WO2012069856A1

WO2012069856A1 - Antimalarial compounds

Info

Publication number: WO2012069856A1
Application number: PCT/GB2011/052345
Authority: WO
Inventors: Paul O'neill; Giancarlo Biagini; Stephen A. Ward; Neil Graham Berry; Gemma Nixon; Richard K. Amewu; Chandrakala Pidathala; Weiqian David Hong; Peter Gibbons; Suet Ching Leung; Bénédicte PACOREL; Raman Sharma; Alexandre S. Lawrenson; Alison E. Shone; Abhishek Srivastava; Ashley J. Warman
Original assignee: Liverpool School Of Tropical Medicine
Priority date: 2010-11-26
Filing date: 2011-11-28
Publication date: 2012-05-31
Also published as: GB201020076D0

Abstract

The present invention relates to antimalarial compounds. More specifically, the present invention relates to novel substituted quinolone derivatives of formula (I) and related quinoline derivatives of formula (II) as defined herein that possess potent antimalarial activity. The present invention also relates to processes for the preparation of these quinolone and quinoline derivatives, to pharmaceutical compositions comprising them and to their use as therapeutic agents for the treatment and/or prevention of malaria.

Description

ANTIMALARIAL COMPOUNDS

FIELD OF THE INVENTION

[0001] The present invention relates to antimalarial compounds. More specifically, the present invention relates to novel substituted quinolone derivatives and related quinoline derivatives that possess potent antimalarial activity. The present invention also relates to processes for the preparation of these quinolone and quinoline derivatives, to pharmaceutical compositions comprising them and to their use as therapeutic agents for the treatment and/or prevention of malaria.

BACKGROUND OF THE INVENTION

[0002] Malaria is a major cause of morbidity and mortality, particularly in tropical and subtropical regions. It is estimated that there are nearly more than 243 million cases of malaria each year, which results in over one million deaths [Snow et al. Nature, 2005, 434, 214-217;

Greenwood et al. Lancet, 2005, 365 1487-1498]. The majority of malaria-related deaths (over 90%) occur in sub-Saharan Africa.

[0003] Malaria is a mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. Five species of the plasmodium parasite can infect humans: the most serious forms of the disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is not generally fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans and can cause severe malaria.

[0004] Malaria is naturally transmitted by the bite of a female Anopheles mosquito. When a mosquito bites an infected person, a small amount of blood is taken, which contains the malaria parasites. These parasites develop within the mosquito, and approximately one week later, when the mosquito takes its next blood meal, the parasites are injected with the mosquito's saliva into the person being bitten. After a period of between two weeks and several months (occasionally years) spent in the liver, the malaria parasites start to multiply within red blood cells, causing symptoms that include fever, and headache. In severe cases, the disease worsens leading to hallucinations, coma, and death. [0005] A wide variety of antimalarial drugs are currently available. However, antimalarial drug therapy is plagued by the emergence of drug resistant strains of malaria. In recent years, the treatment of Plasmodium falciparum infections in endemic countries has been transformed by the use of an antimalarial drug combination, which includes an artemisinin derivative [White et al., Med. Trop. 1998, 58, 54-56]. However, the recent emergence of malarial strains that are resistant to this drug combination in certain Asian countries [Noedl et al, N. Engl. J. Med., 2009, 361, 540-541] highlights the need to develop new and effective antimalarial agents. In particular, there is a need for new antimalarial agents that act by novel mechanisms of action.

[0006] It is therefore an object of the present invention to provide new and potent antimalarial agents.

[0007] It is a further object of the present invention to provide antimalarial agents that act by a novel mechanism of action.

SUMMARY OF THE INVENTION

[0008] The present invention resides in the identification of novel quinolone and quinoline derivatives which display antimalarial activity. Without wishing to be bound by any particular theory, it is believed that the activity of the novel quinolone and quinoline derivatives is at least partially due to their ability to act as inhibitors of parasite mitochondrial type II NADH: quinone oxidoreductase (PfNDH2). PfNDH2 is believed to be a novel antimalarial target that has been identified in the mitochondrion of the human malarial parasite, Plasmodium falciparum [Fisher et al, Trends in Parasitology, 2007, 23, 7, 305-310]. Certain quinolone and quinoline derivatives of the present invention may also function as inhibitors of other enzymes of the mitochondrial electron transport chain, such as, for example, bci.

[0009] Therefore, in a first aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0011] In another aspect, the present invention provides a method of inhibiting parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species in vitro or in vivo, said method comprising contacting said Plasmodium species with an effective amount of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, for use in the inhibition of parasite mitochondrial type II NADH: quinone

oxidoreductase in a Plasmodium species in an individual in need of such inhibition.

[0013] In another aspect, the present invention provides the use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species.

[0014] In another aspect, the present invention provides use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, for the inhibition of parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species in vitro or in vivo.

[0015] In an embodiment, the Plasmodium species is Plasmodium falciparum.

[0016] In a particular embodiment, the Plasmodium species is multi-drug resistant Plasmodium falciparum.

[0017] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein for use in therapy.

[0018] In another aspect the present invention provides a method of treating malaria, said method comprising administering a therapeutically effective amount of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[0019] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of malaria.

[0020] In another aspect, the present invention provides the use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of malaria.

[0021] In another aspect the present invention provides a method of treating malaria, said method comprising administering a therapeutically effective amount of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment in combination with one or more additional antimalarial agents. [0022] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional antimalarial agents for use in the treatment of malaria.

[0023] In another aspect, the present invention provides the use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of malaria in combination with one or more additional antimalarial agents.

[0024] The present invention further provides a method of synthesising a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein.

[0025] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0026] In another aspect, the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0027] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0028] It is to be appreciated that references to "treating" or "treatment" include prophylaxis as well as the alleviation of established symptoms of malaria. "Treating" or "treatment" of malaria therefore includes: (1) preventing or delaying the appearance of clinical symptoms of malaria in a human that may be afflicted with or exposed to malarial parasites, but does not yet experience or display clinical or subclinical symptoms of malaria, (2) inhibiting malaria, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, (3) relieving or attenuating the disease, i.e., causing regression of the malaria infection or at least one of its clinical or subclinical symptoms, or (4) blocking the transmission of malaria by, for example, the eradication of gametocytes.

[0029] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.

[0030] In this specification the term "alkyl" includes both straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only. For example, "(l-6C)alkyl" includes (l-4C)alkyl, (l-3C)alkyl, propyl, isopropyl and i-butyl. A similar convention applies to other radicals, for example "phenyl(l-6C)alkyl" includes phenyl(l-4C)alkyl, benzyl, 1-phenylethyl and

2-phenylethyl.

[0031] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0032] An "alkylene," is an alkyl group that is positioned between and serves to connect two other chemical groups.

[0033] "(3-8C)cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0034] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-l- yl, or cyclooctenyl.

[0035] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0036] The term "(l-3C)alkoxycarbonyl" is used herein to denote a substituent of the formula - C(0)0-(l-3C)alkyl. Accordingly, this term covers methyl, ethyl and propyl ester substituents.

[0037] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic or bicyclic heterocyclic ring system. The term heterocyclyl includes both monovalent species and divalent species. Monocyclic heterocyclic rings contain from about 3 to 10 (suitably from 4 to 7) ring atoms, with from 1 to 4 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulphur in the ring. Bicyclic heterocycles contain from 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulphur containing heterocycles include tetrahydrothienyl, dihydro-l,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. For heterocycles containing sulphur , the oxidized sulphur heterocycles containing SO or S0₂ groups are also included. Particular heterocyclyl groups are saturated monocyclic 4 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur , for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1,1 -dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable heterocyclic ring atom, such as via a carbon or nitrogen atom. [0038] The term "heteroaryl" or "heteroaromatic" means an aromatic mono- or bi-cyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulphur . The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom.

[0039] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, lH-pyrazolo[4,3-d]-oxazolyl,

4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo [2, 1-b] thiazolyl,

imidazo[l,2-b][l,2,4]triazinyl. "Heteroaryl" also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulphur . Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[l,4]dioxinyl, benzo[l,3]dioxolyl, 2,2-dioxo-l,3-dihydro-2-benzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, l,2,3,4-tetrahydro-l,8-naphthyridinyl,

1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b] [1 ,4]oxazinyl

[0040] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0041] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0042] The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0043] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by

heterocyclyl.

[0044] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0045] Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0046] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.

Compounds of the invention

[0047] According to a first aspect of the present invention there is provided a compound of formula I or formula II shown below

I II

wherein:

Y is N or CH;

n is 0, 1 or 2;

X is selected from fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, methoxy, heterocyclyl, a prodrug moiety, with the proviso that when n is 2, each X group present may be the same or different;

R¹ is selected from hydrogen, halo (e.g. chloro or bromo), methyl, ethyl, hydroxyl, CH₂OH,, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -0-, -C(R¹⁰R^u)-O-, -S-, -SO-, -S0₂-, -N(R¹⁰)-, -C(O)-, -CH(OR¹⁰)-, -C(0)N(R¹⁰)-, -N(R¹⁰)C(O)-, -C(0)0-, -OC(O)-, -N(R¹⁰)C(O)N(R^u)-, -S(0)₂N(R¹⁰)-, or -N(R¹⁰)SO₂-, wherein R¹⁰ and R¹¹ are each independently selected from hydrogen or (1-

4C)alkyl;

Q¹ is selected from hydrogen, (l-6C)alkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl or (l-4C)alkoxy;

or L¹ is -O- or -C(R¹⁰Rⁿ)-O- and Q¹ is a prodrug moiety;

R² is a group

-Q³-L²-Q²

wherein: Q 3 is selected from aryl, heterocyclyl or heteroaryl, wherein Q 3 is optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy;

L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, -C(O)-, -CH(OR¹²)-, -C(0)N(R¹²)-, -N(R¹²)C(0)-, -C(0)0-, -OC(O)-, -N(R¹²)C(0)N(R¹³)-,

-S(0)₂N(R¹²)-, or -N(R¹²)S0₂-, wherein R¹² and R¹³ are each independently selected from hydrogen or (l-4C)alkyl;

Q is selected from aryl, heterocyclyl, or heteroaryl, , each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, (l-3C)alkoxycarbonyl (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl or (l-4C)alkoxy, wherein any (l-3C)alkoxycarbonyl, (1- 4C)alkyl or (l-4C)alkoxy group present as a substituent(s) of Q may optionally be substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl;

R is selected from hydrogen, hydroxy, (l-6C)alkyl, aryl or aryl-(l-2C)alkyl;

R⁴ is selected from hydrogen or a prodrug moiety;

or a pharmaceutically acceptable salt thereof.

[0048] According to another aspect of the present invention there is provided a compound of formula I or formula II shown below

wherein:

Y is N or CH;

n is 0, 1 or 2; X is selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, methoxy or a prodrug moiety;

R¹ is selected from hydrogen, methyl, hydroxyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -0-, -C(R¹⁰R^u)-O-, -S-, -SO-, -S0₂-, -N(R¹⁰)-, -C(O)-, -CH(OR¹⁰)-, -C(0)N(R¹⁰)-, -N(R¹⁰)C(O)-, -C(0)0-, -OC(O)-, -N(R¹⁰)C(O)N(R^u)-, -S(0)₂N(R¹⁰)-, or -N(R¹⁰)SO₂-, wherein R¹⁰ and R¹¹ are each independently selected from hydrogen or (1- 4C)alkyl;

or L¹ is -O- or -C(R¹⁰Rⁿ)-O- and Q¹ is a prodrug moiety;

R is selected from (3-8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl, wherein R is optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy, or a group

-IAQ²

wherein:

L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, -C(O)-,

-CH(OR¹²)-, -C(0)N(R¹²)-, -N(R¹²)C(0)-, -C(0)0-, -OC(O)-, -N(R¹²)C(0)N(R¹³)-,

Q is selected from hydrogen, (l-6C)alkyl, aryl, heterocyclyl, heteroaryl, aryl-(l-2C)alkyl, heterocyclyl-(l-2C)alkyl, or heteroaryl-(l-2C)alkyl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl or (l-4C)alkoxy;

R is selected from hydrogen, hydroxy, (l-6C)alkyl, aryl or aryl-(l-2C)alkyl;

R⁴ is selected from hydrogen or a prodrug moiety;

or a pharmaceutically acceptable salt thereof. [0049] When X is a prodrug moiety it is suitably an in vivo hydrolysable ester, such as a phosphate or amino acid ester.

[0050] When Q¹ is a prodrug moiety it is suitably an in vivo hydrolysable ester, such as a phosphate or amino acid ester. [0051] When R⁴ is a prodrug moiety it is suitably an in vivo hydrolysable ester, such as a phosphate or amino acid ester.

[0052] When n is 2, each X group substitutent is selected from the options set out herein and may be the same or different.

[0053] Particular novel compounds of the invention include, for example, compounds of the formula I or formula II, or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of n, X, Y, R 1 , R 2 , Q 3 , L 2 , Q 2 , R 3 and R 4 has any of the meanings defined hereinbefore or in any of paragraphs (1) to (66) hereinafter:-

(1) Y is N;

(2) Y is CH;

(3) n is 0, 1 or 2 and, when n is 1, the X substituent is in the 5-, 6-, 7- or 8-position of the quinolone ring of formula I or the quinoline ring of formula II and, when n is 2, the X substituents are in the 5-, 6- or 7-positions of the quinolone ring of formula I or the quinoline ring of formula II;

(4) n is 0, 1 or 2 and, when n is 1, the X substituent is in the 6- or 7-position and, when n is 2, the X substituents are in the 6- and 7-positions of the quinolone ring of formula I or the quinoline ring of formula II;

(5) n is O or l;

(6) n is 0;

(7) n is i;

(8) n is 2;

(9) X is selected from fluoro, chloro or a prodrug moiety;

(10) X is chloro or a prodrug moiety;

(11) X is chloro;

(12) X is a prodrug moiety;

(13) X is selected from fluoro, chloro, methoxy;

(14) X is fluoro; (15) n is 2 and one X group is fluoro and the other is methoxy (i.e. Xi=F and X₂=OMe);

(16) Ri is selected from hydrogen, methyl, ethyl, hydroxyl, CH₂OH, chloro, bromo, or R¹ is a group of the formula:

-L'-Q¹

wherein:

or L¹ is -O- or -C(R¹⁰Rⁿ)-O- and Q¹ is a prodrug moiety

(17) R¹ is selected from hydrogen, methyl, hydroxyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -0-, -C(R¹⁰R^u)-O-, -N(R¹⁰)-, -C(O)-, -C(0)N(R¹⁰)-, -N(R¹⁰)C(O)-, -C(0)0-, or -OC(O)-, wherein R¹⁰ is selected from hydrogen or (l-2C)alkyl;

Q¹ is selected from hydrogen, (l-4C)alkyl, phenyl, a 4-, 5- or 6-membered heterocyclyl or a 4-, 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy;

or L¹ is -O- or -CH₂-0- and Q¹ is a prodrug moiety;

(18) R¹ is selected from hydrogen, methyl, hydroxyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -C(O)-, -C(0)N(R¹⁰)-, -N(R¹⁰)C(O)-, or -C(0)0-, wherein R¹⁰ is hydrogen or methyl; Q¹ is selected from hydrogen, (l-2C)alkyl or phenyl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy;

or L¹ is -O- or -CH₂-0- and Q¹ is a prodrug moiety;

(19) R¹ is selected from hydrogen, methyl, hydroxyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -C(O)-, -C(0)N(R¹⁰)-, -N(R¹⁰)C(O)-, or -C(0)0-, wherein R¹⁰ is hydrogen or methyl;

Q¹ is selected from hydrogen, (l-2C)alkyl, or phenyl, each of which is optionally substituted with one or more substituents independently selected from halo;

or L¹ is -O- and Q¹ is a prodrug moiety;

(20) R¹ is selected from hydrogen, methyl or R¹ is a group of the formula:

-I^-Q¹

wherein:

L¹ is selected from -C(0)N(R¹⁰)- or -C(0)0-, wherein R¹⁰ is hydrogen;

Q¹ is selected from hydrogen or (l-2C)alkyl;

(21) R¹ is selected from hydrogen, methyl, ethyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -C(0)0-;

Q¹ is selected from hydrogen, and (l-6C)alkyl;

(22) R¹ is selected from hydrogen, methyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is -C(0)0-; Q¹ is selected from hydrogen, (l-6C)alkyl;

R¹ is selected from hydrogen, methyl, CH₂OH, chloro, C0₂H, or C0₂Et;

R 2 is selected from aryl, heterocyclyl or heteroaryl, wherein R 2 is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy or a group

-IAQ²

wherein:

L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, -C(O)-, -CH(OR¹²)-, -C(0)N(R¹²)-, -N(R¹²)C(0)-, -C(0)0-, or -OC(O)-, wherein R¹² and R¹³ are each independently selected from hydrogen or (l-2C)alkyl;

Q is selected from hydrogen, aryl, heterocyclyl or heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy;

R 2 is selected from phenyl or a 5- or 6-membered heteroaryl, wherein R 2 is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl, (l-2C)alkoxy or a group

-IAQ²

wherein:

L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, -C(O)-, -CH(OR¹²)-, -C(0)N(R¹²)-, -N(R¹²)C(0)-, -C(0)0-, or -OC(O)-, wherein R¹² and R¹³ are each independently selected from hydrogen or methyl;

Q is selected from hydrogen, phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6- membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino,

trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy;

R 2 is selected from phenyl or a 5- or 6-membered heteroaryl, wherein R 2 is optionally substituted by one or more substituent groups selected from halo or a group

-L²-Q²

wherein: L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, or -C(O)-, wherein R 12 and R 13 are hydrogen;

Q is selected from phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1- 2C)alkyl or (l-2C)alkoxy;

R is phenyl or a 5- or 6-membered heteroaryl which is substituted by one or more of the

2

substituent options on a R substituent group defined herein;

2

R is phenyl or a 5- or 6-membered heteroaryl which is substituted by one or more of the substituent options on a R substituent group defined herein, with the proviso that the substituent group is not ortho to the point of attachment to the quinolone ring of formula I or the quinoline ring of formula II;

2 2 2

R is phenyl or a 6-membered heteroaryl which is substituted by a group -L -Q as defined herein in the either the meta or para position relative to the point of attachment to the quinolone ring of formula I or the quinoline ring of formula II;

R is a group of formula III or IV shown below

wherein

* indicates the point of attachment to the quinolone ring of formula I or the quinoline ring of formula II;

Ai, A₂, A₃, A4, and A₅ are all carbon atoms, or one, two or three of Ai, A₂, A3, A₄, and A₅ are nitrogen and the others are carbon;

or one, two or three of A₆, A , A₈, A₉, and Ai₀ are selected from N, O or S and the remainder are carbon; R , R , R and R are present only when the valencies of A_{l 5} A₅, A₆ and An respectively permit and, when present, are each independently selected from hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methyl or methoxy;

R 22 , R 23 , R 24 , R 27 and R 28 are present only when the valencies of A₄, A3, A₂, A₈ and A₇ permit and, when present, are each independently selected from hydrogen or a substituent group on a R substituent as defined herein (or in any one of paragraphs (24) to (26) above).

2

(31) R is a group of formula III or IV shown below

wherein

Ai, A₂, A₃, i4, and A5 are all carbon atoms, or one, two or three of A_{l 5} A₂, A₃, A₄, and A5 are nitrogen and the others are carbon;

or one, two or three of A₆, A₇, A₈, A9, and A₁₀ are selected from N, O or S and the remainder are carbon;

R²⁰, R²¹, R²⁵ and R²⁶ are all hydrogen;

R 22 , R 23 , R 24 , 27 and R 2"8° are each independently selected from hydrogen or a substituent group

2

on a R substituent as defined in any one of paragraphs (24) to (26) above, with the proviso that one of R²², R²³, and R²⁴, and one of R²⁷ and R²⁸ is a group -L²-Q². (32) R is a group of formula III or IV shown below

IV

wherein

Ai, A₂, A₃, A4, and A5 are all carbon atoms, or one, two or three of A_l5 A₂, A₃, A₄, and A5 are nitrogen and the others are carbon;

R²⁰, R²¹, R²⁵ and R²⁶ are all hydrogen;

one of R 22 , R 23 , R 24 , and one of R 27 and R 28 is a substituent group on a R 2 substituent as defined hereinbefore (or as defined in any one of paragraphs (24) to (26) above), and preferably is a group -L 2 -Q 2 as defined herein.

(33) R² is a group -Q³-L²-Q² wherein:

Q is selected from aryl, heterocyclyl or heteroaryl optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy;

Q is selected from aryl, heterocyclyl or heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy;

(34) R² is a group -Q³-L²-Q² wherein: Q 3 is selected from aryl, heterocyclyl or heteroaryl, wherein Q 3 is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy;

2

Q is selected from aryl, heterocyclyl or heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, (l-3C)alkoxycarbonyl (e.g. methyl or ethyl ester), amino,

trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl;

(35) R 2 is a group -Q 3 -L 2 -Q 2 wherein:

Q is selected from phenyl, 5- or 6-membered heterocyclyl, heterocyclyl or a 5- or 6- membered heteroaryl, wherein Q is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl,

trifluoromethoxy, (l-2C)alkyl, (l-2C)alkoxy;

Q is selected from phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, (l-3C)alkoxycarbonyl (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (1-

2C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl;

(36) R² is a group -Q³-L²-Q² wherein:

Q is selected from phenyl, 5- or 6-membered heterocyclyl, or a 5- or 6-membered heteroaryl; L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, or -C(O)-, wherein R 12 and R 13 are hydrogen;

2

Q is selected from phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (l-3C)alkoxycarbonyl (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl;

2 3 2 2

(37) R is a group -Q -L -Q wherein:

Q 3 is selected from aryl, heterocyclyl or heteroaryl, wherein Q 3 is optionally substituted by one or more substituents selected from halo;

L 2 is selected from a direct bond, -CR 12 R 13 -, -0-, wherein R 12 and R 13 are each hydrogen; Q is selected from aryl, heterocyclyl, heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, (l-2C)alkoxycarbonyl (e.g. methyl or ethyl ester), trifluoromethyl, trifluoromethoxy, or (l-4C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with a substituent selected from heterocyclyl;

(38) R² is a group -Q³-L²-Q² wherein:

Q 3 is selected from aryl, heterocyclyl, or heteroaryl, wherein Q 3 is optionally substituted by a substituent selected from halo;

L 2 is selected from a direct bond, -CR 12 R 13 -, -0-, wherein R 12 and R 13 are each independently selected from hydrogen;

Q is aryl, which is optionally substituted with a substituent selected from halo, carboxy ester (e.g. methyl or ethyl ester), trifluoromethyl, trifluoromethoxy or (l-4C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with a substituent selected from heterocyclyl;

(39) R² is a group -Q³-L²-Q² wherein:

Q is selected from phenyl, piperidinyl, pyridinyl, or pyrazolyl;

2

L is selected from a direct bond, -CH₂-, or -0-; 2

Q is phenyl, which is optionally substituted with a substituent selected from halo, (1- 2C)alkoxycarbonyl (e.g. methyl or ethyl ester), trifluoromethyl, trifluoromethoxy or (1- 4C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with a substituent selected from heterocyclyl;

Q is phenyl or a 5- or 6-membered heteroaryl which is optionally substituted as defined in any one of paragraphs (33), (34), (36), (37) or (38) herein;

Q is phenyl or a 5- or 6-membered heteroaryl which is optionally substituted as defined in any one of paragraphs (33), (34), (36), (37) or (38) herein, with the proviso that a substituent group is not ortho to the point of attachment to the quinolone ring of formula I or the quinoline ring of formula II;

Q is phenyl or a 6-membered heteroaryl optionally substituted as defined in any one of

2 2

paragraphs (33), (34), (36), (37) or (38) herein, wherein the group -L -Q as defined herein is in either the meta- or para- position relative to the point of attachment to the quinolone ring of formula I or the quinoline ring of formula II;

Q is selected from a group of the formula V, VI, VII, VIII or IX:

VIII IX

wherein

An, Ai2, An and A₁₄ are all carbon, or one or two of An, A₁₂, A₁₃, and A₁₄ are nitrogen and the remainder are carbon; i5, A₁₆, An, and A₁₈, are all carbon, or one or two of A₁₅, A₁₆, An and A₁₈ are nitrogen and the remainder are carbon;

A₂₁ is selected from carbon or nitrogen; A₁₉, A₂o, A₂₂ are all carbon or one or two of A₁₉, A₂o, A₂₂ are selected from N, O or S and the remainder are carbon; and

A₂₃ is carbon or nitrogen;

(44) Q³ is selected from a group of the formula V, VI, VII, VIII or IX:

IX

wherein

An, A₁₂, A₁₃ and A₁₄ are all carbon, or one of An, A₁₂, A₁₃, and A₁₄ is nitrogen and the remainder are carbon;

Ai₅, Ai₆, An, and A₁₈, are all carbon, or one of A₁₅, A₁₆, An and A₁₈ is nitrogen and the remainder are carbon;

A₂₁ is selected from carbon or nitrogen; A₁₉, A₂₀, A₂₂ are all carbon or one of A₁₉, A₂₀, A₂₂ is selected from N, O or S and the remainder are carbon; and

A₂₃ is carbon;

(45) Q is selected from a group of the formula V, VI, or VII:

VIII

wherein

An, Ai2, An and A₁₄ are all carbon, or one of An, A₁₂, A₁₃, and A₁₄ is nitrogen and the remainder are carbon;

Ai5, A₁₆, An, and A₁₈, are all carbon, or one of A₁₅, A₁₆, A₁ and A₁₈ is nitrogen and the remainder are carbon;

one,or two of A₁₉, A₂o, and A₂₁ are selected from N, O or S and the remainder are carbon; and A₂₂ is carbon;

(46) Q is selected from a group of the formula:

(47) Q is selected from a group of the formula:

(48) Q is selected from a group of the formula:

(49) Q is selected from a group of the formula:

Q is 6-membered heterocyclyl optionally substituted as defined herein.

Q 3 is 6-membered heterocyclyl optionally substituted as defined herein, wherein -L 2 -Q 2 is attached to a heteroatom of the 6-membered heterocyclyl, most suitably a heteroatom in the 3, 4, or 5-position relative to the point of attachment to the quinolone ring of formula I or the quinoline ring of formula II;

L is selected from a direct bond, -CH₂-, and -0-;

2

Q is aryl or heteroaryl optionally substituted as defined herein.

2

Q is aryl optionally substituted as defined herein.

Q is phenyl, optionally substituted by one or more halo, methoxy, trifluoromethyl, or triflouromethoxy.

Q is phenyl optionally substituted in the para position by halo, methoxy,

trifluoromethyl, or triflouromethoxy.

Q is phenyl substituted in the para position by more trifluoromethyl or triflouromethoxy.

R is selected from hydrogen, hydroxy, (l-6C)alkyl, phenyl or benzyl;

R is selected from hydrogen, hydroxy, (l-2C)alkyl, phenyl or benzyl;

R is selected from hydrogen, hydroxy or methyl;

R is hydrogen or hydroxyl.

R is hydrogen. R⁴ is selected from hydrogen or a prodrug moiety, which is an in vivo hydrolysable ester; and

R⁴ is selected from hydrogen or a prodrug moiety, which is an in vivo hydrolysable ester formed by a R⁴ group selected from -C(0)-(l-6C)alkyl, -C(0)-aryl, -C(0)-0-(l- 6C)alkyl, -C(0)-0-aryl or a group of the formula:

O

-R_{i e}

ORi5 wherein

* indicates the point of attachment to the oxygen atom in the 4-position of the quinolone ring of formula I or the quinoline ring of formula II;

R¹⁵ is hydrogen, (l-6C)alkyl or aryl and R¹⁶ is OH, (l-6C)alkyl, aryl, -0-(l-6C)alkyl or -O-aryl;

represents an amino acid moiety or a peptide chain formed from two or more amino acids.

R⁴ is selected from hydrogen or a prodrug moiety, which is an in vivo hydrolysable ester formed by a R⁴ group selected from -C(0)-(l-6C)alkyl, -C(0)-aryl, -C(0)-0-(l- 6C)alkyl, -C(0)-0-aryl, -C(0)NR_aRb, wherein R_a and Rb are each independently selected from hydrogen, and (l-4C)alkyl, and wherein R_a and R_b are optionally linked so that, together with the nitrogen atom, they form a heterocyclic ring which optionally comprises one or more additional heteroatoms;

or is selected from a group of the formula:

wherein

R¹⁵ is hydrogen, (l-6C)alkyl, aryl, or aryl(l-4C)alkyl (e.g. benzyl), and R¹⁶ is OH, (1- 6C)alkyl, aryl, -0-(l-6C)alkyl, -O-aryl, or -0-(l-4C)alkyl-aryl (e.g. O-benzyl); or R⁴ represents an amino acid moiety or a peptide chain formed from two or more amino acids.

(66) R⁴ is selected from hydrogen or a prodrug moiety, which is an in vivo hydrolysable ester formed by a R⁴ group selected from-C(0)-0-(l-6C)alkyl, -C(0)NR_aR_b, wherein R_a and R_b are each independently selected from (l-4C)alkyl, wherein R_a and R_b are optionally linked so that, together with the nitrogen atom, they form a heterocyclic ring which optionally comprises an additional internal heteroatom;

or is selected from a group of the formula:

O P R₁₆

OR₁₅ wherein

R¹⁵ is hydrogen, or aryl(l-4C)alkyl (e.g. benzyl), and R¹⁶ is OH, or aryl(l-4C)alkyl-0- (e.g. O-benzyl).

[0054] A particular group of compounds of the invention have the structural formula I shown above.

[0055] A further group of compounds of the invention have the structural formula II shown above.

[0056] In a particular group of compounds of the invention, Y is CH, i.e. the compounds have the structural formulae la or Ila shown below

wherein X, n, R 1 , R2 , R 3 and R 4 have anyone of the definitions set out herein. [0057] Suitably, n is 0, 1 or 2 and any X substituent groups present are positioned in the 6- and/or 7-positions of the quinolone ring of formula I and la or the quinoline ring of formulae II or Ila.

[0058] In a particular group of compounds of the invention, X has any one of the definitions set out in paragraphs (9) to (12) above.

[0059] In a particular group of compounds of the invention, R¹ has any one of the definitions set out in paragraphs (16) to (20) above.

[0060] In a further group of compounds of the invention, R has any one of the definitions set out in paragraphs (21) to 0 above.

[0061] In a further group of compounds of the invention, R has any one of the definitions set out in paragraphs (33) to (54) above.

[0062] In a further group of compounds of the invention, R has any one of the definitions set out in paragraphs (33) to (60) above.

[0063] In a further group of compounds of the invention, Q has any one of the definitions set out in paragraphs (33) to (60) above.

[0064] In a further group of compounds of the invention, L has the definition set out in paragraph (33) above.

[0065] In a further group of compounds of the invention, Q has any one of the definitions set out in paragraphs (33) to (60) above.

[0066] In a further group of compounds of the invention, R has any one of the definitions set out in paragraphs (58) to (62)) above.

[0067] In a further group of compounds of the invention, R⁴ has any one of the definitions set out in paragraphs (63) or (64) above.

[0068] In a particular group of compounds of the invention, Y is CH, i.e. the compounds have the structural formula la above, and:

n is 1,

X is a phosphate or amino acid ester prodrug;

R¹ is selected from hydrogen, methyl or R¹ is a group of the formula -I^-Q¹, wherein L¹ is -C(0)0- and Q¹ is (l-2C)alkyl;

R is a group of formula III or IV

wherein

* indicates the point of attachment to the quinolone ring of formula I;

Ai, A₂, A₃, A4, and A₅ are all carbon atoms, or one or two of Ai, A₂, A3, A₄, and A₅ are nitrogen and the others are carbon;

or one, two or three of A₆, A , A₈, A₉, and Ai₀ are selected from N, O or S and the remainder are carbon;

R²⁰, R²¹, R²⁵ and R²⁶ are all hydrogen;

one of R 22 , R 23 , R 24 is a substituent group -L 2 -Q 2 and the others are hydrogen, and one of

R 27 and R 28 is a substituent group -L 2 -Q 2 and the other is hydrogen

wherein:

L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, or -

C(O)-, wherein R 12 and R 13 are hydrogen;

Q is selected from phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6- membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy; and

R is hydrogen;

or a pharmaceutically acceptable salt thereof.

[0069] In a particular group of compounds of the invention, Y is CH, i.e. the compounds have the structural formula la above, and:

n is 0, 1 or 2,

X is hydrogen, methoxy, fluoro or chloro; R¹ is a group of the formula -I^-Q¹, wherein L¹ is -O- or -CH₂-0- and Q¹ is a phosphate or amino acid ester prodrug moiety;

2

R is a group of formula III or IV

wherein

* indicates the point of attachment to the quinolone ring of formula I;

Ai, A₂, A₃, A4, and A5 are all carbon atoms, or one or two of A_l5 A₂, A₃, A₄, and A5 are nitrogen and the others are carbon;

R²⁰, R²¹, R²⁵ and R²⁶ are all hydrogen;

R 27 and R 28 is a substituent group -L 2 -Q 2 and the other is hydrogen

wherein:

C(O)-, wherein R 12 and R 13 are hydrogen;

Q is selected from phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6- membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy;

R is hydrogen;

or a pharmaceutically acceptable salt thereof. [0070] In a particular embodiment, the compounds have the structure formula I or formula II shown below

I II

wherein:

Y is N or CH; n is 0, 1 or 2;

X is selected from fluoro, chloro, trifluoromethyl, hydroxy, methoxy, heterocyclyl, or a combination thereof (e.g. where n=2);

R¹ is selected from hydrogen, methyl, ethyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is -C(0)0-;

Q¹ is selected from hydrogen, (l-6C)alkyl;

R 2 is a group -Q 3 -L 2 -Q 2 wherein:

Q is selected from aryl, heterocyclyl, heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, carboxy ester (e.g. methyl or ethyl ester), trifluoromethyl, trifluoromethoxy or (l-4C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with a substituent selected from heterocyclyl;

selected from hydrogen, or hydroxy; R is selected from a prodrug moiety;

or a pharmaceutically acceptable salt thereof.

[0071] In a particular embodiment, the compounds have the structure formula I shown below

wherein:

Y is N or CH;

n is 0, 1 or 2;

X is selected from fluoro, chloro, methoxy, or a combination thereof (e.g. where n=2);

R¹ is selected from hydrogen, methyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is -C(0)0-;

Q¹ is selected from hydrogen, (l-6C)alkyl;

R 2 is a group -Q 3 -L 2 -Q 2 wherein:

Q 3 is selected from aryl or heteroaryl, wherein Q 3 is optionally substituted by a substituent selected from halo;

Q is aryl, which is optionally substituted with a substituent selected from halo, carboxy ester

(e.g. methyl or ethyl ester), trifluoromethyl, trifluoromethoxy or (l-4C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with a substituent selected from heterocyclyl;

R is selected from hydrogen, or hydroxy; or a pharmaceutically acceptable salt thereof.

