WO2020047596A1

WO2020047596A1 - Antibacterial compounds and methods of use

Info

Publication number: WO2020047596A1
Application number: PCT/AU2019/050945
Authority: WO
Inventors: Jonathan Baell; Daniel PRIEBBENOW; Lisa BARBARO; Daqing Che
Original assignee: Monash University
Priority date: 2018-09-04
Filing date: 2019-09-04
Publication date: 2020-03-12

Abstract

The present invention generally relates to pyridine derivatives of formula (I) with antibacterial activity, especially anti-tuberculosis activity, and pharmaceutical compositions containing them. Methods of using the compounds to treat bacterial infections, especially tuberculosis infections, are also described.

Description

Antibacterial Compounds and Methods of Use Field of the Invention

[0001] The present invention generally relates to pyridine derivatives with antibacterial activity, especially anti-tuberculosis activity, and pharmaceutical compositions containing them. Methods of using the compounds to treat bacterial infections, especially tuberculosis infections, are also described. Background of the Invention

[0002] Mycobacterium tuberculosis (TB) is currently the biggest infectious killer in the world, fueled by the recent increase in multi-drug resistant infections. In response to the urgent need to combat the rise of resistance, bedaquiline (BDQ) received accelerated approval from the US Food and Drug Administration in 2012. Despite being highly effective against drug-resistant TB as a result of its unique mode of action (inhibition of mycobacterial ATP- synthase), BDQ has been associated with significant toxicities and side effects. For example, BDQ has been associated with hERG mediated cardio toxicity and phospholipidosis. Furthermore, BDQ has a long terminal elimination half-life (due to its lipophilicity) which contributes to toxicity. The high lipophilicity of BDQ (measured log P 7.25) may contribute to the induction of phospholipidosis, observed at high doses in clinical models. The high lipophilicity may also lead to tissue overproportional accumulation at high doses or with daily dosing. Due to these pharmacokinetic properties, bedaquiline is currently dosed three times per week, following a period of once daily loading. Additionally, due to the possibility of tissue overproportional accumulation, efficacy has not been thoroughly explored at higher doses. In light of these toxicities, safety concerns have limited its clinical use.

[0003] There is a need for new treatments for TB, especially multi-drug resistant TB, that have reduced toxicity and/or side effects and/or are suitable for once daily dosing. Summary of the Invention

[0004] In one aspect of the invention, there is provided a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof;

wherein

Ri is selected from one of the following groups:

i) phenyl optionally substituted with one or more substituents

independently selected from Ci-6alkyl, Ci-6alkoxy and halo;

ii) a 5- or 6-membered heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-6alkyl, Ci- 6alkoxy, halo, Ci-6alkylthio, haloalkyl, haloalkoxy or -N(R9)2 iii) benzofuranyl, 2,3-dihydrobenzo[b][2,4]dioxinyl, 2,3-dihydro-lH- indenyl or 5,6,7,8-tetrahydronaphthalenyl;

R₂ is selected from a monocyclic or bicyclic heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-6alkoxy, Ci- ₆haloalkoxy, C3-6cycloalkyloxy, Ci-6alkylthio and N(Ry)2;

R₃ and R₄ are independently selected from hydrogen and Ci-6alkyl;

R₅ and R₇ are independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2- ₆alkynyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, N(R₉)2, -CN, aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2- ₆alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2- ₆alkenyl-, heterocyclylC2-6alkynyl-, C3-6cycloalkyl, C3-6cycloalkylCi-6alkyl-, C3- 6cycloalkylC2-6alkenyl-, C3-6cycloalkylC2-6alkynyl-, halo, -CN and -C(0)Rio; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci- ₆haloalkyl, Ci-6haloalkoxy and S(F)₅; R₆ is selected from aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2-6alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2-6alkenyl-, heterocyclylC2-6alkynyl-, C3- 6cycloalkyl, C₃-6cycloalkylCi-6alkyl-, C₃-6cycloalkylC2-6alkenyl-, C₃-6cycloalkylC2- ₆alkynyl-, halo, -CN and -C(0)Rio; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl, Ci-6haloalkoxy and S(F)₅;

R8 is Ci-6alkyl;

each R9 is independently selected from hydrogen and Ci-6alkyl; and

Rio is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, Ci-6alkoxy and N(R₉)2.

[0005] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as described above, or a

pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

[0006] In a further aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as described above or a pharmaceutically acceptable salt or stereoisomer thereof.

[0007] In yet another aspect of the invention, there is provided a use of a compound of formula (I) as described above or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for treating Mycobacterium tuberculosis infection.

[0008] In yet a further aspect of the present invention, there is provided a compound of formula (I) as described above or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a Mycobacterium tuberculosis infection.

[0009] In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) as described above comprising the step of reacting a compound A

with a compound B

in the presence of a palladium complex, wherein Ri, R₂, R3, R4, R5, R7 and Rs are as defined for formula (I), wherein

(i) X is selected from B(OH)₂, BF3 salt, a boronate ester or a N-methylimino diacetic acid (MID A) protected boronate ester and Y is a leaving group, or

(ii) X is a leaving group and Y is a boronic acid or boronate ester,

Z is an aryl or heteroaryl group, R is halo, Ci-6alkyl, Ci-6alkoxy, -CN, -Ci- ₆haloalkyl, -Ci-6haloalkoxy or S(F)₅ and m is 0, 1 or 2.

Detailed description of the Invention

Definitions

[0010] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below. [0011] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example,“an element” means one element or more than one element.

[0012] As used herein, the term "about" refers to a quantity, level, value, dimension, size, or amount that varies by as much as 30%, 25%, 20%, 15% or 10% to a reference quantity, level, value, dimension, size, or amount.

[0013] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

[0014] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word“comprise” or variations such as“comprises” or“comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

[0015] As used herein, the term "alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, Ci-6alkyl which includes alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, /-propyl, «-butyl, /-butyl, ί-butyl, «-pentyl, 2-methylbutyl,

3-methylbutyl, 4-methylbutyl, «-hexyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 5-methylpentyl, 2-ethylbutyl and 3-ethylbutyl. As used herein, methyl may be represented by“methyl”,“Me”,“CH₃” or may be represented by a bond

[0016] The term“haloalkyl” as used herein refers to an alkyl group in which one or more hydrogen atoms of the alkyl group is replaced with a halo atom. Where

appropriate, the alkyl group may have a specified number of carbon atoms, for example, Ci-6haloalkyl which includes haloalkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, l-fluoroethyl, 2-fluoroethyl, l,l-difluoroethyl, 2,2- fluoroethyl, l,l,2-trifluoroethyl, 2,2,2-trifluoroethyl, l,l,2,2,2-pentafluoroethyl, 3- fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 5-fluoropentyl, 5,5-difluoropentyl, 5,5,5-trifluoropentyl, 6- fluorohexyl, 6,6-difluorohexyl, 6,6,6-trifluorohexyl, chloromethyl, dichloromethyl, trichloromethyl, l-chloroethyl, 2-chloroethyl, l,l-dichloroethyl, 2,2-chloroethyl, 1,1,2- trichloroethyl, 2,2,2-trichloroethyl, l,l,2,2,2-pentachloroethyl, 3-chloropropyl, 3,3- dichloropropyl, 3,3,3-trichloropropyl, 4-chlorobutyl, 4,4-dichlorobutyl, 4,4,4- trichlorobutyl, 5-chloropentyl, 5,5-dichloropentyl, 5,5,5-trichloropentyl, 6-chlorohexyl, 6,6-dichlorohexyl, 6,6,6-trichlorohexyl, bromomethyl, dibromomethyl, tribromomethyl, l-bromoethyl, 2-bromoethyl, l,l-dibromoethyl, 2,2-bromoethyl, l,l,2-tribromoethyl, 2,2,2-tribromoethyl, l,l,2,2,2-pentabromoethyl, 3-bromopropyl, 3,3-dibromopropyl, 3,3,3-tribromopropyl, 4-bromobutyl, 4,4-dibromobutyl, 4,4,4-tribromobutyl, 5- bromopentyl, 5,5-dibromopentyl, 5,5,5-tribromopentyl, 6-bromohexyl, 6,6- dibromohexyl, 6,6,6-tribromohexyl, iodomethyl, diiodomethyl, triiodomethyl, 1- iodoethyl, 2-iodoethyl, l,l-diiodoethyl, 2,2-iodoethyl, l,l,2-triiodoethyl, 2,2,2- triiodoethyl, l,l,2,2,2-pentaiodoethyl, 3-iodopropyl, 3,3-diiodopropyl, 3,3,3- triiodopropyl, 4-iodobutyl, 4,4-diiodobutyl, 4,4,4-triiodobutyl, 5-iodopentyl, 5,5- diiodopentyl, 5,5,5-triiodopentyl, 6-iodohexyl, 6,6-diiodohexyl or 6,6,6-triiodohexyl, and the like.

[0017] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds between carbon atoms and having

2 to 6 carbon atoms. Where appropriate, the alkenyl group may have a specified number of carbon atoms. For example, C2-C6 as in "C2-C6alkenyl" includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0018] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more triple bonds and having 2 to 6 carbon atoms. Where appropriate, the alkynyl group may have a specified number of carbon atoms. For example, C2-C6 as in "C2-C6alkynyl" includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl. [0019] As used herein, the term "cycloalkyl" refers to a saturated cyclic

hydrocarbon. The cycloalkyl ring may include a specified number of carbon atoms.

For example, a 3 to 8 membered cycloalkyl group includes 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0020] As used herein, the term "aryl" is intended to mean any stable, monocyclic or bicyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl and binaphthyl.

[0021] As used herein, the term "halogen" or "halo" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo).

[0022] The term "heteroaryl" as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, lH,3H-l-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, l,2,3-triazolyl, 1,2,4- triazolyl, l,2,4-oxadiazolyl, l,2,4-thiadiazolyl, l,3,5-triazinyl, l,2,4-triazinyl, l,2,4,5-tetrazinyl and tetrazolyl. Particular heteroaryl groups have 5- or 6-membered rings, such as pyrazolyl, furanyl, thienyl, oxazolyl, indolyl, isoindolyl, lH,3H-l- oxoisoindolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, isothiazolyl, l,2,3-triazolyl, l,2,4-triazolyl and l,2,4-oxadiazolyl and l,2,4-thiadiazolyl.

[0023] The term "heterocyclic" or "heterocyclyl" as used herein, refers to a cyclic hydrocarbon in which one to four carbon atoms have been replaced by heteroatoms independently selected from the group consisting of N, N(R_a), S, S(O), S(0)2, O, B, B(R) where R_a is selected from hydrogen, hydroxy, Ci-6alkoxy, Ci-6haloalkyl, Ci-

₆haloalkoxy, aryl optionally substituted with one or more halo atoms such as fluoro, chloro, bromo or iodo, or heteroaryl. A heterocyclic ring may be saturated or unsaturated but not aromatic. Examples of suitable heterocyclyl groups include azetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, dioxazolyl, oxathiozolyl, oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, dithianyl, trithianyl, oxazinyl, borazine, borirane and boroxine.

[0024] As used herein, the terms“alkoxy” and“haloalkoxy” refer to a hydroxy group in which the hydrogen atom has been replaced by an alkyl or haloalkyl group respectively as defined above.

[0025] As used herein, an“alkylthio” group refers to a thiol group (-SH) in which the hydrogen atom has been replaced with an alkyl group as defined above.

[0026] An“arylalkyl”,“heteroaryl alkyl”,“heterocyclylalkyl” or“cycloalkylalkyl” group as used herein refers to an alkyl group in which one hydrogen atom has been replaced with an aryl group, heteroaryl group, heterocyclyl group or cycloalkyl group respectively. Similarly, an“arylalkenyl”,“heteroarylalkenyl”,“heterocyclyl alkenyf’or “cycloalkylalkenyl” group as used herein refers to an alkenyl group in which one hydrogen atom has been replaced with an aryl group, heteroaryl group, heterocyclyl group or cycloalkyl group respectively. Furthermore, an“arylalkynyl”,

“heteroarylalkynyl”,“heterocyclylalkynyl” or“cycloalkylalkynyl” group as used herein refers to an alkynyl group in which one hydrogen atom has been replaced with an aryl group, heteroaryl group, heterocyclyl group or cycloalkyl group respectively.

