INTRODUCTION
[0001] The present invention relates to a combination therapeutic product suitable for use in the treatment of mycobacterial infections, such as tuberculosis.
BACKGROUND OF THE INVENTION
[0002] The WHO recommended first-line treatment for tuberculosis (TB) relies on drugs developed some 40 years ago. There are a number of shortcomings with these drugs including (i) long treatment regimens (6 to 9 months) leading to patient non-compliance, (ii) adverse drug-drug interactions with anti-HIV drugs (HIV/AIDS is a common co-infection) and (iii) limited or no activity against multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb).
[0003] Targeting the Mtb respiratory electron transport chain (ETC) has been shown, to be effective in sterilizing both replicating and dormant Mtb and has led to the recent clinical development and registration of the antitubercular drug bedaquiline (TMC207) for use against MDR TB (1-7). Current inhibitors work by selectiviely targeting single respiratory electron transport chain components. Examples, include bedaquiline targeting the ATPsynthase(2), phenothiazines targeting ndh/ndhA (7) and various inhibitors e.g. imidazopyridines (8), targeting cytochrome bcc (also refered in some publications as bc^). These known inhibitors typically suffer from poor efficacy, with high doses of inhibitor needed in order to be effective at reducing Mtb growth. This low efficacy has limited the clinical utility of these inhibitors because the high dosages required can be associated with adverse effects.

[0004] For example, in one placebo-controlled trial, an increased risk of death was observed with bedaquiline (also known as SIRTURO) treatment (9/79, 1 1.4%) compared to the placebo treatment group (2/81 , 2.5%) (16). This may be linked with the observed QT prolongation that can occur with bedaquiline especially during the initial (loading) treatment phase (400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks with food). Effective treatment at a lower dose of bedaquiline would therefore be very advantageous and may mitigate many of the safety concerns.

[0005] Accordingly, there remains a need for new and effective treatments for mycobacterial infections, such as tuberculosis.

[0006] The present invention was devised with the foregoing in mind.

SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention relates to a combination therapeutic product which comprises one or more respiratory electron transport chain inhibitors as defined herein, or a pharmaceutically acceptable salt thereof, and a cytochrome bd inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the present invention relates to a combination therapeutic product comprising one or more respiratory electron transport chain inhibitors as defined herein, or a pharmaceutically acceptable salt thereof, and a cytochrome bd inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use simultaneously, sequentially or separately in the treatment of a mycobacterial infection.

[0009] In another aspect, the present invention relates to a pharmaceutical composition suitable for use in the treatment of a mycobacterial infection which comprises a combination therapeutic product as defined herein, in association with a pharmaceutically-acceptable excipient or carrier.

[0010] In another aspect, the present invention relates to the use of a combination therapeutic product as defined herein, or a pharmaceutical composition as defined herein, for the manufacture of a medicament for administration simultaneously, sequentially or separately to a patient in need thereof, such as a human, for the treatment or prophylaxis of a mycobacterial infection.

[0011] In another aspect, the present invention relates to a method for the treatment or prophylaxis of a mycobacterial infection comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product, as defined herein, or a pharmaceutical composition, as defined herein, to a patient, such as a human, in need of such treatment.

[0012] In another aspect, the present invention relates to a cytochrome bd inhibitor, as defined herein, for use in the treatment of a mycobacterial infection, wherein the cytochrome bd inhibitor is administered in combination with one or more respiratory electron transport chain inhibitors as defined herein.

[0013] In another aspect, the present invention relates to the use of a cytochrome bd inhibitor as defined herein, in the manufacture of a medicament for use in the treatment of a mycobacterial infection, wherein the cytochrome bd inhibitor is administered in combination with one or more respiratory electron transport chain inhibitors as defined herein.

[0014] In another aspect, the present invention relates to a method for the treatment or prophylaxis of a mycobacterial infection comprising simultaneously, sequentially or separately administering an effective amount of a cytochrome bd inhibitor as defined herein, in combination with one or more respiratory electron transport chain inhibitors as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0015] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0016] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0017] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0018] It is to be appreciated that references to "treating" or "treatment" include prophylaxis as well as the alleviation of established symptoms of a condition. "Treating" or "treatment" of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, 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, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0019] 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 mammal to be treated.

[0020] 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, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl.

[0021] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0022] Unless otherwise specified, the term "alkoxy" as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1 , 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.

[0023] Unless otherwise specified, the term "aryl" as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9 or 10 ring carbon atoms. Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl and the like.

[0024] Unless otherwise specified, the term "halogen" or "halo" as used herein includes reference to F, CI, Br or I. In a particular, halogen may be F or CI, of which CI is more common.

[0025] The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. 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 or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur 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. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0026] 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, 1 H-pyrazolo[4,3-d]-oxazolyl,

4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2, 1-b]thiazolyl, imidazo[1 ,2-b][1 ,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 sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl,

1 ,2,3,4-tetrahydropyrido[2,3-£>]pyrazinyl and 3,4-dihydro-2/-/-pyrido[3,2-£>][1 ,4]oxazinyl.

[0027] Unless otherwise specified, the term "substituted" as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents. The term "optionally substituted" as used herein means substituted or unsubstituted.

[0028] It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person.

[0029] Unless otherwise specified, the term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term "wherein a/any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1 group is optionally

substituted" suitably means that (any) one of the hydrogen radicals of the R1 group is substituted by a relevant stipulated group.

[0030] 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.

[0031] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.