[0072] In a particular embodiment, the compounds have the structure formula I shown below

I

wherein:

Y is N or CH;

n is 0, 1 or 2;

R¹ is selected from hydrogen, methyl, CH₂OH, chloro, C0₂H, or C0₂Et;

R 2 is a group -Q 3 -L 2 -Q 2 wherein:

Q is selected from phenyl, pyridinyl, or pyrazolyl;

L is selected from a direct bond, -CH₂-, or -0-;

Q is phenyl, which is optionally substituted with a substituent selected from halo, carboxy ester (e.g. methyl or ethyl ester), trifluoromethyl, trifluoromethoxy or (l-4C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with a substituent selected from heterocyclyl;

R is selected from hydrogen, or hydroxy;

or a pharmaceutically acceptable salt thereof.

[0073] Particular compounds of the invention include any one of the following:

2- (4-(4-fluorobenzyl)phenyl)-3-methylquinolin(lH)-one 7a

3- methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one 7b

7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7d

3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7e

2-(4-benzylphenyl)-3-methylquinolin-4(lH)-one 7f

7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one 7g 3-methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7h

2- (4-(4-methoxybenzyl)phenyl)-3-methylquinolin-4(lH)-one 7i

7-Chloro-2-(4-(4-fluorobenzyl)phenyl)-3-methylquinolin-4(lH)-one 7j

3- methyl-2-(4-(morpholinomethyl)phenyl)quinolin-4(lH)-one 7k

7-chloro-3-methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 71

6-chloro-3-methyl-2-(3-(3-(trifluoromethoxy)benzyl)phenyl)quinoline-4(lH)-one 7m 2-(4-bromophenyl)-3-methylquinolin-4(lH)-one 7n

6- chloro-7-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7o

7- chloro-6-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7p 7-chloro-2-(2-fluoro-4-(4-(trifluoromethoxy)benzyl)phenyl)-3-methylquinolin-4(lH)-one 7q

3 -methyl-2-(4- (4- (trifluoromethoxy)benzyl)phenyl) -7 - (trifluoromethyl)quinolin-4( 1 H) -one 7r

2-(4-(4-chlorophenoxy)phenyl)-3-methylquinolin-4(lH)-one 7s

2- (2-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)phenyl)-3-methylquinolin-4(lH)-one 7t

3- methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7u

7-fluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7v 7-methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7w

6- chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7x 6,7-difluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7y

7- chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7z 5,7-difluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 8a 2-(6-(2,4-difluorophenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one 8b

2- (6-(4-methoxyphenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one 8c

3-methyl-2-(6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)quinolin-4(lH)-one 8d

3- methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(lH)-one 8e

2- (6-(4-fluorophenoxy)pyridin-3-yl)-3-methylquinolin-4(lH)-one 8f

6- methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 8g

7- methoxy-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)quinolin-4(lH)-one 8h 7-methoxy-3-methyl-2-(5-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 8i

7-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 11a 6,7-difluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one l ib

3- methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,8-naphthyridin-4(lH)-one 11c 6-hydroxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 12a 7-hydroxy-3-methyl-2-(6-(4-(trifluorometh^ 12b 3-methyl-2-(4-(3-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(lH)-one 16

2- (4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19a

6,7-dilluoro-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19b

6,7-dichloro-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19c

6-iluoro-7-methoxy-2-(4-(4-(trilluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19d

6- (4-methylpiperazin-l-yl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)- 19e

7- (4-methylpiperazin-l-yl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH 19f methyl 4-(4-(4-oxo-l,4-dihydroquinolin-2-yl)benzyl)benzoate 19g

3-chloro-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 20a

ethyl 4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)- 1 ,4-dihydroquinoline-3-carboxylate 22a

ethyl 7-chloro-4-oxo-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)-l,4-dihydroquinoline-3- carboxylate 22b

ethyl 7-chloro-4-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-l,4-dihydroquinoline-3- carboxylate 22c

ethyl 4-oxo-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)- 1 ,4-dihydroquinoline-3- carboxylate 22d

3- (hydroxymethyl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 23a 7-chloro-3-(hydroxymethyl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 23b

7-chloro-3-(hydroxymethyl)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one 23c

3-(hydroxymethyl)-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 23d ethyl 2-(4-iodophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxylate 26

ethyl 4-oxo-2-(4'-(trif uoromethoxy)- [1,1 '-biphenyl] -4-yl)- 1 ,4-dihydroquinoline-3- carboxylate 27a

ethyl 2-(4'-chloro-[l,l'-biphenyl]-4-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate 27b 3-(hydroxymethyl)-2-(4'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4(lH)-one 28 4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,4-dihydroquinoline-3-carboxylic acid 31a

3-methyl-2-(4'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4(lH)-one 32a

2-(2'-f uoro-[l,r-biphenyl]-4-yl)-3-methylquinolin-4(lH)-one 32b

2- (2',4'-difluoro-[l,r-biphenyl]-4-yl)-3-methylquinolin-4(lH)-one 32c

3- methyl-2-(2'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)quinolin-4(lH)-one 32d 3- methyl-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-yl)quinolin-4(lH)-one 32e

2-(6-(2-fluorophenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one 32f

4- chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinoline 35a

ethyl 4-chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinoline- 3-carboxylate 35b

4-chloro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolone 35c 4-chloro-2-(l-(4-fluorobenzyl)-lH-pyrazol-4-yl)quinolone 35d

4-chloro-7-methoxy-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl) quinolone 35e 2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one 36a

ethyl 4-oxo-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)-l,4- dihydroquinoline-3- carboxylate 36b

3 -methyl-2-( 1 - (4- (trifluoromethoxy)benzyl) - 1 H-pyrazol-4- yl)quinolin-4( lH)-one 36c

2- ( 1 -(4-fluorobenzyl)- lH-pyrazol-4-yl)quinolin-4( lH)-one 36d

7-methoxy-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one 36e

3- chloro-2-(l-(4-(trif uoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one 37 7-methoxy-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin- 4(1H)- one 41a

7-chloro-3-methyl-2-(l-(4-(trif uoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin- 4(lH)-one 41b

6- f uoro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin- 4(lH)-one 41c

7- f uoro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin- 4(1H) one 41d

3-ethyl-2-( 1 -(4-(trifluoromethoxy)benzyl)- 1 H-pyrazol-4-yl)quinolin-4( 1 H)-one 41 e

6- chloro-3-methyl-2-(l-(4-(trif uoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin- 4(lH)-one 41f

3 -methyl-2-( 1 - (4- (trifluoromethoxy)benzyl) - 1 H-pyrazol-3 - yl)quinolin-4( lH)-one 41g 3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-l,2,3-triazol-4-yl)quinolin-4(lH)-one 47 ethyl (3-methyl-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4-yl) carbonate 48a ethyl (3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl) carbonate 48b

7- chloro-3-methyl-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4-yl ethyl carbonate 48c

l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 50a l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one 50b 7-chloro-l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 50c

dibenzyl (7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl) phosphate 51a

dibenzyl (3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl) phosphate

51b

dibenzyl (3-methyl-2-(4'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4-yl) phosphate 51c

7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl dihydrogen phosphate 52a

3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl dihydrogen phosphate 52b

3-methyl-2-(4'-(trifluoromethoxy)-[ 1 , 1 '-biphenyl] -4-yl)quinolin-4-yl dihydrogen phosphate 52c

3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl morpholine-4- carboxylate 53a

7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl morpholine-4- carboxylate 53b;

or a pharmaceutically acceptable salt thereof.

[0074] The various functional groups and substituents making up the compounds of the formula I or II are typically chosen such that the molecular weight of the compound of the formula I or II does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.

[0075] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphur ic, phosphoric, trifluoroacetic, formic, citric, maleic, fumaric and succinic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or

tris-(2-hydroxyethyl)amine. [0076] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".

Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

[0077] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antimalarial activity.

[0078] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H,

2 H(D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; and O may be in any isotopic form, including ¹⁶0 and¹⁸0; and the like.

[0079] It is also to be understood that certain compounds of the formula I or II may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antimalarial activity.

[0080] It is also to be understood that certain compounds of the formula I or II may exhibit polymorphism, and that the invention encompasses all such forms that possess antimalarial activity. [0081] Compounds of the formula I or II may exist in a number of different tautomeric forms and references to compounds of the formula I or II include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula I or II.

Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

keto enol enolate

[0082] Compounds of the formula I or II containing an amine function may also form N- oxides. A reference herein to a compound of the formula I or II that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4^th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0083] The compounds of formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula I.

[0084] Accordingly, the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a

synthetically-produced compound or a metabolically-produced compound.

[0085] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0086] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and

H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al, Chem. Pharm. Bull, 32, 692 (1984);

g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and

h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987;

i) Optimizing the "drug-like" Properties of Leads in Drug Discovery, edited by Ronald T. Borchardt, Edward H. Kerns, Michael J. Hageman, Dhiren R. Thakker and James L. Stevens, published by Springer in association with The American Associattion of Pharaceutical Scientists, Chapter 10 "Prodrug strategies for Improving Drug-Like Properties"by Valentino J. Stella p 221- 242 (2006).

[0087] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include

Ci_₆alkyl esters such as methyl, ethyl and tert-butyl, Ci_₆alkoxymethyl esters such as

methoxymethyl esters, Ci_₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters,

3-phthalidyl esters, C3_₈cycloalkylcarbonyloxy- Ci_₆alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,

2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and Ci_₆alkoxycarbonyloxy- Ci_₆alkyl esters such as methoxycarbonyloxymethyl and

1 -methoxycarbonyloxyethyl esters .

[0088] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphor amidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-ioalkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-ioalkoxycarbonyl groups such as

ethoxycarbonyl, N,N -(Ci_₆)₂carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.

Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-l-ylmethyl and 4-(Ci_ ₄alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include oc-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0089] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-₄alkylamine such as methylamine, a (Ci_ ₄alkyl)₂amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a Ci_₄alkoxy- C_2- ₄alkylamine such as 2-methoxyethylamine, a phenyl-Ci_₄alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0090] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.

Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci_ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,

N,N-dialkylaminomethyl, morpholinomethyl, piperazin-l-ylmethyl and

4-(Ci_₄alkyl)piperazin- 1 -ylmethyl.

[0091] The in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0092] Particularly suitable prodrug derivatives are the compounds of formula II defined herein which comprise an in vivo hydrolysable ester in the 4-position of the quinoline ring.

[0093] Further suitable prodrug derivatives are the compounds of formula I and/or II defined herein in which X or Q¹ represents an in vivo hydrolysable prodrug moiety (suitably an in vivo phosphate or amino acid ester prodrug moiety). Synthesis

[0094] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0095] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0096] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0097] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0098] For examples of protecting groups see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0099] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [00100] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an

arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or

alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.

Alternatively an acyl group such as a te/t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphur ic or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[00101] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[00102] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a i-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[00103] Resins may also be used as a protecting group.

Synthesis of compounds of formula I

[00104] The methodology employed to synthesise a compound of formula I will vary depending on the nature of the substituent groups R 1 , R2 and R 3. Suitable processes for the preparation of these derivatives comprising particular R 1 , R2 and/or R 3 groups are described further in

Examples 1 to 6 (see the general reaction schemes).

[00105] Once a compound of formula I has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:

(i) removing any protecting groups present;

(ii) converting the compound formula I into another compound of formula I; and/or

(iii) forming a pharmaceutically acceptable salt thereof.

[00106] An example of (ii) above is when a compound of formula I is synthesised and then one or more of the groups R 1 to R 3^J may be further reacted to change the nature of the group and provide an alternative compound of formula I. For example, the compound can be reacted to covert R into a substituent group other than hydrogen.

[00107] In a particular embodiment, compounds of formula I in which X is a phosphate or amino acid ester prodrug moiety can be formed by converting a compound of formula I in which X is OH into a phosphate or an amino acid ester using reactants and reaction conditions well known to those skilled in the art. In a further embodiment, compounds of formula I in which Q¹ is a phosphate or amino acid ester prodrug moiety can be formed by converting a compound of formula I in which L¹ is OH or -CH₂OH into a phosphate or an amino acid ester using reactants and reaction conditions well known to those skilled in the art.

[00108] The resultant compounds of formula I can be isolated and purified using techniques well known in the art.

[00109] In a further aspect of the invention, there is provided a compound of formula I obtainable by a process as defined herein.

[00110] In a further aspect of the invention, there is provided a compound of formula I obtained by a process as defined herein.

[00111] In a further aspect of the invention, there is provided a compound of formula I directly obtained by a process as defined herein.

Synthesis of compounds of formula II

[00112] In a particular aspect, the invention provides a process for the preparation of a compound of formula II as defined herein, the process comprising reacting a compound of formula I as defined herein with a compound of formula A:

R⁴-X

A

wherein R⁴ is as defined hereinbefore and X is a suitable leaving group; and optionally thereafter, if necessary:

(i) removing any protecting groups present;

(iii) forming a pharmaceutically acceptable salt thereof.

[00113] X may be any suitable leaving group which enables the group R⁴ to be coupled to the oxygen atom at the 4-position of the quinolone ring. In an embodiment, X is halo, for example chloro.

[00114] The above process is carried out in the presence of a suitable solvent

[00115] Phosphate and phosphonate prodrugs may be made by the process defined in Example 8.

[00116] In a further aspect of the invention, there is provided a compound of formula II obtainable by a process as defined herein.

[00117] In a further aspect of the invention, there is provided a compound of formula II obtained by a process as defined herein.

[00118] In a further aspect of the invention, there is provided a compound of formula II directly obtained by a process as defined herein.

Biological Activity

[00119] The biological assays described in Examples 9 and 10 herein may be used to measure the pharmacological effects of the compounds of the present invention.

[00120] Although the pharmacological properties of the compounds of the formulae I and II vary with structural change, as expected, the compounds of the invention were found to be active in the assays described in Examples 9 and 10.

[00121] In general, the compounds of the invention demonstrate IC₅₀ values in the Plasmodium falciparum 3D7 (as well as the multi-drug resistant strain TM902CB) whole cell antimalarial activity assay (see Example 9) of less than 5 μΜ. Preferred compounds demonstrate IC₅₀ values of less than 2 μΜ. Most preferred compounds demonstrate IC₅₀ values of less than 500 nM.

[00122] In general, the compounds of the invention demonstrate IC₅₀ values in the PfNDH2 enzyme assay (see Example 9) of less than 80 μΜ. Preferred compounds demonstrate IC₅₀ values of less than 1 μΜ. Most preferred compounds demonstrate IC₅₀ values of less than 250 nM.

[00123] In general, the compounds of the invention demonstrate IC₅₀ values in the bci enzyme assay (see Example 9) of less than 80 μΜ. Preferred compounds demonstrate IC₅₀ values of less than 50 μΜ. Pharmaceutical Compositions

[00124] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

[00125] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[00126] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

[00127] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent the malaria infection, slow its progression or reduce the symptoms associated with the infection.

[00128] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[00129] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I or II will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[00130] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

Therapeutic Uses and Applications

[00131 ] In one aspect, the present invention provides a compound of formula I or Π as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[00132] The compounds of the invention demonstrate anti-malarial activity and target the

PfNDH2 enzyme, which provides a novel mechanism of action.

[00133] In a particular aspect, the present invention provides a method of inhibiting parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species in vitro or in vivo, said method comprising contacting said Plasmodium species with an effective amount of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof.

[00134] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, for use in the inhibition of parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species in an individual in need of such inhibition.

[00135] In another aspect, the present invention provides the use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species.

[00136] In another aspect, the present invention provides use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, for the inhibition of parasite mitochondrial type II NADH: quinone oxidoreductase in a Plasmodium species in vitro or in vivo.

[00137] In an embodiment, the Plasmodium species is Plasmodium falciparum.

Suitably, the compounds of the present invention are used to treat multi-drug resistant

Plasmodium falciparum. [00138] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein for use in therapy.

[00139] In another aspect the present invention provides a method of treating malaria, said method comprising administering a therapeutically effective amount of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a

pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[00140] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of malaria.

[00141] In another aspect, the present invention provides the use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of malaria.

[00142] In another aspect the present invention provides a method of treating malaria, said method comprising administering a therapeutically effective amount of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a

pharmaceutically acceptable salt thereof, to a subject in need of such treatment in combination with one or more additional antimalarial agents.

[00143] In another aspect, the present invention provides a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional antimalarial agents for use in the treatment of malaria.

[00144] In another aspect, the present invention provides the use of a quinolone derivative of formula I or a quinoline derivative of formula II as defined herein, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of malaria in combination with one or more additional antimalarial agents.

[00145] In a particular embodiment, the compounds of the present invention provide a method of treating Plasmodium falciparum. Routes of Administration

[00146] The compounds of the invention or pharmaceutical compositions comprising these

compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action). [00147] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Combination Therapies

[00148] The antimalarial treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, therapy with one or more additional antimalarial agents.

[00149] Examples of agents known to have antimalarial activity and which could be used in combination with the compounds of the present invention include: quinine (and related alkaloids such as quinimax or quinidine), chloroquine, amodiaquine, pyrimethamine, proguanil, sulfonamides (e.g. sulfadoxine or sulfamethoxypyridazine), mefloquine, atovaquone,

primaquine, artemisinin and derivatives (e.g. artemether, artesunate, dihydroartemisinin, and arteether), halofantrine, doxycycline and clindamycin.

[00150] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[00151]According to this aspect of the invention there is provided a combination suitable for use in the treatment of malaria comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more additional anti-malarial agents.

[00152] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of malaria in combination with an anti-tumour agent selected from one or more of: quinine (and related alkaloids such as quinimax or quinidine), chloroquine, amodiaquine, pyrimethamine, proguanil, sulfonamides (e.g. sulfadoxine or sulfamethoxypyridazine), mefloquine, atovaquone, primaquine, artemisinin and derivatives (e.g. artemether, artesunate, dihydroartemisinin, and arteether), halofantrine, doxycycline and clindamycin. [00153] Herein, where the term "combination" is used, it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[00154] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, one or more additional antimalarial agents, and a pharmaceutically acceptable diluent or carrier. Suitably, the one or more additional antimalarial agents are selected from quinine (and related alkaloids such as quinimax or quinidine), chloroquine, amodiaquine, pyrimethamine, proguanil, sulfonamides (e.g. sulfadoxine or sulfamethoxypyridazine), mefloquine, atovaquone, primaquine, artemisinin and derivatives (e.g. artemether, artesunate, dihydroartemisinin, and arteether), halofantrine, doxycycline and clindamycin.

Examples

[0001] The invention will now be illustrated in the following Examples in which, generally:

(i) Unless stated otherwise, operations were carried out at ambient temperature, i.e. in the range 17 to 25°C and optionally under an atmosphere of an inert gas such as nitrogen or argon. (ii) The reaction times that are given are not necessarily the minimum attainable.

(iii) Yields, where present, are not necessarily the maximum attainable, and when necessary, reactions were repeated if a larger amount of the reaction product was required.

(iv) In general, the structures of the end-products were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques.

(v) Unless stated otherwise, compounds containing an asymmetric carbon atom were not resolved.

(vi) Intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC, infra-red (IR) and/or NMR analysis. Example 1 - preparation of compounds of Formula I in which R¹ is methyl and R³ is hydrogen

General reaction scheme

[00155] Scheme 1 below illustrates particular processes used for the preparation of the exemplified compounds of formula I in which R 1 is a methyl group and R 3 is hydrogen.

[00156] In the first route, aldehydes 2 were used in a Grignard reaction to give alcohols 3 in 70- 90% yields. Oxidation using PCC then gives ketones 4 in 80-90% yield. Oxazoles 6 were made from their respective isatoic anhydrides 5 in reasonable yields and are subsequently reacted with ketones 4 in the presence of PTSA to give the desired quinolones 7a-z and 8a-g in 10-45% yields. The second route involves conversion of ketones 4 to diacetals 9 in 60-70% yields, followed by reaction with acid 10 to give quinolones lla-c in 30-60% yields.

Route 1 :

Route 2:

Scheme 1: The synthesis of Core A compounds when R^Me

[00157] 6- and 7-Methoxy compounds 7w and 8g were then demethylated using BBr

to give the respective hydroxy compounds 12a and 12b in good yields.

Scheme 2: The synthesis of Core A compounds containing a hydroxy group. [00158] In order to improve solubility and allow a further point for salt formation quinolone 16 was synthesised with an extended morpholine sise chain.

Scheme 3: The synthesis of extended morpholine side chain quinolone 16. Experimental

General procedure for the preparation of ether [1]

[00159] To a solution of 4-X phenol (12 mmol 1.2 eq) in 10 ml of dry DMF was added 60% NaH (12 mmol, 1.2 eq). The reaction was stirred for a few mins under N₂ atmosphere and then a solution of 2,5-dibromopyridine (10 mmol) in 5 ml of dry DMF was added and the mixture heated at 100° C overnight. The reaction mixture was subsequently cooled to room temp and the solvent removed under vacuum. The residue was dissolved in EtOAc and washed with brine and dried over MgS0₄, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (hexane to 20% EtOAc/hexane) to yield the pure product.

Preparation of 5-bromo-2-(4-(trifluoromethoxy)phenoxy)pyridine la

[00160] Yellow oil (Yield 78%) 1H NMR (400 MHz, CDC1₃) δ 8.20 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.25 (d, J =8.0 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H); MS (ES⁺) m/z 334 (M + H)⁺ Acc Mass Found: 333.9693, calculated 333.9690 for Ci₂H₈N0₂F₃Br.

Preparation of 5-bromo-2-(4-fluorophenoxy)pyridine lb

[00161] Yellow oil (Yield 80%). 1H NMR (400 MHz, CDC1₃) δ 8.20 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.10 (d, J =6.8 Hz, 4H), 6.84 (d, J = 8.7 Hz, 1H); MS (ES⁺) m/z 268 (M + H)⁺ Acc Mass Found: 267.9771, calculated 267.9773 for CnH₈NOFBr.

General procedures for the synthesis of side chain aldehydes [2]

Procedure 1

bisaryl, methyl linker.

Z = halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-4C)alkyl or (1- 4C)alkoxy

[00162] Formylphenylboronic acid (39 mmol, 1.0 eq) was added to a stirred suspension of the substituted l-(bromomethyl)benzene (43 mmol, 1.1 eq),

tetrakis(triphenylphosphine)palladium(0) (0.98 mmol, 0.025 eq) and potassium carbonate (130 mmol, 3.3 eq) in a solution of THF (164 mL) and H₂0 (65 mL). The resulting mixture was heated under reflux for 5 hours at 80°C. The reaction was quenched with HCl and extracted into EtOAc. The combined organic extracts were washed with H₂0, dried over MgS0₄ and concentrated under vacuum. The removal of the solvent afforded a clear colourless oil which was purified by column chromatography (eluting with 2% EtOAc/n-Hexane increasing to 10% EtOAc) to give aldehyde 2.

Procedure 2

2 = bicyclic heterocycle, methyl linker.

2 [00163] Benzylboronic acid (39 mmol, 1.0 eq) was added to a stirred suspension of the substituted aldehyde (43 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium(0) (0.98 mmol, 0.025 eq) and potassium carbonate (130 mmol, 3.3 eq) in a solution of THF (164 mL) and H₂0 (65 mL). The resulting mixture was heated under reflux for 5 hours at 80°C. The reaction was quenched with HCl and extracted into EtOAc. The combined organic extracts were washed with H₂0, dried over MgS0₄ and concentrated under vacuum. The removal of the solvent afforded a clear colourless oil which was purified by column chromatography (eluting with 2% EtOAc/n- Hexane increasing to 10% EtOAc) to give aldehyde 2. Procedure 3

[00164] Potassium carbonate (12.2 g, 88.27 mmol) in distilled water (30 mL) was added anhydrous tetrahydrofuran (80 mL) under Nitrogen. Carboxaldehyde (5.5 g, 29.57 mmol) was added followed by tetrakis(triphenylphosphine)palladium (0) (2.73 g, 2.36 mmol). The mixture was left stirring at room temperature for 5 min under N₂. Boronic acid (6.77 g, 32.88 mmol) was added. The resulting mixture was heated to 80°C for 24 h (followed by tic). The reaction was cooled to room temperature. It was extracted with ethyl acetate (x 3), washed with brine, dried over MgS0₄, filtered and concentrated to oil. The crude product was purified by column chromatography using 10% ethyl acetate in hexane to give the title compound as a white solid.

Procedure 4

Pd(PPh₃)₂Cl₂ (0.15 mmol, 0.05 eq.) and T3u₃P (0.15 mmol 0.05 eq.) was added to a solution of aldehyde (2.91 mmol, 1 eq.) and boronic acid (3.20 mmol, 1.1 eq.) in dioxane (15 mL). 1M Na₂C0₃ (5.81 mmol, 2 eq.) was then added and the solution was degassed for 15 mins and then heated to 100 C for 16 hours. Palladium was removed by filtering through a pad of silica and this was washed with excess EtOAc (100 mL). The filtrate was washed with brine (50 mL) and dried over MgS0₄. The solvent was removed in vacuo and the resulting oil was purified by flash column chromatography (eluting with n-hexane to 30% EtOAc in n-hexane) to give the desired bipyridyl aldehyde.

Procedure 5

[00166] A solution of the bromo pyridine compound (1 mmol) in dry THF (4 ml) was cooled to - 78 °C. A 2.5 M solution of n-BuLi (1.5 mmol, 1.5 eq) was added and stirring continued at -78°C for 20 mins. To the reaction mixture was added dry DMF (1.2 mmol, 1.2 eq) and stirring continued at -78°C for 1 hr followed by quenching with sat. NH₄C1 solution and extraction with EtOAc. The organic layer was dried over MgS0₄, filtered and concentrated under vacuum. The crude product was purified by column chromatography (hexane to 30% EtOAc/hexane) to give the desired compound.

Preparation of l-(4-(4-(Fluorobenzyl)benzaldehyde) 2a

[00167] Aldehyde 2a was prepared according to procedure 1 to give 2a as a clear colourless oil (Yield 32%); 1H NMR (400 MHz, CDC1₃) δ_Η 4.01 (2H, s), 6.90-7.30 (4H, m), 7.30-7.50 (2H, m), 7.90 (2H, m), 9.90 (1H, s) ppm; ¹³C NMR (100 MHz, CDC1₃) 5_C 41.62 (1C, s), 116.07 (2C, s), 116.29 (2C, s), 130.86 (4C, s), 131.24 (2C,s), 131.319 (2C, s) 194.0 (1C, s) ppm.

Preparation of aldehyde 4-(4-(trifluoromethoxy)benzyl)benzaldehyde 2b

[00168] Aldehyde 2b was prepared according to procedure 1 to give 2b as a White powder (Yield 70%); 1H NMR (400MHz, DMSO) δ_Η 4.06 (s, 2H, ArCH₂Ar), 7.15 (d, 2H, J = 8.5 Hz, Ar), 7.20 (d, 2H, J 8.5 Hz, Ar), 7.34 (d, 2H, J = 8.1 Hz, Ar), 7.83 (d, 2H, J = 8.1 Hz, Ar), 9.98 (s, 1H, COH); ¹³C NMR (100MHz, DMSO), 5_C 41.7, 121.6, 130.0, 130.6, 135.3, 138.9, 148.0, 192.3. Preparation of aldehyde 4-benzylbenzaldehyde 2c

[00169] Aldehyde 2c was prepared according to procedure 1 to give 2c as a white solid (Yield 60%); 1H NMR (400 MHz, CDC1₃) δ 10.00 (s, 1H), 7.83 (d, / = 7.9 Hz, 2H), 7.40 (d, / = 7.9 Hz, 2H), 7.35-7.29 (m, 3H), 7.25 (d, / = 7.2 Hz, 2H), 4.09 (s, 2H); MS (ES⁺) m/z 219 (M + Na)⁺.

Preparation of3-(4-(Trifluoromethoxy)benzyl)benzaldehyde 2d

[00170] Aldehyde 2d was prepared according to procedure 1 to give 2d as a clear colourless oil (Yield 40%); 1H NMR (400 MHz, CDC1₃) δ_Η4.01(2Η, s), 7.10 (2H, m), 7.40(2H, m) 7.70 (2H, m) 9.90 (1H, s) ppm; ¹³C NMR (100 MHz, CDC1₃) 5_C 40.10 (1C, s), 121.20 (2C, s), 122.20 (1C, s), 124.75 (1C, s), 128.67 (3C, s), 129.21 (1C, s), 192.69 (1C, s) ppm. Preparation of aldehyde 4-(4-methoxybenzyl)benzaldehyde 2e

[00171] Aldehyde 2e was prepared according to procedure 1 to give 2e as a white solid (Yield 40%); 1H NMR (400 MHz, CDC1₃) δ 10.00 (s, 1H), 7.80 (d, / = 7.9 Hz, 2H), 7.35 (d, 7 =7.9 Hz, 2H), 7.25 (t, / = 7.9 Hz, 1H), 6.78 (d, / = 7.9 Hz, 2H), 6.70 (s, 1H), 4.05 (s, 2H), 3.8 (s, 3H); MS (ES⁺) m/z 244 (M + NH₄)⁺.

Preparation of 2-fluoro-4-(4-( trifluoromethoxy)benzyl)benzaldehyde 2f

[00172] Aldehyde 2f was prepared according to procedure 1 to give 2f as a colourless oil (Yield 82%); 1H NMR (400MHz, CDC1₃) δ 10.30 (s, 1H), 7.80 (t, / = 7.6 Hz, 1H), 7.21-7.15 (m, 4H), 7.09 (d, / = 8.0 Hz, 1H), 6.96 (d, / = 8.2 Hz, 1H), 4.03 (s, 2H).

Preparation of2-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)benzaldehyde 2g

[00173] Aldehyde 2g was prepared according to procedure 2 to give a light yellow oil (Yield 68%) 1H NMR (400MHz, CDC1₃), δ_Η 10.32 (s, 1H, CHO), 8.63 (s, 1H, Ar), 7.84 (t, 1H, J = 7. Hz, Ar), 7.71 -7.64 (m , 2H, Ar), 7.12 (dd, 1H, J = 8.0 Hz, 1.1 Hz, Ar), 7.00 (dd, 1H, J = 11.0Hz, 1.1 Hz, Ar), MS (ES+), [M + H] ⁺ (100), 284.1, HRMS calculated for 284.0699 Ci₄HioNOF₄, found 284.0694.

Preparation of6-(4-( trifluoromethoxy )phenyl )nicotinaldehyde 2h

[00174] Aldehyde 2h was prepared according to procedure 3 to give a white solid (Yield 72%); 1H NMR (400 MHz, CDC1₃) δ 10.16 (s, 1H, CHO), 9.14 (d, / = 1.6 Hz, 1H, H-2), 8.25 (dd, / = 8.2, 2.2 Hz, 1H, H-4), 8.19 - 8.09 (m, 2H, H-8), 7.90 (d, / = 8.2 Hz, 1H, H-5), 7.36 (d, / = 8.1 Hz, 2H, H-9); ¹³C NMR (101 MHz, CDC1₃) δ 190.73 (CHO), 161.06, 152.79 (C-2), 151.25, 137.15, 136.88, 130.45, 129.56 (C-8), 122.11, 121.57 (C-9), 120.88, 119.54; HRMS (ESI) Ci₃H₉N0₂F3 [M+H]⁺ requires 268.0585, found 268.0592.

Preparation of6-(2,4-difluorophenyl)nicotinaldehyde 2i

[00175] Aldehyde 2i was prepared according to procedure 3 to give a white solid (Yield 69%); 1H NMR (400 MHz, CDC1₃) δ 10.15 (s, 1H, CHO), 9.15 (d, / = 2.1 Hz, 1H, H-2), 8.24 (dd, / = 8.2, 2.2 Hz, 1H), 8.15 (td, / = 8.8, 6.6 Hz, 1H, H-12), 7.97 (dd, 7 = 8.1, 1.5 Hz, 1H), 7.11 - 7.02 (m, 1H, H-l l), 6.96 (ddd, J = 11.3, 8.7, 2.5 Hz, 1H, H-9).

Preparation of6-(4-methoxyphenyl)nicotinaldehyde 2j

[00176] Aldehyde 2j was prepared according to procedure 3 to give a white solid (Yield 77 %); 1H NMR (400 MHz, CDC1₃) δ 10.11 (s, 1H, CHO), 9.08 (dd, / = 2.2, 0.8 Hz, 1H, C-2), 8.19 (dd, J = 8.3, 2.2 Hz, 1H, H-4), 8.12 - 8.03 (m, 2H, H-8), 7.85 (d, J = 8.3 Hz, 1H, H-5), 7.08 - 6.98 (m, 2H, H-9), 3.89 (s, 3H); ¹³C NMR (101 MHz, CDC1₃) δ 190.91(C=O), 162.23, 162.06, 153.00, 136.76, 130.89, 129.68, 129.49 (C-8), 120.08, 114.81 (C-9), 55.86.

Preparation of 6'-(trifluoromethyl)-[2,3'-bipyridine]-5-carbaldehyde 2k

[00177] Aldehyde 2k was prepared according to procedure 4 to give a cream solid (Yield 60%); 1H NMR (400 MHz, CDC1₃) 10.20 (s, 1H), 9.39 (s, 1H), 9.22 (s, 1H), 8.62 (dd, / = 8.2, 1.6 Hz, 1H), 8.34 (dd, / = 8.2, 2.2 Hz, 1H), 8.01 (d, / = 8.2 Hz, 1H), 7.86 (d, / = 8.2 Hz, 1H); δ ¹³C NMR (100 MHz, CDC1₃) δ 190.46, 158.27, 152.87, 149.70, 149.35, 149.19, 137.61, 136.78, 136.54, 131.25, 123.19, 121.50, 121.04, 121.01, 120.46; MS (ES⁺) m/z 253 (M + H)⁺ Acc Mass Found: 253.0586, calculated 253.0589 for Ci₂H₈N₂OF₃. Preparation of6-(4-(trifluoromethoxy)phenoxy)nicotinaldehyde 21

[00178] Aldehyde 21 was prepared according to procedure 5 to give a yellow oil (Yield 71%). 1H

NMR (400 MHz, CDC1₃) δ 9.99(s, 1H), 8.62 (s, 1H), 8.22 (d, J

Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H).

Preparation of6-(4-fluorophenoxy)nicotinaldehyde 2m

[00179] Aldehyde 2m was prepared according to procedure 5 to give a yellow oil (Yield 69%). 1H NMR (400 MHz, CDC1₃) δ 9.97(s, 1H), 8.60 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.15-7.09 (m, 4H), 7.05 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDC1₃) δ 189.63, 167.42, 161.64, 159.23, 152.92, 149.14, 139.16, 128.20, 123.53, 123.45, 116.96, 116.73, 112.47.