[0027] It will also be recognised that compounds of the invention possess asymmetric centres and are therefore capable of existing in more than one

stereoisomeric form. The invention thus also relates to compounds in pure or substantially pure isomeric form at one or more asymmetric centres e.g., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution. The compounds of the invention may exist as geometric isomers. The invention also relates to compounds in substantially pure cis (Z) or trans (E) or mixtures thereof.

[0028] The compounds of the invention may be in the form of pharmaceutically acceptable salts. It will be appreciated however that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful as

intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as

hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxy maleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicylic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0029] Base salts include, but are not limited to, those formed with

pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.

[0030] Basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

Compounds and their synthesis

[0031] In one aspect of the invention, there is provided a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof;

wherein

Ri is selected from one of the following groups: i) phenyl optionally substituted with one or more substituents

independently selected from Ci-6alkyl, Ci-6alkoxy and halo;

ii) a 5- or 6-membered heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-6alkyl, Ci- 6alkoxy, halo, Ci-6alkylthio, haloalkyl, haloalkoxy or -N(R₉)2;

iii) benzofuranyl, 2,3-dihydrobenzo[h][2,4]dioxinyl, 2,3-dihydro-lH- indenyl or 5,6,7,8-tetrahydronaphthalenyl;

R₂ is selected from a monocyclic or bicyclic heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-6alkoxy, Ci- ₆haloalkoxy, C₃-6cycloalkyloxy, Ci-6alkylthio and N(R₉₎₂;

R₃ and R₄ are independently selected from hydrogen and Ci-6alkyl;

R₅ and R₇ are independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2- ₆alkynyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, N(R₉)2, -CN, aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2- ₆alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2- ₆alkenyl-, heterocyclylC2-6alkynyl-, C₃-6cycloalkyl, C₃-6cycloalkylCi-6alkyl-, C₃- 6cycloalkylC2-6alkenyl-, C₃-6cycloalkylC2-6alkynyl-, halo, -CN and -C(0)Rio; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci- ₆haloalkyl, Ci-6haloalkoxy and S(F)₅;

R₆ is selected from aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2-6alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2-6alkenyl-, heterocyclylC2-6alkynyl-, C₃- 6cycloalkyl, C3-6cycloalkylCi-6alkyl-, C3-6cycloalkylC2-6alkenyl-, C3-6cycloalkylC2- ₆alkynyl-, halo, -CN and -C(0)Rio; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl and Ci-6haloalkoxy;

R8 is Ci-6alkyl;

each R₉ is independently selected from hydrogen and Ci-6alkyl; and

Rio is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, Ci-6alkoxy and

N(R₉)2.

[0032] In some embodiments, one or more of the following applies: [0033] Ri is selected from phenyl optionally substituted with one, two, three, four or five, especially one or two, substituents independently selected from Ci-₃alkyl, Ci- ₃alkoxy and halo; a 5- or 6-membered nitrogen containing heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-₃alkyl, Ci-₃alkoxy, halo, Ci-₃alkylthio, haloalkyl, haloalkoxy and -N(R9)2; benzofuranyl and tetrahydronaphthyl; especially phenyl optionally substituted with one or two

substituents independently selected from Ci-₃alkoxy and halo; a 6-membered nitrogen containing heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-₃alkyl, Ci-₃alkoxy, halo, -Nth, -NH(Ci-₃alkyl) and - N(Ci-₃alkyl)₂; benzofuranyl and tetrahydronaphthyl; more especially phenyl optionally substituted with one or two substituents independently selected from Ci-₃alkoxy and halo; a pyridinyl group optionally substituted with one or two substituents

independently selected from Ci-₃alkyl, Ci-₃alkoxy, halo, -Nth, -NH(Ci-₃alkyl) and - N(Ci-₃alkyl)₂; benzofuranyl and tetrahydronaphthyl. In particular embodiments, Ri is selected from 2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl, 2,3- dimethoxypyridin-4-yl, l-dimethylamino-6-methoxypyridin-4-yl and 5-isopropoxy-2- methoxypyridin- 3 -y 1.

[0034] R₂ is selected from monocyclic 5 or 6 membered heteroaryl group optionally substituted with one or two substituents independently selected from Ci-6alkoxy, Ci- ₆haloalkoxy, C₃-6cycloalkyloxy, Ci-6alkylthio, Nth, NH(Ci-6alkyl) and N(Ci-6alkyl)₂; especially a 6 membered heteroaryl group optionally substituted with one or two substituents independently selected from Ci-6alkoxy, Ci-6haloalkoxy, C₃-6cycloalkyloxy, Ci-6alkylthio, Nth, NH(Ci-6alkyl) and N(Ci-6alkyl)₂; more especially a 6 membered nitrogen containing heteroaryl group optionally substituted with one or two substituents independently selected from Ci-6alkoxy, Ci-6haloalkoxy, C₃-6cycloalkyloxy, Ci-

₆alkylthio, Nth, NH(Ci-6alkyl) and N(Ci-6alkyl)₂; even more especially a pyridine group optionally substituted with one or two substituents independently selected from Ci-₃alkoxy,-0 CF3, C₃-6cycloalkyloxy and Ci-₃alkylthio. In particular embodiments, R₂ is 2,6-dimethoxypyridin-4-yl, 6-cyclobutyloxy-2-methoxypyridin-4-yl, 2-methoxy-6- trifluoromethoxypyridin-4-yl or 2,6-dimethylthiopyridin-4-yl.

[0035] R3 and R₄ are independently selected from H or Ci-₃alkyl, especially Ci- ₃alkyl, more especially where both R3 and R₄ are methyl. [0036] R₅ is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl,

Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy. N(R9)2, -CN, aryl, heteroaryl, C₃-6cycloalkyl and heterocyclyl, wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci- ₆alkoxy, -CN, Ci-6haloalkyl, Ci-6haloalkoxy, especially hydrogen, Ci-₃alkyl,

C2-₃alkenyl, C2-₃alkynyl, Ci-₃haloalkyl, Ci-₃alkoxy, Ci-₃haloalkoxy, NH2, NH(C 1-3 alkyl), N(Ci-₃alkyl)2 or -CN; more especially hydrogen, Ci-₃alkyl, CF3, Ci-₃alkoxy, CF3O,

NH2, NH(C 1-3 alkyl), N(Ci-₃alkyl)2 and CN, most especially hydrogen.

[0037] R₆ is selected from halo, aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2- ₆alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2-6alkenyl-, heteroarylC2- ₆alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2-6alkenyl-,

heterocyclylC2-6alkynyl-, C₃-6cycloalkyl, C₃-6cycloalkylCi-6alkyl-, C₃-6cycloalkylC2- ₆alkenyl-, C₃-6cycloalkylC2-6alkynyl-; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl, Ci-6haloalkoxy and S(F)₅;

especially bromo, phenyl or 5 or 6 membered heteroaryl wherein each phenyl or heteroaryl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl, Ci-6haloalkoxy and S(F)₅; more especially phenyl or a 6-membered nitrogen containing heteroaryl group wherein each phenyl or heteroaryl is optionally substituted with one or two substituents

independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl, Ci- ₆haloalkoxy and S(F)₅. In some embodiments R₅ is selected from: -Br

[0038] R₇ is is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl,

Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy. N(R9)2, -CN, aryl, heteroaryl, C₃-6cycloalkyl and heterocyclyl, wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci- ₆alkoxy, -CN, Ci-6haloalkyl, Ci-6haloalkoxy, especially hydrogen, Ci-₃alkyl, C2- ₃alkenyl, C2-₃alkynyl, Ci-₃haloalkyl, Ci-₃alkoxy, Ci-₃haloalkoxy, NH2, NH(Ci-₃alkyl), N(Ci-₃alkyl)2 or -CN; more especially hydrogen, Ci-₃alkyl, CF₃, Ci-₃alkoxy, CF₃O,

NFh, NH(C 1-3 alkyl), N(Ci-3alkyl)2 and CN, most especially hydrogen.

[0039] R8 is methyl or ethyl, especially methyl.

[0040] Each R9 is independently selected from hydrogen or Ci-₃alkyl; especially hydrogen or methyl, more especially where each R9 is methyl.

[0041] Rio is selected from Ci-₃alkyl, Ci-₃alkoxy or N(R₉)2, especially Ci-₃alkyl, Ci- ₃alkoxy, NH2, NH(Ci-₄alkyl) or N(Ci-₄alkyl)2, more especially methoxy, NH(Ci-₄alkyl) or N(Ci-₄alkyl)2.

[0042] In particular embodiments, the compound of formula (I) is selected from one of the following:

18

[0043] The compounds of formula (I) have at least two stereogenic centres and therefore may be one of at least 4 diastereoisomers. In some embodiments, the compound is a racemic mixture of diastereoisomers or a mixture in which one, two or three of the diastereoisomers predominate of other diastereoisomers present. In some embodiments, the compound is a pure or substantially pure diastereoisomer. In some embodiments, the disubstituted 4-dialkylaminobutan-2-ol group has the IR,2R, 15,25, IR,2S or 15,25 configuration, especially the 15,25 configuration. By substantially pure is meant at least 90% ee, for example, 95% ee, 98% ee or 99 % ee.

[0044] The compounds of formula (I) may be made using synthetic processes known in the art. In particular embodiments, when the R₆ substituent is an aryl or heteroaryl group, the R₆ substituent is introduced using a Suzuki coupling reaction. In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) comprising the step of reacting a compound A

A with a compound B

B in the presence of a palladium complex, wherein Ri, R₂, R3, R4, R5, R7 and Rs are as defined for formula (I), wherein (i) X is selected from B(OH)₂, BF3 salt, a boronate ester or a N-methylimino diacetic acid (MID A) protected boronate ester and Y is a leaving group, or

(ii) X is a leaving group and Y is a boronic acid or boronate ester,

[0045] In some embodiments, each X is B(OH)₂, BF3 K⁺, a boronate ester selected from 4,4,5,5-tetramethyl-l,3,2-dioxaborolane, bis(neopenylglycolato)diboron, bis(catecholato)diboron or borabicyclo(3.3.l)nonane (9-BBN) or a MIDA protected 4,4,5,5-tetramethyl-l,3,2-dioxaborolane or 9-BBN, more especially B(OH)₂ and Y is halo such as bromo, chloro or iodo or triflate (OTf), mesylate (OMs) or tosylate (OTs) or a pseudohalo group such as cyano, cyapho, isocyano, hydroxy, sulfhydryl, cyanate, isocyanate, fulminate, thiocyanate, isothiocyanate, hypothiocyanite, selenocyanate, azide, N0₂, Co(CO)₄, C(N0₂)₃ or C(CN)₃\ especially bromo.

[0046] In other embodiments, X is halo such as bromo, chloro or iodo or triflate (OTf), mesylate (OMs) or tosylate (OTs) or a pseudohalo group such as cyano, cyapho, isocyano, hydroxy, sulfhydryl, cyanate, isocyanate, fulminate, thiocyanate,

isothiocyanate, hypothiocyanite, selenocyanate, azide, NO_¾ Co(CO)₄, C(N0₂)₃ or C(CN)₃ , especially bromo and Y is B(OH)₂ or a boronate ester such as 4, 4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolane, bis(neopenylglycolato)diboron,

bis(catecholato)diboron or 9-BBN or a MIDA protected 4,4,5,5-tetramethyl-l,3,2- dioxaborolane or 9-BBN, especially 4,4,5,5-tetramethyl-l,3,2-dioxaborolane.

