Pyridine compounds

Abstract

The present invention relates to compounds of Formula (I) wherein R1, R2, R3, R4, ring A, integer m, R5, L, B1, B2, B3, B4 and B5 are as defined herein The compounds of the invention are effective in the treatment or prevention of diseases such as Mycobacterium tuberculosis infections. The present invention also relates to pharmaceutical compositions comprising the compounds of the invention, to processes for synthesising these compounds and to their use for the treatment or prevention of diseases such as Mycobacterium tuberculosis infections.

Description

PYRIDINE COMPOUNDSINTRODUCTION

[0001] The present invention relates to novel pyridine compounds. More specifically, the present invention relates to novel pyridine compounds that are effective in the treatment or prevention of diseases such as mycobacterium tuberculosis infections. The present invention also relates to pharmaceutical compositions comprising the novel pyridine compounds defined herein, to processes for synthesising these compounds and to their use for the treatment or prevention of diseases such as mycobacterium tuberculosis infections.BACKGROUND OF THE INVENTION

[0002] Tuberculosis (TB), an airborne infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a global health problem affecting 25% of the population, and a leading infectious disease killer (1.5 m deaths / year). TB deaths are predicted to double over the next 5 years following the Covid-19 pandemic Drug-resistance is themajor obstacle in the cure and eradication of TB, with >0.5 m new cases of multi drug-resistant TB (MDR-TB) per year, and an increase of extensive (XDR-TB) or untreatable drug-resistant cases. Current antibiotic treatments are long (>6 months), complex (multidrug), cause severe effects, have difficulty penetrating the mycobacterial cell-wall (reducing their efficacy), interact with HIV-therapy, and often fail to clear infection, leading to relapse and drug resistance. Furthermore, MDR / XDR-TB treatments are longer, toxic and less effective (30-54%).

[0003] The high prevalence of tuberculosis is due to the ability of Mtb to evade immune surveillance and replicate in immune cells (specifically macrophages), generating reservoirs of bacteria that promote antibiotic resistance, relapse of disease, and make TB difficult to treat. Survival of Mtb within host cells is maintained by bacteria-secreted factors that prevent phagosomal maturation and thus the natural antimicrobial activity of macrophages and immune response, allowing Mtb to ‘hide’ and replicate in macrophages, giving rise to latent and asymptomatic TB.

[0004] Mycobacterium protein tyrosine phosphatase B (MptpB) is a secreted phosphatase, critical for survival of Mycobacterium in the host macrophages and functions by preventing bacterial transport to phagolysosomes, thus avoiding destruction in the host cells. MptpB promotes bacterial survival by altering the host macrophage signalling pathways. To avoid host immune clearance, MptpB decreases the secretion of inflammatory cytokines and suppresses macrophage apoptosis. It has been shown, using a mptpB deficient mutant strain, that MptpB plays a pivotal role in Mtb survival in macrophages and persistence in guinea pigs. In addition, it has been demonstrated that MptpB chemical inhibition reduces mycobacterial burden in macrophages and animal models of infection.

[0005] The survival mechanisms in Mtb and the MptpB target are conserved in other microbial pathogens, including non-tuberculous mycobacteria (NTM) that cause serious infections.

[0006] Non-tuberculous mycobacteria (NTM) represent over 190 species and subspecies many of which can produce disease in humansof all ages and can affect both pulmonary and extrapulmonary sites. The most common NTM pathogens comprise Mycobacterium avium complex (MAC), which is caused by two main species: Mycobacterium avium and M. intracellulare, as well as Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM, and Mycobacterium abscessus among the rapidly growing NTM. MAC accounts for more than 80% of all pulmonary diseases caused by NTM infections with more than 90% of these infections due to M. avium.

[0007] The lung is the most common organ affected by NTM, which results in clinical presentation mimicking pulmonary tuberculosis (PTB). Pulmonary disease (NTM-PD), a chronic and progressive disease resulting in respiratory and non-respiratory symptoms, such as cough, shortness of breath, fatigue, decreased lung function, and decreased quality of life, is the most common form of NTM disease in patients who are negative for human immunodeficiency virus (HIV). NTM-PD commonly occurs in patients with underlying lung diseases. NTM lung disease is associated with substantially impaired quality of life, increased morbidity and mortality, and high medical costs.

[0008] Disseminated diseases due to NTM are commonly seen in patients who are immunocompromised including patients with advanced HIV infections, immunosuppressive medications, and genetic defects in Th1 immune responses.

[0009] MAC is ubiquitous in distribution. It has been isolated from fresh water and salt water worldwide. The common environmental sources of MAC include piped plumbing systems, such as household and hospital water supplies, bathrooms and hot tubs, as well as aerosolized water, house dust, soil, birds, farm animals, and cigarette components (e.g., tobacco, filters and papers).

[0010] Despite recent advances in the clinical treatments of Mycobacterium tuberculosis and non-tuberculous mycobacteria derived diseases / disorders, there remains a need for novel therapeutic strategies targeting these diseases / disorders.

[0011] The present invention has been devised with the foregoing in mind.SUMMARY OF THE INVENTION

[0012] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0013] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0014] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0015] According to a further aspect of the present invention, there is provided a method of treating a microbial disease in which the inhibition of MptpB is beneficial, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0016] According to a further aspect of the present invention, there is provided a method of treating a microbial disease in which the activity of MptpB is implicated, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0017] According to a further aspect of the present invention, there is provided a method of treating a microbial infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0018] According to a further aspect of the present invention, there is provided a method of treating a mycobacterium infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0019] According to a further aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection ora non-tuberculous mycobacterium infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0020] According to a further aspect of the present invention, there is provided a method of treating pulmonary tuberculosis or non-tuberculous pulmonary disease, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0021] According to a further aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0022] According to a further aspect of the present invention, there is provided a method of treating a multidrug resistant Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0023] According to a further aspect of the present invention, there is provided a method of treating an extremely drug resistant Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0024] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in therapy.

[0025] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial.

[0026] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated.

[0027] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a microbial infection.

[0028] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a mycobacterium infection.

[0029] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or apharmaceutical composition as defined herein, for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection.

[0030] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a pulmonary tuberculosis or non-tuberculous pulmonary disease.

[0031] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a Mycobacterium tuberculosis infection.

[0032] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection.

[0033] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection.

[0034] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial.

[0035] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated.

[0036] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial infection.

[0037] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a mycobacterium infection.

[0038] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection.

[0039] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a pulmonary tuberculosis or non- tuberculous pulmonary disease.

[0040] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a Mycobacterium tuberculosis infection.

[0041] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection.

[0042] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection.

[0043] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0044] According to a further aspect of the present invention, there are provided novel intermediates, as defined herein, which are suitable for use in any one of the synthetic methods set out herein.

[0045] According to a further aspect of the present invention, there is provided a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein.

[0046] According to a further aspect of the invention, there is provided a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein.

[0047] According to a further aspect of the present invention, there is provided apharmaceutical product comprising a combination of the invention as defined herein in association with a pharmaceutically acceptable diluent or carrier.

[0048] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein.

[0049] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a combination of the invention as defined herein in association with a pharmaceutically acceptable diluent or carrier.

[0050] According to a further aspect of the present invention, there is provided a method of reducing I lowering inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0051] According to a further aspect of the present invention, there is provided a method of treating or preventing inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0052] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder associated with inflammation, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0053] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder in which the reduction I lowering of inflammation is beneficial, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0054] According to a further aspect of the present invention, there is provided a method of treating or preventing an inflammatory disease I disorder, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0055] According to a further aspect of the present invention, there is provided a method of treating or preventing a fungal disease I disorder I infection (i.e., mycosis), the method comprising administering to a subject a therapeutically effective amount of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0056] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder I infection associated with fungi, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0057] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the reduction I lowering of inflammation.

[0058] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of inflammation.

[0059] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a disease I disorder associated with inflammation.

[0060] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a disease I disorder in which the reduction I lowering of inflammation is beneficial.

[0061] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of an inflammatory disease I disorder.

[0062] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a fungal disease I disorder / infection (i.e. , mycosis).

[0063] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease I disorder I infection associated with fungi.

[0064] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in in the reduction I lowering of inflammation.

[0065] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of inflammation.

[0066] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder associated with inflammation.

[0067] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder in which the reduction I lowering of inflammation is beneficial.

[0068] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of an inflammatory disease I disorder.

[0069] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a fungal disease I disorder I infection (i.e., mycosis).

[0070] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder I infection associated with fungi.

[0071] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0072] Unless otherwise stated, the following terms used in the specification and claims havethe following meanings set out below.

[0073] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a state I disease I disorder I condition I infection. “Treating” or “treatment” of a state I disease I disorder I condition I infection therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state I disease I disorder / condition I infection developing in a human that may be afflicted with or predisposed to the state I disease I disorder I condition I infection but does not yet experience or display clinical or subclinical symptoms of the state I disease I disorder I condition I infection, (2) inhibiting the state I disease I disorder I condition I infection, 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 I disease I disorder I condition I infection or at least one of its clinical or subclinical symptoms.

[0074] 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.

[0075] The term “MptpB” includes and encompasses all orthologues associated with MptpB (e.g., ptpB or Mav-ptpB). MptpB and MptpB orthologues are well known in the art. Accordingly, the term “MptpB” may be used interchangeably with “MptpB and MptpB orthologues” herein.

[0076] 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 t butyl.

[0077] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0078] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2CH(CH3)CH2-), pentylene (- CH2CH2CH2CH2CH2-), and the like.

[0079] The term “alkyenyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl and but-2, 3-enyl and includes all possible geometric (E / Z) isomers.

[0080] The term “alkynyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0081] “(3-10C)cycloalkyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.

[0082] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and t-butoxy.

[0083] The term “haloalkyl” is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g., fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2 and -CF3.

[0084] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.

[0085] The term “carbocyclyl”, “carbocyclic” or “carbocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s). Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.

[0086] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen (including N+), oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 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 sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro oxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such astetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide. Heterocycles may comprise 1 or 2 oxo (=0) or thioxo (=S) substituents. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2 oxopyrrolidinyl, 2 thioxopyrrolidinyl, 2 oxoimidazolidinyl, 2 thioxoimidazolidinyl, 2 oxopiperidinyl, 2,5 dioxopyrrolidinyl, 2,5 dioxoimidazolidinyl or 2,6 dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, 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 atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0087] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0088] By “spiro bi-cyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0089] 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 ofbasic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0090] 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 b]pyrazinyl and 3,4 dihydro 2H pyrido[3,2 b][1 ,4]oxazinyl.

[0091] 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.

[0092] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0093] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.

[0094] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0095] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0096] 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 a particular embodiment, an aryl is phenyl.

[0097] 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 (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3- 6C)cycloalkyl.

[0098] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. Suitably the term “substituted” means that (any) one of the hydrogen radicals in the relevant group substituted by a relevant stipulated group.

[0099] 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.

[0100] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically (e.g., compounds of formula I, and any subformulae thereof (e.g., compounds of formula II to XV)).Compounds of the invention

[0101] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below:wherein:R1 is selected from: -[CH2]n-C(O)OH; integer n is 0, 1 or 2;R2 is selected from hydrogen, halo, hydroxy, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1- 3C)haloalkoxy, (1-3C)hydroxyalkyl or (1-3C)hydroxyalkoxy;R3 is selected from hydrogen, hydroxy, halo, (1-6C)alkyl, (1-6C)alkoxy, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkylene, (3-8C)cycloalkoxy, (3-8C)cycloalkyl(1-2C)alkylene-O-, wherein any alkyl, alkoxy or alkylene group is optionally substituted by one or more substituent groups independently selected from hydroxy, halo, (1-3C)alkoxy, (1- 3C)haloalkoxy, or amino; wherein any cycloalkyl or cycloalkoxy group is optionally substituted by one or more substituent groups independently selected from hydroxy, halo, (1-3C)alkoxy, amino, (1- 3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl or (1- 3C)hydroxyalkoxy;R4 is selected from hydrogen, halo, hydroxy, (1 -3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1- 3C)haloalkoxy;Ring A is a phenyl ring or a 5- or 6-membered heteroaryl ring; integer m is 0, 1 or 2; each R5 group present is independently selected from hydroxy, halo, cyano, or a group of the formula:-Y R5-QR5 wherein:YR5is absent or O, S, SO, SO2, N(R5a), C(O), C(O)O, OC(O), C(O)N(R5a), N(R5a)C(O), N(R5a)C(O)N(R5b), N(R5a)C(O)O, OC(O)N(R5a), S(O)2N(R5a),N(R5a)SC>2, or C(O)N(R5a)SO2, wherein Rsaand Rsb are each independently selected from hydrogen or (1 -2C)alkyl; andQRS is hydrogen, (1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkylene, heterocyclyl or heterocyclyl(1-3C)alkylene; wherein QRS is optionally further substituted by one or more substituent groups independently selected from oxo, (1-2C)alkyl, (1-2C)alkoxy, halo, cyano, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl or amino;L is a covalent bond, -C(RL)2-, or -C(RL)2-C(RL)2-, wherein each R present is independently selected from hydrogen or methyl;Bi is selected from CH, C-Re or N;B2is selected from CH, C-R? or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH, C-Rg or N;Bs is selected from CH, C-R10 or N; with the proviso that only one, two or three of Bi , B2, B3, B4 and Bs may be N; and wherein Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene optionally substituted by one or more substituents selected from methyl or oxo;Y is absent or O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), N(Ra)C(O)O, OC(O)N(Ra), C(=NRy)N(Ra), N(Ra)C(=NRy), N(Ra)C(=NRy)N(Rb), S(O)2N(Ra), N(Ra)SO2, or C(O)N(Ra)SO2, wherein Raand Rb are each independently selected from hydrogen or (1- 4C)alkyl and Ryis selected from hydrogen, (1 -4C)alkyl, nitro or cyano; l_2is absent or (1-4C)alkylene optionally substituted by one or more substituents selected from methyl or oxo; andQ is hydrogen, (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, cyano, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)PRc(where p is 0, 1 or 2), SO2N(Rd)Rc, N(Rd)SO2Rc,or (CH2)qNRcRd(where q is 1 , 2 or 3); whereinRc, Rd and Reare each independently selected from hydrogen, (1 -6C)alkyl, (3- 6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; and wherein Rg and R are each independently selected from halo, hydroxy, (1- 3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl or (1- 3C)hydroxyalkoxy.Compounds of Formula (I)

