adjusted according to the degree of injury and the patient's response to the active ingredient.

The compound or compounds of the present invention, as well as their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers or diluents, may be presented in the form of pharmaceutical compositions and unit dosage forms. Said pharmaceutical compositions and unit dosage forms may consist of conventional ingredients in conventional proportions, may or may not contain additional active compounds or constituents, and the unit dosage forms may contain any suitable effective amount of the active ingredient in accordance with the prescribed daily dosage regimen. Said pharmaceutical compositions may be used in solid forms such as filled tablets or capsules, semi-solid forms, powders, sustained release formulations, or liquid forms such as solutions, suspensions, emulsions, elixirs or capsules filled for oral administration; or in the form of suppositories for rectal or vaginal use; or in the form of sterile injectable solutions for parenteral use. Typical formulations contain from about 5% to about 95% active compound or compounds (w/w). The terms drug or formulation are intended to include both solid and liquid formulations of the active compounds, and one skilled in the art will appreciate that the active ingredient may be present in various formulations depending on the target organ or tissue and the desired dosage and pharmacokinetic parameters.

As used in this application, the term excipient refers to a compound suitable for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes excipients that are acceptable for both veterinary use, and for pharmaceutical use in humans. The compounds of the present invention may be used alone, but are usually administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers chosen according to the intended route of administration and common pharmaceutical practice.

The phrase pharmaceutically acceptable means suitable for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and is acceptable for both veterinary use and pharmaceutical use in humans.

A pharmaceutically acceptable salt of the active ingredient may also confer on the active ingredient a desired pharmacokinetic property that was not present in the non-salt form, and may even positively influence the pharmacodynamics of said active ingredient in relation to its therapeutic activity in the body. The phrase pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: (1) addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed by organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4methylbicyclopropyl[2,2,2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearins oic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or reacts with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid support may be one or

- 6 040011 more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants or encapsulating material. In powders, the carrier is usually a finely divided solid which is a mixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding power in suitable ratios 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, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Liquid formulations are also suitable for oral administration and include emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared as solutions, such as aqueous propylene glycol solutions, or may contain emulsifying agents such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be obtained by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with a viscous substance such as natural or synthetic gums, gums, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

The compounds of the present invention may be presented as oral dosage forms (eg, by injection, eg, bolus injection or continuous infusion) and may be presented as unit dosage form in ampoules, pre-filled syringes, small volume infusions, or multi-dose containers. with the addition of a preservative. Said compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents, or excipients include propylene glycol, polyethylene glycol, vegetable oils (eg, olive oil), and injectable organic esters (eg, ethyl oleate), and may contain adjuvants such as preservatives, wetting agents, emulsifiers. or suspending agents, stabilizers and/or dispersing agents. Alternatively, the active ingredient may be presented as a powder obtained by aseptic isolation of a sterile solid or by lyophilization from a dilution solution prior to use in a suitable vehicle, eg sterile, pyrogen-free water.

The compounds of the present invention may be presented in topical skin formulations as ointments, creams and lotions, or as transdermal patches. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of a suitable thickener and/or gelling agents. Lotions may be formulated with an aqueous or oily base, and typically also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical use in the oral cavity include lozenges containing the active agents in a flavored base, usually sucrose and gum arabic or tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthrinses containing the active ingredient and a suitable liquid carrier.

The compounds of the present invention may be presented as formulations for administration as suppositories. First, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is melted, and then the active ingredient is homogeneously dispersed, for example by stirring. The molten homogeneous mixture is then poured into suitable sized molds, left to cool and solidify.

The compounds of the present invention may be presented as formulations for vaginal administration. Suitable pessaries, tampons, creams, gels, pastes, foams or sprays are known in the art and contain such carriers in addition to the active ingredient.

The compounds of the present invention may be presented as nasal formulations. Solutions or suspensions are administered directly into the nasal cavity by traditional methods, for example, using a dropper, pipette or spray. The formulations may be presented in single dose or multi-dose form. In the case of a dropper or pipette, this is achieved by the patient injecting an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be achieved, for example, with a metering, atomizing spray pump.

- 7 040011

The compounds of the present invention may be presented as formulations for aerosol administration, in particular inhalation, including intranasal administration. Typically, such compounds have a small particle size, for example, on the order of five (5) microns or less. This particle size can be obtained by methods known in the art, for example by micronization. The active ingredient is provided in a sealed package with a suitable propellant such as a chlorofluorocarbon (CFC), eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoromethane, or carbon dioxide or other suitable gas. The aerosol can traditionally also contain a surfactant such as lecithin. The dose of the drug can be controlled using a metering valve. Alternatively, the active ingredients may be presented in the form of a dry powder, for example a powder mixture of said compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powdered carrier forms a gel in the nasal cavity. The powder composition may be presented in single dose form, for example, in capsules or cartridges, for example of gelatin, or blister packs, from which the powder can be administered by inhalation.

If necessary, the compositions can be prepared with enteric coatings suitable for administration with delayed or controlled release of the active ingredient. For example, the compounds of the present invention may be presented in the form of transdermal or subcutaneous drug delivery devices. Such delivery systems are preferred when sustained release of the compound is desired and when patient compliance is critical. In transdermal delivery systems, often the compound is attached to a solid carrier that adheres to the skin. The subject compound can also be combined with a penetration enhancing agent such as azone (1-dodecylase-cycloheptan2-one). Sustained release delivery systems are administered subcutaneously to the subdermal layer by surgery or injection. Subcutaneous implants encapsulate said compound in a lipid-soluble membrane, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.

Suitable formulations with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. The skilled artisan will be able to make changes to the formulations within the scope of the present disclosure to provide a variety of formulations for a particular route of administration without compromising the stability of the compounds of the present invention or reducing their therapeutic activity.

Modifications of the present compounds to render them more soluble in water or other carrier, for example, can be readily obtained with minor modifications (salification, esterification, etc.) which are well known to those of ordinary skill in the art. It is also well known to one of ordinary skill in the art how to modify the route of administration and dosing schedule of a particular compound in order to adjust the pharmacokinetics of the present compounds in order to obtain the maximum beneficial effect in patients.

Used in this application, the term therapeutically effective amount means the amount required to reduce the symptoms of the disease in the individual. The specified dose is selected in accordance with individual requirements in each case. Said dosage may vary widely depending on a variety of factors such as the severity of the disease being treated, the age and general health of the patient, other drugs the patient is being treated with, the route and form of administration, and the preference and experience of the attending physician. In the case of oral administration, a daily dose of between about 0.01 and about 1000 mg/kg of body weight per day is suitable in monotherapy and/or combination therapy. A preferred daily dose is between about 0.1 and about 500 mg/kg body weight, more preferably 0.1 and about 100 micrograms/kg body weight, and most preferably 1.0 and about 15 mg/kg body weight per day. Thus, for administration to a human weighing 70 kg, the dosage range according to one embodiment of the invention will be from about 70 mg to 7 g per day. The daily dose may be administered in a single dose or in divided doses, typically 1 to 5 doses per day. As a rule, treatment is started with small doses, which are less than the optimal dose of the specified compound. The dose is then increased in small increments until the optimal effect for the individual patient is reached. A person skilled in the treatment of the diseases described in this application, without additional experimentation, based on their own knowledge, experience and description of this application, will be able to determine a therapeutically effective amount of the compounds according to the present invention for a given disease and patient.

Said pharmaceutical preparations are preferably presented in the form of unit dosage forms. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, said package containing discrete amounts of the drug, for example,

- 8 040011 packed tablets, capsules and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, cachet or lozenge as such, or may be an appropriate number of any of these forms in a package.

Examples

The following examples further describe and demonstrate specific embodiments of the invention that are within the scope of the present invention. Methods and formulations are generally given in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). The description is further illustrated by the following examples, which should not be construed as limiting this disclosure in scope or spirit to the specific techniques described herein. It should be understood that the examples are provided to illustrate certain embodiments of the invention, and that no limitation on the scope of the disclosure is thus intended. It should also be understood that reference may be made to various other embodiments, modifications and equivalents as those skilled in the art may contemplate without departing from the spirit of the present disclosure and/or the scope of the appended claims.

Melting points were determined on an Electrothermal 2300 melting point apparatus. NMR spectra were obtained on a Bruker Avance 400 spectrometer at 400 MHz for 1H and at 100 MHz for ¹³ C spectra with internal standard Me ₄ Si. Chemical shifts and coupling constants are recorded in units of ppm. and Hz, respectively. Low resolution atmospheric chemical ionization mass spectra ([M+H]) of the intermediates were measured for methanolic solutions on a ThermoFinnigan Surveyor MSQ mass spectrometer. Thin layer chromatography was performed on silica gel plates with aluminum (Merck 60 F254) with visualization of the components in UV light (254 nm) and/or exposure to I ₂ . Column chromatography was performed on silica gel (Merck 230-400 mesh) unless otherwise noted. The column chromatography alumina was 90 Merck alumina (standard). Analysis of final test compounds was performed on an Agilent 12006110 LCMS using the following conditions; Column: Sunfrie C-18, 4.6x50mm; mobile phase: ACN (0.05%TFA)-water (0.05%TFA); Gradient: 5% ACN to 95% in 1.0 min, hold 1.0 min total 2.5 min; flow rate: 1.8 ml/min; LC detector: UV 214 nm, 254 nm; MS ([M+H]): electrospray ionization at atmospheric pressure; MS cone voltage: (V) Positive 4000, Negative 3000. The purity of all test compounds was determined to be >95%.

Abbreviations:

ACN - acetonitrile;

aq. - water;

bd - wide doublet;

bs - wide singlet;

p-BuLi - p-butyllithium;

d - doublet;

DCM - dichloromethane;

dd - doublet of doublets;

ddd - double doublet of doublets;

dist. - distilled;

DMAP - 4-(dimethylamino)pyridine;

DMF - dimethylformamide;

DMSO - dimethyl sulfoxide;

DPPP - 1,3-bis(diphenylphosphino)propane;

dq - doublet of quartets;

dt - doublet of triplets;

Et2O - diethyl ether;

EtOAc - ethyl acetate;

h - hour;

HPLC - high performance liquid chromatography;

HOAc acetic acid;

m.p. - melting point;

MeOH - methanol;

mesyl - methanesulfonyl;

min - minutes;

p - pentet;

pd - pentet of doublets;

q - quartet;

qt - quartet of triplets;

k.t. - room temperature;

- 9 040011 s - singlet;

sat. - saturated;

sp - septet;

t - triplet;

TFA - trifluoroacetic acid;

TFAA - trifluoroacetic anhydride;

THF - tetrahydrofuran.

I. Preparation of typical intermediates according to the present invention (6-bromo-2-methoxyquinolin-3-yl)boronic acid (1)

B(OH) ₂

Td X N OMe (1)

A solution of 2,2,6,6-tetramethylpiperidine (14.4 ml, 84.8 mmol) in THF (100 ml, Na dist.) at -78°C was treated with p-BuLi (33 ml, 2.5 M in hexanes , 82.5 mmol), then the specified solution was heated to -20°C for 20 min and then 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, dist. Na) was added dropwise and the orange solution was stirred in for 3 h at -78°C, heated to -40°C and then quenched sat. aq. NH ₄ Cl (500 ml). The mixture was diluted with water (1 L) and the white precipitate was filtered off, triturated with hexanes and dried to give Compound 1 (11.17 g, 94%) as a white solid. ¹ H NMR (DMSO-d ₆ ) 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). Found: [M-OH+OMe]=296.2.

2,6-diethoxyisonicotinic acid (2)

ΟγΟΗ χχ EO N OEt (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 minimum amount of water and acidified to pH 3 with 2M HCl. The solid was filtered off and dried to give compound 2 as a white solid (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)

(3)

Oxalyl chloride (0.73 ml, 8.6 mmol) was added to a suspension of compound 2 (1.52 g, 7.20 mmol) in DCM (50 ml, anhydrous) and DMF (0.20 ml, 2.6 mmol) at k.t. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was then cooled to 0°C. N, Odimethylhydroxylamine hydrochloride (0.77 g, 17.89 mmol) and pyridine (1.92 ml, 23.7 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between EtOAc and sat. aq. _NaHC03 . Column chromatography using 3:1 hexanes:EtOAc gave compound 3 (1.26 g, 69%). 1H NMR(CDCl ₃ ) 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). Found: [M+H]=255.1.

-(2,6-Diethoxypyridin-4-yl)-3 -(dimethylamino)propan-1-one (4)

Vinyl magnesium bromide (14.6 ml of a 1N solution in THF, 14.6 mmol) was added to a solution of compound 3 (1.23 g, 4.85 mmol) in dry THF (50 ml) at 0°C. The brown solution was heated to rt. for 1 h, then a solution of 2 N. dimethylamine in THF (14.6 ml, 29.2 mmol) and water (10 ml). The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 4 as a brown oil (1.24 g, 96%). 1H NMR (CDCl ₃ ) 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).

- 10 040011

Found: [M+H]=267.2.

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

A

MeO N OMe (5)

Oxalyl chloride (1.34 ml, 15.8 mmol) was added to a suspension of 2,6-dimethoxyisonicotinic acid compound (2.41 g, 13.2 mmol) in DCM (70 ml) and DMF (0.20 ml, 2. 6 mmol) at RT. The mixture was stirred for 1 h to obtain a colorless solution, which was cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.6 mmol) and pyridine (3.51 ml, 28.9 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between EtOAc and sat. aq. _NaHC03 . Column chromatography with hexanes:EtOAc (2:1) gave compound 5 (2.49 g, 83%). 1 H NMR (CDCl ₃ ) δ 6.47 (s, 2H), 3.93 (s, 6H), 3.58 (br s, 3H), 3.32 (s, 3H). Found: [M+H]=227.2.

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

IjQ

MeO N OMe (6)

Vinylmagnesium bromide (32 ml of a 1N solution in THF, 32 mmol) was added to a solution of compound 5 (2.45 g, 10.8 mmol) in dry THF (100 ml) at 0°C. The brown solution was heated to rt. for 1 h, then dimethylamine (32 ml of a 2N solution in THF, 64 mmol) and water (30 ml) were added. The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated and impurities were eluted with DCM:MeOH (95:5) column chromatography to give compound 6 as an oil (0.81 g, 31%) with DCM:MeOH (9:1). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=239.1.

3-((2,4-Dimethoxybenzyl)(methyl)amino)-1-(2,6-dimethoxypyridin-4-yl)propan-1-one (7)

Μθ uu

OME

XI

MeO N OMe (Ό

Vinylmagnesium bromide (17.7 ml of a 1N solution in THF, 17.7 mmol) was added to a solution of compound 5 (2.00 g, 8.84 mmol) in dry THF (30 ml) at 0°C. The brown solution was heated to rt. for 1 h, 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 rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give a brown oil which was chromatographed. Elution with EtOAc/hexanes gave front fractions, then eluting with EtOAc gave compound 7 (2.27 g, 68%) as a light yellow oil. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=375.3.

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

(8)

To a mixture of compound 1 (1.50 g, 5.32 mmol) and 2-fluoro-3-methoxybenzyl bromide (5.59 mmol) in 1,2-dimethoxyethane (25 ml) in a sealed tube was added 2M Na ₂ CO ₃ solution ( 5 ml) and the mixture was degassed under N ₂ for 15 min, then Pd(PPh ₃ ) 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 r. t., water (100 ml) was added, after which it was extracted with EtOAc (2x125 ml). The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes-EtOAc (100:0 to 95:5) gave compound 8 as a colorless oil which crystallized 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). Found: [M+H]=376.2.

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

- 11 040011

Τ

XXX N OMe (9)

Reaction of compound 1 with 3-fluorobenzyl bromide as described above to give compound 8 gave compound 9 as a white solid after chromatography (88%). 1H NMR (CDCl ₃ ) 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: [M+H]=346.2.

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

IQ

XXX

I (io)

Reaction of compound 1 with 3-methylbenzyl bromide as described above to give compound 8 gave compound 10 as a white solid after chromatography (73%). 1H NMR (CDCl ₃ ) 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: [M+H]=342.1.

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

(AND)

A stirred mixture of compound 1 (1.63 g, 5.79 mmol), 2,3-dimethoxybenzyl bromide (1.60 g, 6.95 mmol) and Cs ₂ CO ₃ (3.78 g, 11.50 mmol)) in toluene (20 ml) and DMF (10 ml) was reduced by bubbling through the indicated nitrogen gas mixture for 10 minutes. Pd(PPh ₃ ) ₄ (0.33 g, 0.29 mmol) was then added and the mixture was stirred under nitrogen at 90° C. for 5 hours. The mixture was diluted with EtOAc and washed with water, then brine. The extract was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The product was chromatographed. Elution with 0-4% EtOAc/hexanes afforded product 11 as a white solid (1.26 g, 56%) which crystallized from methanol as colorless microneedles, mp 93°C. ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=388.3.

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

Me If ons/ (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 TiCl ₄ ( 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 h, heated to rt. for more than 30 min, then poured onto ice, acidified with conc. 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.) afforded compound 12 as a colorless liquid (5.81 g, 60%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=141.1.

(6-Bromo-2-methoxyquinolin-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. and p-BuLi (4.45 mL of 2.5N solution in hexane, 11.1 mmol) was added and the solution was stirred at

- 12 040011

-40°C for 15 min, 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 orange solution was stirred at -78°C for 1.5 h, then a solution of compound 12 (1 .30 g, 9.27 mmol) in THF (10 ml). The mixture was stirred at -78° C. for 3 h, then acetic acid (1.60 mL, 28.0 mmol) was added and the solution was allowed to warm to rt. The mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Chromatography with DCM:hexanes (1:3) eluted the starting materials, then eluting with DCM:hexanes (1:1) gave compound 13 as a white solid (1.97 g, 56%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=378.2.

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

(14)

Triethylsaline (6.8 ml, 42.1 mmol) was added to a solution of compound 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 for half a year at 0°C, then at rt. within 2 hours the Solution was cooled to 0°C, quenched sat. aq. NaHCO ₃ and partitioned between DCM and water. Column chromatography (1:3 DCM:hexanes) gave compound 14 as a white solid (1.70 g, 89%). 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). Found: [M+H]=362.2.

(6-Bromo-2-methoxyquinolin-3-yl)(5-meylthiophen-2-yl)methanol (15)

A solution of 2,2,6,6-tetramethylpiperidne (3.5 ml, 20.6 mmol) in dry THF (20 ml) was cooled to -40°C and p-BuLi (8.0 ml of 2.5 N. solution in hexanes, 20 mmol) and the solution was stirred at -40°C for 15 min, 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 h. 2-carbaldehyde (1.12 g, 16.8 mmol) in THF (10 ml). The mixture was stirred at -78° C. for 3 h, then acetic acid (2.9 mL, 50.7 mmol) was added and the solution was allowed to warm to rt. The mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Chromatography with DCM:hexanes (1:3) eluted unreacted starting materials, then eluting with DCM:hexanes (1:1) gave compound 15 as a white solid (3.37 g, 55%), 1H NMR (CDCl ₃ ) 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). Found: [M+H]=364.1.

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

Triethylsaline (13.6 ml, 84 mmol) was added to a solution of compound 15 (3.75 g, 10.3 mmol) and TFA (7.70 ml, 104 mmol) in DCM (100 ml) at 0°C, then the solution stirred for poluchat r.t. and ice water was added. The solution was divided between sat. aq. NaHCO ₃ and DCM and the aqueous fraction was extracted with DCM, the organic fractions were combined and evaporated. Chromatography (1:3 DCM:hexanes to 1:1 DCM:hexanes) gave compound 16 as a white solid (2.83 g, 79%). ¹ H 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). Found: [M+H]=348.2.

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

- 13 040011

(17)

Mixture of compound 1 (1.00 g, 3.55 mmol), 3-(chloromethyl)-2-methoxypyridine (0.68 g, 4.31 mmol) and Cs ₂ CO ₃ (2.31 g, 7.09 mmol ) in a mixture of toluene:DMF (60 ml, 2:1) was degassed under N2 atmosphere, then Pd(PPh ₃ ) ₄ (0.082 g, 0.071 mmol) was added and the mixture was heated at 80°C for 4 h. The reaction mixture was cooled to rt, filtered through celite, added water (150 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave compound 17 as a white solid (0.94 g, 74%). 1H NMR (CDCl ₃ ) δ 8.08 (dd, J = 5.0, 1.9 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (s, 1H), 7.38 (dd, J = 7.2, 1.9 Hz, 1H), 6.83 (dd, J = 7.2, 5.0 Hz, 1H), 4.07 (s, 3H), 3.96 (s, 2H), 3.95 ( s, 3H). Found: [M+H]=359.6.

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

I (18)

To a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (4.40 g, 27.5 mmol) in DCM (250 ml) was added DMF (0.426 ml), followed by dropwise addition of oxalyl chloride (4. 19 g, 33.0 mmol). The reaction mixture was stirred for 1 h, cooled to 0°C, then N,O-dimethylhydroxylamine hydrochloride (2.95 g, 30.3 mmol) and pyridine (7.32 ml, 90.7 mmol) were added and the reaction mixture stirred at rt. for 18 hours the Mixture was poured into sat. aqueous NaHCO3 (150 ml) and extracted with DCM (3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellowish residue. The crude product 18 was used in the next step without further purification (5.64 g, 100%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=206.5.

-(2,3-Dihydro-1 H-inden-4-yl)-3 -(dimethylamino)propan-1-one (19)

I

Oo (19)

To a solution of compound 18 (5.64 g, 27.5 mmol) in THF (150 ml) at 0°C was added vinylmagnesium bromide (1M solution in THF, 57.7 ml, 57.7 mmol) and the solution was stirred for 3 .5 h at 0°C. Dimethylamine (2M solution in THF, 57.7 ml, 115.5 mmol) was added to the reaction mixture, followed by water (60 ml). After 30 minutes of stirring at rt, the reaction mixture was concentrated under reduced pressure to give a brownish residue. The specified residue was extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 19 as a brown oil (5.66 g, 95%). ¹ H NMR (CDCl ₃ ) δ 7.66 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7, 6 Hz, 1H), 3.24 (t, J = 7.5 Hz, 2H), 3.11 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.5 Hz , 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.27 (s, 6H), 2.04 (t, J = 7.5 Hz, 2H). Found: [M+H]=218.6.