[0047] In some embodiments, the palladium complex is a palladium (0) complex such as Pd(OA_c)₂(P(Ph)₃)₂, Pd(OA_c)₂(P(Ph)₂(Ph-2,4,6-triisopropylphenyl))₂,

PdCl₂(P(Ph)₃)₂, Pd(P(Ph)₃)₄ and PdCl₂[P(Ci-6alkyl₂)(Ph)]₂ where the phenyl group may be substituted with a substituent such as -N(0¾)₂, especially Pd(OA_c)₂(P(Ph)₃)₂ or

Pd(OA_c)₂(P(Ph)₂(Ph-2,4,6-triisopropylphenyl))₂. The palladium complex may be prepared in situ by reacting a palladium (II) compound with a ligand, for example reacting Pd(OA_c)₂ with X-Phos (2’,4^,,6’-triisopropylbiphenyl) to form a Pd(0) complex. In other embodiments, the palladium complex is a palladium (II) complex such as [I,G- bis(diphenylphosphino)ferrocene]dichloropalladium (II). [0048] In some embodiments, the process of preparing the compound of formula (I) further comprises the preparation of a compound A comprising the step of reacting an intermediate C

with an intermediate D

in the presence of a strong base such as anhydrous lithium 2,2,6,6-tetramethyl piperidide, lithium diisopropylamide or lithium /?/.s(tri met h y 1 s i 1 y 1 ) a m i dc . Ri, R₂, R3, R4, R5, R7, R8 and Y are as defined for compound A above.

[0049] In some embodiments, the process of preparing the compound of formula (I) further comprises the preparation of intermediate C comprising the steps of

reacting an alkyl ester

with an amide

in the presence of strong base, followed by reduction. R2, R3 and R₄ are as defined for compound A above.

[0050] In some embodiments, the strong base is lithium diisopropylamide, lithium 2,2,6,6-tetramethyl piperidide, lithium /Asftri methyl si lyljamidc, sodium hydride or potassium i-butoxide, especially lithium diisopropyl amide. [0051] The reduction may be achieved using any suitable reducing agent, for example, LiAlfU or triphenyl borane in the presence of a silane such as 1, 1,3,3 - tetramethyldisiloxane.

[0052] In some embodiments, the process of preparing a compound of formula (I) further comprises the preparation of intermediate D comprising the steps of reacting an intermediate E

with an aldehyde

to give an intermediate F

wherein W is a leaving group, for example, halo, such as chloro, bromo or iodo, tosylate, mesylate or triflate, especially bromo. In some embodiments, both W and Y are the same, especially where both W and Y are both bromo. Ri R₅, R7, Rs and Yare as defined for compound A above. [0053] In some embodiments, the reaction of intermediate E and aldehyde occurs in the present of an organometallic metalation reagent such as /P MgCl-LiCl or .sBuMgCl- LiCl complex.

[0054] Intermediate F may then be reduced to give Intermediate D. Suitable reducing agents include hydrosilanes such as tetraalkyl hydrosilanes, in the presence of a Brpnsted or Lewis acid or an activating nucleophile such as fluoride. An exemplary reducing agent is triethylsilane in the presence of BF₃.0Et_2.

Methods of Treatment

[0055] In another aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt or stereoisomer thereof.

[0056] In yet another aspect of the invention, there is provided a use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for treating a Mycobacterium tuberculosis infection.

[0057] In yet a further aspect of the present invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a Mycobacterium tuberculosis infection.

[0058] In some embodiments, the tuberculosis is a strain susceptible to common antibiotic treatment. In other embodiments, the tuberculosis is a strain that has at least partial resistance to one or more antibiotics commonly used to treat tuberculosis.

Common drugs used to treat tuberculosis are rifampicin, isoniazid, pyrazinamide and ethambutol. In some embodiments, the tuberculosis is multiple drug-resistant tuberculosis. For example, the tuberculosis may be resistant to one or more of rifampicin, isoniazid, pyrazinamide and ethambutol, especially where the tuberculosis is resistant to at least isoniazid or isoniazid and rifampicin.

[0059] The tuberculosis infection may occur in any body part. In some

embodiments, the infection is an infection of the lung, peripheral lymph nodes, kidney, brain, bones, heart, skeletal muscle, pancreas or thyroid, especially tuberculosis infection of the lung. [0060] The subject treated by the method of the present invention is a mammal, for example, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig or non-human primate such as a monkey, chimpanzee, baboon or a rhesus monkey. In particular embodiments, the patient is a human. The term“subject” may be used interchangeably with“patient”.

[0061] In some embodiments, the patient may be suffering from another disease or disorder, for example, a virus, a parasitic infection or diabetes mellitus. In some embodiments, where the patient is a human, the patient may be suffering from human immunodeficiency virus (HIV).

[0062] In some embodiments, the compounds of formula (I) or their

pharmaceutically acceptable salts may be administered together with another therapy. Administration may be in a single composition or in separate compositions

simultaneously or sequentially such that both compounds or therapies are active at the same time in the body. For example, the compounds of formula (I) may be

administered together with one or more antibiotics such as one or more of rifampicin, isoniazid, pyrazinamide, ethambutol, bedaquiline, delamanid, ethionamide, kanamycin, ofloxacin, moxifloxacin, clofazimine, prothionamide and cycloserine/terizidone. In other embodiments, the compounds of formula (I) may be administered together with a treatment for another disease such as HIV. For example, the compounds of the present invention may be administered with an HIV drug selected from abacavir, dolutegravir, lamivudine, rilpivirine, elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, efavirenz, bictegravir, zidovudine, etravirine, nevirapine, delavirdine mesylate, atazanavir, darunavir, lopinavir, ritonavir, fosamprenavir, tipranavir, nelfinavir, indinavir, saquinavfir, efuvirtide and maraviroc or a combination of one or more of these drugs. In some embodiments, the compounds of formula (I) may be administered together with a drug used to treat a parasitic helminth infection, such as benzimidazoles, for example, albendazole and mebendazole;

macrocyclic lactones, for example, ivermectin; praziquantel; oxamniquine and artemisinins. In some embodiments, the compounds for formula (I) may be

administered together with a drug used to treat diabetes mellitus. Such treatments include insulin, and insulin releasing medications, amylinomimetic drugs such as pramlintide; a-glucosidase inhibitors such as acarbose and miglitol; biguanides such as metformin; dopamine agonists such as bromocriptine; DPP-4 inhibitors such as alogliptin, linagliptin, saxagliptin and sitagliptin; incretin mimetics such as albiglutide, dulaglutide, execatide and liraglutide; meglitinidies such as nateglinide and repaglinide; sodium glucose transporter 2 inhibitors such as dapagliflozin, canagliflozin and empagliflozin; sulfonylureas such as glimepiride, glicazide, glipizide, glyburide, chloropropamide, tolazamide and tobutamide; and thiazoloidediones such as rosiglitazone and pioglitazone; or combinations of these drugs.

[0063] The term“treating” as used herein refers to improving at least one symptom of the tuberculosis infection, including curing the infection or improving the symptoms of infection.

[0064] The compounds of the invention may be administered in a therapeutically effective amount. The term“therapeutically effective amount” as used herein means an amount required to reduce the symptoms of the infection or cure the infection. The dose will be adjusted to the individual requirements of the subject being treated and can be within wide limits depending on many factors including severity of the infection, the age and general health of the subject, on concurrent medications with which the subject is also being treated, other diseases from which the subject is suffering and the route of administration. For oral administration, a daily dosage of between about 0.1 and about 1000 mg/kg body weight is a suitable dosage in monotherapy or combination therapy. In some embodiments, the daily dosage is between about 0.1 mg/kg and about 500 mg/kg body weight, 0.1 mg/kg and about 100 mg/kg body weight or 1.0 mg/kg and about 15 mg/kg body weight. Based on a 70 kg person, the dosage range may be in the order of about 70 mg to about 7 g per day. The daily dosage may be administered in a single dosage or may be administer in divided dosages such as 2 to 5 dosages a day. Compositions

[0065] While it is possible that, for use in therapy, a compound of the invention may be administered as a neat chemical, it is preferable to present the active ingredient as a pharmaceutical composition.

[0066] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as described above, or a

pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier. [0067] The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub- cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a

conventional adjuvant, carrier, excipient, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical

compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to two hundred (200) milligrams, per tablet, are accordingly suitable representative unit dosage forms. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of the compound of the invention.

[0068] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0069] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. [0070] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0071] The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0072] For preparing suppositories, a low melting wax, such as admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0073] The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0074] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.

[0075] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

[0076] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0077] For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

[0078] Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0079] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins or formulated with their agents expected to enhance delivery and retention in the nasal mucosa.

[0080] Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

[0081] Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

[0082] The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0083] In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 1 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.

[0084] When desired, formulations adapted to give sustained release of the active ingredient may be employed.

[0085] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0086] In some embodiments, the pharmaceutical composition may include other antibiotics suitable for treating Mycobacterium tuberculosis infection. For example, the pharmaceutical composition may contain one or more of rifampicin, isoniazid, pyrazinamide or ethambutol.

[0087] The invention will now be described with reference to the following Examples which illustrate some preferred aspects of the present invention. However, it is to be understood that the particularity of the following description of the invention is not to supersede the generality of the preceding description of the invention. Examples

Example 1: General Synthetic Procedure

[0088] The compounds of the invention were prepared by the following procedure where an acylpyridine compound was prepared as shown in Scheme 1 or Scheme la:

Scheme la

[0089] A bromopyridine compound was prepared as shown in Scheme 2:

Scheme 2

[0090] The acylpyridine 3 and bromopyridine 5 compounds were coupled and the group equivalent to R₆ was introduced using a Suzuki coupling reaction as shown in Scheme 3 or s:

Scheme 4

[0091] The heteroaryl group shown in Scheme 4 is shown as

indicates that the nitrogen atom may be present at any position in the ring.

[0092] While Schemes 1 to 4 depict the preparation of a particular compounds, a person skilled in the art could adapt this procedure to include other substituents in accordance with the claims using known methods.

Synthesis of Methyl 2,6-dimethoxyisonicotinate (1)

Pyridine Methoxylation

[0093] A solution of 2,6-dichloroisonicotinic acid (0.960 g, 5 mmol) and sodium methoxide (2.16 g, 40 mmol) in MeOH (20 mL, anhydrous) was heated in a microwave reactor at 150 °C for 4 h. After this time, the reaction mixture was cooled to room temperature and transferred into a round bottom flask with an additional 20 mL MeOH. ¾ NMR (400 MHz, MeOD) d = 6.80 (s, 2H), 3.94 (s, 6H) ppm. LR-MS (ESI+) m/z 184.0 [M+H]⁺.

Esterification

[0094] The crude reaction mixture was cooled to 0 °C, followed by the dropwise addition of concentrated H2SO4 (1 mL, 18.8 mmol), and the reaction stirred at reflux for 6 h. After this time, the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was resuspended in CH2CI2 and slowly added to an ice cold solution of Na2C0₃ (saturated, aqueous). The mixture was filtered through a pad of Celite™ and the aqueous layer was extracted with CH2CI2 (x3). The combined organic phases were dried over anhydrous MgSCL, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-5% EtOAc in Pet. Sp.) afforded the title compound 1 as a white solid (0.745 g, 3.78 mmol, 76%). Spectroscopic data are in agreement with the reported literature values.

NMR (400 MHz, CDCb) d = 6.85 (s, 2H), 3.94 (s, 6H), 3.91 (s, 3H) ppm. LR-MS (ESI+) m/z : 198.0 [M+H]⁺.

3-(2,6-Dimethoxypyridin-4-yl)-A,A-dimethyl-3-oxopropanamide (2)

Keto : Enol = 1 : 4.3

[0095] To a solution of anhydrous diisopropylamine (5.93 mL, 42.0 mmol) in THF (100 mL, anhydrous) at -78 °C, and under an atmosphere of nitrogen, was slowly added rz-BuLi (29.1 mL, 1.34 M in hexanes, 39.0 mmol). The mixture was stirred at -78 °C for 1 h, followed by the dropwise addition of A, A-di methyl acetamide (3.07 mL, 33.0 mmol). The reaction mixture was kept stirring at -78 °C for 1 h, followed by the dropwise addition of a solution of 1 (5.92 g, 30.0 mmol) in THF (30 mL, anhydrous). The resulting yellow solution was reacted for an additional 1 h, followed by the addition of NH4CI (saturated, aqueous) to quench the reaction. The reaction mixture was diluted with additional THF, and the organic phase was separated. The aqueous phase was saturated with NaCl and extracted with THF (x5). The combined organic layers were dried over anhydrous MgSCL, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-10% MeOH in CH2CI2) afforded the title compound 2 as a pale-yellow solid (6.72 g, 26.7 mmol, 89%).