Preparation of4-(3-methoxybenzyl)benzaldehyde 2n

[00180] Aldehyde 2n was prepared according to procedure 1 to give a white solid (Yield 78%); 1H NMR (400 MHz, CDC1₃) 9.97 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.23 (dd, / = 7.8, 7.8 Hz, 1H), 6.78 (dd, / = 8.0, 2.0 Hz, 2H), 6.72 (s, 1H), 4.02 (s, 2H), 3.77 (s, 3H); δ ¹³C NMR (100 MHz, CDC1₃) δ 192.39, 160.25, 148.65, 141.71, 135.11, 130.46, 130.39, 130.09, 129.97, 121.78, 115.34, 112.03, 55.58, 42.50; MS (ES⁺) m/z 227 (M + H)⁺ .

Preparation of 5-(4-(trifluoromethoxy)phenyl)nicotinaldehyde 2o

[00181] Prepared according to the general procedure for the synthesis of side chain aldehydes 2, procedure 3 (pale grey solid, 96%). 1H NMR (400 MHz, CDC1₃) δ 10.21 (s, 1H), 9.09 (d, / = 1.7 Hz, 1H), 9.07 (d, / = 2.2 Hz, 1H), 8.34 (t, / = 2.1 Hz, 1H), 7.67 (d, / = 8.8 Hz, 2H), 7.38 (d, / = 8.0 Hz, 2H). ¹³C NMR (101 MHz, CDC1₃) δ 190.92, 153.38, 151.41, 150.24, 136.48, 135.40, 134.04, 131.82, 129.17, 122.18. ESI HRMS: m/z calculated for Ci₄Hi₃N0₃F₃ ([M+CH₃OH+H]⁺) 300.0848 , found 300.0847. General procedure for the preparation of alcohols [3]

[00182] Aldehyde 2 (20 mmol, 1.0 eq) was dissolved in ether (40 mL) and cooled to 0°C under nitrogen. Ethyl magnesium bromide (24 mmol, 1.2 eq) was added dropwise and the reaction stirred at 0°C for 1 hour. The solution was then quenched with 1M HC1 and extracted with EtOAc (2 x 40 mL). The organic portions were combined, dried over MgS0₄ and the solvent removed in vacuo. Where necessary the crude product was purified by flash column

chromatography (eluting with 5%-20% EtOAC in hexane) to give alcohol 3.

Preparation of l-(4-(4-fluorobenzyl)phenyl)propan-l-ol 3a

[00183] Clear colourless oil (Yield 97%); 1H NMR (400 MHz, CDC1₃) δ_Η 7.0-7.20 (8H, m), 4.3(1H, t), 3.90 (2H, s), 2.0 (1H, s), 1.89 (2H, m), 0.91 (3H,t); ¹³C NMR (100 MHz, CDC1₃) δ, 130.71, 130.64, 126.20, 76.21, 41.17, 32.25,10.61; HRMS calcd for Ci₆Hi₇FO [M+Na]⁺

267.1161 found 267.1155.

Preparation of l-(6-bromopyridin-3-yl)propan-l-ol 3b

[00184] Yellow oil (Yield 68%); 1H-NMR (CDC1₃, 400 MHz): δ 8.32 (d, / = 2.5 Hz, 1H), 7.58 (dd, 7 = 8.2, 2.5 Hz, 1H), 7.47 (d, 7 = 8.2 Hz, 1H), 4.85 - 4.51 (m, 1H), 1.91 - 1.66 (m, 2H), 0.94 (t, / = 7.4 Hz, 3H); ¹³C NMR (CDC1₃, 101MHz): δ 148.44, 141.35, 139.48, 136.55, 128.44, 73.25, 32.26, 10.30. MS (m/z) 216.0020 (C1+, M+H); Anal. Calcd for C₈Hi₀NOBr: C, 44.47; H, 4.66; N, 6.48. Found: C, 43.56; H, 4.89; N, 6.94.

Preparation ofl-(4-(4-( trifluoromethoxy )benzyl)phenyl)propan-l -ol 3c

[00185] Oil (Yield 99%); 1H NMR (400MHz, DMSO) δ_Η 7.25 (2H, J = 8.0 Hz, Ar), 7.17 (d, 2H, J = 8.6 Hz, Ar), 7.13 (d, 2H, J = 8.3 Hz, Ar), 7.11 (d, 2H, J = 8.3 Hz, Ar), 4.53 (t, 1H, J = 6.6Hz, CH), 3.95 (s, 2H, ArCH₂Ar), 2.12 (s, 1H, OH), 1.64-1.84 (m, 2H, CH₂), 0.88 (t, 3H, J = 7.4 Hz, CH₃); ^1JC NMR (100MHz, DMSO), 5_C 148.0, 140.2, 130.5, 129.3, 126.7, 121.4, 76.2, 41.3, 32.3,10.6; MS (ES+), [M + H] ⁺ (100), 333.0, HRMS calculated for 333.1078 Ci₇Hi₇Na0₂F₃, found 333.1062.

Preparation of l-(4-benzylphenyl)propan-l-ol 3d

[00186] Colourless oil (Yield 72%); 1H NMR (400 MHz, CDC1₃): 7.33 (d, J=7.9Hz, 2H), 7.27- 7.23 (m, 5H), 7.20 (d, J=7.9Hz, 2H), 4.60 (t, /= 6.8Hz, 1H), 4.00 (s, 2H), 1.80 (m, 2H), 0.95 (t, J=7.6Rz, 3H); ¹³C NMR (100 MHz, CDC1₃): 142.8, 141.5, 140.8, 129.6, 129.4, 126.9, 126.5, 76.3, 42.0, 32.2, 10.6; MS (ES+) m/z 249.1[M+NH₄]⁺.

Preparation of l-(3-(4-(Trifluoromethoxy)benzyl)phenyl)propan-l-ol 3e

[00187] Clear colourless oil (Yield 78%); 1H NMR (400 MHz, CDC1₃) δ_Η 7.10 (8H, m), 5.50 (1H, t), 3.95 (2H,s), 2.0 (1H, s), 1.75 (2H, m), 0.95 (3H, t); ¹³C NMR (100 MHz, CDC1₃) 5_C 130.51, 127.77, 126.27, 124.43, 121.44, 76.32, 41.63, 32.35,10.95.

Preparation of 1 -(4-(4-methoxybenzyl)phenyl)propan-l -ol 3f

[00188] Clear colourless oil (Yield 71%); 1H NMR (400 MHz, CDC1₃): 7.33 (d, J=7.9Hz, 2H), 7.24-7.02 (m, 3H), 6.82 (d, J=7.9Hz, 2H), 6.75 (s, 1H), 4.57 (t, J=6.8Hz, 1H), 3.92 (s, 2H), 3.80 (s, 3H), 1.8 (m, 2H), 0.90 (t, /= 7.2Hz, 3H); ¹³C NMR (100 MHz, CDC1₃): 160, 144, 143, 141, 131, 130, 127, 122, 115, 111, 77, 57, 42, 32, 11.0; MS (ES+) m/z 274.3 [M+NH₄]⁺.

Preparation of l-( 2-fluoro-4-(4-( trifluoromethoxy )benzyl)phenyl)propan-l -ol 3g

[00189] Oil (Yield 88%); 1H NMR (400MHz, CDC1₃) δ 7.35 (t, J = 7.8 Hz, 1H), 7.17-7.11 (m, 4H), 6.94 (d, / = 7.8 Hz, 1H), 6.79 (d, / = 8.2 Hz, 1H), 4.85 (t, / = 6.4 Hz, 1H), 3.91 (s, 2H), 2.69 (brs, 1H), 1.79-1.70 (m, 2H), 0.89 (t, / = 7.4 Hz, 3H); ¹³C NMR (100MHz, CDC1₃), δ

161.57, 159.13, 148.19, 148.18, 142.01, 139.52, 130.54, 130.03, 129.89, 125.06, 125.03, 121.49, 116.04, 115.82, 69.77, 40.95, 31.31, 10.27; MS (ES+) m/z 351 [M + Na]⁺ Acc Mass Found 351.0983, calculated 351.0984 for Ci₇Hi₆0₂F₄Na.

Preparation of l-(4-(4-Chlorophenoxy)phenyl)propan-l-ol 3h

[00190] Colourless oil (1.8672 g, Yield 84%); 1H NMR (400 MHz, CDC1₃) δ_Η 0.98 (3H, t), 1.70 (2H, m), 5.60 (1H, t), 6.90 (3H, m), 7.28 (3H, m) ppm; ¹³C NMR (100 MHz, CDC1₃) 5_C 10.57 (1C, s), 32.35 (1C, s), 119.23 (2C,s), 120.38 (2C, s), 127.94 (2C, s), 130.12 (2C, s) ppm.

Preparation of l-( 2-fluoro-4-( (6-( trifluoromethyl)pyridin-3-yl )methyl )phenyl)propan-l -ol 3i

[00191] Colorless oil (Yield 88%) 1H NMR (400MHz, CDC1₃), δ_Η 8.59 (s, 1H, Ar), 7.66-7.60 (m, 2H, Ar), 7.42 (t, 1H, 7.8 Hz, Ar), 6.97 (dd, 1H, 7.9 Hz, 1.5 Hz, Ar), 6.82 (dd, 1H, J = 11.0 Hz, 1.5 Hz, Ar), 4.91 (t, 1H, J = 6.5 Hz, CH), 4.04 (s, 2H, ArCH₂Ar), 2.26 (bs, 1H, OH), 1.86- 1.73 (m, 2H, CH₂), 0.94 (t, 3H, J = 7.4 Hz, CH₃) ¹³C NMR (100MHz, CDC1₃), 5_C 161.6, 159.2, 150.2, 139.6, 137.9, 130.6, 128.3, 125.1, 120.8, 116.2, 115.9, 69.9, 38.6, 31.4, 10.3 MS (ES+), [M + H] ⁺ (100), 314.1, HRMS calculated for 314.1168 Ci₆Hi₆NOF₄, found 314.1164.

Preparation ofl-(6-(4-( trifluoromethoxy )phenyl )pyridin-3-yl )propan-l -ol 3j

[00192] Colourless oil (Yield 73 %); (Rf = 0.38, 50% Ethyl acetate in hexane); 1H NMR (400 MHz, CDC1₃) δ 8.58 (d, / = 2.1 Hz, 1H, H-2), 8.06 - 7.95 (m, 2H, H-8), 7.76 (dd, / = 8.2, 2.2 Hz, 1H, H-4), 7.67 (d, 7 = 8.2 Hz, 1H, H-5), 7.30 (d, / = 8.1 Hz, 2H, H-9), 4.68 (t, / = 6.5 Hz, 1H, CHOH), 2.56 (s, 1H, OH), 1.96 - 1.71 (m, 2H, CH₂), 0.95 (t, / = 7.4 Hz, 3H, CH₃); ¹³C NMR (101 MHz, CDC1₃) δ 155.66, 150.24, 148.30 (C-2), 138.99, 138.10, 135.04, 128.72 (C-8), 121.46 (C-9), 120.88 (d, J = 257 Hz, OCF₃), 120.65, 73.76 (CHOH), 32.29 (CH₂), 10.30 (CH₃); HRMS (ESI) Ci₅Hi₅N0₂F₃ [M+H]⁺ requires 298.1055, found 298.1043; Anal. Ci₅Hi₄N0₂F₃ requires C 60.06%, H 4.75%, N 4.71%, found C 60.41%, H 4.81%, N 4.77%. Preparation ofl-(6-( 2,4-difluorophenyl)pyridin-3-yl )propan-l -ol 3k

[00193] Yellow oil (Yield 65 %); 1H NMR (400 MHz, CDC1₃) δ 8.66 (s, IH, H-2), 8.00 (td, / = 8.8, 6.7 Hz, IH, H-12), 7.77 (dd, 7 = 8.2, 2.1 Hz, IH), 7.74 (ddd, / = 8.2, 2.0, 1.0 Hz, IH), 7.04 - 6.97 (m, IH, H-l l), 6.92 (ddd, / = 11.3, 8.8, 2.5 Hz, IH, H-9), 4.72 (td, / = 6.6, 3.6 Hz, IH, CHOH), 2.02 - 1.95 (br. s, IH, OH), 1.95 - 1.75 (m, 2H, CH₂), 0.98 (t, / = 7.4 Hz, 3H, CH₃); HRMS (ESI) C₁₄H₁₄NOF₂ [M+H]⁺ requires 250.1043, found 250.1049.

Preparation of l-(6-(4-methoxyphenyl)pyridin-3-yl)propan-l-ol 31

[00194] Pale yellow solid (Yield 69 %); 1H NMR (400 MHz, CDC1₃) δ 8.59 (d, / = 2.2 Hz, IH, H-2), 8.02 - 7.92 (m, 2H, H-8), 7.74 (dd, / = 8.2, 2.3 Hz, IH, H-4), 7.67 (dd, / = 8.2, 0.7 Hz, IH, H-5), 7.04 - 6.96 (m, 2H, H-9), 4.69 (td, / = 6.7, 3.0 Hz, IH, OH), 3.87 (s, 3H, OCH₃), 1.93 (t, / = 3.8 Hz, IH, CH), 1.91 - 1.73 (m, 2H, CH₂), 0.96 (t, / = 7.4 Hz, 3H, CH₃). ¹³C NMR (101 MHz, CDC1₃) δ 169.50, 160.82, 156.92, 148.14 (C-2), 134.78, 132.19, 128.51 (C-8), 120.00, 114.53 (C-9), 74.04, 55.77, 32.25, 10.39; MS (CI) m/z 244.2 [M+H]+; Anal. Ci₅Hi₇N0₂ requires C 74.05%, H 7.04%, N 5.76%, found C 74.03%, H 7.16%, N 5.63%.

Preparation of l-(6'-(trifluoromethyl)-[2,3'-bipyridin] -5-yl)propan-l-ol 3m

[00195] White solid (Yield 70%); 1H NMR (400 MHz, CDC1₃) 9.28 (s, IH), 8.71 (s, IH), 8.51 (dd, / = 8.2, 2.0 Hz, IH), 7.86 (dd, / = 8.1, 2.2 Hz, IH), 7.80 (d, / = 8.8 Hz, 2H), 4.77 (m, IH), 2.18 (bs, IH), 1.86 (q, / = 7.2 Hz, 2H), 0.99 (t, / = 7.4 Hz, 3H); δ ¹³C NMR (100 MHz, CDC1₃) δ 152.77, 148.93, 148.67, 140.32, 137.66, 135.96, 135.23, 121.12, 120.88, 120.86, 32.43, 10.24; MS (ES⁺) m/z 283 (M + H)⁺ Acc Mass Found: 283.1056, calculated 283.1058 for Ci₄Hi₄N₂OF₃. Preparation ofl-(6-(4-( trifluoromethoxy )phenoxy )pyridin-3-yl )propan-l -ol 3n

[00196] Yellow oil (Yield 72%). 1H NMR (400 MHz, CDC1₃) δ 8.02 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.50 (t, J = 6.6 Hz, 1H), 3.38 (brs, 1H), 1.83-1.62 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz,

CDC1₃) δ 162.95, 152.98, 145.78, 138.22, 135.79, 122.76, 122.45, 111.88, 73.21, 32.12, 10.27.

Preparation of l-( 6-(4-fluorophenoxy )pyridin-3-yl)propan-l -ol 3o

[00197] Yellow oil (Yield 80%). 1H NMR (400 MHz, CDC1₃) δ 7.99 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.06-7.03 (m, 4H), 6.80 (d, J = 8.2 Hz, 1H), 4.48 (t, J = 8.0 Hz, 1H), 3.75 (bs, 1H), 1.75- 1.63 (m, 2H), 0.85 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 163.41, 161.12, 158.71, 150.33, 145.75, 138.09, 135.45, 122.97, 122.89, 116.76, 116.53, 111.41, 73.13, 32.11, 10.35; MS (ES⁺) m/z 270 (M + Na)⁺ Acc Mass Found: 270.0902, calculated 270.0906 for

Preparation of 1 -(4-(3-methoxybenzyl)phenyl)propan-l -ol 3p

[00198] White solid (Yield 76%); 1H NMR (400 MHz, CDC1₃) 7.25-7.16 (m, 5H), 6.77 (dd, / = 7.2, 7.2 Hz, 2H), 6.73 (s, 1H), 4.55 (t, / = 6.7 Hz, 1H), 3.94 (s, 2H), 3.76 (s, 3H), 1.80 (bs, 1H), 1.79 (m, 2H), 0.90 (t, / = 7.2 Hz, 3H); δ ¹³C NMR (100 MHz, CDC1₃) δ 179.85, 160.11, 143.07, 142.83, 140.62, 129.84, 129.34, 126.55, 121.77, 115.23, 111.68, 55.55, 42.05, 32.23, 10.63; MS (ES⁺) m/z 257 (M + H)⁺

Preparation of tert-butyl 4-(l -hydroxypropyl)piperidine-l -carboxylate 3q

[00199] Prepared according to the general procedure for the preparation of alcohols 3. (Colorless liquid, 78%); 1H NMR (400MHz, CDC1₃), δ_Η 4.12 (bs, 2H, CH₂), 3.34-3.29 (m, 1H, CH), 2,67 (bs, 2H, CH₂), 1.91-1.10(m, 15H, CH/CH₂/CH₃), 0.97 (t, 3H, J = 7.4 Hz, CH₃); MS (ES+), [M + Na] ⁺ (100), , HRMS calculated for C₂₆Hi₉N0₄F₃NaCl, found.

Preparation ofl-(5-(4-( trifluorom hoxy )phenyl )pyridin-3-yl )propan-l -ol 3r

[00200] Prepared according to the general procedure for the preparation of alcohols 3. (clear yellow oil 32%). 1H NMR (400 MHz, CDC1₃) δ 8.73 (s, 1H), 8.57 (s, 1H), 7.88 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.77 (t, J = 6.2 Hz, 1H), 2.11 (s, 1H), 1.96 - 1.76 (m, 2H), 0.98 (t, / = 7.4 Hz, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 149.68, 147.70, 147.47, 140.20, 136.90, 135.62, 132.34, 129.05, 121.97, 73.92, 32.52, 10.35. ESI HRMS: m/z calculated for Ci₅Hi₅N0₂F₃ ([M+H]⁺) 298.1055 , found 298.1051.

General procedure for the preparation of ketones [4]

[00201] Pyridinium chlorochromate (30 mmol, 1.5 eq) was added to a solution of alcohol 3 (20 mmol, 1.0 eq) in DCM (35 mL) and the resulting mixture was stirred under nitrogen at room temperature (rt) for 1-2 hours. The reaction was then diluted with ether (500 mL) and filtered though a silica pad. The filtrate was concentrated under vacuum to give the crude product as a clear colourless oil. Where necessary purification by column chromatography (eluting with 5%- 10% EtOAc in hexane) gave ketone 4.

Preparation of 1 -(4-(4-fluorobenzyl)phenyl)propan-l -one 4a

[00202]Clear colourless oil (Yield 97%); 1H NMR (400 MHz, CDC1₃) δ_Η 7.9 (2H, m), 7.1 (2H, m), 7.0 (2H, m), 3.90 (2H, s), 3.0 (2H, q),1.20 (3H, t); ¹³C NMR (100 MHz, CDC1₃) 5_C 135.54, 130.71, 129.39, 115.72, 41.43, 32.13, 8.69; HRMS calcd for Ci₆Hi₅FO [M+Na]⁺ 265.0999 found 265.0997.

Preparation of 1 -(6-bromopyridin-3-yl)propan-l -one 4b

[00203] White solid (Yield 80%); MP 101 - 103°C; 1H-NMR (CDC1₃, 400 MHz): δ 8.91 (d, / = 2.1 Hz, 1H), 8.08 (dd, / = 8.3, 2.5 Hz, 1H), 7.61 (dd, / = 8.3, 0.6 Hz, 1H), 3.00 (q, / = 7.2 Hz, 2H), 1.25 (t, J = 12 Hz, 3H).

Preparation ofl-(4-(4-( trifluoromethoxy )benzyl)phenyl)propan-l -one 4c

[00204] White powder (Yield 99%); 1H NMR (400MHz, CDC1₃) δ_Η 7.91(d, 2H , J = 8.2 Hz, Ar), 7.25 (d, 2H, J = 8.2 Hz, Ar), 7.18 (d, 2H, J = 8.6 Hz, Ar), 7.13 (d, 2H, J = 8.6 Hz, Ar), 4.02 (s, 2H, ArCH₂Ar), 2.97 (q, 2H, J = 7.2 Hz, COCH₂), 1.21 (t, 3H, J = 7.2 Hz, CH₃); ¹³C NMR (lOOMHz, CDC1₃), 5c 200.8, 148.2, 146.1, 139.3, 135.7, 130.5, 129.5, 128.8, 119.6, 41.5, 32.1, 8.7; MS (ES+), [M + Na] ⁺ (100), 331.0, HRMS calculated for 331.0922 Ci₇Hi₅0₂F₃Na, found 331.0911.

Preparation of 1 -(4-benzylphenyl)propan-l -one 4d

[00205] White powder (Yield 94%); 1H NMR (400 MHz, CDC1₃): 7.94 (d, J=7.9Hz, 2H), 7.36 (d, J=7.9Hz, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=7.9Hz, 2H ), 4.05 (s, 2H), 3.00 (q, J=7.6Hz, 2H), 1.25 (t, /= 7.2Hz, 3H). ¹³C NMR (100 MHz, CDC1₃): 200.9, 146.9, 135.4, 129.5, 129.4, 129.3, 127.6, 126.9, 42.5, 32.2, 8.7. MS (ES+) m/z 247.1for [M+NH₄]⁺ and 279.2 for

[(M+CH₃OH)+Na]⁺.

Preparation of 1 -(3-(4-(trifluoromethoxy)benzyl)phenyl)propan-l -one 4e

[00206]Clear colourless oil (Yield 81.9%); 1H NMR (400 MHz, CDC1₃) δ_Η 7.80 (2H, m), 7.35 (2H, m), 7.15 (2H, m), 4.05 (2H, s), 3,0 (2H, q), 1.20 (3H, t); ¹³C NMR (100 MHz, CDC1₃) 5_C 133.80, 130.51, 127.60, 126.61, 121.55, 41.45, 32.27,8.61.

Preparation of 1 -(4-(4-methoxybenzyl)phenyl)propan-l -one 4f

[00207] White powder (Yield 90%); 1H NMR (400MHz, CDC1₃) δ_Η 7.91(d, 2H , J = 8.2 Hz, Ar), 7.25 (d, 2H, J = 8.2 Hz, Ar), 7.18 (d, 2H, J = 8.6 Hz, Ar), 7.13 (d, 2H, J = 8.6 Hz, Ar), 4.02 (s, 2H, ArCH₂Ar), 3.73 (s, 3H, CH₃), 2.97 (q, 2H, J = 7.2 Hz, COCH₂), 1.21 (t, 3H, J = 7.2 Hz, CH₃).

Preparation of 1 -(4-(4-Chlorophenoxy)phenyl)propan-l -one 4g

[00208] Colourless oil (1.45 g, yield 91%); 1H NMR (400 MHz, CDC1₃) δ_Η 1.20 (3H, m), 3,0 (2H, q), 7.0 (3H, m), 7.30 (2H, d), 7.90 (2H, m) ppm; ¹³C NMR (100 MHz, CDC1₃) 5_C 8.96 (IC, s) 31.97 (IC, s), 117. 89 (2C, s), 121.78 (2C, s), 130.15 (2C, d), 199.68 (IC, s) ppm. Anal. Calcd for Ci₅Hi₃Cl 0₂: C, 69.10%; H, 5.03%; Found C, 68.56%; H, 5.008%.

Preparation of l-( 2-fluoro-4-(4-( trifluoromethoxy )benzyl)phenyl)propan-l -one 4h

[00209] Oil (Yield 88%); 1H NMR (400MHz, CDC1₃) δ Missing; MS (ES+) m/z 349 [M + Na]⁺ Acc Mass Found 349.0827, calculated 349.0828 for Ci₇Hi₄0₂F₄Na.

Preparation of 1 -(2-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)phenyl)propan-l -one 4i

[00210]White powder (Yield 66%) 1H NMR (400MHz, CDC1₃), δ_Η 7.85 (t, 1H, J = 7.8 Hz, Ar), 7.68-7.62 (m, 2H, Ar), 7.06 (dd, 1H, J = 8.0 Hz, 1.4 Hz, Ar), 6.94 (dd, 1H, J = 11.7 Hz, 1.4 Hz, Ar), 4.11 (s, 2H, ArCH₂Ar), 8.62 (s, 1H, Ar), 2.98 (q, 2H, J = 7.2 Hz, CH₂CO), 1.19 (t, 3H, J = 7.2 Hz, CH₃) ¹³C NMR (100MHz, CDC1₃), δ_α 199.0, 163.8, 161.3, 150.7, 145.3, 138.6, 138.0, 131.7, 125.3, 124.6, 120.9, 117.5, 117.2, 37.7, 37.2, 8.4 MS (ES+), [M + Na] ⁺ (100), 334.1, HRMS calculated for 334.0831 Ci₆Hi₃NOF₄Na, found 334.0821.

Preparation of 1 -(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)propan-l -one 4j

[00211] White solid. (Yield 85 %); 1H NMR (400 MHz, CDC1₃) δ 9.24 (d, / = 2.2 Hz, 1H, H-2), 8.32 (dd, / = 8.3, 2.2 Hz, 1H, H-4), 8.18 - 8.04 (m, 2H, H-8), 7.83 (dd, / = 8.3, 0.6 Hz, 1H, H-5), 7.35 (d, / = 8.1 Hz, 2H, H-9), 3.07 (q, J = 12 Hz, 2H, CH₂), 1.28 (t, / = 7.2 Hz, 3H, CH₃); ¹³C NMR (101 MHz, CDC1₃) δ 199.55 (C=0), 159.63, 151.00, 150.15 (C-2), 137.15, 136.80, 130.98, 129.30 (C-8), 121.54 (C-9), 120.84 (q, / = 257 Hz, OCF₃), 120.46, 32.60 (CH₂), 8.35 (CH₃); HRMS (ESI) Ci₅Hi₃N0₂F₃ [M+H]⁺ requires 296.0898, found 296.0901; Anal. Ci₅Hi₂N0₂F₃ requires C 61.02%, H 4.10%, N 4.74%, found C 60.42%, H 4.23%, N 4.40%.

Preparation of l-(6-( 2,4-difluorophenyl)pyridin-3-yl )propan-l -one 4k

[00212] Yellow solid (Yield, 70 %); 1H NMR (400 MHz, CDC1₃) δ 9.25 (d, / = 1.6 Hz, 1H, H-2), 8.30 (dd, / = 8.3, 2.3 Hz, 1H), 8.11 (td, J = 8.9, 6.6 Hz, 1H, H-12), 7.89 (dd, / = 8.3, 1.4 Hz, 1H), 7.09 - 7.01 (m, 1H, H-l l), 6.95 (ddd, 7^" = 11.3, 8.7, 2.5 Hz, 1H, H-9), 3.06 (q, / = 7.2 Hz, 2H, CH₂), 1.28 (t, / = 7.2 Hz, 3H, CH₃); HRMS (ESI) Ci₄Hi₂NOF₂[M+H]⁺ requires 248.0887, found 248.0892;

Preparation of 1 -(6-(4-methoxyphenyl)pyridin-3-yl)propan-l -one 41

[00213] White solid (Yield 82 %); 1H NMR (400 MHz, CDC1₃) δ 9.20 (dd, / = 2.3, 0.8 Hz, 1H, H-2), 8.27 (dd, / = 8.4, 2.3 Hz, 1H, H-4), 8.09 - 7.98 (m, 2H, H-8), 7.78 (dd, / = 8.4, 0.8 Hz, 1H, H-5), 7.14 - 6.95 (m, 2H, H-9), 3.89 (s, 3H, OCH₃), 3.05 (q, / = 7.2 Hz, 2H, CH₂), 1.27 (t, / = 7.2 Hz, 3H, CH₃); ¹³C NMR (101 MHz, CDC1₃) δ 199.71 (C=0), 161.73, 160.77, 150.13 (C-2), 136.55 (C-4), 131.16, 130.09, 129.18 (C-8), 119.67 (C-5), 114.72 (C-9), 55.83 (OCH₃), 32.47 (CH₂), 8.44 (CH₃); MS (CI) Ci₅Hi₆N0₂ [M+H]⁺ 242.2; Anal. Ci₅Hi₅N0₂ requires C 74.67%, H 6.27%, N 5.81%, found C 74.44%, H 6.53%, N 5.64%.

Preparation of l-(6'-(trifluoromethyl)-[2,3'-bipyridin] -5-yl)propan-l -one 4m

[00214] White solid (Yield 90%); 1H NMR (400 MHz, CDC1₃) 9.37 (s, IH), 9.30 (s, IH), 8.59 (dd, 7 = 8.2, 1.9 Hz, IH), 8.39 (dd, / = 8.3, 2.2 Hz, IH), 7.94 (d, 7 = 8.3 Hz, IH), 7.84 (d, 7 = 8.2 Hz, IH), 3.09 (q, / = 7.2 Hz, 2H), (t, / = 7.2 Hz, 3H); δ ¹³C NMR (100 MHz, CDC1₃) δ 199.31, 156.85, 150.50, 149.41, 149.06, 137.10, 136.75, 136.52, 131.92, 121.09, 120.99, 120.96, 32.75, 8.29; MS (ES⁺) m/z 281 (M + H)⁺ Acc Mass Found: 281.0911, calculated 281.0902 for

C₁₄H₁₂N₂OF₃.

Preparation ofl-(6-(4-( trifluoromethoxy )phenoxy )pyridin-3-yl )propan-l -one 4n

[00215] Yellow oil (Yield 78%). 1H NMR (400 MHz, CDC1₃) δ 8.67 (s, IH), 8.20 (d, J = 8.0 Hz, IH), 7.18 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.0 Hz, IH), 2.85 (q, J = 8.0 Hz, 2H), 1.13 (t, J = 8.0 Hz, 3H).

Preparation of l-( 6-(4-fluorophenoxy )pyridin-3-yl)propan-l -one 4o

[00216] Yellow oil (Yield 80%). 1H NMR (400 MHz, CDC1₃) δ 8.76 (s, IH), 8.28 (d, J = 8.2 Hz, IH), 7.13-7.11 (m, 4H), 6.98 (d, J = 8.2 Hz, IH), 2.94 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 198.56, 166.53, 161.57, 159.14, 149.40, 149.35, 139.63, 128.37, 123.47, 123.39, 116.93, 116.69, 111.66, 32.20, 8.42; MS (ES⁺) m/z 268 (M + Na)⁺ Acc Mass Found: 268.0753, calculated 268.0750 for Ci₄Hi₂N0₂FNa.

Preparation of 1 -(4-(3-methoxybenzyl)phenyl)propan-l -one 4p

[00217] Prepared by the general procedure for the preparation of ketone 3. Colourless oil (Yield 93%); 1H NMR (400 MHz, CDC1₃) 7.89 (d, / = 8.4 Hz, 2H), 7.28 (d, / = 8.4 Hz, 2H), 7.22 (dd, / = 7.6, 7.6 Hz, IH), 6.76 (m, 2H), 6.71 (s, IH), 4.00 (s, 2H), 3.77 (s, 3H), 2.97 (q, / = 7.2 Hz, 2H), 1.21 (t, J = 7.3 Hz, 3H); δ ¹³C NMR (100 MHz, CDC1₃) δ 200.90, 160.21, 146.73, 142.06, 135.44, 130.01, 129.49, 128.71, 121.76, 115.27, 111.95, 55.57, 42.30, 32.13, 8.71; MS (ES⁺) m/z 255 (M + H)⁺ Preparation of l-(4-(morpholinomethyl)phenyl)propan-l-ol 4q

[00218] To a solution of 4-cyanobenzylbromide (2.28g, 11.6 mmol) in 25 ml of anhydrous acetonitrile was added morpholine (1.5 ml, 17.4 mmol) followed by K₂CO₃ (0.69 g, 5mmol). The reaction was stirred at rt under N₂ atm for 30 min and subsequently quenched with water and extracted with ethylacetate. The organic layer was dried over MgS0₄ and concentrated in vacuo. The crude product was purified by column chromatography (hexane - 30% EtOAc/hexane)..

[00219] White solid (Yield 96%); 1H NMR (400 MHz, CDC1₃) δ 7.61 (d, J=7.9 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 3.71(s, 4H), 3.55(s, 2H), 2.44(s, 4H); ¹³C NMR (100 MHz, CDC1₃): 144.2, 132.5, 129.8, 119.2, 111.3, 67.2, 63.1, 54.1.

[00220] To a solution of cyano compound (1.01 g, 5 mmol) in 5 ml of dry THF at 0 °C was added a 1M solution EtMgBr in THF (6 ml, 6 mmol) and Cul (5 mg, 0.05 mmol). The reaction mixture was allowed to warm to rt and stirred at rt overnight. The reaction was quenched with 2N HC1 and extracted with EtOAc, organic extracts were dried over MgS0₄ and concentrated in vacuo. The crude product was purified by column chromatography to give 4q.

[00221] White solid (Yield 77%); 1H NMR (400 MHz, CDC1₃) δ 7.92 (d, / = 8.3 Hz, 2H), 7.43 (d, / = 8.3 Hz, 2H), 3.78 - 3.67 (m, 4H), 3.55 (s, 2H), 3.00 (q, / = 7.2 Hz, 2H), 2.52 - 2.40 (m, 4H), 1.27 - 1.15 (t, J=7.2 Hz, 3H). MS (ES⁺) m/z 234 (M + H)⁺ Acc Mass Found: 234.1502, calculated 234.1494 for Ci₄H₂₀NO₂

Preparation of 1 -(4-(4-(trifluoromethoxy)phenoxy)phenyl)propan-l -one 4r

[00222] 4-Tri-fluoromethoxy-phenyl boronic acid (1.34 g, 6.5 mmol) was added to a solution of 4' -hydroxypropiophenone (0.75 g, 5 mmol) and copper (II) acetate (0.91 g, 5 mmol) in DCM (40 mL). Freshly prepared 4 Amolecular sieves were added and the flask was placed under an inert atmosphere of nitrogen. Triethylamine (3.5 mL, 25 mmol) was added and the resultant green solution was stirred at room temperature for 24 hours. The solution was filtered through a pad of silica gel and washed with excess EtOAc. The filtrate was concentrated under vacuum to afford a yellow oil. The product was purified by column chromatography (eluting with 15% EtOAc in n- hexane) to yield ketone 4r. [00223] Clear oil. (Yield 63 %); 1H NMR (400 MHz,CDCl₃) δ_Η7.97 (d, 2H, J = 8.8, Ar), 7.24 (d, 2H, J = 8.5, Ar), 7.08 (d, 2H, J = 8.8, Ar), 7.02 (d, 2H, J = 8.8, Ar), 2.98 (q, 2H, J = 7.2, CH₂), 1.23 (t, 3H, J = 7.2, CH₃); ¹³C NMR (100MHz, CDC1₃), 5_C 199.8, 161.5, 154.5, 132.6, 130.7, 123.2, 121.4, 118.0, 32.0, 8.7; HRMS calcd for Ci₆Hi₃0₃F₃Na [M+Na]⁺ 333.0715 found

333.0713.