(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)methanol (20) no.

od (20)

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 13 g, 56.0 mmol). The reaction mixture was stirred at 0°C for 10 min and stirred for an additional 18 h at rt. Water (150 ml) was added to the reaction mixture and the reaction mixture was extracted with EtOAc (2x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 20 as a yellow oil (3.22 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H-18]=149.5.

- 14 040011

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

A solution of compound 20 (3.75 g, 32.3 mmol) in diethyl 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 rt. over 1 hour. Water (10 ml) was added carefully to quench excess reagent and the mixture was diluted with diethyl ether and washed with water (3x50 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 21 as a brown solid (4.61 g, 62%). ¹ H NMR (CDCl ₃ ) 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]doxin-5-yl)methyl)-2-methoxyquinoline (22) co

XXX

W/ N O I (22)

A mixture of compound 1 (4.42 g, 15.4 mmol), compound 21 (4.6 g, 20.0 mmol) and Cs ₂ CO ₃ (11.54 g, 0.77 mmol) in toluene:DMF ( 60 ml, 2:1) was degassed under N ₂ atmosphere, then Pd(PPh ₃ ) ₄ (0.890 g, 0.77 mmol) was added and the mixture was heated at 110° C. for 4 h. , filtered through a celite plug, added water (150 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave compound 22 as a white solid (3.1 g, 52%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=386.6.

3-Benzyl-6-iodine-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, then p-BuLi (2M solution in cyclohexane, 5.48 ml, 11.0 mmol) to give a dark purple solution. After 60 seconds, iodine (1.74 g, 7.31 mmol) in THF (23 ml) was added and the resulting red solution was stirred at -78° C. for 10 minutes. Water (20 ml) was added to the resulting solution, which was extracted with EtOAc (3x30 ml), dried with MgSO ₄ , filtered and the solvent was evaporated to give an orange oil. MeOH (10 ml) was added to the mixture and sonicated until a white solid formed. The solid was filtered to give compound 23 as a white solid (1.77 g, 52%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=376.6.

2,6-bis(Ethylthio)isonicotinic acid (24) o^one (24)

Ethanthiol (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. To the solution was added 2,6-dichloroisonicotinic acid (3.17 g, 13.0 mmol) in DMF (5 ml) dropwise. 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 with 2M HCl solution. The aqueous solution was extracted with EtOAc (3x30 ml), dried with MgSO4, filtered and the solvent was evaporated to give compound 24 as a yellow solid, which was used in the next step without further purification (2.82 g, 89%). ' and NMR (CDCl ₃ ) δ 7.40 (s, 2H), 3.19 (q, J = 7.3 Hz, 4H), 1.39 (t, J = 7.3 Hz, 6H). discover

- 15 040011 but: [M+H]=244.5.

2,6-bis(Ethylthio)-N-methoxy-N-methylisonicotinamide (25)

To a solution of compound 24 (3.24 g, 13.3 mmol) in DCM (150 ml) was added DMF (0.206 ml), after which oxalyl chloride (1.37 ml, 16.0 mmol) was added dropwise. The mixture was stirred at rt. for 2 h, then cooled to 0°C and added N,O-dimethylhydroxylamine hydrochloride (1.43 g, 14.6 mmol) and then pyridine (3.55 ml, 43.9 mmol) and the resulting mixture was stirred at k.t. for 18 hours the Mixture was poured into sat. NaHCO ₃ (150 ml) was extracted with DCM (150 ml) and EtOAc (100 ml). The combined organic phase was dried with Na ₂ SO ₄ and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (1:1) gave compound 25 as a colorless oil (3.65 g, 96%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=287.5.

1-(2,6-bis(Ethylthio)pyridin-4-yl)-3-(dimethylamino)propan-1-one (26)

To a solution of compound 25 (3.65 g, 12.7 mmol) in THF (150 ml) at 0°C was added vinylmagnesium bromide (1M solution in THF, 31.5 ml, 31.5 mmol) and then stirred at 0 °C over 4 hours. Dimethylamine (2M solution in THF, 31.5 ml, 63.0 mmol) was added followed by water (60 ml). After 30 min stirring at rt. the reaction mixture was concentrated under reduced pressure to give a brownish residue. The specified residue was extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. Purification by flash column chromatography using EtOAc:MeOH (9:1) gave compound 26 as a yellow oil (2.51 g, 66%). ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=299.6.

2,6-bis(Methylthio)isonicotinic acid (27)

To a solution of 2,6-dichloroisonicotinic acid (4.00 g, 20.8 mmol) in DMF (40 ml) at 0° C. was added sodium thiomethoxide (4.38 g, 65.5 mmol). 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 a 2M HCl solution. The aqueous solution was extracted with EtOAc (3x40 ml), dried with MgSO ₄ , filtered and concentrated under reduced pressure to give compound 27 as an orange solid, which was recrystallized from methanol (4.01 g, 90%). 1 H NMR (CDCl ₃ ) δ 7.44 (s, 2H), 2.61 (s, 6H). Found: [M+H]=216.5.

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

To a solution of compound 27 (5.03 g, 23.4 mmol) in DCM (200 ml) was added DMF (0.362 ml), after which oxalyl chloride (2.41 ml, 28.0 mmol) was added dropwise. The mixture was stirred at rt. for 2 h, 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) and the resulting mixture was stirred at r. .T. for 18 hours the Mixture was poured into sat. NaHCO ₃ (150 ml) was extracted with DCM (150 ml) and EtOAc (100 ml). The organic phase was dried with Na ₂ SO ₄ and concentrated to give compound 28 as a yellow oil, which was used in the next step without further purification (4.96 g, 82%). 1 H NMR (CDCl ₃ ) δ 7.04 (s, 2H), 3.56 (s, 3H), 3.33 (s, 3H), 2.60 (s, 6H). Found: [M+H]=259.5.

1-(2,6-bis(Methylthio)pyridin-4-yl)-3-(dimethylamino)propan-1-one (29)

- 16 040011

To a solution of compound 28 (4.96 g, 19.2 mmol) in THF (90 ml) at 0°C was added vinylmagnesium bromide (1M solution in THF, 40.3 ml, 40.3 mmol) and the solution was stirred at 0° C over 1 hour. Dimethylamine (2M solution in THF, 40.3 ml, 80.6 mmol) was added followed by water (60 ml). After 30 minutes of stirring at r.t. the reaction mixture was concentrated under reduced pressure to give a brownish residue. The specified residue was extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 29 as a brown oil (4.87 g, 94%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=271.6.

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

XXX/ N O (30)

A mixture of compound 1 (3.00 g, 10.5 mmol), 1-(bromomethyl)-2-fluoro-3-methylbenzene (4.24 g, 20.9 mmol) and Cs ₂ CO ₃ (7.87 g, 24.2 mmol) to toluene:DMF (60 ml, 2:1) was degassed under N ₂ nitrogen, then Pd(PPh ₃ ) ₄ (0.607 g, 0.525 mmol) was added and the mixture was heated at 90° C. for 2 h. The reaction mixture was cooled to rt, filtered through a Celite plug, water (150 ml) was added and the mixture was extracted with EtOAc (3x100 ml). The organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave compound 30 as a white solid (2.87 g, 76%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=360.6.

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

ΟγΟΗ (31)

To a mixture of methyl 2-methoxy-6-(methylthio)isonicotinate (WO 2010/036632) (2.07 g, 9.71 mmol) in MeOH:THF:H ₂ O (60 ml, 1:1:1) was added the hydrochloride lithium (0.697 g, 29.1 mmol). The reaction mixture was stirred at rt. within 24 hours Under reduced pressure, the solvent was removed, was added water (50 ml) and the mixture was washed with EtOAc (50 ml), which was then removed. To the aqueous layer was added 2M HCl (50 ml) which was extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 31 as a white solid (1.70 g, 88%). 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). Found: [M+H]=200.5.

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

VX (32)

To a solution of compound 31 (1.70 g, 8.53 mmol) in DCM (200 ml) was added DMF (0.13 ml), after which oxalyl chloride (0.88 ml, 10.2 mmol) was added dropwise. The mixture was stirred at rt. for 2 h. 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) and the resulting mixture was stirred at r.t. . for 18 hours the Mixture was poured into sat. NaHCO ₃ (150 ml) and extracted with DCM (150 ml) and EtOAc (100 ml). The combined organic phase was dried with Na ₂ SO ₄ and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (4:1) gave compound 32 as a yellow oil (2.07 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=243.5.

- 17 040011

-(Dimethylamino)-1 -(2-methoxy-6-(methylthio)pyridin-4-yl)propan-1-one (33)

(33)

To a solution of compound 32 (2.07 g, 8.54 mmol) in THF (100 ml) at 0°C was added vinylmagnesium bromide (1M solution in THF, 17.9 ml, 17.9 mmol) and the solution was stirred at 0° C over 3 hours. Dmethylamine (2M solution in THF, 17.9 ml, 35.9 mmol) was added followed by water (40 ml). After 30 min stirring at rt. the reaction mixture was concentrated under reduced pressure to give a brownish residue. The specified residue was extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 33 as a brown oil (2.17 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=255.6.

Methyl 2-(difluoromethoxy)-6-methoxyisonicotinate (34)

F \? O N O (34)

To a solution of methyl 2-hydroxy-6-methoxyisonicotinate (WO 2009/083553) (3.00 g, 16.4 mmol) in DMF (40 ml) was added sodium chlorodifluoroacetate (7.50 g, 49.2 mmol) and K2CO3 ( 2.73 g, 21.3 mmol). The reaction mixture was stirred at 80°C for 72 h, then washed with water (50 ml) and was extracted with EtOAc (3x30 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (1:1) afforded compound 34 as a white solid (2.02 g, 52%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=234.5.

2-(Difluoromethoxy)-6-methoxyisonicotinic acid (35) o _v oh

I

F pO Ν O (35)

To a solution of compound 34 (2.02 g, 8.66 mmol) in MeOH:THF:H ₂ O (60 ml, 1:1:1) was added lithium hydroxide (0.62 g, 26.0 mmol) and the reaction mixture stirred at rt. for 72 hours. The solvent st=was removed under reduced pressure, water (50 ml) was added and the mixture was washed with EtOAc (50 ml) which was then removed. 2M HCl (50 ml) was added to the aqueous layer, then extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 35 as a white solid (1.90 g, 99%). 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). Found: [M+H]=220.6.

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

(36)

To a solution of 35 (1.70 g, 8.53 mmol), hydroxybenzotriazole (1.29 g, 9.54 mmol), N,Odimethylhydroxylamine hydrochloride (1.27 g, 13.0 mmol) and 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide (1.48 g, 9.54 mmol) in DCM (50 ml) DMF (4.83 ml, 34.7 mmol) was added. The reaction mixture was stirred at rt. within 24 hours the Reaction mixture was washed with water (100 ml) and was extracted with DCM (3x50 ml). The organic phase was dried with Na2SO4 and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (1:1) gave compound 36 as a yellow oil (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). Found: [M+H]=26z.5.

- (2- (Difluoromethoxy) -6-methoxypyridin-4-yl) -3 - (dimethylamino) propan-1 -one (3 7)

- 18 040011

I

(37)

To a solution of compound 36 (1.85 g, 7.06 mmol) in THF (100 ml) at 0°C was added vinylmagnesium bromide (1M solution in THF, 14.8 ml, 14.8 mmol) and the solution was stirred at 0° C over 3 hours. Dimethylamine (2M solution in THF, 14.8 ml, 29.7 mmol) was added followed by water (40 ml). After 30 min stirring at rt. the reaction mixture was concentrated under reduced pressure to give a brownish residue. The specified residue was extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 37 as a brown oil (1.92 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=275.6.

(2,6-bis(methylthio)pyridin-4-yl)methanol (3 8) .one (38)

To a solution of compound 27 (6.12 g, 28.4 mmol) in THF (100 ml, dist. Na) at 0°C was added borane dimethyl sulfide complex (8.09 ml, 85.3 mmol) and then trimethylborate (9 .68 ml, 85.3 mmol). The reaction mixture was heated to rt. 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 (3x50 ml) and the organic phase was dried with Na2SO4 and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (4:1) gave compound 38 as a white solid (4.56 g, 80%). 1H NMR (CDCl ₃ ) δ 6.87 (t, J = 0.7 Hz, 2H), 4.61 (s, 2H), 2.58 (s, 6H). Found: [M+H]=202.5.

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

.....ί.....

(39)

Phosphorus tribromide (2.97 ml, 31.4 mmol) was added to a solution of compound 38 (5.26 g, 26.1 mmol) in DCM (300 ml) at 0°C. The reaction mixture was stirred at rt. for 18 h and the solvent was removed under reduced pressure. The residue was diluted with DCM (100 ml) and quenched with ice water (100 ml), then the organic phase was washed with sat. aq. NaHCO3, dried with Na2SO4 and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (6:1) gave compound 39 as a white solid (3.44 g, 50%). ¹ H NMR (CDCl ₃ ) δ 6.86 (s, 2H), 4.23 (s, 2H), 2.58 (s, 6H). Found: [M+H]=264.4.

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

O X I (40)

A mixture of compound 1 (4.31 g, 15.0 mmol), compound 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 atmosphere, then Pd(PPh ₃ ) ₄ (0.867 g, 0.75 mmol) was added and the mixture was heated at 90°C for 2 h. The reaction mixture was cooled to rt, filtered through Celite stopper, water (150 ml) was added and the mixture was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave compound 40 as a white solid (2.91 g, 46%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=421.8.

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

- 19 040011

(41)

Lithium aluminum hydride (8.09 ml, 85.3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at rt. for an additional 24 hours. The reaction mixture was washed with water (100 ml) and was extracted with EtOAc (3x50 ml). The organic phase was dried with Na ₂ SO ₄ and concentrated under reduced pressure to give compound 41 as a yellow oil (2.45 g, 99%). 1H NMR (CDClj) 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). Found: [M+H-18]=131.5.

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

(42)

To a solution of compound 41 (4.33 g, 36.4 mmol) in DCM (50 ml) at 0° C. was added thionyl chloride (2.45 g, 16.5 mmol). The reaction mixture was stirred at rt. within 24 h 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 sat. aq. NaHCO ₃ , dried with Na ₂ SO ₄ and concentrated to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (1:1) afforded compound 42 as a colorless oil (2.36 g, 86%). ¹ H 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). Found: [M+H]=167.5.

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

(43)

A mixture of compound 1 (3.69 g, 12.9 mmol), compound 42 (2.36 g, 14.2 mmol) and Cs ₂ CO ₃ (9.67 g, 29.7 mmol) in toluene:DMF ( 60 ml, 2:1) was degassed under N2, then Pd(PPh ₃ ) ₄ (0.745 g, 0.645 mmol) was added and the mixture was heated at 90°C for 3 h. The reaction mixture was cooled to rt, filtered through a Celite pad, water (150 ml) was added and the mixture was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave compound 43 as a yellow oil (4.70 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=368.5.

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

(44)

To a solution of 1-tetrahydronaphthoic acid (5.70 g, 32.3 mmol) in THF (100 ml, dist. Na) at 0°C was added lithium aluminum hydride (2.46 g, 64.7 mmol) in small portions. The reaction mixture was stirred at 0°C for 30 minutes and then stirred for an additional 24 h at rt. The reaction mixture was washed with water (100 ml) and was extracted with EtOAc (3x50 ml). The organic phase was dried with Na ₂ SO ₄ and concentrated under reduced pressure to give compound 44 as a colorless oil (5.23 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H-18]=145.5.

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

- 20 040011

To a solution of compound 44 (5.24 g, 32.3 mmol) in DCM (200 ml) at 0° C. was added thionyl chloride (8.45 g, 71.1 mmol). The reaction mixture was stirred at rt. for 24 h, 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 sat. aq. NaHCO ₃ , dried with Na ₂ SO ₄ and concentrated to give compound 45 as a brown oil (3.25 g, 56%). 1H NMR (CDCl ₃ ) 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-tetrahydronaphthalen-1-yl)methyl)quinolone (46)

A mixture of compound 1 (4.69 g, 16.4 mmol), compound 45 (3.25 g, 18.0 mmol) and Cs ₂ CO ₃ (12.29 g, 37.7 mmol) in toluene:DMF ( 60 ml, 2:1) was degassed under N2, then Pd(PPh ₃ ) ₄ (0.948 g, 0.82 mmol) was added and the mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to rt, filtered through a celite plug, water (150 ml) was added and the mixture was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave compound 46 as a white solid (4.64 g, 74%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=382.1.

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

To a suspension of 6-fluoronicotinic acid (2.00 g, 14.20 mmol) in anhydrous DCM (56 mL) was added 8 drops of anhydrous DMF under nitrogen flow. Oxalyl chloride (1.4 ml, 17.0 mmol) was added slowly. Upon addition, the evolution of gas bubbles was observed. The resulting mixture was stirred at room temperature for 1.5 hours, after which it became clear. The mixture was cooled to 2° C., 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 rt. during the night. The mixture was treated with sat. aq. NaHCO ₃ solution until gas evolution stops. The organic layer was collected. The aqueous phase was further extracted with EtOAc (2x). The organic extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the crude product. Flash chromatography of the crude product using 1-3% MeOH in DCM as eluents gave product 47 as a light brown oil. Yield = 1.96 g, 75%. 1H NMR (CDCl ₃ ) 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 thick-walled glass tube was loaded with a solution of compound 47 (2.13 g, 11.60 mmol) and diethylamine (2.4 ml, 23.20 mmol) in anhydrous acetonitrile (12 ml). The mixture was sealed in a test tube and heated under reflux for 3 hours. The solvent was removed and the residue was treated with sat. aq. NaHCO ₃ solution and extracted with DCM (5x). The combined extract was washed with brine, dried (MgSO ₄ ) and concentrated to give the crude product as a brown oil. 1H NMR analysis of the crude product showed a mixture of product and starting compound in a ratio of 10:7. The mixture was again placed under the reaction conditions indicated above and left

- 21 040011 for overnight reaction. The workup shown above gave the crude product as a brown oil (2.58 g) which was used directly in the next step. 1H NMR analysis confirmed the identity and purity of the diethylaminopyridine intermediate. ¹ H NMR (CDCl ₃ ) 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 at -78° C. under nitrogen in one portion. The mixture was maintained at -78°C for 30 minutes, then at 2°C for 75 minutes. The mixture was quenched dropwise with water until gas evolution ceased. 1M Sodium hydroxide solution (16 ml) was added and the resulting mixture of yellow light was stirred for 30 minutes. The aqueous mixture was extracted with EtOAc (2x) and the combined extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the crude product as a yellow oil. Flash chromatography of the crude product using 4:1 then 3:1 hexanes/EtOAc as eluents gave product 48 as a colorless oil. Yield = 1.42 g, 75%. 1H NMR (CDCl ₃ ) 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-methoxyquinolin-3-yl)(6-(diethylamino)pyridin-3-yl)methanol (49)

n-BuLi (4.4 ml, 8.760 mmol) was added at -30° C. under nitrogen atmosphere to a solution of freshly distilled 2,2,6,6-tetramethylpiperidine (1.6 ml, 9.557 mmol) in freshly distilled THF (13 ml). The mixture was maintained at approximately -30°C for 15 min, then cooled to -78°C. A solution of 6bromo-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 that temperature for 75 minutes. A solution of compound 48 (1.42 g, 7.964 mmol) in dry THF (6 ml) was added dropwise at -78°C, the reaction mixture remained orange-brown and the mixture was stirred at -78°C for 2.5 h. The mixture was quenched acetic acid (0.68 ml) at -65 °C. Water was added, the aqueous mixture was extracted with EtOAc (2x) and the combined extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the crude product as a yellow solid. Flash chromatography of the product using 10-100% EtOAc in hexanes as eluent gave product 49 as a gray-white solid. Yield = 1.90 g, 57%. 1H NMR (CDCl ₃ ) δ 8.15 (1H, d, J = 2.4 Hz), 8.01 (1H, s), 7.88 (1H, d, J = 2.1 Hz), 7, 69 (1H, d, J = 8.9 Hz), 7.65 (1H, dd, J = 2.1, 9.0 Hz), 7.40 (1H, dd, J = 2.5, 9, 0 Hz), 6.42 (1H, d, J = 8.9 Hz), 5.94 (1H, d, J = 3.7 Hz), 4.04 (3H, s), 3.50 (4H , dq, J = 1.7, 7.1 Hz), 2.65 (1H, d, J = 3.9 Hz), 1.17 (6H, t, J = 7.0 Hz).

-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-K,K-diethylpridin-2-amine (50)

To a solution of compound 49 (1.90 g, 4.56 mmol) in freshly distilled THF (19 ml) at 2°C under nitrogen atmosphere was added sodium borohydride (0.86 g, 23.0 mmol) in 3 parts over 10 min. . The mixture was stirred at 2-4°C for 1 hour. The mixture was again cooled to 2°C and aluminum trichloride (1.83 g, 13.70 mmol) was added in 4 replicates over 15 minutes. The mixture was stirred at 2° C. for 10 min, then refluxed for 2 h. The mixture was then carefully quenched with water at 2° C. until gas evolution ceased. The white suspension was filtered through celite. The milky white filtrate was diluted with water and the organic phase was collected. The aqueous phase was extracted with EtOAc (3x). The organic extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the crude product as a brownish residue. Flash chromatography of the crude product using 10% EtOAc in hexanes as eluent gave product 50 as a white solid. Yield = 1.39 g, 76%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=400.8.

2,3-Difluoroisonicotinic acid (51)

- 22 040011

To a solution of n-BuLi (26.1 ml, 52.09 mmol) in THF (70 ml, Na dist.) at -78°C was added N,N-diisopropylamine (7.30 ml, 52.09 mmol) in succession and 2,3-difluoropyridine (5.00 g, 43.41 mmol). The resulting mixture was stirred at -78° C. for 1 hour and then poured onto crushed dry ice (excess). The reaction mixture was left to heat to rt. for 1 h, and after evaporation of excess dry ice and THF, the residue was taken up in water (100 ml) and washed with EtOAc (2x50 ml). The aqueous layer was then acidified to pH 1 and extracted with EtOAc (2x100 ml). The combined organic extracts were dried and evaporated to give product 51. Yield = 2.39 g, 35%. 1H NMR (CDCl ₃ ) 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). Found: [M-H]=158.5.