NMR (400 MHz, CDCb) d = 6.77 (s, 2H), 4.00 (s, 2H), 3.95 (s, 6H), 3.02 (s, 3H), 2.99

(s, 3H) ppm. Enol peaks:

NMR (400 MHz, CDCb) d = 15.21 (s, 1H), 6.64 (s, 2H), 5.79 (s, 1H), 3.94 (s, 6H), 3.06 (br. s, 6H) ppm. LR-MS (ESI+) m/z: 253.0 [M+H]⁺.

HR-MS (ESI+) m/z [M = C12H16N2O4]: [M+H] ⁺ calc’d 253.1183, found 253.1183. l-(2,6-Dimethoxypyridin-4-yl)-3-(dimethylamino)propan-l-one (3)

[0096] A solution of 2 (2.52 g, 10.0 mmol) in THF (20 mL, anhydrous) was added dropwise to a vigorously stirred suspension of LiAlH₄ in THF (50 mL, anhydrous) at -40 °C and under an atmosphere of nitrogen. The reaction mixture was warmed to room temperature and stirred for 2 h. Upon completion, the reaction mixture was cooled to -40 °C and treated sequentially with the dropwise addition of H2O (1.5 mL), NaOH (1.5 mL, 4 M, aqueous) and H2O (4.5 mL). The mixture was warmed to room

temperature, stirred for 15 min, and dried over Na₂S0₄ for 30 min, followed by filtration. The filtrate was concentrated under reduced pressure and purification of the crude mixture by silica gel flash chromatography (0-10% MeOH in CH2CI2) afforded the title compound 3 as a yellow oil (1.46 g, 6.13 mmol, 61%). Spectroscopic data are in agreement with the reported literature values.

NMR (400 MHz, CDCb) d = 6.73 (s, 2H), 3.94 (s, 6H), 3.06 (t, / = 7.2 Hz, 2H), 2.73 (t, / = 7.2 Hz, 2H), 2.27 (s, 6H) ppm.

LR-MS (ESI+) m/z 239.0 [M+H]⁺.

Alternative Preparation of l-(2,6-Dimethoxypyridin-4-yl)-3- (dimethylamino)propan-l-one (3)

[0097] To a flask containing 2 in CH2CI2 (12.5 mL) was added BPhs (0.121 mg, 0.500 mmol) and TMDS (1.80 mL, 10.0 mmol). The reaction was stirred at room temperature and monitored by TLC. After 1 h, the solvent was removed under reduced pressure, and purification of the crude mixture by silica gel flash chromatography (0-2% MeOH/1% EtsN in CH2CI2) afforded the title compound 3 as a yellow oil (0.911 g, 4.16 mmol, 83%). Spectroscopic data are in agreement with the literature reported values. 'H NMR (400 MHz, CDCb) d = 6.73 (s, 2H), 3.94 (s, 6H), 3.06 (t, 7 = 12 Hz, 2H), 2.73 (t, J = 12 Hz, 2H), 2.27 (s, 6H). LR-MS (ESI+) m/z 239.0 [M+H]⁺.

(5-Bromo-2-methoxypyridin-3-yl)(2-fluoro-3-methoxyphenyl)methanol (4)

[0098] To a solution of 3,5-dibromo-2-methoxypyridine (8.01 g, 30.0 mmol) in

THF (60 mL, anhydrous) at -78 °C and under an atmosphere of nitrogen was added z^'PrMgCl· LiCl (42.7 mL, 0.84 M in THF, 36.0 mmol) dropwise. The reaction was stirred at this temperature for 2 h, followed by the addition of a solution of 2-fluoro-3- methoxybenzaldehyde (6.94 g, 45.0 mmol) in THF (25 mL, anhydrous). The reaction mixture was allowed to warm to room temperature after 30 min at -78°C and kept stirring for an additional 2 h. After this time, the reaction was quenched with a solution of NH4CI (saturated, aqueous), the organic phase separated and the aqueous phase extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over anhydrous MgSCri, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-20% EtOAc in Pet. Sp.) afforded the title compound 4 as a white solid (4.65 g, 13.6 mmol, 45%).

NMR (400 MHz, CDCb) d = 8.12 (d, 7 = 2.4 Hz, 1H), 7.66 (dt, 7 = 2.4, 0.8 Hz, 1H), 7.08 (td, 7 = 8.0, 1.5 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.22 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H) ppm. LR-MS (ESI+) m/z : 341.9 [M+H]⁺. HR-MS (ESI+) m/z [M = CwHisBrFNCb]: [M+H] ⁺ calc’d 342.0136, found 342.0138.

5-Bromo-3-(2-fluoro-3-methoxybenzyl)-2-methoxypyridine (5)

[0099] To a solution of 4 (1.97 g, 5.75 mmol) in CH2CI2 (20 mL, anhydrous) under an atmosphere of nitrogen was added triethylsilane (7.34 mL, 46.0 mmol), and the mixture cooled to 0 °C. Boron trifluoride diethyl etherate (5.67 mL, 46.0 mmol) was added dropwise to the cooled reaction mixture, and the solution stirred at reflux for 16 h. Upon completion, the reaction mixture was cooled to room temperature and added to an ice cold solution of K2CO3 (20% w/v, aqueous). The solution was filtered through a pad of Celite™ with the aid of CH2CI2, and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (x3) and the combined organic layers dried over anhydrous MgS0₄, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-25% EtOAc in Pet. Sp.) afforded the title compound 5 as a white solid on standing (1.71 g, 5.26 mmol, 91%).

NMR (400 MHz, CDCb) d = 8.05 (d, / = 2.4 Hz, 1H), 7.36 (dd, / = 2.3, 0.9 Hz, 1H), 7.00 (td, / = 8.0, 1.5 Hz, 1H), 6.87 (td, / = 8.1, 1.5 Hz, 1H), 6.79 - 6.70 (m, 1H), 3.94 (s, 3H), 3.90 (br. s, 2H), 3.89 (s, 3H) ppm. LR-MS (ESI+) m/z: 325.9 [M+H]⁺. HR-MS (ESI+) m/z [M = CwHisBrFNCE]: [M+H] ⁺ calc’d 326.0186, found 326.0188.

l-(5-Bromo-2-methoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4- (dimethylamino)-l-(2-fluoro-3-methoxyphenyl)butan-2-ol (6)

[00100] To a solution of anhydrous 2,2,6,6-tetramethylpiperidine (0.203 mL, 1.20 mmol) in THF (2 mL, anhydrous) at 0 °C and under an atmosphere of nitrogen was added rc-BuLi (0.974 mL, 1.15 M in hexanes, 1.12 mmol) dropwise. The mixture was stirred at -78 °C for 1 h, after which a solution of 5 (0.286 g, 1.20 mmol) in THF (2 mL, anhydrous) was added dropwise to give a deep rust coloured solution. The reaction mixture was kept stirring at -78 °C for 2 h, after which a solution of 3 (0.261 g, 0.800 mmol) in THF (2 mL, anhydrous) was added dropwise. The mixture was stirred at -78 °C for 4 h, and upon completion the reaction was quenched with NH4CI (saturated, aqueous) and diluted with EtOAc. The organic phase was separated, and the aqueous layer extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over anhydrous MgSCL, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-5% MeOH in CH2CI2) afforded the title compound 6 as a 1:1 mixture of diastereomers (0.204 g, 0.361 mmol, 45%). LR- MS (ESI+) m/z : 583.9 [M+H]⁺. HR-MS (ESI+) m/z [M = C26H_3iBrFN₃0₅]: [M+H] ⁺ calc’d 564.1504, found 564.1517.

[00101] A portion of this product was further separated by preparative HPLC

(eluent: 30% ultrapure H2O/0.l% TFA in MeOH/0.l% TFA; column: Agilent Pursuit XRs Cl 8, 10 mih, 10 mih, 250 x 21.2 mm) into diastereomer A (first to elute) and diastereomer B (second to elute), as the TFA salt.

Diastereomer A (7)

[00102]

11.88 (br s, 1H), 8.37 (d, / = 8.8 Hz, 1H), 8.23 (s, 1H), 8.00 (d, / = 7.4 Hz, 1H), 7.83 (d, / = 8.0 Hz, 1H), 7.67 (d, / = 8.0 Hz, 1H),

7.64 - 7.52 (m, 3H), 7.46 (t, / = 7.4 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.30 (t, / = 7.3 Hz, 1H), 5.47 (s, 1H), 3.68 (s, 3H), 3.28 (s, 3H), 3.14 (t, / = 11.7 Hz, 1H), 3.02 (td, / =

12.3, 11.7, 5.5 Hz, 1H), 2.54 (s, 6H), 2.49 (s, 3H), 2.30 (t, / = 11.2 Hz, 1H), 2.13 - 1.98 (m, 2H) ppm.

Diastereomer B (8)

[00103]

12.84 (br s, 1H), 8.44 (d, J = 8.8 Hz, 1H),

8.23 (s, 1H), 7.86 (d, 7 = 8.1 Hz, 1H), 7.78 (d, / = 7.4 Hz, 1H), 7.70 - 7.59 (m, 2H),

7.53 - 7.47 (m, 1H), 7.32 - 7.27 (m, 1H), 7.06 - 6.94 (m, 2H), 6.97 - 6.86 (m, 3H),

5.61 (s, 1H), 4.10 (s, 3H), 4.02 (s, 3H), 3.19 - 2.95 (m, 2H), 2.66 - 2.38 (m, 6H), 2.39 - 2.17 (m, 1H), 2.15 - 1.96 (m, 1H) ppm.

2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3-methoxyphenyl)-l- (2-methoxy-5-phenylpyridin-3-yl)butan-2-ol (9)

General Suzuki Coupling Procedure:

[00104] To a microwave tube was added 6 (282 mg, 0.500 mmol), Pd(OAc)₂ (5.61 mg, 5 mol%), X-Phos (23.8 mg, 10 mol%), K3PO4 (318 mg, 0.618 mmol), the desired aryl or heteroaryl boronic acid (1.0 mmol) and toluene (2 mL, degassed). The reaction mixture was heated in a microwave reactor at 130 °C for 1 h. After this time the reaction mixture was filtered through a pad of Celite™ with the aid of EtOAc, and the filtrate washed saturated NH4CI (aq). The layers were separated, the aqueous layer extracted with EtOAc (x2), and the combined organic layers were washed with brine, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure.

Purification by silica gel flash chromatography (0-5% MeOH in CH2CI2) afforded the title compound 9 as a 1:1 mixture of diastereomers (211 mg, 0.375 mmol, 75%). LR- MS (ESI+) m/z: 561.9 [M+H]⁺. HR-MS (ESI+) m/z [M = C32H36FN3O5]: [M+H] ⁺ calc’d 562.2712, found 562.2721.

[00105] A portion of this product was further separated by preparative HPLC (eluent: 40% ultrapure H₂O/0.l% TFA in MeOH/0.l% TFA; column: Bondysil-C8 column, 10 pm, 250 x 20 mm) into diastereomer A (first to elute) and diastereomer B (second to elute), as the TFA salt.