Combination therapeutic products of the present invention

[0032] It will be appreciated by a person skilled in the art that the term "combination therapeutic product" refers to the net combined product resulting from the administration one or more components either simultaneously, sequentially or separately, in order to induce a therapeutic effect.

[0033] Furthermore, it will be appreciated that in administering the one or more components either simultaneously, sequentially or separately, the therapeutic product affords a superior therapeutic effect to that achieved upon administration of one of the components of the combination therapeutic product alone, and at its conventional dose. The superior therapeutic effect may be measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one of the components of the combination therapeutic product alone, and at its conventional dose.

[0034] For example, the effect of the combination therapeutic product is beneficial if the effect is therapeutically superior to the effect achievable with the respiratory electron transport chain inhibitor alone or with the cytochrome bd inhibitor alone. Further, the effect of the combination therapeutic product is defined as affording a beneficial effect if one of the components is dosed at its conventional dose (or lower) and the other component is dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent (or higher) to that achievable on dosing conventional amounts of the components of the combination therapeutic product alone.

[0035] It should also be appreciated that according to the present invention a combination therapeutic product is defined as affording a synergistic effect if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that expected to be achievable on dosing both of the components of the combination therapeutic product together at their conventional dose

(for example the combination effect is greater than the sum of the single agent effects). Suitably, the combination product of the present invention does provide a synergistic effect.

[0036] According to one aspect of the present invention, there is provided a combination therapeutic product comprising one or more respiratory electron transport chain inhibitors and a cytochrome bd inhibitor, or a pharmaceutically acceptable salt thereof. The combination therapeutic product may comprise between 1 and 3 respiratory electron transport chain inhibitors. Most suitably, the combination therapeutic product comprises one respiratory electron transport chain inhibitor.

[0037] According to another aspect of the present invention, there is provided a combination therapeutic product comprising one or more respiratory electron transport chain inhibitors and a cytochrome bd inhibitor for use simultaneously, sequentially or separately in the treatment of a mycobacterial infection. The combination therapeutic product may comprise between 1 and 3 respiratory electron transport chain inhibitors. Most suitably, the combination therapeutic product comprises one respiratory electron transport chain inhibitor.

[0038] According to a further aspect of the present invention there is provided a cytochrome bd inhibitor for use in the treatment of a mycobacterial infection, administered in combination with one or more respiratory electron transport chain inhibitors. The cytochrome bd inhibitor may be administered in combination with between 1 and 3 respiratory electron transport chain inhibitors. Most suitably, the cytochrome bd inhibitor is administered in combination with one respiratory electron transport chain inhibitor.

[0039] It will be appreciated that the combination therapeutic product of the present invention, or indeed the cytochrome bd inhibitor administered in combination with one or more respiratory electron transport chain inhibitors, may be used to treat any suitable mycobacterial infection. Suitably, the mycobacterial infection is selected from Buruli Ulcers, leprosy, Hansen's disease or tuberculosis. More suitably, the mycobacterial infection is selected from leprosy or tuberculosis. Yet more suitably, the mycobacterial infection is tuberculosis. Most suitable, the mycobacterial infection is multidrug resistant tuberculosis.

Cytochrome bd inhibitors

[0040] Cytochrome bd is a respiratory quinol: 02 oxidoreductase found in many prokaryotes, including a number of pathogens. The main bioenergetic function of the enzyme is the production of a proton motive force by the vectorial charge transfer of protons. (9) Suitably, the cytochrome bd inhibitors of the present invention may be any compound, or pharmaceutically acceptable salt thereof, capable of inhibiting any cytochrome bd respiratory oxygen reductase. However more suitably, the cytochrome bd inhibitors of the present invention may be any compound capable of inhibiting mycobacterial cytochrome bd.

[0041] In an embodiment of the present invention, the cytochrome bd inhibitor is a quinolone compound or an analogue thereof.

[0042] In another embodiment of the present invention, the cytochrome bd inhibitor is 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, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, methoxy, heterocyclyl, a prodrug moiety, or a combination thereof (e.g. where n=2);

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

-U-Q1

wherein:

L1 is absent or selected from -0-, -C(R10R11)-O-, -S-, -SO-, -SO2-, -N(R10)-, - C(O)-, -CH(OR10)-, -C(0)N(R10)-, -N(R10)C(O)-, -C(0)0-, -OC(O)-, - N(R10)C(O)N(R11)-, -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, (1-6C)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, (1-4C)alkyl or (1-4C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-w1-z1

wherein:

W1 is absent or selected from -Ο-,-S-, -N(R14)- or -C(O)-, wherein R14 is selected from hydrogen or (1-4C)alkyl;

Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heteroaryl or (3- 6C)heterocycyl, wherein Z1 is optionally substituted with one or more substituents selected from halo, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

or L1 is -O- or -C(R10R11)-O- and Q1 is a prodrug moiety;

R2 is a group

-L2-Q3-L3-Q2

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

Q3 is absent or 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, (1-4C)alkyl or (1- 4C)alkoxy;

L3 is selected from a direct bond, -(CR12R13)q-, -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 (1-4C)alkyl and q is an integer selected from 1 or 2;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, heteroaryl or cycloalky, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, carboxy ester (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (1- 4C)alkyl or OR15, wherein R15 is selected from (1-4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 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, heteroaryl or NR16R17, wherein R16 and R17 are independently selected from H, (1-4C)alkyl, aryl, aryl(1-2C)alkyl or C(0)0(1-4C)alkyl;