3-Fluoro-2-methoxyisonicotinic acid (52)

Sodium (0.79 g, 33.09 mmol) was added portionwise to MeOH (60 ml) over half an hour. Compound 51 (2.39 g, 15.04 mmol) was then added and the reaction mixture was heated at reflux for 2 hours. The solution was cooled and the solvent was evaporated. The residue was taken up in water (100 ml) and washed with EtOAc (2x50 ml). Then the aqueous layer was acidified to pH 1 and was extracted with EtOAc (2x100 ml). The combined organic extracts were dried and evaporated to give product 52. Yield = 2.23 g, 87%. ¹ H NMR (DMSO-d6) δ 14.6-12.8 (1H, br s), 8.05 (1H, d, J = 5.2 Hz), 7.28 (1H, dd, J = 4 .7, 4.9 Hz), 3.97 (3H, s). Found: [M-H]=170.5.

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

(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 compound 52 (13.03 mmol) in THF (80 ml, dist. Na) at 0 °C, and the solution was heated to rt. 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 (CDCl ₃ ) 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)

(54)

To a solution of compound 53 (1.89 g, 12.03 mmol) and triethylamine (2.52 ml, 18.05 mmol) in DCM (30 ml, anhydrous) at r.t. mesyl chloride (1.12 ml, 14.44 mmol) was added dropwise. After 15 min, the reaction mixture was diluted with DCM (20 ml) and the organic layer was washed with sat. NaHCO ₃ , dried and evaporated. The residue was dissolved in acetone (60 ml, anhydrous), lithium bromide (in excess) was added, and the mixture was heated at 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 (CDCl ₃ ) 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). Found: [M+H]=220.2.

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

^Br \zWA

Td d N OMe (55)

Mixture of compound 1 (2.56 g, 9.09 mmol), compound 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. Pd(PPh ₃ ) ₄ (0.42 g, 0.363 mmol) was then added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 4 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc 19:1) gave product 55. Yield = 1.76 g, 51%. ¹ H NMR (CDCl ₃ ) 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), 7.6 4 (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). Found: [M+H]=377.2.

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

- 23 040011 he I

(56)

To a solution of 2,6-dimethoxypyridine (10 g, 71.84 mmol) and Ν,N-diisopropylamine (0.50 ml, 3.59 mmol) in THF (200 ml, dist. Na) at -40°C in an atmosphere p-BuLi (43.10 mL, 86.21 mmol) was added dropwise. The resulting solution was stirred at -40°C for 5 min and then heated to 0°C and stirred at the same temperature for an additional 3 hours. The solution was then cooled again to -40°C and triisopropyl borate (24.87 ml, 107.76 mmol) and the mixture was stirred at rt. for an additional 1 hour. Water (50 ml) was added and the solvent was removed under vacuum. 1M NaOH (100 ml) was added to the residue and the aqueous layer was washed with EtOAc (2x100 ml). The aqueous layer was then acidified to pH 3 and a solid precipitated. This solid was filtered and dried to give product 56. Yield = 8.10 g, 61%. 1H NMR (DMSO-d ₆ ) 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-Dimethoxypyridin-3-ol (57)

(57)

To a solution of compound 56 (8.00 g, 43.49 mmol) in THF (150 ml, dist. Na) at 0°C was added dropwise 32% peracetic acid in acetic acid (21.53 ml, 86.98 mmol) for more than 10 min. The resulting solution was stirred at room temperature. within 2 hours

Then 10% sodium sulfite solution (75 ml) was added and the mixture was stirred at rt. within 0.5 hours the Solvent was evaporated and the residue was divided between EtOAc and water. The aqueous layer was extracted twice and the organic layer was dried and evaporated. Column chromatography with hexanes/EtOAc 9:1 gave product 57. Yield = 6.05 g, 90%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=156.7.

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

Ο Ν O (58)

To a solution of compound 57 (6.45 g, 40.97 mmol) in DMF (70 ml, anhydrous) at 0° C. was added 60% sodium hydride in mineral oil (41.97 g, 9.16 mmol) in portions. The mixture was heated to rt. and stirred for 1 h. Then 1-chloro-2-methoxyethane (4.37 ml, 47.11 mmol) was added and the resulting mixture was stirred at rt. for an additional 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 hexanes/EtOAc 19:1 gave product 58. Yield: 8.14 g, 93%. 1H NMR (CDCl ₃ ) δ 7.41-7.33 (1H, m), 6.26-6.17 (1H, m), 5.15 (2H, d, J = 1.9 Hz), 3 .98 (3H, d, J = 1.8 Hz), 3.87 (3H, d, J = 2.0 Hz), 3.77 (2H, dq, J = 1.8, 7.1 Hz) , 1.22 (3H, dt, J = 2.9, 7.0 Hz).

3-Hydroxy-2,6-dimethoxyisonicotinic acid (59) o^one

ΟΝΟ (59)

To a solution of compound 58 (4.95 g, 23.24 mmol) and N,N-diisopropylamine (0.16 ml, 1.16 mmol) in THF (80 ml, dist. Na) at -40°C under nitrogen atmosphere p-BuLi (17.43 mL, 34.86 mmol) was added dropwise. The resulting solution was stirred at -40°C for 5 min, and then heated to 0°C and stirred at the same temperature for an additional 3 hours. The solution was then cooled again to -40°C, and dry ice (20 g, excess ), and the mixture was stirred at rt. for another 1 h. Water (25 ml) was added and the solvent was removed under vacuum. 1M NaOH (100 ml) was added to the residue and the aqueous layer was washed with EtOAc (2x100 ml). The aqueous layer was then acidified to pH 1 using conc. hydrochloric acid and precipitated a solid. This solid was filtered off and dried to give product 59. Yield = 3.85 g, 83%. 1 H NMR (DMSO-d ₆ ) δ 6.52 (1H, s), 3.90 (3H, s), 3.79 (3H, s). Found: [M+H]=200.5.

Methyl 2,3,6-trimethoxyisonicotinate (60)

- 24 040011

A mixture of compound 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. Methyl iodide (3.61 mL, 58.03 mmol) was then added and the mixture was stirred at the same temperature for 2 hours. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated. Column chromatography with hexanes/EtOAc 9:1 gave product 60. Yield = 3.63 g, 96%. ¹ H NMR (CDCl ₃ ) 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 compound 60 (3.60 g, 55.86 mmol) in 1M NaOH (100 ml) was heated at 50° C. for 2 hours. The reaction mixture was cooled and washed with EtOAc (2x50 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)

I O^N^ / γ o -Υ,ο^ .XX^ ΟΝΟ (62)

Oxalyl chloride (1.46 ml, 16.90 mmol) was added to a solution of compound 61 (3.00 g, 14.08 mmol) in DCM (60 ml, anhydrous) and DMF (0.22 ml, 2.82 mmol) at rt. The mixture was stirred at rt. for 1 h, and the solvent was evaporated and the residue was washed with benzene (2 x 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 successively and the mixture was stirred at rt. for 2 h, then divided between EtOAc and sat. aq. _NaHC03 . Column chromatography with hexanes/EtOAc 9:1 gave product 62. Yield = 2.89 g, 80%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=257.6.

-(Dimethylamino)-1 -(2,3,6-trimethoxypyridin-4-yl)propan-1-one (63)

I

Ol/xl..

.L,o^ ΑX.

ΟΝΟ (63)

Vinylmagnesium bromide in THF (1 N, 22.13 ml, 22.13 mmol) was added to a solution of compound 62 (2.70 g, 10.54 mmol) in THF (80 ml, dist. Na) at 0°C, then the yellow-orange solution was heated to rt. over 1 hour. Dimethylamine in THF (2N, 22.13 mL, 44.27 mmol) was added followed by water (30 mL). The solution was stirred at rt. over 1 h, 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 (CDCl ₃ ) 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). Found: [M-Me ₃ N]=224.5.

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

HCk

X .° (64)

Borandimethyl 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, dist. Na) at 0°C, and the solution was heated to rt. and stirred overnight. The mixture was then cooled to 0° C. and quenched with MeOH (10 ml). The solvent was 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

- 25 040011 (CDCi ₃ ) 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). Found: [M-OH]=139.7.

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

To a solution of compound 64 (2.35 g, 15.05 mmol) and triethylamine (3.15 ml, 22.58 mmol) in DCM (50 ml, anhydrous) at r.t. mesyl chloride (1.41 ml, 18.06 mmol) was added dropwise. After 15 min, the reaction mixture was diluted with DCM (50 ml) and the organic layer was washed with sat. aq. NaHCO ₃ , dried and evaporated. The residue was dissolved in acetone (100 ml, anhydrous), lithium bromide (excess) was added and the mixture heated at 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 65. Yield = 3.00 g, 91%. 1H NMR (CDCi ₃ ) δ 7.16-7.07 (2H, m), 6.90 (1H, dd, J = 8.3, 8.4 Hz), 4.45 (2H, s), 3 .89 (3H,s).

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

I

xxx n ome (66)

Mixture of compound 1 (3.51 g, 12.45 mmol), compound 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(PPh ₃ ) ₄ (0.58 g, 0.50 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 5 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc 19:1) gave product 66. Yield = 2.10 g, 41%. 1H NMR (CDC13) 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). Found: [M+H]=376.0.

3-(Ethoxymethoxy)-2,6-dimethoxyisonicotinaldehyde (67)

(67)

To a solution of compound 58 (4.00 g, 18.78 mmol) and Ν,N-diisopropylamine (0.13 ml, 0.94 mmol) in THF (60 ml, dist. Na) at -40°C under nitrogen atmosphere p-BuLi (14.09 mL, 28.17 mmol) was added dropwise. The resulting solution was stirred at -40°C for 5 min and then heated to 0°C and stirred at the same temperature for an additional 3 hours. The solution was then cooled again to -40°C and 1-formylpiperidine (3 .75 ml, 33.80 mmol) and the mixture was stirred at rt. for another 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 layer was dried and evaporated. Column chromatography with hexanes/EtOAc 19:1 gave product 67. Yield = 2.30 g, 51%. 1H NMR (CDCi 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 = 10.1 Hz), 1.21 (3H, t, J = 7.1 Hz).

3-Hydroxy-2,6-dimethoxyisonicotinaldehyde (68)

A solution of compound 67 (2.30 g, 9.54 mmol) and 3M hydrochloric acid (60 ml) in THF (30 ml, dist. Na) was heated at 40°C for 1.5 h. Then the solution was cooled, diluted with water , and the pH was adjusted to 7 with NaHCO3. The aqueous layer was then extracted three times with EtOAc and the organic layer was dried and evaporated. Column chromatography with hexanes/EtOAc 19:1 gave product 68. Yield = 1.36 g, 78%. 1H NMR(CDCi ₃ ) δ 9.96 (1H, s), 9.61 (1H, s), 6.46 (1H, s), 4.06 (3H, s), 3.91 (3H, s ).

2,3,6-Trimethoxyisonicotinaldehyde (69)

- 26 040011

(69)

A mixture of compound 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. Methyl iodide (0.56 mL, 8.86 mmol) was then added and the mixture was stirred at the same temperature for 2 hours. 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(CDCl ₃ ) 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)

(70)

A mixture of compound 69 (1.40 g, 7.11 mmol) and sodium borohydride (0.54 g, 14.21 mmol) in MeOH (30 ml, anhydrous) was stirred at rt. within 1 hour Then the solvent was removed and the residue was divided between EtOAc and water. The organic layer was dried and evaporated to give product 70. Yield = 1.35 g, 95%. ¹ H 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)

(71)

To a solution of compound 70 (1.35 g, 6.78 mmol) and triethylamine (1.42 ml, 10.78 mmol) in DCM (20 ml, anhydrous) at r.t. mesyl chloride (0.63 ml, 8.14 mmol) was added dropwise. After 15 minutes, the reaction mixture was diluted with DCM (20 ml) and the organic layer was washed with sat. aq. NaHCO ₃ , 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 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 71. Yield = 1.69 g, 95%. 1H NMR (CDCl ₃ ) δ 6.27 (1H, s), 4.40 (2H, s), 3.98 (3H, s), 3.87 (3H, s), 3.87 (3H, s ). Found: [M+H]=262.5.

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

(72)

Mixture of compound 1 (1.89 g, 6.69 mmol), compound 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(PPh ₃ ) ₄ (0.29 g, 0.26 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 4 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc 19:1) gave product 72. Yield = 1.44 g, 54%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=420.0.

Methyl 2-(dimethylamino)-6-(ethylthio)isonicotinate (73)

(73)

A glass tube was charged with 2-chloro-6-(dimethylamino)isonicotinate (WO 2010/100475) (2.44 g, 11.40 mmol), rac-bis(diphenylphosphino)-1,1'-binaphthol (0.71 g , 1.140 mmol) and cesium carbonate (4.43 g, 13.60 mmol) in a continuous stream of nitrogen. 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 again purged with nitrogen. Ethanethiol (1.0 ml, 13.60 mmol) was added and the mixture was sealed in a test tube and heated at 150°C in

- 27 040011 for 22 hours The mixture was filtered through celite, washing with EtOAc. The filtrate was concentrated in a fume hood by heating the solution and blowing it with air. A crude orange solid was obtained. Flash chromatography of the product using 2-5% diethyl ether in hexane gave product 73 as a yellow crystalline solid. Yield = 2.42 g, 88%. %. ¹ H NMR (CDClj) 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). Found: [M+H]=241.5.

(2-(Dimethylamino)-6-(ethylthio)pyridin-4-yl)methanol (74) un γ I (74)

To a solution of compound 73 (1.64 g, 6.824 mmol) in freshly distilled THF (66 ml) at 2° C. under nitrogen atmosphere was added lithium aluminum hydride (0.31 g, 8.189 mmol) in 3 replicates. The mixture was stirred at 2°C for 15 min, then at rt. for 1 h. The mixture was carefully quenched with water at 2° C. until gas evolution ceased. 1M NaOH (20 ml) was added. The mixture was stirred for 5 min, then decanted to remove aluminum salts, which were filtered through celite. The aqueous mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (3x). The combined organic extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography using hexanes/EtOAc 4:1 to give product 74 as a brown oil. Yield = 1.30 g, 90%. 1H NMR (CDCl ₃ ) 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 (3, s), 1.37 (3H, t, J = 7.3 Hz). Found: [M+H]=213.5.

4-(Bromomethyl)-6-(ethylthio)-N,N-dimethylpyridin-2-amine (75) γ I (75)

Triethylamine (0.59 ml, 4.26 mmol) was added dropwise to a solution of 74 (0.60 g, 2.84 mmol) in anhydrous DCM (10 ml) at 2°C under nitrogen atmosphere, followed by mesyl chloride (0 .26 ml, 3.41 mmol). The mixture was stirred from 2°C to 5°C for over 1 h. The mixture was quenched with sat. aq. NaHCO ₃ solution. The aqueous mixture was extracted with DCM (3x). The combined extract was washed with brine, dried (MgSO ₄ ) and concentrated to give the crude product as a light brown oil. The crude intermediate was dissolved in acetone (20 ml). Lithium bromide (0.99 g, 11.36 mmol) was added and the suspension stirred at rt. within 2.5 hours Flash chromatography using hexane/Et ₂ O 98:2 provided product 75 as a brown solid. The reaction was repeated in a volume of 3.29 mmol and the products were combined. Total Yield = 1.39 g, 82%. ¹ H NMR (CDCl ₃ ) 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 (3H, t, J = 7.2 Hz). Found: [M+H]=275.5.

4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-(ethylthio)-N,N-dimethylpyridin-2-amine (76)

(76)

A mixture of compound 1 (1.42 g, 5.05 mmol), compound 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 flushed with nitrogen. Pd(PPh ₃ ) ₄ (0.29 g) was added. The mixture was again purged with nitrogen and heated at 85° C. under nitrogen for 2.5 hours. The mixture was partitioned between water and EtOAc. The aqueous mixture was extracted with EtOAc (2x). The extract was washed with water, brine, dried (MgSO ₄ ) and concentrated to give the crude product as an orange oil which was chromatographed using 2-5% Et ₂ O in hexanes as eluent to yield 76 product as a light brown solid. yellow color. Recrystallization from DCM/MeOH gave a white solid. Yield = 1.25 g, 57%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=432.1.

2,5-Dimethoxynicotinaldehyde (77)

- 28 040011

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. Methyl iodide (1.56 mL, 25.08 mmol) was then added and the mixture was stirred at the same temperature for 2 hours. The resulting solution was diluted with EtOAc and washed three times with brine. The organic layer was dried and evaporated to give product 77, identical to the compound described in Organic & Biomolecular Chemistry, 6(8), 1364-1376; 2008. Yield = 2.70 g, 77%.

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

A mixture of compound 77 (2.70 g, 16.15 mmol) and sodium borohydride (1.22 g, 32.30 mmol) in methanol (60 ml, anhydrous) was stirred at rt. within 1 hour Then the solvent was removed and the residue was divided between EtOAc and water. The organic layer was dried and evaporated to give product 78. Yield: 2.74 g, 99%. 1H NMR (CDCl ₃ ) 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)

To a solution of compound 78 (2.65 g, 15.66 mmol) and triethylamine (3.27 ml, 23.49 mmol) in DCM (45 ml, anhydrous) at r.t. mesyl chloride (13.46 ml, 18.79 mmol) was added dropwise. After 15 min, the reaction mixture was diluted with DCM (25 ml) and the organic layer was washed with sat. NaHCO ₃ , dried and evaporated. The residue was dissolved in acetone (90 ml, anhydrous), lithium bromide (excess) was added and the mixture heated at 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%. 1H 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)

Mixture of compound 1 (3.40 g, 12.06 mmol), compound 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(PPh ₃ ) ₄ (0.057 g, 0.48 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 4 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc 19:1) gave product 80. Yield = 3.60 g, 69%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=389.8.

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

To a mixture of compound 57 (8.05 g, 51.9 mmol) and imidazole (7.42 g, 108.99 mmol) in DMF (130 ml) at rt. triisopropylsilyl chloride (13.33 ml, 62.23 mmol) was added and the resulting mixture was stirred at rt. for 2 hours Then the solution was divided between EtOAc and water, and the aqueous layer was extracted three times. The combined organic layers were washed with brine three times, dried and evaporated. Column chromatography with hexanes/EtOAc 19:1 gave product 81. Yield: 15.59 g, 96%. 1H NMR (CDCl ₃ ) δ 7.07 (1H, d, J = 8.2 Hz), 6.13 (1H, d, J = 8.2 Hz), 3.92 (3H,

- 29 040011

s), 3.86 (3H, s), 1.27-1.18 (3H, t), 1.08 (18H, d, J = 7.1 Hz). Found: [M+H]=312.8.

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

(82)

To a solution of compound 81 (8.00 g, 25.69 mmol) and N,N-diisopropylamine (0.18 ml, 1.28 mmol) in

THF (100 ml, dist. Na) p-BuLi (15.41 ml, 30.83 mmol) was added dropwise at -40° C. under nitrogen. The resulting solution was stirred at -40°C for 5 min, and then heated to 0°C and stirred at the same temperature for an additional 3 hours. The solution was then cooled again to -40°C, and formylpiperidine (4 .28 ml, 38.54 mmol), and the mixture was stirred at rt. for another 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 layer was dried and evaporated. Column chromatography with hexanes/EtOAc 49:1 gave product 82. Yield = 7.55 g, 87%. 1H NMR (CDCl ₃ ) 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). Found: [M-CHO] ⁺ = 312.8.

-hydroxy-2,6-dimethoxynicotinaldehyde (83) o . ΙΛ O N O

I (83)

Tetrabutylammonium fluoride in THF (1 N, 33.36 ml, 33.36 mmol) was added to a solution of compound 82 (7.55 g, 22.24 mmol) in THF (35 ml, dist. Na) at 0°C. The reaction mixture was then heated to rt. and stirred for 4 h. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc three times and the organic layer was dried and evaporated. Column chromatography with DCM followed by DCM/EtOAc 3:1 gave product 83. Yield = 3.15 g, 77%. 1H NMR (CDCl ₃ ) 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) o aX Ο N O

I

A mixture of compound 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. Methyl iodide (1.29 mL, 20.64 mmol) was then added and the mixture was stirred at the same temperature for 2 hours. 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%. 1 H NMR (CDCy δ 10.21 (1H, s), 7.53 (1H, s), 4.10 (3H, s), 4.02 (3H, s), 3.87 (3H, s).

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

N-V%

A U ^β ΎΧλ ^οη I (85)

A solution of 2,2,6,6-tetramethylpiperidine (3.59 ml, 21.03 mmol) in THF (40 ml, Na dist.) was cooled to -40°C, p-BuLi (10.52 ml, 21. 03 mmol) and the solution was stirred at -40°C for 15 min, then cooled to -78°C. A solution of 6-bromo-2-methoxyquinoline (17.53 mmol) in THF (40 ml, dist. Na) was added dropwise, the resulting orange solution was stirred at -78°C for 1.5 h, then a solution of compound 84 ( 3.42 g, 17.53 mmol) in THF (40 ml, dt. Na). The mixture was stirred at -78°C for 2 h, then acetic acid (2.5 ml) was added and the solution was left to warm to rt. The solvent was removed and the residue was partitioned between EtOAc and water, and the organic layer was dried and evaporated. Column chromatography with 9:1 hexanes/EtOAc and 4:1 hexanes/EtOAc gave the product as a white solid. Yield = 5.50 g, 72%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=436.1.

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

- 30 040011

(86)

Trifluoroacetic acid (11.30 ml, 148.2 mmol) and triethylsilane (17.76 ml, 111.2 mmol) were added successively to a solution of compound 85 (5.35 g, 12.35 mmol) in DCM (125 ml) and the solution was stirred for 1 h at rt, then ice water was added. The solution was divided between sat. aq. NaHCO ₃ and DCM and the aqueous fraction was extracted with DCM. The organic fractions were combined, dried and evaporated. Column chromatography with hexanes/EtOAc 9:1 gave product 86 as a white solid. Yield = 4.45 g, 86%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=419.0.