Diastereomer A (10)

[00106] ^lH NMR (400 MHz, CDCb) d = 12.57 (br s, 1H), 8.65 (d, 7 = 2.4 Hz, 1H), 8.08 (d, 7 = 2.4 Hz, 1H), 7.46 - 7.42 (m, 4H), 7.38 - 7.29 (m, 1H), 7.03 - 6.96 (m, 2H),

6.89 - 6.82 (m, 1H), 6.56 (s, 2H), 5.26 (s, 1H), 3.89 (s, 3H), 3.84 (s, 9H), 3.34 (t, 7 = 11.4 Hz, 1H), 2.71 - 2.55 (m, 6H), 2.39 - 2.19 (m, 2H), 2.04 (t, 7 = 11.1 Hz, 1H) ppm. Diastereomer B (11)

[00107] ^lH NMR (400 MHz, CDCb) d = 12.03 (br s, 1H), 8.27 (d, 7 = 2.4 Hz, 1H), 7.98 (d, 7 = 2.1 Hz, 1H), 7.67 (ddd, 7 = 7.8, 6.2, 1.5 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.40

(t, 7 = 7.5 Hz, 2H), 7.32 (t, 7 = 7.3 Hz, 1H), 6.84 (td, 7 = 8.2, 1.5 Hz, 1H), 6.65 (td, 7 = 8.1, 1.3 Hz, 1H), 6.51 (s, 2H), 5.38 (s, 1H), 4.12 (s, 3H), 3.86 (s, 6H), 3.72 (s, 3H), 3.28 (t, 7 = 11.8 Hz, 1H), 2.66 (s, 3H), 2.63 (s, 3H), 2.47 - 2.36 (m, 1H), 2.35 - 2.23 (m,

1H), 2.09 (t, 7 = 11.6 Hz, 1H) ppm.

[00108] FTsing the General Suzuki Coupling Procedure above, the following compounds were synthesized.

Example 2: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)- l-(2-methoxy-5-(p-tolyl)pyridin-3-yl)butan-2-ol (12)

[00109] FR-MS (ESI+) m/z 575.9 [M+H]⁺. HR-MS (ESI+) m/z [M =

C33H38FN3O5]: [M+H] ⁺ calc’d 576.2868, found 576.2876.

Diastereomer A (13) [00110]

11.06 (br s, 1H), 8.81 (s, 1H), 8.12 (s, 1H), 7.27 (d, 7 = 8.0 Hz, 2H), 7.20 (d, 7 = 9.6 Hz, 2H), 6.94 (t, 7 = 8.0 Hz, 1H), 6.86 - 6.75 (m, 2H), 6.45 (br s, 2H), 5.15 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.79 (s, 6H), 3.35 - 3.21 (m, 1H), 2.64 (s, 3H), 2.62 (s, 3H), 2.34 (s, 3H), 2.31 - 2.18 (m, 2H), 2.09 - 1.92 (m, 1H) ppm.

Diastereomer B (14)

[00111]

11.09 (br s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.61 (t, 7 = 7.1 Hz, 1H), 7.38 (d, 7 = 7.8 Hz, 2H), 7.22 (d, 7 = 7.6 Hz, 2H), 6.85 (t, 7 = 8.1 Hz, 1H), 6.67 (t, 7 = 8.1 Hz, 1H), 6.49 (s, 2H), 5.37 (s, 1H), 4.21 (s, 3H), 3.87 (s, 6H), 3.73 (s, 3H), 3.33 - 3.21 (m, 1H), 2.69 (s, 3H), 2.67 (s, 3H), 2.45 - 2.27 (m, 5H),

2.18 - 2.02 (m, 1H) ppm.

Example 3: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(2-methoxy-5-(/n-tolyl)pyridin-3-yl)butan-2-ol (15)

[00112] LR-MS (ESI+) m/z : 575.9 [M+H]⁺. HR-MS (ESI+) m/z [M =

C33H38FN3O5]: [M+H] ⁺ calc’d 576.2868, found 576.2879.

Diastereomer A (16)

[00113] ^lH NMR (400 MHz, CDCb) d = 12.62 (br s, 1H), 8.61 (d, 7 = 2.4 Hz, 1H), 8.05 (d, 7 = 2.4 Hz, 1H), 7.31 (t, 7 = 7.5 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.15 (d, 7 = 7.6 Hz, 1H7.03 - 6.93 (m, 2H), 6.90 - 6.81 (m, 1H), 6.57 (s, 2H), 5.25 (s, 1H), 3.89 (s, 3H), 3.84 (s, 6H), 3.82 (s, 3H), 3.41 - 3.28 (m, 1H), 2.69 - 2.58 (m, 6H), 2.44 (s, 3H), 2.39 - 2.20 (m, 2H), 2.11 - 1.99 (m, 1H) ppm.

Diastereomer B (17)

[00114]

11.17 (br s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.62 (ddd, 7 7.8, 6.2, 1.5 Hz, 1H), 7.35 7.25 (m, 3H), 7.16 (d, 7 = 7.0 Hz, 1H), 6.86

(td, 7 = 8.1, 1.5 Hz, 1H), 6.67 (td, 7 = 8.2, 1.4 Hz, 1H), 6.49 (s, 2H), 5.37 (s, 1H), 4.20 (s, 3H), 3.87 (s, 6H), 3.73 (s, 3H), 3.27 (t, 7 = 11.5 Hz, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.48 - 2.22 (m, 5H), 2.10 (t, 7 = 11.0 Hz, 1H) ppm. Example 4: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(2-methoxy-5-(o-tolyl)pyridin-3-yl)butan-2-ol (18)

[00115] LR-MS (ESI+) m/z: 576.0 [M + H]⁺. HR-MS (ESI+) m/z [M =

CssHssFNsOs]: [M+H] ⁺ calc’d 576.2868, found 576.2882.

Diastereomer A (19)

[00116]

11.69 (br s, 1H), 8.07 (s, 1H), 7.80 (d, 7 = 1.9 Hz, 1H), 7.55 (t, 7 = 6.7 Hz, 1H), 7.23 (t, 7 = 2.8 Hz, 4H), 6.82 (td, 7 = 8.2, 1.5 Hz, 1H), 6.65 (td, 7 = 8.1, 1.3 Hz, 1H), 6.48 (s, 2H), 5.37 (s, 1H), 4.15 (s, 3H), 3.86 (s, 6H), 3.73 (s, 3H), 3.26 (t, 7 = 11.4 Hz, 1H), 2.68 (s, 3H), 2.66 (s, 3H), 2.50 - 2.37 (m, 1H),

2.34 - 2.22 (m, 1H), 2.19 - 2.07 (m, 4H) ppm.

Diasteromer B (20)

[00117]

11.76 (br s, 1H), 8.36 (d, 7 = 1.9 Hz, 1H), 7.80 (d, 7 = 2.3 Hz, 1H), 7.26 - 7.12 (m, 3H), 6.98 (dd, 7 = 7.3, 1.3 Hz, 1H), 6.94 (d, 7 = 7.9 Hz, 1H), 6.89 (t, 7 = 6.8 Hz, 1H), 6.81 (t, 7 = 8.0 Hz, 1H), 6.42 (s, 2H), 5.22 (s,

1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.80 (s, 6H), 3.32 - 3.17 (m, 1H), 2.59 (s, 3H), 2.57 (s, 3H), 2.29 - 2.15 (m, 2H), 2.02 (s, 3H), 2.01 - 1.89 (m, 1H) ppm.

Example 5: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(5-(4-fluorophenyl)-2-methoxypyridin-3-yl)butan-2-ol

[00118] LR-MS (ESI+) m/z: 579.8 [M+H]⁺. HR-MS (ESI+) m/z [M =

C32H35F2N3O5]: [M+H] ⁺ calc’d 580.2618, found 580.2625.

Diastereomer A (22) [00119] ^ln NMR (400 MHz, CDCb) d = 11.35 (br s, 1H), 8.72 (d, 7 = 1.7 Hz, 1H),

8.12 (d, 7 = 2.1 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.14 (t, 7 = 8.6 Hz, 2H), 7.01 (t, 7 = 8.0 Hz, 1H), 6.92 - 6.85 (m, 2H), 6.52 (br s, 2H), 5.23 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.86 (s, 6H), 3.43 - 3.27 (m, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.42 - 2.23 (m, 2H), 2.14 - 1.94 (m, 1H) ppm.

Diastereomer B (23)

[00120]

11.11 (br s, 1H), 8.26 (d, 7 = 1.3 Hz, 1H), 8.02 (d, 7 = 1.7 Hz, 1H), 7.63 (ddd, 7 = 7.8, 6.1, 1.5 Hz, 1H), 7.45 (dd, 7 = 8.6, 5.3 Hz, 2H), 7.09 (t, 7 = 8.6 Hz, 2H), 6.86 (td, 7 = 8.2, 1.3 Hz, 1H), 6.67 (td, 7 = 8.2, 1.4 Hz, 1H), 6.50 (s, 2H), 5.37 (s, 1H), 4.17 (s, 3H), 3.87 (s, 6H), 3.73 (s, 3H), 3.29 (t, 7 = 11.4

Hz, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.50 - 2.22 (m, 2H), 2.08 (t, 7 = 11.2 Hz, 1H) ppm. Example 6: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(5-(3-fluorophenyl)-2-methoxypyridin-3-yl)butan-2-ol (24)

[00121] LR-MS (ESI+) m/z: 580.1 [M+H]⁺. HR-MS (ESI+) m/z [M =

C32H35F2N3O5] : [M+H] ⁺ calc’d 580.2618, found 580.2631.

Diastereomer A (25)

[00122] ^lH NMR (400 MHz, CDCb) d = 12.09 (br s, 1H), 8.63 (d, 7 = 2.4 Hz, 1H), 8.08 (d, 7 = 2.5 Hz, 1H), 7.39 (td, 7 = 8.0, 6.0 Hz, 1H), 7.21 (dt, 7 = 7.7, 1.2 Hz, 1H), 7.11 (dt, 7 = 10.1, 2.1 Hz, 1H), 7.08 - 6.96 (m, 2H), 6.93 (ddd, 7 = 7.9, 5.9, 1.7 Hz, 1H),

6.86 (td, 7 = 8.1, 1.3 Hz, 1H), 6.55 (br s, 2H), 5.24 (s, 1H), 3.89 (s, 3H), 3.85 (s, 9H), 3.40 - 3.30 (m, 1H), 2.67 (s, 3H), 2.64 (s, 3H), 2.39 - 2.20 (m, 2H), 2.15 - 1.93 (m, 1H) ppm.

Diastereomer B (26)

[00123] ^lH NMR (400 MHz, CDCb) d = 12.64 (br s, 1H), 8.22 (d, 7 = 2.3 Hz, 1H),

7.91 (d, 7 = 2.4 Hz, 1H), 7.72 (ddd, 7 = 7.9, 6.1, 1.6 Hz, 1H), 7.35 (td, 7 = 7.9, 5.9 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.20 (dt, 7 = 10.1, 2.1 Hz, 1H), 7.04 - 6.96 (m, 1H), 6.85 (td, 7 = 8.2, 1.6 Hz, 1H), 6.65 (td, 7 = 8.3, 1.5 Hz, 1H), 6.53 (s, 2H), 5.38 (s, lH), 4.lO (s, 3H), 3.86 (s, 6H), 3.72 (s, 3H), 3.29 (t, 7 = 11.7 Hz, 1H), 2.64 (s, 3H), 2.59 (s, 3H), 2.42 (td, 7 = 12.1, 6.9 Hz, 1H), 2.23 (t, 7 = 7.6 Hz, 1H), 2.09 - 2.04 (m, 1H) ppm.

Example 7: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(5-(2-fluorophenyl)-2-methoxypyridin-3-yl)butan-2-ol (27)

[00124] LR-MS (ESI+) mlz: 579.8 [M+H]⁺. HR-MS (ESI+) m/z [M =

C32H35F2N3O5] : [M+H] ⁺ calc’d 580.2618, found 580.2627.

Diastereomer A (28)

[00125] ^lH NMR (400 MHz, CDCb) d = 12.47 (br s, 1H), 8.60 (d, 7 = 0.8 Hz, 1H), 8.06 (t, 7 = 2.0 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.24 - 7.15 (m, 1H), 7.18 - 7.08 (m, 1H),

7.03 - 6.96 (m, 2H), 6.91 - 6.80 (m, 1H), 6.53 (br s, 2H), 5.27 (s, 1H), 3.89 (s, 3H),

3.85 (s, 6H), 3.84 (s, 3H), 3.38 - 3.27 (m, 1H), 2.63 (s, 3H), 2.61 (s, 3H), 2.41 - 2.17 (m, 2H), 2.10 - 1.93 (m, 1H) ppm.