[0102] Particular compounds of the Formula (I) include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of Ri, integer n, R2, R3, R4, ring A, integer m, R5, L, Bi , B2, B3, B4 and B5, and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (72) hereinafter:(1) R1 is -[CH2]n-C(O)OH where n is 0 or 1 ;(2) R1 is -[CH2]-C(O)OH or R1 is -C(O)OH;(3) Ri is -C(O)OH;(4) R2 is selected from hydrogen, halo, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl or (1-2C)hydroxyalkoxy;(5) R2 is selected from hydrogen, fluoro, chloro, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)fluoroalkyl, (1-2C)fluoroalkoxy, (1-2C)hydroxyalkyl or ( 1 -2 C) hydroxy alkoxy;(6) R2 is selected from hydrogen, fluoro, chloro, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)fluoroalkyl or (1-2C)fluoroalkoxy;(7) R2 is hydrogen;(8) R3 is selected from hydrogen, hydroxy, halo, (1-6C)alkyl, (1-6C)alkoxy, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkylene, (3-8C)cycloalkoxy, or (3- 8C)cycloalkyl(1-2C)alkylene-O-; wherein any alkyl or alkoxy group is optionally substituted by one or more substituent groups independently selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, or amino; and wherein any cycloalkyl or cycloalkoxy group is optionally substituted by one or more substituent groups independently selected from hydroxy, halo, (1-2C)alkoxy, amino, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1- 2C)hydroxyalkyl or (1-2C)hydroxyalkoxy;(9) R3 is selected from hydrogen, hydroxy, fluoro, chloro, (1-6C)alkyl, (1-6C)alkoxy, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkylene, or (3-8C)cycloalkoxy, wherein any alkyl or alkoxy group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, halo, (1-2C)alkoxy or (1- 2C)fluoroalkoxy;and wherein any cycloalkyl or cycloalkoxy group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1- 2C)alkoxy, amino, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)fluoroalkyl, or (1-2C)fluoroalkoxy;(10) R3 is selected from hydrogen, hydroxy, fluoro, chloro, (1 -6C)alkyl, or (3-8C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy or (1- 2C)fluoroalkoxy; and wherein any cycloalkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy, amino, (1- 2C)alkyl, (1-2C)alkoxy, (1-2C)fluoroalkyl, or (1-2C)fluoroalkoxy;(11) R3 is selected from hydroxy, fluoro, chloro, (1 -6C)alkyl, or (3-8C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy or (1- 2C)fluoroalkoxy; wherein any cycloalkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy, amino, (1- 2C)alkyl, (1-2C)alkoxy, (1-2C)fluoroalkyl, or (1-2C)fluoroalkoxy;(12) R3 is selected from hydroxy, fluoro, chloro, (1-6C)alkyl, or (3-6C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy or (1- 2C)fluoroalkoxy; wherein any cycloalkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy, amino, (1- 2C)alkyl, (1-2C)alkoxy, (1-2C)fluoroalkyl, or (1-2C)fluoroalkoxy;(13) R3 is selected from hydroxy, fluoro, chloro, (1 -6C)alkyl, or (3-6C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more fluoro;(14) R3 is selected from (1 -6C)alkyl or (3-6C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more fluoro;(15) R3 is selected from hydrogen, fluoro, chloro, methyl, isopropyl, 2-methylpropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl;(16) R3 is selected from fluoro, chloro, methyl, isopropyl, 2-methylpropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl;(17) R3 is selected from methyl, isopropyl, 2-methylpropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl;(18) R3 is cyclopropyl;(19) R4 is selected from hydrogen, halo, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;(20) R4 is selected from hydrogen, fluoro, chloro, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;(21) R4 is selected from hydrogen or methyl;(22) R4 is hydrogen;(23) Ring A is a phenyl ring or a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S;(24) Ring A is a phenyl ring or a 5- or 6-membered heteroaryl ring comprising one or two heteroatoms selected from N, O or S;(25) Ring A is a phenyl ring;(26) integer m is 0 or 1 ;(27) integer m is 0;(28) each R5 group present is independently selected from hydroxy, halo, cyano or a group of the formula:-Y R5-QR5 wherein:YR5is absent or O, S, SO, SO2, N(R5a), C(O), C(O)N(R5a), N(R5a)C(O), N(R5a)C(O)O, OC(O)N(R5a), S(O)2N(R5a) or N(R5a)SO2, wherein R5ais selected from hydrogen or (1 -2C)alkyl; andQRS is hydrogen, (1 -4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkylene, 4-to 6-membered heterocyclyl, or [4- to 6-membered heterocyclyl](1- 2C)alkylene; wherein QRS is optionally further substituted by one or more substituent groups independently selected from oxo, (1-2C)alkyl, (1-2C)alkoxy, halo, cyano, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl or amino;(29) each Rs group present is independently selected from hydroxy, halo, cyano or a group of the formula:-Y RS-QRS wherein:YR5is absent or O, SO2, N(R5a), C(O), C(O)N(R5a), N(R5a)C(O), S(O)2N(R5a) or N(Rsa)SO2, wherein Rsais selected from hydrogen or (1 -2C)alkyl; andQRS is hydrogen, (1 -4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkylene, 4-to 6-membered heterocyclyl, or [4- to 6-membered heterocyclyl](1- 2C)alkylene; wherein QRS is optionally further substituted by one or more substituent groups independently selected from oxo, (1-2C)alkyl, (1-2C)alkoxy, halo, cyano, (1- 2C)haloalkyl or (1-2C)haloalkoxy;(30) each Rs group present is independently selected from hydroxy, halo, cyano or a group of the formula:-Y R5-QR5 wherein:YR5is absent or O, SO2, N(R5a), C(O), C(O)N(R5a), N(R5a)C(O), S(O)2N(R5a) or N(R5a)SC>2, wherein Rsa is selected from hydrogen or (1 -2C)alkyl; andQRS is hydrogen, (1 -4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkylene, 4-to 6-membered heterocyclyl, or [4-to 6-membered heterocyclyl](1- 2C)alkylene; wherein QRS is optionally further substituted by one or more halo atoms;(31) each Rs group present is independently selected from hydroxy, halo, cyano or a group of the formula:-Y RS-QRS wherein:YR5is absent or O, SO2, N(R5a), C(O)N(R5a), N(R5a)C(O), S(O)2N(R5a) or N(R5a)SO2, wherein Rsa is selected from hydrogen or methyl; and QRS is hydrogen or (1 -4C)alkyl; wherein QRS is optionally further substituted by one or more fluoro atoms;(32) each Rs group present is independently selected from hydroxy, halo, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl or (1- 2C)hydroxyalkoxy;(33) each Rs group present is independently selected from hydroxy, fluoro, chloro, (1- 2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl or (1- 2C)hydroxyalkoxy;(34) each Rs group present is independently selected from (1-2C)alkoxy, (1-2C)fluoroalkyl, (1-2C)fluoroalkoxy, (1-2C)hydroxyalkyl or (1-2C)hydroxyalkoxy;(35) each Rs group present is independently selected from fluoro, chloro, (1 -2C)alkyl, (1- 2C)alkoxy, (1-2C)fluoroalkyl, or (1-2C)fluoroalkoxy;(36) each Rs group present is (1-2C)fluoroalkoxy;(37) L is selected from a covalent bond, -C(RL)2-, or -C(RL)2-C(RL)2-, wherein each R present is hydrogen;(38) L is selected from a covalent bond or -CH2-;(39) L is a covalent bond;(40) Bi is selected from CH, C-Re or N;B2is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH, C-Rg or N;Bs is selected from CH, C-R10 or N; with the proviso that only one or two of Bi , B2, B3, B4 and B5 may be N;(41) Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH or C-Rg;B5 is selected from CH or C-R10; with the proviso that only one or two of Bi , B2 or B3 may be N;(41a) Bi is selected from C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH or C-Rg;B5 is selected from CH or C-R10; with the proviso that only one or two of Bi , B2 or B3 may be N;(41 b) Bi is selected from CH, C-Re or N;B2 is selected from C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH or C-Rg;B5 is selected from CH or C-R10; with the proviso that only one or two of Bi , B2 or B3 may be N;(41c) Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from C-Rs or N;B4 is selected from CH or C-Rg;B5 is selected from CH or C-R10; with the proviso that only one or two of Bi , B2 or B3 may be N;(41d) Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is C-Rg;B5 is selected from CH or C-R10; with the proviso that only one or two of Bi , B2 or B3 may be N;(41e) Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH or C-Rg;B5 is C-R10;with the proviso that only one or two of Bi , B2 or B3 may be N;(42) Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH;B5 is selected from CH; with the proviso that only one or two of Bi , B2 or B3 may be N;(42a) Bi is selected from C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH;B5 is selected from CH; with the proviso that only one or two of Bi , B2 or B3 may be N;(42b) Bi is selected from CH, C-Re or N;B2 is selected from C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH;B5 is selected from CH; with the proviso that only one or two of Bi , B2 or B3 may be N;(42c) Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from C-Rs or N;B4 is selected from CH;B5 is selected from CH; with the proviso that only one or two of Bi , B2 or B3 may be N;(43) Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), N(Ra)C(O)O, OC(O)N(Ra), S(O)2N(Ra) or N(Ra)SO2, wherein Raand Rb are each independently selected from hydrogen or (1-4C)alkyl;L2 is absent or (1-4C)alkylene; andQ is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl;wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, cyano, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NRcRd, ORC, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)PRc(where p is 0, 1 or 2), SC>2N(Rd)Rc, N(Rd)SC>2Rc,or (CH2)qNRcRd(where q is 1 , 2 or 3); wherein Rc, Rdand Reare each independently selected from hydrogen, (1 -4C)alkyl, (3- 6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;(44) Re, R? and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, S, SO, SO2, N(Ra), C(O), C(O)N(Ra), N(Ra)C(O), S(O)2N(Ra) or N(Ra)SO2, wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, phenyl, (3- 6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, NRcRd, ORC, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)PRC(where p is 0, 1 or 2), SO2N(Rd)Rc, or N(Rd)SO2Rc, wherein Rcand Rdare each independently selected from hydrogen or (1 -2C)alkyl;(45) Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, phenyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, NRcRd, or ORCwherein Rcand Rd are each independently selected from hydrogen or (1- 2C)alkyl;(45a) Re, R? and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is (1-4C)alkyl, phenyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, NRcRd, or ORCwherein Rcand Rd are each independently selected from hydrogen or (1- 2C)alkyl;(46) Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, phenyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, or (1-2C)haloalkoxy;(46a) Rs, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;I_2 is absent or (1-3C)alkylene; andQ is (1 -4C)alkyl, phenyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, or (1-2C)haloalkoxy;(47) Re, R? and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, or 5- or 6-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, or (1-2C)haloalkoxy;(47a) Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is (1 -4C)alkyl, or 5- or 6-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, or (1-2C)haloalkoxy;(48) Rs, R7 and Rs are each independently selected from halo, cyano, hydroxy, (1 -2Calkyl), (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, 5- or 6-membered heterocyclyl, (5- or 6-membered heterocyclyl)(1-2Calkoxy) or C(O)N(Ra)Rb, wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;(49) Rs, R7 and Rs are each independently selected from fluoro, chloro, cyano, hydroxy, - CF3, methoxy, -OCF3, -OCH2CF3, tetrahydropyran, morpholine (i.e., morpholino), -O- CH2CH2-morpholine (i.e., morpholino), -O-CH2-tetrahydropyran or C(O)NMe2;(50) one of Re, R? and Rs is a group of the formula -L1-Y-L2-Q as defined in claim 1 , or any one of paragraphs (43) to (49) above, and the others are selected from hydrogen or halo;(51) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in claim 1 , or any one of paragraphs (43) to (49) above, and the others are selected from hydrogen, fluoro or chloro;(52) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (45) above, and the others are selected from hydrogen or halo;(52a) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (45a) above, and the others are selected from hydrogen or halo;(53) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (45) above, and the others are selected from hydrogen, fluoro or chloro;(54) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (47) above, and the others are selected from hydrogen or halo;(54a) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (47a) above, and the others are selected from hydrogen or halo;(55) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (47) above, and the others are selected from hydrogen, fluoro or chloro;(56) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (48) above, and the others are selected from hydrogen or halo;(57) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (48) above, and the others are selected from hydrogen, fluoro or chloro;(58) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (49) above, and the others are selected from hydrogen or halo;(59) one of Re, R7 and Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (49) above, and the others are selected from hydrogen, fluoro or chloro;(60) R7 is a group of the formula -L1-Y-L2-Q as defined in claim 1 , or any one of paragraphs(43) to (49) above, and Re and Rs are selected from hydrogen, fluoro or chloro;(61) R7 is a group of the formula -L1-Y-L2-Q as defined in paragraph (45) above, and Re andRs are selected from hydrogen, fluoro or chloro;(62) R7 is a group of the formula -L1-Y-L2-Q as defined in paragraph (47) above, and Re andRs are selected from hydrogen, fluoro or chloro;(63) R7 is a group of the formula -L1-Y-L2-Q as defined in paragraph (48) above, and Re andRs are selected from hydrogen, fluoro or chloro;(64) R7 is a group of the formula -L1-Y-L2-Q as defined in paragraph (49) above, and Re andRs are selected from hydrogen, fluoro or chloro;(65) Rs is a group of the formula -L1-Y-L2-Q as defined in claim 1 , or any one of paragraphs(43) to (49) above, and Re and R? are selected from hydrogen, fluoro or chloro;(66) Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (45) above, and Re andR? are selected from hydrogen, fluoro or chloro;(67) Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (47) above, and Re andR? are selected from hydrogen, fluoro or chloro;(68) Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (48) above, and Re andR7 are selected from hydrogen, fluoro or chloro;(69) Rs is a group of the formula -L1-Y-L2-Q as defined in paragraph (49) above, and Re andR7 are selected from hydrogen, fluoro or chloro;(70) Rg and R10 are each independently selected from halo, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl or (1- 2C)hydroxyalkoxy;(71) Rg and R10 are each independently selected from halo, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;(72) Rg and R10 are each independently selected from halo, hydroxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy.

[0103] Suitably, R1 is as defined in paragraph (1) above. More suitably, R1 is as defined in paragraph (2) above. Most suitably, R1 is as defined in paragraph (3) above.

[0104] Suitably, integer n is as defined in paragraph (1) above. Most suitably, integer n is 0.

[0105] Suitably, R2 is as defined in paragraph (4) above. More suitably, R2 is as defined in paragraph (5) above. Even more suitably, R2 is as defined in paragraph (6) above. Most suitably, R2 is as defined in paragraph (7) above.

[0106] Suitably, R3 is as defined in paragraph (8) above. More suitably, R3 is as defined in paragraph (9) above. Even more suitably, R3 is as defined in paragraph (10) above. Even more suitably, R3 is as defined in paragraph (11) above. Even more suitably, R3 is as defined in paragraph (12) above. Even more suitably, R3 is as defined in paragraph (13) above. Even more suitably, R3 is as defined in paragraph (14) above. Even more suitably, R3 is as defined in paragraph (15) above. Even more suitably, R3 is as defined in paragraph (16) above. Yet still even more suitably, R3 is as defined in paragraph (17) above. Most suitably, R3 is as defined in paragraph (18) above.

[0107] Suitably, R4 is as defined in paragraph (19) above. More suitably, R4 is as defined in paragraph (20) above. Even more suitably, R4 is as defined in paragraph (21) above. Most suitably, R4 is as defined in paragraph (22) above.

[0108] Suitably, ring A is as defined in paragraph (23) above. More suitably, ring A isas defined in paragraph (24) above. Most suitably, ring A is as defined in paragraph (25) above.

[0109] Suitably, integer m is as defined in paragraph (26) above. Most suitably, integer m is as defined in paragraph (27) above.

[0110] Suitably, Rs is as defined in paragraph (28) above. More suitably, Rs is as defined in paragraph (29) above. Even more suitably, Rs is as defined in paragraph (30) above. Even more suitably, Rs is as defined in paragraph (31) above. Even more suitably, Rs is as defined in paragraph (32) above. Even more suitably, Rs is as defined in paragraph (33) above. Even more suitably, Rs is as defined in paragraph (34) above. Even more suitably, Rs is as defined in paragraph (35) above. Most suitably, Rs is as defined in paragraph (36) above.

[0111] Suitably, L is as defined in paragraph (37) above. More suitably, L is as defined in paragraph (38) above. Most suitably, L is as defined in paragraph (39) above.

[0112] Suitably, Bi, B2, B3, B4 and Bs are as defined in paragraph (40) above. More suitably, Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above. More suitably, Bi , B2, B3, B4 and Bs are as defined in paragraph (41a) above. More suitably, Bi, B2, B3, B4 and Bs are as defined in paragraph (41 b) above. More suitably, Bi, B2, B3, B4 and Bs are as defined in paragraph (41c) above. More suitably, Bi, B2, B3, B4 and Bs are as defined in paragraph (41 d) above. More suitably, Bi, B2, B3, B4 and Bs are as defined in paragraph (41 e) above. Most suitably, Bi , B2, B3, B4 and Bs are as defined in paragraph (42) above. In an embodiment, Bi , B2, B3, B4 and Bs are as defined in paragraph (42a) above. In an embodiment, Bi , B2, B3, B4 and Bs are as defined in paragraph (42b) above. In an embodiment, Bi , B2, B3, B4 and Bs are as defined in paragraph (42c) above. In an embodiment, at least one of Bi , B2, B3, B4 and Bs is not CH. In an embodiment, not all of Bi, B2, B3, B4 and Bs are CH. In an embodiment, one, two, three or four of Bi , B2, B3, B4 and Bs are CH. In an embodiment, two, three or four of Bi , B2, B3, B4 and Bs are CH. In an embodiment, three or four of Bi , B2, B3, B4 and Bs are CH. In an embodiment, four of Bi , B2, B3, B4 and Bs are CH.

[0113] Suitably, Re, R7 and Rs are as defined in paragraph (43) above. More suitably, Re, R7 and Rs are as defined in paragraph (44) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (45) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (45a) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (46) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (46a) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (47) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (47a) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (48) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (49) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (50) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (51) above. Even more suitably, Re, R7 and Rs are as defined in paragraph (52) above. Even more suitably, Re, R7and Rs are as defined in paragraph (52a) above. Even more suitably, Re, R? and Rs are as defined in paragraph (53) above. Even more suitably, Re, R? and Rs are as defined in paragraph (54) above. Even more suitably, Re, R? and Rs are as defined in paragraph (54a) above. Even more suitably, Re, R? and Rs are as defined in paragraph (55) above. Even more suitably, Re, R? and Rs are as defined in paragraph (56) above. Even more suitably, Re, R? and Rs are as defined in paragraph (57) above. Even more suitably, Re, R? and Rs are as defined in paragraph (58) above. Even more suitably, Re, R? and Rs are as defined in paragraph (59) above. Even more suitably, Re, R? and Rs are as defined in paragraph (60) above. Even more suitably, Re, R? and Rs are as defined in paragraph (61) above. Even more suitably, Re, R? and Rs are as defined in paragraph (62) above. Even more suitably, Re, R? and Rs are as defined in paragraph (63) above. Even more suitably, Re, R? and Rs are as defined in paragraph (64) above. Even more suitably, Re, R? and Rs are as defined in paragraph (65) above. Even more suitably, Re, R? and Rs are as defined in paragraph (66) above. Even more suitably, Re, R? and Rs are as defined in paragraph (67) above. Even more suitably, Re, R? and Rs are as defined in paragraph (68) above. Even more suitably, Re, R? and Rs are as defined in paragraph (69) above.

[0114] Suitably, Rg and Rw are as defined in paragraph (70) above. More suitably, Rg and R are as defined in paragraph (71) above. Most suitably, Rg and R are as defined in paragraph (72) above.

[0115] In a particular group of compounds, the compound has the structural formula II or III shown below:IIwherein:Ri, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10 are as defined hereinbefore; and in formula II, A1, A3, A4 and As are each independently selected from C-H or N, with the proviso that only one, two or three of A1, A3, A4 and As may be N; and in formula III, A1, A2, A4 and As are each independently selected from C-H or N, with the proviso that only one, two or three of A1, A2, A4 and As may be N.

[0116] Suitably, the compounds of the invention have a structure of formula II as defined herein.

[0117] Suitably, the compounds of the invention have a structure of formula III as defined herein.

[0118] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L,Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (1) above;R2 is as defined in paragraph (4) above;R3 is as defined in paragraph (8) above;R4 is as defined in paragraph (19) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (28) above;L is as defined in paragraph (37) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (40) above;Re, R7 and Rs are as defined in paragraph (43) above;Rg and R10 are as defined in paragraph (70) above; in formula II, A1, A3, A4 and As are each independently selected from C-H or N, with the proviso that only one or two of A1, A3, A4 and As may be N; and in formula III, A1, A2, A4 and As are each independently selected from C-H or N, with the proviso that only one or two of A1 , A2, A4 and As may be N.