Ethyl 2-(dimethylamino)-6-methoxyisonicotinate (87)

-T

I I (87)

A glass tube was charged with ethyl 2-chloro-6-methoxyisonicotinate (WO 2009/024905) (4.01 g, 18.60 mmol), diphenylphosphino-1,1'-binaphthol (1.85 g, 2.976 mmol) and cesium carbonate (8.49 g, 26.10 mmol) in a continuous stream of nitrogen. 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 again purged with nitrogen. Dimethylamine in tetrahydrofuran (2N, 11.2 ml, 22.3 mmol) was added and the mixture was sealed in a tube and heated at 80° C. for 19.5 hours. The mixture was filtered through celite, washed with EtOAc. The filtrate was concentrated in vacuo to give the crude product as a dark red liquid. Flash column chromatography of the crude product using 3-10% Et ₂ O in hexanes gave product 87 as a yellow crystalline solid. Yield = 3.36 g, 80%. ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=225.5.

(2-(Dimethylamino)-6-methoxypyridin-4-yl)methanol (88) no.

^N^N^O I I (88)

Lithium aluminum hydride (0.73 g, 19.3 mmol) was added to a solution of compound 87 (3.31 g, 14.8 mmol) in freshly distilled THF (70 ml) at 2°C under nitrogen atmosphere in 3 series of experiments. The mixture was stirred at 2° C. for 10 min, then at RT for 1 h. The mixture was carefully quenched with water at 2° C. until gas evolution ceased. 1M NaOH (30 ml) was added and the mixture was stirred for 1 h, then the aqueous mixture was diluted with water and extracted with EtOAc (3x). The combined organic extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give product 88 as a light yellow oil which was used without further purification. Yield = 2.69 g, >99%. 1H NMR (CDCl ₃ ) δ 6.05 (1H, d, J = 0.4 Hz), 5.97 (1H, d, J = 0.4 Hz), 4.59 (2H, d, J = 4 .8 Hz), 3.88 (3H, s), 3.06 (6H, s), 1.70 (1H, t, J = 5.6 Hz).

4-(Bromomethyl)-6-methoxy-N,N-dimethylpyridin-2-amine (89)

Λ

I I (89)

To a solution of compound 88 (3.30 g, 18.1 mmol) in anhydrous DCM (54 ml) at 2° C. under nitrogen atmosphere was added triethylamine (3.8 ml, 27.2 mmol) followed by mesyl chloride ( 1.7 ml, 21.7 mmol). The mixture was stirred at 2°C for 10 min, then at rt. for 2 h. The mixture was quenched with sat. aq. NaHCO3 solution. The aqueous mixture was extracted with DCM (2x) and the combined extract was washed with brine, dried (MgSO ₄ ) and concentrated to give the 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 heated at reflux for

- 31 040011

h. Flash chromatography using a mixture of 3-5% Et ₂ O in hexanes as eluent gave product 89 as a mobile yellow oil. Yield = 3.78 g, 85%. 1H NMR (CDCl ₃ ) δ

6.02 (1H, d, J = 0.8 Hz), 6.00 (1H, d, J = 0.4 Hz), 4.27 (2H, s), 3.88 (3H, s), 3.06 (6H, s).

4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-methoxy-N,N-dimethylpyridin-2-amine (90)

I

(90)

A mixture of compound 1 (4.34 g, 15.4 mmol), compound 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(PPh ₃ ) ₄ (0.890 g, 0.774 mmol) was added and the mixture was again purged with nitrogen and heated to 85° C. under nitrogen for 3.5 hours. The mixture was partitioned between water and EtOAc and the mixture was extracted with EtOAc (2x). The extract was washed with water (2x), brine, dried (MgSO ₄ ) and concentrated to give the crude product as a brown solid which was chromatographed using 3-10% Et ₂ O in hexanes as eluent to give 90 product as light yellow solid. Yield = 3.69 g, 60%. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=402.0.

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

H 0^0 . Xd Ν Ν O I I (91)

To a solution of compound 87 (6.77 g, 30.2 mmol) in EtOH (150 mL) was added NaOH at rt. (30.2 ml, 60.4 mmol). The mixture was stirred at rt. over 2 hours then concentrated in vacuo to a light yellow solution which was then diluted in water. The aqueous mixture was acidified to pH ~2 with 2M HCl, resulting in the precipitation of bright yellow solids. These solids were collected by filtration, washed with water and dried at ambient conditions to give compound 91 as a bright yellow powder. Yield = 5.60 g, 95%. 1H NMR (DMSOd ₆ ) 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) ^N^N^O I I (92)

To a suspension of compound 91 (0.75 g, 3.81 mmol) in anhydrous DMF (22 ml) was added triethylamine (1.6 ml, 11.4 mmol), the mixture was cooled to 2°C. Ethyl chloroformate (0.62 ml, 4.19 mmol) was added dropwise and gas evolved. The mixture was stirred from 2°C to rt. for 2.5 h and then treated with N,Odimethylhydroxylamine hydrochloride (0.557 g, 5.71 mmol) at 2° C. under nitrogen. The mixture was stirred to rt. during the night. The mixture was diluted in water and the aqueous mixture was extracted with EtOAc (4x) and the organic extract was washed with water, brine, dried (MgSO ₄ ) and concentrated to give the crude product. It was purified by repeated flash chromatography eluting with 4:1 hexanes/EtOAc followed by 2:1 as eluent to give product 92 as a yellow oil. Yield = 0.70 g, 77%. 1H NMR (CDCI3) 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)propan-1-one (93) I . Xd N N O I I (93)

To a solution of compound 92 (2.53 g, 10.60 mmol) in freshly distilled THF (96 ml) at 2°C under nitrogen atmosphere was added vinylmagnesium bromide in THF (1 N, 21.1 ml, 21.10 mmol). The mixture was stirred at 2°C for 20 min, then at rt. within 75 min. Dimethylamine in THF (2N, 21.1 mL, 42.20 mmol) was added followed by water (40 mL). The mixture was stirred at rt. for 1 h. The aqueous mixture was partitioned between water and EtOAc and the organic phase was separated and the aqueous phase was extracted

- 32 040011

EtOAc (2x). The organic extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude product as a tan oil. Flash chromatography of the product using 2-8% MeOH in DCM as eluent gave compound 93 as a yellow oil which crystallized at -20°C. Yield = 1.91 g, 72%. ¹ H NMR (CDC13) δ 6.47 (1H, d, J = 1.0 Hz), 6.39 (1H, d, J = 1.0 Hz), 3.91 (3H, s), 3, 10 (6H, s), 3.06 (2H, t, J = 7.0 Hz), 2.72 (2H, t, J = 7.1 Hz), 2.27 (6H, h).

Ethyl 2-(dimethylamino)-6-ethoxyisonicotinate (94) . λΧ NN O ¹ <

(94)

Ethyl 2-chloro-6-ethoxyisonicotinate (WO 2010/080864) (1.00 g, 4.37 mmol), diphenylphosphino-1,1'-binaphthol (0.44 g, 0.70 mmol) and cesium carbonate (1.99 g, 6.12 mmol) under nitrogen flow conditions. 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 again purged with nitrogen. Dimethylamine in THF (2N, 2.6 mL, 5.246 mmol) was added and the mixture was sealed in a tube and heated at 80° C. overnight. The mixture was filtered through Celite, washed with EtOAc and the filtrate concentrated in vacuo to give the crude product as a dark red liquid. Flash chromatography using 2-4% Et ₂ O in hexanes gave product 94 as a light yellow oil. Yield = 0.85 g, 82%. ¹ H NMR (CDCI3) 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-dimethylpyridin-2-amine (95)

A

I y (95)

To a solution of compound 94 (4.40 g, 18.50 mmol) in freshly distilled THF (90 ml) at -78° C. under nitrogen atmosphere was added lithium aluminum hydride (0.91 g, 24.0 mmol) in 3 replicates. The mixture was stirred at -78°C for 15 min, then at rt. for 1 h. The mixture was carefully quenched with water at 2° C. until gas evolution ceased. 1M NaOH (32 ml) was added and the mixture was stirred for 1 h, then the aqueous mixture was diluted with water and extracted with EtOAc (3x). The combined organic extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a product which was purified by flash chromatography eluting with 6:1 hexanes/EtOAc followed by 4:1 hexanes/EtOAc to give alcohol intermediate as a light yellow oil. Yield = 3.27 g, 90%. The substance was directly used in the next step without further characterization.

Triethylamine (3.5 ml, 25.0 mmol) was added dropwise to a solution of the alcohol intermediate (3.27 g, 16.7 mmol) in anhydrous DCM (50 mL) at 2° C. under nitrogen atmosphere, followed by mesyl chloride (1.6 ml, 20.0 mmol). The mixture was stirred at 2°C for 10 min, then at rt. for 0.5 h. The mixture was quenched with sat. aq. NaHCO ₃ solution. The aqueous mixture was extracted with DCM (3x) and the combined extract was washed with brine, dried and concentrated to give the crude product as a brown oil. The product was diluted in acetone (60 ml), lithium bromide (1.42 g) was added. And the suspension was refluxed for 2 hours. Flash chromatography using 2-3% Et ₂ O in hexanes as eluent gave product 95 as a mobile yellow oil. Yield = 3.84 g, 89%. ¹ H NMR (CDCl ₃ ) δ 6.011 (1H, s), 5.99 (1H, s), 4.30 (2H, q, J = 6.8 Hz), 4.27 (2H, s), 3 .05 (6H, s), 1.37 (3H, t, J = 7.2 Hz).

4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-ethoxy-CH-dimethylpyridin-2-amine (96)

A mixture of compound 1 (4.13 g, 14.7 mmol), compound 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 again purged 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 (2x). The extract was washed with water (2x), brine, dried and concentrated to give the crude product as a brown oil. It was chromatographed using 3-10% Et ₂ O in hexanes as eluent with

- 33 040011 yield of product 96 as a yellow solid (3.83 g) which was triturated in diethyl ether to give the pure product as a pale yellow solid. exit =

3.51 g, 57%. Ή NMR (CDCl ₃ ) δ 7.76 (1H, d, J = 2.2 Hz), 7.68 (1H, d, J = 8.8 Hz), 7.61 (1H, dd, J = 2 .2, 8.8 Hz),

7.55 (1H, s), 5.91 (1H, s), 5.84 (1H, s), 4.30 (2H, q, J = 7.1 Hz), 4.07 (3H, s ), 3.87 (2H, s), 3.03 (6H, s), 1.36 (3H, t, J = 7.1 Hz).

5-Isopropoxy-2-methoxynicotinaldehyde (97)

I (97)

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. Isopropyl iodide (0.78 mL, 7.84 mmol) was then added and the mixture was stirred at the same temperature for 2 hours. 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%. ' and NMR (CDClj) δ 10.34 (1H, s), 8.07 (1H, d, J = 3.2 Hz), 7.66 (1H, d, J = 3.2 Hz), 4, 48 (1H, sp, J = 6.1 Hz), 4.03 (3H, s), 1.33 (6H, d, J = 4.8 Hz).

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

I (98)

A mixture of compound 97 (0.90 g, 4.61 mmol) and sodium borohydride (0.35 g, 9.22 mmol) in MeOH (15 ml, anhydrous) was stirred at rt. within 1 hour Then the solvent was removed and the residue was divided between EtOAc and water. The organic layer was dried and evaporated. Column chromatography with hexanes/EtOAc 9:1 gave product 98. Yield = 0.68 g, 75%. 1H NMR (CDCl ₃ ) 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, br s), 1.32 (6H, d, J = 6.1 Hz).

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

(99)

To a solution of compound 98 (0.68 g, 3.45 mmol) and triethylamine (0.72 ml, 5.18 mmol) in DCM (10 ml, anhydrous) at r.t. mesyl chloride (0.32 ml, 4.14 mmol) was added dropwise. After 15 min, the reaction mixture was diluted with DCM (10 ml) and the organic layer was washed with sat. NaICO ₃ , dried and evaporated. The residue was redissolved in acetone (20 ml, anhydrous), lithium bromide (excess) was added, and the mixture was refluxed for 30 min. 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%. 1H NMR (CDCl ₃ ) δ 7.76 (1H, dd, J = 2.6, 3.4 Hz), 7.25 (1H, dd, J = 2.4, 2.4 Hz), 4.5 (2H, d, J = 2.2 Hz), 4.42 (1H, sp, J = 2.6, 6.0 Hz), 3.96 (3H, d, J = 2.9 Hz), 1 .32 (6H, dd, J = 3.0, 6.1 Hz).

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

O'

(100)

Mixture of compound 1 (0.80 g, 2.82 mmol), compound 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. Pd(PPh ₃ ) ₄ (0.12 g, 0.11 mmol) was then added and the mixture heated to 80° C. under nitrogen for 4 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc 19:1) gave product 100. Yield = 0.57 g, 48%. 'H NMR (CDCl ₃ ) δ 7.77 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 2.9 Hz), 7.69 (1H, d, J = 8.9 Hz), 7.62 (1H, dd, J = 2.2, 8.9 Hz), 7.56 (1H, s), 7.02 (1H, d, J = 2.9 Hz) , 4.38 (1H, sp, J = 6.0 Hz), 4.08 (3H, s), 3.92 (2H, s), 3.90 (3H, s), 1.29 (6H, d, J = 6.1 Hz).

1-(6-Bromo-2-methoxyquinolin-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1 -(3 -fluorophenyl)butan-2-ol (101)

- 34 040011

(101)

The product was obtained from compounds 9 and 7 (using the general coupling procedure described below). Flash chromatography of the crude product using hexane/EtOAc mixtures with increasing eluent concentration gave a 1:1 mixture of diastereomers 101 as a light yellow foam (65%). 1H NMR (CDCl ₃ ) δ 8.71 (1H, s), 8.69 (1H, s), 8.12 (1H, bs), 7.81 (2H, m), 7.65 (1H, d , J = 8.9 Hz), 7.59 (1H, dd, J = 2.2, 8.9 Hz), 7.53 (1H, dd, J = 2.0, 8.8 Hz), 7 .50 (1H, d, J = 8.81 Hz), 7.43 (1H, dt, J = 2.4, 10.5 Hz), 7.39 (1H, d, J = 7.8 Hz) , 7.25-7.17 (2H, m), 7.07 (1H, d, J = 7.8 Hz), 7.0 (1H, d, J = 8.0 Hz), 6.98- 6.92 (2H, m), 6.87 (1H, dt, J = 1.8, 8.4 Hz), 6.67 (1H, dt, J = 1.8, 9.2 Hz), 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 shaded by the water peak). One OH is implicit. Found: [M+H]=720.1.

1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-4-(methylamino)butan-2-ol (102 )

(102)

To a solution of compound 101 (2.50 g, 3.471 mmol) and in anhydrous DCM (80 ml) at 2° C. under nitrogen were added triethylamine (1.1 ml) and trifluoroacetic anhydride (0.97 ml) in succession. The mixture was stirred at rt. for 2 h. The mixture was washed with sat. aq. NaHCO ₃ (2x), dried (MgSO ₄ ) and concentrated in vacuo to give the 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 min, then overnight stored at 4°C. The mixture was serially diluted with water and extracted with EtOAc (3x). The combined extract was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give a crude product which was purified by column chromatography using 0-5% MeOH in DCM as eluent. Product 102 was eluted as a 1:1 mixture of diastereomers. 1H NMR (CDCl ₃ ) 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), 7.03-6.95 (1H, m), 6.90 (1H, dt, J = 2.6, 8, 5 Hz), 6.69 (1H, dt, J = 2.6, 8.4 Hz), 6.47 (4H, bs), 4.88 (1H, s), 4.72 (1H, s) , 4.12(3H, 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). Found: [M+H]=569.9.

2,4-Dichlorothiazole (103)

(103)

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

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

A solution of 2,2,6,6-tetramethylpiperidine (4.28 ml, 25.2 mmol) in THF (50 ml, Na dist.) was cooled to 40°C, p-BuLi (12.60 ml, 25.2 mmol) and the solution was stirred at -40°C for 15 min, for

- 35 040011 thus cooled to -78°C. A solution of 6-bromo-2-methoxyquinoline (5.00 g, 21 mmol) in THF (50 ml, Na dist.) was added dropwise, the orange solution was stirred at -78°C for 1.5 h, then DMF was added (2.19 ml, 31.5 mmol) and the solution was heated to rt. Acetic acid (3 ml) was added and the solvent was removed and the residue was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography with 4:1 hexanes/DCM followed by 1:1 hexanes/DCM followed by 1:4 hexanes/DCM gave product 104 as a white solid. Yield = 3.00 g, 53%. ¹ H NMR (CDCl ₃ ) 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-methoxyquinolin-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 dist.) was cooled to -40°C, p-BuLi (3.33 ml, 6.65 mmol) was added and the solution was stirred at -40°C for 15 min, then cooled to -78°C. A solution of compound 103 (0.98 g, 6.043 mmol) in THF (20 ml, Na dist.) was added dropwise, the orange solution was stirred at -78°C for 2 h, then a solution of compound 104 (1.78 g , 6.043 mmol) in THF (20 ml, dist. Na). The mixture was stirred at -78°C for 2 h, then water (20 ml) was added and the solution was allowed to boil to rt. The solvent was removed and the residue was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography with hexanes/EtOAc 9:1 gave product 105 as a white solid. Yield = 1.98 g, 78%. 1 H NMR (CDCl ₃ ) 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). Found: [M+H]=421.9.

5-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-2,4-dichlorothiazole (106)

Trifluoroacetic acid (3.35 ml, 43.80 mmol) and triethylsilane (5.74 ml, 39.92 mmol) were added successively to a solution of compound 105 (1.84 g, 4.38 mmol) in DCM (50 ml), the solution was stirred for 3 h at reflux, and then the solution was cooled and added to ice water. The solution was divided between sat. aq. NaHCO ₃ and DCM and the aqueous fraction was extracted with DCM, the organic fractions were combined, dried and evaporated. Column chromatography with hexanes/EtOAc 19:1 gave product 106. Yield = 1.10 g, 62%. 1H NMR (CDCl ₃ ) δ 7.84 (1H, d, J = 2.0 Hz), 7.75 (1H, s), 7.70 (1H, d, J = 8.9 Hz), 7, 66 (1H, dd, J = 2.1, 8.8 Hz), 4.13 (2H, s), 4.12 (3H, s).

5-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-4-chloro-2-methoxythiazole (107)

Sodium methoxide (0.20 g, 3.71 mmol) was added to a suspension of compound 106 (1.00 g, 2.78 mmol) in MeOH (50 ml, anhydrous) and the mixture was stirred at reflux for 18 h The solution was then cooled and the solvent removed and the residue partitioned between EtOAc and water. The organic fraction was dried and evaporated. Column chromatography with hexanes/EtOAc 19:1 gave product 106. Yield = 0.50 g, 45%. 1H NMR (CDCl ₃ ) 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 ). Found: [M+H]=399.1.

1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-((2,4-dimethoxybenzyl)( methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)butan-2-ol (108)

- 36 040011

The product was prepared from compounds 22 and 7 using the general coupling procedure described below. Column chromatography with a 1:1 mixture of EIOAstexanes gave the front fractions, then compound 108 as a mixture of isomers (66%), as a yellow foam. 1H NMR (CDCl ₃ , 400 MHz) δ 8.69 (s, 1H), 8.46 (s, 1H), 7.93 (bs, 2H), 7.79 (d, J = 2.0 Hz, 2H), 7.64 (d, J = 8.9 Hz, 1H), 7.59-7.50 (m, 4H), 7.16 (dd, J = 5.9, 3.6 Hz, 1H ), 7.00 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.70-6.60 (m, 3H), 6.586.45 (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). Found: [M+H]=760.2.

1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4- yl)-4-(methylamino)butan-2-ol (109)

To a solution of compound 108 (4.13 g, 5.43 mmol) in DCM (100 ml) cooled to 0°C was added triethylamine (1.67 ml, 11.9 mmol) and trifluoroacetic anhydride (1.51 ml, 10.9 mmol). The reaction mixture was stirred for 1 h, poured into sat. aq. NaHCO ₃ (150 ml), extracted with DCM (3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellowish residue. The crude material was dissolved in MeOH (150 ml) and cooled to -78°C. Cesium carbonate (4.42 g, 13.6 mmol) in water (3 ml) was added and the reaction mixture was stirred at -20°C for 72 h. Water (150 ml) was added to the reaction mixture and extracted with EtOAc (3x100 ml) . The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellowish residue. Column chromatography with EtOAc gave front fractions followed by racemate A of compound 109 (35%). Elution with EtOAc:MeOH (6:1) gave racemate B of compound 109 (28%).

Racemate A, white solid. 1H NMR (CDCl ₃ , 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, NH not observed) Found: [M+H]=610.1.

Racemate B, white solid. 1H NMR (CDCl ₃ , 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), 4.424 .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), 1.851.80 (m, 2H). Found: [M+H]=610.1. (OH, NH were not observed). Found: [M+H]=610.1

1-(6-Bromo-2-methoxyquinolin-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1-(5 -methylthiophen-2-yl)butan-2-ol (110)

The specified product was obtained from compounds 16 and 7 using the General method of binding described below. Column chromatography with 9:1 hexanes:EtOAc eluted the unreacted quinolone 16, while 3:1 hexanes:EtOAc eluted compound 110 (67%) as a white foam, as a 1:1 mixture of diastereomers. 0.95. 'H NMR (CDCl ₃ ) δ 8.60 (s, 1H), 8.53 (s, 0.95 H), 8.05-8.25 (bs, 1.7 H), 7.81 (dd , J = 11.6, 2.2 Hz, 2H), 7.66 (d, J= 8.9 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 'H ), 7.47-7.54 (m, 1.95 H), 7.09 (d, J = 8.4 Hz, 1H),

- 37 040011

6.90-6.95 (m, 1.95 N), 6.48-6.55 (m, 3.8 N), 6.38-6.40 (m, 4.1 N), 6.35 (bs, 1.4 N), 6.28-6.31 (m, 1.4 N), 5.15 (s,

1H), 5.08 (s, 0.95 N), 4.09-4.15 (m, 3.5 N), 3.88-3.92 (m, 8.6 N), 3.75 (bs, 2.7H), 2.40-2.54 (m, 2.4 H), 2.39 (d, J = 0.9 Hz, 3H), 2.29 (d, J = 0, 9 Hz, 3H), 2.08-2.19 (m, 1.6 H), 2.04-2.07 (m, 3.7 H), 1.79-1.89 (m, 4, 2H), 1.591.59 (m, 2H plus additional signals hidden by water). Found: [M+H]=722.4.