Diastereomer B (29)

[00126] ^lH NMR (400 MHz, CDCb) d = 12.02 (br s, 1H), 8.27 (t, 7 = 2.1 Hz, 1H),

7.99 (dd, 7 = 2.5, 1.2 Hz, 1H), 7.61 (ddd, 7 = 7.9, 6.2, 1.5 Hz, 1H), 7.46 (td, 7 = 7.8, 1.9 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.19 (td, 7 = 7.5, 1.3 Hz, 1H), 7.09 (ddd, 7 = 10.7, 8.2, 1.3 Hz, 1H), 6.84 (td, 7 = 8.1, 1.5 Hz, 1H), 6.65 (td, 7 = 8.2, 1.5 Hz, 1H), 6.49 (s, 2H), 5.37 (s, 1H), 4.10 (s, 3H), 3.86 (s, 6H), 3.72 (s, 3H), 3.30 - 3.18 (m, 1H), 2.66 (s, 3H), 2.63 (s, 3H), 2.46 - 2.28 (m, 2H), 2.16 - 2.06 (m, 1H) ppm.

Example 8: l-(5-(4-chlorophenyl)-2-methoxypyridin-3-yl)-2-(2,6- dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3-methoxyphenyl)butan-2- ol (30)

[00127] LR-MS (ESI+) m/z: 595.8 [M+H]⁺. HR-MS (ESI+) m/z [M =

C32H35CIFN3O5]: [M+H] ⁺ calc’d 596.2322, found 596.2335.

Diastereomer A (31)

[00128] ^lH NMR (400 MHz, CDCb) d = 12.70 (br s, 1H), 8.61 (d, / = 2.2 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 6.98 (p, J =

7.2, 6.5 Hz, 2H), 6.86 (t, / = 8.1 Hz, 1H), 6.55 (s, 2H), 5.24 (s, 1H), 3.89 (s, 3H), 3.84 (s, 6H), 3.82 (s, 3H), 3.34 (t, / = 11.2 Hz, 1H), 2.67 - 2.58 (m, 6H), 2.40 - 2.18 (m, 2H), 2.11 - 1.96 (m, 1H) ppm.

Diastereomer B (32)

[00129] ^lH NMR (400 MHz, CDCb) d = 12.48 (br s, 1H), 8.20 (d, / = 2.4 Hz, 1H),

7.89 (d, / = 2.3 Hz, 1H), 7.71 (t, / = 7.1 Hz, 1H), 7.43 (d, / = 8.5 Hz, 2H), 7.35 (d, / = 8.4 Hz, 2H), 6.84 (td, / = 8.1, 1.3 Hz, 1H), 6.64 (td, / = 8.1, 1.1 Hz, 2H), 6.53 (s, 2H), 5.38 (s, 1H), 4.10 (s, 3H), 3.86 (s, 6H), 3.72 (s, 3H), 3.29 (t, / = 11.8 Hz, 1H), 2.64 (s, 3H), 2.59 (s, 3H), 2.50 - 2.36 (m, 1H), 2.32 - 2.17 (m, 1H), 2.05 (t, / = 11.4 Hz, 1H) ppm.

[00130] A portion of diastereomer B was further separated by chiral HPLC (eluent: hexane/EtOH/isopropylamine, 80/20/0.1; column: Chiralpak IG, 5 pm, 250 x 4.6 mm) into its enantiomers Bl (33) (first to elute) and B2 (34) (second to elute).

Example 9: l-(5-(3-chlorophenyl)-2-methoxypyridin-3-yl)-2-(2,6- dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3-methoxyphenyl)butan-2- ol (35)

[00131] LR-MS (ESI+) m/z 576.0 [M + H]⁺. HR-MS (ESI+) m/z [M =

C32H35CIFN3O5]: [M+H] ⁺ calc’d 596.2322, found 596.2337.

Diastereomer A (36)

[00132] ^lH NMR (400 MHz, CDCb) d = 12.33 (br s, 1H), 8.60 (d, / = 2.4 Hz, 1H), 8.04 (d, / = 2.4 Hz, 1H), 7.39 - 7.28 (m, 4H), 7.00 (t, / = 8.0 Hz, 1H), 6.94 (ddd, / = 7.8, 5.9, 1.6 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.56 (br s, 2H), 5.24 (s, 1H), 3.89 (s, 3H), 3.85 (s, 6H), 3.83 (s, 3H), 3.35 (t, 7 = 11.4 Hz, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 2.40 - 2.20 (m, 2H), 2.05 (t, 7 = 11.6 Hz, 1H) ppm.

Diastereomer B (37)

[00133]

12.23 (br s, 1H), 8.21 (d, 7 = 2.3 Hz, 1H), 7.90 (d, 7 = 2.1 Hz, 1H), 7.70 (ddd, 7 = 7.9, 6.1, 1.5 Hz, 1H), 7.45 (t, 7 = 1.8 Hz, 1H),

7.39 (dt, 7 = 7.3, 1.5 Hz, 1H), 7.35 - 7.26 (m, 2H), 6.85 (td, 7 = 8.1, 1.5 Hz, 1H), 6.65 (td, 7 = 8.2, 1.4 Hz, 1H), 6.52 (s, 2H), 5.38 (s, 1H), 4.10 (s, 3H), 3.86 (s, 6H), 3.72 (s, 3H), 3.29 (t, 7 = 11.7 Hz, 1H), 2.65 (s, 3H), 2.61 (s, 3H), 2.49 - 2.34 (m, 1H), 2.34 - 2.18 (m, 1H), 2.12 - 2.04 (m, 1H) ppm.

Example 10: l-(5-(2-chlorophenyl)-2-methoxypyridin-3-yl)-2-(2,6- dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3-methoxyphenyl)butan-2- ol (38)

[00134] LR-MS (ESI+) mlz: 596.0 [M + H]⁺. HR-MS (ESI+) m/z [M =

C32H35CIFN3O5]: [M+H] ⁺ calc’d 596.2322, found 596.2335.

Diastereomer A (39)

[00135] ^lH NMR (400 MHz, CDCb) d = 12.8 (br s, 1H), 8.17 (d, 7 = 2.4 Hz, 1H), 7.89 (s, 1H), 7.64 (t, 7 = 7.0 Hz, 1H), 7.50 - 7.36 (m, 3H), 7.33 - 7.27 (m, 2H), 6.84 - 6.79 (m, 1H), 6.64 (t, 7 = 8.2 Hz, 1H), 6.50 (s, 1H), 5.38 (s, 1H), 4.10 (s, 3H), 3.85 (s, 6H), 3.73 (s, 3H), 3.29 - 3.10 (m, 1H), 2.68 - 2.56 (m, 6H), 2.52 - 2.22 (m, 2H), 2.20 -

2.05 (m, 1H) ppm.

Diastereomer B (40)

[00136]

10.92 (br s, 1H), 8.62 (s, 1H), 8.01 (d, 7 = 2.3 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.35 - 7.31 (m, 2H), 7.19 - 7.15 (m, 1H), 7.01 (td, 7 = 8.0, 1.3 Hz, 1H), 6.94 - 6.85 (m, 2H), 6.48 (s, 2H), 5.27 (s, 1H), 3.98 (s, 3H), 3.90 (s,

3H), 3.87 (s, 6H), 3.40 - 3.27 (m, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.44 - 2.24 (m, 2H), 2.20 - 1.98 (m, 1H) ppm. Example 11: 4-(5-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-2-hydroxybutyl)-6-methoxypyridin-3-yl)benzonitrile (41)

[00137] LR-MS (ESI+) m/z: 587.0 [M + H]⁺. HR-MS (ESI+) m/z [M =

C33H35FN4O5]: [M+H] ⁺ calc’d 587.2664, found 588.2674.

Diastereomer A (42)

[00138]

11.31 (br s, 1H), 8.68 (d, / = 2.3 Hz, 1H),

8.14 (d, / = 2.5 Hz, 1H), 7.72 (d, / = 8.4 Hz, 2H), 7.53 (d, / = 8.4 Hz, 2H), 6.99 (t, / = 8.0 Hz, 1H), 6.87 (t, 2H), 6.53 (br s, 2H), 5.24 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.85 (s, 6H), 3.42 - 3.30 (m, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.42 - 2.21 (m, 2H), 2.13 - 1.95

(m, 1H) ppm.

Diastereomer B (43)

[00139] ^lH NMR (400 MHz, CDCb) d = 11.88 (br s, 1H), 8.25 (d, / = 2.4 Hz, 1H), 7.94 (d, / = 2.3 Hz, 1H), 7.75 - 7.64 (m, 3H), 7.61 (d, / = 8.5 Hz, 2H), 6.85 (td, / = 8.2, 1.5 Hz, 1H), 6.66 (td, / = 8.2, 1.4 Hz, 1H), 6.52 (s, 2H), 5.39 (s, 1H), 4.11 (s, 3H), 3.86

(s, 6H), 3.72 (s, 3H), 3.31 (t, / = 11.8 Hz, 1H), 2.66 (s, 3H), 2.61 (s, 3H), 2.49 - 2.38 (m, 1H), 2.32 - 2.19 (m, 1H), 2.12 - 1.94 (m, 1H) ppm.

[00140] A portion of diastereomer B was further separated by chiral HPLC (eluent: hexane/EtOH/isopropylamine, 80/20/0.1; column: Chiralpak IG, 5 pm, 250 x 4.6 mm) into its enantiomers Bl (44) (first to elute) and B2 (45) (second to elute).

Example 12: 3-(5-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-2-hydroxybutyl)-6-methoxypyridin-3-yl)benzonitrile (46)

[00141] LR-MS (ESI+) m/z: 587.0 [M + H]⁺. HR-MS (ESI+) m/z [M =

C33H35FN4O5]: [M+H] ⁺ calc’d 587.2664, found 587.2672.

Diastereomer A (47)

[00142] ^ln NMR (400 MHz, CDCb) d = 10.83 (br s, 1H), 8.66 (d, 7 = 2.0 Hz, 1H), 8.12 (d, 7 = 2.4 Hz, 1H), 7.69 - 7.62 (m, 3H), 7.56 (t, 7 = 7.7 Hz, 1H), 7.00 (t, 7 = 8.0

Hz, 1H), 6.89 (t, 7 = 8.0 Hz, 1H), 6.82 (t, 7 = 6.9 Hz, 1H), 6.54 (br s, 2H), 5.22 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.88 (s, 6H), 3.44 - 3.29 (m, 1H), 2.72 (s, 3H), 2.71 (s, 3H), 2.40 - 2.28 (m, 2H), 2.17 - 2.05 (m, 1H) ppm.

Diastereomer B (48)

[00143] ^ln NMR (400 MHz, CDCb) d = 12.07 (br s, 1H), 8.22 (d, 7 = 2.3 Hz, 1H),

7.90 (d, 7 = 2.3 Hz, 1H), 7.79 - 7.68 (m, 3H), 7.59 (d, 7 = 7.6 Hz, 1H), 7.50 (t, 7 = 7.8

Hz, 1H6.87 (td, 7 = 8.1, 1.5 Hz, 1H), 6.66 (td, 7 = 8.2, 1.4 Hz, 1H), 6.53 (br s, 2H), 5.39

(s, 1H), 4.11 (s, 3H), 3.86 (s, 6H), 3.73 (s, 3H), 3.31 (t, 7 = 11.7 Hz, 1H), 2.67 (s, 3H),

2.61 (s, 3H), 2.50 - 2.36 (m, 1H), 2.32 - 2.19 (m, 1H), 2.09 - 2.02 (m, 1H) ppm.

Example 13: 2-(5-(2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-2-hydroxybutyl)-6-methoxypyridin-3-yl)benzonitrile (50)

[00144] LR-MS (ESI+) m/z: 586.8 [M+H]⁺. HR-MS (ESI+) m/z [M =

C33H35FN4O5] : [M+H] ⁺ calc’d 587.2664, found 587.2672.