[0119] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:Ri is as defined in paragraph (2) above;R2 is as defined in paragraph (5) above;R3 is as defined in paragraph (9) above;R4 is as defined in paragraph (20) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (29) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (45) above;Rg and R10 are as defined in paragraph (71) above; in formula II, A1 , A3, A4 and As are each independently selected from C-H or N, with the proviso that only one of A1, A3, A4 and As may be N; and in formula III, A1, A2, A4 and As are each independently selected from C-H or N, with the proviso that only one of A1 , A2, A4 and As may be N .

[0120] In the aforementioned embodiment wherein Re, R7 and Rs are as defined in paragraph (45), Re, R7 and Rs may instead be as defined in paragraph (45a) above.

[0121] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L,Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (6) above;R3 is as defined in paragraph (10) above;R4 is as defined in paragraph (21) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (30) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Rs, R7 and Rs are as defined in paragraph (47) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0122] In the aforementioned embodiment wherein Rs, R7 and Rs are as defined in paragraph (47), Rs, R7 and Rs may instead be as defined in paragraph (47a) above.

[0123] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L,Bi , B2, B3, B4 and Bs, Rs, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (11) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (30) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (49) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0124] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (12) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (31) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (51) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0125] In the compounds of formulae II or III above, R1, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (13) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (32) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (53) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0126] In the compounds of formulae II or III above, Ri, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (14) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (33) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (55) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0127] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (15) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (34) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (57) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0128] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (16) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (35) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, 7 and Rs are as defined in paragraph (59) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0129] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (17) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (61) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0130] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (18) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (63) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0131] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;Rs is as defined in paragraph (18) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (66) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0132] In the compounds of formulae II or III above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and Bs, Re, R7, Rs, Rg and R10 have the definitions set out below:R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (18) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and Bs are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (69) above;Rg and R10 are as defined in paragraph (72) above; in formula II, A1 , A3, A4 and As are C-H; and in formula III, A1 , A2, A4 and As are C-H.

[0133] In any of the aforementioned embodiments wherein Bi, B2, B3, B4 and Bs are as defined in paragraph (41), Bi , B2, B3, B4 and Bs may instead be as defined in paragraph (41a) above. In any of the aforementioned embodiments wherein Bi , B2, B3, B4 and Bs are as defined in paragraph (41), Bi , B2, B3, B4 and Bs may instead be as defined in paragraph (41b) above. In any of the aforementioned embodiments wherein Bi , B2, B3, B4 and Bs are as defined in paragraph (41), Bi , B2, B3, B4 and Bs may instead be as defined in paragraph (41c) above. In any of the aforementioned embodiments wherein Bi , B2, B3, B4 and Bs are as defined in paragraph (41), Bi , B2, B3, B4 and Bs may instead be as defined in paragraph (41 d) above. In any of the aforementioned embodiments wherein Bi, B2, B3, B4 and Bs are as defined in paragraph (41), Bi , B2, B3, B4 and Bs may instead be as defined in paragraph (41 e) above.

[0134] In a further group of compounds, the compound has any one of the structural formulae IV to XV shown below:VIwherein, and when present:Ri, R2, R3, R4, Rs, integer m, L, Bi, B2, B3, B4 and B5, Re, R7, Rs, Rg and R10 are each as defined hereinbefore.

[0135] Suitably, the compounds of the invention have a structure of formula IV as defined herein.

[0136] Suitably, the compounds of the invention have a structure of formula V as defined herein.

[0137] Suitably, the compounds of the invention have a structure of formula VI as defined herein.

[0138] Suitably, the compounds of the invention have a structure of formula VII as defined herein.

[0139] Suitably, the compounds of the invention have a structure of formula VIII as defined herein.

[0140] Suitably, the compounds of the invention have a structure of formula IX as defined herein.

[0141] Suitably, the compounds of the invention have a structure of formula X as defined herein.

[0142] Suitably, the compounds of the invention have a structure of formula XI as defined herein.

[0143] Suitably, the compounds of the invention have a structure of formula XII as defined herein.

[0144] Suitably, the compounds of the invention have a structure of formula XIII as defined herein.

[0145] Suitably, the compounds of the invention have a structure of formula XIV as defined herein.

[0146] Suitably, the compounds of the invention have a structure of formula XV as defined herein.

[0147] In the compounds of formulae IV to XV above, Ri, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (1) above;R2 is as defined in paragraph (4) above;R3 is as defined in paragraph (8) above;R4 is as defined in paragraph (19) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (28) above;L is as defined in paragraph (37) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (40) above;Re, R7 and Rs are as defined in paragraph (43) above; andRg and R10 are as defined in paragraph (70) above.

[0148] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (2) above;R2 is as defined in paragraph (5) above;R3 is as defined in paragraph (9) above;R4 is as defined in paragraph (20) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (29) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (45) above; andRg and R10 are as defined in paragraph (71) above.

[0149] In the aforementioned embodiment wherein Re, R7 and Rs are as defined in paragraph (45), Re, R7 and Rs may instead be as defined in paragraph (45a) above.

[0150] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (6) above;R3 is as defined in paragraph (10) above;R4 is as defined in paragraph (21) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (30) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Rs, R7 and Rs are as defined in paragraph (47) above; andRg and R10 are as defined in paragraph (72) above.

[0151] In the aforementioned embodiment wherein Rs, R7 and Rs are as defined in paragraph (47), Rs, R7 and Rs may instead be as defined in paragraph (47a) above.

[0152] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Rs, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (11) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (30) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Rs, R7 and Rs are as defined in paragraph (49) above; andRg and R10 are as defined in paragraph (72) above.

[0153] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Rs, R7, Rs, Rg and R10, when present, have the definitions set out below:Ri is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (12) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (31) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (51) above; andRg and R10 are as defined in paragraph (72) above.

[0154] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (13) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (32) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (53) above; andRg and R10 are as defined in paragraph (72) above.

[0155] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (14) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (33) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Rs, R7 and Rs are as defined in paragraph (55) above; andRg and R10 are as defined in paragraph (72) above.

[0156] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Rs, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (15) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (34) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (57) above; andRg and R10 are as defined in paragraph (72) above.

[0157] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (16) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (35) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (59) above; andRg and R10 are as defined in paragraph (72) above.

[0158] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (17) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Rs, R7 and Rs are as defined in paragraph (61) above; andRg and R10 are as defined in paragraph (72) above.

[0159] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Rs, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;Rs is as defined in paragraph (18) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (63) above; andRg and R10 are as defined in paragraph (72) above.

[0160] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (18) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Re, R7 and Rs are as defined in paragraph (66) above; andRg and R10 are as defined in paragraph (72) above.

[0161] In the compounds of formulae IV to XV above, R1, R2, R3, R4, Rs, integer m, L, Bi , B2, B3, B4 and B5, Re, R7, Rs, Rg and R10, when present, have the definitions set out below: R1 is as defined in paragraph (3) above;R2 is as defined in paragraph (7) above;R3 is as defined in paragraph (18) above;R4 is as defined in paragraph (22) above; integer m is as defined in paragraph (26) above;Rs is as defined in paragraph (36) above;L is as defined in paragraph (38) above;Bi , B2, B3, B4 and B5 are as defined in paragraph (41) above;Rs, R7 and Rs are as defined in paragraph (69) above; andRg and R10 are as defined in paragraph (72) above.

[0162] In any of the aforementioned embodiments wherein Bi, B2, B3, B4 and B5 are as defined in paragraph (41), Bi , B2, B3, B4 and B5 may instead be as defined in paragraph (41a) above. In any of the aforementioned embodiments wherein Bi , B2, B3, B4 and B5 are as defined in paragraph (41), Bi , B2, B3, B4 and B5 may instead be as defined in paragraph (41b) above. In any of the aforementioned embodiments wherein Bi , B2, B3, B4 and B5 are as definedin paragraph (41), Bi , B2, B3, B4 and B5 may instead be as defined in paragraph (41c) above. In any of the aforementioned embodiments wherein Bi , B2, B3, B4 and B5 are as defined in paragraph (41), Bi , B2, B3, B4 and B5 may instead be as defined in paragraph (41 d) above. In any of the aforementioned embodiments wherein Bi, B2, B3, B4 and B5 are as defined in paragraph (41), Bi , B2, B3, B4 and B5 may instead be as defined in paragraph (41 e) above.

[0163] Particular compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, include any of the following:5-Methyl-3-[3-(4-tetrahydropyran-4-ylphenyl)phenyl]pyridine-2-carboxylic acid;3-[3-[3-(trifluoromethyl)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3-[3-(trifluoromethyl)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid; 5-methyl-3-[3-[2-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid; 5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid; 5-Cyclopentyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid; 5-isopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid; 5-isobutyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-cyclobutyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;3-[3-[3-(Trifluoromethoxy)phenyl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxylic acid; 5-Chloro-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3'-(trifluoromethyl)-3-biphenylyl]-2-pyridinecarboxylic acid;3-(3'-chloro-4'-morpholino-3-biphenylyl)-5-cyclopropyl-2-pyridinecarboxylic acid;5-cyclobutyl-3-(3'-trifluoromethoxy-3-biphenylyl)-2-pyridinecarboxylic acid;3-(4'-hydroxy-3-biphenylyl)-5-isopropyl-2-pyridinecarboxylic acid; and 5-isopropyl-3-(4'-methoxy-3-biphenylyl)-2-pyridinecarboxylic acid.

[0164] In an embodiment, the compound is 5-cyclopropyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (50; MRT00264881).

[0165] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound of the formula (I) 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 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.Salts, isomers and prodrugs

[0166] 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 examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic 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.

[0167] 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”.

[0168] 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).

[0169] It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

[0170] 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 1 H, 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 and18O; and the like.

[0171] It is also to be understood that certain compounds of the Formula (I) 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 antiproliferative activity.

[0172] It is also to be understood that certain compounds of the Formula (I) may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

[0173] Compounds of the Formula (I) may exist in a number of different tautomeric forms and references to compounds of the Formula (I) 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). 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

[0174] Compounds of the Formula (I) containing an amine function may also form N- oxides. A reference herein to a compound of the Formula (I) 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, 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.

[0175] 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), or sub-formulae la to Id, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an aminogroup in a compound of the Formula (I), or sub-formulae la to Id.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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 (1-6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3- phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl 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 (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

[0180] 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 phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1- 10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C)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-1 -ylmethyl and 4-(1-4C)alkylpiperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0181] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to Id, 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 (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl]2amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0182] 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 (1-10C)alkanoyl 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-1 -ylmethyl and 4-(1-4C)alkyl)piperazin-1- ylmethyl.

[0183] 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 prodrug).

[0184] Though the present invention may relate to any compound 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 compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0185] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.Synthesis

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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 t-butoxycarbonyl group, an aryl methoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, forexample 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 terf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric 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.

[0193] 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.

[0194] 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 t-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.

[0195] Resins may also be used as a protecting group.

[0196] 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);(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or(iv) forming a prodrug thereof.

[0197] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups may be further reacted to change the nature of the group and provide an alternative compound of Formula (I).

[0198] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.

[0199] The compounds of Formula (I) may be synthesised by the general synthetic routes shown in the Examples section below, specific examples of which are described in more detail in the Examples.Pharmaceutical Compositions

[0200] 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, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0201] 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).

[0202] 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.

[0203] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0204] 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.

[0205] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I 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.

[0206] 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 to75 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

[0207] According to a further aspect of the present invention, there is provided a method of treating a microbial disease in which the inhibition of MptpB is beneficial, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0208] According to a further aspect of the present invention, there is provided a method of treating a microbial disease in which the activity of MptpB is implicated, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0209] According to a further aspect of the present invention, there is provided a method of treating a microbial infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0210] According to a further aspect of the present invention, there is provided a method of treating a mycobacterium infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0211] According to a further aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0212] According to a further aspect of the present invention, there is provided a method of treating pulmonary tuberculosis or non-tuberculous pulmonary disease, the method comprising administering to a subject a therapeutically effective amount of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0213] According to a further aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0214] According to a further aspect of the present invention, there is provided a method of treating a multidrug resistant Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0215] According to a further aspect of the present invention, there is provided a method of treating an extremely drug resistant Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0216] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in therapy.

[0217] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial.

[0218] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated.

[0219] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a microbial infection.

[0220] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a mycobacterium infection.

[0221] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection.

[0222] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a pulmonary tuberculosis or non-tuberculous pulmonary disease.

[0223] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a Mycobacterium tuberculosis infection.

[0224] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection.

[0225] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection.

[0226] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial.

[0227] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated.

[0228] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial infection.

[0229] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a mycobacterium infection.

[0230] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection.

[0231] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a pulmonary tuberculosis or non- tuberculous pulmonary disease.

[0232] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a Mycobacterium tuberculosis infection.

[0233] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection.

[0234] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection.

[0235] The compounds of the present invention may be used to treat any microbe that is known to be associated with MptpB activity and MptpB orthologue activity. The compounds of the invention may be used to treat an infection caused by any such microbes. Examples of infections that may be treated include infections caused by any one of the following: Mycobacterium sp. (e.g., Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycobacterium avium, Mycobacterium avium (paratuberculosis), Mycobacterium smegmatis, Mycobacterium vanbaalenii, Mycobacterium gilvum, Mycobacterium bovis, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium abscessus (e.g., ATCC 19977), Mycobacterium abscessus subspecies, Mycobacterium avium complex (intracellulare, avium, chimaera), Mycobacterium bovis, Mycobacterium kansasii, Mycobacterium ulcerans (Buruli), Mycobacterium marinum);Nocardia sp. (e.g., Nocardia farcinica);Acidovorax sp. (e.g., Acidovorax avenae subsp. Citrulli);Escherichia coli;Delftia sp. (e.g., Delftia acidovorans);Rhodopseudomonas sp. (e.g., Rhodopseudomonas palustris);Bradyrhizobium sp. (e.g. Bradyrhizobium japonicum);Lactobacillus sp. (e.g., Lactobacillus reuteri, Lactobacillus helveticus, Lactobacillus brevis, Lactobacillus acidophilus, Lactobacillus plantarum);Pseudomonas sp. (e.g., Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas entomophila, Pseudomonas fluorescens, Pseudomonas putida);Acinetobacter baumannii (e.g., ATCC 19606 or BAA 1605);Aspergillus sp. (e.g., Aspergillus clavatus, Aspergillus oryzae, Aspergillus fumigatus, Aspergillus terreus, Aspergillus oryzae);Bacillus sp. (e.g., Bacillus cereus subsp. Cytotoxis, Bacillus pumilus);Burkholderia sp.(Burkholderia pseudomallei and Burkholderia cepacea (B.cepacea));Desulfotalea sp. (e.g., Desulfotalea psychrophila);Streptomyces sp. (e.g., Streptomyces diastaticus Streptomyces coelicolor Streptomyces avermitilis);Salinispora sp. (e.g. Salinispora tropica, Salinispora arenicola);Novosphingobium sp. (e.g., Novosphingobium aromaticivorans);Rhodococcus sp.;Nocardia sp. (e.g., Nocardia farcinica);Erythrobacter sp. (e.g., Erythrobacter litoralis);Caulobacter sp. (e.g., Caulobacter crescentus);Sphingopyxis sp. (e.g., Sphingopyxis alaskensis);Klebsiella sp. (e.g., Klebsiella pneumoniae subsp. pneumoniae);Serratia sp. (e.g., Serratia proteamaculans);Erwinia sp. (e.g., Erwinia carotovora subsp. Atroseptica);Bdellovibrio sp. (e.g., Bdellovibrio bacteriovorus);Neosartorya sp. (e.g., Neosartorya fischeri);Clostridium sp. (e.g., Clostridium difficile, Clostridium auris, Clostridium perfringens);Ajellomyces sp. (e.g., Ajellomyces capsulata);Magnaporthe sp. (e.g., Magnaporthe grisea);Botryotinia sp. (e.g., Botryotinia fuckeliana);Sclerotinia sp. (e.g., Sclerotinia sclerotiorum);Yersinia sp. (e.g., Yersinia enterocolitica);Phaeosphaeria sp. (e.g., Phaeosphaeria nodorum);Providencia stuartii;Emericella sp. (e.g., Emericella nidulans);Pichia sp. (e.g., Pichia stipites, Pichia guilliermondii);Lodderomyces sp. (e.g., Lodderomyces elongisporus);Vanderwaltozyma sp. (e.g., Vanderwaltozyma polyspora);Candida sp. (e.g., Candida albicans, Candida auris);Debaryomyces sp. (e.g., Debaryomyces hansenii);Kluyveromyces sp. (e.g., Kluyveromyces lactis);Ashbya sp. (e.g., Ashbya gossypii);Neosartorya sp. (e.g., Neosartorya fischeri, Neurospora crassa);Coccidioides sp. (e.g., Coccidioides immitis);Emericella sp. (e.g., Emericella nidulans);Leishmania sp. (e.g., Leishmania infantum, Leishmania major (LM1));Magnaporthe sp. (e.g., Magnaporthe grisea);Ajellomyces sp. (e.g., Ajellomyces capsulate);Botryotinia sp. (e.g., Botryotinia fuckeliana);Sclerotinia sp. (e.g., Sclerotinia sclerotiorum);Phaeosphaeria sp. (e.g., Phaeosphaeria nodorum);Coccidioides sp. (e.g., Coccidioides immitis);Chaetomium sp. (e.g., Chaetomium globosum);Yarrowia sp. (e.g., Yarrowia lipolytica);Emericella sp. (e.g., Emericella nidulans);Trichomonas sp. (e.g., Trichomonas vaginalis);Methylibium sp. (e.g., Methylibium petroleiphilum);Janibacter sp.;Congregibacter sp. (e.g., Congregibacter litoralis);Acidiphilium sp. (e.g., Acidiphilium cryptum);Roseiflexus sp.;Frankia sp.;Salinispora sp. (e.g., Salinispora arenicola);Coprinopsis sp. (e.g., Coprinopsis cinerea Okayama);Faecalibacterium sp. (e.g., Faecalibacterium prausnitzii);Listeria sp. (e.g., Listeria monocytogenes - Lmo1800, Listeria monocytogenes - Lmo1935, Listeria innocua);Ralstonia sp. (e.g., Ralstonia eutropha);Stigmatella sp. (e.g., Stigmatella aurantiaca);Frankia sp. (e.g., Frankia alni);Ralstonia sp. (e.g., Ralstonia metallidurans, Ralstonia eutropha);Thermobifida sp. (e.g., Thermobifida fusca);Leifsonia sp. (e.g., Leifsonia xyli subsp. Xyli);Enterococcus sp. (e.g., Enterococcus faecalis and Enterococcus faecium);Acinetobacter sp. (e.g., acinetobacter baumanii (e.g., ATCC 19606 or BAA 1605));Enterobacteriacea sp.;Salmonella sp.;Salmonella enterica subsp. eterica ;Staphylococcus sp. (e.g., Staphylococcus aureus, Staphylococcus hominis, Staphylococcus epidermidis, Staphylococcus caprae);Shigella spp (e.g., dysenteriae);Morganella morgani;Prevotella intermedia;Porphyromonas gingivalis;Legionella pneumophila;Cryptococcus species; orStreptococcus sp. (e.g. Streptococcus pneumoniae).