1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(methylamino)-1-(5-methylthiophen-2-yl)butan-2 -ol (111)

Triethylamine (0.63 ml, 4.5 mmol) and trifluoroacetic anhydride (0.54 ml, 4.1 mmol) were added successively to a solution of compound 110 (1.459 g, 2.02 mmol) in DMF (30 ml) at 0° WITH. The solution was stirred at rt. for 1 h and then divided between DCM and sat. aq. NaHCO ₃ , the organic layer was dried and evaporated to give an oil which was dissolved in MeOH (50 ml) and cooled to 0°C. Cs ₂ CO ₃ (1.64 g, 5.03 mmol) in water (10 ml) was added and the mixture was stirred at 4°C for 16 h. The mixture was diluted with water, then extracted with EtOAc, column chromatography (EtOAc) gave the compound 111 (0.876 g, 76%) as a white foam as a 1:0.7 mixture of diastereomers. Ή NMR (CDCl ₃ ) δ 8.54 (s, 1H), 8.51 (s, 0.7H), 7.89 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 1.6 Hz, 0.7 H), 7.68 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7, 47-7.53 (m, 1.5 H), 6.91 (d, J = 3.4 Hz, 0.7 H), 6.51-6.56 (m, 3.6 H), 6, 38-6.43(m, 1.4H), 6.29-6.33(m, 1H), 5.18(s, 1H), 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, 3.3 Hz, 1H), 2.55 (dt, J = 12.6, 3.0 Hz, 1H), 2.342.45 (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 signals hidden by water). Found: [M+H]=572.1.

1-(Benzofuran-7-yl)ethan-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 death was shaken until an exothermic reaction occurred. The remaining solution was added and the mixture was heated at reflux for 1 h, cooled and transferred by cannula to a dry flask. 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 h, then partitioned between EtOAc and water, the organic fractions were dried and evaporated. Non-polar impurities were eluted by column chromatography with hexanes:DCM (1:1), elution with DCM afforded compound 112 (1.21 g, 72%). 1H NMR (CDCl ₃ ) 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). Found: [M - H2O] = 145.

1-(Benzofuran-7-yl)ethan-1-one (113)

A mixture of compound 112 (1.16 g, 7.15 mmol) and MnO ₂ (3.10 g, 35.6 mmol) in benzene (40 ml) was heated under reflux for 1 h, filtered through celite and the solvent was evaporated. Column chromatography with hexanes:DCM (3:1 to 1:1) gave compound 113 (0.98 g, 86%). 'H NMR (CDCl ₃ ) 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). Found: [M+H]=161.1.

1-(Benzofuran-7-yl)-3-(dimethylamino)propan-1-one (114)

A mixture of compound 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 heated under reflux in a sealed tube for 18 h. The solvent was evaporated and the solid residue was triturated with Et ₂ O and filtered. This solid was washed with Et ₂ O, dissolved as and

- 38 040011 was made basic with 2M NaOH, then extracted with EtOAc (3x100 ml). The organic fractions were dried and evaporated to give compound 114 (4.63 g, 69%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=218.2.

(5,6-Dimethoxypyridin-3-yl)methanol (115) he Y _w OMe XX N OMe (115) p-BuLi (4.90 ml, 2.0 M in cyclohexanes, 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 cream-colored precipitate was stirred at -35°C for 0.5 h, then DMF was added ( 4.90 ml, 63.7 mmol). The mixture was stirred at -35° C. for 1 h, then quenched with water and partitioned between EtOAc and water, the organic layer was dried and evaporated. The crude aldehyde was dissolved in MeOH (50 ml) and cooled to -40°C, NaBH ₄ (1.20 g, 32 mmol) was added and the mixture was stirred at -40°C for 1 h and then quenched with water. The mixture was partitioned between EtOAc and water, the organic fractions were dried and evaporated. Column chromatography using a mixture of hexanes:EtOAc (2:1) gave compound 115 (4.02 g, 74%). ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=170.2.

(5-Bromomethyl)-2,3-dimethoxypyridine (116) Br

XX N OME (116)

A solution of compound 115 (3.98 g, 23.6 mmol) in DCM (anhydrous, 80 ml) at 0° C. was treated with triethylamine (6.6 ml, 47.4 mmol) followed by mesyl chloride (2.73 ml, 35 .3 mmol), the mixture was stirred at 0° C. for 1 h and then partitioned between DCM and water. The organic layer was dried and evaporated and the residue was dissolved in acetone (100 ml), LiBr (117 mmol) was added and the mixture was heated under reflux for 1 h and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) gave compound 116 (3.36 g, 61%) which was contaminated with the corresponding chlorine derivative (0.30 g, 7%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=232.4.

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

(117)

A mixture of compound 1 (4.02 g, 14.3 mmol), compound 116 (3.34 g, 14.4 mmol) and Cs ₂ CO ₃ (9.3 g, 28.5 mmol) in toluene (80 ml, anhydrous) and DMF (40 ml, anhydrous) were purged with nitrogen. Pd(PPh ₃ ) ₄ (0.33 g, 0.3 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 4 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated . Column chromatography (95:5 DCM:EtOAc) gave the product, which was recrystallized from MeOH to give compound 117 (3.85 g, 69%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=389.1 (2,3-Dimethoxypyridin-4-yl)methanol (118) .N^OMe

Y^OMe

ΌΗ (118)

A warm solution of 2,3-dimethoxyisonicotnaldehyde (0.68 g, 4.10 mmol) in EtOH (5 ml) was added dropwise to a suspension of NaBH ₄ (0.08 g, 2.04 mmol) in EtOH (10 ml) at - 40°C, gas evolution occurred and the mixture was stirred at -40°C for 45 minutes. The mixture was quenched with brine (10 ml) and diluted with water (10 ml) then extracted with ether (3x50 ml). Column chromatography (1:1 hexanes:EtOAc) gave compound 118 (0.69 g, 98%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=170.2.

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

- 39 040011 yOMe bg (119)

A solution of compound 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, then treated with mesyl chloride (1.95 ml , 25.2 mmol). The cloudy suspension was stirred at 0° C. for 1 h and partitioned between DCM and water. The organic fraction was dried and evaporated to give the crude mesylate. The crude mesylate was dissolved in acetone (100 ml) and LiBr (14.5 g, 167 mmol) was added. The mixture was heated under reflux for 1 h, evaporated and the residue was partitioned between DCM and water. The organic fraction was dried and evaporated. Column chromatography (DCM) gave compound 119 (3.53 g, 91%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=232.4.

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

N^OMe

A _0M e ^Br xxx ^^N^OMe (120)

A mixture of compound 1 (10.28 g, 36.5 mmol), compound 119 (8.64 g, 36.5 mmol) and Cs ₂ CO ₃ (24.0 g, 73.7 mmol) in DMF:toluene (1 :2, 200 ml) was purged with nitrogen. Pd(PPh ₃ ) 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, column chromatography using a gradient mixture of hexanes:DCM in a ratio of 3:1 to a mixture of DCM:EtOAc in a ratio of 95:5 gave compound 120 (8.65 g, 61%). ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=389.1

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

Oxalyl 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 r.t. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (3.31 g, 3.39 mmol) and pyridine (7.5 ml, 9.27 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between EtOAc and sat. aq. _NaHC03 . Column chromatography (3:1 hexanes:EtOAc) gave compound 121 (6.32 g, 100%). ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=206.2.

-(Benzofuran-2-yl)-3-(dimethylamino)propan-1-one (122)

(122)

Vinyl magnesium bromide (58 ml, 58 mmol, 1M in THF) was added to a solution of compound 121 (3.95 g, 19.2 mmol) in THF (200 ml, anhydrous) at 0°C, the brown solution was heated to rt . for 1 h, then dimethylamine (58 ml, 116 mmol, 2M in THF) and water (40 ml) were added. The solution was stirred at rt. for 1 h, and then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 122 (4.17 g, 100%). 1H NMR(CDCl ₃ ) 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). Found: [M+H]=218.2.

Methyl benzofuran-5-carboxylate (123)

MeO ₂ C

(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) was purified in a Berghof high pressure reactor and then purged three times with carbon monoxide. The mixture was heated to 80°C for 18

- 40 040011 h under pressure of carbon monoxide 60 psi, cooled and divided between EtOAc and water. Column chromatography with 3:1 hexanes:DCM eluted trace impurities, while DCM elution afforded compound 123 (2.77 g, 78%). 1H NMR (CDCl ₃ ) δ 8.35 (d, J=

1.4 Hz, 1H), 8.03 (dd, J = 8.7, 1.7 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.53 (dt, J = 8.7, 0.8 Hz, 1H), 6.84 (dd, J =

2.2, 1.0 Hz, 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 compound 123 (2.77 g, 15.7 mmol) in THF (40 ml) and MeOH (40 ml) and the solution was stirred at k.t. for 18 h and then evaporated. The residue was dissolved in water (50 ml) and acidified with conc. HCl to pH 2. The precipitate was dissolved in EtOAc, the organic layer was dried and evaporated to give compound 124 (2.49 g, 98%). 1H NMR(DMSO-d ₆ ) δ 12.86 (s, 1H), 8.30 (d, J = 1.4 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 8.6, 1.8 Hz, 1H), 7.68 (dt, J = 8.6, 0.7 Hz, 1H), 7.08 (dd, J = 2, 2, 0.9 Hz, 1H).

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

Oxalyl chloride (1.55 ml, 18.3 mmol) was added to a suspension of compound 124 (2.48 g, 15.3 mmol) in DCM (100 ml, anhydrous) and DMF (0.05 ml, 0.64 mmol) at k.t. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,Odimethylhydroxylamine hydrochloride (1.64 g, 16.8 mmol) and pyridine (3.71 mL, 45.9 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between EtOAc and sat. aq. _NaHC03 . Column chromatography with DCM:EtOAc 95:5 gave compound 125 (2.28 g, 73%) as a pale brown oil. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=206.2.

-(Benzofuran-5-yl)-3-(dimethylamino)propan-1-one (126)

Vinylmagnesium bromide (33.2 ml, 1M in THF, 33.2 mmol) was added to a solution of compound 125 (2.27 g, 11.1 mmol) in THF (100 ml, dist. Na) at 0°C, brown solution the colors were stirred at 0°C for 1 h, then dimethylamine (33.2 ml, 2M in THF, 66.4 mmol) and water (20 ml) were added. The solution was stirred at rt. for 1 h, and then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 126 (2.33 g, 97%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=218.2.

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

Trimethylborate (3.88 ml, 34.2 mmol) and borane-dimethyl sulfide (3.25 ml, 34.3 mmol) were added successively to a solution of 2,6-diethoxyisonicotinic acid (2) (2.41 g, 11.4 mmol ) in THF (100 ml, dist. Na) at 0°C and the mixture was stirred at rt. within 18 hours the Solution was cooled to 0°and carefully added methanol to extinguish the excess borane. Removing the solvent gave a solid which was partitioned between EtOAc and water, the organic layer was dried and evaporated. Column chromatography (3:1 hexanes:EtOAc) gave compound 127 (2.13 g, 95%). 1H NMR(DMSO-d ₆ ) 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). Found: [M+H]=198.1.

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

A solution of compound 127 (2.07 g, 10.5 mmol) in DCM (100 ml, anhydrous) at 0°C in succession

- 41 040011 was treated with triethylamine (2.93 ml, 21.0 mmol) and mesyl chloride (1.22 ml, 15.8 mmol), the mixture was stirred at 0°C for 1 h, then partitioned between DCM and water. The organic layer was dried and evaporated and the residue was dissolved in acetone (100 ml), LiBr (9.15 g, 105 mmol) was added and the mixture heated at reflux for 1 h, then evaporated. The residue was partitioned between DCM and water and the organic layer was dried and evaporated. Column chromatography (DCM) gave compound 128 (2.63 g, 92%). ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=260.5.

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

EtCL .OEt A

XXX NOM (129)

Mixture of compound 1 (2.20 g, 7.80 mmol), compound 128 (2.13 g, 8.20 mmol) and Cs ₂ CO ₃ (5.13 g, 15.6 mmol) in toluene (40 ml) and DMF (20 ml) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.18 g, 0.156 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Non-polar impurities were eluted by column chromatography with hexanes:DCM 3:1, elution with hexanes:DCM 1:1 gave compound 129 (2.35 g, 72%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=417.1.

Benzofuran-4-yl trifluoromethanesulfonate (130)

OSOjCFj(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) at 0° C. was treated with TFAA (4.92 ml, 29.2 mmol) and then stirred at 0° C. for 2 hours. The mixture was partitioned between DCM and water; organic fractions were dried and evaporated. Column chromatography (hexanes) gave compound 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). Found: [M+H]=267.0.

Methyl benzofuran-4-carboxylate (131)

O^OMe oz (131)

A mixture of compound 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) was purified in a Berghof pressure reactor and then purged three times with carbon monoxide. The mixture was heated to 80° C. for 1 h under 60 psi carbon monoxide, cooled and partitioned between EtOAc and water. Column chromatography with 3:1 hexanes:DCM eluted trace impurities, while DCM elution afforded compound 131 (2.08 g, 81%). 1H NMR (CDCl ₃ ) δ 7.99 (dd, J = 7.7, 0.9 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.70 (dt, J = 8.2, 0.9 Hz, 1H), 7.33-7.39 (m, 2H), 3.99 (s, 3H).

Benzofuran-4-carboxylic acid (132)

(132)

A solution of LiOH (1.44 g, 34.3 mmol) in water (20 ml) was added to a solution of compound 131 (2.02 g, 11.4 mmol) in THF (20 ml) and MeOH (20 ml) and the solution was stirred at k.t. for 16 h and then evaporated. The residue was dissolved in water (50 ml) and acidified with conc. HCl and the precipitate was filtered off and dried to give compound 132 (1.83 g, 99%). 1H NMR(DMSO-d ₆ ) 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). Found: [M-N] = 161.1.

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

- 42 040011

Oxalyl chloride (1.14 ml, 13.5 mmol) was added to a suspension of compound 132 (1.82 g, 11.2 mmol) in DCM (100 ml, anhydrous) and DMF (0.2 ml, 2.5 mmol) at k.t. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,Odimethylhydroxylamine hydrochloride (1.31 g, 13.5 mmol) and pyridine (2.72 ml, 33.6 mmol) were added successively and the mixture was stirred at rt. for 18 h, then partitioned between DCM and water. Column chromatography with DCM:EtOAc 95:5 gave compound 133 (2.13 g, 93%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=206.2.

-(Benzofuran-4-yl)-3-(dimethylamino)propan-1-one (134)

I co(134)

Vinyl magnesium bromide (20.5 ml, 20.5 mmol) was added to a solution of compound 133 (2.11 g, 10.3 mmol) in THF (100 ml, dist. Na) at 0°C, the brown solution was heated to .T. for 1 h, then dimethylamine in THF (20.5 ml, 2 M, 41 mmol) and water (20 ml) were added. The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 134 (1.83 g, 82%). ¹ H 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). Found: [M+H]=218.2.

Methyl benzo[b]thiophene-7-carboxylate (135)

COjM© (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 heated under reflux for 3 h. The solvent was evaporated and the residue was dissolved in DMF (100 ml), MeI (6.0 ml, 9.6 mmol) and K ₂ CO ₃ (27.0 g, 19.5 mmol) and the mixture was stirred at rt. for 1 h, 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), polyphosphoric acid (33 g) was added and the mixture was heated to 130° C. for 2 h. The viscous residue was poured onto ice and extracted with EtOAc, the organic layers were washed with water, brine, dried and evaporated. Column chromatography with 10:1 hexanes:EtOAc gave compound 135 (6.46 g, 52%). 1H NMR (CDCl ₃ ) 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)

CO ₂ H (136)

A solution of LiOH (2.10 g, 87.7 mmol) in water (25 ml) was added to a solution of compound 135 (5.61 g, 29.2 mmol) in THF (50 ml) and MeOH (50 ml) and the solution was stirred at k.t. for 18 h, then evaporated. The residue was dissolved in water (150 ml) and acidified to pH 2 with conc. HCl. The precipitate was extracted into EtOAc, the organic fractions were dried and evaporated to give compound 136 (4.69 g, 90%). 1H NMR(DMSO-d ₆ ) 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). Found: [M-H] = 177.1.

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

OME JSC

CO(137)

Oxalyl chloride (2.67 ml, 31.6 mmol) was added to a suspension of compound 136 (4.69 g, 26.3 mmol) in DCM (200 ml, anhydrous) and DMF (0.5 ml, 6.5 mmol) at k.t. The mixture was stirred at rt. for 1 h, then cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (3.08 g,

- 43 040011

31.6 mmol) and pyridine (6.38 ml, 78.9 mmol) and the mixture was stirred at RT. for 18 h, then divided between EtOAc and sat. aq. _NaHC03 . Compound 137 (5.48 g, 94%) was obtained by column chromatography with DCM. 1H NMR (CDCl ₃ ) 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).

Found: [M+H]=222.1.

-(Benzo[b]thiophen-7-yl)-3-(dimethylamino)propan-1-one (138) (138)

Vinylmagnesium bromide (49 ml, 1 M, 49 mmol) was added to a solution of compound 137 (5.38 g, 24.3 mmol) in THF (250 ml, dist. Na) at 0°C, the brown solution was heated to r. T. for 1 h and then added dimethylamine in THF (49 ml, 2 M, 98 mmol) and water (25 ml). The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 138 (5.45 g, 96%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=234.1.

Methyl 2-hydroxy-6-methoxyisonicotinate (139)

O^^OMe

xd

HO N OMe (139)

A suspension of 2,6-dihydroxyisonicotinic acid (10.00 g, 64.5 mmol) in MeOH (60 ml) was treated dropwise with H ₂ SO ₄ (10 ml, 18.4 M, 184 mmol). The solution was heated at reflux for 72 h and then evaporated. The residue was treated with sat. aq. NaHCO ₃ to pH 8 and extracted with EtOAc (3x200 ml). The organic extracts were washed with sat. aq. NaHCO ₃ and brine, then dried and evaporated to give compound 139 (3.55 g, 30%). 1H NMR (DMSO-d ₆ ) δ 11.2 (bs, 1H), 6.61 (bs, 2H), 3.84 (s, 3H), 3.83 (s, 3H). Found: [M+H]=184.2.

Methyl 2-isopropoxy-6-methoxyisonicotinate (140)

(140)

A solution of compound 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 rt. over 24 h, more 2-iodopropane (3.43 ml, 34.3 mmol) was added and the mixture was stirred for an additional 72 h, then partitioned between EtOAc and water and the aqueous layer was further extracted with EtOAc. The organic fractions were washed with water, dried and evaporated. Compound 140 (6.21 g, 100%) was obtained by chromatography (DCM). ¹ H NMR (CDCl ₃ ) 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). Found: [M+H]=226.2.

2-Isopropoxy-6-methoxyisonicotinic acid (141)

(141)

A solution of LiOH (1.98 g, 82.7 mmol) in water (60 ml) was added to a solution of compound 140 (6.20 g, 27.5 mmol) in MeOH (60 ml) and THF (60 ml) and the solution was stirred at k.t. for 18 h and then evaporated. The residue was dissolved in water (150 ml) and acidified to pH 3 with 2M HCl. The precipitate was filtered off and dried to give compound 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). Found: [M+H]=212.1.

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

OME

(142)

Oxalyl chloride (1.75 ml, 20.7 mmol) was added to compound 141 (3.65 g, 17.3 mmol) in DCM (100 ml, anhydrous) and DMF (0.3 ml) at rt. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,O-dimethylhydro- 44 040011 xylamine hydrochloride (2.03 g, 20.8 mmol) and pyridine (4.2 ml, 51.9 mmol) were added successively and the mixture was stirred at rt. for 18 h, then partitioned between EtOAc and water. Column chromatography with hexanes:EtOAc 3:1 gave compound 142 (4.58 g, 100%), which was used directly in the subsequent synthesis of compound 143. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=255.2.

-(Dimethylamino)-1 -(2-isopropoxy-6-methoxypyridin-4-yl)propan-1-one (143)

I. XX 'ryu n ome (143)

Vinylmagnesium bromide (36 ml, 1 M, 36 mmol) was added to a solution of compound 142 (4.54 g, 17.9 mmol) in THF (200 ml, dist. Na) at 0°C, the brown solution was heated to r. T. for 1 h, then was added dimethylamine in THF (36 ml, 2 M, 72 mmol) and water (30 ml). The solution was stirred at rt. for 1 h and then partitioned between EtOAc and water. Column chromatography using a gradient of 97.5:2.5 DCM:MeOH to 95:5 DCM:MeOH gave compound 143 (3.58 g, 75%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=267.2.

Methyl 2-ethoxy-6-methoxyisonicotinate (144)

O^^OMe lX EIU N OMe (144)

A solution of compound 139 (6.96 g, 38.0 mmol) in DMF (100 mL, anhydrous) was treated with K ₂ CO ₃ (6.57 g, 47.6 mmol) followed by iodoethane (3.85 mL, 47.6 mmol). The mixture was stirred at rt. within 24 h, divided between EtOAc and water and the aqueous layer was extracted with EtOAc. The organic fractions were washed with water, dried and evaporated to give compound 144 (6.20 g, 77%) by chromatography (DCM). ¹ H 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). Found: [M+H]=212.1.

2-Ethoxy-6-methoxyisonicotinic acid (145) o^one XX EIO N OMe (145)

A solution of LiOH (2.10 g, 87.7 mmol) in water (60 ml) was added to a solution of compound 144 (6.20 g, 29.4 mmol) in MeOH (60 ml) and THF (60 ml), the solution was stirred at k.t. for 18 h and then evaporated. The residue was dissolved in water (150 ml) and acidified to pH 3 with 2M HCl. The precipitate was filtered off and dried to give compound 145 (5.61 g, 97%) as a white solid. 1H NMR(DMSO-d ₆ ) 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). Found: [M+H]=198.2.

2-Ethoxy-N,6-dimethoxy-N-methylisonieotinamide (146)

OME

XX EY Ν OME (146)

Oxalyl chloride (2.18 ml, 25.8 mmol) was added to a suspension of compound 145 (4.23 g, 21.5 mmol) in DCM (100 ml, anhydrous) and DMF (0.3 ml) at rt. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (2.51 g, 25.8 mmol) and pyridine (5.2 ml, 64.3 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between DCM and sat. aq. _NaHC03 . Column chromatography with 3:1 hexanes:EtOAc gave compound 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). Found: [M+H]=241.1.