Diastereomer A (50)

[00145] ^lH NMR (400 MHz, CDCb) d = 11.67 (br s, 1H), 8.52 (d, 7 = 2.3 Hz, 1H), 8.11 (d, 7 = 2.4 Hz, 1H), 7.75 (d, 7 = 7.8 Hz, 1H), 7.65 (td, 7 = 7.7, 1.3 Hz, 1H), 7.44 (t, 7 = 7.6 Hz, 1H), 7.32 (d, 7 = 7.8 Hz, 1H), 7.09 (t, 7 = 6.8 Hz, 1H), 7.03 (t, 7 = 8.0 Hz, 1H), 6.87 (t, 7 = 8.0 Hz, 1H), 6.49 (s, 2H), 5.30 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.85 (s, 6H), 3.34 - 3.22 (m, 1H), 2.66 (s, 3H), 2.64 (s, 3H), 2.38 - 2.21 (m, 2H), 2.08 (d, 7 =

12.4 Hz, 1H) ppm.

Diastereomer B (51) [00146]

11.64 (br s, 1H), 8.25 (d, 7 = 2.3 Hz, 1H), 8.05 (d, 7 = 2.3 Hz, 1H), 7.72 (dd, 7 = 7.8, 1.2 Hz, 1H), 7.66 (td, 7 = 7.6, 1.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.44 (td, 7 = 7.5, 1.3 Hz, 1H), 6.83 (td, 7 = 8.0, 1.3 Hz, 1H), 6.66 (td, 7 = 8.2, 1.3 Hz, 1H), 6.48 (s, 2H), 5.37 (s, 1H), 4.11 (s, 3H), 3.86 (s, 6H), 3.73 (s, 3H), 3.20 - 3.10 (m, 1H), 2.66 (s, 3H), 2.65 (s, 3H), 2.49 - 2.34 (m, 2H), 2.18 - 2.06

(m, 1H) ppm.

Example 14: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(2-methoxy-5-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)butan- 2-ol (52)

[00147] LR-MS (ESI+) m/z: 645.8 [M+H]⁺. HR-MS (ESI+) m/z [M =

C33H35F4N3O6]: [M+H] ⁺ calc’d 646.2535, found 646.2538.

Diastereomer A (53)

[00148]

12.29 (br s, 1H), 8.63 (d, 7 = 2.5 Hz, 1H), 8.06 (d, 7 = 2.4 Hz, 1H), 7.44 (d, 7 = 8.7 Hz, 2H), 7.28 (d, 7 = 8.0 Hz, 2H), 7.03 - 6.92

(m, 2H), 6.86 (td, 7 = 8.0, 1.7 Hz, 1H), 6.54 (br s, 2H), 5.25 (s, 1H), 3.89 (s, 3H), 3.84 (s, 9H), 3.34 (t, 7 = 11.1 Hz, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 2.38 - 2.21 (m, 2H), 2.05 (t, 7 = 10.9 Hz, 1H) ppm.

Diastereomer B (54)

[00149] ^lH NMR (400 MHz, CDCb) d = 12.19 (br s, 1H), 8.14 (s, 1H), 7.85 (d, 7 =

2.3 Hz, 1H), 7.63 (t, 7 = 6.8 Hz, 1H), 7.45 (d, 7 = 8.6 Hz, 2H), 7.16 (d, 7 = 8.1 Hz, 2H), 6.77 (t, 7 = 7.7 Hz, 1H), 6.57 (t, 7 = 7.9 Hz, 1H), 6.45 (br s, 2H), 5.31 (s, 1H), 4.03 (s, 3H), 3.79 (s, 6H), 3.64 (s, 3H), 3.21 (t, 7 = 11.2 Hz, 1H), 2.57 (s, 3H), 2.52 (s, 3H), 2.44 - 2.30 (m, 1H), 2.19 (s, 1H), 2.00 (t, 7 = 11.1 Hz, 1H) ppm.

[00150] A portion of diastereomer B was further separated by chiral HPLC (eluent: hexane/IPA/ CfhCh/dicthylamine, 80/10/10/0.1; column: Chiralpak IG, 5 pm, 250 x 4.6 mm) into its enantiomers B l(55) (first to elute) and B2 (56) (second to elute). Example 15: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(6-methoxy-[3,4'-bipyridin]-5-yl)butan-2-ol (58)

Step 1: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-3-yl)butan-2-ol (57)

[00151] To a reaction flask was added 6 (1.00 g, 1.77 mmol), E pim (0.810 g, 3.19 mmol), Pd(dppf)Ch (0.129 mg, 10 mol%), KOAc (0.782, 7.97 mmol), and l,4-dioxane (10 mL, degassed), and the reaction mixture was heated at 85 °C for 21 h. After this time the reaction mixture was cooled to room temperature and filtered through a pad of Celite™ with the aid of EtOAc. The filtrate washed with a solution of NH₄Cl

(saturated, aqueous). The layers were separated, the aqueous layer extracted with EtOAc (x2), and the combined organic layers were washed with brine, dried over anhydrous MgS0₄, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-5% MeOH in CH2CI2) afforded the title compound 57 as brown residue (0.940 mg, 1.54 mmol, 87%, dr = 1:1). HR-MS (ESI+) m/z [M = C₃₂H4₃BFN₃O7]: [M+H] ⁺ calc’d 612.3257, found 612.3264. Step 2: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(6-methoxy-[3,4'-bipyridin]-5-yl)butan-2-ol (58)

General Suzuki Coupling Procedure:

[00152] To a reaction tube was added 57 (122 mg, 0.200 mmol), Pd(dppf)Ch (14.6 mg, 10 mol%), K2CO3 (82.9 mg, 0.600 mmol), the desired pyridyl bromide (0.300 mmol) and l,4-dioxane/water (4:1, 1 mL, degassed). The reaction mixture was heated at 80 °C for 16 h. After this time the reaction mixture was cooled to room temperature and filtered through a pad of Celite™ with the aid of EtOAc. The filtrate washed with a solution of NH4CI (saturated, aqueous), the aqueous layer extracted with EtOAc (x2), and the combined organic layers were washed with brine, dried over anhydrous MgSCU, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-5% MeOH in CH2CI2) afforded the desired Suzuki-coupled product as a 1:1 mixture of diastereomers (103 mg, 0.183 mmol, 92%). A portion of this product was further separated by preparative HPLC (eluent: gradient of 10 to 100% ultrapure H2O/0.l% TFA in MeC/0.l% TFA over 12 min; column: Phenomenex Luna C8(2), 5 pm, 250 x 21.2 mm) into diastereomer A (first to elute) and diastereomer B (second to elute), as the TFA salt.

[00153] LR-MS (ESI+) m/z: 563.9 [M+H]⁺. HR-MS (ESI+) m/z [M =

C31H35FN4O5]: [M+H] ⁺ calc’d 563.2664, found 563.2675.

Diastereomer A (59)

[00154] ^lH NMR (400 MHz, CDCb) d = 11.73 (br s, 1H), 8.90 - 8.73 (m, 3H), 8.32 (d, / = 2.4 Hz, 1H), 7.91 (s, 2H), 6.99 (t, / = 8.0 Hz, 1H), 6.92 - 6.80 (m, 2H), 6.53 (br s, 2H), 5.23 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.84 (s, 6H), 3.40 - 3.25 (m, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.43 - 2.22 (m, 2H), 2.15 - 2.01 (m, 1H) ppm.

Diastereomer B (60)

[00155]

11.91 (br s, 1H), 8.69 (s, 2H), 8.35 (d, J = 2.3 Hz, 1H), 8.03 (d, / = 2.3 Hz, 1H), 7.96 (s, 2H), 7.66 (t, / = 6.8 Hz, 1H), 6.80 (td, / =

8.2, 1.4 Hz, 1H), 6.60 (td, / = 8.3, 1.3 Hz, 1H), 6.46 (br s, 2H), 5.33 (s, 1H), 4.09 (s, 3H), 3.80 (s, 6H), 3.65 (s, 3H), 3.24 (t, / = 11.7 Hz, 1H), 2.61 (s, 3H), 2.56 (s, 3H), 2.41 - 2.31 (m, 1H), 2.27 - 2.15 (m, 1H), 1.94 (t, / = 11.4 Hz, 1H) ppm.

[00156] FTsing the General Suzuki Coupling Procedure above, the following compounds were synthesized.

Example 16: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(6-methoxy-[3,3'-bipyridin]-5-yl)butan-2-ol (61)

[00157] LR-MS (ESI+) m/z: 563.9 [M+H]+. HR-MS (ESI+) m/z [M =

C31H35FN4O5]: [M+H] ⁺ calc’d 563.2664, found 563.2677.

Diastereomer A (62)

[00158] ^lH NMR (400 MHz, CDCb) d = 11.75 (br s, 1H), 8.85 (m, 2H), 8.71 (s, 1H), 8.34 (d, 7 = 7.9 Hz, 1H), 8.15 (s, 1H), 7.91 (br s, 1H), 7.00 (t, 7 = 7.9 Hz, 1H), 6.88 (m, 2H), 6.53 (s, 2H), 5.25 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.85 (s, 6H), 3.41 - 3.26 (m, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 2.38 - 2.22 (m, 2H), 2.11 - 2.01 (m, 1H) ppm.

Diastereomer B (63)

[00159] ^lH NMR (400 MHz, CDCb) d = 12.15 (br s, 1H), 8.93 (br s, 1H), 8.79 (br s, 1H), 8.58 (d, 7 = 7.6 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.84 (br s, 1H), 7.72 (t, 7 = 7.1 Hz, 1H), 6.84 (t, 7 = 8.0, 1H), 6.66 (t, 7 = 7.9 Hz, 1H), 6.54 (br s, 2H), 5.40 (s, 1H),

4.13 (s, 3H), 3.85 (s, 6H), 3.72 (s, 3H), 3.32 (t, 7 = 11.6 Hz, 1H), 2.67 (s, 3H), 2.60 (s, 3H), 2.51 - 2.35 (m, 1H), 2.28 (s, 1H), 2.02 (t, 7 = 11.3 Hz, 1H) ppm.

Example 17: 2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-l-(2-fluoro-3- methoxyphenyl)-l-(6-methoxy-[3,3'-bipyridin]-5-yl)butan-2-ol (64)

[00160] HR-MS (ESI+) m/z [M = C31H35FN4O5]: [M+H] ⁺ calc’d 563.2664, found 563.2674.

Diastereomer A (65)

[00161]

11.73 (br s, 1H), 9.15 (br s, 1H), 8.77 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.86 (d, 7 = 7.3 Hz, 1H), 7.70 (s, lH), 7.l3 (s, 1H), 7.03 (s, 1H), 6.88 (t, 7 = 7.3 Hz, 1H), 6.48 (s, 2H), 5.30 (s, 1H), 3.88 (s, 6H), 3.83 (s, 6H), 3.33 - 3.17 (m, 1H), 2.80 - 2.54 (m, 6H), 2.46 - 2.23 (m, 2H), 2.19 - 2.03 (m, 1H) ppm.

Diastereomer B (66)

[00162]

11.46 (br s, 1H), 9.08 (s, 1H), 8.50 (d, 7 = 2.2 Hz, 1H), 8.35 (t, 7 = 7.8 Hz, 1H), 8.31 - 8.22 (m, 1H), 8.03 (d, 7 = 8.0 Hz, 1H), 7.77

(t, 7 = 6.1 Hz, 1H), 7.70 (ddd, 7 = 7.8, 6.1, 1.5 Hz, 1H), 6.82 (td, 7 = 8.1, 1.5 Hz, 1H), 6.64 (td, 7 = 8.2, 1.4 Hz, lH), 6.5l (s, 2H), 5.41 (s, 1H), 4.15 (s, 3H), 3.86 (s, 6H), 3.70 (s, 3H), 3.26 - 3.12 (m, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 2.52 - 2.37 (m, 2H), 2.07 - 1.95 (m, 1H) ppm.