Preparation of tert-butyl 4-propionylpiperidine-l-carboxylate 4s

[00224] Prepared according to the general procedure for the preparation of ketones 4. (Colorles oil, 65%); 1H NMR (400MHz, CDC1₃), δ_Η 4.77 (bs, 2H, CH₂), 2.77 (t, 2H, J = 12.2 Hz, CH₂), 2.50-2.43 (m, 1H, CH), 2.48 (q, 2H, J = 7.3 Hz, CH₂CO), 1.80 (d, 2H, J = 12.2 Hz, CH₂), 1.58 1.47 (m, 2H, CH₂), 1.45 (s, 9H, CH₃), 1.05 (t, 3H, J = 7.3 Hz, CH₃); MS (ES+), [M + Na] ⁺ (100), 264.2.

Preparation ofl-(5-(4-( trifluoromethox )phenyl )pyridin-3-yl )propan-l -one 4t

[00225] H₂0 was solvated in 15 mL of DCM by drawing the solvent mixture into and expelling it from a disposable pipette several times. The wet DCM was added slowly to a vigorously stirring solution of alcohol (280 mg, 0.94 mmol, 1.0 eq.) and DMP (599 mg, 1.41 mmol, 1.5 eq.) in 5 mL of DCM. The cloudy mixture was left for 15 minutes and then diluted with ether, concentrated on rotavap. The residue was taken up in 30 mL of ether and washed with 20 mL of 1:1 10% Na₂S₂0₃/ sat.NaHC0₃, followed by water and brine. The aqueous washings were back-extracted with ether and this organic layer was washed with water and brine. The combined organic layer was dried over MgS0₄ and evaporated to dryness to yield a desired product (247 mg, 92%).1H

NMR (400 MHz, CDC1₃) δ 9.17 (d, / = 2.0 Hz, 1H), 8.98 (d, / = 2.3 Hz, 1H), 8.41 (t, / = 2.2 Hz, 1H), 7.65 (d, / = 8.8 Hz, 2H), 7.37 (d, / = 8.0 Hz, 2H), 3.10 (q, / = 7.2 Hz, 2H), 1.29 (t, / = 7.2 Hz, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 199.73, 152.00, 150.05, 148.85, 135.97, 135.91, 133.88, 132.48, 129.14, 122.11, 32.84, 8.32. ESI HRMS: m/z calculated for Ci₅Hi₃N0₂F₃ ([M+H]⁺) 296.0898 , found 296.0899.

Preparation of 1 -(piperidin-4-yl)propan-l -one 4u

O [00226] To a stirred solution (1.5g, 6.22 mmol) of tert-butyl 4-propionylpiperidine-l-carboxylate in THF (lOmL) was added 2 mL of concentrated HC1 and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized by adding drops of NaOH and extracted with EtOAc (3 x 20mL). The combined organic layer was dried with Mg₂S0₄ and concentrated go give the desired product. (Colorless liquid, 75%); 1H NMR (400MHz, CDC1₃), δ_Η 3.15 (dt, 2H, J = 12.6 Hz, 3.6 Hz, CH₂), 2.71 (bs, 1H, NH), 2.70-2.62 (m, 2H, CH₂), 2.47 (q, 2H, J = 7.3 Hz, CH₂CO), 1.85-1.80 (m, 2H, CH₂), 1.77-1.66 (m,lH, CH), 1.62-1.49 (m, 2H, CH₂), 1.05 (t, 3H, J = 7.3 Hz, CH₃); MS (CI+), [M + H] ⁺ (100), 142.2.

Preparation ofl-(l-(4-( trifluoromethoxy )benzyl )piperidin-4-yl)propan-l -one 4v

[00227] 4-Trifluoromethoxy benzyl bromide (1.52g, 5.94 mmol) was first added to a solution of l-(piperidin-4-yl)propan-l-one (0.7g, 4.95 mmol) in DMF (20mL) followed by K₂C0₃ (1.4g, 9.9 mmol) and heated overnight at 120°C. The DMF was removed under vacuum and the crude mixture was partitioned between water (10 mL) in EtOAc (30 mL). The organic layer was washed with brine and concentrated. Purification by flash column chromatography afforded the desired product. (Colorless oil, 50%); 1H NMR (400MHz, CDC1₃), δ_Η 7.33 (d, 2H, J = 8.3 Hz, Ar), 7.15 (d, 2H, J = 8.3 Hz, Ar), 3.48 (s, 2H, NCH₂Ar), 2.88 (dd, 2H, J = 8.6 Hz, 3.1 Hz, CH₂), 2.47 (q, 2H, J = 7.3 Hz, CH₂CO), 2.32 (tt, 1H, J = 11.4 Hz, 3.9 Hz, CH), 2.09-1.96 (m, 2H, CH₂), 1.80 (d, 2H, J = 11.3 Hz, CH₂), 1.74-1.62 (m, 2H, CH₂), 1.04 (t, 3H, J = 7.3 Hz, CH₃); MS (ES+), [M + H] ⁺ (100), 316.2, HRMS calculated for 316.1524 Ci₆H₂iN0₂F₃, found 316.1525.

General procedure for the preparation of oxazole [6]

[00228] The appropriately substituted isobenzofuran-l,3-dione 5 (10 mmol, 1.0 eq) was suspended in chlorobenzene (25 mL) under nitrogen and stirred for 5 minutes. 2-amino-2- methylpropan-l-ol (14mmol, 1.4 eq) was added to the suspension via a syringe followed by zinc chloride (1 mmol, 0.1 eq). The mixture was heated to 140 C and was allowed to reflux for 18 hours. The solvent was removed under vacuum and the crude product extracted with EtOAc (2 x 25 mL), washed with brine, dried over MgS0₄ and concentrated under vacuum to afford a brown crystalline solid. Purification by column chromatography (eluting with n-hexane increasing to 10% EtOAc/n-Hexane) gave oxazole 6. Preparation of2-( 5,5-dimethyl-4,5-dihydrooxazol-2-yl)aniline 6a

[00229] White solid (Yield 45%); 1H NMR (400 MHz, CDC1₃): δ 7.67 (d, / = 7.9 Hz, 1H), 7.27 7.10 (m, 1H), 6.65 (m, 2H), 6.08 (s, 2H, NH₂), 3.97 (s, 2H), 1.35 (s, 6H). ¹³C NMR (101 MHz, CDC1₃): δ 162.47, 148.93, 132.27, 129.88, 116.41, 116.02, 109.73, 77.75, 68.23, 29.15.

Preparation of 5-chloro-2-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)aniline 6b

[00230] White solid (Yield 43%); 1H NMR (400 MHz, CDC1₃) δ 7.51 (d, / = 8.5 Hz, 1H), 6.61 (s, 1H), 6.54 (d, / = 8.5 Hz, 1H), 6.13 (s, 2H, NH₂), 3.92 (s, 2H), 1.29 (s, 6H). MS (CI) m/z 225 (M + H)⁺ Acc Mass Found: 225.0790, calculated 225.0789 for CnHi₄N₂OCl.

Preparation of4-Chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline 6c

[00231] Yellow/ brown powder (Yield 47 %); 1H NMR (400 MHz, CDC1₃) δ_Η 7.60 (1H, m), 7.10 (1H, m), 6.51 (1H, d), 3.9 (1H, s), 1.30 (6H, s); ¹³C NMR (100 MHz, CDC1₃) δ_α 132.12, 129.25, 110.64, 77.13, 68.44, 29.06.

Preparation 6d

[00232] Yellow solid (Yield 56 %); 1H NMR (400 MHz, CDC1₃) δ 7.76 (d, / = 8.2 Hz, 1H, H-3), 6.92 (s, 1H, H-6), 6.86 (d, / = 8.3 Hz, 1H, H-4), 6.31 (s, 2H, NH₂), 4.02 (s, 2H, CH₂), 1.38 (s, 6H, CH₃); HRMS (ESI) Ci₂Hi₄N₂OF₃ [M+H]⁺ requires 259.1058, found 259.1065. Preparation of2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-methoxyaniline 6e

[00233] White solid (126 mg, 10.5%); 1H NMR (400 MHz, CDC1₃) δ 1H NMR (400 MHz, CDC1₃) δ 7.59 (d, / = 8.8 Hz, 1H), 6.25 (dd, / = 8.8, 2.5 Hz, 1H), 6.18 (d, / = 2.4 Hz, 1H), 6.14 (s, 2H), 3.96 (s, 2H), 3.78 (s, 3H), 1.35 (s, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 162.94, 162.29, 150.57, 131.39, 103.87, 103.49, 99.63, 68.02, 55.54, 29.19. ES HRMS: m/z calculated for C12H17N2O2 ([M+H]⁺) 221.1285, found 221.1285.

Preparation of2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluoroaniline 6f

[00234] Yellow solid (Yield 60 %); 1H NMR (400 MHz, CDC1₃) δ 7.64 (dd, / = 9.3, 6.6 Hz, 1H, H-3), 6.38 - 6.32 (m, 2H, H-4 + H-5), 6.26 (s, 2H, NH₂), 3.98 (s, 2H, CH₂), 1.36 (s, 6H, CH₃).

¹³C NMR (101 MHz, CDC1₃) δ 165.59 (d, / = 248.3 Hz, C-F), 161.86 (C=N), 150.84, 132.05 (C- 3), 106.29, 103.99, 101.77, 77.44 (OCH₂), 68.20 (C(CH₃)₂), 29.11 (CH₃).

HRMS (CI) CiiHi₄N₂OF [M+H]⁺ requires 209.1085, found 209.1084; Preparation of4-chloro-2-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluoroaniline 6g

[00235] White solid (41% yield); 1H NMR (400 MHz, CDC1₃) δ 7.68 (d, / = 8.35 Hz, 1H), 6.35 (d, / = 10.97, 1H), 6.20 (bs, 2H), 3.86 (s, 2H), 1.26 (s, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 160.16, 159.55, 157.67, 147.86, 130.33, 106.46, 105.55, 101.71, 67.01, 27.60; HRMS (ESI) CnHi₃N₂OFCl [M+H]⁺ requires 243.0700, found 243.0695.

Preparation of 5-chloro-2-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)-4-fluoroaniline 6h

[00236] White solid (30% yield); 1H NMR (400 MHz, CDC1₃) δ 7.35 (d, / = 10.03 Hz, 1H), 6.63 (d, / = 6.21, 1H), 5.95 (bs, 2H), 3.91 (s, 2H), 1.28 (s, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 159.72, 159.69, 149.53, 147.19, 144.23, 123.62, 115.32, 107.20, 67.17, 27.60; HRMS (ESI) CiiHi₃N₂OFCl [M+H]⁺ requires 243.0700, found 243.0696.

Preparation of2-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)-3,5-difluoroaniline 6i

[00237] White solid (Yield 52%); 1H NMR (400 MHz, CDC1₃) 6.44 (bs, 2H), 6.43-6.09 (m, 2H), 4.05 (s, 2H), 1.36 (s, 6H); δ ¹³C NMR (100 MHz, CDC1₃) δ 166.24, 166.07, 165.39, 165.23, 163.77, 163.60, 162.84, 160.67, 160.63, 151.82, 151.74, 151.67, 151.60, 97.92, 97.88, 97.67, 97.64, 96.08, 95.97, 93.40, 93.13, 92.86, 66.83, 29.02; MS (ES⁺) m/z 227 (M + H)⁺.

Preparation of2-( 5,5-dimethyl-4,5-dihydrooxazol-2-yl)-4,5-difluoroaniline 6j

[00238]W ite solid (Yield 55%); 1H NMR (400 MHz, CDC1₃) 7.48 (dd, / = 11.5, 9.0 Hz, 1H), 6.45 (dd, / = 12.1, 6.7 Hz, 1H), 6.08 (bs, 2H), 4.00 (s, 2H), 1.36 (s, 6H); δ ¹³C NMR (100 MHz, CDC1₃) δ 161.16, 154.29, 151.94, 146.36, 146.26, 143.33, 140.99, 117.98, 117.96, 117.79, 117.76, 105.16, 103.79, 103.59, 68.50, 29.06.

Preparation of 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-methoxyaniline 6k

[00239] Yellow solid (1.06 g, 48.4%); 1H NMR (400 MHz, CDC1₃) δ 7.21 (d, / = 3.0 Hz, 1H), 6.86 (dd, / = 8.8, 3.0 Hz, 1H), 6.66 (d, / = 8.8 Hz, 1H), 5.76 (s, 2H), 4.00 (s, 2H), 3.76 (s, 3H), 1.37 (s, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 162.22, 150.98, 143.41, 120.80, 117.60, 112.71, 109.86, 68.37, 56.32, 29.13. General procedure for the synthesis of quinolones [7 and 8] [1]

7 and 8

[00240] The appropriately substituted oxazole 5 (4 mmol, 1 eq) was added to a solution of ketone 4 (4 mmol, 1 eq) and para-toluenesulfonic acid (20 mol%) in n-Butanol (10 mL). The reaction mixture was heated to 130°C under nitrogen and stirred for 24 hours. The solvent was removed under vacuum and water (20 mL) added. The aqueous solution was extracted with EtOAc (3 x 20 mL), dried over MgS0₄ and concentrated under vacuum. The product was purified by column chromatography (eluting with 20% -80% EtOAc in n-hexane) to give quinolone 7.

Preparation of2-(4-(4-fluorobenzyl)phenyl)-3-methylquinolin( lH)-one 7a

[00241] White powder. (Yield 20%); 1H NMR (400 MHz, MeOD) δ_Η 7.3 (6H, m), 7.0 (1H, m), 4.1 (2H, s), 3.65 ( 1H, s), 2.1 (3H, s); HRMS calcd for C₂₃Hi₈FNO [M-H]^~ 343.1372 found 342.1279; Anal. Calcd for C₂₃Hi₈FNO: C, 80.45%; H, 5.28%; N, 4.08%; F, 5.53%; Found C, 77.88%; H, 5.18%; N 4.07%; F, 5.5%.

Preparation of 3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one 7b

[00242] White solid (Yield 28%); M.P 207-208 °C; 1H NMR (400 MHz, CDC1₃) δ 8.24 (d, / = 8.2 Hz, 1H), 7.61 (d, / = 8.3 Hz, 1H), 7.54 (t, / = 7.5 Hz, 1H), 7.42 (d, / = 8.5 Hz, 2H), 7.31 - 7.17 (m, 3H), 7.03 (dd, / = 8.6, 6.9 Hz, 4H), 2.02 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ

179.14, 158.36, 155.06, 148.33, 145.44, 139.67, 131.94, 130.92, 130.58, 125.83, 123.79, 123.76,

123.15, 120.76, 118.57, 118.17, 116.35, 12.76; MS (ES⁺) m/z 412 (M + H)⁺ Acc Mass Found: 412.1175, calculated 412.1161 for C₂₃Hi₇N0₃F₃.

Preparation of2-(6-bromopyridin-3-yl)-3-methylquinolin-4(lH)-one 7c

[00243] White solid (Yield 30%); MP 283 - 284 °C; 1H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.64 (d, / = 2.4 Hz, 1H), 8.13 (d, / = 7.6 Hz, 1H), 8.02 (dd, / = 8.2, 2.4 Hz, 1H), 7.90 (d, / = 8.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.56 (d, 7 = 8.2 Hz, 1H), 7.33 (t, J = 1.5 Hz, 1H), 1.89 (s, 3H); ES+ HRMS: m/z found 315.0130, [Ci₅HnN₂OBr + H]⁺ requires 315.0133.

Preparation of 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one

7d

[00244] White solid (Yield 30%); MP 240-242 °C; 1H NMR (400 MHz, CDC1₃) δ 8.27 (d, / = 8.8 Hz, 1H), 7.62 (s, lH),7.52-7.45 (m, 4H), 7.43-7.34 (m, 3H), 7.24 (d, J = 1.9 Hz, 2H), 4.15 (s, 2H), 2.05 (s, 3H); MS (ES⁺) m/z 444 (M + H)⁺ Acc Mass Found: 444.0962, calculated 444.0978 for C₂₄H₁₈NO₂F₃CI.

Preparation of 3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7e

[00245] White powder (Yield 36%); M.P 212-214 °C; 1H NMR (400MHz, DMSO) δ_Η 2.01 (s, 3H, J = CH₃), 3.96 (s, 2H, ArCH₂Ar), 7.11 (d, 2H, J = 8.1 Hz, Ar), 7.16 (d, 2H, J = 8.6 Hz, Ar), 7.20 (d, 2H, J = 8.0 Hz, Ar), 7.26 (dt, 1H, J = 1.5 Hz, 8.1 Hz, Ar), 7.9 (d, 2H, J = 8.1 Hz, Ar), 7.56 (dt, 1H, J = 1.4 Hz, 8.3Hz, Ar), 7.60 (d, 1H, J = 8.1 Hz, Ar), 8.27 (d, 1H, J = 8.3 Hz, Ar), 8.98 (s, 1H, NH); ¹³C NMR (100MHz, DMSO), δ_α 12.9, 41.3, 116.6, 118.0, 121.5, 123.8, 126.4, 129.4, 130.6, 132.0, 133.8, 139.5, 142.4, 149.0, 178.7; MS (ES+), [M + H] ⁺ (100), 410.1, HRMS calculated for 410.1368 C₂₄Hi₉N0₂F₃, found 410.1348.

Preparation of2-(4-benzylphenyl)-3-methylquinolin-4( lH)-one 7f

[00246] White solid (Yield 42%); M.P 200-201°C; 1H NMR (400 MHz, MeOD) 8.29 (d, / = 8.73 Hz, 2H ), 7.65-7.02 (m, 12H), 4.10 (s, 2H), 2.05 (s, 3H); ¹³C NMR (100 MHz, MeOD ) 180.4, 151.8, 145.3, 142.6, 141.3, 134.6, 133.4, 130.7, 130.8, 130.5, 130.4 130, 127.7, 126.6, 125.1, 124.9, 119.6, 117.2, 43.2, 12.5; MS (ES+) m/z 326 [M+H]⁺. Preparation of 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one

[00247] White solid (Yield 32%); M.P = 290-292 °C; 1H NMR (400 MHz, CDC1₃) δ 8.27 (d, / = 8.7 Hz, IH), 7.51-7.40 (m, 3H), 7.28-7.22 (m, 3H), 7.18-7.05 (m, 4H), 2.06 (s, 3H); MS (ES⁺) m/z 446 (M + H)⁺ Acc Mass Found: 446.0750, calculated 446.0771 for C₂₃Hi₆N0₃F₃Cl.

Preparation of 3-methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 7h

[00248] White solid (Yield 30%); M.P: 183-184 °C; 1H NMR (400 MHz, CDC1₃) δ 11.16 (s, IH), 8.12 (d, / = 8.2 Hz, IH), 7.84 (d, / = 8.1 Hz, IH), 7.67 - 7.51 (m, IH), 7.32 - 7.16 (m, 4H), 7.15 - 6.93 (m, 5H), 3.79 (s, 2H), 1.84 (s, 3H). ¹³C NMR (100 MHz, CDC1₃) δ 178.81, 148.83, 148.04, 141.25, 140.09, 139.43, 135.97, 131.83, 130.47, 130.04, 129.54, 128.99, 127.20, 125.90, 124.02, 123.62, 121.38, 118.79, 116.24, 41.19, 12.79; MS (ES⁺) m/z 410 [M + H]⁺ Acc Mass Found: 410.1367, calculated 410.1368 for C₂4Hi₉N0₂F₃. Preparation of2-(4-(4-methoxybenzyl)phenyl)-3-methylquinolin-4(lH)-one 7i

[00249] White solid (Yield 32%); M.P 193°C; 1H NMR (400 MHz, MeOD) 8.32 (d, / = 8.02 Hz, IH ), 7.70 (d, / = 7.97 Hz, IH), 7.60-7.52 (m, 4H), 7.45-7.36 (m, 4H), 7.20 (d, J = 1.91 Hz, IH), 6.92-6.88 (m, IH), 4.05 (s, 2H), 3.75 (s, 3H), 2.05 (s, 3H); ¹³C NMR (100 MHz, MeOD ) 180.4, 151.8, 145.3, 142.6, 141.3, 134.6, 133.4, 130.7, 130.8, 130.5, 130.4 130, 127.7, 126.6, 125.1, 124.9, 119.6, 117.2, 43.2, 12.5; MS (ES+) m/z 326 [M+H]⁺.

Preparation of 7-Chloro-2-(4-(4-fluorobenzyl)phenyl)-3-methylquinolin-4( lH)-one 7j

[00250] White powder (Yield 16%); 1H NMR (400 MHz, CDC1₃) δ_Η 8.3 (IH, m), 7.25-7.50 (8H, m), 7.0 (IH, m), 4.10 (2H, s), 2.0 (3H, s); HRMS calcd for C₂₃Hi₇ClFNO [M-H]^" 376.090 found 376.0887.

Preparation of 3-methyl-2-(4-(morpholinomethyl)phenyl)quinolin-4(lH)-one 7k

[00251] White powder (Yield 32%); M.P: 230-232°C; 1H NMR (400 MHz, MeOD) δ 8.29 (d, / = 8.3 Hz, IH), 7.66 (t, / = 8.3 Hz, IH), 7.61 - 7.48 (m, 5H), 7.39 (t, / = 8.1 Hz, IH), 4.90 (s, 2H), 3.77 - 3.69 (m, 4H), 2.51 (d, / = 4.0 Hz, 4H), 2.04 (s, 3H); MS (ES⁺) m/z 335 (M + H)⁺ Acc Mass Found: 335.1753, calculated 335.1760 for C₂iH₂₃N₂0₂.

Preparation of 7-chloro-3-methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one

71

[00252] White powder (Yield 30%); M.P 176-177 °C; 1H NMR (400 MHz, CDC1₃) δ 8.42 (s, IH), 8.24 (d, / = 8.7 Hz, IH), 7.46 (t, / = 7.6 Hz, IH), 7.32 (dd, / = 15.7, 8.5 Hz, 5H), 7.25 - 7.18 (m, 2H), 7.14 (d, / = 8.3 Hz, 2H), 4.04 (s, 2H), 2.01 (s, 3H); MS (ES⁺) m/z 444 [M + H]⁺ Acc Mass Found: 444.0959, calculated 444.0978 for C₂₄Hi₈N0₂F₃Cl.

Preparation of 6-chloro-3-methyl-2-(3-(3-( trifluoromethoxy)benzyl)phenyl)quinoline-4( lH)-one 7m

[00253] White powder (Yield 20%); 1H NMR (400 MHz, CDC1₃) δ_Η 4.10 (2H, s), 7.10-7.40 (8H, m), 7.50 (2H, m), 8.20 (IH, s), 8.40 (IH, s) ppm; HRMS calcd for C₂₄Hi₇ClF₃N0₂ [M-H]^" 443.0900 found 442.0835; Anal. Calcd for C₂₄Hi₇Cl F₃N0₂: C, 64.95%; H, 3.86%; N, 3.16%; F, 12.84%; CI, 7.99% Found C, 63.92%; H, 4.05%; N 3.38%; F, 11.90%; CI, 7.40%.

Preparation of2-(4-bromophenyl)-3-methylquinolin-4( lH)-one 7n

[00254] White solid (Yield 30%); MP 251 - 253 °C; 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 8.12 (d, / = 8.1 Hz, 1H), 7.80 (d, / = 8.3 Hz, 1H), 7.68 - 7.46 (m, 4H), 7.31 (t, / = 7.1 Hz, 1H), 1.88 (s, 3H); ES+ HRMS: m/z found 314.0180, [Ci₆Hi₂NOBr+H]⁺ requires 314.0181; Anal. Calcd for Ci₆Hi₂NOBr: C, 61.17; H, 3.85; N, 4.46. Found: C, 61.04; H, 4.00; N, 4.84. Preparation of 6-chloro-7-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin- 4(lH)-one 7o

[00255] White solid (Yield 34%); m.p. 245-246 °C; 1H NMR (400 MHz, MeOD) δ 8.21 (d, / = 8.2 Hz, 1H), 7.55-7.40 (m, 7H), 7.32-7.28 (d, / = 8.2 Hz, 2H), 4.19 (s, 2H), 1.88 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 175.5, 159.9, 157.4, 148.6, 147.1, 143.0, 140.9, 139.5, 139.4, 132.9, 130.9, 129.5, 129.3, 127.5, 121.7, 121.5, 121.0, 119.2, 115.8, 115.6, 115.5, 105.6, 105.4, 12.4; MS (ES⁺) m/z 462 (M + H)⁺ Acc Mass Found: 462.0869, calculated 462.0884 for

C₂₄H₁₇N0₂F₄C1.

Preparation of 7-chloro-6-fluoro-3-methyl-2-( 4-(4-( trifluoromethoxy )benzyl )phenyl )quinolin- 4(lH)-one 7p

[00256] White solid (Yield 27%); m.p. 243-245 °C; 1H NMR (400 MHz, MeOD) δ 8.27 (d, / = 8.8 Hz, 1H), 7.62-7.45 (m, 5H), 7.43-7.34 (m, 2H), 7.26 (d, / = 8.0 Hz, 2H), 4.11 (s, 2H), 1.89 (s, 3H); MS (ES⁺) m/z 462 (M + H)⁺ Acc Mass Found: 462.0870, calculated 462.0884 for

Preparation of 7-chloro-2-(2-fluoro-4-(4-(trifluoromethoxy)benzyl)phenyl)-3-methylquinolin- 4(lH)-one 7q

[00257] White solid (Yield 35%); m.p. 215-216°C; 1H NMR (400 MHz, CDC1₃) δ 8.28 (d, / = 8. Hz, 1H), 7.36-7.01 (m, 9H), 4.05 (s, 2H), 1.97 (s, 3H); MS (ES+) m/z 462 [M+H]⁺ Acc Mass Found: 462.0877, calculated 462.0884 for C₂₄Hi₇N0₂F₄Cl. Preparation of 3-methyl-2-(4-(4-( trifluoromethoxy)benzyl)phenyl)-7-( trifluoromethyl)quinolin- 4(lH)-one 7r

[00258] White solid (Yield 24%); m.p. 245-247 °C; 1H NMR (400 MHz, MeOD) δ 8.31 (d, / = 8.4 Hz, IH), 7.85 (s, IH), 7.60-7.40 (m, H), 7.35-7.25 (d, / = 8.0 Hz, IH), 4.12 (s, 2H), 1.95 (s, 3H); MS (ES⁺) m/z 478 (M + H)⁺ Acc Mass Found: 478.1230, calculated 478.1242 for

Preparation of2-(4-(4-chlorophenoxy)phenyl)-3-methylquinolin-4(lH)-one 7s

[00259] White powder (Yield 8.5%); m.p. 295-297 °C; 1H NMR (400 MHz, MeOD) δ_Η 2.10 (3H, s), 4.10 (IH, m), 7.10 (IH, m), 7.20 (IH, m), 7.40 (lH,m) 7.60 (IH, m) ppm. MS (ES⁺) m/z 362 (M+H)⁺ C₂₂Hi₇N0₂ Cl requires 362.0948, found 362.0946. CHN requires C: 73.01%, H: 4.46%, N: 3.87, found C: 71.32%, H: 4.20%, N: 3.46%.

Preparation of 2-(2-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)phenyl)-3-methylqum 4(lH)-one 7t

[00260] White powder (Yield 52%); m.p. 236-238 °C; 1H NMR (400MHz, CDC1₃), δ_Η 12.26 (s, IH, NH), 8.46 (s, IH, Ar), 8.09 (d, IH, J = 8.3 Hz, Ar), 7.94 (d, IH, J = 8.3Hz, Ar), 7.60 (t, IH, J = 7.6 Hz, Ar), 7.53 (s, 2H, Ar), 7.22 (t, 2H, J = 7.6 Hz, Ar), 6.68 (d, IH, J = 7.9 Hz, Ar), 6.68 (d, IH, J = 10.3 Hz, Ar), 3.88 (s, 2H, ArCH₂Ar), 1.85 (s, 3H, CH₃); ¹³C NMR (100MHz, CDC1₃), 5_C 182.2, 164.8, 161.8, 153.6, 145.6, 143.1, 146.6, 141.7, 135.3, 134.8, 129.0, 128.4, 127.1, 124.3, 121.4, 120.1, 41.8, 15.6; HRMS (ESI) C₂₃Hi₇N₂OF₄ [M+H]⁺ requires 413.1277, found 413.1283. Preparation of3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one 7u

[00261] White solid (Yield 69 %); m.p. 277-278 °C; 1H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.37 - 8.31 (m, 2H), 8.25 (d, 7 = 8.2 Hz, 1H), 8.17 (dd, 7 = 8.2, 2.2 Hz, 1H), 8.15 (dd, 7 = 7.0, 1.5 Hz, 1H), 7.65 (ddd, 7 = 8.2, 6.8, 1.4 Hz, 1H), 7.60 (d, 7 = 7.7 Hz, 1H), 7.55 (d, 7 = 8.2 Hz, 2H), 7.33 (ddd, 7 = 8.0, 6.8, 1.2 Hz, 1H), 1.96 (s, 3H); ¹³C NMR (101 MHz, DMSO) δ 176.98, 155.52, 149.75, 144.79, 139.95, 138.49, 137.46, 131.83, 130.30, 129.34, 129.17 (C-8'X 125.37, 123.50, 123.22, 121.70, 120.35, 119.18, 118.51, 115.59, 12.39; HRMS (ESI) C₂₂H₁₆N₂O₂F₃ [M+H]⁺ requires 397.1164, found 397.1173. Anal. C₂₂H₁₅N₂O₂F₃ requires C 66.67%, H 3.81%, N 7.07%, found C 66.77%, H 3.73%, N 6.98%.

Formulation as the phosphoric acid salt 7u-S

[00262] 7u (97.3 mg, 0.25 mmol) in ethanol (15 mL) was added 85% phosphoric acid (0.03 mL, 2 equiv). The clear solution was stirred at r.t. for ~1 h. The solvent was then removed on rotary until 2-3 mL left. Diethyl ether (-20 mL) was added and the solid was filtered. The solid was further washed with diethyl ether and dried under high vacuum to give 7u-S as a pale yellow solid.

Preparation of 7-fluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)- one 7v

[00263]Pale yellow solid (Yield 30 %); m.p. 317 - 319 °C; 1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.90 (d, 7 = 1.8 Hz, 1H), 8.39 - 8.31 (m, 2H), 8.24 (t, 7 = 8.7 Hz, 1H), 8.22 - 8.11 (m, 2H), 7.55 (d, 7 = 8.2 Hz, 2H), 7.30 (dd, 7 = 10.1, 2.4 Hz, 1H), 7.20 (td, 7 = 8.8, 2.5 Hz, 1H), 1.95 (s, 3H); HRMS (ESI) C₂₂Hi₄N₂0₂F4²³Na [M+Na]⁺ requires 437.0889, found 437.0905. Preparation of 7-methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quino 4(lH)-one 7w

[00264] White solid (Yield 23 %); m.p. 324 - 325 °C. 1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.88 (d, / = 2.1 Hz, 1H), 8.34 (d, / = 8.8 Hz, 2H), 8.24 (d, / = 8.3 Hz, 1H), 8.15 (dd, / = 8.2, 2.3 Hz, 1H), 8.04 (d, / = 8.9 Hz, 1H), 7.55 (d, / = 8.3 Hz, 2H), 6.99 (d, J = 2.2 Hz, 1H), 6.93 (dd, / = 9.0, 2.4 Hz, 1H), 3.84 (s, 3H), 1.93 (s, 3H); HRMS (ESI) CasHigNaOsFs [M+H]⁺ requires 427.1270, found 427.1280. Anal. C₂₃H₁₇N₂O₃F₃ requires C 64.79%, H 4.02%, N 6.57%, found C 64.65%, H 3.88%, N 6.47%.

Preparation of 6-chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)- one 7x

[00265] White solid (Yield 34%); m.p. >300 C; 1H NMR (400 MHz, DMSO) δ 11.96 (bs, 1H), 8.90 (s, 1H), 8.34 (d, / = 8.7 Hz, 2H), 8.25 (d, / = 8.1 Hz, 1H), 8.17 (d, / = 8.1 Hz, 1H), 8.08 (s, 1H), 7.65 (m, 2H), 7.55 (d, / = 8.1 Hz, 2H), 1.96 (s, 3H); ¹³C NMR (100 MHz, DMSO) δ

175.84, 155.66, 149.73, 145.23, 138.51, 137.41, 132.03, 130.00, 129.19, 127.81, 124.38, 124.24, 121.71, 121.06, 120.38, 119.18, 116.13, 12.40; HRMS (ESI) C₂₂Hi5N₂0₂F3³⁵Cl [M+H]⁺ requires 431.0774, found 431.0755.

Preparation of 6, 7-difluoro-3-methyl-2-( 6-(4-( trifluoromethoxy)phenyl)pyridin-3-yl)quinolin- 4(lH)-one 7y

[00266] White solid (Yield 41%); m.p. 288-290 C; 1H NMR (400 MHz, DMSO) δ 11.96 (bs, 1H), 8.90 (s, 1H), 8.34 (d, / = 8.0 Hz, 2H), 8.26 (d, / = 8.3 Hz, 1H), 8.16 (dd, / = 8.2, 2.2 Hz, 1H), 7.99 (dd, / = 10.7, 9.1 Hz, 1H), 7.54 (m, 3H), 1.95 (s, 3H); ^1JC NMR (100 MHz, DMSO) δ 175.73, 155.73, 149.69, 145.42, 138.51, 137.38, 136.96, 136.86, 129.91, 129.20, 121.71, 120.42, 115.55, 112.56, 112.38, 106.55, 106.38, 12.29; HRMS (ESI) C₂₂Hi₄N₂0₂F₅[M+H]⁺ requires 433.0975, found 433.0967.

Preparation of 7-chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quino one 7z

[00267] White solid (Yield 30 %); m.p. 317 - 318 °C; 1H NMR (400 MHz, DMSO) δ 11.82 (s, 1H, N-H), 8.91 (s, 1H), 8.34 (d, J = 8.7 Hz, 2H), 8.26 (d, J = 8.1 Hz, 1H), 8.21 - 8.05 (m, 2H), 7.61 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.35 (dd, J = 8.7, 1.5 Hz, 1H), 1.95 (s, 3H, CH₃); HRMS (ESI) C₂₂Hi₅N₂0₂F₃ ³⁵Cl [M+H]⁺ requires 431.0774, found 431.076 (100 %), C₂₂Hi₅N₂0₂F₃ ³⁷Cl [M+H]⁺ requires 433.0745, found 433.0757 (32 %).