-(Dimethylamino)-1 -(2-ethoxy-6-methoxypyridin-4-yl)propan-1-one (147)

- 45 040011

Vinylmagnesium bromide (16.6 ml, 1 M, 16.6 mmol) was added to a solution of compound 146 (2.00 g, 8.30 mmol) in THF (100 ml, dist. Na) at 0°C, brown solution heated to rt for 1 h, then dimethylamine in THF (2M, 16.6 ml, 33.2 mmol) and water (25 ml) were added. The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated, column chromatography of the residue (DCM:MeOH 95:5) gave compound 147 (1.40 g, 67%). 'H 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). Found: [M+H]=253.2.

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

PrCX___.N^OMe

V he (148)

Trimethylborate (6.81 ml, 59.6 mmol) and borane dimethyl sulfide complex (5.66 ml, 59.7 mmol) were added successively to a solution of compound 141 (6.30 g, 29.8 mmol) in THF (100 ml, dist. Na) at 0°C, the mixture was stirred at room temperature. within 18 hours the Solution was cooled to 0°C and quenched with methanol. Removal of the solvent gave a white solid which was partitioned between EtOAc and water, the organic layer was dried and evaporated to give compound 148 (5.86 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=212.2 (M - OH + MeO).

4-(Bromomethyl)-2-isopropoxy-6-methoxypyridine (149) PrCk .OMe (149)

A solution of compound 148 (5.86 g, 29.9 mmol) in DCM (100 ml, anhydrous) at 0° C. was treated with triethylamine (8.3 ml, 59.5 mmol) followed by mesyl chloride (3.47 ml, 44 .8 mmol), the mixture was stirred at 0° C. for 1 h, then partitioned between DCM and water. The organic layer was dried and evaporated and the residue was dissolved in acetone (200 ml), LiBr (25.9 g, 299 mmol) was added and the mixture heated at reflux for 1 h and then evaporated. The remainder was separated with DCM and water; the organic fraction was dried and evaporated. Compound 149 (6.98 g, 90%) was obtained by column chromatography (DCM). 1H NMR (CDCI3) 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). Found: [M+H]=260.1

6-Bromo-3 -((2-isopropoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (150) iprO^N^OMe and

XXX ^NOMe (150)

Mixture of compound 1 (7.45 g, 26.4 mmol), compound 149 (6.84 g, 26.4 mmol) and Cs ₂ CO ₃ (17.3 g, 52.7 mmol) in toluene (100 ml) and DMF (50 ml) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.61 g, 0.528 mmol) was added, the mixture was purged with nitrogen and then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Impurities were eluted by column chromatography with 3:1 hexanes:DCM, then eluting with 1:1 hexanes:DCM gave compound 150 (8.59 g, 78%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=417.1.

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

MeO N OEt (151)

Trimethylborate (6.06 ml, 53.1 mmol) and then borane dimethyl sulfide (5.04 ml, 53.1 mmol) were added to a solution of compound 145 (5.24 g, 26.6 mmol) in THF (100 ml, dist. Na) at 0°C, and the mixture was stirred at room temperature. within 18 hours the Solution was cooled to 0°C and quenched with methanol. Removal of the solvent gave a solid which was partitioned between EtOAc and water, the organic layer was dried and evaporated to give compound 151 (4.79 g, 98%). 1H NMR (CDCl ₃ ) 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,

- 46 040011

1H), 1.39 (t, J = 7.1 Hz, 3H). Found: [M + H] = 184.2.

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

A solution of compound 151 (4.72 g, 25.9 mmol) in DCM (100 ml, anhydrous) at 0°C was treated successively with triethylamine (7.22 ml, 51.8 mmol) and mesyl chloride (3.00 ml, 38 .8 mmol), the mixture was stirred at 0° C. for 1 h, then partitioned between DCM and water. The organic layer was dried and evaporated and the residue was dissolved in acetone (200 ml), LiBr (22.5 g, 259 mmol) was added and the mixture heated at reflux for 1 h, then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) gave compound 152 (5.78 g, 91%). 1H NMR(CDα ₃ ) 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). Found: [M+H]=246.0.

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

Mixture of compound 1 (6.61 g, 23.4 mmol), compound 152 (5.77 g, 23.4 mmol) and Cs ₂ CO ₃ (15.25 g, 46.5 mmol) in toluene (100 ml) and DMF (50 ml) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.54 g, 0.465 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Impurities were eluted by column chromatography with 3:1 hexanes:DCM, then eluting with 1:1 hexanes:DCM afforded compound 153 (6.69 g, 71%). ¹ H 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). Found: [M+H]=403.1.

Ethyl 2-ethoxy-6-hydroxyisonicotinate (154)

A suspension of 2,6-dihydroxyisonicotinic acid (40.00 g, 258 mmol) in EtOH (300 ml) was treated dropwise with H ₂ SO ₄ (40 ml, 18.4 M, 752 mmol). The solution was heated under reflux for 72 h, then evaporated; the residue was treated with sat. aq. NaHCO ₃ to pH 8 and then extracted with EtOAc (3x500 ml). The organic extracts were washed with sat. aq. NaHCO ₃ , brine, then dried and evaporated to give compound 154 (10.86 g, 20%). 1H NMR(DMSO-d ₆ ) 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). Found: [M+H]=212.2.

Ethyl 2-ethoxy-6-isopropoxyisonicotinate (155)

A solution of compound 154 (10.82 g, 51.2 mmol) in DMF (125 mL, anhydrous) was treated with K ₂ CO ₃ (8.65 g, 62.5 mmol) followed by 2-iodopropane (6.4 mL, 64 mmol). The mixture was stirred at rt. over 48 h, 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 h, partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc . The organic fractions were washed with water, dried and evaporated. Compound 155 (11.56 g, 89%) was obtained by chromatography (DCM). ¹ H 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). Found: [M+H]=254.1.

2-Ethoxy-6-isopropoxyisonicotinic acid (156)

- 47 040011

A solution of LiOH (3.25 g, 136 mmol) in water (60 ml) was added to a solution of compound 155 (11.42 g, 45.1 mmol) in THF (60 ml) and MeOH (60 ml), the solution was stirred at .T. for 18 h and then evaporated. The residue was dissolved in water (150 ml) and acidified to pH 3 with 2 M HCl. The precipitate was filtered off and dried to give compound 156 (10.03 g, 99%). 1H NMR(DMSO-d ₆ ) 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). Found: [M+H]=226.1.

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

ome

(157)

Oxalyl chloride (3.13 ml, 37 mmol) was added to compound 156 (6.95 g, 30.8 mmol) in DCM (100 ml, anhydrous) and DMF (5.2 mmol) at rt. The mixture was stirred at rt. within 1 h 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 successively and the mixture was stirred at rt. for 18 h, then partitioned between EtOAc and water. The organic fractions were washed with water, dried and evaporated. Column chromatography with DCM:EtOAc 95:5 gave compound 157 (7.98 g, 97%). 1H NMR(CDCl ₃ ) 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). Found: [M+H]=269.2.

-(Dimethylamino)-1 -(2-ethoxy-6-isopropoxypyridin-4-yl)propan-1-one (158)

I

(158)

Vinylmagnesium bromide (40 ml, 1M in THF, 40 mmol) was added to a solution of compound 157 (5.33 g, 19.9 mmol) in THF (100 ml, dist. Na) at 0°C, the brown solution was stirred at 0 °C for 1 h and then dimethylamine (40 ml, 2M in THF, 80 mmol) and water (40 ml) were added. The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 158 (5.57 g, 100%) as a brown oil. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=281.7.

Methyl 2-methoxy-6-propoxyisonicotinate (159)

(159)

A solution of compound 139 (6.00 g, 32.8 mmol) in DMF (100 mL, anhydrous) was treated with K ₂ CO ₃ (6.80 g, 49.2 mmol) followed by 1-iodopropane (4.8 mL, 49 .2 mmol). The mixture was stirred at rt. within 48 h, divided between EtOAc and water and the aqueous layer was extracted with EtOAc. The organic fractions were washed with water, dried and evaporated. Compound 159 (6.59 g, 89%) was obtained by column chromatography (DCM). ¹ H 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). Found: [M+H]=226.1.

2-Methoxy-6-propoxyisonicotinic acid (160)

(160)

A solution of LiOH (2.04 g, 85.2 mmol) in water (60 ml) was added to a solution of compound 159 (6.40 g, 28.4 mmol) in THF (60 ml) and MeOH (60 ml), the solution was stirred at k.t. for 18 h and then evaporated. The residue was dissolved in water (200 ml) and acidified to pH 3 with 2 M HCl. The precipitate was filtered off and dried to give compound 160 (5.39 g, 90%). 1H NMR (DMSO-d ₆ ) 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). Found: [M+H]=212.1.

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

- 48 040011

Trimethylborate complex (5.8 ml, 50.8 mmol) and dimethyl sulfide borane (4.8 ml, 50.6 mmol) were added successively to a solution of compound 160 (5.39 g, 25.5 mmol) in THF (100 ml, dist. Na) at 0°C, and the mixture was stirred at room temperature. within 16 hours the Solution was cooled to 0°and carefully added methanol to quench the reaction. Removing the solvent gave a solid which was partitioned between EtOAc and water, the organic layer was dried and evaporated. Column chromatography (3:1 hexanes:EtOAc) gave compound 161 (5.04 g, 100%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=198.2.

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

A solution of compound 161 (5.00 g, 25.4 mmol) in DCM (100 ml, anhydrous) at 0°C was treated with triethylamine (7.07 ml, 50.7 mmol) followed by mesyl chloride (2.94 ml, 38.0 mmol), the mixture was stirred at 0° C. for 1 h, then partitioned between DCM and water. The organic layer was dried and evaporated, the residue was dissolved in acetone (150 ml), LiBr (22.0 g, 253 mmol) was added and the mixture was heated under reflux for 1 h and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) gave compound 162 (6.15 g, 93%) as a colorless oil. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=260.5.

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

Mixture of compound 1 (6.62 g, 23.5 mmol), compound 162 (6.11 g, 23.5 mmol) and Cs ₂ CO ₃ (15.3 g, 47.0 mmol) in toluene (66 ml) and DMF (33 ml) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.54 g, 0.47 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated . Column chromatography with 1:1 DCM:hexanes gave a product containing impurities, which was rechromatographed using a 2:1 hexanes:DCM gradient to 1:1 hexanes.-DCM to give compound 163 (6 .63 g, 68%). 1H NMR (CDCl ₃ ) 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). Found: [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 heated at reflux for 18 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. Recrystallization from MeOH gave compound 164 (11.63 g, 92%). 1H NMR (CDCl ₃ ) 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-methoxyquinolin-3 -yl) 1 (165)

A solution of anhydrous 2,2,6,6,-tetramethylpiperidine (6.7 ml, 39.7 mmol) in THF (70 ml, Na dist.) at -40°C was treated with p-BuLi (19.8 ml, 2M in cyclohexane, 39.7 mmol), then the solution was stirred at 40°C for 5 min and then cooled to -78°C. A solution of compound 164 (6.35 g, 32.9 mmol) and triisopropyl borate (9.1 ml, 39.7 mmol) in THF (50 ml, dist. Na) and an orange solution were added dropwise.

- 49 040011 was stirred for 3 h at -78°C, then quenched sat. aq. NH ₄ Cl and ice. The precipitate was filtered off, triturated with hexanes and dried to give compound 165 (5.84 g, 75%). 1H NMR (DMSOd6) 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). Found: [M-OH+OMe]=252.2.

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

(166)

A mixture of compound 165 (5.00 g, 21.1 mmol), 1-(bromomethyl)-2-fluoro-3-methoxybenzene (4.61 g, 21.0 mmol) and Cs ₂ CO ₃ (13.7 g, 42.0 mmol) in toluene (100 ml) and DMF (50 ml) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.49 g, 0.42 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated . Column chromatography with 3:1 hexanes:DCM eluted impurities, while eluting with 1:1 hexanes:DCM gave compound 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). Found: [M+H]=332.1.

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

OME

(167)

Oxalyl chloride (2.76 ml, 32.6 mmol) was added to compound 160 (5.74 g, 27.2 mmol) in DCM (100 ml, anhydrous) and DMF (0.4 ml, 5.2 mmol) at rt. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,Odimethylhydroxylamine hydrochloride (3.18 g, 32.6 mmol) and pyridine (6.6 ml, 81.6 mmol) were added successively and the mixture was stirred at rt. for 18 h, then partitioned between DCM and water. Column chromatography on alumina with DCM provided compound 167 (6.29 g, 91%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=255.1.

-(Dimethylamino)-1 -(2-methoxy-6-propoxypyridin-4-yl)propan-1-one (168)

(168)

Vinylmagnesium bromide (43 ml, 1M in THF, 43 mmol) was added to a solution of compound 167 (5.78 g, 21.7 mmol) in THF (100 ml, dist. Na) at 0°C, the brown solution was stirred at 0 °C for 1 h and then dimethylamine (43 ml, 2M in THF, 86 mmol) and water (40 ml) were added. The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 168 (5.75 g, 100%). 1H NMR(CDCl ₃ ) 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). Found: [M+H]=267.2.

Benzofuran-7-ylmethanol (169)

(169)

A solution of methyl benzofuran-7-carboxylate (3.59 g, 20.4 mmol) in Et ₂ O (100 ml, Na dist.) at 0°C was treated with LiAlH ₄ (1.54 g, 40.6 mmol), then stirred at rt. for 3 h and quenched with ice. The mixture was partitioned between Et2O and sat. aq. sodium potassium tartrate and then filtered through celite. The aqueous layer was extracted with Et ₂ O and the organic phases were combined and dried. Column chromatography (0-5% EtOAc:DCM) gave compound 169 (2.60 g, 86%). 1H NMR (CDCl ₃ ) δ 7.65 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 7.7, 1.2 Hz, 1H), 7.31 (dd, J = 7.3, 0.6 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 5.02 (d , J = 6.2 Hz, 2H), 1.93 (t, J = 6.2 Hz, 1H).

7-(Bromomethyl)benzofuran (170)

- 50 040011

A solution of compound 169 (4.72 g, 31.8 mmol) in DCM (100 ml, anhydrous) at 0°C was treated successively with triethylamine (8.9 ml, 63.9 mmol) followed by mesyl choride (3.70 ml, 47.8 mmol), the mixture was stirred at 0° C. for 1 h, then partitioned between DCM and water. The organic layer was dried and evaporated and the residue was dissolved in acetone (200 ml), LiBr (27.6 g, 318 mmol) was added and the mixture heated at reflux for 0.5 h and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Compound 170 (6.08 g, 90%) was obtained by column chromatography (DCM). 1H NMR (CDCl ₃ ) δ 7.69 (d, J = 2.2 Hz, 1H), 7.57 (dd, J = 7.7, 1.2 Hz, 1H), 7.32 (dd, J = 7.4, 0.7 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 4.81 (s , 2H).

-(Benzofuran-7-ylmethyl)-6-bromo-2-methoxyquinoline (171)

Mixture of compound 1 (8.00 g, 28.4 mmol), compound 170 (5.99 g, 28.4 mmol) and Cs ₂ CO ₃ (18.5 g, 56.7 mmol) in toluene (100 ml) and DMF (50 ml) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.66 g, 0.57 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated . Impurities were eluted by column chromatography with 3:1 hexanes:DCM, followed by 1:1 hexanes:DCM, then DCM afforded compound 171 (6.95 g, 67%). 'H NMR (CDCl ₃ ) 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). Found: [M+H]=368.8.

Methyl 2-cyclobutoxy-6-methoxyisonicotinate (172)

A solution of compound 139 (3.00 g, 16.4 mmol) in DMF (50 ml, anhydrous) was treated with K ₂ CO ₃ (4.52 g, 32.7 mmol) and then with bromocyclobutane (2.00 ml, 25.0 mmol). The mixture was stirred at rt. for 48 h, partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic fractions were washed with water, dried and evaporated. Column chromatography (DCM) gave compound 172 (2.21 g, 57%). ¹ H NMR(CDCl ₃ ) 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). Found: [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 compound 172 (2.20 g, 9.29 mmol) in MeOH (20 ml) and THF (20 ml); the solution was stirred at room temperature. for 18 h and then evaporated. The residue was dissolved in water (80 ml) and acidified to pH 3 with 2 M HCl. The precipitate was filtered off and dried to give compound 173 (2.02 g, 97%). 1H NMR (DMSO-d ₆ ) 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), 2.142.22 (m, 2H) , 1.74-1.83 (m, 1H), 1.59-1.72 (m, 1H). Found: [M+H]=224.2.

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

- 51 040011

Oxalyl chloride (0.45 ml, 5.32 mmol) was added to a suspension of compound 173 (1.00 g, 4.48 mmol) in DCM (50 ml, anhydrous) and DMF (0.2 ml) at rt. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. AOdimethylhydroxylamine hydrochloride (0.52 g, 5.33 mmol) and pyridine (1.09 mL, 13.5 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between DCM and sat. aq. _NaHC03 . Column chromatography on alumina with DCM gave compound 174 (1.01 g, 85%). 1H NMR (CDCI3) 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). Found: [M+H]=267.2.

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

I z ^N XV° jQ O N OMe 6 (175)

Vinylmagnesium bromide (8.0 ml, 1 M, 8.0 mmol) was added to a solution of compound 174 (1.02 g, 3.84 mmol) in THF (50 ml, dist. Na) at 0°C, brown solution heated to rt for 1 h, then dimethylamine in THF (8.0 ml, 2M, 16.0 mmol) and water (10 ml) were added. The solution was stirred at rt. for 1 h, and then partitioned between EtOAc and water. The solution was dried and evaporated, column chromatography (95:5 DCM:MeOH) gave compound 175 (1.05 g, 97%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=279.2.

(2-Ethoxy-6-isopropoxypyridin-4-yl)methanol (176) jun

Chl

EY N O'Pr (176)

Trimethylborate (3.03 ml, 26.7 mmol) and then borane dimethyl sulfide (2.53 ml, 26.7 mmol) were added to a solution of compound 156 (3.00 g, 13.3 mmol) in THF (50 ml, dist. Na) at 0°C and the resulting mixture was stirred at room temperature. within 18 hours the Solution was cooled to 0°and in order to quench the reaction, carefully added methanol. With the removal of the solvent, a solid was obtained, partitioned between EtOAc and water, the organic layer was dried and evaporated. Column chromatography (3:1 hexanes:EtOAc) gave compound 176 (2.72 g, 97%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=212.2.

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

A

EtO^N O'Pr (177)

A solution of compound 176 (2.60 g, 12.3 mmol) in DCM (50 ml, anhydrous) at 0°C was treated successively with triethylamine (3.43 ml, 24.6 mmol) followed by mesyl chloride (1.43 ml, 18.5 mmol), the mixture was stirred at 0° C. for 1 h, then partitioned between DCM and water. The organic layer was dried and evaporated and the residue was dissolved in acetone (100 ml), LiBr (10.7 g, 123 mmol) was added and the mixture heated at reflux for 1 h and then evaporated. The residue was partitioned between DCM and water; the organic fraction was dried and evaporated. Column chromatography (DCM) gave compound 177 (3.04 g, 100%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=274.1

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

A mixture of compound 1 (11.6 mmol), compound 177 (3.18 g, 11.6 mmol) and Cs ₂ CO ₃ (7.56 g, 23.2 mmol) in toluene (66 ml) and DMF (33 ml ) was purged with nitrogen. Pd(PPh ₃ ) ₄ (0.27 g, 0.23 mmol) was added, the mixture was purged with nitrogen, then heated to 80° C. under nitrogen for 3 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Impurities were eluted by column chromatography with 3:1 hexanes:DCM, then elution with DCM afforded compound 178 (3.42 g, 68%) as a white solid. 1H NMR (CDCl ₃ ) 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). Found: [M+H]=431.1 (6-Chloro-2-methoxyquinolin-3-yl)(m-tolyl)methanol (179)

p-BuLi (12.4 ml, 2M in cyclohexanes, 24.8 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (4.18 ml, 24.8 mmol) in THF (50 ml, dist. Na) at -40°C and the solution was stirred for 5 min, then cooled to -78°C. A solution of compound 164 (4.00 g, 20.7 mmol) in THF (40 ml, Na dist.) was added and the solution was stirred at -78 for 1.5 h, then a solution of t-toluylaldehyde (2.49 g , 20.7 mmol) in THF (10 ml, dist, Na). The solution was stirred at -78° C. for 3 h then acetic acid (3.55 ml, 62.0 mmol) was added, the mixture was partitioned between EtOAc and water and the aqueous was extracted with EtOAc, the organic fractions were combined and evaporated. Column chromatography (3:1 hexanes:DCM to 2:1 hexanes:DCM to DCM and then 95:5 DCM:EtOAc) gave compound 179 (3.39 g, 55%) as a white solid. 1H NMR(CDCl ₃ ) 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). Found: [M+H]=314.1.

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

A solution of compound 179 (3.36 g, 11.3 mmol) in DCM (60 ml) was treated with trifluoroacetic acid (8.4 ml, 113 mmol) and then with triethylsilane (14.5 ml, 89.9 mmol). The solution was heated under reflux for 18 h, neutralized with sat. aq. NaHCO ₃ and separated with water. The organic phase was dried and evaporated, column chromatography (3:1 hexanes:DCM) gave compound 180 (2.27 g, 67%). ¹ H NMR (CDCl ,) 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). Found: [M+H]=298.1.

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

Borane-dimethylsulfide (4.60 ml, 48.5 mmol) and trimethylborate (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, dt Na) at 0°C, then the solution was stirred at rt. for 18 h, cooled to 0°C, quenched Meon and evaporated. The residue was partitioned between EtOAc and water and the organic layer was dried and evaporated. Column chromatography (2:1 hexanes:EtOAc) gave compound 279 (2.72 g, 98%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=170.1.

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

MeOx-Ns^OMe σ

Br (280)

A solution of compound 279 (1.57 g, 9.30 mmol) in DCM (40 ml, anhydrous) at 0°C was treated with triethylamine (2.60 ml, 18.6 mmol) followed by mesyl chloride (1.08 ml, 13 .9 mmol), the mixture was stirred at 0° C. for 1 h, then partitioned between DCM and water. The organic layer 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 heated at reflux for 1 h, then evaporated. The residue was partitioned between DCM and water and the organic layer was dried and evaporated. Compound 280 (1.96 g, 91%) was obtained by column chromatography (DCM). 1 H NMR (CDCl ₃ ) δ 6.32 (s, 2H), 4.29 (s, 2H), 3.91 (s, 6H). Found: [M+H] = 232.0.