R3 is selected from hydrogen, hydroxy, (1-6C)alkyl, aryl or aryl-(1-2C)alkyl;

R4 is selected from hydrogen, (1-4C)alkyl or a prodrug moiety;

or a pharmaceutically acceptable salt thereof

[0043] Particular cytochrome bd inhibitors of the invention include, for example, compounds of the formula (I) or (II), or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of R1 , R2, R3, R4, X, Y, n and any associated substituent group has any of the meanings defined hereinbefore or in any of paragraphs (1) to (20) hereinafter: - (1) Y is CH;

(2) X is selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, methoxy or heterocyclyl;

(3) X is selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy or methoxy;

(4) X is selected from fluoro, chloro or methoxy;

(5) X is selected from fluoro or methoxy;

(6) R1 is selected from hydrogen, methyl, ethyl, hydroxyl, CH2OH, halo, or R1 is a group of the formula:

-U-Q1

wherein:

L1 is absent or selected from -0-, -S-, -SO-, -SO2-, -N(R10)-, -C(O)-, - C(0)N(R10)-, -N(R10)C(O)-, -C(0)0-, -OC(O)-, -S(0)2N(R10)-, or -N(R10)SO2-, wherein R10 is selected from hydrogen or (1-4C)alkyl;

Q1 is selected from hydrogen, (1-6C)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, (1-4C)alkyl or (1-4C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or selected from -0-,-S- or -N(R14)- wherein R14 is selected from hydrogen or (1-4C)alkyl;

Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heteroaryl or (3- 6C)heterocycyl, wherein Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

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

-U-Q1

wherein:

L1 is absent or selected from -0-, -S-, -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 (1-4C)alkyl;

Q1 is selected from hydrogen, (1-6C)alkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or selected from -O- or -N(R14)- wherein R14 is selected from hydrogen or (1-2C)alkyl;

Z1 is selected from (1-6C)alkyl, aryl or heteroaryl, wherein Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

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

-U-Q1

wherein:

L1 is absent or selected from -C(0)N(R10)-, -N(R10)C(O)-, -C(0)0- or -OC(O)- wherein R10 is selected from hydrogen or (1-4C)alkyl;

Q1 is selected from hydrogen, (1-6C)alkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or -0-;

Z1 is selected from (1-4C)alkyl, aryl or heteroaryl, wherein Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-2C)alkyl or (1-2C)alkoxy;

(9) R1 is selected from hydrogen, methyl, ethyl, hydroxy, halo, or R1 is a group of the formula:

-U-Q1

wherein:

L1 is absent or selected from -C(0)N(R10)- or -C(0)0- , wherein R10 is selected from hydrogen or (1-2C)alkyl;

Q1 is selected from hydrogen, (1-6C)alkyl, aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-2C)alkyl or (1- 2C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or -0-;

Z1 is selected from (1-4C)alkyl, aryl or heteroaryl, wherein Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-2C)alkyl or (1-2C)alkoxy;

(10) R1 is selected from hydrogen, methyl, ethyl, hydroxy, halo, or R1 is a group of the formula:

-U-Q1

wherein:

L1 is absent or -C(0)0-;

Q1 is selected from hydrogen, (1-6C)alkyl or aryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, or (1-2C)alkyl; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or -0-;

Z1 is selected from (1-4C)alkyl or aryl, wherein Z1 is optionally substituted with one or more substituents selected from

trifluoromethyl, trifluoromethoxy or (1-2C)alkyl;

R2 is a group

-L2-Q3-L3-Q2

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl; Q3 is absent or selected from aryl, heterocyclyl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

L3 is selected from a direct bond, -(CR12R13)q -, -0-, -S-, -SO-, -SO2-, - N(R12)-, -C(O)-, -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 (1-4C)alkyl and wherein q is an integer selected from 1 or 2;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, carboxy ester (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 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, heteroaryl or NR16R17, wherein R16 and R17 are independently selected from H, (1-4C)alkyl, aryl, aryl(1-2C)alkyl or C(0)0(1-4C)alkyl; R2 is a group

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl; Q3 is absent or selected from aryl, heterocyclyl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

L3 is selected from a direct bond, -CR12R13-, -0-, -S-, -SO-, -SO2-, - N(R12)-, -C(O)-, -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 (1-4C)alkyl;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, carboxy ester (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 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, heteroaryl or NR16R17, wherein R16 and R17 are independently selected from H, (1-4C)alkyl, aryl, aryl(1-2C)alkyl or 0(0)0(1 -4C)alkyl; R2 is a group

-L2-Q3-L3-Q2

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl; Q3 is absent or selected from aryl, heterocyclyl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

L3 is selected from a direct bond, -(CR12R13)q-, -0-, -S-, -SO-, -SO2-, - N(R12)-, -C(0)-, -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 (1-4C)alkyl and wherein q is an integer selected from 1 or 2;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, carboxy ester (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 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, heteroaryl or NR16R17, wherein R16 and R17 are independently selected from H, (1-4C)alkyl, aryl, aryl(1-2C)alkyl or C(0)0(1-4C)alkyl;

(14) R2 is a group

-L2-Q3-L3-Q2

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl; Q3 is absent or selected from aryl, heterocyclyl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-2C)alkyl or (1-2C)alkoxy;