Example 18: Minimum Inhibitory Concentration (MIC) Assay using Resazurin

[00163] The compounds were tested for activity against tuberculosis MTB H37Rv strain. Rifampacin was used as the positive control and samples without added drug or compound were used as negative controls. The compounds were dissolved in 0.1% DMSO in triple distilled water (TDW). The bacteria were grown in 7H9 media supplemented with ADC enrichment. The following protocol was used.

1. The compounds were serially diluted (1:2 dilutions) in a 96 well plate. Starting concentrations of these compounds are usually 100 mM and at a final volume of 10 pL. Rifampicin was used as the positive control.

2. Mtb H37Rv was grown to an OD of 0.6-0.8 and then on the day of the assay, the culture was diluted to an OD of 0.001 and 90 pL of bacterial suspension was added to the 96 well plate with the compounds.

3. The plate was incubated for 7 days at 37 °C. 10 pL of Resazurin (0.05%) in sterile twice distilled water was added to the wells and incubated continued for a further 24 h.

4 On day 8 the fluorescence was read. Resazurin- excitation 544 nm and emission

590 nm.

5. The results were calculated using Excel and presented Mtb survival as a

percentage of negative control (no drugs controls). [00164] The results are shown in Table 1. Based on these results, it is suggested that

Diastereomer A contains IR,2S and IS,2R stereoisomers and Diasteroisomer B contains 15,25 and IS,2R stereoisomers, Diastereoisomer B 1 is the IR,2R enantiomer and Diastereomer B2 is the lS,2S enantiomer.

Table 1

Example 18: FASTPatch® hERG assay protocol

[00165] The hERG potassium channels (KCNH2 gene, a surrogate for IKr, the rapidly activating, delayed rectifier cardiac potassium current) were stably expressed in HEK293 cells. Test articles were prepared by diluting stock solutions into an appropriate HEPES -buffered physiological saline solution with no more than 0.3% DMSO. Each test article formulation was sonicated (Model 2510/5510, Branson Ultrasonics, Danbury, CT) at room temperature to facilitate dissolution. A glass-lined 96-well compound plate was loaded with the appropriate amounts of test and control solutions, and placed in the plate well of the QPatch HT® or QPatch HTX® (Sophion Bioscience A/S, Denmark). In preparation for a recording session, intracellular solution (130 mM K-Asp, 5 mM MgCh, 5 mM EGTA, 4 mM Tris-ATP) was loaded into the intracellular compartments of the QPlate and cell suspension was pipetted into the extracellular compartments. Vehicle was applied via the QPatch robot pipetting system to naive cells for a 5-10 minute exposure interval. After vehicle application, the test article concentrations were applied in at least three minute intervals in at least two cells (n >2, where n = the number of cells/concentration). Each solution exchange was performed multiple times through the microfluidic flow channel, which resulted in 100% replacement of the compound in the QPlate. Onset and block of hERG current was measured using a stimulus voltage pattern consisting of a 500 ms prepulse to -40 mV (leakage subtraction), a 2-second activating pulse to +40 mV followed by a 2- second test pulse to -40 mV. The pulse pattern was repeated continuously at 10 s intervals from a holding potential of -80 mV. Peak tail current was be measured during the -40 mV test pulse. Leakage current was calculated from the current amplitude evoked by the -40 mV prepulse and subtracted from the total membrane current record.

[00166] Concentration-response data were fit to an equation of the form:

% Inhibition = { l-l/[l+([Test]/IC50) N]}*100

where [Test] was the test article concentration, IC50 was the test article concentration at half-maximal inhibition, N was the Hill coefficient and % Inhibition was the percentage of current inhibited at each test article concentration. Nonlinear least squares fits were solved with the Solver add-in for Excel 2003 (Microsoft, WA) and the IC50 was calculated.

[00167] Bedaquiline was evaluated at 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mM.

Compound 32 was evaluated at 0.1, 1, 3, 10, 33.33, 50, 75 and 100 pM. Cisapride (0.05 pM) was used as a positive control.

[00168] The results are shown in Table 2.

Table 2

[00169] The results suggest that compound 32 has lower inhibitory activity of hERG and therefore suggests a lower risk of cardiotoxicity in comparison to Bedaquiline.

Claims

The claims defining the invention are as follows:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof;

wherein

Ri is selected from one of the following groups:

i) phenyl optionally substituted with one or more substituents

independently selected from Ci-6alkyl, Ci-6alkoxy and halo; ii) a 5- or 6-membered heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-6alkyl, Ci-6alkoxy, halo, Ci-6alkylthio, haloalkyl, haloalkoxy or -N(R9)2;

iii) benzofuranyl, 2,3-dihydrobenzo[h][2,4]dioxinyl, 2,3-dihydro- lH-indenyl or 5,6,7,8-tetrahydronaphthalenyl;

R₂ is selected from a monocyclic or bicyclic heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-6alkoxy, Ci- ₆haloalkoxy, C₃-6cycloalkyloxy, Ci-6alkylthio and N(Ry)2;

R₃ and R₄ are independently selected from hydrogen and Ci-6alkyl;

R₅ and R₇ are independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2- ₆alkynyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, N(R₉)2, -CN, aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2- ₆alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2- ₆alkenyl-, heterocyclylC2-6alkynyl-, C₃-6cycloalkyl, C₃-6cycloalkylCi-6alkyl-, C₃- 6cycloalkylC2-6alkenyl-, C₃-6cycloalkylC2-6alkynyl-, halo, -CN and -C(0)Rio; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci- ₆haloalkyl, Ci-6haloalkoxy and S(F)₅

R₆ is selected from aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2-6alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2-6alkenyl-, heterocyclylC2-6alkynyl-, C3- 6cycloalkyl, C₃-6cycloalkylCi-6alkyl-, C₃-6cycloalkylC2-6alkenyl-, C₃-6cycloalkylC2- ₆alkynyl-, halo, -CN and -C(0)Rio; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl, Ci-6haloalkoxy and S(F)₅;

R8 is Ci-6alkyl;

each R9 is independently selected from hydrogen and Ci-6alkyl; and

N(R₉)2.

2. The compound according to claim 1 wherein Ri is selected from phenyl optionally substituted with one or two substituents independently selected from Ci- ₃alkoxy and halo; a 6-membered nitrogen containing heteroaryl group optionally substituted with one, two or three substituents independently selected from Ci-₃alkyl, Ci-₃alkoxy, halo, -NFh, -NH(Ci-₃alkyl) and -N(C 1-3 alky 1)2; benzofuranyl and tetrahydronaphthyl.

3. The compound according to claim 1 or claim 2 wherein Ri is selected from phenyl optionally substituted with one or two substituents independently selected from Ci-₃alkoxy and halo; a pyridinyl group optionally substituted with one or two substituents independently selected from Ci-₃alkyl, Ci-₃alkoxy, halo, -NFh, -NH(Ci- ₃alkyl) and -N(Ci-₃alkyl)2; benzofuranyl and tetrahydronaphthyl.

4. The compound according to any one of claims 1 to 3 wherein R2 is selected from a 6 membered heteroaryl group optionally substituted with one or two substituents independently selected from Ci-6alkoxy, Ci-6haloalkoxy, C₃-6cycloalkyloxy, Ci- ₆alkylthio, NFh, NH(Ci-6alkyl) and N(Ci-6alkyl)2.

5. The compound according to claim 4 wherein R2 is selected from a pyridine group optionally substituted with one or two substituents independently selected from Ci-₃alkoxy, CF3, C₃-6cycloalkyloxy and Ci-₃alkylthio.

6. The compound according to any one of claims 1 to 5 wherein R₃ and R₄ are each methyl.

7. The compound according to any one of claims 1 to 6 wherein Rs is hydrogen, Ci-salkyl, CFs, Ci-salkoxy, OCFs, NFh, NH(C 1-3 alkyl), N(Ci-3alkyl)₂ or CN.

8. The compound according to any one of claims 1 to 7 wherein R₆ is selected from halo, aryl, arylCi-6alkyl-, arylC2-6alkenyl-, arylC2-6alkynyl-, heteroaryl, heteroarylCi-6alkyl-, heteroarylC2-6alkenyl-, heteroarylC2-6alkynyl-, heterocyclyl, heterocyclylCi-6alkyl-, heterocyclylC2-6alkenyl-, heterocyclylC2-6alkynyl-, C3- 6cycloalkyl, C₃-6cycloalkylCi-6alkyl-, C₃-6cycloalkylC2-6alkenyl- and C₃-6cycloalkylC2- ₆alkynyl-; wherein each aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci- ₆alkoxy, -CN, Ci-6haloalkyl and Ci-6haloalkoxy.

9. The compound according to claim 8 wherein R₆ is selected from bromo or a phenyl or a 6-membered nitrogen containing heteraryl group wherein each phenyl or heteroaryl is optionally substituted with one or two substituents independently selected from halo, Ci-6alkyl, Ci-6alkoxy, -CN, Ci-6haloalkyl and Ci-6haloalkoxy.

10. The compound according to any one of claims 1 to 9 wherein R₇ is hydrogen, Ci-salkyl, CF₃, Ci-salkoxy, OCF₃,NH₂, NH(C 1-3 alkyl), N(Ci-3alkyl)₂ or CN.

11. The compound according to any one of claims 1 to 10 wherein Rs is methyl.

12. The compound according to claim 1 selected from:

13. A compound according to claim 12 selected from:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

15. A process for the preparation of a compound according to any one of claims 1 to 13 comprising the step of reacting a compound A

with a compound B

in the presence of a palladium complex, wherein Ri, R₂, R3, R4, R5, R7 and Rs are as defined for formula (I) in claim 1, wherein

(i) X is selected from B(OH)₂, BF3 salt, a boronate ester or a N-methylimino diacetic acid (MID A) protected boronate ester and Y is a leaving group, or (ii) X is a leaving group and Y is selected from a boronic acid or boronate ester, Z is an aryl or heteroaryl group, R is halo, Ci-6alkyl, Ci-6alkoxy, -CN, -Ci- ₆haloalkyl, -Ci-6haloalkoxy or S(F)₅ and m is 0, 1 or 2.

16. The process according to claim 13 wherein each X is selected from B(OH)₂,

BF3 , K⁺, a boronate ester selected from 4,4,5,5-tetramethyl-l,3,2-dioxaborolane or - borabicyclo(3.3.l)nonane (9-BBN) or a MIDA protected 4,4,5,5-tetramethyl-l,3,2- dioxaborolane or 9-BBN.

17. The process according to claim 13 or claim 14 wherein Y is halo, triflate, mesylate or tosylate.

18. The process according to any one of claims 13 to 17 wherein the palladium complex is selected from Pd(OA_c)₂(P(Ph)₃)_2’ Pd(OA_c)₂(P(Ph)₂(Ph-2,4,6- triisopropylphenyl))₂ and [ 1 , 1’ -bis(diphenylphosphino)ferrocene]dichloropalladium (II).

19. The process according to any one of claims 13 to 18 further comprising the preparation of a compound A, wherein compound A is prepared by a process comprising the step of reacting an intermediate C

with an intermediate D

in the presence of a strong base; wherein Ri, R2, R3, R4, R5, R7 and Rs are as defined for compound A in claim 14.

20. The process according to claim 19 further comprising the preparation of an intermediate C comprising the steps of

reacting an alkyl ester

with an amide

in the presence of strong base, followed by reduction; wherein R₂, R3 and R₄ are as defined for compound A in claim 13.

21. The process according to claim 19 further comprising the preparation of intermediate D comprising the steps of reacting an intermediate E

with an aldehyde

to give intermediate F

F wherein W is a leaving group and wherein Ri, R₅, R7, Rs and Y are defined for compound A in claim 14; and reducing intermediate F to give intermediate D as defined in claim 19.

22. A method of treating a Mycobacterium tuberculosis infection comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or stereoisomer thereof.

23. Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for treating a Mycobacterium tuberculosis infection

24. A compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a Mycobacterium tuberculosis infection.