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

- 53 040011

Mixture of compound 1 (2.20 g, 7.80 mmol), compound 280 (1.93 g, 8.30 mmol), Cs ₂ CO ₃ (5.10 g, 15.7 mmol) and Pd(PPh ₃ ) ₄ (0.45 g, 0.39 mmol) in DMF (10 ml) and toluene (20 ml) was purged with nitrogen, then heated to 80° C. for 4 h under nitrogen atmosphere. The mixture was partitioned between EtOAc and water and the organic layer was dried and evaporated. Non-polar impurities were eluted by column chromatography (3:1 hexanes:DCM), elution with DCM afforded compound 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, 2.2Hz, 1H), 7.57(s, 1H), 6.17(s, 2H), 4.06(s, 3H), 3.92(s, 2H), 3.89(s, 6H). Found: [M+H] = 389.1.

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

Oxalyl 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 rt. The mixture was stirred at rt. within 1 h to obtain a colorless solution, which was cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (1.46 ml, 17.3 mmol) and pyridine (3.82 ml, 47.2 mmol) were added successively and the mixture was stirred at rt. for 18 h, then divided between EtOAc and sat. aq. _NaHC03 . Column chromatography with hexanes:EtOAc 1:1 gave compound 282 as an oil (1.50 g, 49%). 'H NMR (CDCl ₃ ) δ 7.15 (s, 2H), 3.56 (s, 3H), 3.35 (s, 3H), 2.57 (s, 6H). Found: [M+H]=195.1.

3-(Dimethylamino)-1-(2,6-dimethylpyridin-4-yl)propan-1-one (283)

A solution of vinylmagnesium bromide in THF (1N, 22.0 ml, 22 mmol) was added to a solution of compound 282 (1.43 g, 7.37 mmol) in THF (100 ml, dist. Na) at 0°C, brown the solution was heated to rt. for 1 h, then dimethylamine in THF (2N, 22.0 ml, 44 mmol) and water (20 ml) were added. The solution was stirred at rt. for 1 h, then partitioned between EtOAc and water. The solution was dried and evaporated to give compound 283 as a yellow oil (1.54 g, 99%). 1H NMR (CDCl ₃ ) 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). Found: [M+H]=207.2.

II. Obtaining typical embodiments of the invention.

Example 1 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1(m-tolyl)butan-2-ol (181)

General binding technique.

p-BuLi (2.63 ml of a 2N solution in cyclohexane, 5.26 mmol) was added at -30° C. under dry nitrogen to a solution of dry diisopropylamine (0.74 ml, 5.26 mmol) in dry THF (6 ml) and the solution was stirred at the same temperature for 10 min, then cooled to -78°C. A solution of compound 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 give a maroon solution. A solution of dry compound 6 (1.15 g, 4.82 mmol) in dry THF (7 ml) was added and the reaction mixture was stirred at the same temperature for 4 hours. HOAc (0.90 ml) was added and the reaction mixture was heated to r.m. m. Water (100 ml) was added and the reaction mixture was extracted with EtOAc (2x). The combined organic extract was washed with sat. aq. NaHCO ₃ solution, and brine, then dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure. The residue was purified by flash column chromatography. Elution with 0-10% MeOH/DCM provided front fractions of unreacted compound 10, after which product 181 was obtained as a mixture of diastereomers in a ratio of 1:1 (0.91 g, 36%). Found: [M+H]=580.1.

- 54 040011

The following compounds were synthesized using the general binding methodology. Each compound product was separated into its four optical isomers using preparative chiral HPLC.

Example 2 2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol (182) (182)

By coupling 3-benzyl-6-bromo-2-methoxyquinoline and compound (114). Column chromatography of the crude product with 0-5% MeOH:DCM gave the front fractions and then compound 182. Found: [M+H]=544.9.

Example 3 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2(3-fluorophenyl)butan-2-ol (183) (183)

By coupling compound 117 and 3-(dimethylamino)-1-(3-fluorophenyl)propan-1-one. Column chromatography of the crude product with 0-5% MeOH:DCM gave the front fractions and then compound 183. Found: [M+H]=583.9.

Example 4 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2(m-tolyl)butan-2-ol (184)

MeO^.N.

(184)

By coupling compound 120 and 3-(dimethylamino)-1-(m-tolyl)propan-1-one. Column chromatography of the crude product with 0-5% MeOH:DCM gave the front fractions and then compound 184. Found: [M+H]=580.0.

Example 5 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1(2-fluoro-3-methoxyphenyl)butane -2-ol (185) (185)

Coupling of Compound 8 and Compound 4. Column chromatography of the crude product with 0-5% MeOH:DCM gave front fractions followed by Compound 185. Found: [M+H]=642.1.

Example 6 2-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol (186) (186)

By coupling compound 9 and compound 122. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 186. Found: [M+H]=562.9.

Example 7 2-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)4-(dimethylamino)butan-2 -ol (187)

- 55 040011

Coupling of Compound 120 and Compound 122. Column chromatography of the crude product with 0-5% MeOH:DCM gave front fractions followed by Compound 187. Found: [M+H]=606.1.

Example 8 2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol (188)

By coupling compound 9 and compound 114. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 188. Found: [M+H]=562.9.

Example 9 dimethylamino)butan-2-ol (189)

By coupling compound 120 and compound 6. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 189. Found: [M+H]=627.1.

Example 10 2-(Benzofuran-5-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4yl)-4-(dimethylamino)butan-2- ol (190)

By coupling compound 120 and compound 126. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 190. Found: [M+H]=606.1.

Example 11 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(5-methylthiophen-2-yl)butane -2-ol (191)

By coupling compound 16 and compound 6. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 191. Found: [M+H]=586.1.

Example 12 2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,6-diethoxypyridin-4-yl)4-(dimethylamino)butan-2 -ol (192)

Coupling of compound 129 and compound 114. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 192. Found:

[M+H]=634.2.

Example 13 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-fluoro-3-methoxyphenyl)butane -2-ol (193)

Coupling of Compound 8 and Compound 6. Column chromatography of the crude product with 0-5% MeOH:DCM gave front fractions followed by Compound 193. Found: [M+H]=614.0.

Example 14 2-(Benzofuran-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol (194)

Coupling of 3-benzyl-6-bromo-2-methoxyquinoline and compound 134. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 194. Found: [M+H]=544.5.

Example 15 2-(Benzo[b]thiophen-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol (195)

(195)

By coupling 3-benzyl-6-bromo-2-methoxyquinoline and compound 138. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 195. Found: [M+H]=561.0.

Example 16 1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2isopropoxy-6-methoxypyridin-4-yl) butan-2-ol (196)

By coupling compound 8 and compound 143. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 196. Found: [M+H]=642.1.

Example 17 1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4yl)-1-(2-fluoro-3-methoxyphenyl) butan-2-ol (197)

By coupling compound 8 and compound 147. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 197. Found: [M+H]=627.7.

Example 18 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2-isopropoxy-6-methoxypyridin-4 -yl)butan-2-ol (198)

- 57 040011

Coupling of compound 120 and compound 143. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 198. Found:

[M+H]=655.1.

Example 19 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-isopropoxy-6-methoxypyridin-4 -yl)butan-2-ol (199)

By coupling compound 150 and compound 6. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 199. Found: [M+H]=655.0.

Example 20 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2-ethoxy-6-methoxypyridin-4 -yl)butan-2-ol (200)

By coupling compound 120 and compound 147. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 200. Found: [M+H]=641.2.

Example 21 2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl) butan-2-ol (201)

Coupling of compound 150 and compound 114. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 2012 Found: [M+H]=634.1.

Example 22 2-ol (202)

(202)

By coupling compound 153 and compound 114. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 202. Found: [M+H]=620.1.

Example 23 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2-ethoxy-6-isopropoxypyridin-4 -yl)butan-2-ol (203)

By coupling compound 120 and compound 158. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 203. Found: [M+H]=669.0.

Example 24 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2-ethoxy-6-isopropoxypyridin-4 -yl)butan-2-ol (204)

- 58 040011

By coupling compound 281 and compound 158. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 204. Found: [M+H]=669.0.

Example 25 2-ol (205)

By coupling compound 10 and compound 143. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 205. Found: [M+H]=607.7.

Example 26 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-methoxy-6-propoxypyridin-4 -yl)butan-2-ol (206)

By coupling compound 163 and compound 6. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 206. Found: [M+H]=654.7.

Example 27

By coupling compound 166 and compound 4. Column chromatography of the crude product 0-3% MeOH:DCM gave front fractions and then compound 207. Found: [M+H]=597.8.

Example 28 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2-methoxy-6-propoxypyridin-4 -yl)butan-2-ol (208)

By coupling compound 120 and compound 168. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 208. Found: [M+H]=654.7.

Example 29 1-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-

By coupling compound 171 and compound 6. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 209. Found:

[M+H]=605.7.

Example 30 dimethylamino)butan-2-ol (210)

By coupling compound 120 and compound 175. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 210. Found: [M+H]=666.7.

Example 31 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-ethoxy-6-isopropoxypyridin-4 -yl)butan-2-ol (211)

By coupling compound 178 and compound 6. Column chromatography of the crude product 0-5% MeOH:DCM gave front fractions and then compound 211. Found: [M+H]=669.0.

Example 32 1-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1(m-tolyl)butan-2-ol (212)

Coupling of Compound 180 and Compound 4. Column chromatography of the crude product with 0-3% MeOH:DCM gave front fractions followed by Compound 212. Found: [M+H]=564.0.

Example 33 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2,5-dimethylthiophen-3-yl )butan-2-ol (213)

Coupling compound 14 and compound 6. Column chromatography with EtOAc:hexanes (1:3) eluted unreacted compound 14 while hexanes:EtOAc (1:1) afforded 213. Found: [M+H]=600, 1.

Example 34 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1(m-tolyl)butan-2-ol (214)

Coupling of compound 10 and compound 4. Column chromatography with EtOAc:hexanes (1:9) gave front fractions, then eluting with EtOAc:hexanes (1:4) gave compound 214. Found: [M+H]=608.2 .

Example 35

- 60 040011

By coupling compound 11 and compound 4. By column chromatography with a mixture of

EtOAc:hexanes (1:9) gave front fractions, then eluting with EtOAc:hexanes (1:1) gave compound 215. Found: [M+H]=654.1.

Example 36 dimethylamino)butan-2-ol (216)

Coupling of Compound 120 and Compound 4. Column chromatography with EtOAc:hexanes (1:4) followed by EtOAc gave front fractions followed by Compound 216. Found: [M+H]=655.1.

Example 37 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6dimethylpyridin-4-yl)butan-2- ol (217)

Coupling of compound 11 and compound 283. Column chromatography with MeOH:DCM (0-8%) gave front fractions, then compound 217. Found: [M+H]=594.1.

Example 38 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-methoxypyridin-3-yl)butane -2-ol (218)

Coupling of Compound 17 and Compound 6. Column chromatography with EtOAc:hexanes (1:1) then EtOAc gave front fractions followed by Compound 218. Found: [M+H]=597.1.

Example 39 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(3-fluorophenyl)butan-2-ol (219)

By coupling compound 9 and compound 6. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 219. Found: [M+H]=584.1.

Example 40 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamin-1-phenylbutan-2-ol ( 220)

(220)

Coupling of 3-benzyl-6-bromo-2-methoxyquinoline and compound 19. Column chromatography with EtOAc:hexanes (1:1) gave front fractions, then compound 220. Found: [M+H]=545.3.

Example 41 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6dimethoxypyridin-4 -yl)-4-(dimethylamino)butan-2-ol (221)

- 61 040011

By coupling compound 22 and compound 6. By column chromatography with a mixture of

EtOAc:hexanes (1:1) gave front fractions, then compound 221. Found: [M+H]=624.1.

Example 42 2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinolin-3-yl)-1phenylbutan-2-ol (222)

Coupling of compound 23 and compound 6. Column chromatography with EtOAc:hexanes (3:7) gave front fractions, then compound 222. Found: [M+H]=614.1.

Example 43 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin -5-yl)-4-(dimethylamino)butan-2-ol (223)

Coupling of compound 22 and compound 4. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 223. Found: [M+H]=652.2.

Example 44 3-methoxyphenyl)butan-2-ol (224)

Coupling of compound 8 and compound 26. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 224. Found: [M+H]=674.1.

Example 45 3-methoxyphenyl)butan-2-ol (225)

Coupling of compound 8 and compound 29. Column chromatography with EtOAc:hexanes (1:1) then EtOAc gave the front fractions and then compound 225. Found: [M+H]=646.0.

Example 46 2-(2,6-bis(Methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl) -4-(dimethylamino)butan-2-ol (226)

Vg

(226)

Coupling of compound 120 and compound 29. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave the front fractions and then compound 226. Found: [M+H]=659.1.

Example 47 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1(2-fluoro-3-methylphenyl)butane -2-ol (227)

- 62 040011

Coupling of compound 30 and compound 4. Column chromatography with EtOAc:hexanes (1:1) gave front fractions, then compound 227. Found: [M+H]=626.1.

Example 48 1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2methoxy-6-(methylthio)pyridine-4 -yl)butan-2-ol (228)

Coupling of compound 8 and compound 33. Column chromatography with EtOAc:hexanes (1:1) then EtOAc gave the front fractions and then compound 228. Found: [M+H]=630.0.

Example 49 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4(dimethylamino)-1-(2-fluoro-3 -methoxyphenyl)butan-2-ol (229)

Coupling of compound 8 and compound 37. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 229. Found: [M+H]=650.0.

Example 50 1-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl) -4-(dimethylamino)butan-2-ol (230)

Coupling of compound 40 and compound 6. Column chromatography with EtOAc:hexanes (1:1) gave front fractions, then compound 230. Found: [M+H]=658.9.

Example 51 4-(dimethylamino)butan-2-ol (231)

Coupling of compound 120 and compound 37. Column chromatography with EtOAc:hexanes (1:1) then EtOAc gave the front fractions and then compound 231. Found: [M+H]=663.0.

Example 52 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl) -4-(dimethylamino)butan-2-ol (232)

- 63 040011

Coupling of compound 43 and compound 6. Column chromatography with EtOAc:hexanes (1:1) gave front fractions, then compound 232. Found: [M+H]=605.7.

Example 53 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(5,6,7,8-tetrahydronaphthalene -1-yl)butan-2-ol (233)

Coupling of compound 46 and compound 6. Column chromatography with EtOAc:hexanes (1:4) gave front fractions, then compound 233 Found: [M+H]=619.7.

Example 54 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4(dimethylamino)-1-(2-fluoro-3 -methylphenyl)butan-2-ol (234)

Coupling of compound 30 and compound 37. Column chromatography with EtOAc:hexanes (1:4) gave front fractions, then compound 234. Found: [M+H]=633.7.

Example 55 3-methylphenyl)butan-2-ol (235)

Coupling of compound 30 and compound 29. Column chromatography with EtOAc:hexanes (1:4) gave front fractions, then compound 235. Found: [M+H]=629.6.

Example 56 2-(2,6-bis(Methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol (236)

Coupling of compound 22 and compound 29. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave front fractions and then compound 236. Found: [M+H]=656.0.

Example 57 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-

Coupling of compound 30 and compound 6. Column chromatography with EtOAc:hexanes (1:1) gave front fractions, then compound 237. Found: [M+H]=598.0.

Example 58 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1 4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol (238)

- 64 040011

Coupling of compound 22 and compound 37. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 238. Found: [M+H]=659.9.

Example 59 (dimethylamino)butan-2-ol (239)

Coupling of compound 50 and compound 4. Column chromatography of the crude product using hexane/ethyl acetate gave compound 239. Found: [M+H] = 666.1.

Example 60 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(3-fluoro-2-methoxypyridin-4 -yl)butan-2-ol (240)

By coupling compound 55 and compound 6. Column chromatography with hexane/EtOAc 9:1 eluted unreacted starting compound XX, then chromatography with hexane/EtOAc 1:2 gave compound 240. Found: [M+H] = 614.9.

Example 61 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2,3,6-trimethoxypyridin-4 -yl)butan-2-ol (241)

By coupling compound 120 and compound 63. Column chromatography with DCM/EtOAc 1:1 followed by EtOAc eluted compound 241. Found: [M+H]=656.6.

Example 62 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(3-fluoro-4-methoxyphenyl)butane -2-ol (242)

By coupling compound 66 and compound 6. Column chromatography with hexane/EtOAc 9:1 eluted the unreacted starting compound, then eluted with hexane/EtOAc 1:1 to give compound 242. Found: [M+H] = 613, 7.

Example 63 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2,3,6-trimethoxypyridin-4 -yl)butan-2-ol (243)

(243)

Coupling of compound 72 and compound 6. Column chromatography with hexane/EtOAc 2:1 eluted the unreacted starting compound, then chromatography with hexane/EtOAc 1:1 gave compound 243. Found: [M+H] = 656 .7.

- 65 040011

Example 64 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-(dimethylamino)-6-( ethylthio)pyridin-4-yl)butan-2-ol (244)

Coupling of compound 76 and compound 6. Column chromatography of the crude product eluting with 10-50% EtOAc/hexane gave compound 244. Found: [M+H]=669.7.

Example 65 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-( dimethylamino)butan-2-ol (245)

By coupling compound 80 and compound 6. Column chromatography with 1:1 hexane/EtOAc eluted the unreacted starting compound, then 1:3 hexane/EtOAc followed by 19:1 EtOAc/MeOH eluted compound 245 Found: [M+H]=627.0

Example 66 -yl)butan-2-ol (246)

Coupling of compound 86 and compound 6. Column chromatography with hexane/EtOAc 2:1 eluted the unreacted starting compound, then chromatography with hexane/EtOAc 1:1 gave compound 246. Found: [M+H]=656 .7.

Example 67 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-(dimethylamino)-6-methoxypyridine -4-yl)butan-2-ol (247)

Coupling of compound 90 and compound 6. Column chromatography of the crude product eluting with DCM to remove unreacted starting compound and then with hexane/EtOAc mixtures with increasing eluent concentration gave compound 247. Found: [M+H]=639.7.

Example 68 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)2-(2-(dimethylamino)-6-methoxypyridine -4-yl)butan-2-ol (248)

By coupling compound 120 and compound 93. Repeated flash chromatography of the crude product, eluting with DCM to remove unreacted starting compound, and then with hexane/EtOAc mixtures with increasing concentration of eluent, afforded compound 248. Found: [M+H]=639.7 .

Example 69 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(2-(dimethylamino)-6-ethoxypyridine -4-yl)butan-2-ol (249)

- 66 040011

(249)

Coupling of compound 96 and compound 6. Repeated flash chromatography of the crude product using hexane/EtOAc mixtures with increasing eluent concentration afforded compound 249. Found: [M+H]=653.7.

Example 70 1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(5-isopropoxy-2-methoxypyridin-3 -yl)butan-2-ol (250)

(250)

Coupling of compound 100 and compound 6. Column chromatography of the crude product using 0-5% MeOH/DCM gave compound 250. Found: [M+H]=654.7.

Example 71 1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(4-chloro-2-methoxythiazol-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4 -(dimethylamino)butan-2-ol (251)

(251)

By coupling compound 107 and compound 6. Column chromatography with hexane/EtOAc 9:1 eluted the unreacted starting compound, then hexane/EtOAc 4:1 followed by hexane/EtOAc 2:1 eluted the compound 251. Found: [M+H]=636.6.

Example 72 3-(1-(2,5-Dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2hydroxybutyl)-2-methoxyquinolin-6-carbonitrile (252)

(252)

General procedure for cyanidation.

A solution of compound 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 tri(o-tolyl)phosphine (0.044 g, 0.145 mmol), zinc dust (0.006 g, 0.097 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.067 g, 0.073 mmol) were added and the reaction mixture was again purged with nitrogen and heated for another 10 min at 55°C. Zinc cyanide (0.063 g, 0.533 mmol) was then added and the reaction mixture was heated to 65°C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc three times. The organic layer was washed three times with brine, dried and evaporated. Column chromatography with hexane/EtOAc 1:1 followed by hexane/EtOAc 1:3 gave compound 252 (0.41 g, 74%) as a foamy solid. Found: [M+H]=573.8.

The following compounds were prepared using the General Cyanidation Method. Each bound product was separated 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-carbonitrile (253)

By cyanidation of compound 186 using the general procedure for cyanidation. The crude product was purified by column chromatography. Elution with 0-6% MeOH:DCM afforded compound 253. Found: [M+H]=510.1.

Example 74 3-(2-(Benzofuran-7-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2methoxyquinoline-6-carbonitrile (254)

By cyanidation of compound 188 using the general cyanidation procedure.

The crude product was purified by column chromatography. Elution with 0-6% MeOH:DCM afforded compound 254. Found: [M+H]=510.2.

Example 75 255)

By cyanidation of compound 191 using the general procedure for cyanidation. The crude product was purified by column chromatography. Elution with 0-6% MeOH:DCM afforded compound 255. Found: [M+H]=533.2.

Example 76 6-carbonitrile (256)

By cyanidation of compound 199 using the general procedure for cyanidation. The crude product was purified by column chromatography. Elution with 0-6% MeOH:DCM afforded compound 256. Found: [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- carbonitrile (257)

By cyanidation of compound 201 using the general procedure for cyanidation. The crude product was purified by column chromatography. Elution with 0-6% MeOH:DCM afforded compound 257. Found: [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- carbonitrile (258)

By cyanidation of compound 111 using the general procedure for cyanidation. The crude product was purified by column chromatography. Elution with 0-10% MeOH:DCM afforded compound 258. Found: 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-carbonitrile (259)

- 68 040011

By cyanidation of compound 211 using the general procedure for cyanidation. The crude product was purified by column chromatography. Elution with 0-5% MeOH:DCM afforded compound 259. Found: [M+H]=615.8.

Example 80 3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile (260)

By cyanidation of compound 219 using the general procedure for cyanidation. Column chromatography with EtOAc:hexanes (1:1) gave the front fractions, then compound 260. Found: [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-carbonitrile (261)

By cyanidation of compound 221 using the general procedure for cyanidation. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 261. Found: [M+H]=571.0.