L3 is selected from a direct bond, -CR12R13-, -0-, -S-, -N(R12)-, -C(O)-, -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 (1-2C)alkyl;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 may be further optionally substituted with one or more substituents independently selected from halo, hydroxyl, amino, trifluoromethyl, trifluoromethoxy or NR16R17, wherein R16 and R17 are independently selected from H, (1-4C)alkyl, aryl, aryl(1-2C)alkyl or C(0)0(1-4C)alkyl;

(15) R2 is a group

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl;

Q3 is absent or selected from aryl, heterocyclyl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy or (1-2C)alkyl;

L3 is selected from a direct bond, -CR12R13-, -0-, -S- or -N(R12)-, wherein R12 and R13 are each independently selected from hydrogen or (1-2C)alkyl;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 may be further optionally substituted with one or more substituents independently selected from halo, trifluoromethyl, trifluoromethoxy or NR16R17, wherein R16 and R17 are independently selected from H, (1- 4C)alkyl, or aryl(1-2C)alkyl;

R2 is a group

wherein:

L2 is absent or (1-3C)alkylene;

Q3 is absent or selected from aryl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy or (1-2C)alkyl;

L3 is selected from a direct bond, -CR12R13-, -0-, -S- or -N(R12)-, wherein R12 and R13 are each independently selected from hydrogen or (1-2C)alkyl;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 may be further optionally substituted with one or more substituents independently selected from halo, trifluoromethyl, trifluoromethoxy or NR16R17, wherein R16 and R17 are independently selected from H or aryl(1-2C)alkyl;

R3 is selected from hydrogen, hydroxy, (1-4C)alkyl, aryl or aryl-(1-2C)alkyl; (18) R3 is selected from hydrogen, hydroxy, (1-4C)alkyl, phenyl or phenyl-(1- 2C)alkyl;

(19) R3 is selected from hydrogen, hydroxy or (1-4C)alkyl;

(20) R3 is selected from hydrogen or hydroxy;

(21) R4 is selected from hydrogen or (1-4C)alkyl;

(22) R4 is (1-4C)alkyl.

[0044] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0045] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0046] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one)].

[0047] Suitably an aryl group is phenyl.

[0048] Suitably, Y is CH.

[0049] Suitably, X is as defined in any one of paragraphs (2) to (5) above. Most suitably, X is as defined in paragraph (5).

[0050] Suitably, R1 is as defined in any one of paragraphs (6) to (10) above. Most suitably, R1 is as defined in paragraph (10).

[0051] Suitably, R2 is as defined in any one of paragraphs (11) to (16) above. Most suitably, R2 is as defined in paragraph (16).

[0052] Suitably, R3 is as defined in any one of paragraphs (17) to (20) above. Most suitably, R3 is as defined in paragraph (20).

[0053] Suitably, R4 is as defined in any one of paragraphs (21) to (22) above. Most suitably, R4 is (1-4C)alkyl.

[0054] In a particular group of cytochrome bd inhibitors of the invention, Y is CH, i.e. the compounds have either the structural formula la or I la (sub-definitions of formulae I and II) shown below:

Formula la Formula lib

wherein n, X, R1 , R2 and R3 each have any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[0055] In an embodiment of the cytochrome bd inhibitors of formulae la or lla:

n is 0, 1 or 2;

X is as defined in any one of paragraphs (2) to (5) above;

R1 is as defined in any one of paragraphs (6) to (10) above;

R2 is as defined in any one of paragraphs (1 1) to (16) above;

R3 is as defined in any one of paragraphs (17) to (20) above; and

R4 is as defined in any one of paragraphs (21) to (22) above.

[0056] In another embodiment of the cytochrome bd inhibitors of formulae la or lla:

n is 0, 1 or 2;

X is as defined in any one of paragraphs (3) to (5) above;

R1 is as defined in any one of paragraphs (8) to (10) above;

R2 is as defined in any one of paragraphs (15) to (16) above;

R3 is as defined in any one of paragraphs (18) to (20) above; and

R4 is as defined paragraphs (22) above.

[0057] In another embodiment of the cytochrome bd inhibitors of formulae la or lla:

n is 0, 1 or 2;

X is as defined in paragraph (5) above;

R1 is as defined in any one of paragraphs (9) to (10) above;

R2 is as defined in any one of paragraphs (15) to (16) above;

R3 is as defined in any one of paragraphs (19) to (20) above; and

R4 is as defined paragraphs (22) above.

[0058] Particular cytochrome bd inhibitors of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:

3-Methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (CK-3-22);

2- (6-(4-Fluorophenoxy)pyridin-3-yl)-3-methylquinolin-4(1 H)-one (CK-3-14);

7-Methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (RKA-259);

3- Methyl-2-(4-(piperidin-1-yl)phenyl)quinolin-4(1 H)-one (RKA-307);

7-Methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (RKA-310);

5,7-Difluoro-3-methyl-2-(4-(piperidin-1-yl)phenyl)quinolin-4(1 H)-one (MTD-403);

2-(4-Benzylphenyl)-3-methylquinolin-4(1 H)-one (CK-2-88);

2- (4-Benzylphenyl)-4-methoxy-3-methylquinoline (CK-3-23);

3- Methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (CK-2-63);

2-Methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (PG-203);

2-(4-(4-(Trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (RKA-70);

1- Hydroxy-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (RKA-73);

2- (4-(4-Fluorobenzyl)phenyl)-3-methylquinolin-4(1 H)-one (LT-9);

Ethyl 4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-1 ,4-dihydroquinoline-3-carboxylate (GN-171);

3- Methyl-2-(6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)quinolin-4(1 H)-one (PG-128);

3-Methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(1 H)-one (SL-2-25);

Ethyl 2-(4'-chloro-[1 ,1 '-biphenyl]-4-yl)-4-oxo-1 ,4-dihydroquinoline-3-carboxylate (WDH-1 U-10);

2- (1-(4-(Trifluoromethoxy)benzyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-1W-5 );

3- Methyl-2-(1-(4-(trifluoromethoxy)benzyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-2A-9).