[0236] In particular, the compounds of the present invention may be used to treat infections caused by any one of the following:Mycobacterium sp. (e.g., Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycobacterium avium, Mycobacterium avium (paratuberculosis), Mycobacterium smegmatis, Mycobacterium vanbaalenii, Mycobacterium gilvum, Mycobacterium bovis, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium abscessus (e.g., ATCC 19977));Lactobacillus sp. (e.g., Lactobacillus reuteri, Lactobacillus helveticus, Lactobacillus brevis, Lactobacillus acidophilus, Lactobacillus plantarum);Pseudomonas sp. (e.g., Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas entomophila, Pseudomonas fluorescens, Pseudomonas putida);Aspergillus sp. (e.g., Aspergillus clavatus, Aspergillus oryzae, Aspergillus fumigatus, Aspergillus terreus, Aspergillus oryzae);Bacillus sp. (e.g., Bacillus cereus subsp. Cytotoxis, Bacillus pumilus);Streptomyces sp. (e.g., Streptomyces diastaticus Streptomyces coelicolor Streptomyces avermitilis);Clostridium sp. (e.g., Clostridium difficile, Clostridium auris, Clostridium perfringens);Candida sp. (e.g., Candida albicans, Candida auris);Enterococcus sp. (e.g., Enterococcus faecalis);Acinetobacter sp. (e.g., acinetobacter baumanii (e.g., ATCC 19606 or BAA 1605)); Enterobacteriacea sp.;Salmonella sp.;Staphylococcus sp. (e.g., Staphylococcus aureus);Shigella; orStreptococcus sp. (e.g., Streptococcus pneumoniae).

[0237] In an embodiment, the compounds of the present invention may be used to treat infections caused by any one of the following:Mycobacterium sp. (e.g., Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycobacterium avium, Mycobacterium avium (paratuberculosis), Mycobacterium smegmatis, Mycobacterium vanbaalenii, Mycobacterium gilvum, Mycobacterium bovis, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium abscessus (e.g., ATCC 19977));Pseudomonas sp. (e.g., Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas entomophila, Pseudomonas fluorescens, Pseudomonas putida);Clostridium sp. (e.g., Clostridium difficile, Clostridium auris, Clostridium perfringens);Candida sp. (e.g. Candida albicans, Candida auris);Enterococcus sp. (e.g., Enterococcus faecalis);Acinetobacter sp. (e.g., acinetobacter baumanii (e.g., ATCC 19606 or BAA 1605));Enterobacteriacea sp.;Salmonella sp.;Staphylococcus sp. (e.g., Staphylococcus aureus);Shigella; orStreptococcus sp. (e.g., Streptococcus pneumoniae).

[0238] In a further embodiment, the compounds of the present invention may be used to treat infections caused by any one of the following:Mycobacterium sp. (e.g., Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycobacterium avium, Mycobacterium avium (paratuberculosis), Mycobacterium smegmatis, Mycobacterium vanbaalenii, Mycobacterium gilvum, Mycobacterium bovis, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium abscessus (e.g., ATCC 19977));Pseudomonas aeruginosa;Clostridium difficile;Candida auris;Enterococcus faecaium; acinetobacter baumanii (e.g., ATCC 19606 or BAA 1605);Enterobacteriacea;Salmonella sp.;Staphylococcus aureus;Shigella; orStreptococcus pneumoniae.

[0239] According to a further aspect of the present invention, there is provided a method of reducing I lowering inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, ora pharmaceutical composition as defined herein.

[0240] According to a further aspect of the present invention, there is provided a method of treating or preventing inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0241] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder associated with inflammation, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0242] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder in which the reduction I lowering of inflammation is beneficial, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0243] According to a further aspect of the present invention, there is provided a method of treating or preventing an inflammatory disease I disorder, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0244] According to a further aspect of the present invention, there is provided a method of treating or preventing a fungal disease I disorder I infection (i.e., mycosis), the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0245] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder I infection associated with fungi, the method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein.

[0246] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the reduction I lowering of inflammation.

[0247] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of inflammation.

[0248] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a disease I disorder associated with inflammation.

[0249] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of a disease I disorder in which the reduction I lowering of inflammation is beneficial.

[0250] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment or prevention of an inflammatory disease I disorder.

[0251] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a fungal disease I disorder / infection (i.e. , mycosis).

[0252] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease I disorder I infection associated with fungi.

[0253] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in in the reduction I lowering of inflammation.

[0254] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of inflammation.

[0255] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder associated with inflammation.

[0256] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder in which the reduction I lowering of inflammation is beneficial.

[0257] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of an inflammatory disease I disorder.

[0258] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a fungal disease I disorder I infection (i.e., mycosis).

[0259] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder I infection associated with fungi.

[0260] The inflammatory disease I disorder may be any disease I disorder associated with inflammation. For example, the inflammatory disease I disorder may be selected from the group consisting of: Acne vulgaris; acute inflammation; Addison’s disease; allergic reactions; allergies; Alzheimer’s disease; ankylosing spondylitis; aplastic anaemia; asthma; atherosclerosis; autoimmune vasculitis; cancer; celiac disease; chronic inflammatory demyelinating polyneuropathy (Cl DP); chronic obstructive pulmonary disease (COPD); colitis; diverticulitis; endometriosis; familial Mediterranean fever; fatty liver disease; glomerulonephritis; Grave’s disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; headaches, including chronic headaches and migraine; haemolytic anaemia; hidradenitis suppurativa; HIV and AIDS; hypersensitivity reactions; immune-mediated inflammatory disease (IMID); inflammatory bowel disease such as Crohn’s disease and ulcerative colitis; inflammatory myopathies; interstitial cystitis; leukocyte defects; lichen planus; mast cell activation syndrome; mastocytosis; mental health conditions where inflammation and / orautoimmunity is a co-morbid or causative factor, including; depression, schizophrenia, and anxiety; multiple sclerosis; myasthenia gravis; obesity; otitis; pain, including acute and chronic pain; Parkinson’s disease; pelvic Inflammatory disorder; peripheral ulcerative keratitis; pernicious anaemia; pharmacological inflammatory response; pneumonia; prostatitis; psoriasis; psoriatic arthritis; reperfusion injury; rheumatic fever; rheumatoid arthritis; rhinitis; sarcoidosis; scleroderma; Sjogren’s syndrome; systemic lupus erythematosus (SLE); transplant rejection syndrome; type I diabetes; type II diabetes; vasculitis; and vitiligo. Suitably, the inflammatory disease I disorder is selected from the group consisting of: Alzheimer’s disease; asthma, cancer; endometriosis; fatty liver disease; inflammatory bowel disease; Parkinson’s disease; rheumatoid arthritis; obesity; type I diabetes; and type II diabetes.

[0261] The fungal disease I disorder I infection (i.e. , mycosis) may be any disease I disorder / infection associated with fungi, such as superficial fungal infections, subcutaneous fungal infections and / or deep fungal infections. For example, the fungal disease I disorder I infection may be selected from the group consisting of: ringworm (dermatophytosis); onychomycosis; cryptococcus infections; candidiasis (e.g., vaginal, vulvovaginal, oropharyngeal and esophageal candidiasis); athlete’s foot; tinea versicolor / pityriasis versicolor; sporotrichosis (rose gardener’s disease); chromoblastomycosis; eumycetoma; mycetoma; histoplasmosis; paracoccidioidomycosis; coccidioidomycosis (Valley fever); blastomycosis; aspergillosis; urinary tract infections; periotonitis (e.g., Candida peritonitis); abscess; systemic Candida infections; pneumonia; candidemia; yeast infections; oral thrush; diaper rash; skin infections; candidal urinary tract infection; invasive candidiasis; pneumocystis pneumonia (PJP); mucormycosis; cryptococcosis; fungal nail infection; fungal eye infection; and talaromycosis (penicilliosis).Routes of Administration

[0262] 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).

[0263] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., by a patch, plaster, etc.); transmucosal (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

[0264] The compounds of the invention may be administered as the sole therapeutic agent, or they may be administered in combination with one or more additional anti-infective agents. The anti-infective agents selected may be, for example, the standard of care therapy for the infection concerned.

[0265] In one aspect, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein.

[0266] In another aspect, the present invention provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein.

[0267] In another aspect, the present invention provides a pharmaceutical product comprising a combination of the invention as defined herein in association with a pharmaceutically acceptable diluent or carrier. Accordingly, the present invention provides a pharmaceutical product comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0268] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein.

[0269] In another aspect, the present invention provides a pharmaceutical composition comprising a combination of the invention as defined herein in association with a pharmaceutically acceptable diluent or carrier. Accordingly, the present invention provides a pharmaceutical composition comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.Combination therapies with antibiotics

[0270] Antibiotics are an example of anti-infective agents useful in the present invention. The antibiotic may be selected from the following:(i) Penicillins (i.e., beta-lactam antibiotics), such as amoxicillin, amoxicillin / clavulanate, ampicillin, ampicillin / sulbactam dicloxacillin, oxacillin, penicillin V potassium, piperacillin / tazobactam, penicillin g benzathine, penicillin V, and nafcillin;(ii) Tetracyclines, such as demeclocycline, doxycycline, eravacycline, minocycline, omadacycline, oxytetracycline, sarecycline, and tetracycline;(iii) Cephalosporins, such as cefadroxil, cefazolin, cephradine, cephalexin, cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, loracarbef, cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftriaxone, cefepime, and ceftaroline;(iv) Fluoroquinolones, such as cinoxacin, ciprofloxacin, delafloxacin, qemifloxacin, levofloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, and sparfloxacin;(v) Lincomycins, such as clindamycin and lincomycin;(vi) Macrolides, such as azithromycin, clarithromycin, erythromycin, and fidaxomicin (ketolide);(vii) Sulfonamides, such as sulfacetamide topical, sulfadiazine, sulfamethoxazole / trimethoprim, sulfisoxazole, acetazolamide, bumetanide, celecoxib, chlorothiazide, chlorthalidone, dapsone, dorzolamide ophthalmic, furosemide, glibenclamide, gliclazide, glipizide, glyburide, hydrochlorothiazide (HCTZ), indapamide, probenecid, sulfasalazine, sumatriptan, and tolbutamide;(viii) Glycopeptides, such as dalbavancin, oritavancin, teicoplanin, telavancin, and vancomycin;(ix) Aminoglycosides, such as paromomycin, amikacin, gentamicin, streptomycin, neomycin, tobramycin, and plazomicin;(x) Carbapenems, such as imipenem, cilastatin, meropenem, and ertapenem;(xi) Ansamycins, such as geldanamycin, macbecin, herbimycin A, naphthomycin, ansatrienin(mycotrienin), 17-AAG, 17-DMAG, awamycin, ansathiazin, macbecin I, and rifamycins (e.g., rifampicin);(xii) Tuberculosis specific antibiotics, such as rifampicin, isoniazid, pyrazinamide, ethambutol, ethambutol hydrochloride;(xiii) Diarylquinolines, such as bedaquiline;(xiv) Oxazolidinones, such as linezolid; and(xv) Other antibiotics, such as delamanid.

[0271] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently anantibiotic, as defined herein. Suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0272] In another aspect, the present invention provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antibiotic, as defined herein.

[0273] In another aspect, the present invention provides a pharmaceutical product comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antibiotic, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0274] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antibiotic, as defined herein.

[0275] In another aspect, the present invention provides a pharmaceutical composition comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antibiotic, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0276] In a particular embodiment, each additional anti-infective agent is independently selected from the group consisting of clarithromycin, rifampicin, and ethambutol.

[0277] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti-infective agent is independently selected from the group consisting of clarithromycin, rifampicin, and ethambutol. Suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.Combination therapies with antifungals

[0278] Antifungals are another example of anti-infective agents useful in the present invention. The antifungal may be selected from the following:(i) Triazoles, such as fluconazole, itraconazole, posaconazole, and voriconazole;(ii) Imidazoles, such as clotrimazole, econazole nitrate, ketoconazole, tioconazole, and miconazole;(iii) Polyenes, such as amphotericin B and nystatin;(iv) Echinocandin antifungals, such as anidulafungin, caspofungin, and micafungin;(v) Other antifungals, such as flucytosine, griseofulvin, terbinafine, rezafungin, ibrexafungerp, olorofim, and fosmanogepix.

[0279] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antifungal, as defined herein. Suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0280] In another aspect, the present invention provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antifungal, as defined herein.

[0281] In another aspect, the present invention provides a pharmaceutical product comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antifungal, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0282] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antifungal, as defined herein.

[0283] In another aspect, the present invention provides a pharmaceutical composition comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an antifungal, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0284] In a particular embodiment, each additional anti-infective agent is independently selected from the group consisting of fluconazole, itraconazole, posaconazole, and voriconazole.

[0285] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one ormore additional anti-infective agents, wherein each additional anti-infective agent is independently selected from the group consisting of fluconazole, itraconazole, posaconazole, and voriconazole. Suitably, the anti-infective agent is voriconazole.

[0286] In a particular embodiment, each additional anti-infective agent is independently selected from the group consisting of flucytosine, griseofulvin, terbinafine, rezafungin, ibrexafungerp, olorofim, and fosmanogepix.

[0287] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti-infective agent is independently selected from the group consisting of flucytosine, griseofulvin, terbinafine, rezafungin, ibrexafungerp, olorofim, and fosmanogepix. Suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e. , 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.Combination therapies with anti-inflammatories

[0288] Anti-inflammatories are another example of anti-infective agents useful in the present invention. The anti-inflammatory may be selected from aminosalicylates and corticosteroids.

[0289] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an anti-inflammatory, as defined herein. Suitably, the compound of the invention is 5-cyclopropyl- 3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0290] In another aspect, the present invention provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an anti-inflammatory, as defined herein.

[0291] In another aspect, the present invention provides a pharmaceutical product comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an anti-inflammatory, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0292] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an anti-inflammatory, as defined herein.

[0293] In another aspect, the present invention provides a pharmaceutical composition comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently an anti-inflammatory, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0294] In embodiments wherein the inflammatory disease I disorder is inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, the anti-infective agent may be an anti-inflammatory, such as aminosalicylates and corticosteroids.Combination therapies with other anti-infective agents

[0295] Immunosuppressants, anti-TNFalpha drugs, JAK inhibitors, disease-modifying antirheumatic drugs (DMARDs), glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) are all examples of other anti-infective agents useful in the present invention.

[0296] Accordingly, the present invention provides a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently selected from the group consisting of immunosuppressants, anti-TNFalpha drugs, JAK inhibitors, DMARDs, glucocorticoids and NSAIDs, as defined herein. Suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e. , 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0297] In another aspect, the present invention provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently selected from the group consisting of immunosuppressants, anti- TNFalpha drugs, JAK inhibitors, DMARDs, glucocorticoids and NSAIDs, as defined herein.

[0298] In another aspect, the present invention provides a pharmaceutical product comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently selected from the group consisting of immunosuppressants, anti-TNFalpha drugs, JAK inhibitors, DMARDs, glucocorticoids and NSAIDs, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0299] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infectiveagent is independently selected from the group consisting of immunosuppressants, anti- TNFalpha drugs, JAK inhibitors, DMARDs, glucocorticoids and NSAIDs, as defined herein.

[0300] In another aspect, the present invention provides a pharmaceutical composition comprising a combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each anti-infective agent is independently selected from the group consisting of immunosuppressants, anti-TNFalpha drugs, JAK inhibitors, DMARDs, glucocorticoids and NSAIDs, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

[0301] In embodiments wherein the inflammatory disease I disorder is inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, the anti-infective agent may be selected from the group consisting of immunosuppressants, anti-TNFalpha drugs, and JAK inhibitors.

[0302] In embodiments wherein the inflammatory disease I disorder is rheumatoid arthritis, the anti-infective agent may be selected from the group consisting of DMARDs, glucocorticoids and NSAIDs.Administration

[0303] The conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment (e.g., the compound of the invention and each additional anti-infective agents). Such combination products employ the compounds of the present invention within the dosage range described herein and the anti- infective agent within its approved dosage range.