Preparation of 5, 7-difluoro-3-methyl-2-( 6-(4-( trifluoromethoxy )phenyl)pyridin-3-yl )quinolin- 4(lH)-one 8a

[00268] White solid (Yield 33%); m.p. 288-290 C; 1H NMR (400 MHz, DMSO) δ 11.85 (bs, 1H), 8.89 (s, 1H), 8.33 (d, J = 8.7 Hz, 2H), 8.25 (d, J = 8.2 Hz, 1H), 8.15 (dd, J = 8.2, 2.3 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.14 - 7.07 (m, 2H), 1.87 (s, 3H); ¹³C NMR (100 MHz, DMSO) δ 175.25, 155.72, 149.69, 144.27, 138.45, 137.39, 129.70, 129.20, 121.70, 120.42, 117.69, 99.53, 12.15; HRMS (ESI) C₂₂Hi₄N₂0₂F₅ [M+H]⁺ requires 433.0975, found 433.0967.

Preparation of2-(6-(2,4-difluorophenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one 8b

[00269] White solid (Yield 20%); m.p. 308-309 °C; 1H NMR (400 MHz, MeOD) δ 8.88 (d, / = 1.6 Hz, IH), 8.31 (d, / = 8.5 Hz, IH), 8.13 (dd, / = 8.2, 2.3 Hz, IH), 8.10 - 7.96 (m, 2H), 7.71 (t, / = 7.0 Hz, IH), 7.61 (d, / = 8.5 Hz, IH), 7.43 (t, J = 12 Hz, IH), 7.17 (t, / = 9.2 Hz, 2H), 2.11 (s, 5H); HRMS (ESI) C₂₁H₁₅N₂OF₂ [M+H]⁺ requires 349.1152, found 349.1153.

Preparation of2-(6-(4-methoxyphenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one 8c

[00270] White solid (Yield 52 %); m.p. 288 °C; 1H NMR (400 MHz, MeOD) δ 8.76 (dd, / = 2.1, 1.0 Hz, IH), 8.31 (dd, 7 = 8.3, 1.1 Hz, IH), 8.09 - 7.95 (m, 4H), 7.70 (ddd, / = 8.4, 6.9, 1.5 Hz, IH), 7.62 (d, 7 = 8.2 Hz, IH), 7.42 (ddd, / = 8.1, 6.9, 1.1 Hz, IH), 7.15 - 7.05 (m, 2H), 3.89 (s, 3H), 2.11 (s, 3H); HRMS (ESI) C₂₂H₁₉N₂O₂ [M+H]⁺ requires 343.1447, found 343.1450.

Preparation of 3-methyl-2-(6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)quinolin-4(lH)-one 8d

[00271]White solid (Yield 52%); m.p. 293-295°C; 1H NMR (400 MHz, DMSO) δ 11.80 (bs, IH), 9.57 (s, IH), 8.99 (s, IH), 8.85 (d, / = 8.0 Hz, IH), 8.43 (d, / = 8.2 Hz, IH), 8.27 (d, / = 8.2, 2.0 Hz, IH), 8.16 (d, / = 8.1 Hz, IH), 8.11 (d, / = 8.3 Hz, IH), 7.67 (m, IH), 7.60 (d, / = 7.7 Hz, IH), 7.34 (t, / = 7.2 Hz, IH) 1.87 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 176.97, 153.22, 150.20, 148.86, 147.27, 144.51, 139.96, 138.78, 136.92, 136.69, 131.89, 131.89, 131.40, 125.39, 123.52, 123.43, 123.28, 121.50, 121.38, 120.70, 118.53, 115.68; HRMS (ESI) C₂₁H₁₅N₃OF₃ [M+H]⁺ requires 382.1167, found 382.1164.

Preparation of 3-methyl-2-( 6-(4-( trifluoromethoxy )phenoxy )pyridin-3-yl)quinolin-4( lH)-one 8e

[00272] White solid (Yield 25%); m.p. 264-268 °C; 1H NMR (400 MHz, CDC1₃) δ 8.23 (s, IH), 8.19 (d, / = 8.2 Hz, IH), 7.95 (d, / = 8.2 Hz, IH), 7.60 (t, / = 8.2 Hz, IH), 7.49 (d, / = 8.2 Hz, IH), 7.33-7.19 (m, 5H), 7.12 (d, / = 8.6 Hz, IH, 1.97 (s, 3H); HRMS (ESI) C₂₂Hi₆N₂0₃F₃

[M+H]⁺ requires 413.1113, found 413.1115.

Preparation of2-(6-(4-fluorophenoxy)pyridin-3-yl)-3-methylquinolin-4(lH)-one 8f

[00273]White solid (Yield 28%); m.p. 275-278°C ; 1H NMR (400 MHz, CDC1₃) δ 8.34 (s, IH), 8.28 (d, / = 8.2 Hz, IH), 8.06 (d, / = 8.2 Hz, IH), 7.69 (t, / = 8.2 Hz, IH), 7.61 (d, / = 8.6 Hz, IH), 7.41 (t, / = 8.2 Hz, IH), 7.24-7.19 (m, 5H), 2.06 (s, 3H); HRMS (ESI) C₂₁H₁₆N₂O₂F

[M+H]⁺ requires 347.1196, found 347.1211.

Preparation of 6-methoxy-3 -methyl-2-( 6-( 4-( trifluoromethoxy )phenyl)pyridin-3-yl)quinolin- 4(lH)-one 8g

[00274] White solid (Yield 34%); m.p. >300 C; 1H NMR (400 MHz, DMSO) δ 11.96 (bs, IH), 8.90 (s, IH), 8.34 (d, / = 8.7 Hz, 2H), 8.25 (d, / = 8.1 Hz, IH), 8.17 (d, / = 8.1 Hz, IH), 8.08 (s, IH), 7.65 (m, 2H), 7.55 (d, / = 8.1 Hz, 2H), 1.96 (s, 3H); ¹³C NMR (100 MHz, DMSO) δ 175.84, 155.66, 149.73, 145.23, 138.51, 137.41, 132.03, 130.00, 129.19, 127.81, 124.38, 124.24, 121.71, 121.06, 120.38, 119.18, 116.13, 12.40; HRMS (ESI) C₂₂Hi₅N₂0₂F₃ ³⁵Cl [M+H]⁺ requires 431.0774, found 431.0755.

Preparation of 7-methoxy-3-methyl-2-( l-(4-( trifluoromethoxy )benzyl )piperidin-4-yl)quinol 4(lH)-one 8h

[00275] Prepared according to the general procedure for the synthesis of quinolones 7 and 8. (White powder, 44%); 1H NMR (400MHz, DMSO), δ_Η 10.62 (s, IH, NH), 7.93 (d, IH, J = 8.9 Hz, Ar), 7.47 (d, 2H, J = 8.3 Hz, Ar), 7.35 (d, 2H, J = 8.3 Hz, AR), 7.21 (d, IH, J = 2.4 Hz, Ar), 6.82 (dd, IH, J = 8.9 Hz, 2.4 Hz, Ar), 3,82 (s, 3H, OCH₃), 3.55 (s, 2H, NCH₂Ar), 3.02-2.87 (m, 4H, CH₂), 2.18-2.04 (m, 3H, CH₂), 2.01 (s, 3H, CH₃/CH), 1.67 (d, 2H, J = 10.7 Hz, CH₂) ¹³C NMR (lOOMHz, DMSO), 5_C 176.3, 161.6, 151.5, 147.7, 141.5, 131.0, 127.0, 121.1, 117.7, 113.1, 99.0, 61.8, 55.6, 53.6, 29.5, 10.2 MS (ES+), [M + H] ⁺ (100), 447.2, HRMS calculated for 447.1896 C₂₄H₂₆N₂O₃F₃, found 447.1891. Preparation of 7-methoxy-3-methyl-2-( 5-(4-( trifluoromethoxy )phenyl )pyridin-3-yl)quinolin- 4(lH)-one 8i

00276/Prepared according to the general procedure for the synthesis of quinolones 7 and 8. (Pale yellow solid 34%); 1H NMR (400 MHz, DMSO) δ 11.57 (s, 1H), 9.10 (d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.35 (t, J = 2.2 Hz, 1H), 8.05 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 8.9, 2.4 Hz, 1H), 3.84 (s, 3H), 1.94 (s, 3H). ESI HRMS: m/z calculated for C₂₃Hi₈N₂0₃F3 ([M+H]⁺) 427.1270, found 427.1272.

Yields

[00277] Table 1 below shows the yields obtained for compounds 7a-z and 8a-g. synthesised by route 1 of Scheme 1 :

Table 1

General procedure for the synthesis of dicetal [9]

4 9

[00278] Ketone 4 (4.5 mmol, 1.0 eq) was dissolved in methanol (40 mL) and trimethyl orthoformate (45 mmol, 10 eq) and para-toluenesulfonic acid (0.45 mmol, 0.1 eq) were added. The reaction was heated at reflux overnight and then allowed to cool. Most of the methanol was removed in vacuo (10 mL remained) and ether (50 mL) was added. The solution was washed with sodium bicarbonate and brine, dried over MgS0₄ and the solvent removed to give diacetal 9.

Preparation of l-(l,l-dimethoxypropyl)-4-(4-(trifluoromethoxy)benzyl)benzene 9a

[00279] Colorless oil (Yield 89%); 1H NMR (400MHz, CDC1₃) δ_Η 7.39 (d, 2H, J = 8.2 Hz, Ar), 7.20 (d, 2H, J = 8.6 Hz, Ar), 7.15 (d, 2H, J = 8.6 Hz, Ar), 7.12 (d, 2H, J = 8.2 Hz, Ar), 3.97 (s, 2H, ArCH₂Ar), 3.15 (s, 6H, OCH₃), 1.89 (q, 2H, J = 7.5 Hz, CH₂), 0.59 (t, 3H, J = 7.5 Hz, CH3); MS (ES+), [M + Na] ⁺ (100), 376.9, HRMS calculated for 377.1340 Ci₉H₂iNa0₃F₃, found 377.1326.

General procedure for the synthesis of quinolones [11]

[00280] Diacetal 9 (3.26 mmol, 1.0 eq) and the appropriately substituted acid 10 (3.26 mmol, 1.0 eq) in Dowtherm A (4 mL) were heated at 240°C overnight. The reaction was allowed to cool and hexane added. The resulting dark brown precipitate was filtered off and washed with hexane. Purification by flash column chromatography (eluting with EtOAc) gave the required quinolones 11.

Preparation of 7-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 11a

[00281]Οΐΐ white powder (Yield 44%); 1H NMR (400MHz, DMSO) δ_Η 2.02 (s, 3H, CH₃), 4.02 (s, 2H, ArCH₂Ar), 6.95-7.06 (m, 1H, Ar), 7.14 (d, 2H, J = 8.2 Hz, Ar), 7.20 (d, 2H, J = 8.6 Hz, Ar), 7.28 (d, 2H, J = 8.6 Hz, Ar), 7.41 (d, 2H, J = 8.2 Hz, Ar), 7.80 (dd, 1H, J = 7.8 Hz, 8.4 Hz,Ar), 8.25-8.34 (m, 1H, Ar); ¹³C NMR (100MHz, DMSO), 5_C 13.1, 41.4, 107.3, 113.6, 117.1, 122.7, 129.2, 131.3, 132.0, 134.1, 139.9, 144.8, 152.2, 178.7; MS (ES+), [M + H] ⁺ (100), 428.0, HRMS calculated for 428.1274 C₂4Hi₈N0₂F4, found 428.1278.

Preparation of 6, 7-difluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)- one lib

[00282]W ite powder (Yield 39%); 1H NMR (400MHz, DMSO) δ_Η 2.05 (s, 3H, CH₃), 4.01 (s, 2H, ArCH₂Ar), 7.13 (d, 2H, J = 8.1 Hz, Ar), 7.20 (d, 2H, J = 8.7 Hz, Ar), 7.28 (d, 2H, J = 8.4 Hz, Ar), 7.41 (d, 2H, J = 8.1 Hz, Ar), 7.80 (dd, 1H, J = 8.1 Hz, 8.7 Hz, Ar), 8.02 (dd, 1H, J = 8.6 Hz, 8.8Hz, Ar), 9.80 (s, 1H, NH); ¹³C NMR (100MHz, DMSO), 5_C 13.0, 42.2, 107.3, 113.6, 117.1, 122.7, 130.6, 130.8, 131.9, 134.3, 142.0, 145.0, 152.3, 178.7; MS (ES+), [M + Na] ⁺ (100), 468.0, HRMS calculated for 468.0999 C₂₄Hi₆N0₂F₅Na, found 468.1011.

Preparation of 3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,8-naphthyridin-4(lH)-one 11c

[00283] Off white powder (Yield 44%); m.p. 236-238 °C; 1H NMR (400MHz, CDC1₃) δ_Η 11.44 (s, 1H, NH), 8.66 (dd, 1H, J = 8.0 Hz, 1.8 Hz, Ar), 7.47 (d, 2H, J = 8.2 Hz, Ar), 7.40 (d, 2H, J = 8.2 Hz, Ar), 7.31 (d, 2H, J = 8.6 Hz, Ar), 7.28 (dd, 1H, J = 4.7 Hz, 1.8 Hz, Ar), 7.22 (d, 2H, J = 8.6 Hz, Ar), 6.84 (dd, 1H, J = 8.0 Hz, 4.7 Hz, Ar), 4.11 (s, 2H, ArCH₂Ar), 2.05 (s, 3H, CH₃); ¹³C NMR (lOOMHz, CDC1₃), 5_C 179.0, 152.0, 150.2, 148.3, 143.1, 139.5, 137.0, 133.8, 130.6, 129.9, 129.5, 121.9, 119.4, 119.0, 118.2, 41.6, 12.7; MS (ES+), [M + H] ⁺ (100), 411.0, HRMS calculated for 411.1320 C₂₃Hi₈N₂0₂F₃, found 411.1322.

Yields

[00284] Table 2 below shows the yields obtained for the synthesis of compounds l la-c synthesised by Route 2 of Scheme 1.

Table 2

General procedure for the synthesis of quinolones [12a-b]

[00285] Quinolone 7 and 8 (0.04 mmol) in anhydrous toluene (10 mL) was cooled to 0°C. Boron tribromide 1.0 M in dichloromethane (0.13 mL, 0.12 mmol, 3 equiv) was added. The mixture was stirred at room temperature for ½ h then was heated to reflux for 18 h. The mixture was cooled to 0°C and methanol was added. The solution was evaporated and the residue triturated with diethyl ether. The crude product was purified by column chromatography using 10% methanol in dichloromethane to give the desired hydroxyl quinolone 12.

Preparation of 6-hydroxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin- 4(lH)-one 12a

[00286] White solid (Yield 49%); m.p. decomposed at 250 °C; 1H NMR (400 MHz, DMSO) δ 11.66 (bs, 1H), 9.67 (s, OH), 8.88 (s, 1H), 8.34 (d, / = 8.0 Hz, 2H), 8.23 (d, / = 8.0 Hz, 1H), 8.14 (dd, / = 8.1, 2.3 Hz, 1H), 7.55 (d, / = 8.2 Hz, 2H), 7.47(m, 2H), 7.17 (dd, / = 8.9, 2.8 Hz, 1H), 1.97 (s, 3H); ¹³C NMR (100 MHz, DMSO) δ 176.24, 155.37, 153.73, 149.75, 149.69, 143.82, 138.47, 137.49, 133.68, 129.14, 122.33, 121.70, 120.31, 120.08, 113.75, 107.51, 12.48; HRMS (ESI) C₂₂Hi₆N₂0₃F₃ [M+H]⁺ requires 413.1122, found 413.1113.

Preparation of 7-hydroxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinol 4(lH)-one 12b

[00287] White solid (Yield 68 %); 1H NMR (400 MHz, MeOD) δ 8.81 (dd, / = 2.2, 1.0 Hz, 1H), 8.33 - 8.20 (m, 2H), 8.17 - 8.13 (m, 1H), 8.11 (dd, / = 8.2, 1.0 Hz, 1H), 8.08 (dd, / = 8.2, 2.2 Hz, 1H), 7.45 (dd, / = 8.9, 0.9 Hz, 2H), 6.92 (dd, / = 8.9, 2.3 Hz, 1H), 6.89 (m, 1H), 2.06 (s, 3H); ¹³C NMR (101 MHz, MeOD) δ 199.27, 178.62, 161.39, 156.56, 155.27, 150.26, 149.03, 145.49, 141.82, 137.97, 137.26, 130.10, 128.66, 126.87, 120.95, 120.26, 117.19, 115.18, 114.82, 112.86, 100.31, 11.01; HRMS (ESI) C₂₂Hi₆N₂0₃F₃ [M+H]⁺ requires 413.1113, found 412.1102.

General procedure for the preparation of alcohol [14]

[00288] Benzyl-ketone 13 (2.0 mmol, 1 eq.) was added to DCM (50 mL) and cooled to - IOC. 1M BBr₃ (4.0 mmol, 2 eq.) was added and the solution was left to stir at -IOC for 2 hours. Ice water was added to quench the reaction followed by additional DCM (50 mL). This was washed with sat. NaHC0₃ (30 mL), brine (30 mL) and then dried over MgS0₄. The crude solid was purified by flash column chromatography (eluting with n-hexane to 20% EtOAc in n-hexane) to give the desired compound as a white solid.

Preparation of 1 -(4-(3-hydroxybenzyl)phenyl)propan-l -one 14a

[00289] White solid (Yield 53%); 1H NMR (400 MHz, CDC1₃) 7.89 (d, / = 8.4 Hz, 2H), 7.28 (d, / = 8.4 Hz, 2H), 7.16 (dd, / = 7.6, 7.6 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.70 (dd, / = 8.2, 2.4 Hz, 1H), 6.65 (s, 1H), 5.17 (bs, 1H), 3.97 (s, 2H), 2.97 (q, / = 7.2 Hz, 2H), 1.21 (t, J = 7.3 Hz, 3H); δ ¹³C NMR (100 MHz, CDC1₃) δ 201.30, 156.30, 146.75, 142.32, 135.39, 130.21, 129.54, 128.76, 121.74, 116.29, 113.81, 42.12, 32.16, 8.73; MS (ES⁺) m/z 241 (M + H)⁺

General procedure for the preparation of morpholine [15]

[00290] m-Hydroxy benzyl-ketone 14 (1.50 mmol, leq.) was added to dry acetone (15 mL) with K₂C0₃ (7.5 mmol, 5.0 eq.). Chloroethyl morpholine hydrochloride (3.50 mmol, 2.3 eq.) was added and the solution was heated to 60C overnight. The reaction was filtered to remove salt and washed with excess MeOH. The crude oil was purified by flash column chromatography (eluting with EtOAc to 10% MeOH in EtOAc) to give the desired compound as a colourless oil.

Preparation of l-(4-(3-(2-morpholinoethoxy)benzyl)phenyl)propan-l-one 15a

[00291] Colourless oil (Yield 64%); 1H NMR (400 MHz, MeOD) 7.90 (d, / = 8.4 Hz, 2H), 7.31 (d, / = 8.8 Hz, 2H), 7.19 (dd, / = 7.6, 7.6 Hz, 1H), 6.78 (m, 3H), 4.08 (t, / = 5.5 Hz, 2H), 3.99 (s, 2H), 3.68 (t, / = 4.7 Hz, 4H), 3.01 (q, 7 = 7.3 Hz, 2H), 2.75 (t, / = 5.5 Hz, 2H), 2.56 (t, / = 4.7 Hz, 4H), 1.16 (t, J = 7.3 Hz, 3H); δ ¹³C NMR (100 MHz, MeOD) δ 201.46, 159.03, 147.05, 141.99, 134.83, 129.28, 128.83, 128.02, 121.27, 115.03, 112.00, 66.21, 64.91, 57.38, 53.76, 41.27, 31.21, 7.26; MS (ES⁺) m/z 354 (M + H)⁺ Acc Mass Found: 354.2070, calculated 354.2069

General procedure for the preparation of quinolone [16]

[00292] The appropriately substituted oxazole 6 (4 mmol, 1 eq) was added to a solution of ketone 39 (4 mmol, 1 eq) and triflic acid (20 mol%) in n-Butanol (10 mL). The reaction mixture was heated to 130°C under nitrogen and stirred for 24 hours. The solvent was removed under vacuum and water (20 mL) added. The aqueous solution was extracted with EtOAc (3 x 20 mL), dried over MgS0₄ and concentrated under vacuum. The product was purified by column

chromatography (eluting with 20% -80% EtOAc in n-hexane) to give quinolone 16.

Preparation of 3-methyl-2-(4-(3-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(lH)-one 16

[00293] White solid (Yield 31%): m.p. 79-81 C; 1H NMR (400 MHz, MeOD) δ 8.26 (d, / = 8.3 Hz, 1H), 7.57 (m, 2H), 7.36 (m, 5H), 7.18 (t, / = 8.0 Hz, 1H), 6.80 (m, 3H), 4.08 (t, / = 5.5 Hz, 2H), 4.00 (s, 2H), 3.68 (m, 4H), 2.77 (t, J = 5.5 Hz, 2H), 2.57 (m, 4H), 2.01 (s, 3H); ¹³C NMR (100 MHz, MeOD) δ 178.62, 159.00, 149.80, 143.24, 142.39, 139.45, 132.80, 131.58, 129.30, 128.91, 128.72, 124.82, 123.35, 123.19, 121.29, 117.76, 115.39, 115.12, 111.82, 67.25, 64.85, 57.38, 53.73, 41.21, 11.41; MS (ES⁺) m/z 455 (M + H)⁺ Acc Mass Found: 455.2333, calculated 455.2335 for C₂₉H₃iN₂0₃; Anal. Calcd for C₂₉H₃₀N₂O₃: C, 76.63%; H, 6.65%; N, 6.16%; Found C, 76.20%; H, 6.71%; N 6.06%. Example 2 - Preparation of compounds of formula I in which R¹ is hydrogen and R³ is hydrogen

General reaction scheme

[00294] Scheme 2 below shows the synthesis of compounds of formula I in which R 1 and R 3 = H. Aldehydes 2 were converted to ketoesters 17 in 40-50% yields. Reaction with a range of anilines gives amine 18 in 70-80% yields. Refluxing 18 in Dowtherm A gives the desired quinolones 19 in good yields.

Scheme 4: The synthesis of compounds of formula I in which R¹ and R³ = H Experimental

General procedure for the preparation of ketoester 17

[00295] Aldehyde 2 (14 mmol, 1.0 eq) and Niobium Chloride (0.70 mmol, 5 mol %) were dissolved in DCM (140 mL) under nitrogen. Ethyl diazoacetate (15% in DCM, 16.8 mmol, 1.2 eq) was added drop wise and the reaction stirred at room temperature overnight. Water (140 mL) was added and the layers separated. The aqueous portion was extracted with DCM (3 x 140 mL) and the combined organic portions dried over MgS0₄, filtered and the solvent removed in vacuo. The resulting orange oil was purified by flash column chromatography (eluting with n-hexane to 80% EtOAc in n-hexane) to give the desired ketoester 17.

Preparation of ethyl 3-oxo-3-(4-(4-( trifluoromethoxy )benzyl )phenyl )propanoate 17a

[00296] Colorless oil (Yield 68%); 1H NMR (400MHz, DMSO) δ_Η 1.25 (t, 3H, J = 7.2 Hz, CH₃), 3.96 (s, 2H, COCH₂CO), 4.04 (s, 2H, ArCH₂Ar), 4.21 (q, 2H, J = 7.2 Hz, OCH₂), 7.14 (d, 2H, J = 8.6 Hz, Ar), 7.19 (d, 2H, J = 8.5 Hz, Ar), 7.28 (d, 2H, J = 8.6 Hz, Ar), 7.89 (d, 2H, J = 8.5, Hz, Ar); ¹³C NMR (100MHz, DMSO), 5_C 14.5, 41.5, 46.3, 61.9, 121.6, 129.4, 129.7, 130.6, 134.8, 148.2, 168.5, 192.5 MS (ES+), [M + Na] ⁺ (100), 389.1, HRMS calculated for 389.0977

Ci₉Hi₇0₄NaF₃, found 389.0969.

Preparation of methyl 4-(4-(3-ethoxy-3-oxopropanoyl)benzyl)benzoate 17b

[00297] Colorless oil (Yield 49%); 1H NMR (400MHz, CDC1₃) δ_Η 7.97 (d, 2H, J = 8.3 Hz, Ar, 7.88 (d, 2H, J = 8.3 Hz, Ar), 7.28 (d, 2H, J = 8.3 Hz, Ar), 7.24 (d, 2H, J = 8.3 Hz, Ar), 4.20 (q, 2H, OCH2), 3.96 (s, 2H, ArCH₂Ar), 3.89 (4H, CH₂), 1.25 (t, 3H, CH₃) MS (ES+), [M + Na] ⁺ (100), 363.1 HRMS calculated for 363.1208 C₂oH₂₀0₅Na, found 363.1201.

General procedure for the preparation of amine [18]

17 18, 70 - 80%

[00298] Ketoester 17 (5.00 mmol, 1.0 eq), appropriately substituted aniline (25 mmol, 5.0 eq) and acetic acid (25 mmol, 5.0 eq) in ethanol (6.5 mL) were heated at reflux for 2-3 hours. The reaction was cooled and the solvent removed in vacuo. The resulting residue was dissolved in DCM (30mL) and the washed with 5% HCl (30 mL) and water (30 mL). The organic portion was dried over MgS0₄, filtered and concentrated under vacuum to give the desired amine 18.

Preparation of(E)-ethyl 3-(phenylamino)-3-(4-(4-(trifluoromethoxy)benzyl)phenyl)acrylate 18a

[00299] 'Colorless oil (Yield, 78%); 1H NMR (400MHz, DMSO) δ_Η 1.31 (t, 3H, J = 7.1Hz, CH₃), 3.95 (s, 2H, ArCH₂Ar), 4.20 (q, 2H, J = 7.1Hz, OCH₂), 4.99 (s, 1H, CH), 6.66 (d, 2H, J = 7.5 Hz, Ar), 6.91 (t, 1H, J = 7.4 Hz, Ar), 7.05 -7.15 (m, 8H, Ar), 7.28 (d, 2H, J = 8.0 Hz, Ar), 10.27 (s, 1H, NH) ¹³C NMR (100MHz, DMSO), 5_C 14.9, 41.3, 59.7, 91.5, 121.5, 121.6, 123.3, 129.0, 129.4, 130.6, 134.5, 139.6, 140.9, 142.3, 159.2, 170.3 MS (ES+), [M + Na] ⁺ (100), 464.1, HRMS calculated for 464.1449 C₂₅H₂₂N0₃NaF₃, found 464.U49. Preparation of(E)-ethyl 3- ( ( 3,4-difluorophenyl )amino)-3-(4-(4-( trifluoromethoxy ) benzyl )phenyl )acrylate 18b

[00300] Colorless oil (Yield, 64%); 1H NMR (400MHz, CDC1₃) δ_Η 10.20 (s, IH, NH), 7.25 (dd, 3H, J = 6.6 Hz, 1.5 Hz, Ar), 7.15 (s, 3H, Ar), 7.11 (d, 2H, j = 8.2 Hz, Ar), 6.94-6.83 (m, IH, Ar), 6.45-6.38 (m , 2H, Ar), 5.03 (s, IH, CH), 4.20 (q, 2H. J = 7.1 Hz, Ar), 3.98 (s, 2H, ArCH₂Ar), 1.31 (t, 3H. J = 7.1 Hz, CH₃).

Preparation of (E)-ethyl 3-((3,4-dichlorophenyl)amino)-3-(4-(4-(trifluoromethoxy) benzyl )pheny I )acry late 18c

[00301] Colorless oil (Yield, 66%); 1H NMR (400MHz, CDC1₃) δ_Η 10.26 (s, IH, NH), 7.28-7.25 (m, 2H, Ar), 7.18-7.05 (m, 7H, Ar), 6.68 (d, IH, J = 2.6 Hz, Ar), 6.48 (dd, IH, J = 8.7 Hz, 2.6 Hz, Ar), 5.06 (s, IH, CH), 4.20 (q, 2H, J = 7.1 Hz, OCH₂), 3.98 (s, 2H, ArCH₂Ar), 1.31 (t, 3H, J = 7.1 Hz, CH₃) MS (ES+), [M + H] ⁺ (100), 510.1, HRMS calculated for 510.0851 C₂₅H₂iN0₃F₃, found 510.0855.

Preparation of (E)-ethyl 3-((3-fluoro-4-methoxyphenyl)amino)-3-(4-(4-(trifluoromethoxy) benzyl )pheny I )acry late 18d

[00302] Colorless oil (Yield, 72%); 1H NMR (400MHz, CDC1₃) δ_Η 10.23 (s, IH, NH),7.25 (d, 2H, J = 7.7 Hz, Ar), 7.14 (bs, 4H, Ar), 7.08 (d, 2H, J = 8.1 Hz, Ar), 6.70 (t, IH, J = 9.0 Hz, Ar), 6.50-6.44 (m, IH, Ar), 6.37 (dd, IH, J = 12.6 Hz, 2.6 Hz, Ar), 4.97 (s, IH, CH), 4.19 (q, 2H, OCH₂), 3.96 (s, 2H, ArCH₂Ar), 3.79 (s, 3H, OCH₃), 1.31 (t, 3H, J = 7.1 Hz, CH₃) ¹³C NMR (lOOMHz, CDC1₃), δ_α 170.4, 159.5, 142.8, 139.5, 133.9, 130.5, 129.5, 128.9,126.9, 121.4, 118.4, 113.8, 111.8,91.5, 59.8, 56.9, 41.4, 15.1.

Preparation of (E)-ethyl 3-((4-(4-methylpiperazin-l-yl)phenyl)amino)-3-(4-(4- (trifluoromethoxy)benzyl)phenyl)acrylate 18e

[00303] Colorless oil (Yield 56%); 1H NMR (400MHz, CDC1₃), δ_Η 10.19 (s, IH, NH), 7.25 (d, 2H, J = 8.4 Hz, Ar), 7.14 (d, 4H, J = 4.8 Hz, Ar), 7.06 (d, 2H, J = 8.4 Hz, Ar), 6.66 (d, 2H, J = 9.1 Hz, Ar), 6.60 (d, 2H J = 9.1 Hz, Ar), 4.19 (s, IH, CH), 3.96 (s, 2H, ArCH₂Ar), 3.15 (t, 4H, J = 5.0 Hz, NCH₂), 2.70 (t, 4H, J = 5.0 Hz, CH₂N), 2.42 (s, 3H, NCH₃), 1.30 (t, 3H, J = 7.1 Hz, CH₃) ¹³C NMR (100MHz, CDC1₃), 5_C 183.2, 171.1, 166.8, 160.2, 149.7, 139.5, 134.6, 131.0, 129.3, 128.9, 123.7, 121.4, 116.8, 110.5, 90.1, 56.0, 51.3, 49.3, 45.7, 41.4, 15.1 MS (ES+), [M + H] ⁺ (100), 540.2, HRMS calculated for 540.2474 C₃₀H₃₃N₃O₃F₃, found 540.2472.

Preparation of (E)-ethyl 3-((3-(4-methylpiperazin-l-yl)phenyl)amino)-3-(4-(4- ( trifluoromethoxy )benzyl )phenyl )acrylate 18f

[00304] Colorless oil (Yield 52%); 1H NMR (400MHz, CDC1₃), δ_Η 10.26 (s, IH, NH), 7.29 (d, 2H, J = 8.1 Hz, Ar), 7.15 (bs, 4H, Ar), 7.10 (d, 2H, J = 8.1 Hz, Ar), 6.96 (t, IH, J = 8.0 Hz, Ar), 6.48 (dd, IH, J = 8.2 Hz, 2.0 Hz, Ar), 6.18 (dd, 2H, 10.5 Hz, J = 2.0 Hz, Ar), 4.92 (s, IH, CH), 4.19 (q, 2H, J = 7.1 Hz, OCH₂), 4.0 (s, 2H, ArCH₂Ar), 2.95 (t, 4H, J = 4.7 Hz, NCH₂), 2.51 (t, 4H, J = 4.7 Hz, CH₂N), 2.34 (s, 3H, NCH₃), 1.31 (t, 3H, J = 7.1 Hz, CH₃) ¹³C NMR (100MHz, CDC1₃), 5c 170.5, 159.1, 151.6, 148.1, 142.2, 141.6, 139.6, 134.8, 130.5, 129.5, 129.3, 128.8, 121.4, 114.0, 111.3, 110.7, 59.7, 55.0, 48.8, 46.0, 41.3, 15.0 MS (ES+), [M + H] ⁺ (100), 540.2, HRMS calculated for 540.2474 C₃₀H₃₃N₃O₃F₃, found 540.2468.

Preparation of (E)-methyl 4-(4-(3-ethoxy-3-oxo-l-(phenylamino)prop-l-en-l-yl)benzyl)benzoate

18g

[00305] Colorless oil (Yield, 72%); 1H NMR (400MHz, CDC1₃) δ_Η 10.31 (s, IH, NH), 7.95 (dd, 2H, J = 5.8 Hz, 4.1 Hz, Ar), 7.27 (d, 2H, J = 8.2 Hz, Ar), 7.20 (d, 2H, J = 8.2 Hz, Ar), 7.12-7.02 (m, 4H, Ar), 6.90 (t, IH, J = 7.4 Hz, Ar), 6.55 (d, 2H, J = 7.6 Hz, Ar), 4.98 (s, IH, CH), 4.19 (q, 2H, J = 7.1Hz, OCH₂), 3.99 (s, 2H, ArCH₂Ar), 3.89 (s, 3H, OCH₃), 1.30 (t, 3H, J = 7.1 Hz, CH₃) ¹³C NMR (100MHz, CDC1₃), 5_C 170.8,167.5, 159.2, 146.7, 142.2, 141.1, 134.9, 130.3, 129.4, 129.0, 123.7, 123.1, 91.5, 59.5, 52.6, 42.0, 14.1 MS (ES+), [M + Na] ⁺ (100), 438.2, HRMS calculated for 438.1681 C₂₆H₂₅N0₄Na, found 438.1677. General procedure for the preparation of quinolone [19]

[00306] Amine 18 (3.5 mmol, 1.0 eq) was dissolved in Dowtherm A (4 mL) and heated at 240°C for 30 minutes. The reaction was cooled, diluted with n-hexane and the resulting precipitate filtered off to give a pale brown solid. Washing with EtOAc gave a cream solid and no further purification was required to give quinolone 19.