Ethyl 4-oxo-2-(4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)-1 ,4-dihydroquinoline-3-carboxylate (WDH-1V-10);

Ethyl 2-(4'-chloro-[1 ,1 '-biphenyl]-4-yl)-4-oxo-1 ,4-dihydroquinoline-3-carboxylate (WDH-1V- 9);

3-lsopropyl-2-(1-(4-(trifluoromethoxy)benzyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-2G-6);

3-Methyl-2-(1-(4-(trifluoromethoxy)phenethyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-2R-4);

3-Methyl-2-(4'-(trifluoromethoxy)-[1 , 1'-biphenyl]-4-yl)quinolin-4(1 H)-one (SL-2-34);

3-Methyl-2-(2'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-yl)quinolin-4(1 H)-one (SL-2-36);

2- (2'-Fluoro-[1 , 1 '-biphenyl]-4-yl)-3-methylquinolin-4(1 H)-one (SL-3-3);

3- Methyl-2-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)quinolin-4(1 H)-one (RKA 142);

2- (4-((4,4-Difluorocyclohexyl)oxy)phenyl)-3-methylquinolin-4(1 H)-one (PG105);

3- Methyl-2-(4-(3-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(1 H)-one (PG201);

2- (Hydroxymethyl)-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (PG208);

7- Hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (SCR-05- 01 D);

8- Hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (SCR-06- 03D);

5- Methoxy-3-methyl-2-(6-(4-(trifluoro

(SCR-04-04);

6- Methoxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (SCR-05- 03);

3- Methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-2-58);

3-Methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-2-67);

2-(4-(4-Methoxybenzyl)phenyl)-3-methylquinolin-4(1 H)-one (CK-2-96);

2- (4-Benzylphenyl)-3-methylquinolin-4(1 H)-one (CK-2-88);

6-Fluoro-7-hydroxy-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-3-68);

3- Methyl-2-(4-(4-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-4-2);

3-Methyl-2-(4-(3-(2-morpholinoethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (CK-4-15); or 3-Methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (CK-3-22).

[0059] Other compounds suitable for use as a cytochrome bd inhibitor of the present invention are described in WO2012069586, the entire contents of which are incorporated herein by reference.

[0060] The various functional groups and substituents making up the cytochrome bd inhibitors of formula I or II are typically chosen such that the molecular weight of the compound of formula I or II does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 700, or less than 650, or less than 600. More preferably, the molecular weight is less than 550 and, for example, is 500 or less.

[0061] A suitable pharmaceutically acceptable salt of a cytochrome bd inhibitor 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, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a cytochrome be inhibitor 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.

[0062] 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-lngold-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".

[0063] The cytochrome bd inhibitors 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 cytochrome bd activity.

[0064] The present invention also encompasses cytochrome be inhibitors of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.

[0065] It is also to be understood that certain cytochrome bd inhibitors of 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 cytochrome bd activity.

[0066] Cytochrome bd inhibitors of formula I or II may exist in a number of different tautomeric forms and references to cytochrome bd inhibitors of 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 formulae 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

[0067] Cytochrome bd inhibitors of formula I or II containing an amine function may also form N-oxides. A reference herein to a cytochrome bd inhibitor of formulae I or II that contains an amine function also includes the N-oxide. Where a cytochrome bd inhibitor 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, 4th 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.

[0068] The cytochrome bd inhibitors of formula I or II may be administered in the form of a pro-drug which is broken down in the human or animal body to release a cytochrome bd inhibitor of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a cytochrome bd inhibitor of the invention. A pro-drug can be formed when the cytochrome bd inhibitor 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 cytochrome bd inhibitor of formula I or II. [0069] Accordingly, the present invention includes those cytochrome bd inhibitors of formula I or II 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 cytochrome bd inhibitors of formula I or II that are produced by organic synthetic means and also such cytochrome bd inhibitors that are produced in the human or animal body by way of metabolism of a precursor compound, that is a cytochrome bd inhibitor of formula I or II may be a synthetically-produced compound or a metabolically-produced compound.

[0070] A suitable pharmaceutically acceptable pro-drug of a cytochrome bd inhibitor of formula I or II 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.

[0071] 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. 1 13-191 (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.

[0072] A suitable pharmaceutically acceptable pro-drug of a cytochrome bd inhibitor of formula I or II that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a cytochrome bd inhibitor of formula I or II 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 te/f-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-1 , 3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci-6alkoxycarbonyloxy- Ci-6alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0073] A suitable pharmaceutically acceptable pro-drug of a cytochrome bd inhibitor of formula I or II 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 cytochrome bd inhibitor of formula I or II 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 phosphoramidic 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 ^carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(Ci-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0074] A suitable pharmaceutically acceptable pro-drug of a cytochrome bd inhibitor of formula I or II 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, /V-ethyl-/V-methylamine or diethylamine, a Ci-4alkoxy- C^alkylamine such as 2-methoxyethylamine, a phenyl-Ci-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0075] A suitable pharmaceutically acceptable pro-drug of a cytochrome bd inhibitor of formula I or II 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, /V-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and

4- (Ci-4alkyl)piperazin-1-ylmethyl.