[0304] The term “combination” may refer to simultaneous, separate or sequential administration. In one aspect, “combination” refers to simultaneous administration. In another aspect, “combination” refers to separate administration. In a further aspect, “combination” refers to sequential administration. Where the administration is simultaneous, the individual components (e.g., the compound of the invention and each additional anti-infective agents) may be administered as a combined pharmaceutical composition or as separate formulations delivered at the same time. 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.

[0305] In certain embodiments, the pharmaceutical product / composition is provided as a single combined formulation, in which both the compound of the invention and each additional anti-infective agents are included in a single dosage form, where compatible. Such combinedformulations may include, for example, co-formulated tablets, capsules, injectable solutions, lyophilised powders for reconstitution, or any other suitable pharmaceutical dosage form.

[0306] In other embodiments, the pharmaceutical product / composition is provided as a kit of parts, wherein the compound of the invention and each additional anti-infective agents are supplied in separate formulations but are intended for conjoint use. The kit may include: i) a first container comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally together with one or more pharmaceutically acceptable excipients; and ii) a second container comprising each additional anti-infective agents, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally together with one or more pharmaceutically acceptable excipients.

[0307] The kit may further comprise written instructions setting out the recommended dosing regimen for the combined administration of the two agents. In certain embodiments, the kit may also include devices, such as syringes, oral dosing aids or prefilled pens, to facilitate administration.Therapeutic uses and applications of the combination therapies

[0308] According to an aspect of the present invention, there is provided a method of treating a microbial disease in which the inhibition of MptpB is beneficial, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0309] According to an aspect of the present invention, there is provided a method of treating a microbial disease in which the activity of MptpB is implicated, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0310] According to an aspect of the present invention, there is provided a method of treating a microbial infection, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product / composition comprising the combination, as defined herein.

[0311] According to an aspect of the present invention, there is provided a method of treating a mycobacterium infection, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product / composition comprising the combination, as defined herein.

[0312] According to an aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection ora non-tuberculous mycobacterium infection,the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0313] According to an aspect of the present invention, there is provided a method of treating pulmonary tuberculosis or non-tuberculous pulmonary disease, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0314] According to an aspect of the present invention, there is provided a method of treating a Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product / composition comprising the combination, as defined herein.

[0315] According to an aspect of the present invention, there is provided a method of treating a multidrug resistant Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0316] According to an aspect of the present invention, there is provided a method of treating an extremely drug resistant Mycobacterium tuberculosis infection, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0317] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in therapy.

[0318] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial.

[0319] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated.

[0320] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a microbial infection.

[0321] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a mycobacterium infection.

[0322] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection.

[0323] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a pulmonary tuberculosis or non-tuberculous pulmonary disease.

[0324] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a Mycobacterium tuberculosis infection.

[0325] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection.

[0326] According to an aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection.

[0327] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial.

[0328] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated.

[0329] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a microbial infection.

[0330] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a mycobacterium infection.

[0331] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium infection.

[0332] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a pulmonary tuberculosis or non-tuberculous pulmonary disease.

[0333] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a Mycobacterium tuberculosis infection.

[0334] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection.

[0335] According to an aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection.

[0336] The combinations, as defined herein, and the pharmaceutical products I compositions comprising the combinations, as defined herein, may be used to treat any microbe that is known to be associated with MptpB activity and MptpB orthologue activity. The combinations, as defined herein, and the pharmaceutical products I compositions comprising the combinations, as defined herein, may be used to treat an infection caused by any such microbes. Examples of infections that may be treated are described herein.

[0337] In the aforementioned therapeutic uses and applications, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti-infective agents is an antibiotic, as defined herein. Suitably, each antibiotic is independently selected from the group consisting of: penicillins, tetracyclines, cephalosporins, fluoroquinolones, lincomycins, macrolides, sulfonamides, glycopeptides, aminoglycosides,carbapenems, ansamycins, tuberculosis specific antibiotics, diarylquinolines, oxazolidinones, and other antibiotics, as defined herein. Most suitably, each antibiotic is independently selected from the group consisting of clarithromycin, rifampicin, and ethambutol. Accordingly, in the aforementioned therapeutic uses and applications, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti-infective agent is independently selected from the group consisting of clarithromycin, rifampicin, and ethambutol. Most suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0338] According to a further aspect of the present invention, there is provided a method of reducing I lowering inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product / composition comprising the combination, as defined herein.

[0339] According to a further aspect of the present invention, there is provided a method of treating or preventing inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0340] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder associated with inflammation, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0341] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder in which the reduction I lowering of inflammation is beneficial, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0342] According to a further aspect of the present invention, there is provided a method of treating or preventing an inflammatory disease I disorder, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0343] According to a further aspect of the present invention, there is provided a method of treating or preventing a fungal disease I disorder I infection (i.e., mycosis), the method comprising administering to a subject a therapeutically effective amount of acombination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0344] According to a further aspect of the present invention, there is provided a method of treating or preventing a disease I disorder I infection associated with fungi, the method comprising administering to a subject a therapeutically effective amount of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein.

[0345] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the reduction I lowering of inflammation.

[0346] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of inflammation.

[0347] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a disease I disorder associated with inflammation.

[0348] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a disease I disorder in which the reduction I lowering of inflammation is beneficial.

[0349] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of an inflammatory disease I disorder.

[0350] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a fungal disease I disorder / infection (i.e., mycosis).

[0351] According to a further aspect of the present invention, there is provided a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, for use in the treatment or prevention of a disease I disorder I infection associated with fungi.

[0352] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in in the reduction I lowering of inflammation.

[0353] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of inflammation.

[0354] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder associated with inflammation.

[0355] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder in which the reduction I lowering of inflammation is beneficial.

[0356] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of an inflammatory disease I disorder.

[0357] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a fungal disease I disorder I infection (i.e., mycosis).

[0358] According to a further aspect of the present invention, there is provided the use of a combination, as defined herein, or a pharmaceutical product I composition comprising the combination, as defined herein, in the manufacture of a medicament for use in the treatment or prevention of a disease I disorder I infection associated with fungi.

[0359] The inflammatory disease I disorder may be any one of those described herein.

[0360] The fungal disease / disorder / infection (i.e., mycosis) may be any one of those described herein.

[0361] In the aforementioned therapeutic uses and applications in relation to inflammatory diseases I disorders, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti-infective agent is an antibiotic, as defined herein. Suitably, each antibiotic is independently selected from the group consisting of: penicillins, tetracyclines, cephalosporins, fluoroquinolones, lincomycins, macrolides, sulfonamides, glycopeptides, aminoglycosides, carbapenems, ansamycins, tuberculosis specific antibiotics, diarylquinolines, oxazolidinones, and other antibiotics, as defined herein. Most suitably, each antibiotic is independently selected from the group consisting ofclarithromycin, rifampicin, and ethambutol. Accordingly, in the aforementioned therapeutic uses and applications in relation to inflammatory diseases I disorders, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti- infective agent is independently selected from the group consisting of clarithromycin, rifampicin, and ethambutol. Most suitably, the compound of the invention is 5-cyclopropyl-3- [3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0362] In the aforementioned therapeutic uses and applications in relation to inflammatory diseases I disorders, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-infective agents, wherein each additional anti-infective agent is an antiinflammatory, as defined herein. Suitably, each anti-inflammatory is independently selected from the group consisting of aminosalicylates and corticosteroids. Most suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine- 2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0363] In the aforementioned therapeutic uses and applications in relation to fungal diseases I disorders I infections, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti- infective agents, wherein each additional anti-infective agent is an antifungal, as defined herein. Suitably, each antifungal is independently selected from the group consisting of: triazoles; imidazoles; polyenes; echinocandin antifungals; and other antifungals, as defined herein. Suitably, each antifungal is independently selected from the group consisting of: fluconazole; itraconazole; posaconazole; voriconazole; clotrimazole; econazole nitrate; ketoconazole; tioconazole; miconazole; amphotericin B; nystatin; anidulafungin; caspofungin; micafungin; flucytosine, griseofulvin, terbinafine, rezafungin, ibrexafungerp, olorofim, and fosmanogepix. Most suitably, each antifungal is independently selected from the group consisting of: fluconazole; itraconazole; posaconazole; and voriconazole. Accordingly, in the aforementioned therapeutic uses and applications in relation to fungal diseases I disorders I infections, the combination suitably comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti- infective agents, wherein each additional anti-infective agent is independently selected from the group consisting: fluconazole; itraconazole; posaconazole; and voriconazole. Most suitably, the anti-infective agent is voriconazole. Most suitably, the compound of the invention is 5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (i.e., 4881), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0364] It will be understood that in the aforementioned therapeutic uses and applications, the combination may be administered simultaneously, sequentially, or separately.EXAMPLES

[0365] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.FiguresFigure 1. Study schedules for mouse (A) and guinea pig (B) tolerability and guinea pig efficacy (C) studies, [n] denotes number of animals involved.Figure 2. Study schedule for mouse efficacy study, [n] denotes number of animals involved.Figure 3. Overview of the chemical series, physicochemical and in-vitro DMPK profile of the representative compounds tested from series S3 in comparison with C13 (MRT00254683).Figure 4. Weight measurements in grams for all guinea pigs for the duration of the study. Eight guinea pigs from each of the three groups (CPD04881 , Rifampicin and untreated) are identified by individual identification number in legend. Animals were challenged with M. tuberculosis H37Rv at day 0. Treatment was given daily by passive oral delivery between 4 and 8 weeks post-challenge (in the chronic phase of disease).Figure 5. Clinical scoring of animals receiving treatment during the dosing time period.Figure 6. Bacterial burden (expressed as Log CFU / ml on the Y-axis) in lung and spleen, across the three groups (X axis), following treatment for 4 weeks, starting 4 weeks postchallenge after challenge and dosing. Points indicate individual animals, with means and standard deviations plotted as horizontal and vertical bars. Statistical analyses using Mann- Whitney test denoted as: ns: not significant, *: P<0.05 and **: P<0.01.Figure 7. Histopathology analyses measuring histopathology score in lung (A) and spleen (B), % area of lesions in both lung (C) and spleen (D), and number of necrotic foci in the lung (E). Points indicate individual animals, with means and standard deviations plotted as horizontal and vertical bars. Statistical analyses using Mann-Whitney test denoted as: ns: not significant, *: P<0.05, **: P<0.01 , and *** P<0.001.Figure 8. Weight of individual mice within treatment groups during the study period represented as total body weight in grams (g). Weight of individual mice receiving treatment of A - compound 04881 , B - clarithromycin, and C - untreated.Figure 9. Clinical scores of animals receiving treatment during the dosing period.Figure 10. Comparison of bacterial burden of M. avium infection within lung (A) and spleen (B) tissues of mice. Data is represented as median ± interquartile range. Statistical analysis shows multiple t tests with post-hoc Mann-Whitney test (P values: ns=>0.05, *=<0.05, **=<0.01).Figure 11. A. baumannii ATCC 19606. At 3-hour timepoint, a dose-response effect was seen with 4881 , where the highest concentrations (20-80 pM) show the most growth inhibition. CC is control untreated.Figure 12. A. baumannii BAA 1605. At 3-hour timepoint, a dose-response effect was seen with 4881 , where the highest concentrations (20-80 pM) show the most growth inhibition. CC is control untreated.Figure 13. M. abscessus ATCC 19977. A dose-response effect was seen with 4881 , where the highest concentrations performed well in this assay, particularly in terms of growth inhibition in a concentration dependent manner. CC is control untreated.Figure 14. Study schedule for mouse efficacy study, [n] denotes number of animals in each group. CLR denotes Clarithromycin, RIF denotes Rifampicin, and EMB denotes Ethambutol. *denotes groups where animals left the study early.Figure 15. Bacterial burden in lung and spleen. Data are expressed as CFU per gram of tissue (A and B) and CFU / mL of total tissue homogenate (C and D). The bacterial burden in the lung was measured immediately prior to treatment at 4 weeks post-infection (pre-treatment), and after 6 weeks of daily oral delivery of specific therapeutic regimens. Data are presented as box and whisker plots. Mann-Whitney statistical tests compare groups against Carrier only, and side-by-side comparison of standard of care regimen with and without the addition of 4881 (20mg / kg).*:P=<0.05, **:P=<0.01, ns: not statistically significant.Figure 16. Weight of individual mice within each group during the study period, represented as total body weight in grams (g):A - Untreated Day 1 post challenge necropsy;B - Untreated Week 4 post challenge necropsy;C - Carrier only - dashed plot shows animal 97742;D - 4881 (50 mg / kg);E - 4881 (20 mg / kg) - dashed plot shows animal 97595;F - Clarithromycin (100 mg / kg) - dashed plot shows animal 00481 , smaller (and lower) dashed plot shows animal 95497;G - Clarithromycin (100 mg / kg) + 4881 (20 mg / kg);H - Clarithromycin (100 mg / kg) + Ethambutol (100 mg / kg);I - Clarithromycin (100 mg / kg) + Ethambutol (100 mg / kg) + 4881 (20 mg / kg);J - Clarithromycin (100 mg / kg) + Rifampicin (10 mg / kg) - dashed plot shows animal 00292;K - Clarithromycin (100 mg / kg) + Rifampicin (10 mg / kg) + 4881 (20 mg / kg) - dashed plot shows animal 98008;L - Clarithromycin (100 mg / kg) + Rifampicin (10 mg / kg) + Ethambutol (100 mg / kg); andM - Clarithromycin (100 mg / kg) + Rifampicin (10 mg / kg) + Ethambutol (100 mg / kg) + 4881 (20 mg / kg).Figure 17. Clinical scores of groups 1-12.Figure 18. Histopathology analyses of lung and spleen. The histology scores were recorded as the lesion area represented as a percentage of the total tissue section of the lung (A) andspleen (B). Ziehl-Nelsen (ZN) staining was used to determine the % of mycobacteria staining within the lung (C) and spleen (D).Figure 19. Heatmap of cytokine / chemokine responses in sera from M. avium infected Balb / c mice under different treatment regimes. Cytokine and chemokine responses were normalised and presented in the heatmap as a fraction.Figure 20. A review of cytokine / chemokine responses towards M. avium infection and standard of care drug treatment.Figure 21 .Intracellular killing of A.fumigatus: A - % Internalised A. fumigatus killed using 4881 alone. B - % Internalised A. fumigatus killed using 4881 in combination with Voriconazole.Experimental MethodsMaterials and general methods

[0366] Reagents used were purchased from Aldrich, Activate Scientific, Fluorochem, Enamine and Apollo Scientific.1H and13C NMR spectra were obtained using a JEOL 500 MHz NMR spectrometer. HR-MS were obtained using a Thermo Fischer Q-Exactive. Normal phase purification was carried out on a Dalton Isolera Four using SNAP KP-Sil column (10 g to 50g) with a mobile phase from petroleum ether (PE), ethyl acetate (EA), dichloromethane (DCM) or methanol (MeOH) as specified. Reverse phase purification was carried out on a Dalton Isolera Four using a Biotage SNAP Ultra C18 column (12 g) with a mobile phase from methanol, acetonitrile, water (0.1 % TFA) and water (0.1 % NH3) as specified. The purity of all final tested compounds was established to be >95% by AgilentTechnologies 6120 quadrupole LC-MS by using acetonitrile and water (containing 0.1% TFA or 0.1% NH3 as specified) as the mobile phase (gradient 5-100% acetonitrile, flow rate 3 ml / min, runtime 3.20 mins), with UV monitoring at a wavelength of 254 nm.Organic SynthesisExample 1 - synthesis of 5-Methyl-3-[3-(4-tetrahydropyran-4-ylphenyl)phenyl]pyridine- 2-carboxylic acid (45; MRT00264582)Methyl 3-bromo-5-methyl-pyridine-2-carboxylate

[0367] 3-Bromo-5-methyl-pyridine-2-carboxylic acid (2.00 g, 9.26 mmol) was dissolved in methanol (10 ml) and sulfuric acid (2.74 ml, 46.3 mmol) was added. The reaction mixture was heated to 90 °C for 15 hours. The reaction mixture was neutralised through theaddition of sat. sodium bicarbonate solution (10 ml) and extracted with EtOAc (3x 10 ml). The combined organic extracts were passed through a phase separation cartridge and concentrated in vacuo to give methyl 3-bromo-5-methyl-pyridine-2-carboxylate (1.76 g, 82.8% Yield).1H NMR (500 MHz, DMSO-d6) 8.43 (1 H, d, J=1 .6 Hz) 8.09-8.06 (1 H, m), 3.85 (3H, s), 2.32 (3H, s);13C NMR (126 MHz, DMSO-d6) 166.05, 149.06, 147.20, 142.04, 138.18, 117.51 , 53.22, 17.75; LC-MS (MeCN, pH1) RT = 1.55 mins, MH+ = 230.1 / 232.0; HR-MS: M+ = 229.9817, C8H9BrNO2requires 229.9817.Methyl 3-(3-hydroxyphenyl)-5-methyl-pyridine-2-carboxylate