Example 82 3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6 -carbonitrile (262)

n (262)

By cyanidation of compound 229 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (1:2) followed by EtOAc gave the front ends and then compound 262. Found: [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-carbonitrile (263)

(263)

By cyanidation of compound 231 using the general procedure for cyanidation. Column chromatography with EtOAc:hexanes (1:2) followed by EtOAc gave the front ends and then compound 263. Found: [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-carbonitrile (264)

- 69 040011

By cyanidation of compound 223 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (1:1) gave the front fractions, then compound 264. Found: [M+H]=599.2.

Example 85 3-(1-(2,3-Dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2hydroxybutyl)-2-methoxyquinoline -6-carbonitrile (265)

By cyanidation of compound 232 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (1:1) gave the front fractions, then compound 265. Found: [M+H]=552.9.

Example 86 3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinolin-6-carbonitrile (266)

By cyanidation of compound 237 using the general procedure for cyanidation. Column chromatography with EtOAc:hexanes (1:1) gave the front fractions, then compound 266. Found: [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-carbonitrile (267)

By cyanidation of compound 228 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (1:3) gave the front fractions, then compound 267. Found: [M+H]=576.8.

Example 88 3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6 -carbonitrile (268)

By cyanidation of compound 234 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (2:1) gave the front fractions, then compound 268. Found: [M+H]=580.8.

Example 89 3-(2-(2,6-bis(Methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2hydroxybutyl)-2-methoxyquinoline-6 -carbonitrile (269)

- 70 040011

By cyanidation of compound 235 using the general procedure for cyanidation. Column chromatography with EtOAc:hexanes (2:1) gave the front fractions, then compound

269. Found: [M+H]=576.7.

Example 90 )-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile (270)

By cyanidation of compound 236 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (1:1) followed by EtOAc gave compound 270. Found: [M+H]=602.7.

Example 91 3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin5-yl)-4-(dimethylamino) -2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile (271)

By cyanidation of compound 238 using the general cyanidation procedure. Column chromatography with EtOAc:hexanes (2:1) followed by EtOAc gave the fronts followed by compound 271. Found: [M+H]=606.8.

Example 92 3-(2-(2,6-Diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinolin-6-carbonitrile (272)

By cyanidation of compound 227 using the general procedure for cyanidation. Column chromatography with EtOAc:hexanes (1:1) gave the front fractions, then compound 272. Found: [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-carbonitrile (273)

By cyanidation of compound 109 using the general procedure for cyanidation. Column chromatography with EtOAc followed by EtOAc:MeOH (4:1) gave compound 273. Found: [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-carbonitrile (274)

- 71 040011

(274)

By cyanidation of compound 248 using the general procedure for cyanidation except that the reaction mixture was heated at 45°C overnight. Flash chromatography of the crude product using hexane/EtOAc mixtures with increasing eluent concentration gave compound 274 as a bright yellow foam. Found: [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-carbonitrile (275)

(275)

By cyanidation of compound 249 using the general procedure cyanidation except that the reaction mixture was heated at 55°C during the night. Column chromatography of the crude product using hexane/EtOAc mixtures with increasing eluent concentration gave compound 275. Found: [M+H]=600.8.

Example 96 6-carbonitrile (276)

(276)

Cyanidation of compound 250 using the general procedure for cyanidation except that the reaction mixture was heated at 60° C. for 2 hours. Column chromatography of the crude product using hexanes/EtOAc mixtures with increasing concentration of eluent gave compound 276. Found: [M +H]=601.8.

Example 97 3-(2-(2,6-Dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)2-methoxyquinoline-6-carbonitrile (277)

By cyanidation of compound 102 using the general procedure cyanidation except that the reaction mixture was heated at 40°C during the night. Compound 277 was obtained by column chromatography of the crude product using hexane/EtOAc mixtures with increasing eluent concentration and finally 5% MeOH in EtOAc. Found: [M+H] = 516.8.

Example 98 methoxyquinoline-6-carbonitrile (278)

By cyanidation of compound 246 using the general procedure for cyanidation. Compound 278 was obtained by column chromatography of the crude product using 1:1 hexanes/EtOAc. Found: [M+H] = 603.8.

Example 99 Anti-replication activity of M. tuberculosis H ₃₇ Rv.

- 72 040011

The minimum inhibitory concentration (MIC) of representative compounds against M. tuberculosis H ₃₇ Rv (ATCC 27294) was assessed by microplate assay using the Alamar Blue reagent (MABA) using 7H12 medium (Collins, L., and SG Franzblau. 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). Cultures were inhibited in 200 ml medium in 96-well plates for 7 days at 37°C. Added Alamar Blue and Tween 80 and continued incubation for 24 hours at 37°C. Fluorescence was determined at excitation/emission wavelengths of 530/590 nm, respectively. MICs were determined at the minimum concentration providing a 90% reduction in fluorescence relative to controls.

MIC data for typical compounds according to the invention are presented in table. 1.

Table 1

Example M. tuberculosis MIC (µg/mL) cLogP MWt 1 <0.02 6.3 580.51 2 0.07 6.64 545.47 3 0.47 5.59 584.48 4 0.02 5.55 580.51 5 0.02 6.86 642.56 7 0.03 5.61 606.51 9 <0.02 4.77 627.53 10 0.03 5.61 606.51 eleven <0.02 5.94 586.54 12 <0.01 7.41 634.56 13 <0.02 5.8 614.5 14 0.06 6.64 545.47 15 0.02 7.11 561.53 16 <0.02 6.64 642.56 17 <0.01 6.33 628.53 18 <0.01 5.61 655.58 19 <0.01 6.36 655.58 20 <0.02 5.3 641.56 21 <0.02 7.19 634.56

- 73 040011

- 74 040011

64 0.01 6.68 670.66 65 <0.02 5.12 627.53 66 <0.01 5.15 657.55 67 0.01 5.83 640.57 68 0.01 5.08 640.57 69 <0.004 6.36 654.59 70 <0.004 5.96 655.58 71 0.03 5.68 637.97 72 <0.01 3.76 573.64 73 0.08 5.42 509.57 74 0.04 5.42 509.57 75 0.19 4.59 532.65 76 <0.02 5 601.69 77 <0.02 5.84 580.67 78 0.09 4.01 518.63 79 0.01 5.53 615.72 80 0.03 4.58 530.39 81 0.02 4.36 570.64 82 <0.02 4.89 596.6 83 <0.02 3.86 609.62 84 0.03 5.42 598.69

85 0.02 5.45 552.66 86 <0.02 5.08 544.63 87 0.02 4.79 576.68 88 0.01 5.53 580.6 89 0.02 5.74 576.75 90 0.01 5.02 602.77 91 0.02 4.81 606.62 92 <0.02 6.14 572.67 93 0.01 3.78 556.62 94 0.06 3.73 586.68 95 0.03 5.01 600.71 96 <0.004 4.6 601.7 97 0.01 4 516.57 98 <0.01 3.79 603.67

The invention is further described using the following numbered paragraphs: 1. Compound of formula (I)

CH ₃ including any of its stereochemically isomeric forms, where

R ₁ is -phenyl, optionally mono- or bi-substituted independently with lower alkyl, halogen or alkoxy, 5- or 6-membered heteroaryl, optionally mono-, bi- or tri-substituted independently with lower alkyl, halogen, alkoxy, -SCH3, SCH2CH3, - N(CH2CH ₃ )2 or -N(CH ₃ )2, benzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or 5,6,7,8-tetrahydronaphtha

- 75 040011 len-1-yl;

R2 and _R3 are independently hydrogen or lower alkyl;

R4 is -phenyl, optionally mono- or bi-substituted independently with halogen or lower alkyl, 5- or 6-membered heteroaryl, optionally mono-, bi- or tri-substituted independently with alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy, or - N(CH ₃ ) ₂ , benzofuranyl, benzo[b]thiophenyl or 2,3-dihydro-1H-indenyl; And

R ₅ is halogen or cyano, or a pharmaceutically acceptable salt thereof.

2. The compound according to paragraph 1, wherein R1 is unsubstituted phenyl.

3. The compound according to paragraph 1, wherein R1 is phenyl mono- or bi-substituted independently with lower alkyl, halogen or alkoxy.

4. The compound according to paragraph 1, in which R1 is an unsubstituted 5- or 6-membered heteroaryl.

5. The compound according to paragraph 1, wherein R1 is pyridinyl.

6. The compound according to paragraph 1, in which R1 is a 5- or 6-membered heteroaryl, mono-, bi- or tri-substituted independently with lower alkyl, halogen, alkoxy, -SCH ₃ , -SCH ₂ CH ₃ , N(CH2CH3)2 or -N-(CH3)2.

7. The compound according to paragraph 1, in which R1 is pyridinyl mono-, bi- or tri-substituted independently with lower alkyl, halogen, alkoxy, -SCH ₃ , -SCH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ or - N(CH3)2.

8. The compound according to paragraph 1 wherein R1 is pyridinyl mono- or bi-substituted independently with lower alkyl, halogen, alkoxy, -SCH3, -SCH2CH3, -N(CH2CH3)2 or -N-(CH3)2.

9. The compound according to paragraph 1, in which R1 is benzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or 5,6 ,7,8-tetrahydro naphthalen-1-yl.

10. A compound according to paragraph 1, wherein R2 and _R3 independently of one another are hydrogen or methyl.

11. The compound according to paragraph 1, in which both R ₂ and R ₃ are methyl.

12. The compound according to paragraph 1, in which R ₄ represents unsubstituted phenyl.

13. The compound according to paragraph 1, wherein R ₄ is phenyl mono- or bi-substituted independently with halogen or lower alkyl.

14. The compound according to paragraph 1, in which R ₄ represents an unsubstituted 5- or 6-membered heteroaryl.

15. The compound according to paragraph 1, wherein R4 is pyridinyl.

16. A compound according to paragraph 1 wherein R4 is 5- or 6-membered heteroaryl, mono-, bi- or tri-substituted independently with alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy, or -N(CH3)2.

17. The compound according to paragraph 1, wherein R4 is pyridinyl, mono-, bi- or tri-substituted independently with alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy or -N(CH ₃ )2.

18. The compound according to paragraph 1, wherein R4 is pyridinyl mono- or bisubstituted independently with alkoxy, -O-cycloalkyl, -S-lower alkyl, difluoromethoxy or -N(CH ₃ )2.

19. The compound according to paragraph 1, wherein R4 is benzofuranyl, benzo[b]thiophenyl or 2,3-dihydro-1H-indenyl.

20. The compound according to paragraph 1, in which R ₅ represents halogen.

21. The compound according to paragraph 1, in which R ₅ represents bromine, chlorine or iodine.

22. The compound according to paragraph 1, in which R ₅ represents bromine.

23. The compound according to paragraph 1, in which R ₅ represents cyano.

24. A compound according to paragraph 1, wherein said compound is

1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(ttolyl)butan-2-ol;

2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;

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

-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(t-tolyl)butan-2-ol;

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

2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2ol;

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

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

- 76 040011

1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)4-(dimethylamino)butan- 2-ol;

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

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

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

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

2-(benzofuran-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;

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

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

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

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

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

-(6-bromo-2-methoxyquinolin-3-yl)-1 -(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy6-methoxypyridin-4-yl)butan- 2-ol;

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

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

-(6-bromo-2-methoxyquinolin-3-yl)-1 -(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy6-isopropoxypyridin-4-yl)butan- 2-ol;

-(6-bromo-2-methoxyquinolin-3-yl)-1 -(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy6-isopropoxypyridin-4-yl)butan- 2-ol;

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

1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy6-propoxypyridin-4-yl)butane -2-ol;

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

-(6-bromo-2-methoxyquinolin-3-yl)-1 -(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy6-propoxypyridin-4-yl)butan- 2-ol;

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

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

1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy6-isopropoxypyridin-4-yl)butane -2-ol;

1-(6-chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(mtolyl)butan-2-ol;

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

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

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

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

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

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

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

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

- 77 040011

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

2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinolin-3-yl)-1-phenylbutan2-ol;

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

2-(2,6-bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro3-methoxyphenyl)butane -2-ol;

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

2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin4-yl)-4-(dimethylamino )butan-2-ol;

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

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

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

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

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

1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydro-III-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)4-( dimethylamino)butan-2-ol;

1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8tetrahydronaphthalene-1-yl )butan-2-ol;

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

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

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

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

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

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

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

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

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

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

1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2(dimethylamino)-6-(ethylthio)pyridine -4-yl)butan-2-ol;

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

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

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

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

1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2(dimethylamino)-6-ethoxypyridine-4- yl) butan-2-ol;

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

1-(6-bromo-2-methoxyquinolin-3-yl)-1-(4-chloro-2-methoxythiazol-5-yl)-2-(2,6-dimethoxypyridin-4yl)-4-(dimethylamino)butane -2-ol;

- 78 040011

3-(1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinolin-6-carbonitrile;

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

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

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

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

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

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

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

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

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

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

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

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

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

3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybugyl)-2methoxyquinolin-6-carbonitrile;

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

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

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

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-carbonitrile;

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-carbonitrile;

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

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-carbonitrile;

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

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

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

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

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

25. A pharmaceutical composition containing a therapeutically effective amount of a compound according to paragraph 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition containing a therapeutically effective amount of a compound according to paragraph 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A method for the treatment of tuberculosis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to paragraph 1 or a pharmaceutically acceptable thereof

- 79 040011 lemoy salt and a pharmaceutically acceptable carrier.

28. A method of treating tuberculosis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to 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 changes may be made to specific embodiments, but they will still fall within the scope of the appended claims.

Claims (22)

CLAIM 1. Compound of formula (I) CH ₃ or any of its stereochemically isomeric forms, where R ₁ is -5- or 6-membered heteroaryl, optionally mono-, bi- or tri-substituted independently with C ₁ . ₆ alkyl, halogen, C ₁ . ₁₀ alkoxy, -SCH ₃ , -SCH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ or -N(CH ₃ ) ₂ , benzofuranil, 2,3-dihydrobenzo[b][1,4]dioxin-5- yl, 2,3-dihydro-1H-inden-4-yl or 5,6,7,8-tetrahydro-naphthalen-1-yl; R ₂ and R ₃ , independently of each other, are hydrogen or C ₁ . ₆ alkyl; R ₄ is -5- or 6-membered heteroaryl, mono-, bi- or trisubstituted independently with C ₁ . ₁₀ alkoxy, -O-C ₃ . ₈ cycloalkyl, -SC ₁ . ₆ alkyl, difluoromethoxy or -N(CH ₃ ) ₂ , benzofuranyl, benzo[b]thiophenyl or 2,3-dihydro-1H-indenyl; And R5 is halo or cyano, where heteroaryl is heteroaryl containing 1-4 heteroatoms selected from N, O, or S, or 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol; 2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methoxyphenyl)butan-2-ol ; 2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2ol; 2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methoxyphenyl)butan-2-ol ; 2-(benzo[b]thiophen-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)-1-(2fluoro-3-methoxyphenyl)butan-2 -ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)-1(m-tolyl)butan-2-ol; 1-(6-chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methoxyphenyl)butan-2-ol ; 1-(6-chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)butan-2-ol ; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)butan-2-ol ; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamino)-1-phenylbutan-2-ol; 2-(2,6-bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro3-methoxyphenyl)butane -2-ol; - 80 040011 2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2fluoro-3-methoxyphenyl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methylphenyl)butan-2-ol ; 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-methoxy-6(methylthio)pyridin-4-yl )butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl )butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl )butan-2-ol; 2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2fluoro-3-methylphenyl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3methylphenyl)butan-2-ol ; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-4methoxyphenyl)butan-2-ol ; 3-(2-(benzofuran-2-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6carbonitrile; 3-(2-(benzofuran-7-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2methoxyquinoline-6-carbonitrile; 3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2hydroxybutyl)-2-methoxyquinolin-6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2methoxyquinolin-6-carbonitrile; 3-(4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4yl)butyl)-2-methoxyquinoline-6- carbonitrile; 3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2hydroxybutyl)-2-methoxyquinolin-6-carbonitrile; 3-(2-(2,6-bis(methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6- carbonitrile; 3-(2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2methoxyquinolin-6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that R1 is an unsubstituted 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S. 3. A compound according to claim 1, characterized in that R1 is pyridinyl. 4. The compound according to claim 1, characterized in that R1 is a 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, mono-, bi- or tri-substituted independently with C1-6 alkyl, halogen, Smoalkoxy, -SCH3, -SCH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ or -N-(CH ₃ ) ₂ . 5. The compound according to claim 1, characterized in that R1 is pyridinyl mono-, bi- or trisubstituted independently with C ₁ . ₆ alkyl, halogen, _C1-10 alkoxy, -SCH3, -SCH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ or -N(CH3) 2 . 6. The compound according to claim 1, characterized in that R1 is pyridinyl mono- or bisubstituted independently with C ₁ . ₆ alkyl, halogen or C ₁ . ₁₀ alkoxy, -SCH3, -SCH2CH3, -N(CH ₂ CH ₃ ) ₂ or -N(CH3)2. 7. The compound according to claim 1, characterized in that R1 is benzofuranyl, 2,3dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or 5, 6,7,8-tetrahydro naphthalen-1-yl. 8. A compound according to claim 1, characterized in that R2 and R3 are independently hydrogen or methyl. 9. A compound according to claim 1, characterized in that R2 and R3 are both methyl. 10. The compound according to claim 1, characterized in that R4 is a 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, mono-, bi- or trisubstituted independently with _C1-10 alkoxy, -O-C ₃ - ₈ cycloalkyl, -SC ₁ . ₆ alkyl, difluoromethoxy or -N(CH ₃ ) ₂ . 11. A compound according to claim 1, characterized in that R4 is pyridinyl mono-, bi- or trisubstituted independently with C ₁ . ₁₀ alkoxy, -O-C ₃ . ₈ cycloalkyl, -SC ₁ . ₆ alkyl, difluoromethoxy or -N(CH3)2. 12. The compound according to claim 1, characterized in that R ₄ is pyridinyl, mono- or bisubstituted independently with C1_ ₁₀ alkoxy, -O-C ₃ . ₈ cycloalkyl, -SC ₁ . ₆ alkyl, difluoromethoxy or -N(CH ₃ ) ₂ . - 81 040011 13. A compound according to claim 1, wherein R ₄ is benzofuranyl, benzo[b]thiophenyl or 2,3-dihydro-1H-indenyl. 14. A compound according to claim 1, characterized in that R5 is halogen. 15. A compound according to claim 1, characterized in that R ₅ is bromine, chlorine or iodine. 16. The compound according to claim 1, characterized in that R ₅ represents bromine. 17. A compound according to claim 1, characterized in that R ₅ is cyano. 18. The connection, which is 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(m-tolyl)butan-2-ol; 2-(benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4(dimethylamino)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)4-(dimethylamino)butan- 2-ol; 2-(benzofuran-5-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4(dimethylamino)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5methylthiophen-2-yl)butan-2-ol ; 2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,6-diethoxypyridin-4-yl)-4(dimethylamino)butan-2-ol; 2-(benzofuran-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2isopropoxy-6-methoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2isopropoxy-6-methoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy6-methoxypyridin-4-yl)butane -2-ol; 2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6methoxypyridin-4-yl)butan-2-ol ; 2-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)butan-2 -ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy6-isopropoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy6-isopropoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy6-propoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy6-propoxypyridin-4-yl)butane -2-ol; 1-(benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol ; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino )butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy6-isopropoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5-dimethylthiophen-3-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)4-(dimethylamino)butan- 2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2methoxypyridin-3-yl)butan-2-ol ; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4- yl)-4-(dimethylamino)butan-2-ol; 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinolin-3-yl)-1-phenylbutan2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5- yl)-4-(dimethylamino)butan-2-ol; 2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4yl)-4-(dimethylamino )butan-2-ol; 1-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4yl)-4-(dimethylamino )butan-2-ol; - 82 040011 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4- (dimethylamino)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydro-III-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)4-( dimethylamino)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8tetrahydronaphthalene-1-yl )butan-2-ol; 2-(2,6-bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4] dioxin-5-yl)-4-(dimethylamino)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4] dioxin-5-yl)-4-(dimethylamino)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(6-(diethylamino)pyridin-3yl)-4-(dimethylamino)butan- 2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-2methoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6trimethoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6trimethoxypyridin-4-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-(ethylthio) pyridin-4-yl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)4-(dimethylamino)butan- 2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6trimethoxypyridin-3-yl)butane -2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4 -yl)butan-2-ol; 1 -(6-bromo-2-methoxyquinolin-3-yl)-1 -(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridine-4 -yl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridine-4 -yl)butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-isopropoxy-2-methoxypyridin-3-yl )butan-2-ol; 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(4-chloro-2-methoxythiazol-5-yl)-2-(2,6-dimethoxypyridin-4yl)-4-(dimethylamino)butane -2-ol; 3-(1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinolin-6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-methylthiophen-2-yl)butyl)-2methoxyquinolin-6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6 -carbonitrile; 3-(2-(benzofuran-7-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4yl)butyl)-2-methoxyquinoline-6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)-1-(5-methylthiophen-2-yl)butyl)-2methoxyquinolin-6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2hydroxybutyl)-2-methoxyquinolin-6-carbonitrile; 3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2hydroxybutyl)-2 -methoxyquinoline-6-carbonitrile; 3-(2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinolin- 6-carbonitrile; 3-(2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2hydroxybutyl)-2 -methoxyquinoline-6-carbonitrile; 3-(1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinolin- 6-carbonitrile; 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-carbonitrile; 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-carbonitrile; 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-carbonitrile; 3-(1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4yl)-2-hydroxybutyl)-2-methoxyquinoline-6- carbonitrile; - 83 040011 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)2-hydroxybutyl)-2-methoxyquinolin- 6-carbonitrile; 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6 -carbonitrile; or 3-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trim ethoxypyridin-3 yl)butyl)-2-methoxyquinoline- 6-carbo nitrile; or any stereochemically isomeric forms thereof, or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition for the treatment of tuberculosis, containing a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 20. A pharmaceutical composition for the treatment of tuberculosis, comprising a therapeutically effective amount of a compound according to claim 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 21. A method for treating tuberculosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound at π. 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 22. A method of treating tuberculosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.