[0076] The in vivo effects of a cytochrome bd inhibitor of formula I or II may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a cytochrome bd inhibitor of formula I or II. As stated hereinbefore, the in vivo effects of a cytochrome bd inhibitor of formula I or II may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0077] Though the present invention may relate to any cytochrome bd inhibitor or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any cytochrome bd inhibitor or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

Respiratory electron transport chain inhibitors

[0078] It will be understood that the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting a protein complex or enzyme found along the respiratory electron transport chain of a particular organism. Suitably, the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting a protein complex or enzyme found along the respiratory electron transport chain of a mycobacterium. Most suitably, the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting a protein complex or enzyme found along the respiratory electron transport chain of Mycobacterium tuberculosis (Mtb).

[0079] Details of the protein complexes and enzymes found along the respiratory electron transport chain of Mycobacterium tuberculosis are described in Methods in enzymology, 456, P303-320.

[0080] In an embodiment, the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting one or more targets selected from cytochrome bcc, protonmotive NADH dehydrogenase (complex I, nuo), cytochrome bcc oxidase (aa3) and Fi Fo ATPase. Suitably, the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting one or more targets selected from cytochrome bcc, cytochrome bcc oxidase (aa3) and Fi Fo ATPase. More suitably, the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting one or more targets selected from cytochrome bcc or Fi Fo ATPase. Most suitably, the respiratory electron transport chain inhibitor of the present invention comprises any compound capable of inhibiting cytochrome bcc.

[0081] In another embodiment, the respiratory electron transport chain inhibitor of the present invention is a cytochrome bcc or F1 F0 ATPase inhibitor. Suitably, the respiratory electron transport chain inhibitor of the present invention is a cytochrome bcc inhibitor.

[0082] The various functional groups and substituents making up the respiratory electron transport chain inhibitors of the present invention are typically chosen such that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 700, or less than 650, or less than 600. More preferably, the molecular weight is less than 550 and, for example, is 500 or less.

[0083] In another embodiment, the respiratory electron transport chain inhibitor of the present invention is selected from lansoprazole, bedaquiline (TMC207), MTC420, AWE402, Q203, Isoniazid, phenothiazines or any suitable prodrug or analogue thereof. Suitably, the respiratory electron transport chain inhibitor of the present invention is selected from bedaquiline (TMC207), MTC420, AWE402, Q203, Isoniazid, phenothiazines or any suitable prodrug or analogue thereof. More suitably, the respiratory electron transport chain inhibitor of the present invention is selected from bedaquiline (TMC207), MTC420, AWE402 or any suitable prodrug or analogue thereof. Most suitably, the respiratory electron transport chain inhibitor of the present invention is bedaquiline (TMC 207) or any suitable prodrug or analogue thereof.

[0084] Structures of non-limiting examples of suitable respiratory electron transport chain

[0085] As described hereinabove, one or more respiratory electron transport chain inhibitors may be administered in combination with the cytochrome bd inhibitor described hereinabove.

Biological Activity

[0086] The Mtb cytochrome bd inhibition assay described in accompanying Example section, or elsewhere in the literature, may be used to measure the pharmacological effects of the cytochrome bd inhibitors of the present invention.

[0087] Although the pharmacological properties of the cytochrome bd inhibitors described herein vary with structural change, as expected, the cytochrome bd inhibitors of the invention were found to be active in these assays.

[0088] The cytochrome bd inhibitors of the invention demonstrate a IC50 of 20 μΜ or less in the Mtb cytochrome bd inhibition assay described herein, with preferred cytochrome bd inhibitors of the invention demonstrating an IC50 of 5 μΜ or less and the most preferred cytochrome bd inhibitors of the invention demonstrating an IC50 of 1 μΜ or less.

Pharmaceutical Compositions

[0089] According to a further aspect of the invention there is provided a pharmaceutical composition suitable for use in the treatment of a mycobacterial infection which comprises a combination therapeutic product, as defined herein, in association with a pharmaceutically-acceptable excipient or carrier. For example, solid oral forms may contain, together with the active compounds, diluents, such as, for example, lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, such as, for example, silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; such as, for example, starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, such as, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as, for example, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical compositions may be manufactured in by conventional methods known in the art, such as, for example, by mixing, granulating, tableting, sugar coating, or film coating processes.

[0090] The pharmaceutical 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). Suitably, oral or parenteral administration is preferred. Most suitably, oral administration is preferred.

[0091] The pharmaceutical 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.

[0092] The amount of active ingredient(s) 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.

CLAIMS
1. A combination therapeutic product comprising one or more respiratory electron transport chain inhibitors, or a pharmaceutically acceptable salt thereof, and a cytochrome bd inhibitor, or a pharmaceutically acceptable salt thereof.

2. A combination therapeutic product according to claim 1 , wherein the one or more respiratory electron transport chain inhibitors or a pharmaceutically acceptable salt thereof, is an inhibitor of the respiratory electron transport chain in a mycobacterium.

3. A combination therapeutic product according to claims 1 or 2, wherein the one or more respiratory electron transport chain inhibitors or a pharmaceutically acceptable salt thereof, is an inhibitor of the respiratory electron transport chain in Mycobacterium tuberculosis.

4. A combination therapeutic product according to any one of claims 1 to 3, wherein the cytochrome bd inhibitor, or a pharmaceutically acceptable salt thereof, is an inhibitor of cytochrome bd in Mycobacterium.