[0368] Methyl 3-bromo-5-methyl-pyridine-2-carboxylate (0.500g, 2.17 mmol), 3- hydroxyphenylboronic acid (0.330 g, 2.39 mmol), Pd(dppf)Cl2 (0.177 g, 0.217 mmol) and K3PO4 (0.951 g, 4.35 mmol) were dissolved in 1 ,4-dioxane (15 ml) and water (4 ml). Solution heated to 80 °C for 1 hour. The reaction mixture was dry loaded onto a 25 g silica column and purified by flash chromatography (gradient elution 20 to 50% ethyl acetate in petroleum ether) to give methyl 3-(3-hydroxyphenyl)-5-methyl-pyridine-2-carboxylate (0.430 g, 81.3% Yield).1H NMR (500 MHz, DMSO-d6) 9.60 (1 H, s), 8.45-8.37 (1 H, m), 7.74-7.67 (1 H, m), 7.22 (1 H, t, J=7.7 Hz), 6.79-6.76 (1 H, m), 6.74-6.69 (2H, m), 3.62 (3H, s), 2.36 (3H, s);13C NMR (126 MHz, DMSO-d6) 167.90, 157.99, 148.65, 146.77, 139.18, 138.65, 135.97, 135.52, 130.17, 119.14, 115.60, 115.40, 52.58, 18.18; LC-MS (MeCN, pH1) RT = 1.22 mins, MH+ = 244.2; HR-MS: M+ = 244.0970, C14H14NO3 requires 244.0974.Methyl 5-methyl-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate

[0369] Methyl 3-(3-hydroxyphenyl)-5-methyl-pyridine-2-carboxylate (0.430 g, 1.77 mmol) and pyridine (0.286 ml, 3.54 mmol) were combined in DCM (10 ml). Trifluoromethanesulfonic anhydride (1M in DCM) (1.86 ml, 1.86 mmol) added and stirred at RT overnight. 2M HCI (2.00 ml, 4.00 mmol) added and stirred for 5 minutes. The aqueous was extracted with DCM (2 x 10 ml) and the combined organic extracts were passed through a phase separation cartridge. Solution was dry loaded onto a 25 g silica column and purified by flash chromatography (gradient elution 0 to 50% ethyl acetate in petroleum ether) to give methyl 5-methyl-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate (0.430 g,64.8% Yield).1H NMR (500 MHz, DMSO-d6) 8.51 (1 H, d, J=2.9 Hz), 7.77 (1 H, d, J=2.9 Hz), 7.64 (1 H, t, J=7.7 Hz), 7.56-7.52 (1 H, m), 7.49-7.47 (1 H, m), 7.47-7.44 (1 H, m), 3.62 (3H, s), 2.39 (3H, s);13C NMR (126 MHz, DMSO-d6) 167.02, 149.62, 149.49, 146.01 , 141.01 , 39.39, 136.52, 134.47, 131.47, 129.30, 121.71 , 120.07, 117.53, 52.66, 18.16; LC-MS (MeCN, pH1) RT = 1.99 mins, MH+ = 376.1 ; HR-MS: M+ = 376.0467, C15H13F3NO5S requires 376.04675-Methyl-3-[3-(4-tetrahydropyran-4-ylphenyl)phenyl]pyridine-2-carboxylic acid (45)

[0370] Methyl 5-methyl-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate (0.150 g, 0.400 mmol), 4,4,5,5-tetramethyl-2-(4-tetrahydropyran-4-ylphenyl)-1 ,3,2- dioxaborolane (0.127 g, 0.440 mmol), Pd(dppf)Cl2 (0.033 g, 0.040 mmol) and K3PO4 (0.175 g, 0.800 mmol) were dissolved in 1 ,4-dioxane (2 ml) and water (0.3 ml). Solution heated to 80 °C for 30 minutes. The reaction mixture was dry loaded onto a 10 g silica column and purified by flash chromatography (gradient elution 0 to 50% ethyl acetate in petroleum ether) to give methyl 5-methyl-3-[3-(4-tetrahydropyran-4-ylphenyl)phenyl]pyridine-2-carboxylate as a residue. The residue was dissolved in DMSO (1 ml) and purified by reverse-phase flash chromatography (12 g C18 column, pH1 buffer, gradient elution from 10 to 80% acetonitrile) to give methyl 5-methyl-3-[3-(4-tetrahydropyran-4-ylphenyl)phenyl]pyridine-2-carboxylate (0.150 g, 0.387 mmol). The ester was dissolved in methanol (5 ml) and 2M NaOH (1.94 ml, 3.87 mmol) was added and the mixture stirred at RT for 30 minutes. The solvent was removed in vacuo before 2M HCI (3.87 ml, 7.74 mmol) was added and the aqueous extracted with EtOAc (2 x 10 ml). The combined organic extracts were passed through a phase separation cartridge and concentrated in vacuo to give 45 as a crystalline solid (0.120 g, 80.5% Yield).1H NMR (500 MHz, DMSO-d6) 8.44 (1 H, d, J=1 .6 Hz), 7.84 (1 H, d, J=1 .6 Hz), 7.67-7.64 (2H, m), 7.61 (2H, d, J=7.7 Hz), 7.51 (1 H, t, J=7.7 Hz), 7.39-7.36 (1 H, m), 7.34 (2H, d, J=7.7 Hz), 3.96-3.91 (2H, m), 3.46-3.39 (2H, m), 2.83-2.75 (1 H, m), 2.38 (3H, s), 1.73-1.62 (4H, m);13C NMR (126 MHz, DMSO-d6) 168.88, 148.24, 147.91 , 146.00, 140.85, 139.44, 138.78, 138.20, 135.63, 134.97, 129.73, 127.89 (2), 127.62, 127.41 (2), 126.99, 126.67, 67.82 (2), 40.84, 34.02 (2), 18.27; LC-MS (MeCN, pH1) RT = 1.41 mins, MH+ = 374.1 ; HR-MS: M+ = 374.1754, C24H24NO3 requires 374.1756.

[0371] Using an analogous synthetic methodology to Example 1 above, the following compounds were synthesised:Example 2 - 3-[3-[3-(trifluoromethyl)phenyl]phenyl]pyridine-2-carboxylic acid (43; MRT00262213)1H NMR (500 MHz, DMSO-d6) 13.39 (1 H, br s), 8.60 (1 H, dd, J=1.7, 4.5 Hz), 8.05-7.99 (3H, m), 7.80-7.76 (2H, m), 7.75-7.57 (2H, m), 7.62-7.54 (2H, m), 7.49-7.43 (1 H, m);13C NMR (126 MHz, DMSO-d6) 169.02, 151.15, 148.38, 141.35, 139.42, 139.08, 138.82, 134.78, 131.63, 130.68, 130.28, 129.97, 128.66, 127.50, 127.20, 125.84, 125.51 , 124.83, 123.85; LC-MS (MeCN, pH1) RT = 1.54 mins, MH+ = 344.1 ; HR-MS: M+ = 344.0896, C19H13NO2F3 requires 344.0898.Example 3 - 5-methyl-3-[3-[3-(trifluoromethyl)phenyl]phenyl]pyridine-2-carboxylic acid (44; MRT00265126)1H NMR (500 MHz, DMSO-d6) 13.13 (1 H, br s), 8.46-8.39 (1 H, m), 8.03-7.98 (2H, m), 7.84- 7.81 (1 H, m), 7.78-7.74 (2H, m), 7.73-7.67 (2H, m), 7.57-7.53 (1 H, m), 7.44-7.41 (1 H, m), 2.38 (3H, s);13C NMR (126 MHz, DMSO-d6) 169.02, 148.56, 148.10, 141.41 , 139.30, 139.28, 139.23, 135.45, 134.78, 131.50, 130.67, 130.43, 129.84, 128.62, 127.48, 127.08, 125.82, 124.86, 123.84, 18.31 ; LC-MS (MeCN, pH1) RT = 1.61 mins, MH+ = 358.1 ; HR-MS: M+ = 358.1052, C20H15NO2F3 requires 358.1055.Example 4 - 5-methyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (46; MRT00264531)1H NMR (500 MHz, DMSO-d6) 13.18 (1 H, br s), 8.45-8.43 (1 H, m), 7.87-7.82 (1 H, m), 7.77- 7.71 (3H, m), 7.69-7.67 (1 H, m), 7.60 (1 H, t, J=7.70 Hz), 7.55 (1 H, t, J=7.70 Hz), 7.44-7.41 (1 H, m), 7.39-7.36 (m, 1 H), 2.39 (3H, s);13C NMR (126 MHz, DMSO-d6) 168.97, 149.60, 148.58, 147.98, 142.78, 139.23, 139.13, 135.56, 134.64, 131.58, 129.96, 128.67, 127.33, 126.98, 126.49, 125.10, 121.66, 120.63, 119.92, 17.84; LC-MS (MeCN, pH1) RT = 2.03 mins, MH+ = 374.2; HR-MS: M+ = 374.0999, C20H15F3NO3 requires 374.1004.Example 5 - 5-methyl-3-[3-[2-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (47; MRT00264703)1H NMR (500 MHz, DMSO-d6) 13.16 (H, br s), 8.45-8.42 (1 H, m), 7.77-7.75 (1 H, m), 7.59-7.56 (1 H, m), 7.55-7.46 (6H, m), 7.45-7.42 (1 H, m), 2.37 (3H, s);13C NMR (126 MHz, DMSO-d6) 168.82, 151.74, 148.52, 148.00, 145.68, 139.04, 138.54, 136.72, 135.52, 134.58, 133.47, 132.20, 130.22, 129.29, 129.20, 129.00, 128.60, 128.25, 122.01 , 18.2; LC-MS (MeCN, pH1) RT = 1.67 mins, MH+ = 374.1 ; HR-MS: M+ = 374.0997, C20H15F3NO3 requires 374.1004.Example 6 - 5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (48; MRT00264704)1H NMR (500 MHz, DMSO-d6) 13.20 (1 H, m), 8.43-8.45 (1 H, m), 7.82 (2H, d, J=8.1 Hz), 7.72- 7.67 (2H, m), 7.54 (1 H, t, J=7.7 Hz), 7.45 (2H, d, J=8.2 Hz), 7.43-7.40 (1 H, m), 2.38 (3H, s);13C NMR (126 MHz, DMSO-d6) 169.03, 148.54, 148.10, 139.67, 139.47, 139.43, 139.17, 139.09, 135.47, 134.74, 129.85, 129.29(2), 128.31 , 128.24, 127.33, 126.93, 122.12(2), 18.29; LC-MS (MeCN, pH1) RT = 1.67 mins, MH+ = 374.1 ; HR-MS: M+ = 374.1001 , C20H15F3NO3 requires 374.1004.Example 7 - synthesis of 5-Cyclopentyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (51 ; MRT00264888) Methyl 3-bromo-5-chloro-pyridine-2-carboxylate

[0372] 3-Bromo-5-chloro-pyridine-2-carboxylic acid (3.00 g, 12.7 mmol) was dissolved in methanol (10 ml) and sulfuric acid (2.03 ml, 38.1 mmol) was added. The reaction mixture was heated to 90 °C for 3 hours. The reaction mixture was neutralised through the addition of sat. sodium bicarbonate solution (10 ml) and extracted with EtOAc (3x 10 ml). The combined organic extracts were passed through a phase separation cartridge and concentrated in vacuo to give methyl 3-bromo-5-chloro-pyridine-2-carboxylate (3.09 g, 97.2% Yield). 1 H NMR (500 MHz, DMSO-d6) 8.70 (1 H, d, J=2.0 Hz), 8.54 (1 H, d, J=2.0 Hz), 3.88 (3H, s); 13C NMR (126 MHz, DMSO-d6) 164.92, 148.63, 147.26, 141.46, 133.68, 117.88, 53.04; LC-MS (MeCN, pH1) RT = 1.52 mins, MH+ = 250.0 / 252.1 ; HR-MS: M+ = 249.9271 , C7H6BrCINO2requires 249.9270.Methyl 5-chloro-3-(3-hydroxyphenyl)pyridine-2-carboxylate

[0373] Methyl 3-bromo-5-chloro-pyridine-2-carboxylate (2.00 g, 7.98 mmol), 3- hydroxyphenylboronic acid (1.32 g, 9.58 mmol), Pd(dppf)Ch (0.652 g, 0.798 mmol) and K3PO4 (3.49 g, 16.0 mmol) were dissolved in 1 ,4-dioxane (15 ml) and water (4 ml). Solution heated to 80 °C for 2 hours. The reaction mixture was dry loaded onto a 25 g silica column and purified by flash chromatography (gradient elution 0 to 40% ethyl acetate in petroleum ether) to give methyl 5-chloro-3-(3-hydroxyphenyl)pyridine-2-carboxylate (1.35 g, 64.1% Yield).1H NMR (500 MHz, DMSO-d6) 9.68 (1 H, s), 8.65 (1 H, d, J=2.3 Hz), 8.07 (1 H, d, J=2.3 Hz), 7.24 (1 H, t, J=7.7 Hz), 6.84-6.80 (1 H, m), 6.79-6.76 (1 H, m), 6.76-6.74 (1 H, m), 3.65 (3H, s);13C NMR (126 MHz, DMSO-d6) 167.13, 158.11 , 147.63, 146.91 , 137.95, 137.61 , 137.39, 133.21 , 130.39, 119.24, 116.15, 115.30, 52.99; LC-MS (MeCN, pH1) RT = 1.05 mins, MH+ = 264.1 ; HR-MS: M+ = 264.0426, C13H11CINO3 requires 264.0427.Methyl 5-chloro-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate

[0374] Methyl 5-chloro-3-(3-hydroxyphenyl)pyridine-2-carboxylate (1.35 g, 5.12 mmol) and pyridine (0.828 ml, 10.2 mmol) were combined in DCM (20 ml). Trifluoromethanesulfonic anhydride (1M in DCM) (6.14 ml, 6.14 mmol) added and stirred at RT overnight. 2M HCI (7.00 ml, 14.0 mmol) added and stirred for 30 minutes. The aqueous was extracted with DCM (2 x 10 ml) and the combined organic extracts were passed through a phase separation cartridge. Solution was dry loaded onto a 25 g silica column and purified by flash chromatography (gradient elution 0 to 50% ethyl acetate in petroleum ether) to givemethyl 5-chloro-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate (1.81 g, 89.3% Yield).1H NMR (500 MHz, DMSO-d6) 8.75 (1 H, d, J=2.3 Hz), 8.17 (1 H, d, J=2.3 Hz), 7.68- 7.63 (1 H, m), 7.59-7.56 (2H, m), 7.53-7.50 (1 H, m), 3.64 ( 3H, s);13C NMR (126 MHz, DMSO- d6) 166.29, 149.69, 147.88, 146.97, 139.40, 138.83, 136.19, 133.58, 131.58, 129.54, 122.10, 121.89, 120.04, 53.02; LC-MS (MeCN, pH1) RT = 2.01 mins, MH+ = 396.1 ; HR-MS: M+ = 395.9920, C14H10CIF3NO5S requires 395.9920.Methyl 5-chloro-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylate

[0375] Methyl 5-chloro-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate (1.81 g, 4.57 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (1.04 g, 5.03 mmol), Pd(dppf)Cl2 (0.373 g, 0.457 mmol) and K3PO4 (2.00 g, 9.15 mmol) were dissolved in 1 ,4-dioxane (10 ml) and water (2 ml). Solution heated to 80 °C for 2 hours. The reaction mixture was dry loaded onto a 25 g silica column and purified by flash chromatography (gradient elution 0 to 20% ethyl acetate in petroleum ether) to give methyl 5-chloro-3-[3-[3- (trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylate (1.15 g, 61.7% Yield). Material purity 60-70%. Not purified further and used crude in subsequent reactions.1H NMR (500 MHz, DMSO-d6) 8.71 (1 H, d, J=2.3 Hz), 8.31 (1 H, d, J=2.3 Hz), 7.81-7.77 (3H, m), 7.74-7.72 (1 H, m), 7.61 (1 H, t, J=8.0 Hz), 7.57 (1 H, t, J=7.7 Hz), 7.41-7.35 (2H, m), 3.65 (3H, s);13C NMR (126 MHz, DMSO-d6) N / A, used crude; LC-MS (MeCN, pH1) RT = 2.16 mins, MH+ = 408.1 ; HR-MS: M+ = 408.0615, C20H14CIF3NO3 requires 408.0614.5-Cyclopentyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (51)

[0376] Methyl 5-chloro-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylate(0.090g, 0.221 mmol, Pd(dppf)Ch (0.018 g, 0.0221 mmol) was dissolved in 1 ,4-dioxane (1 ml) and the reaction mixture was degassed and placed under a nitrogen atmosphere, cyclopentylzinc bromide (0.5 mol / L in THF) (0.880 ml, 0.441 mmol) was added and the reaction mixture was heated to 70 °C for 1 hour. The reaction mixture was dry loaded onto a 10 g silica column and purified by flash chromatography (gradient elution 0 to 40% ethyl acetate in petroleum ether) to give a coloured residue. The residue was dissolved in DMSO (1 ml) and purified by reverse-phase flash chromatography (12 g C18 column, pH1 buffer,gradient elution from 10 to 80% acetonitrile) to give methyl 5-cyclopentyl-3-[3-[3- (trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylate (0.080 g, 82.1% Yield) as a colourless residue. The residue was dissolved in methanol (5 ml) and 2M NaOH (0.680 ml, 1.36 mmol) was added and the mixture stirred at RT for 1 hour. Solvent removed in vacuo before 2M HCI (1.36 ml, 2.72 mmol) and the aqueous extracted with EtOAc (2 x 10 ml). The combined organic extracts were passed through a phase separation cartridge and concentrated in vacuo to give 50 as a crystalline solid (0.020 mg, 27.9% Yield).1H NMR (500 MHz, DMSO-d6) 8.50 (1 H, d, J=2.1 Hz), 7.83 (1 H, d, J=2.1 Hz), 7.76-7.71 (3H, m), 7.67 (1 H, br s), 7.60 (1 H, t, J=7.7 Hz), 7.55 (1 H, t, J=7.7 Hz), 7.46-7.42 (1 H, m), 7.39-7.35 (1 H, m), 3.09 (1 H, quin, J=8.5 Hz), 2.12- 2.02 (2H, m), 1.83-1.73 (2H, m), 1.68-1.59 (4H, m);13C NMR (126 MHz, DMSO-d6) 169.14, 149.58, 148.33, 147.23, 143.46, 142.60, 139.26, 139.20, 137.11 , 134.90, 131.44, 129.83, 128.69, 127.38, 126.98, 126.55, 121.89, 120.66, 120.07, 43.01 , 34.20 (2), 25.42 (2); LC-MS (MeCN, pH1) RT = 1.32 mins, MH+ = 428.2; HR-MS: M+ = 428.1476, C24H21F3NO3 requires 428.1474.