[0002] Preparation of2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19a

[00307] White powder (Yield 70%); 1H NMR (400MHz, DMSO) δ_Η 4.10 (s, 2H, ArCH₂Ar), 6.36 (s, 1H, CH), 7.32 (d, 2H, J = 8.1 Hz, Ar), 7.36 (dt, 1H, J = 1.0 Hz, 8.0 Hz, Ar), 7.42 (d, 2H, J = 8.6 Hz, Ar), 7.48 (d, 2H, J = 8.2 Hz, Ar), 7.68 (dt, 1H, J = 1.4 Hz, 8.2 Hz, Ar), 7.74-7.82 (m, 3H, Ar), 8.10 (dd, 1H, J = 1.0Hz, 8.0 Hz, Ar), 10.75 (s, 1H, NH); ¹³C NMR (100MHz, DMSO), 5_C 41.5, 107.3, 119.2, 121.6, 123.7, 125.0, 128.1, 129.7, 130.9, 132.2, 140.8, 143.9, 177.2; MS (ES+), [M + H] ⁺ (100), 396.2, HRMS calculated for 396.1211 C₂₃Hi₇N0₂F₃, found 396.1207. Preparation of6, 7-difluoro-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19b

[00308] White powder (Yield 67%); m.p. 278-280 °C; 1H NMR (400MHz, DMSO), δ_Η 11.83 (1H, NH), 7.95 (dd, 1H. J = 10.8 Hz, 8.9 Hz, Ar), 7.76 (d, 2H, J = 8.3 Hz, Ar), 7.48 (dd, 1H, J = 11.4 Hz, 6.9 Hz, Ar), 7.41 (d, 2H, J = 8.7 Hz, Ar), 7.31 (d, 2H, J = 8.7 Hz, Ar), 6.36 (d, 1H, J = 1.7 Hz, Ar), 4.10 (s, 2H, ArCH₂Ar); ¹³C NMR (100MHz, DMSO), 5_C 175.9, 150.8, 147.1, 144.2, 140.8, 132.0, 130.9, 129.8, 128.0, 121.6, 112.4, 107.1, 40.3; MS (ES+), [M + H] ⁺ (100), 432.1, HRMS calculated for 432.1023 C₂₃Hi₅N0₂F₅, found 432.1010

Preparation of 6, 7-dichloro-2-(4-(4-( trifluoromethoxy)benzyl)phenyl)quinolin-4( lH)-one 19c

[00309] White powder (Yield 72%); m.p. 286-288 °C; 1H NMR (400MHz, DMSO), δ_Η 11.79 (s, 1H, NH), 8.17 (s, 1H, Ar), 7.78 (bs, 3H, Ar), 7.48 (d, 2H, J = 8.0 Hz, Ar), 7.41 (d, 2H, J = 8.6 Hz, Ar), 7.31 (d, 2H, J = 8.6 Hz, Ar), 6.38 (s, 1H, CH), 4.10 (s, 2H, ArCH₂Ar); ¹³C NMR (lOOMHz, DMSO), 5_C 172.9, 147.1, 144.2, 140.8, 130.9, 129.7, 128.4, 128.0, 121.6, 119.6, 40.5; MS (ES+), [M + H] ⁺ (100), 464.0, HRMS calculated for 464.0432 C₂₃H₁₅NO₂F₃CI₂, found 464.04243.

Preparation of 6-fluoro-7-methoxy-2-(4-(4-( trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 19d

[00310] Off white powder (Yield 56%); m.p. 286-288 °C; 1H NMR (400MHz, DMSO), δ_Η 11.67 (s, 1H, NH), 7.75 (d, 2H, J = 8.1 Hz, Ar), 7.65 (d, 1H, J = 9.4 Hz, Ar), 7.54 (d, 1H, J = 11.9 Hz, Ar), 7.47 (d, 2H, J = 8.1 Hz, Ar), 7.41 (d, 2H, J = 8.6 Hz, Ar), 7.31 (d, 2H, J = 8.6 Hz, Ar), 6.32 (s, 1H, CH), 4.10 (s, 2H, ArCH₂Ar), 3.93 (s, 3H, OCH₃); ¹³C NMR (lOOMHz, DMSO), 5_C 176.0, 149.7, 143.9, 140.9, 132..3, 130.9, 129.7, 127.9, 121.6, 106.7, 56.4; MS (ES+), [M + H] ⁺ (100), 444.1, HRMS calculated for 444.1223 C₂₄Hi₈N0₃F4, found 444.1223.

Preparation of 6-(4-methylpiperazin-l-yl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin- 4(lH)-one 19e

[00311] Brown powder (Yield 56%); m.p. 198-200 °C; 1H NMR (400MHz, CDC1₃), δ_Η 11.54 (s, 1H, NH), 7.74 (d, 2H, J = 8.2 Hz, Ar), 7.64 (d, 1H, J = 8.7 Hz, Ar), 7.49 (d, 1H, J = 8.7 Hz, Ar), 7.45 (d, 2H, J = 8.2 Hz, Ar), 7.43 (s, 1H, Ar), 7.41 (d, 2H, J = 8.0 Hz, Ar), 7.31 (d, 2H, J = 8.0 Hz, Ar), 6.24 (s, 1H, CH), 4.08 (s, 2H, ArCH₂Ar), 3.18 (t, 4H, J = 4.6 Hz, CH₂N), 2.50 (t, 4H, J = 4.6 Hz, NCH₂), 2.24 (s, 3H, NCH₃); ¹³C NMR (lOOMHz, CDC1₃), 5_C 178.5, 153.1, 152.5, 148.9, 143.6, 140.9, 132.8, 130.8, 129.8, 127.8, 122.8, 121.5, 119.9, 107.1, 54.9, 48.9, 46.2, 42.2; MS (ES+), [M + H] ⁺ (100), 494.2, HRMS calculated for 494.2055 C₂₈H₂₇N₃0₂F₃, found 494.2068. Preparation of 7-(4-methylpiperazin-l-yl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin- 4(lH)-one 19f

[00312] Brown powder (Yield 48%); m.p. 248-250 °C; 1H NMR (400MHz, CDC1₃), δ_Η 10.56 (s, 1H, NH), 8.11 (d, 1H, J = 9.1 Hz, Ar), 7.26 (d, 2H, J = 7.9 Hz, Ar), 7.26 (d, 2H, J = 7.9 Hz, Ar), 7.18 (d, 2H, J = 7.9 Hz, Ar), 7.11 (d, 2H, J = 8.9 Hz, Ar), 7.08 (d, 2H, J = 8.9 Hz, Ar), 6.96 (s, 1H, Ar), 6.91 (d, 1H, J = 9.1 Hz, Ar), 6.33 (s, 1H, CH), 3.91 (s, 2H, ArCH₂Ar), 3.28 (t, 4H, J = 4.6 Hz, NCH₂), 2.51 (t, 4H, J = 4.6 Hz, CH₂N), 2.30 (s, 3H, NCH₃); ¹³C NMR (100MHz, CDC1₃), 5c 179.9, 154.0, 143.4, 139.3, 130.5, 130.0, 127.6, 127.0, 121.5, 114.2, 107.9, 106.6, 101.0, 54.9, 47.9, 46.3, 41.0; MS (ES+), [M + H] ⁺ (100), 494.2, HRMS calculated for 494.2055 C₂₈H₂₇N₃0₂F₃, found 494.2068.

Preparation of methyl 4-(4-(4-oxo-l,4-dihydroquinolin-2-yl)benzyl)benzoate 19g

[00313] White powder (Yield 63%); m.p. 280-282 °C; 1H NMR (400MHz, DMSO), δ_Η 11.66 (s, 1H, NH), 8.09 (dd, 1H, J = 8.1 Hz, 1.4 Hz, Ar), 7.92 (d, 2H, J = 8.2 Hz, Ar), 7.78 (d, 2H, J = 8.2 Hz, Ar), 7.74 (d, 1H, J = 8.5 Hz, Ar), 7.70-7.61 (m, 1H, Ar), 7.47 (d, 2H, J = 8.2 Hz, Ar), 7.44 (d, 2H, J = 8.2 Hz, Ar), 7.33 (t, 1H, J = 7.5 Hz, Ar), 6.32 (s, 1H, CH), 4.14 (s, 2H, ArCH₂Ar), 3.84 (s, 3H, CH₃); ¹³C NMR (100MHz, DMSO), 5_C 182.1, 166.5, 147.0, 143.5, 140.9, 132.1, 129.8, 129.4, 128.1, 125.1, 123.6, 119.0, 107.5, 52.4, 41.0; MS (ES+), [M + H] ⁺ (100), 370.1, HRMS calculated for 370.1443 C₂₄H₂₀NO₃, found 370.1435.

Yields

[00314] Table 3 below shows the yields obtained during the synthesis of compounds 19a-g. Table 3

Example 3 - Preparation of compounds of formula I in which R¹ CI and R³ is hydrogen

General reaction scheme

[00315] Scheme 5 shows the synthesis of 3-chloroquinolone 20a. 19a was reacted with sodium dichloroisocyanate to give quinolone 20a in 64% yield.

Scheme 5: The synthesis of chloroquinolone 20a. Experimental

General procedure for the preparation of quinolone [20]

[00316] Sodium dichloroisocyanurate (0.20 mmol) was added in one portion to a stirred solution of quinolone 19a (0.37mmol) in a mixture of methanol (10 mL), 2M NaOH (2mL), and water (2mL). After 2 hours of stirring, the methanol was slowly evaporated under vacuum and the resulting residue dissolved in ethyl acetate and washed with brine. The organic layer was dried with MgS0₄ and concentrated to give the respective chloro compound 20a.

Preparation of3-chloro-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 20a

[00317] Light orange (Yield 64%); m.p. 116-118 °C; 1H NMR (400MHz, MeOD) δ_Η 7.85 (dd, 1H, J = 8.0 Hz, 1.2 Hz, Ar), 7.55 (d, 2H, J = 8.3 Hz, Ar), 7.48 (ddd, 1H, J = 8.6 Hz, 7.2 Hz, 1.6 Hz, Ar), 7.36 (d, 2H, J = 8.3 Hz, Ar), 7.34 (d, 2H, J = 8.2 Hz, Ar), 7.20 (d, 2H„ J = 8.2 Hz, Ar), 7.00 (dd, 1H, J = 8.3 Hz, 1.0 Hz, Ar), 6.90 (ddd, 1H, J = 8.2 Hz, 7.2 Hz, 1.0 Hz, Ar), 4.08 (s, 2H, ArCH₂Ar); ¹³C NMR (100MHz, MeOD), 5_C 182.4, 146.4, 142.7, 140.4, 136.0, 131.1, 130.2, 129.9, 128.9, 128.2, 127.9, 120.8, 119.0, 115.7, 115.0, 40.2; MS (ES+), [M + H] ⁺ (100), 430.0, HRMS calculated for 430.0822 C₂₃H₁₇NO₂F₃, found 430.0815.

Example 4 - Preparation of compounds of formula I in which R¹ is CO2R and R³ is hydrogen

General reaction scheme

[00318] Quinolones 23a-dwere synthesised by reacting isatoic anhydride 21 with diketone 17 in the presence of sodium hydride to give ester 22. Ester 22 was then reduced to alcohol 23 using either LAH or L1BH₄ (Scheme 6).

Scheme 6: The synthesis of quinolones 23. [00319] Ester and methyl alcohol groups were also synthesized by reaction of amine ester 24 with oxalyl chloride. The product from this reaction was used crude and heated in Dowtherm to give iodo quinolone 26, subsequent Suzuki reaction gave bisaryl ester quinolone compounds 27a and 27b in 53% and 75% yields. Reduction of quinolone 27b to methyl alcohol 28 was achieved using LiBH₄ in 66% yield.

Scheme 7: Synthesis of quinolones 27a-b and 28.

[00320] Scheme 8 shows the route used when

Compound 29 was treated with oxalyl chloride to give diketone 30 in 40-60% yield. Heating diketone 30 in Dowtherm A gives the quinolone acid 31 in 40% yield.

Scheme 8: The synthesis of quinolone 31 when R¹

Experimental

General procedure for the synthesis of quinolone [22]

[00321] β-Keto-ester 21 (2.0 mmol, 1 eq.) was added to DMF (15 mL) and NaH (2.0 mmol, 1 eq.) The flask was flushed with nitrogen and stirred at room temperature for 15 minutes. Isatoic anhydride (2.0 mmol, 1 eq.) was added in DMF (5 mL) and heated to reflux for 16 hours. DMF removed in vacuo and EtOAc (100 mL) was added to dissolve the residue. This was washed with water (30 mL), brine (30 mL) and then dried over MgS0₄. The brown solid was purified by flash column chromatography (eluting with EtOAc to 5% MeOH in EtOAc) to give the desired 3-ester quinolone 22.

Preparation of ethyl 4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,4-dihydroquinoline-3- carboxylate 22a

[00322] White solid (Yield 95%); m.p. 231-232 °C; 1H NMR (400MHz, CDC1₃) δ_Η 1.25 (t, 3H, CH₂CH₃), 3.81 (q, 2Η, CH₂CH₃), 4.05 (s, 2H, CH₂), 7.15 (m, 2Η, Ar), 7.25 (m, 4Η, Ar), 7.70 (bs, 2Η, Ar), 7.90 (bs, 1Η, Ar), 8.05 (bs, 1Η, Ar), 8.50 (bs, 1Η, Ar), 8.85 (bs, 1Η, Ar); ¹³C NMR (100MHz, CDC1₃), 5c 14.1, 41.4, 61.4, 114.1, 114.8, 121.8, 122.7, 124.8, 126.7, 129.2, 129.8, 130.8, 133.8, 136.2, 140.8, 142.8, 145.7, 159.7, 166.4, 174.5; MS (ES+), [M + H] ⁺ (100), 468, HRMS calculated for 468.1423 C₂₆H₂iN0₄F₃, found 468.1409.

Preparation of ethyl 7-chloro-4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,4- dihydroquinoline-3-carboxylate 22b

[00323] White solid (Yield 30%); m.p. 201-202 °C; 1H NMR (400 MHz, MeOD) δ 8.28 (d, / = 8.7 Hz 1H), 7.69(s, 1H), 7.55 (d, / = 8.7 Hz, 2H), 7.45 (d, / = 7.8 Hz, 3H), 7.37 (d, / = 8.6 Hz, 2H), 7.23 (d, / = 8.3 Hz, 2H, 4.13 (s, 2H), 4.06 (q, / = 7.1 Hz, 2H), 0.92 (t, J = 1.1 Hz, 3H); MS (ES⁺) m/z 502 (M + Na)⁺ Acc Mass Found: 502.1032, calculated 502.1033 for C₂₆H₂₀NO₄F₃Cl. Preparation of ethyl 7-chloro-4-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-l,4- dihydroquinoline-3-carboxylate 22c

[00324] White solid (Yield 30%); 1H NMR (400 MHz, MeOD) δ 8.26 (d, / = 8.8 Hz 1H), 7.48(s, 1H), 7.70 (d, / = 8.7 Hz, 2H), 7.48 (d, / = 8.2 Hz, 1H), 7.38 (d, / = 8.6 Hz, 2H), 7.18 (d, / = 8.8 Hz, 4H), 4.18 (q, / = 7.2 Hz, 2H), 1.14 (t, / = 7.1 Hz, 3H); MS (ES⁺) m/z 504 (M + H)⁺ Acc Mass Found: 504.0825, calculated 504.0826 for C25H18NO5F3CI.

Preparation of ethyl 4-oxo-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)-l,4-dihy

3-carboxylate 22d

[00325] White solid (Yield 28%); m.p. decomposed at 250 °C; 1H NMR (400 MHz, DMSO) δ 12.31 (bs, 1H), 8.88 (s, 1H), 8.33 (d, / = 8.9 Hz, 2H), 8.25 (d, / = 8.3 Hz, 1H), 8.14 (m, 2H), 7.76 (dd, / = 8.2, 8.0 Hz, 1H), 7.68 (d, / = 8.1 Hz, 1H), 7.55 (d, / = 8.1 Hz, 2H), 7.44 (dd, /= 7.0, 7.0 Hz, 1H), 4.02 (q, / = 7.1, 2H), 0.94 (t, / = 7.1 Hz, 3H) ; ¹³C NMR (100 MHz, DMSO) δ 173.90, 166.31, 156.24, 149.83, 148.94, 147.13, 139.91, 137.77, 137.21, 133.06, 129.24, 129.16, 125.42, 125.20, 124.71, 121.76, 120.30, 119.19, 116.06, 60.71, 14.08; HRMS (ESI)

C₂₄Hi₇N₂0₄F3²³Na [M+Na]⁺ requires 477.1038, found 477.1022.

General procedure for the synthesis of quinolone [23]

Procedure 1

[00326] Ester quinolone 22 (0.25 mmol, 1 eq.) was added to dry THF (30 mL) and cooled to 0C. L1AIH₄ (0.50 mmol, 2 eq.) was added and the solution was allowed to stir at room temperature for 2 hours. EtOAc (5mL) was added and the solvent was removed in vacuo. The cream solid was purified by flash column chromatography (eluting with EtOAc to 5% MeOH in EtOAc) to give the desired 3-methyl-hydroxy-quinolone 23.

Procedure 2

[00327] Ester quinolone 22 (0.25 mmol, 1 eq.) was added to dry THF (30 mL) and cooled to 0C. L1AIH₄ (0.50 mmol, 2 eq.) was added and the solution was allowed to stir at room temperature for 2 hours. EtOAc (5mL) was added and the solvent was removed in vacuo. The cream solid was purified by flash column chromatography (eluting with EtOAc to 5% MeOH in EtOAc) to give the desired 3-methyl-hydroxy-quinolone 23.

Preparation of 3-(hydroxymethyl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one 23a

[00328] Compound 23a was prepared according to procedure 1 to give a white powder (Yield 95%) Mtp. 128-130 °C 1H NMR (400MHz, CDC1₃), δ_Η 4.07 (s, 2H, ArCH₂Ar), 4.43 (s, 2H, CH₂OH), 7.16 (d, 2H, J = 8.5 H, Ar), 7.22 (d, 2H, J = 8.5 Hz, Ar), 7.32 (d, 2H, J = 7.7 Hz, Ar), 7.38 (t, 1H, J = 7.4 Hz, Ar), 7.48 (d, 2H, J = 7.7 Hz, Ar), 7.62 (t, 1H, J = 7.4 Hz, Ar), 8.37 (d, 2H, J = 7.0 Hz, Ar) ¹³C NMR (100MHz, CDC1₃), 5_C 41.4, 57.5, 119.3, 122.3, 125.1, 125.6, 126.4, 130.0, 130.5, 131.4, 133.6, 138.6, 141.3, 141.8, 144.9, 148.9, 149.7, 153.3, 180.1 MS (ES+), [M + Na] ⁺ (100), 448.1, HRMS calculated for 448.1136 C₂₄Hi₈N0₃F₃Na, found

448.1147.

Preparation of 7-chloro-3-(hydroxymethyl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin- 4(lH)-one 23b

[00329] Compound 23b was prepared according to procedure 1 to give a white solid (Yield 46%); m.p. 204-207 °C; 1H NMR (400 MHz, MeOD) δ 9.12 (s, 1H), 8.22 (d, / = 8.7 Hz 1H), 7.45-7.41 (m, 3H), 7.29-7.25 (m, 3H), 7.19 (d, / = 8.8 Hz, 2H), 7.14 (d, / = 8.7 Hz, 2H), 4.50 (s, 2H), 4.01 (s, 2H); MS (ES⁺) m/z 482 (M + Na)⁺ Acc Mass Found: 482.0741, calculated 482.0747 for

Preparation of 7-chloro-3-(hydroxymethyl)-2-( 4-(4-( trifluoromethoxy )phenoxy )phenyl )quinolin- 4(lH)-one 23c

[00330] Compound 23c was prepared according to procedure 1 to give a white solid (Yield 48%); m.p. 158-161 °C; 1H NMR (400 MHz, MeOD) δ 8.29 (d, / = 8.7 Hz 1H), 7.74 (d, / = 8.7 Hz, 1H), 7.67 (s, 1H), 7.43-7.37 (m, 3H) 7.25-7.21 (m, 4H), 4.52 (s, 2H); MS (ES⁺) m/z 484 (M + Na)⁺ Acc Mass Found: 484.0546, calculated 484.0539 for

Preparation of 3-(hydroxymethyl)-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)- one 23d

[00331] Compound 23d was prepared according to procedure 2 to give a white solid (Yield 40%); m.p 288-290 °C; 1H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 8.37 (d, / = 8.3 Hz, 1H), 8.28 (d, / = 8.9 Hz, 3H), 8.15 (d, / = 8.2 Hz, 1H), 7.76 (dd, / = 8.2, 8.0 Hz, 1H), 7.68 (d, / = 8.2 Hz, 1H), 7.49 (m, 3H), 4.51 (s, 2H); ¹³C NMR (100 MHz, MeOD) δ 178.50, 157.03, 149.03, 148.56, 140.05, 138.06, 137.18, 132.43, 129.03, 128.72, 125.09, 124.52, 124.02, 120.97, 120.14, 118.84, 118.05, 55.78; HRMS (ESI) C₂₂Hi₅N₂0₃F3²³Na [M+Na]⁺ requires 435.0932, found 435.0942.

Preparation of ethyl 3-(4-iodophenyl)-3-(phenylamino)acrylate 24

[00332]To a solution of aniline (2.93g, 2.86ml, 31.4mmol) in EtOH (10ml), acetic acid (1.89g, 1.80ml, 31.4mmol) was added, followed by the addition of a solution of ethyl (4-iodobenzoyl) acetate in EtOH (10ml). The resulting solution was heated to reflux for at least 4 hours. EtOH was removed in vacuo, and the residue dissolved in DCM. The DCM solution was then washed with water, 5%HCl_(aq.) and brine, and dried with Na₂S0₄. The DCM was removed in vacuo to give the crude product as a yellow solid. The crude product was purified by column

chromatography eluting with 5% EtOAc in hexane to give the title product (1.06, 86%) as a pale yellow crystalline solid. 1H NMR (400 MHz, CDC13) δ 10.23 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.17 - 7.02 (m, 5H), 6.94 (t, J = 6.9 Hz, 1H), 6.66 (d, J = 7.5 Hz, 2H), 4.97 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). Preparation of ethyl 2-(4-iodophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxylate 26

[00333] A solution of ethyl 3-(4-iodophenyl)-3-(phenylamino)acrylate in Et₂0 was cooled to 0°C. (COCl)₂ was added to the solution dropwise. After the addition, 1,4-dioxane was added to the reaction mixture, and the reaction allowed to warm to room temperature. Et₂0 and the HC1 side product were removed in vacuo carefully. The precipitate formed after the evaporation was isolated by filtration to give 25. 25 was used directly in the next step without any further purification.

[00334] A solution of 25 in Dowtherm was heat to 240°C for 30min. After cooling to room temperature, the solution was diluted with hexane. The precipitate is formed during the process was collected by filtration to give the title produce (l.Og, 91%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 12.08 (s, 1H), 8.12 (dd, J = 8.1, 1.1 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.73 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.45 - 7.34 (m, 3H), 4.00 (q, J = 7.1 Hz, 2H), 0.96 (t, J = 7.1 Hz, 3H). General procedure for the synthesis of quinolones [27a-b]

[00335] To a suspension of ethyl 2-(4-iodophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxylate (210mg, 0.5mmol) in DMF (10ml) were added x-boronic acid (l.Ommol), PdCl₂(dppf) (37mg, 0.05mmol) and K₂C0₃ (207mg, 1.5mmol). The reaction mixture was degassed and kept stirring at 120°C for 1 day.

[00336] The DMF was then removed in vacuo. The residue redissolved in 20% MeOH in DCM, and filtered through a pad of silica. The silica pad was washed further with 20% MeOH in DCM (100ml). All solvents in the filtrate were removed in vacuo to give the crude product. The crude product was purified by flash column chromato graph eluting with 5% MeOH in DCM to give the desired quinolone 27. Preparation of ethyl 4-oxo-2-(4'-(trifluoromethoxy)-[l,l '-biphenyl] -4-yl)-l ,4-dihydroquinoline- 3-carboxylate 27a

[00337] White solid (Yield 53%); m.p. 241-243 °C; 1H NMR (400 MHz, DMSO) δ 12.15 (s, IH), 8.14 (d, J = 7.8 Hz, IH), 7.94 - 7.87 (m, 4H), 7.78 - 7.67 (m, 3H), 7.52 (d, J = 8.0 Hz, 2H), 7.42 (ddd, J = 8.1, 6.5, 1.7 Hz, IH), 7.32 (d, J = 7.7 Hz, IH), 4.02 (q, J = 7.1 Hz, 2H), 0.95 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) δ 174.32, 166.63, 149.35, 140.82, 139.92, 138.71, 136.53, 133.49, 132.90, 129.33, 129.18, 127.33, 125.33, 122.04, 120.04, 119.18, 115.84, 107.49, 106.43, 60.64, 14.01; HRMS (ESI) C₂5Hi₉N0₄F3 [M+H]⁺ requires 454.1266, found 454.1263. Preparation of ethyl 2-(4'-chloro-[ 1,1 '-biphenyl] -4-yl)-4-oxo-l,4-dihydroquinoline-3- carboxylate 27b

[00338] White solid (Yield 75%); m.p. 228-230 °C; 1H NMR (400 MHz, DMSO) δ 12.12 (s, IH), 8.14 (d, J = 7.9 Hz, IH), 7.90 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.4 Hz, 4H), 7.58 (d, J = 8.6 Hz, 2H), 7.42 (ddd, J = 8.1, 6.4, 1.7 Hz, IH), 4.02 (q, J = 7.1 Hz, 2H), 0.96 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO) δ 166.65, 158.47, 149.33, 149.23, 148.87, 140.94, 139.94, 138.18, 133.44, 132.88, 129.46, 129.32, 128.99, 127.13, 125.32, 125.02, 124.47, 119.19, 60.64, 14.03; HRMS (ESI) C₂₄Hi₈N0₃NaCl [M+Na]⁺ requires 426.0873 and 428.0843, found 426.0856 and 428.0850.

Preparation of 3-(hydroxymethyl)-2-(4'-(trifluoromethoxy)-[ 1 ,1 ' -biphenyl] -4-yl)quinolin-4(lH)- one 28

[00339] To a suspension of quinolone 27a (25mg, 0.055mmol) in toluene, a solution of LiBH₄ in THF (2M, 28ul, 0.055mmol) was added. The resulting mixture was heated to 100°C and kept stirring for 2 hours. The reaction mixture was cooled to room temperature and a few drops of water are used to quench the reaction. The crude material was isolated by removing all solvents in vacuo and purified by flash column chromato graph eluting with 5% MeOH in DCM to give quinolone 28.

[00340]White solid (Yield 66%); 1H NMR (400 MHz, Acetone) δ 10.80 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.94 - 7.87 (m, 4H), 7.82 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.39 (ddd, J = 8.1, 5.8, 2.3 Hz, 1H), 4.49 (s, 2H); 13C NMR (101 MHz, Acetone) δ 169.04, 145.41, 141.82, 140.98, 140.05, 137.01, 132.87, 132.15, 130.65, 129.75, 128.01, 126.13, 124.16, 122.48, 120.63, 120.49, 119.02, 118.95, 59.15; HRMS (ESI) C₂₃H₁₆N0₃F₃Na [M+Na]⁺ requires 434.0980, found 434.0961.

General procedure for the synthesis of diketone [29]

30

[00341] Amine 29(2.25 mmol, 1.0 eq) was dissolved in ether (10 mL) and cooled to 5 °C. Oxalyl chloride (2.48 mmol, 1.0 eq) was added dropwise. The reaction was allowed to warm to room temperature over 1 hour and was subsequently heated at 50 °C for a further hour. A yellow orange precipitate was seen. The reaction was cooled and placed in the fridge overnight. The precipitate was filtered off, washed with ether and dried under vacuum to give the desired diketone 30.

Preparation of ethyl 4, 5-dioxo-l -phenyl-2-( 4-(4-( trifluoromethoxy )benzyl)phenyl)-4, 5-dihydro- lH-pyrrole-3-carboxylate 30a

[00342] Orange solid (Yield 45%); 1H NMR (400MHz, CDC1₃) δ_Η 1.15 (t, 3H, CH₂CH₃), 3.88 (s, 2Η, CH₂), 4.22 (q, 2Η, CH₂CH₃), 6.95 (m, 2H, Ar), 7.10 (m, 6H, Ar), 7.20 (m, 2H, Ar), 7.28 (m, 3H, Ar); ^1JC NMR (100MHz, CDC1₃), 5_C 14.2, 41.3, 61.4, 104.9, 114.8, 128.0, 128.1, 128.9, 129.2, 129.6, 129.7, 130.0, 132.7, 133.8, 140.7, 145.1, 158.7, 161.5, 172.2, 173.7.

General procedure for the synthesis of quinolone [31]

[00343]Diketone 12 (0.50 mmol, 1.0 eq) was dissolved in Dowtherm A (10 mL) and heated at reflux for 3 hours. The reaction was allowed to cool and hexane added. The resulting precipitate was filtered and washed with hexane to give the desired quinolone 31.

Preparation of4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,4-dihydroquinoline-3- carboxylic acid 31a

[00344] White solid (Yield 40%); 1H NMR (400MHz, CDC1₃) δ_Η 4.05 (s, 2H, CH₂), 7.15 (m, 2Η, Ar), 7.25 (m, 4Η, Ar), 7.65 (d, 2Η, J=8.1 Hz, Ar), 7.80 (m, 1H, Ar), 7.95 (m, 1H, Ar), 8.25 (d, 1H, J=8.34 Hz, Ar), 8.75 (d, 1H, J=8.16 Hz, Ar); ¹³C NMR (100MHz, CDC1₃), 5_C 41.4, 114.5, 114.8, 121.4, 122.3, 124.3, 126.3, 129.1, 129.8, 130.7, 133.5, 136.0, 140.7, 142.4, 145.1, 159.4, 166.2, 173.5. MS (ES+), [M + H] ⁺ (100), 439, HRMS calculated for 439.3814 C₂4Hi₆N0₄F3, found 439.3825.

Yields

[00345] Table 4 below shows the yields obtained for compounds 23a-d synthesised by Scheme 6. Table 4: Quinolones synthesised when R^CC^Et and CH₂OH.

Example 5- Preparation of compounds of formula I in which R¹ is methyl, R³ is hydrogen and R² is a bis-aryl substituent

General procedure for the synthesis of quinolones [32]

[00346] Quinolone 7c or 7n (1 mmol, 1.0 eq), PdCl₂(dppf) (5 mol%) and potassium carbonate (3 mmol, 3 equiv) in anhydrous 1,4-dioxane (10 mL) were stirred for 5 min under N₂. Boronic acid (2 mmol, 2 equiv) was added. The reaction was evacuated and backfilled with N₂ (this sequence was carried out three times). The reaction mixture was heated to 100°C for 1 day. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a pad of MgSCv silica. The silica pad was further washed with ethyl acetate. The filtrate was evaporated and the crude material was purified by flash chromatography on silica gel to give the desired quinolone 32.

Preparation of 3-methyl-2-(4'-(trifluoromethoxy)-[l,l '-biphenyl] -4-yl)quinolin-4( 1 H)-one 32a

[00347] Pink solid (Yield 60%); MP 295 - 296 °C; 1H NMR (400 MHz, MeOD-d4) δ 8.32 (dd, / = 8.5, 1.7 Hz, 1H), 7.91 - 7.80 (m, 4H), 7.77 - 7.61 (m, 4H), 7.42 (m, 3H), 2.11 (s, 3H); ¹³C NMR (101 MHz, MeOD-d4) δ 142.30, 133.00, 130.76, 129.85, 128.54, 126.29, 126.22, 124.90, 124.58, 122.71, 122.59, 90.67, 66.81, 49.42, 49.21, 49.00, 48.79, 48.57, 15.50; ES+ HRMS: m/z found 396.1198, [C₂₃Hi₆N0₂F₃ + H]⁺ requires 396.1211.

Preparation of 2-(2'-fluoro-[ 1,1 '-biphenyl] -4-yl)-3-methylquinolin-4(lH)-one 32b

[00348] Brown solid (Yield 69 %); m.p. 320 - 322 °C; 1H NMR (400 MHz, MeOD) δ 8.31 (dd, / = 8.3, 0.9 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.72 - 7.65 (m, 3H), 7.64 - 7.56 (m, 2H), 7.62 - 7.38 (m, 2H), 7.32 (td, / = 7.5, 1.2 Hz, 1H), 7.25 (ddd, / = 11.0, 8.2, 1.1 Hz, 1H), 2.11 (s, 3H); HRMS (ESI) C₂₂Hi₇NOF [M+H]⁺ requires 330.1294, found 330.1297.

Preparation of 2-(2',4'-difluoro-[ 1,1 '-biphenyl] -4-yl)-3-methylquinolin-4(lH)-one 32c

[00349] Brown solid (Yield 65%); m.p. >315 °C; 1H NMR (400 MHz, DMSO) δ 11.66 (s, 1H, N- H), 8.14 (d, / = 7.8 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.71 - 7.65 (m, 3H), 7.65 - 7.60 (m, 2H), 7.49 - 7.40 (m, 1H), 7.34 - 7.29 (m, 1H), 7.29 - 7.22 (m, 1H), 1.95 (s, 3H, CH₃);HRMS (ESI) C₂₂Hi₆NOF₂ [M+H]⁺ requires 348.1200, found 348.1183.

Preparation of 3-methyl-2-(2'-(trifluoromethyl)-[l,l '-biphenyl] -4-yl)quinolin-4( 1 H)-one 32d

[00350]Pa\e pink solid (Yield 50%); m.p. 270 - 271 °C; 1H NMR (400 MHz, CDC1₃) δ 8.42 (dd, / = 8.1, 0.7 Hz, 1H), 8.22 (s, 1H), 7.80 (d, / = 7.8 Hz, 1H), 7.67 - 7.46 (m, 7H), 7.42 - 7.29 (m, 4H), 2.14 (s, 3H); HRMS (ESI) C₂₃Hi₇NOF₃ [M+H]⁺ requires 380.1262, found 380.1262. Preparation of 3-methyl-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-yl)quinolin-4(lH)-one 32e

[00351] Pink solid (Yield 68%); MP 279 - 280 °C; 1H NMR (400 MHz, MeOD) δ 8.84 (dd, / = 2.3, 0.9 Hz, 1H), 8.31 (dd, / = 8.5, 1.6 Hz, 1H), 8.16 (dd, / = 8.1, 2.3 Hz, 1H), 7.89 (d, / = 7.8 Hz, 1H), 7.83 - 7.68 (m, 4H), 7.62 (t, 7 = 7.9 Hz, 1H), 7.43 (ddd, / = 8.1, 6.9, 1.2 Hz, 1H), 2.10 (s, 3H); ES+ HRMS: m/z found 381.1197, [C₂₂H₁₅N₂OF₃ + H]⁺ requires 381.1215.