5. A combination therapeutic product according to any one of claims 1 to 4, wherein the cytochrome bd inhibitor, or a pharmaceutically acceptable salt thereof, is an inhibitor of cytochrome bd in Mycobacterium tuberculosis.

6. A combination therapeutic product according to claim 3, wherein the one or more respiratory electron transport chain inhibitors is selected from the group consisting of: a cytochrome bcc inhibitor; a protonmotive NADH dehydrogenase (complex I, nuo) inhibitor; cytochrome bcc oxidase (aa3) inhibitor; and/or a Fi Fo ATPase inhibitor; or a pharmaceutically acceptable salt thereof.

7. A combination therapeutic product according to any one of claims 1 to 6, wherein the cytochrome bd inhibitor is 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, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, methoxy, heterocyclyl, a prodrug moiety, or a combination thereof (e.g. where n=2);

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

-U-Q1

wherein:

L1 is absent or selected from -0-, -C(R10R11)-O-, -S-, -SO-, -SO2-, -N(R10)-, - C(O)-, -CH(OR10)-, -C(0)N(R10)-, -N(R10)C(O)-, -C(0)0-, -OC(O)-, - N(R10)C(O)N(R11)-, -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, (1-6C)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, (1-4C)alkyl or (1-4C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or selected from -0-,-S- or -N(R14)- -C(O)-, wherein R14 is selected from hydrogen or (1-4C)alkyl;

Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl heteroaryl or (3- 6C)heterocycyl, wherein Z1 is optionally substituted with one or more

substituents selected from halo, cyano, nitro, hydroxy, amino,

trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or (1-4C)alkoxy;

or L1 is -O- or -C(R10R11)-O- and Q1 is a prodrug moiety;

R2 is a group

wherein:

L2 is absent or (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

Q3 is absent or 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, (1-4C)alkyl, (1- 4C)alkoxy;

L3 is selected from a direct bond, -(CR12R13)q-, -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 (1-4C)alkyl, and wherein q is an integer selected from 1 or 2;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, nitro, hydroxy, carboxy, carboxy ester (e.g. methyl or ethyl ester), amino, trifluoromethyl, trifluoromethoxy, (1- 4C)alkyl or OR15, wherein R15 is selected from (1-4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 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, heteroaryl or NR16R17, wherein R16 and R17 are independently selected from H, (1-4C)alkyl, aryl, aryl(1-2C)alkyl or C(0)0(1-4C)alkyl;

R3 is selected from hydrogen, hydroxy, (1-6C)alkyl, aryl or aryl-(1-2C)alkyl;

R4 is selected from hydrogen, (1-4C)alkyl or a prodrug moiety;

or a pharmaceutically acceptable salt thereof.

8. A combination therapeutic product according to claim 7, wherein the cytochrome bd inhibitor is a compound of formula I or formula II, shown below:

wherein:

n is 0, 1 or 2;

X is selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy or methoxy;

R1 is selected from hydrogen, methyl, ethyl, hydroxy, halo, or R1 is a group of the formula:

-U-Q1

wherein:

L1 is absent or selected from -C(0)N(R10)- or -C(0)0- , wherein R10 is selected from hydrogen or (1-2C)alkyl;

Q1 is selected from hydrogen, (1-6C)alkyl, aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-2C)alkyl or (1- 2C)alkoxy; or

Q1 is optionally substituted with a group of the formula:

-W1-Z1

wherein:

W1 is absent or -0-;

Z1 is selected from (1-4C)alkyl, aryl or heteroaryl, wherein Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, (1-2C)alkyl or (1-2C)alkoxy;

R2 is a group

-L2-Q3-L3-Q2

wherein:

L2 is absent or (1-3C)alkylene;

Q3 is absent or selected from aryl or heteroaryl, wherein Q3 is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy or (1-2C)alkyl;

L3 is selected from a direct bond, -CR12R13-, -0-, -S- or -N(R12)-, wherein R12 and R13 are each independently selected from hydrogen or (1-2C)alkyl;

Q2 is selected from (1-6C)alkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, trifluoromethyl, trifluoromethoxy, (1-4C)alkyl or OR15, wherein R15 is selected from (1- 4C)alkyl or aryl, and wherein any carbon atom of the substituent(s) of Q2 may be further optionally substituted with one or more substituents independently selected from halo, trifluoromethyl, trifluoromethoxy or NR16R17, wherein R16 and R17 are independently selected from H or aryl(1-2C)alkyl;

R3 is selected from selected from hydrogen, hydroxy or (1-4C)alkyl;

R4 is selected from hydrogen or (1-4C)alkyl;

or a pharmaceutically acceptable salt thereof.