[0377] Using an analogous synthetic methodology to Example 1 above, the following compounds were synthesised:Example 8 - 5-isopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (49; MRT00262212)1H NMR (500 MHz, DMSO-d6) 8.53-8.46 (1 H, m), 7.84-7.81 (1 H, m), 7.76-7.69 (3H, m), 7.66 (1 H, s), 7.59 (1 H, t, J=7.7 Hz), 7.55 (1 H, t, J=7.7 Hz), 7.44 (1 H, d, J=7.7 Hz), 7.37 (1 H, d, J=7.7 Hz), 3.04 (1 H, spt, J=6.9 Hz), 1.27 (6H, d, J=6.9 Hz);13C NMR (126 MHz, DMSO-d6) 169.02, 149.54, 148.70, 146.96, 145.63, 142.81 , 139.30, 139.23, 136.58, 134.87, 131.58, 129.96, 128.79, 127.48, 127.05, 126.57, 121.70, 120.68, 120.03, 31.60, 23.84 (2); LC-MS (MeCN, pH1) RT = 1.20 mins, MH+ = 402.0; HR-MS: M+ = 402.1318, C22H19NO3F3 requires 402.1317.Example 9 - Analytical data for 5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid (50; MRT00264881)1H NMR (500 MHz, DMSO-d6) 13.12 (1 H, br s), 8.41 (1 H, d, J=2.3 Hz), 7.77-7.69 (3H, m), 7.68-7.66 (1 H, br s), 7.60 (1 H, t, J=7.7 Hz), 7.56 (1 H, d, J=2.3 Hz), 7.53 (1 H, t, J=7.7 Hz), 7.42 (1 H, d, J=7.7 Hz), 7.39-7.35 (1 H, m), 2.10-2.02 (1 H, m), 1.08-1.01 (2H, m), 0.93-0.87 (2H, m);13C NMR (126 MHz, DMSO-d6) 168.87, 149.55, 146.16, 142.61 , 141.92, 139.38, 139.04, 135.09, 134.53, 131.44, 129.72, 128.69, 127.49, 126.96, 126.58, 121.72, 121.46, 120.62, 120.04, 13.21 , 10.50 (2); LC-MS (MeCN, pH1) RT = 1.85 mins, MH+ = 400.2; HR-MS: M+ = 400.1162, C22H17F3NO3 requires 400.1161.Example 10 - 5-isobutyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid (52; MRT00265043)1H NMR (500 MHz, DMSO-d6) 13.21 (1 H, br s), 8.42 (1 H, d, J=1 .7 Hz), 7.81 (1 H, d, J=1 .7 Hz), 7.77-7.70 (3H, m), 7.68 (1 H, br s), 7.60 (1 H, t, J=7.7 Hz), 7.55 (1 H, t, J=7.7 Hz), 7.46-7.42 (1 H, m), 7.40-7.35 (1 H, m), 2.57 (2H, d, J=7.1 Hz), 1.96-1.87 (1 H, m), 0.88 (6H, d, J=6.3 Hz);13C NMR (126 MHz, DMSO-d6) 168.94, 149.52, 148.72, 148.51 , 142.76, 139.24, 139.17, 139.08, 138.75, 134.75, 131.50, 129.86, 128.71 , 127.43, 127.07, 126.61 , 121.65, 120.63, 120.09, 41.46, 29.83, 22.54 (2); LC-MS (MeCN, pH1) RT = 1.31 mins, MH+ = 416.2; HR-MS: M+ = 416.1473, C23H21 F3NO3 requires 416.1474.Example 11 - 5-cyclobutyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2- carboxylic acid (53; MRT00266860)1H NMR (500 MHz, DMSO-d6) 8.47 (1H, d, J=1.9 Hz), 7.84 (1H, d, J=1.9 Hz), 7.76-7.72 (3H, m), 7.67 (1H, br s), 7.62-7.57 (1 H, m), 7.57-7.53 (1 H, m), 7.46-7.43 (1 H, m), 7.39-7.35 (1H, m), 3.65 (1H, quin, J=8.9 Hz), 2.31 (2H, s), 2.25-2.16 (2H, m), 2.05-1.96 (1 H, m), 1.88-1.78 (1 H, m);13C NMR (126 MHz, DMSO-d6) 168.94, 149.50, 148.43, 142.96, 142.76, 139.25, 139.15, 136.71 , 134.99, 131.48, 129.70, 128.83, 127.47, 126.93, 126.40, 121.74, 120.59, 120.08, 119.62, 37.34, 29.67 (2), 18.52; LC-MS (MeCN, pH1) RT = 1.97 mins, MH+ = 414.1; HR-MS: M+ = 414.1314, C23H19F3NO3 requires 414.1317.Example 12 - 3-[3-[3-(Trifluoromethoxy)phenyl]phenyl]-5-(trifluoromethyl)pyridine-2- carboxylic acid (54; MRT00264880)5-(T rifluoromethyl)-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate (0.080 g, 0.186 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (0.046 g, 0.224 mmol), Pd(dppf)Cl2 (0.015 g, 0.0186 mmol) and K3PO4 (0.082 g, 0.373 mmol) were dissolved in 1 ,4-dioxane (2 ml) and water (0.3 ml). Solution heated to 80 °C for 2 hours. The reaction mixture was dry loaded onto a 10 g silica column and purified by flash chromatography (gradient elution 0 to 30% ethyl acetate in petroleum ether) to give methyl 3-[3-[3-(trifluoromethoxy)phenyl]phenyl]- 5-(trifluoromethyl)pyridine-2-carboxylate as a residue. The residue was dissolved in DMSO (1 ml) and purified by reverse-phase flash chromatography (12 g C18 column, pH1 buffer,gradient elution from 10 to 80% acetonitrile) to give methyl 3-[3-[3- (trifluoromethoxy)phenyl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxylate (0.050 g, 0.113 mmol). The ester was dissolved in methanol (5 ml) and 2M NaOH (1.94 ml, 3.87 mmol) was added and the mixture stirred at RT for 30 minutes. The solvent was removed in vacuo before 2M HCI (3.87 ml, 7.74 mmol) was added and the aqueous extracted with EtOAc (2 x 10 ml). The combined organic extracts were passed through a phase separation cartridge and concentrated in vacuo to give 54 as a crystalline solid (0.060 g, 71.7% Yield).1H NMR (500 MHz, DMSO-d6) 9.04-9.00 (1 H, m), 8.47 (1 H, d, J=2.3 Hz), 7.86-7.84 (1 H, m), 7.82-7.77 (2H, m), 7.72 (1 H, br s), 7.64-7.57 (2H, m), 7.55-7.52 (1 H, m), 7.41-7.36 (1 H, m);13C NMR (126 MHz, DMSO-d6) 168.23, 154.81 , 149.51 , 145.18, 142.44, 139.41 , 137.25, 136.33, 134.75, 131.50, 130.08, 128.83, 127.86, 127.67, 126.64, 126.44, 124.90, 122.71 , 120.67, 120.15; LC- MS (MeCN, pH1) RT = 1.99 mins, MH+ = 427.1 ; HR-MS: M+ = 428.0723, C2OHI2F6N03 requires 428.0721.Example 13 - synthesis of 5-Chloro-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine- 2-carboxylic acid (55; MRT00264889)Methyl 5-chloro-3-[3-(trifluoromethylsulfonyloxy)phenyl]pyridine-2-carboxylate (1.81 g, 4.57 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (1.04 g, 5.03 mmol), Pd(dppf)CI2(0.373 g, 0.457 mmol) and K3PO4 (2.00 g, 9.15 mmol) were dissolved in 1 ,4-dioxane (10 ml) and water (2 ml). Solution heated to 80 °C for 2 hours. The reaction mixture was dry loaded onto a 25 g silica column and purified by flash chromatography (gradient elution 0 to 20% ethyl acetate in petroleum ether) to give methyl 5-chloro-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2- carboxylate (1.15 g, 2.82 mmol). A 100 mg sample of 5-chloro-3-[3-[3- (trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylate was dissolved in DMSO (1 ml) and purified by reverse-phase flash chromatography (12 g C18 column, pH1 buffer, gradient elution from 10 to 80% acetonitrile) to give methyl 3-[3-[3-(trifluoromethoxy)phenyl]phenyl]-5- (trifluoromethyl)pyridine-2-carboxylate (0.090 g, 0.221 mmol). The ester was dissolved in methanol (5 ml) and 2M NaOH (1.10 ml, 2.21 mmol) was added and the mixture stirred at RT for 30 minutes. The solvent was removed in vacuo before 2M HCI (2.21 ml, 4.41 mmol) wasadded and the aqueous extracted with EtOAc (2 x 10 ml). The combined organic extracts were passed through a phase separation cartridge and concentrated in vacuo to give 55 as a crystalline solid (0.060 g, 69.1% Yield).1H NMR (500 MHz, DMSO-d6) 13.58 (1 H, br s), 8.67 (1 H,d, J=2.3 Hz), 8.24 (1 H, d, J=2.3 Hz), 7.81-7.76 (3H, m), 7.73-7.71 (1 H, m), 7.60 (1 H, t, J=8.0 Hz), 7.57 (1 H, t, J=7.7 Hz), 7.49-7.47 (1 H, m), 7.40-7.36 (1 H, m);13C NMR (126 MHz, DMSO-d6) 13C NMR (126 MHz, DMSO-d6) 168.77, 149.00, 148.90, 147.76, 146.45, 145.52, 139.41 , 138.09, 135.87, 135.69, 134.79, 134.14, 133.75, 131.96, 130.29, 129.87, 129.58, 127.47, 122.06; LC-MS (MeCN, pH1) RT = 1.97 mins, MH+ = no ion; HR-MS: M+ = no ion, C19H12CIF3NO3 requires 394.0458.MptpB Inhibition assay

[0378] A duplicated 10-point dose response curve was acoustically dispensed (ECHO,Labcyte UK) from 10 mM compound stocks in 100% DMSO. Compounds were transferred into a black low volume 384 well microplate (Corning 3820) in a 3.16-fold dilution series with a top concentration of 10pM. Up to 50 nl of DMSO was added to normalise well concentrations across the plate including control wells. A final concentration of 500 pM previously purified MptpB was added to each well in freshly prepared reaction buffer (20 mM Bis-Tris propane pH 7, 50 mM NaCI, 1 mM TCEP, 0.01% BSA & 0.01 %v / v Brij35) in a volume of 4 pl. Columns 23 and 24 were kept as no enzyme negative controls. The plates were incubated at 22 °C for 45 min to equilibrate. The reaction was initiated by the addition of 1 pl 500 pM DiFMUP (6,8- difluoro-4-methylumbelliferyl phosphate, Thermo Fisher) to each well giving a final reaction volume of 5 pl and substrate concentration of 100 pM. The plate was equilibrated by centrifugation at 1000xRCF for 2min. the plate was then incubated for 13 min at 22 °C. The reaction was terminated by the addition of 2.5 pl 2M NaOAc pH 2. Fluorescence was recorded using a Clariostar plate reader (BMG Labtech, UK) at excitation 360 nm / emission 460 nm and converted to percent activity against control wells. Data were transformed using Activity base (IDSB, UK) and pICso values determined.

[0379] The plC50 values obtained for the exemplified compounds are shown in Table A below:Table AInfection studiesBacterial strains and cell culture growth conditions

[0380] THP1 and J774A.1 monocyte / macrophage cell lines (ATCC) were cultured in Roswell Park Memorial Institute- 1640 medium (RPMI) (R8758-Sigma-Aldrich) containing L- glutamine supplemented with 10% heat inactivated fetal bovine serum (FBS, Invitrogen) at 37 °C in 5% CO2. Mtb strain H37Rv, was grown on Middlebrook 7H9 broth (BD Diagnostics) at 37 °C in 5% CO2 or Middlebrook 7H10 agar, both supplemented with 0.05% Tween 80, 0.2% glycerol and 10% OADC (Oleic Albumin Dextrose Catalase from Becton Dickinson Microbiology Systems). Starter cultures were prepared adding 1 ml of mid-log phase Mtb stock into 20 ml of fresh Middlebrook 7H9 broth and incubated static for 4 to 6 days prior to being used in infection or extracellular assays.Cytotoxicity assays

[0381] MTT assay, a colorimetric assay using the tetrazolium dye MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was performed as described previously (Mosmann, 1983). J774A.1 macrophages were seeded in 96-well cell culture plates, flat bottom (Corning) at a density of 6 x 103cells (in 200 pl RPMI with FBS 1%) and left to adhere overnight. The following day media was removed and fresh RPMI (FBS 1 %) was added with inhibitors dissolved in DMSO. At 24 h media was removed, cells were washed twice with Dulbecco’s PBS and fresh RPMI was added with inhibitors. After 48 h, cells were washed once with PBS and 200 pl of fresh RPMI was added (without inhibitors). At 72 h, media was removed and changed for 200 pl of fresh RPMI. Cell viability was assessed by adding 50 pl of filter sterilised MTT (5 mg / ml in PBS) to each well followed by a 2 h incubation period at 37 °C in 5% CO2. Media was removed and the blue formazan crystals trapped in the cells were dissolved by adding 200 pl of DMSO and 25 pl of Sorensen’s glycine buffer. The absorbance at 570 nm was measured in a plate reader. Controls without the inhibitors were included: anegative control was DMSO at 0.1 %, 0.3% or 0.8% concentration and a control with RPMI media only. Data is plotted as percentage of macrophage viability at 72 h relative to the control RPMI media only. Each assay was performed in triplicate in at least three independent experiments.Mycobacterial extracellular growth measurements

[0382] Extracellular growth was monitored by optical density (OD) and CFU determinations.

[0383] The effect of MptpB inhibitors on Mtb extracellular growth was assessed by adding 10 pM of the compounds in 25 ml of Middlebrook 7H9 broth containing ~ 4.4 x 107CFUs. Compounds were added only in day 0 and culture was grown statically over 9 days at 37 °C in 5% CO2. Mycobacterial growth was monitored by OD at 600 nm. The negative control was DMSO at 0.1 % without inhibitors. Statistical significance was evaluated by two-way ANOVA followed by a multiple comparison analyses of variance by Bonferroni test (GraphPad Prism 7.01 for Windows). Differences were considered significant at the 95% level of confidence. For all extracellular cultures, experiments were performed in triplicate in at least two independent experiments. Linear regression and the coefficient of determination (R2) were used to test the relationship of two variables, calculated by GraphPad Prism 7.01 for Windows.Macrophage infections

[0384] The effect of MptpB compounds on the intracellular growth of Mtb strain was measured by CFU determination. THP1 cells were seeded in 24-well cell culture plates, flat bottom (Corning) at a density of 1 x 105cells per well (in 500 pl media) and treated with 200 nM PMA (phorbol 12-myristate-13-acetate) for 2 h to differentiate them into adherent, wellspread macrophages. After treatment, media was changed for fresh RPMI (with 10% FBS) and cells incubated overnight. The following day, media was removed and cells were washed with PBS and 500 pl of fresh RPMI was added containing either inhibitors. Next, cells were infected with Mtb at a multiplicity of infection (MOI) of 5:1 (bacteria:macrophage). After 4 h of infection, THP1 cells were washed three times with PBS and fresh RPMI was added containing the compounds. After 24 h, media was removed and cells were washed twice with PBS prior to the addition of RPMI containing the compounds. At 72 h post infection cells were lysed with ice-cold water, serially diluted in PBS containing 0.05% Tween 80 and plated onto 7H 10 agar along with the cell-pelleted supernatants. Colonies were counted after 14 days. All experimental points were plated as 10-fold dilutions in triplicate in at least two independent experiments. Data is plotted as percentage of Mtb survival calculated from the average CFU / ml at 72 h. A negative control containing DMSO at 0.1 % - 0.8% concentration was included. Statistical significance was evaluated by one-way ANOVA followed by a multiplecomparison analyses of variance by Dunnett’s test (GraphPad Prism 7.01 for Windows). Differences were considered significant at the 95% level of confidence.Cocktail doses

[0385] The minimum inhibitory concentrations (MIC) reported for isoniazid (H) and rifampicin (R) (Suo et al., 1988) were selected as the starting point to choose the doses of H and R to be used in the cocktail. Pyrazinamide (Z) was chosen at a concentration 10 times lower its MIC (Salfinger and Heifets, 1988). Starting with a stock of HRZ comprising H at 0.25 pg / ml, R at 0.5 pg / ml and Z at 5 pg / ml all dissolved in DMSO, serial dilutions were performed using sterile distilled water. Serial dilutions were tested in macrophages infected with Mtb H37Rv as explained above.Animal studies. Efficacy in vivo

[0386] The work consisted of three separate studies. The first two studies examined the tolerability of a MptpB inhibitor compound in both mice and guinea pigs in preparation for use in efficacy studies. The third study evaluated the efficacy of the inhibitor compound in the guinea pig model of chronic tuberculosis disease.

[0387] The University of Manchester provided UKHSA (UK Health Security Agency) with a compound candidate for tolerability testing and evaluation of efficacy. UKHSA performed a series of studies to determine the tolerability and efficacy of the compound. The compound had demonstrated efficacy in in vitro experiments against mycobacteria. These studies were designed to confirm efficacy in vivo.