Preparation of2-( 6-( 2-fluorophenyl)pyridin-3-yl)-3-methylquinolin-4( lH)-one 32f

[00352] Pale brown solid (Yield 65 %); m.p. 269 - 270 °C. 1H NMR (400 MHz, MeOD) δ 8.88 (dd, J = 2.3, 0.9 Hz, 1H), 8.32 (ddd, / = 8.3, 1.4, 0.5 Hz, 1H), 8.14 (dd, / = 8.2, 2.3 Hz, 1H), 8.04 (ddd, / = 8.2, 2.0, 0.9 Hz, 1H), 8.00 (td, / = 7.8, 1.8 Hz, 1H), 7.71 (ddd, / = 8.4, 6.9, 1.5 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.57 - 7.49 (m, 1H), 7.43 (ddd, / = 8.2, 6.9, 1.2 Hz, 1H), 7.37 (td, 7 = 7.6, 1.2 Hz, 1H), 7.30 (ddd, / = 11.4, 8.3, 1.0 Hz, 1H), 2.12 (s, 3H); HRMS (ESI) C₂iHi₆N₂OF

[M+H]⁺ requires 331.1247, found 331.1239. Yields

[00353] Table 5 below shows the yields obtained during the synthesis of compounds 32a-f.

Table 5

Example 6 - Preparation of compounds of formula I in which R¹ and R³ are hydrogen and R² is a bis-aryl substituent comprising a 5-membered heteroaryl ring

General Reaction Scheme

[00354] Compounds comprising a 5-membered heteroaryl at the 2 position on the quinolone ring were prepared as shown in Scheme 9. Chloroquinoline was treated with m-CPBA and subsequently POBr₃ to give bromo quinoline 33. This was then reated with boronic ester 34 to give 2-substituted chloro quinoline 35. Treatment with acetic acid in water then gives quinolone 36.

Scheme 9: Synthesis of quinolones 36a-e containing a 5-membered heteroaryl ring in the 2- position

[00355] Scheme 10 shows the coversion of quinolone 36a to 3-chloroquinolone 37.

Scheme 10: Synthesis of 3-chloro quinolone 37.

[00356] A further range of quinolones containing a 5-membered heterocyclic ring were synthesised using the methodology depicted in Scheme 11. Iodo side chain 38 was synthesised from the reaction of iodopyrazole with the respective bromobenzyl compound. Reaction of 38 with aldehyde 39 gave compound 40 in good yields. Cyclisation with oxazoline 6 as previously described gave quinolones 41a-g.

Scheme 11: Synthesis of quinolones 41a-g containing a 5-membered heteroaryl ring in the 2- position.

[00357] Scheme 12 shows the synthesis of quinolone 47 containing a triazole as the 5-membered ring heterocycle.

Scheme 12: Synthesis of quinolone 47 containing a 5-membered triazole ring in the 2-position. Experimental

General procedure for the synthesis of chloroquinoline [33]

[00358] To 4-chloroquinoline (6.0mmol) in CHC1₃ (50mL), was added mCPBA (1.24g, 7.2mmol, 1.2eq.). The resulting mixture was kept at room temperature for 4 hours. The reaction was washed with NaHC0₃(sat.) to remove m-chlorobenzoic acid side product and the water layer extracted with DCM (25mL x 2). The organic layers were combined, washed with brine and dried with MgSC The solvent was removed in vacuo to give the N-oxide as a yellow solid which was used directly in the next step without further purification.

[00359] POBr₃(l .72g, 6.0mmol, 1.Oeq.) was added to a solution of the N-oxide in CHC1₃ (25mL). The resulting mixture was stirred at room temperature for 90 minutes. The reaction was quenched with ice- water and neutralized to pH=7 with Na₂C0₃ (sat.). The organic layer was separated, and the water layer extracted with DCM (30mL x 2). The organic portions were combined, washed with brine and dried with MgS0₄. After removal of all organic solvents, the crude product was a yellow solid. The crude product was purified by flash column

chromato graph (eluting with 10% EtOAc in hexane) to give 33.

Preparation of 2-bromo-4-chloroquinoline 33a

[00360] Off white solid (yield 72% over 2 steps); 1H NMR (400 MHz, CDC13) δ 8.21 (d, J = 7.1 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.80 (t, J = 7.0 Hz, 1H), 7.72 - 7.64 (m, 2H).

Preparation of 2-bromo-4-chloro-7 -methoxyquinoline 33b

[00361] Colorless crystalline solid (71% yield); 1H (400 MHz, CDC13) δ 8.06 (d, J = 9.2 Hz, 1H), 7.50 (s, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 9.2, 2.5 Hz, 1H), 3.95 (s, 3H). Preparation of2-bromo-4-chloro-3-methylquinoline 33c

/003627Colorless crystalline solid (72% yield) ;1H NMR (400 MHz, CDC13) δ 8.24 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.82 (t, J = 7.1 Hz, 1H), 7.65 (t, J = 7.3 Hz, 1H), 2.55 (s, 3H).

Preparation of ethyl 2-bromo-4-chloroquinoline-3-carboxylate 33d

[00363] Colorless crystalline solid (75% yield); 1H (400 MHz, CDC13) δ 8.24 (dd, J = 8.4, 0.8 Hz, 1H), 8.08 (dd, J = 8.5, 0.6 Hz, 1H), 7.84 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.72 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H). General Procedure for the synthesis of boronic ester [34]

34

[00364] To a solution of 4-pyrazole boronic acid pinacol ester (l.Og, 5.0mmol) in DMF (lOmL), 4-(trifluoromethoxy) benzyl bromide (1.45g, 5.5mmol, l.leq) and Cs₂C0₃(1.81g, 5.5mmol, l.leq) were added. The resulting mixture was stirred at 90°C overnight. DMF was removed in vacuo and the residue dissolved in water and extracted with DCM (25mL x 3). The organic layers were combined, washed with brine and dried with MgS0₄. The solvent was removed in vacuo to give the crude product, which was purified by flash column chromatograph (eluting with 20% EtOAc in DCM) to give 34.

Preparation of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(4-(trifluoromethoxy)benzyl)- ΙΗ-pyrazole 34a

[00365] Colourless oil (Yield 81%); 1H NMR (400 MHz, CDC13) δ 7.83 (s, 1H), 7.70 (s, 1H), 7.28 - 7.22 (m, 2H), 7.18 (d, J = 8.8 Hz, 2H), 5.31 (s, 2H), 1.31 (s, 12H). Preparation of l-(4-fluorobenzyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole

34b

[00366]Pale yellow oil (82% yield): 1H (400 MHz, CDC13) δ 7.81 (s, 1H), 7.66 (s, 1H), 7.25 7.16 (m, 2H), 7.09 - 6.98 (m, 2H), 5.27 (s, 2H), 1.30 (s, 12H).

General procedure for the synthesis of chloroquinoline 35

\ ^0 ?' 10% PdCI₂(dppf), CI

[00367]To a solution of 2-bromo-4-chloroquinoline 33 (l.Ommol) in Dioxane (20mL), the boronic acid pinacol ester 34 (268mg, l.Ommol, l.Oeq), PdCl₂(dppf) (73mg, O.lOmmol, O.lOeq) and

(413mg, 2.5mmol, 2.5eq) were added. The reaction mixture was degassed and heated to reflux for 24 hours. The resulting mixture was filtered through a pad of silica to remove the Pd catalyst and the inorganic salts. The crude product was a yellow solid and was purified by flash column chromatograph (eluting with 10% EtOAc in DCM) to give 35.

Preparation of4-chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinoline 35a

[00368]Pale yellow solid (Yield 63%); 1H NMR (400 MHz, CDC13) δ 8.20 - 8.11 (m, 3H), 8.02 (dd, J = 8.5, 0.4 Hz, 1H), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.69 (s, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.39 (s, 2H). Preparation of ethyl 4-chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinoline- 3- carboxylate 35b

[00369] Pale yellow crystalline solid (68% yield); 1H (400 MHz, CDC13) δ 8.22 (dd, J = 8.4, 0.9 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.79 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.63 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 5.36 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.34 - 1.29 (t, J = 7.2 Hz, 3H).

Preparation of 4-chloro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolone 35c

[00370] Pale yellow crystalline solid (38% yield); 1H (400 MHz, CDC13) δ 8.19 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.57 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 5.40 (s, 2H), 2.73 (s, 3H).

Preparation of4-chloro-2-(l-(4-fluorobenzyl)-lH-pyrazol-4-yl)quinolone 35d

[00371] Off-white solid (36% yield); 1H (400 MHz, CDC13) δ 8.20 - 8.12 (m, 2H), 8.09 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.67 (s, 1H), 7.55 (ddd, J = 8.1, 6.9, 1.0 Hz, 1H), 7.30 (dd, J = 8.5, 5.3 Hz, 2H), 7.06 (t, J = 8.6 Hz, 2H), 5.35 (s, 2H). 4-chloro-7-methoxy-2-( 1 -(4-( trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)

[00372] Off-white solid (53% yield); 1H (400 MHz, CDC13) δ 8.13 (s, 1H), 8.09 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.54 (s, 1H), 7.36 - 7.29 (m, 3H), 7.24 - 7.15 (m, 3H), 5.38 (s, 2H), 3.96 (s, 3H).

General procedure for the synthesis of quinolone [36]

Procedure 1

[00373] AcOH (8mL) was added to a suspension of 4-chloroquinoline 35 (0.5mmol) in water (2mL). The resulting mixture was heated to 120°C overnight. NH₄ ^»H₂0(aq) was then used to basify the resulting solution. During the basification, some precipitate was formed. The precipitate was separated by filtration to give the crude product. The crude product was purified by flash column chromatograph eluting with 5-10% MeOH in DCM to give the desired compound.

Procedure 2

[00374]To a solution of 4-chloroquinoline (0.16mmol) in DMF (6ml), HCOOH (85% in H₂0, 2ml) was added. The resulting mixture was heated to 140°C for 4 hours. All solvents and HCOOH were removed in vacuo to give the crude product. The crude product was purified by flash column chromatograph eluting with 5% MeOH in DCM to give the title compound. Preparation of2-(l-(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl)quinolin-4( lH)-one 36a

[00375] Compound 36a was prepared according to procedure 1 to give a white solid (Yield 67%); 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.42 (q, J = 8.8 Hz, 4H), 7.30 (ddd, J = 8.1, 5.7, 2.4 Hz, 1H), 6.40 (s, 1H), 5.48 (s, 2H); ES HRMS: m/z found 386.1106, C₂₀H₁₅N₃O₂F₃ ([M+H]⁺) requires 386.1116.

Preparation of ethyl 4-oxo-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)-l,4- dihydroquinoline-3-carboxylate 36b

[00376] Compound 36b was prepared according to procedure 2 to give a white solid (71% yield); Melting point: 208-210°C;lH (400 MHz, DMSO) δ 11.75 (s, 1H), 8.26 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.87 (s, 1H), 7.73 - 7.65 (m, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.42 - 7.34 (m, 3H), 5.50 (s, 2H), 4.09 (dd, J = 7.1 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H); 13C (101 MHz, DMSO) δ 173.97, 167.36, 156.87, 148.28, 141.10, 140.05, 139.18, 136.74, 132.74, 131.20, 130.23, 125.15, 124.60, 124.14, 121.64, 118.85, 115.06, 114.72, 61.01, 54.50, 14.06. ES HRMS: m/z found 480.1156, C₂₃Hi₈N₃0₄F₃Na requires 480.1147.

Preparation of 3-methyl-2-( 1 -(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one

36c

[00377] Compound 36c was prepared according to procedure 1 to give a white solid in 47% yield. Melting point: 193~195°C. NMR: 1H (400 MHz, DMSO) δ 11.28 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.96 (s, 1H), 7.66 - 7.54 (m, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 7.0 Hz, 1H), 5.50 (s, 2H), 2.09 (s, 3H); 13C (101 MHz, DMSO) δ 176.79, 148.21, 147.86, 147.44, 140.46, 139.90, 137.01, 131.82, 131.49, 130.09, 125.32, 123.17, 122.80, 121.62, 118.27, 116.24, 114.25, 54.48, 12.52. ES HRMS: m/z found 400.1261, C₂₁H₁₇N₃O₂F₃ requires 400.1273.

Preparation of2-(l-(4-fluorobenzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one 36d

[00378] Compound 36d was prepared according to procedure 1 to give a white solid in 79% yield. Melting point: 308-310°C. NMR: 1H (400 MHz, DMSO) δ 11.39 (s, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.72 - 7.59 (m, 2H), 7.45 - 7.34 (m, 2H), 7.29 (t, J = 7.1 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.40 (s, 1H), 5.42 (s, 2H); 13C (101 MHz, DMSO) δ 177.05, 160.93, 143.37, 140.63, 138.37, 133.43, 131.98, 130.46, 130.17, 125.28, 125.04, 123.28, 118.44, 116.89, 115.73, 105.16, 54.85. ES HRMS: m/z found 320.1188, C₁₉H₁₅N₃OF requires 320.1199.

Preparation of 7-methoxy-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)- one 36e

[00379] Compound 36e was prepared according to procedure 1 to give an off-white solid in 89% yield. Melting point: 266~268°C. NMR: 1H (400 MHz, DMSO) δ 11.23 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 6.0 Hz, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.9, 2.4 Hz, 1H), 6.32 (d, J = 1.7 Hz, 1H), 5.48 (s, 2H), 3.87 (s, 3H); 13C (101 MHz, DMSO) δ 176.67, 162.17, 150.28, 148.28, 142.96, 142.35, 141.40, 138.30, 136.74, 134.38, 130.12, 126.86, 121.65, 119.58, 117.05, 113.17, 104.96, 55.77, 54.76. ES HRMS: m/z found 416.1234, C₂₁H₁₇N₃O₃F₃ requires 416.1222. Preparation of 3-chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one 37

[00380] To a suspension of 2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)- one (64mg, 0.17mmol) in MeOH (5ml) and NaOH(aq.) (1M in H₂0, 1ml), sodium

dichloroisocyanurate (21mg, 0.091mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by acidification with HCl(aq.) (2M in H₂0, 0.5ml), and was filtered. The filter cake was washed thoroughly with MeOH/DCM (1:1, 40ml). The filtrate and the wash solution were combined and concentrated in vacuo to give the crude product as a white solid. The crude product is purified by flash column chromatograph eluting with 10% MeOH in DCM to give the title compound (40mg, 56%) as a white solid.

[00381] Melting point: 255~257°C. NMR: 1H (400 MHz, DMSO) δ 11.81 (s, 1H), 8.69 (s, 1H), 8.15 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.75 - 7.65 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 - 7.33 (m, 3H), 5.53 (s, 2H);13C (101 MHz, DMSO) δ 171.16, 156.30, 147.81, 140.55, 139.93, 138.86, 136.33, 132.45, 131.95, 129.73, 124.94, 123.55, 123.00, 121.17, 118.25, 113.72, 112.22, 54.06. ES HRMS: m/z found 420.0727 and 422.0714, C₂₀H₁₄N₃O₂F₃CI requires 420.0727 and

422.0697.

General procedure for the synthesis of iodo pyrazole 38

[00382] To a stirring suspension of 4-iodo-lH-pyrole (1.94g, lO.Ommol) and K₂C0₃ (3.46g,

25mmol) in acetone, 4-(trifluoromethoxy)benzyl bromide (1.71ml, 20.5mmol) was added. The resulting mixture was heated to reflux for 3 hours. After that, the reaction mixture was cooled to room temperature and filtered to remove the insoluble salt. The filtrate was concentrated to give the crude product as a pale yellow oil. The crude product was purified by flash column chromatograph eluting with 10-20% EtOAc in hexane to give the title product. Preparation of 4-iodo-l-(4-(trifluoromethoxy)benzyl)-lH-pyrazole 38a

[00383] Colorless oil. (99% Yield); 1H (400 MHz, CDC13) δ 7.56 (s, 1H), 7.43 (s, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 5.30 (s, 2H).

Preparation of ^'3-iodo-l -(4-( trifluoromethoxy )benzyl)-l H-pyrazole 38b

[00384]Pale yellow solid (71% yield). 1H (400 MHz, CDC13) δ 7.28 - 7.17 (m, 5H), 6.46 (d, J = 2.3 Hz, 1H), 5.32 (s, 2H).

General Procedure for the synthesis of ketone [40]

[00385]To a suspension of Pd₂(dba)₃ (42mg, 0.046mmol), dppp (59mg, 0.14mmol) and 4A M.S (5g). in DMF (20ml), 4-iodo-l-(4-(trifluoromethoxy)benzyl)-l H-pyrazole (1.7g, 4.6mmol), propionaldhyde (1.0ml, 23mmol) and pyrrolidine (0.78ml, 9.2mmol) were added. The resulting mixture was degassed and heated to 110°C for 6 hours under N₂. After that, the reaction mixture was diluted with 40% EtOAc in hexane (20ml) and filtered through a pad of silica. The silica pad was washed with further 40% EtOAc in hexane (100ml). After removal of solvents from the filtrate the crude product was isolated as a yellow oil. The crude product is purified by flash column chromatograph eluting with 40-60% EtOAc in hexane to give the title compound. Preparation of l-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)propan-l-one 40a

[00386] Brown solid (37% Yield); 1H (400 MHz, CDC13) δ 7.95 (s, 1H), 7.90 (s, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 5.32 (s, 2H), 2.78 (q, J = 7.3 Hz, 2H), 1.18 (t, J = 7.3 Hz, 3H).

Preparation of l-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)butan-l-one 40b

[00387] Pale yellow solid (53% yield); 1H (400 MHz, CDC13) δ 7.95 (s, 1H), 7.89 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 5.32 (s, 2H), 2.71 (t, J = 7.4 Hz, 2H), 1.79 - 1.66 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

Preparation of l-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-3-yl)propan-l-one 40c

[00388]Pale yellow solid (41% yield). 1H (400 MHz, CDC13) δ 7.38 (d, J = 2.4 Hz, 1H), 7.29 - 7.16 (m, 4H), 6.82 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 3.03 (q, J = 7.4 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H).

Preparation of 7-methoxy-3-methyl-2-( l-(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl )quinolin- 4(lH)-one 41a

[00389] Compound 41a was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (42% yield). Melting point: 171-173°C. NMR: 1H (400 MHz, DMSO) δ 11.12 (s, 1H), 8.43 (s, 1H), 8.02 - 7.92 (m, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.9, 2.4 Hz, 1H), 5.50 (s, 2H), 3.83 (s, 3H), 2.07 (s, 3H); 13C (101 MHz, DMSO) δ 175.94, 161.37, 147.74, 141.13, 139.46, 139.31, 136.59, 131.23, 129.59, 126.72, 121.19, 118.67, 117.21, 115.87, 113.30, 112.66, 98.45, 55.19, 54.01, 11.95. ES HRMS: m/z found 430.1392, CaiHigNsOsFs requires 430.1379.

Preparation of 7-chloro-3-methyl-2-( 1 -(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl)quinolin- 4(lH)-one 41b

[00390] Compound 41b was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (59% yield). Melting point: 223-225°C. NMR: 1H (400 MHz, DMSO) δ 11.33 (s, 1H), 8.46 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 0.5 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.28 (dd, J = 8.7, 2.0 Hz, 1H), 5.51 (s, 2H), 2.08 (s, 3H); 13C (101 MHz, DMSO) δ 176.26, 162.24, 148.23, 140.81, 140.55, 139.87, 136.94, 136.07, 131.90, 130.11, 127.75, 123.21, 121.73, 121.64, 117.32, 115.99, 114.96, 54.51, 12.41. ES HRMS: m/z found 456.0683 and 458.0667, C₂₁H₁₅N₃O₂F₃CI requires 456.0703 and 458.0673.

Preparation of 6-fluoro-3-methyl-2-( 1 -(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl)quinolin- 4(lH)-one 41c

[00391] Compound 41c was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (47% yield). Melting point: 210-212°C. NMR: 1H (400 MHz, DMSO) δ 11.46 (s, 1H), 8.46 (s, 1H), 7.97 (s, 1H), 7.75 - 7.65 (m, 2H), 7.53 (td, J = 8.7, 3.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H), 2.09 (s, 3H); 13C (101 MHz, DMSO) δ 175.98, 159.51, 148.20, 140.75, 139.91, 136.99, 136.60, 131.90, 130.09, 124.12, 121.64, 121.10, 120.60, 120.34, 116.03, 113.72, 109.20, 54.48, 12.50. ES HRMS: m/z found 418.1190, C₂₁H₁₆N₃O₂F₄ requires 418.1179. Preparation of 7-fluoro-3-methyl-2-( 1 -(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl)quinolin- 4(1H) one 41d

[00392] Compound 41d was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (55% yield). Melting point: 214-216°C. NMR: IH (400 MHz, DMSO) δ 11.33 (s, IH), 8.45 (s, IH), 8.13 (dd, J = 9.0, 6.5 Hz, IH), 7.96 (s, IH), 7.46 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.32 (dd, J = 10.4, 2.5 Hz, IH), 7.12 (td, J = 8.8, 2.5 Hz, IH), 5.51 (s, 2H), 2.08 (s, 3H); 13C (101 MHz, DMSO) δ 176.27, 162.69, 148.23, 145.17, 141.06, 140.83, 139.83, 136.96, 131.83, 130.09, 128.77, 121.63, 120.25, 116.04, 114.51, 111.84, 103.00, 54.50, 12.36. ES HRMS: m/z found 440.1014, C₂₁H₁₅N₃O₂F₄ requires 440.0998.

Preparation of 3-ethyl-2-( 1 -(4-( trifluoromethoxy )benzyl)-lH-pyrazol-4-yl)quinolin-4( lH)-one 41 e

[00393] Compound 41e was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (65% yield). Melting point: 142~144°C.NMR: IH (400 MHz, DMSO) δ 11.29 (s, IH), 8.37 (s, IH), 8.08 (d, J = 8.0 Hz, IH), 7.88 (s, IH), 7.59 (d, J = 3.5 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.26 (ddd, J = 8.1, 4.6, 3.4 Hz, IH), 5.51 (s, 2H), 2.60 - 2.43 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H); 13C (101 MHz, DMSO) δ 176.37, 161.96, 148.21, 140.28, 139.93, 139.61, 137.07, 131.56, 131.23, 130.10, 125.29, 123.67, 122.81, 121.62, 121.05, 118.27, 115.86, 54.42, 19.61, 14.47. ES HRMS: m/z found 414.1432, C₂₂H₁₉N₃O₂F₃ requires 414.1429.

Preparation of 6-chloro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH^yrazol-4-yl)quinolin- 4(lH)-one 41f

[00394] Compound 41f was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (48% yield). Melting point: 228-230°C.NMR: 1H (400 MHz, DMSO) δ 11.47 (s, 1H), 8.46 (s, 1H), 8.01 (dd, J = 1.9, 1.0 Hz, 1H), 7.97 (s, 1H), 7.69 - 7.60 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 5.50 (s, 2H), 2.09 (s, 3H); 13C (101 MHz, DMSO) δ 175.62, 163.90, 148.21, 140.91, 139.93, 138.45, 136.96, 131.95, 131.69, 130.09, 127.40, 124.19, 124.07, 121.63, 120.80, 115.95, 114.73, 54.50, 12.51. ES HRMS: m/z found 456.0691 and 458.0677, C₂₁H₁₅N₃O₂F₃CI requires 456.0703 and 458.0673.

Preparation of 3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-3-yl)quinolin-4(lH)-one

41g

[00395] Compound 41g was prepared according to the general procedure for the synthesis of quinolones 7 and 8. White solid (52% yield). Melting point: 63~65°C.NMR: 1H (400 MHz, DMSO) δ 11.38 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.0 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 5.55 (s, 2H), 2.13 (s, 3H); 13C (101 MHz, DMSO) δ 177.20, 159.88, 148.21, 146.08, 140.39, 139.81, 136.99, 132.40, 131.61, 129.96, 125.27, 123.23, 122.90, 121.66, 118.69, 115.18, 108.12, 54.65, 12.29. ES HRMS: m/z found 400.1291, C₂iHi₇N₃0₂F₃ requires 400.1273.

Preparation of (E)-ethyl 2-methyl-3-(phenylamino)but-2-enoate 42

[00396] Aniline (4.55ml, 50 mmol), ethyl-2-methyl acetoacetate (7 ml, 50 mmol), anhy. MgS0₄ (6g, 50 mmol) and a catalytic amount of con.HCl were vigorously stirred in 60 ml of toluene at rt for 24hr. After removing the MgS0₄ by filtration, the solvent was removed in vacuo. The crude product was purified by column chromatography to give 42.

[00397] Yellow oil (Yield 40%); 1H NMR (400 MHz, CDC1₃) δ 10.91 (s, 1H, NH), 7.34-7.28 (i 2H), 7.12 (m, 1H ), 7.02 (d, J=7.5 Hz, 2H), 4.18 (q, J= 7.5 Hz, 2H), 2.05 (s, 3H), 1.86(s, 3H), 1.28 (t, J=7.4Hz, 3H). Preparation of 2,3-dimethylquinolin-4( 1H)-

[00398] Ethyl-3-anilino-2-methyl crotonate (1.88g, 8.6 mmol) in Dowtherm (10 ml) was heated at 220 °c for 1 hr. After the reaction mixture had cooled to rt, 20 ml of hexane was added and stirred for 10 min. The precipitate formed was collected by filtration and washed with hexane to give 43.

[00399] White solid (Yield 65%); 1H NMR (400 MHz, DMSO) δ 8.26 (d, / = 8.1 Hz, 1H), 7.75- 7.66 (m, 1H), 7.60 (d, / = 8.3 Hz, 1H), 7.41 (t, / = 7.5 Hz, 1H), 2.54 (s, 4H), 2.17 (s, 3H).

Preparation of 2,3-dimethylquinolin-4-yl acetate 44

[00400] To a solution of 2,3-dimethylquinolone (173 mg, 1 mmol) in 4 ml of anhy.THF was added t-BuOK (168 mg, 1.5 mmol) and the reaction stirred for 5 mins. Acetic anhydride

(0.283ml, 3 mmol) was then added and the mixture stirred at rt for 1 hr. The reaction was quenched with water and extracted with EtOAc and the organic extracts washed with brine, dried over MgS0₄ and concentrated in vacuo. The crude product was purified by column

chromatography to give 44.

[00401] White solid (Yield 80%); 1H NMR (400 MHz, CDC1₃) δ 8.04 (d, / = 8.4 Hz, 1H), 7.77 (d, / = 8.3 Hz, 1H), 7.64 (t, J= 8.5 Hz, 1H), 7.48 (t, / = 8.4 Hz, 1H), 2.72 (s, 3H), 2.52 (s, 3H), 2.24 (s, 3H).

Preparation of 2-formyl-3 -methylquinolin-4-yl acetate 45

[00402] A solution of 2,3-dimethyl-4-acetoxyquinoline (129 mg, 0.6 mmol), Se0₂ (lOOmg, 0.9 mmol), 1 ml of water and 10 ml of 1,4-dioxane was refluxed for 3 hr. The solvent was removed under vacuum and the residue was dissolved in ethylacetate and washed with satd. NaHC0₃, water and dried over MgS0₄. The solvent was concentrated in vacuo and the crude product was purified by column chromatography to give 45. [00403] White solid (Yield 90%); 1H NMR (400 MHz, CDC1₃): δ 10.32 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.82-7.76 (m, 2H), 7.71(t, J=8.4Hz, 1H), 2.61(s, 3H), 2.55 (s, 3H).

Preparation of 3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-l,2,3-triazol-4-yl)quinolin-4(lH one 47

[00404] The aldehyde (137 mg, 0.6 mmol), 2-oxopropyldiazodimethyl phosphonate (230 mg, 1.2 mmol) and K₂C0₃ (248 mg, 1.8 mmol) were suspended in MeOH-THF (1: 1, 4 ml) under N₂ atmosphere. The reaction mixture was stirred at rt for 2 hr. When all the starting aldehyde was converted into the intermediate alkyne 46, Cul (26 mg, 0.12 mmol) and 4-trifluromethoxy benzyl azide (130 mg, 0.6 mmol) were added and the reaction mixture was stirred at rt for 2 hr. The reaction mixture was diluted with water and extracted with ethylacetate. The organic phase was washed with a sat.NH₄Cl solution, brine and dried over MgS0₄ and the solvent was removed in vacuo and the crude product was purified by column chromatography to give 47.

[00405] White solid (Yield 62%); M.P: 206-207 °C; 1H NMR (400 MHz, MeOD) δ 8.62 (s, 1H),

8.25 (d, / = 8.5 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.53 (d, / = 8.7 Hz, 2H), 7.41 - 7.27 (m, 3H), 5. (s, 2H), 2.24 (s, 3H); MS (ES⁺) m/z 401 (M + H)⁺ Acc Mass Found: 401.1214, calculated 401.1225 for C₂oHi₆N₄0₂F₃.

Yields

[00406] Table 6 below shows the yields obtained during the synthesis of compounds 36a-e.

Table 6

[00407] Table 7 below shows the yields obtained during the synthesis of compounds 41a-g.

Table 7

Example 6 - Preparation of compounds of formula I in which R³ is OH

General Reaction Scheme

[00408] Compounds comprising a hydroxyl group in the 1 -position of the quinolone ring were prepared as shown in Scheme 5. Synthesis of the N-OH compounds was achieved by reacting a quinolone with ethyl chloroformate to give ester 48 in 60-99% yield. This was then oxidised using m-CPBA to give the N-oxide 49 which was used crude in the final step. Reaction with KOH gives the desired N-hydroxy compound 50 in 80-98% yield (Scheme 13).

49, used crude

Scheme 13: Synthesis of quinolones 50

Experimental

General procedure for the synthesis of ester [48]^[2]

[00409] A mixture of t-BuOK (6.25 mmol, 1.25 eq) and quinolone (5 mmol, 1.0 eq) in anhydrous THF (36 mL) was stirred for 1 hour at room temperature. Ethyl chloroformate (5.5 mmol, 1.1 eq) was added and stirring continued for 30 min. The reaction was quenched with water (10 mL) and concentrated in vacuo. Water (10 mL) was added to the residue and the product extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgS0₄ and concentrated. The resulting residue was purified by flash column chromatography (eluting with 1:1 DCM:hexane) to give the desired ester 48.

Preparation of ethyl ( 3-methyl-2-(4-(4-( trifluoromethoxy )benzyl )phenyl )quinolin-4-yl) carbonate 48a

[00410]White powder (Yield 98%); 1H NMR (400MHz, CDC1₃) δ_Η 1.45 (t, 3H, J = 7.1 Hz, CH₃), 2.34 (s, 3H, CH₃), 4.06 (s, 2H, ArCH₂Ar), 4.41 (q, 2H, J = 7.1 Hz, OCH₂), 7.15 (d, 2H, J = 8.0 Hz, Ar), 7.24 (d, 2H, J = 8.9 Hz, Ar), 7.31 (d, 2H, J = 8.0 Hz, Ar), 7.55 (d, 2H, J = 8.1 Hz, Ar), 7.58 (dt, 1H, J = 1.2 Hz, 8.1 Hz,Ar), 7.71 (dt, 1H, J = 1.2 Hz, 8.2 Hz, Ar), 7.88 (d, 1H, J = 8.3 Hz, Ar), 8.15 (d, 1H, J = 8.3 Hz, Ar); ¹³C NMR (100MHz, CDC1₃), 5_C 14.2, 14.6, 41.4, 66.1, 1290.9, 121.5, 121.6, 121.9, 127.5, 129.4, 129.8, 130.6, 140.0, 141.2, 148.1, 152.7, 152.7, 161.9; MS (ES+), [M + H] ⁺ (100), 482.2, HRMS calculated for 482.1579 C₂₇H₂₃N0₄F₃, found

482.1561. Preparation of ethyl (3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl) carbonate 48b

[00411] Colourless solid. (Yield 60 %); 1H NMR (400 MHz,CDCl₃) δ_Η 1.46 (t, 3H, J = 7.2, CH₃), 2.36 (s, 3H, CH₃), 4.42 (q, 2H, J = 7.1, CH₂), 7.07-7.28 (m, 6H, Ar), 7.56-7.64 (m, 3H,Ar), 7.72 (t, 1H, J = 7.6, Ar), 7.89 (d, 1H, J = 8.4, Ar) 8.15 (d, 1H, J = 8.4, Ar) ppm; ¹³C NMR (100MHz, CDC1₃), 5c 14.2, 14.6, 66.1, 120.9, 121.4, 121.6, 121.9, 127.5, 129.4, 129.9, 130.6, 139.8, 141.2, 148.1, 152.7, 152.9, 161.8; HRMS calcd for C₂₆H₂iN0₅F₃ [M+H]⁺ 484.1372 found 484.1358.

Preparation of 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl ethyl carbonate 48c

[00412] White powder (Yield 67%); 1H NMR (400 MHz, CDC1₃) δ 8.15 (s, 1H), 7.82 (d, J Hz, 1H), 7.59 - 7.48 (m, 3H), 7.31 (d, / = 8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.16 (d, / = Hz, 2H), 4.41 (q, / = 7.1 Hz, 4H), 4.06 (s, 2H), 2.32 (s, 3H), 1.45 (t, / = 7.1 Hz, 3H).

General procedure for the synthesis of N-oxide [49]

[00413] A solution of quinoline 48 (3.15 mmol, 1.0 eq) and m-CPBA (77% purity, 3.39 mmol, 1.08 eq) were suspended in anhydrous DCM (15 mL) and stirred for 3 hours at room

temperature. The solution was washed with 0.5M aqueous Na₂C0₃ (2 x 5mL) and water (5 mL), dried over MgS0₄ and the solvent removed in vacuo. The residue was used crude in the next step without any further purification. General procedure for the synthesis of N-hydroxy quinolone [50]

[00414] Aq 5M KOH (2.5 mL) was added to a solution of N-oxide 49 (1 mmol) in EtOH (5mL). After 1 hour at room temperature water (15 mL) was added and the pH adjusted to 1-2 using cone HC1 to give a milky solution which soon crystallized. The product was collect under vacuum and washed with water to give the desired N-hydroxy quinolone 50.

Preparation of l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH

50a

[00415] White powder (98.4%); 1H NMR (400MHz, DMSO) δ_Η 1.77 (s, 3H, CH₃), 4.09 (s, 2H, ArCH₂Ar), 7.33 (2H, J = 8.0 Hz, Ar), 7.37 (d, 2H, J = 8.2 Hz, Ar), 7.39 (t, 1H, J = 7.8 Hz, Ar), 7.42 (d, 2H, J = 8.2Hz, Ar), 7.45 (d, 2H, J = 8.6 Hz, Ar), 7.75 (dt, 1H, J = 1.4 Hz, 8.6 Hz, Ar), 7.81 (d, 1H, J = 8.2 Hz, Ar), 8.21 (dd, 1H, J = 8.2 Hz, Ar), 11.45 (bs, 1H, OH); ¹³C NMR

(lOOMHz, DMSO), 5_C 13.3, 115.1, 121.5, 123.4, 125.5, 128.9, 129.7, 130.8, 132.3, 139.9, 140.8, 141.9, 147.1, 149.6, 178.2; MS (ES+), [M + H] ⁺ (100), 426.1, HRMS calculated for 426.1317 C₂₄Hi₉N0₃F₃, found 426.1299.