9. A combination therapeutic product according to claims 7 or 8, wherein the cytochrome bd inhibitor is selected from:

3-Methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (CK-3-22);

2- (6-(4-Fluorophenoxy)pyridin-3-yl)-3-methylquinolin-4(1 H)-one (CK-3-14);

7-Methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (RKA-259);

3- Methyl-2-(4-(piperidin-1-yl)phenyl)quinolin-4(1 H)-one (RKA-307);

7-Methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (RKA-310);

5,7-Difluoro-3-methyl-2-(4-(piperidin-1-yl)phenyl)quinolin-4(1 H)-one (MTD-403);

2-(4-Benzylphenyl)-3-methylquinolin-4(1 H)-one (CK-2-88);

2- (4-Benzylphenyl)-4-methoxy-3-methylquinoline (CK-3-23);

3- Methyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (CK-2-63); 2-Methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (PG-203);

2-(4-(4-(Trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (RKA-70);

1- Hydroxy-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (RKA-73);

2- (4-(4-Fluorobenzyl)phenyl)-3-methylquinolin-4(1 H)-one (LT-9);

Ethyl 4-oxo-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)-1 ,4-dihydroquinoline-3-carboxylate (GN-171);

3- Methyl-2-(6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)quinolin-4(1 H)-one (PG-128);

3-Methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(1 H)-one (SL-2-25);

Ethyl 2-(4'-chloro-[1 ,1 '-biphenyl]-4-yl)-4-oxo-1 ,4-dihydroquinoline-3-carboxylate (WDH-1 U-10);

2- (1-(4-(Trifluoromethoxy)benzyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-1W-5 );

3- Methyl-2-(1-(4-(trifluoromethoxy)benzyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-2A-9).

Ethyl 4-oxo-2-(4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)-1 ,4-dihydroquinoline-3-carboxylate (WDH-1V-10);

Ethyl 2-(4'-chloro-[1 ,1 '-biphenyl]-4-yl)-4-oxo-1 ,4-dihydroquinoline-3-carboxylate (WDH-1V- 9);

3-lsopropyl-2-(1-(4-(trifluoromethoxy)benzyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-2G-6);

3-Methyl-2-(1-(4-(trifluoromethoxy)phenethyl)-1 H-pyrazol-4-yl)quinolin-4(1 H)-one (WDH-2R-4);

3-Methyl-2-(4'-(trifluoromethoxy)-[1 , 1'-biphenyl]-4-yl)quinolin-4(1 H)-one (SL-2-34);

3-Methyl-2-(2'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-yl)quinolin-4(1 H)-one (SL-2-36);

2- (2'-Fluoro-[1 , 1 '-biphenyl]-4-yl)-3-methylquinolin-4(1 H)-one (SL-3-3);

3- Methyl-2-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)quinolin-4(1 H)-one (RKA 142);

2- (4-((4,4-Difluorocyclohexyl)oxy)phenyl)-3-methylquinolin-4(1 H)-one (PG105);

3- Methyl-2-(4-(3-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(1 H)-one (PG201);

2-(Hydroxymethyl)-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (PG208);

7- Hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (SCR-05-01 D);

8- Hydroxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (SCR-06-03D);

5-Methoxy-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(1 H)-one (SCR-04-04);

6-Methoxy-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (SCR-05- 03);

3-Methyl-2-(3-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-2-58);

3-Methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-2-67);

2-(4-(4-Methoxybenzyl)phenyl)-3-methylquinolin-4(1 H)-one (CK-2-96);

2- (4-Benzylphenyl)-3-methylquinolin-4(1 H)-one (CK-2-88);

6-Fluoro-7-hydroxy-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-3-68);

3- Methyl-2-(4-(4-(2-morpholinoethoxy)benzyl)phenyl)quinolin-4(1 H)-one (CK-4-2);

3-Methyl-2-(4-(3-(2-morpholinoethoxy)phenoxy)phenyl)quinolin-4(1 H)-one (CK-4-15); or 3-Methyl-2-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)quinolin-4(1 H)-one (CK-3-22).

10. A combination therapeutic product comprising one or more respiratory electron transport chain inhibitors as defined in any one of claims 1 , 2, 3 or 6, or a pharmaceutically acceptable salt thereof, and a cytochrome bd inhibitor as defined in any one of claims 1 , 4, 5 or 7 to 9, or a pharmaceutically acceptable salt thereof, for use simultaneously, sequentially or separately in the treatment of a mycobacterial infection.

11. A combination therapeutic product according to claim 10, wherein the mycobacterial infection is tuberculosis.

12. A combination therapeutic product according to claims 10 or 11 , wherein the mycobacterial infection is multidrug resistant tuberculosis.

13. A pharmaceutical composition suitable for use in the synergistic treatment of a mycobacterial infection which comprises a combination therapeutic product according to any one of claims 1 to 9, in association with a pharmaceutically-acceptable excipient or carrier.

14. The use of a combination therapeutic product according claim to any one of claims 1 to 9, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for administration simultaneously, sequentially or separately to a patient in need thereof, such as a human, for the treatment or prophylaxis of a mycobacterial infection.

15. A method for the treatment or prophylaxis of a mycobacterial infection comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9, to a patient, such as a human, in need of such treatment.

16. A cytochrome bd inhibitor according to any one of claims 1 , 4, 5 or 7 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of a mycobacterial infection, wherein the cytochrome bd inhibitor is administered in combination with one or more respiratory electron transport chain inhibitors as defined in any one of claims 1 , 2, 3 or 6.

17. A cytochrome bd inhibitor according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the mycobacterial infection is tuberculosis.

18. A cytochrome bd inhibitor according to claims 1 or 2, wherein the mycobacterial infection is multidrug resistant tuberculosis.

19. A method for the treatment or prophylaxis of a mycobacterial infection comprising simultaneously, sequentially or separately administering an effective amount of a cytochrome bd inhibitor, as defined in any one of claims 1 , 4, 5 or 7 to 9, or a pharmaceutically acceptable salt thereof, in combination with one or more respiratory electron transport chain inhibitors as defined in any one of claims 1 , 2, 3 or 6, or a pharmaceutically acceptable salt thereof.