Preparation of 1 -hydroxy-3-methyl-2-(4-(4-( trifluoromethoxy )phenoxy )phenyl )quinolin-4( 1H)- one 50b

[00416] Colourless solid. (Yield 83 %); 1H NMR (400 MHz,DMSO) δ_Η 1.96 (s, 3H, CH₃), 3.91 (s, 1H, OH), 7.19 (d, 2H, J = 9.0, Ar), 7.20-7.50 (m, 7H, Ar), 7.81 (m, 1H, Ar), 8.00 (m, 1H, Ar), 8.21 (d, 1H, J = 8.4, Ar) ppm; ¹³C NMR (lOOMHz, DMSO), 5_C 13.4, 115.2, 121.5, 123.3, 123.6, 125.5, 128.9, 129.8, 130.8, 131.0, 132.3, 139.8, 140.8, 141.9, 147.1, 149.7; HRMS calcd for C₂₃Hi₇N0₄F₃ [M+H]⁺ 428.1110 found 428.1106. Preparation of 7-chloro-l -hydroxy-3-methyl-2-( 4-(4-( trifluoromethoxy )benzyl )phenyl )quinolin- 4(lH)-one 50c

[00417] White solid (Yield 80%); M.P: 246-247 °C; 1H NMR (400 MHz, MeOD) δ 8.34 (d, J = 8.7 Hz, 1H), 7.96 (d, / = 1.7 Hz, 1H), 7.45 (ddd, / = 16.1, 9.3, 5.3 Hz, 6H), 7.37 (d, / = 8.2 Hz, 2H), 7.27 (d, / = 7.9 Hz, 1H), 4.16 (s, 2H), 1.92 (s, 3H); MS (ES⁺) m/z 482 (M + Na)⁺ Acc Mass Found: 482.0751, calculated 482.0747 for C₂₄Hi₇N0₃F₃NaCl

Yields

[00418] Table 8 below shows the yields obtained during the synthesis of compounds 50a-c. Table 8

Example 7 - Preparation of compounds of formula II in which R⁴ is an phosphate/phosphonate ester

Experimental

General procedure for the synthesis of phosphonate [51]^[3]

[00419] Sodium hydride (0.57 mmol, 2.5 eq) was added at 0°C to a stirred solution of quinolone (0.23 mmol, 1.0 eq) in dry THF (10 mL). After 1 hr, tetrabenzyl pyrophosphate (0.19 mmol, 0.8 eq) was added and the stirring continued for 20 minutes. The mixture was filtered and the filtrate concentrated under vacuum at a temperature below 35°C. The residue was dissolved in DCM, washed with NaHC0₃ aq, dried over MgS04 and concentrated under vacuum to give

phosphonate 51. Where necessary the product was purified by flash column chromatography (eluting with 10% ethyl acetate in n-hexane).

Preparation of dibenzyl (7-chloro-3-methyl-2-(4-(4-( trifluoromethoxy)benzyl)phenyl)quinolin-4- yl) phosphate 51a

[00420]White solid (Yield 87%); 1H NMR (400 MHz, CDC1₃) δ 8.06 (s, 1H), 7.92 (d, J =8.2 Hz, 1H), 7.52 (d, /= 806 Hz, 1H), 7.38 (d, /= 8.2 Hz, 2H), 7.26-7.18 (m, 14H), 7.10 (d, J= 8.2Hz), 5.06 (m, 4H), 4.02 (s, 2H), 2.32 (s, 3H). ³¹P NMR (162 MHz , CDC1₃) δ -4.81. Preparation of dibenzyl (3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl) phosphate 51b

[00421] White solid (Yield 80%); MP 106 °C; 1H NMR (400 MHz, CDC1₃) δ 8.87 (d, / = 2.2 Hz, 1H), 8.18 (d, / = 8.8 Hz, 1H), 8.10 (dd, / = 8.3, 3.5 Hz, 3H), 7.97 (dd, / = 8.2, 2.1 Hz, 1H), 7.83 (d, 7 = 8.2 Hz, 1H), 7.77 - 7.65 (m, 1H), 7.59 - 7.48 (m, 1H), 7.41 - 7.27 (m, 12H), 5.15 (dd, / = 9.0, 3.4 Hz, 4H), 2.44 (s, 3H); ³¹P NMR (162 MHz, CDC1₃) δ -5.85; ES+ HRMS: m/z found 657.1797, [C₃₆H₂₈N₂0₅F₃P + H]⁺ requires 657.1766.

Preparation of dibenzyl (3-methyl-2-(4'-(trifluoromethoxy)-[l,l '-biphenyl]-4-yl)quinolin-4-yl) phosphate 51c

[00422] Oil (Yield 80%); 1H NMR (400 MHz, CDC1₃) δ 8.17 (d, / = 7.9 Hz, 1H), 8.10 (d, / = 8.4 Hz, 1H), 7.70 (d, / = 8.3 Hz, 1H), 7.66 (d, / = 7.7 Hz, 4H), 7.60 (d, / = 8.3 Hz, 2H), 7.51 (t, / = 8.1 Hz, 1H), 7.36 - 7.27 (m, 12H), 5.25 - 5.05 (dd, / = 8.8, 1.8 Hz, 4H), 2.43 (s, 3H); ¹³C NMR (101 MHz, CDC1₃) δ 164.64, 153.37, 149.22, 140.29, 140.17, 139.92, 135.59, 130.09, 129.91, 129.63, 129.25, 129.04, 128.94, 128.56, 127.44, 127.20, 122.50, 122.12, 121.74, 121.69, 70.96, 15.42; ³¹P NMR (162 MHz, CDC1₃) δ -5.84; ES+ HRMS: m/z found 656.1804, [C₃₇H₂₉N₂0₅F₃P + H]⁺ requires 656.1814.

General procedure for the synthesis of phosphate pro-drug [52]

[00423] A suspension of phosphate 51 (0.18 mmol, l.Oeq) in anhydrous methanol (10 mL) was subjected to hydrogenation in the presence of 10% Pd/C (50 mg) at room temperature for 10 minutes. The catalysts and any precipitates were filtered off and the methanol portion analysed by tic. If the phosphate was in the methanol portion work-up A was followed, if the phosphate was isolated with the catalyst work-up B was followed.

[00424] Work-up A: The solvent was removed in vacuo to give the desired phosphate pro-drug 52 and no further purification was required.

[00425] Work-up B: The catalysts and precipitate isolated by filtration were dissolved in 10% NaHC0₃ solution then filtered. The filtrate was acidified with IN HCl and the solid collected by filtration and washed with acetone to give the desired phosphate pro-drug 52.

Preparation of 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl dihydrogen phosphate 52a

[00426] White solid (Yield 80%); M.P 201-203 °C; 1H NMR (400 MHz, CDC1₃) δ 11.82 (s, 1H), 11.62 (s, 1H), 8.32 (d, J=8.2Hz, 1H), 8.26 (d, J= 8.0 Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 8.06 (s, 1H), 7.91 (t, J= 8.2 Hz, 1H), 7.82 (t, J= 8.1 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.56 (d, J= 8.2 Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H), 7.46-7.32 (m, 12H), 4.12 (s, 2H), 4.09 (s, 2H), 2.40 (s, 3H), 2.37 (s, 3H). ³¹P NMR (162 MHz , CDC1₃) δ -5.027, -5.396; MS (ES^") m/z 522 (M -H)^~ Acc Mass Found: 522.0471, calculated 522.0485 for C₂₄Hi₇N0₅F₃PCl.

Preparation of 3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl dihydrogen phosphate 52b

[00427] Pale yellow solid (Yield 70%); MP 257 - 258 °C; 1H NMR (400 MHz, DMSO) δ 11.77 (s, 2H), 8.91 (s, 1H), 8.37 - 8.27 (m, 3H), 8.17 (dd, / = 6.9, 1.7 Hz, 2H), 8.02 (d, J = 8.4 Hz, 1H), 7.76 (t, / = 7.6 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.54 (m, 2H), 2.46 (s, 3H); ³¹P NMR (162 MHz, DMSO) δ -1.17, -5.89.

Preparation of 3-methyl-2-(4'-(trifluoromethoxy)-[l,l '-biphenyl] -4-yl)quinolin-4-yl dihydrogen phosphate 52c

[00428]Pale yellow solid (Yield 71%); MP 201 - 202 °C; 1H NMR (400 MHz, DMSO) δ 11.66 (s, 2H), 8.14 (d, / = 7.8 Hz, 1H), 8.02 (d, / = 12.0 Hz, 1H), 7.91 (d, / = 8.2 Hz, 2H), 7.85 (s, 1H), 7.69 (ddt, 7 = 32.1, 27.6, 11.3 Hz, 4H), 7.51 (d, / = 8.3 Hz, 2H), 7.37 - 7.26 (m, 1H), 2.45 (s, 3H); ³¹P NMR (162 MHz, DMSO) δ -1.16. ES- HRMS: m/z found 474.0704,

[C₂₃Hi₇N0₅F₃P-H]^" requires 474.0718. ES- HRMS: m/z found 475.0665, [C₂₂Hi₆N₂0₅F₃P - H]^~ requires 475.0671.

Yields

[00429] Table 9 below shows the yields obtained during the synthesis of compounds 52a-c. Table 9

Example 8 - Preparation of compounds of formula II in which R⁴ is a carbamate

Experimental

General procedure for the synthesis of carbamate pro-drug 53

[00430] To quinolone 7 or 8 (0.31 mmol) in anhydrous THF was added ¾uOK (52.7 mg, 0.47 mmol) at room temperature. The mixture was stirred for 1/2 h. 4-Morpholinecarbonyl chloride (0.05 mL, 0.41 mmol) was added. The mixture was stirred for further 2 h (followed by tic). The reaction was quenched by brine and was extracted with ethyl acetate, dried over Na₂S0₄, filtered and concentrated to an oil. The crude product was purified by column chromatography using 20% ethyl acetate in hexane to give the title compound. Preparation of 3-methyl-2-(6-(4-( trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl morpholine-4-carboxylate 53a

[00431]White solid (125 mg, Yield 78 %); m.p. 150 - 151 °C; 1H NMR (400 MHz, CDC1₃) δ 8.96 (dd, / = 2.2, 0.8 Hz, 1H), 8.15 (d, / = 8.4 Hz, 1H), 8.13 - 8.10 (m, 2H), 8.08 (dd, / = 8.1, 2.3 Hz, 1H), 7.91 - 7.81 (m, 2H), 7.73 (ddd, / = 8.4, 6.9, 1.4 Hz, 1H), 7.60 (ddd, / = 8.2, 6.9, 1.1 Hz, 1H), 7.36 (d, / = 8.0 Hz, 2H), 3.91 (m, 2H), 3.89 (m, 2H), 3.85 (m, 2H), 3.67 (m, 2H), 2.40 (s, 3H); HRMS (ESI) C₂₇H₂₃N₃0₄F₃ [M+H]⁺ requires 510.1641, found 510.1637.

Preparation of 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl morpholine-4-carboxylate 53b

[00432] White solid (Yield 66%); m.p. 148-150 °C; 1H NMR (400 MHz, CDC1₃) δ 8.12 (s, 1H), 7.74 (d, / = 8.9 Hz, 1H), 7.53 (d, / = 8.1 Hz, 2H), 7.49 (d, / = 8.9 Hz, 1H), 7.30 (d, / = 8.1 Hz, 2H), 7.24 (d, / = 8.9 Hz, 2H), 7.14 (d, / = 8.8 Hz, 2H), 4.06 (s, 2H), 3.87-3.83 (m, 6H), 3.65 (brs, 2H), 2.30 (s, 3H); MS (ES⁺) m/z 557 (M + H)⁺ Acc Mass Found: 557.1443, calculated 557.1455 for C29H25N2O4F3CI.

Example 9 - In Vitro Biological Tests

Culturing of Plasmodium falciparum parasites in vitro - 3D7

[00433] Cultivation of Plasmodium falciparum was carried out following a modified method of the one described by Trager and Jensen ^[4]. Plasmodium falciparum parasites were kept in constant culture in suspension containing O positive human erythrocytes (2.8% haematocrit; 1ml washed erythrocytes in 35ml culture) and culture media, under an atmosphere of 3% CO₂, 4% (¾ and 93% N₂ in sterile 160 ml culture flasks (Nunc Rosklide, Denmark). The cultures were maintained at 37 °C and all culture work was carried out under aseptic conditions in a laminar flow hood (class II biological safety cabinet, Nuaire). The strains of Plasmodium falciparum used throughout this work were 3D7, a chloroquine sensitive strain originating from a case at Schiphol Airport, The Netherlands and TM90C2B, a multi-drug-resistant parasite resistant to 4- amino quinolines, atovaquone and pyrimethamine/sulphadoxine.

[00434] Type O positive human blood, which had been screened and proved to be negative for HIV, HCV, HBsAg and syphilis, was obtained from the National Blood Service blood bank at Speke. The blood was aliquoted under aseptic conditions into 50ml centrifuge tubes. Before use for parasite cultivation the blood was washed with wash media containing RPMI-1640 (Sigma, Poole, UK) supplemented with 0.02mg/ml gentamycin (Sigma, Poole, UK. Wash media was added to the blood to fill the 50ml centrifuge tube and this was centrifuged at 3000 x g for 5 min (accuSpinlR, Fisher Scientific). After centrifugation the supernatant and buffer coat were removed by aspiration. This washing step was repeated twice more when using wash media. Washed blood was stored at 4°C and used for no longer than 6 days.

[00435] Culture media used for parasites grown in RPMI-1640 media supplemented with 25mM HEPES pH 7.4, 0.25% ^w/_v Albumax II (GIBCO, Invitrogen), 36μΜ hypoxanthine (Sigma, Poole, UK) and 0.02mg/ml gentamycin. HEPES was used as the buffering agent to prevent the acidification of the culture during parasite growth. A stock solution of 1M HEPES was prepared in distilled water with the pH adjusted to 7.4 with 5M NaOH. This was filter sterilised and stored at 4°C for no longer than 30 days.

[00436] The parasite cultures were kept under an atmosphere of 3% C0₂, 4% 0₂ and 93% N₂. This was achieved by using a pipette fitted with a 0.22μπι filter (Millipore) to pass the gas into the culture flask. The flasks were flushed with gas for between 30 s and 1 min then the lid was quickly and tightly replaced and the flasks returned to the 37 °C incubator.

In Vitro Sensitivity Assay

[00437] Parasites used for in vitro sensitivity assays were synchronised at ring stage, using 5% ^w/_v sorbitol, one full asexual cycle before use. Inocula for use in the assays were diluted in culture media to a final parasitaemia of 1% (using uninfected RBCs washed 4 times in RPMI-1640 wash media) and a haematocrit of 1%, giving an end haematocrit in the assay of 0.5 % after 50% dilution to give the final assay volume. [00438] Eight serial dilutions of drug were made in culture media. The assays were performed in flat bottomed sterile 96- well tissue culture plates (Nunc). First 50μ1 of each drug dilution was added to 3 wells, with concentration increasing from left to right in the 96-well plate. Each plate was used for two compounds, with rows B to D used for one compound and E to G for another. In each plate column 1 was used for the negative growth control with ΙΟΟμΜ chloroquine.

Columns 6 and 11 were used as the positive growth control with 50μ1 of the media and 50μ1 of inoculum. The outside wells in rows A and H and column 12 were not used as it is known that growth is poorer in these, instead ΙΟΟμΙ of media was added to all wells in these to prevent evaporation in the neighbouring wells. The plates were placed in a gas-tight, humidified incubation chamber and gassed for 4 minutes with the gas mixture used for parasite growth (3% C0₂, 4% 0₂ and 93% N₂), then incubated at 37°C for 48 hours (one full asexual cycle).

[00439] Plates were removed from the chambers after 48 hours and ΙΟΟμΙ of lysis buffer combined with the fluorescent dye sybr green (0.2μ1 sybr green / 1ml lysis buffer). The lysis buffer contained Tris (20mM, pH 7.5); EDTA (5 mM); Saponin (0.008 % (w/v); Triton X-100 (0.08% v/v) ^[5]. Plates were then incubated in the dark for 1 hour and subsequently read with a Varioskan fluorescence reader, at 485 nm excitation and 535 nm emission using Skanit software. The mean values were then calculated using excel and transferred to the Grafit Programme (Erithacus software, Kent UK) where the IC₅₀ value (the inhibitory concentration where parasite growth is 50% of the control) was determined by the non-linear regression analysis of the logarithm of concentrations plotted against the parasite growth inhibition. The experiments were conducted at least 4 times.

Measurement of the Inhibitory Concentration (IC50) against P NDH2

[00440] Inhibitory concentrations (IC₅₀) of all compounds against recombinant PfNDH2 were determined using the rate of ubiquinone (Qi) reduction, analysed spectrophotometrically, as an indicator of inhibition. The PfNDH2 gene (PlasmoDB number PFI0735c) was expressed in the E. coli NADH dehydrogenase knockout strain ANN0222 and cultured as described by Fisher et al.^[6] NADH oxidation and Qi reduction were measured simultaneously at 340 nm and 283 nm respectively. An assay volume of 700 μΐ containing 50 mM Potassium phosphate, 2 mM EDTA Buffer (pH 7.4), 14 mM KCN (pH 7.5), 0.2 mM NADH, 0.6 μg ml^"1 of PfNDH2, and 1 μΐ of ciprofloxacin compound (variable concentration; diluted in DMSO) was prepared in a 1 cm quartz cuvette. Note that the reagents were added to the cuvette in this order and that no reaction detergent was used as they have been linked to the non-enzymatic oxidation of NADH ^{[6 7]}. Exact concentrations of NADH and Qi were calculated using the Beer-Lambert Law (NADH; 8340 = 6.21 mM^"1 cm^"1 and Qi; 8275 = 14.9 mM^"1 cm^"1) and the PfNDH2 concentration was determined using a Bradford Assay ^[8]. KCN was added to prevent the endogenous oxidation of Qi through E. coli cytochrome bo and bd ^[6]. The cuvette was monitored using a Varian Cary 4000® (Varian Inc., United States) spectrophotometer. The reaction was initiated by the addition of 0.05 mM Qi to the cuvette 12 s after the trace was started. As the reaction is biphasic ^[6] only the rate of the first linear phase was calculated; from time point 0 to 18 s post initiation and expressed as Abs min ^_1. Enzyme activity was calculated as the observed rate minus the rate of the negative control and as a percentage of the average positive control (no compound). A known Type II NADH: Quinone oxidoreductase inhibitor, l-hydroxy-2-dodecyl-4(lH)quinolone (HDQ) ^[9], was used as a negative control at a concentration of 14 μΜ. Dose-response curves were plotted from 6-8 concentration points over a dilution series ranging from 70 μΜ to 0.014 nM depending on the activity of the compound. IC50S were calculated using Graft software (Erithacus software, United Kingdom). Each compound was tested in duplicate.

Measurement ofbci activity

[00441] Cytochrome c reductase activity measurements were assayed in 50 mM potassium phosphate, pH 7.5, 2 mM EDTA, 10 mM KCN and 30 uM equine cytochrome c at room temperature. Cytochrome c reductase activity was initiated by the addition of decylubiquinol (50 uM). Reduction of cytochrome c was monitored in a Cary 4000 UV-visable spectrophotometer (Varian, Inc., Palo Alto, CA) at 550 versus 542 nm. Initial rates (computer-fitted as zero-order kinetics) were measured as a function of decylubiquinol concentration. The cytochrome b content of membranes was determined from the dithionite-reduced minus ferricyanide-oxidized difference spectra, using 8502-575 = 28.5 mM^"1 cm^_1.^[10] Turnover rates of cytochrome c reduction were determined using 8550-542 = 18.1 mM^"1 cm^_1.^[11]

[00442] Inhibitors of bc_\ activity were added without prior incubation. DMSO in the assays did not exceed 0.3% (v/v). IC₅₀ values were calculated using the four-parameter logistic method (Grafit). The equilibrium dissociation constant (K) of inhibitor binding to bcl was determined using the Cheng-Prusoff equation. ^[12] In vitro data

[00443] The table below summarises all the in vitro data gathered for the exemplified compounds. Specifically, whole cell antimalarial activity has been investigated on the 3D7 strain of

Plasmodium falciparum. Two enzyme assays generating IC₅₀ data against the parasitic mitochondrial enzymes PfNDH2 and bc_\ have also been carried out. It is believed from those compounds we have complete data for, that some compounds act selectively against the PfNDH2 enzyme and some have a dual mode of action working against both PfNDH2 and bc_\.

Table 9: Summary of in vitro biological data for exemplified compounds ordered by PfNDH2 activity.

ND - Not determined.

Example 10 - In Vivo Full Suppressive 4-day Peters' Test

[00444] Blood collected from the donor mouse is diluted with PBS to produce an infective inoculum that contains 4 x 10⁶ parasitised red blood cells (pRBC) per mouse. Mice are infected randomly from pooled groups with 0.2ml of the parasite suspension via intravenous (i.v) route (day 0). Mice are randomised and placed back into the cages in groups of five and kept at 22°C in SPF environment.

[00445] For oral administration, parent compounds are dissolved in standard suspending formula (SSV) and pro-drugs are dissolved in Na₂C0₃. Experimental groups are treated orally (p.o by oral gavage) with 0.1 ml and subsequently treated on days 1, 2 and 3. On day 4 all mice are blood filmed and euthanased under a home office schedule 1 method (rising levels of C02).

Parasitaemia is determined by microscopic examination of Giemsa stained blood films and the microscopic counts for each mouse are processed using MICROSOFT ® EXCEL, and expressed as % inhibition from arithmetic mean parasitaemias of each group in relation to the untreated group.

In vivo data

[00446] Table 10: In vivo standard 4 day test of three key parent compounds and their phosphate and carbamate prodrugs.

% Parasite Clearance on Day 4 (20 nig/kg po)

Compound Vehicle

SSV DET Na₂CQ₃

Atovaquone 100 100

7e 100 100

7d 59 100

22b 100 95.4

7u 87.5 100

7u-S 100

52a - - 100 % Parasite Clearance on Day 4 (20 nig/kg po)

Compound Vehicle

SSV DET Na₂CQ₃

53b - - 100

52b - - 100

53a 100 a 4-Day suppressive activity of key compounds in male CD-I mice infected with Plasmodium berghei. Mice were exposed to the infection via intraperitoneal injection and then orally dosed with the relevant compound. Data were obtained from 5 mice per group. Table 11. In vivo (oral) antimalarial activities of quinolones versus Plasmodium berghei.

Compound ED₅₀ (mg/kg) ED₉₀ (mg/kg)

7u 12.75 27.3

7u-S 1.87 4.72

7v 2.6 6.5

7w 3.3 7.6

Atovaquone 0.07 0.11

Abbreviations. NADH - nicotinamide adenine dinucleotide. bcl - ubihydroquinone. PTSA - para-toluene sulfonic acid. LAH - lithium aluminium hydride. DMF - dimethylformamide. m- CPBA - meta-c loro per benzoic acid. KOH - potassium hydroxide. THF - tetrahydrofuran. DCM - dichloromethane. NADPH - nicotinamide adenine dinucleotide phosphate. NMP - N- methyl-2-pyrrolidone. SSV - standard suspension vehicle. DET - 5% DMSO and 5% EtOH in tetraglycol. HEPES - (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid)

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[10] W. H. Vanneste, Biochimica Et Biophysica Acta 1966, 113, 175.

[11] E. Margoliash, O. F. Walasek, Methods Enzymol 1967, 10, 339.

[12] Y. Cheng, W. H. Prusoff, Biochemical Pharmacology 1973, 22, 3099.

Claims

1. A com ound of formula I or formula II shown below

I II

wherein:

Y is N or CH;

n is 0, 1 or 2;

X is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, methoxy, heterocyclyl, or a prodrug moiety, with the proviso that when n is 2, each X group present may be the same or different;

-L'-Q¹

wherein:

or L¹ is -O- or -C(R¹⁰Rⁿ)-O- and Q¹ is a prodrug moiety;

R² is a group

-Q³-L²-Q² wherein:

Q³ is selected from aryl, heterocyclyl or heteroaryl, wherein Q³ is optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl,

trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy;

-CH(OR¹²)-, -C(0)N(R¹²)-, -N(R¹²)C(0)-, -C(0)0-, -OC(O)-, -N(R¹²)C(0)N(R¹³)-, -S(0)₂N(R¹²)-, or -N(R¹²)S0₂-, wherein R¹² and R¹³ are each independently selected from hydrogen or (l-4C)alkyl;

Q is selected from aryl, heterocyclyl, or heteroaryl, , each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, (l-3C)alkoxycarbonyl (e.g. methyl or ethyl ester), amino,

trifluoromethyl, trifluoromethoxy, (l-4C)alkyl or (l-4C)alkoxy, wherein any (l-4C)alkyl or (l-4C)alkoxy substituent group group present is optionally further substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl;

R is selected from hydrogen, hydroxy, (l-6C)alkyl, aryl or aryl-(l-2C)alkyl;

R⁴ is selected from hydrogen or a prodrug moiety;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein one of X, Q¹ and R⁴ is an in vivo hydrolysable ester prodrug moiety, such as a phosphate or amino acid ester.

3. A compound according to claim 1 or claim 2, wherein Y is CH.

4. A compound according to any one of the preceding claims, wherein when n is 1, the X substituent is in the 5-, 6- or 7-position of the quinolone ring of formula I or the quinoline ring of formula II and, when n is 2, the X substituents are in the 5-, 6- and/or 7-positions of the quinolone ring of formula I or the quinoline ring of formula II.

5. A compound according to any one of claims 1 to 3, wherein n is 0.

6. A compound according to any one of the preceding claims, wherein X is selected from fluoro, chloro, hydroxy, methoxy.

7. A compound according to any one of the preceding claims, wherein R¹ is selected from hydrogen, methyl, hydroxyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L'-Q¹

wherein:

L¹ is selected from -0-, -C(R¹⁰R^u)-O-, -N(R¹⁰)-, -C(O)-, -C(0)N(R¹⁰)-, -N(R¹⁰)C(O)-,

-C(0)0-, or -OC(O)-, wherein R¹⁰ is selected from hydrogen or (l-2C)alkyl;

or L¹ is -O- or -CH₂-0- and Q¹ is a prodrug moiety;

8. A compound according to claim 7, wherein R¹ is selected from hydrogen, methyl, hydroxyl, CH₂OH, chloro, or R¹ is a group of the formula:

-L^l-Q^l

wherein:

or L¹ is -O- and Q¹ is a prodrug moiety;

9. A compound according to any one of the preceding claims, wherein R 2 is a group -Q 3 -

L 2 -Q 2 wherein: Q 3 is selected from aryl, heterocyclyl, or heteroaryl, wherein Q 3 is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino,

trifluoromethyl, trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy;

2

Q is selected from aryl, heterocyclyl or heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, (l-3C)alkanoxycarnonyl (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy, wherein any (l-3C)alkanoxycarnonyl, (1-

2C)alkyl or (l-2C)alkoxy substituent group on Q may be further optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl.

2 3 2 2

10. A compound according to claim 9, wherein R is a group -Q -L -Q wherein:

Q is selected from aryl, heterocyclyl or heteroaryl optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl,

trifluoromethoxy, (l-4C)alkyl, (l-4C)alkoxy;

Q is selected from aryl, heterocyclyl or heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromoxy, (l-2C)alkyl or (l-2C)alkoxy.

11. A compound according to claim 9, wherein R 2 is a group -Q 3 -L 2 -Q 2 wherein: Q is selected from phenyl, 5- or 6-membered heterocyclyl, heterocyclyl or a 5- or 6- membered heteroaryl, wherein Q is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl, (l-2C)alkoxy; L² is selected from a direct bond, -CR¹²R¹³-, -0-, -S-, -SO-, -S0₂-, -N(R¹²)-, -C(O)-, -CH(OR¹²)-, -C(0)N(R¹²)-, -N(R¹²)C(0)-, -C(0)0-, or -OC(O)-, wherein R¹² and R¹³ are each independently selected from hydrogen or methyl;

Q is selected from phenyl, a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl; each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, (l-3C)alkoxycarbonyl (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (l-2C)alkyl or (l-2C)alkoxy, wherein any carbon atom of the substituent(s) of Q may be further optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxyl, carboxy, carboxy ester, amino, trifluoromethyl, trifluoromethoxy, heterocyclyl, aryl, or heteroaryl;

12. A compound according to any one of the preceding claims, wherein R is selected from hydrogen, hydroxy, (l-2C)alkyl, phenyl or benzyl.

13. A compound according to any one of the preceding claims, wherein R⁴ is selected from hydrogen or a prodrug moiety, which is an in vivo hydrolysable ester.

14. A compound according to any one of the preceding claims, which is sleeted from anyone of the following:

2-(4-(4-fluorobenzyl)phenyl)-3-methylquinolin(lH)-one;

3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one;

7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

2- (4-benzylphenyl)-3-methylquinolin-4(lH)-one;

7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one

3- methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one

2- (4-(4-methoxybenzyl)phenyl)-3-methylquinolin-4(lH)-one

7-Chloro-2-(4-(4-fluorobenzyl)phenyl)-3-methylquinolin-4(lH)-one

3- methyl-2-(4-(morpholinomethyl)phenyl)quinolin-4(lH)-one

7-chloro-3-methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

6-chloro-3-methyl-2-(3-(3-(trifluoromethoxy)benzyl)phenyl)quinoline-4(lH)-one;

2-(4-bromophenyl)-3-methylquinolin-4(lH)-one; 6- chloro-7-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

7- chloro-6-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one; 7-chloro-2-(2-fluoro-4-(4-(trifluoromethoxy)benzyl)phenyl)-3-methylquinolin-4(lH)-one; 3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-7-(trifluoromethyl)quinolin-4(lH)-one; 2- (4- (4-chlorophenoxy)phenyl) -3 -methylquinolin-4( 1 H) -one ;

2- (2-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)phenyl)-3-methylquinolin-4(lH)-one;

3- methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

7-fluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

7-methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

6- chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

6,7-difluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

7- chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

5,7-difluoro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one; 2-(6-(2,4-difluorophenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one;

2- (6-(4-methoxyphenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one;

3- methyl-2-(6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)quinolin-4(lH)-one;

3-methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(lH)-one;

2- (6-(4-fluorophenoxy)pyridin-3-yl)-3-methylquinolin-4(lH)-one;

6- methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

7- methoxy-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)quinolin-4(lH)-one; 7-methoxy-3-methyl-2-(5-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one; 7-fluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

6,7-difluoro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

3- methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,8-naphthyridin-4(lH)-one;

6- hydroxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

7- hydroxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one; 3-methyl-2-(4-(3-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(lH)-one;

2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

6,7-difluoro-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

6,7-dichloro-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

6-fluoro-7-methoxy-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

6- (4-methylpiperazin-l-yl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

7- (4-methylpiperazin-l-yl)-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one; methyl 4-(4-(4-oxo- 1 ,4-dihydroquinolin-2-yl)benzyl)benzoate; 3-chloro-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

ethyl 4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,4-dihydroquinoline-3-carboxylate; ethyl 7-chloro-4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-l,4-dihydroquinoline-3- carboxylate;

ethyl 7-chloro-4-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-l,4-dihydroquinoline-3- carboxylate;

ethyl 4-oxo-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)- 1 ,4-dihydroquinoline-3- carboxylate;

3 -(hydroxymethyl) -2- (4- (4- (trifluoromethoxy)benzyl)phenyl)quinolin-4( 1 H) -one ;

7-chloro-3-(hydroxymethyl)-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

7-chloro-3-(hydroxymethyl)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one;

3-(hydroxymethyl)-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(lH)-one; ethyl 2-(4-iodophenyl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate;

ethyl 4-oxo-2-(4'-(trif uoromethoxy)-[l, -biphenyl]-4-yl)-l,4-dihydroquinoline-3- carboxylate;

ethyl 2-(4'-chloro-[l,l'-biphenyl]-4-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate;

3- (hydroxymethyl)-2-(4'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4(lH)-one;

4- oxo-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)- 1 ,4-dihydroquinoline-3-carboxylic acid; 3-methyl-2-(4'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4(lH)-one;

2-(2'-f uoro-[l, -biphenyl]-4-yl)-3-methylquinolin-4(lH)-one;

2- (2',4'-difluoro-[l,r-biphenyl]-4-yl)-3-methylquinolin-4(lH)-one;

3- methyl-2-(2'-(trifluoromethyl)-[l, -biphenyl]-4-yl)quinolin-4(lH)-one;

3- methyl-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-yl)quinolin-4(lH)-one;

2-(6-(2-f uorophenyl)pyridin-3-yl)-3-methylquinolin-4(lH)-one;

4- chloro-2-( 1 -(4-(trifluoromethoxy)benzyl)- 1 H-pyrazol-4-yl)quinoline;

ethyl 4-chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinoline- 3-carboxylate;

4-chloro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolone;

4-chloro-2-(l-(4-f uorobenzyl)-lH-pyrazol-4-yl)quinolone;

4-chloro-7-methoxy-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl) quinolone;

2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one;

ethyl 4-oxo-2-(l -(4-(trifluoromethoxy)benzyl)- lH-pyrazol-4-yl)- 1 ,4- dihydroquinoline-3- carboxylate;

3 -methyl-2-( 1 - (4- (trifluoromethoxy)benzyl) - 1 H-pyrazol-4- yl)quinolin-4( 1 H) -one ;

2-( 1 -(4-fluorobenzyl)- lH-pyrazol-4-yl)quinolin-4( lH)-one; 7-methoxy-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one;

3-chloro-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one;

7-methoxy-3-methyl-2-(l-(4-(trilluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)- one;

7-chloro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one;

6- lluoro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one;

7- lluoro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one; 3-ethyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin-4(lH)-one;

6- chloro-3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-pyrazol-4-yl)quinolin- 4(lH)-one; 3 -methyl-2-( 1 - (4- (trifluoromethoxy)benzyl) - 1 H-pyrazol-3 - yl)quinolin-4( 1 H) -one ;

3-methyl-2-(l-(4-(trifluoromethoxy)benzyl)-lH-l,2,3-triazol-4-yl)quinolin-4(lH)-one; ethyl (3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl) carbonate;

ethyl (3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl) carbonate;

7- chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4-yl ethyl carbonate; l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one;

l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one;

7-chloro-l-hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(lH)-one; dibenzyl (7-chloro-3-methyl-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4-yl) phosphate;

dibenzyl (3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl) phosphate; dibenzyl (3-methyl-2-(4'-(trif uoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4-yl) phosphate; 7-chloro-3-methyl-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4-yl dihydrogen phosphate;

3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl dihydrogen phosphate;

3-methyl-2-(4'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)quinolin-4-yl dihydrogen phosphate; 3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4-yl morpholine-4- carboxylate;

7-chloro-3-methyl-2-(4-(4-(trif uoromethoxy)benzyl)phenyl)quinolin-4-yl morpholine-4- carboxylate;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

16. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use as a medicament.

17. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of malaria.

18. A method of treating malaria, said method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

19. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in combination with one or more additional antimalarial agents for use in the treatment of malaria.

20. A method of treating malaria, said method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment in combination with one or more additional antimalarial agents.