[0388] In the tolerability studies, six guinea pigs and five mice, were each dosed daily, by the oral route of delivery, for seven days, with the compound. Animals were monitored throughout the studies and histopathological analyses were performed to determine tolerability.

[0389] Once tolerability had been confirmed, guinea pigs were infected by the aerosol route Mycobacterium tuberculosis strain H37Rv. Four weeks following infection, guinea pigs were treated with the compound, once daily by the oral route. Efficacy of the compound was measured by a reduction in bacterial burden and pathology, compared to control groups, during chronic tuberculosis disease in guinea pigs.Methods

[0390] The study was conducted according to UK Home Office Legislation for animal experimentation under a Project Licence (P9EFCFD9C) that was approved by a local animal welfare and ethical review body (AWERB) at PHE Porton. Ten adult female Balb / c mice aged eight weeks and forty-eight female adult Dunkin-Hartley guinea pigs (300-400g in weight), freefrom pathogen-specific infection, were purchased from an approved supplier (Envigo, UK) and used in these studies. Group sizes for the efficacy study were determined by statistical power calculations (Minitab version 16) performed on previous data with the aim to reliably detect a difference between the mean colony forming units (CFU) per ml of homogenised tissue of 1.0 log (SD: 0.69; confidence: 95%; Power: 80).

[0391] Individual animals were randomly assigned to groups; mice and guinea pigs were subcutaneously administered RFID microchips to uniquely identify each animal and enable blinding of the analyses wherever possible. Throughout the study the animals were housed in the Biological Investigations Group (BIG) facility and had free access to chow and water. The rooms meet the Home Office guidelines for environmental control. The health and welfare of each animal was monitored and assessed regularly.

[0392] The agreed study schedules were as follows (see Figure 1):(A) Mouse tolerability study Groups [n=5]1) 100mg / kg compound 4881(B) Guinea pig tolerability study Groups [n=6]1) 100mg / kg compound 4881(C) Guinea pig efficacy study Groups [n=8]1) no treatment control2) 100mg / kg compound 48813) 50mg / Kg Rifampicin (positive control)Reagents

[0393] Pathogen: The challenge strain for the efficacy study was M. tuberculosis H37Rv, delivered by the aerosol route at a targeted inhaled retained dose of 20 - 50 colony forming units (CFU) per animal.

[0394] Antibiotics: Rifampicin 2mg / ml solution (Sigma).

[0395] Test compound: Compound 4881 (dry powder).Experimental Procedures

[0396] All guinea pigs were challenged at day 0. Aerosol challenge was performed within ACDP containment level 3 facilities. The animals were challenged using a contained Henderson apparatus in conjunction with an AeroMP control unit. Fine particle aerosols of M tuberculosis, with a mean diameter of 2 pm, were generated in a Collison nebulizer and delivered directly to the snout of each animal. The AeroMP is a platform system designed to manage the aerosol generation, characterization and sampling processes via a dashboard software laptop system. The aerosol management platform controls, monitors, and records all relevant parameters during an aerosol procedure including air flow rate, temperature, andrelative humidity. The bacterial suspension, stored at -80°C, was thawed and diluted in sterile distilled water to achieve a target concentration of 2 x 105 CFU / ml, which was placed in the Collison nebulizer. Based upon historical data this concentration will result in an estimated retained, inhaled dose of approximately 20-50 CFU to the lungs of each animal. The nebulizer suspension of M. tuberculosis was plated onto Middlebrook 7H11 OADC selective agar to evaluate retrospectively that the expected concentration had been achieved. A sample was taken during the exposure period to determine the concentration of bacteria in the aerosol. The number of viable bacteria recovered from lungs (n=4) removed at necropsy one day postchallenge was used as the confirmation of the inhaled and retained dose.Drug preparationDrug preparation for mice

[0397] All drugs given to mice were formulated with DMA (10%) + 20% (w / v / in saline) HP-b-CD (90%). Amount of drug per week was calculated based on the average body weight of mice in study. The table below is an example of the amount of drug formulation component in each 100 pl dose for an average mouse body weight of 20g. Enough volume of drug compound was prepared each week to allow for daily dosing of each mouse in each group and allowing spare for loss of compound in the barrel of the needle when loaded into separate gavage syringes.Table 1. Drug preparation formice

[0398] Drug formulations were prepared weekly and stored at 4-8°C until ready for use. Prior to use, formulations were warmed to room temperature and agitated with gentle vortex for five seconds. 100 pl of the appropriate formulation was given once daily by oral gavage.Drug preparation for guinea pigs

[0399] All drugs given to guinea pigs were formulated with sucrose (40% v / v) in PBS, pumpkin puree (20%), vitamin C (50mg / kg) and Lactinex BD probiotic (10mg). Amount of drug per week was calculated based on the average body weight of guinea pigs in study. The table below is an example of the amount of each drug formulation component in each 1 ml dose for an average guinea pig body weight of 500g. Enough volume of each drug compound was prepared each week to allow for daily dosing of each guinea pig in each group and allowingspare for loss of compound in the barrel of the needle when loaded into separate gavage syringes.Table 2. Drug preparation for guinea pigs

[0400] Drug formulations were prepared weekly, pre-loaded into syringes, capped and stored at 4-8°C until ready for use. Prior to use, formulations were warmed to room temperature. 1ml of the appropriate formulation was given once daily by passive oral delivery to the back of the mouth.Clinical monitoring

[0401] Throughout the studies, the body weight of each animal was measured and recorded daily (tolerance studies) or at least weekly (efficacy study) to monitor health and to determine pre-defined humane end-point criteria. A humane endpoint is reached when 20% loss of maximal body weight is observed following drug delivery and / or aerosol challenge with M. tuberculosis. Other factors such as lethargy, ruffled fur and laboured breathing would also be considered in the decision to humanely euthanise an animal.

[0402] A scoring system was developed (Table 3) to monitor for early signs of reaction to drug treatment and disease progression. For all studies, animals were monitored daily during the period of drug treatment.Table 3. Clinical scoring system to determine animal welfareMouse and guinea pig tolerability studies

[0403] At the end of study (Day 8), all mice were killed by cervical dislocation, and guinea pigs were killed by overdose with sodium pentobarbital delivered by the intraperitoneal route. The following tissues were removed at necropsy for histopathological investigation: brain, eye, salivary gland, lymph node, lung, spleen, kidney, liver, heart, reproductive tract, pancreas, and gastro-intestinal tract. All excised tissues were immediately placed into 10% formalin solution.Guinea pig efficacy study

[0404] At day 1 post-challenge, 4 animals were killed by overdose with sodium pentobarbital. The lungs were aseptically removed for bacterial load analysis and these samples were processed on the day of necropsy.

[0405] At the end of the efficacy study the remaining 8 animals in each of the four groups were killed by overdose with sodium pentobarbital, delivered by the intraperitoneal route. Lungs and spleen were aseptically removed. The lungs were dissected to allocate specific lobes for bacteriology and histology, using the same lobes for each animal. The approximate same spleen section was taken for bacterial load analysis. All samples were stored at -20° C before being processed in a single batch.Bacterial load Assay

[0406] Whole lungs from day 1 post-challenge were homogenized in 2ml sterile phosphate buffered saline (PBS), and the entire homogenate was plated onto Middlebrook 7H11 OADC selective agar supplemented with adult bovine serum (10% v / v), Fungizone (50mg / L), polymixin B (200,000iu / L), trimethoprim lactate (0.001 % v / v, amoxacillin (100mg / L) and lysed ovine blood (5% v / v).

[0407] The remaining lung and spleen samples were thawed, homogenized in 5ml PBS, serially diluted in PBS and 100 l of each dilution plated, in duplicate onto Middlebrook 7H11 OADC selective agar.

[0408] All agar plates containing tissue homogenates were bagged, sealed and incubated at 37°C for up to 4 weeks. Following incubation, colonies were enumerated to determine the colony forming units (CFU) per plate and from this, the concentration of bacilli per ml of each sample was calculated. Bacterial load data (except for day 1 tissues) were expressed as Log CFU / ml.Histopathology analyses

[0409] Tissues in 10% formalin solution were fixed for at least 24 hours before being processed for wax embedding. Sections of 5 pm were cut at the widest lobe diameter and placed onto glass slides and stained with haematoxylin and eosin. Tissue sections were analysed by an experienced veterinary pathologist.

[0410] Lung lobe and spleen cross-sections in the efficacy study were analysed blind by an experienced veterinary pathologist using an established protocol to determine disease severity score and numbers of lesions. The group mean of these values were calculated from two lung lobes (left middle, left caudal) and one spleen section per animal.Statistical Analysis

[0411] All data were exported from Microsoft Excel, graphs generated and statistically analysed in GraphPad Prism, v9. A normality test was performed on the bacterial load data from the guinea pig efficacy study to determine which statistical tests will be applied. Statistically significant differences in bacterial load and histopathology data between treatment and control groups

[0412] Normality tests were applied to all data to determine choice of statistical test used in analyses. Tissues were compared by non-parametric analysis, determined using the Mann-Whitney test.Evaluation of the efficacy of an MptpB inhibitor compound in the UKHSA mouse model of M. avium infection

[0413] The study evaluated the efficacy of a MptpB inhibitor compound in the UKHSA mouse model of Mycobacterium avium (M. avium) infection. The University of Manchester provided UKHSA with the inhibitor candidate for evaluation of efficacy against M. avium infection in mice. Previous work with the University of Manchester had shown the compound to be tolerated well within the mouse model (Report - UKHSA project number 113007). Previous studies had also demonstrated the compound to have efficacy in both in vitro and in vivo experiments against mycobacteria.

[0414] Mice were infected via the aerosol route with M. avium strain Chester (NCTC 13034 / ATCC 25291). Six mice were culled at one-day post infection to determine the inhaled and retained M. avium dose. Four weeks following infection, groups of mice were treated with the compound, once daily, by the oral route. Efficacy of the compound was measured by a reduction in bacterial burden and pathology, compared to positive and negative control groups, during M. avium disease in mice.MethodsAnimals and study design

[0415] The study was conducted according to UK Home Office Legislation for animal experimentation under a Project License (P9EFCFD9C) that was approved by a local animal welfare and ethical review body (AWERB) at UKHSA Porton. Fifty-four adult female Balb / c mice aged six to eight weeks, free from pathogen-specific infection, were purchased from an approved supplier (Envigo, UK) and used in this study.

[0416] Group sizes for the efficacy study were determined by statistical power calculations (Minitab version 16) performed on previous data with the aim to reliably detect a difference between the mean colony forming units (CFU) per ml of homogenised tissue of 1.0 log (SD: 0.61 ; confidence: 95%; Power: 80).

[0417] Individual mice were randomly assigned to groups and were subcutaneously administered RFID microchips to uniquely identify each animal and enable blinding of the analyses wherever possible. Throughout the study the animals were housed in the Biological Investigations Group (BIG) facility and had free access to food and water. The rooms meet the Home Office guidelines for environmental control. The health and welfare of each animal was monitored and assessed regularly.

[0418] The agreed study schedules were as follows (see Figure 2):Mouse efficacy study:Groups 1-5 [n=6], no treatment controlGroup 6 [n=6], 100mg / Kg Compound 04881Group 7 [n=6], 100mg / Kg Clarithromycin (positive control)Group 8 [n=6], no treatment controlReagents

[0419] Pathogen: The challenge strain for the efficacy study was M. avium Chester (NCTC 13034 / ATCC 25291), delivered by the aerosol route at a targeted inhaled retained dose of -3x104 colony forming units (CFU) per animal.

[0420] Antibiotics: Clarithromycin 50mg / mL stock solution (Sigma SBR00011).

[0421] Test compound: Compound 4881 (dry powder).Experimental Procedures

[0422] All mice were challenged at day 0. Aerosol challenge was performed within ACDP containment level 3 facilities. The animals were challenged using a contained Henderson apparatus in conjunction with an AeroMP control unit. Fine particle aerosols of M. tuberculosis, with a mean diameter of 2pm, were generated in a Collison nebulizer and delivered directly to the snout of each animal. The AeroMP is a platform system designed to manage the aerosol generation, characterisation and sampling processes via a dashboard software laptop system. The aerosol management platform controls, monitors, and records allrelevant parameters during an aerosol procedure including air flow rate, temperature, and relative humidity. The bacterial suspension, stored at -80°C, was thawed and diluted in sterile distilled water to achieve a target concentration of 1 x 108 CFU / mL, which was placed in the Collison nebulizer. Based upon historical data this concentration will result in an estimated retained, inhaled dose of approximately 3-4 x 104 CFU to the lungs of each animal. The nebulizer suspension of M. tuberculosis was plated onto Middlebrook 7H11 OADC selective agar to evaluate retrospectively that the expected concentration had been achieved. A sample was taken during the exposure period to determine the concentration of bacteria in the aerosol. The number of viable bacteria recovered from lungs (n=6) removed at necropsy one day postchallenge was used as the direct confirmation of the inhaled and retained dose.Drug Preparation

[0423] All drugs given to mice were formulated with DMA (10%) + 20% (w / v / in saline) HP-b-CD (90%). Amount of drug per week was calculated based on the average body weight of mice in study. The table below is an example of the amount of each drug formulation component in each 100 pl dose for an average mouse body weight of 20g. Enough volume of each drug compound was prepared each week to allow for daily dosing of each mouse in each group and allowing spare for loss of compound in the barrel of the needle when loaded into separate gavage syringes.Table 4. Drug preparation for mice

[0424] Drug formulations were prepared weekly and stored at 4-8°C until ready for use. Prior to use, formulations were warmed to room temperature and agitated with gentle vortex for five seconds. 100 pl of the appropriate formulation was given once daily by oral gavage.Clinical Monitoring

[0425] Throughout the studies, the body weight of each animal was measured and recorded weekly to monitor health and to determine pre-defined humane end-point criteria. A humane endpoint is reached when 20% loss of maximal body weight is observed followingdrug delivery and / or aerosol challenge with M. avium. Other factors such as lethargy, ruffled fur and laboured breathing would also be considered in the decision to humanely euthanise an animal.Clinical scoring system

[0426] A scoring system was developed (Table 5) to monitor for early signs of reaction to drug treatment and disease progression. For all studies, animals were monitored daily during the period of drug treatment.Table 5 - Clinical scoring system used to score effects of drug treatment and disease progression.Mouse Efficacy Study

[0427] At day 1 post-challenge, 6 animals were killed via cervical dislocation. The lungs were aseptically removed for bacterial load analysis and these samples were processed on the day of necropsy.

[0428] Animals from groups 2-5 [n=6] were killed via cervical dislocation at weeks 2, 4, 6, 8 and 10 post-challenge, respectively. Lungs and spleen were aseptically removed for bacterial load analysis and stored at -20°C until processed.

[0429] At the end of the efficacy study the remaining 6 animals in each of the four groups (6-9) were killed by cervical dislocation. Lungs and spleen were aseptically removed and stored at -20° C prior to being processed to determine bacterial load in a single batch.Bacterial load assay

[0430] Whole lungs from day 1 post-challenge were homogenized in 2 mL sterile phosphate buffered saline (PBS), and the entire homogenate was plated onto Middlebrook 7H11 OADC selective agar supplemented with adult bovine serum (10% v / v), Fungizone (50mg / L), polymixin B (200,000iu / L), trimethoprim lactate (0.001 % v / v, amoxacillin (100mg / L) and lysed ovine blood (5% v / v).

[0431] The remaining lung and spleen samples were thawed, homogenized in 1 mL PBS, serially diluted in PBS and 100 pl of each dilution plated, in duplicate onto Middlebrook 7H11 OADC selective agar.

[0432] All agar plates containing tissue homogenates were bagged, sealed, and incubated at 37°C for up to 4 weeks. Following incubation, colonies were enumerated to determine the colony forming units (CFU) per plate and from this, the concentration of bacilli per mL of each sample was calculated. Bacterial load data (except for day 1 tissues) were expressed as Log CFU / mL.Statistical Analysis

[0433] All data were exported from Microsoft Excel, graphs generated and statistically analysed in GraphPad Prism, v9. A normality test was performed on the bacterial load data from the mouse efficacy study to determine which statistical tests will be applied. Statistically significant differences in bacterial load and histopathology data between treatment and control groups.

[0434] Normality tests were applied to all data to determine choice of statistical test used in the analyses. Tissues were compared by non-parametric analysis, determined using the Mann-Whitney test.Results and discussion - part ASummary

[0435] The compounds of the present invention described herein offer a novel mode of action, as they target the secreted survival factor Mycobacterium protein tyrosine phosphatase B (MptpB) and orthologues thereof. The compounds of the invention are validated non-bactericidal antibiotic agents, which increase pathogen killing inside host cells by blocking MptpB function. MptpB inhibitors have good pharmacological properties, oral bioavailability and pharmacokinetic profile. They show efficacy in decreasing the bacterial burden in a TB guinea pig model of infection and improvement in the spleen and lungs’ pathology. It has also been shown in macrophage infections to enhance the efficacy of SOC antibiotics against Mtb and M. avium. Furthermore, the compounds of the invention reduce M. avium infection in a chronic mouse model. In addition to Mycobacterium and NTM species, MptpB target is present in many important pathogens causing AMR infections and listed in the WHO / CDC priority list, such as Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae and Acitenobacter baumannii. Therefore, it is expected that the use of MptpB inhibitors have a wider application in the treatment of difficult to manage chronic infections. Potential uses include the treatment of susceptible and drug resistant tuberculosis, NTM pulmonary diseases (NTM-PD), NTM and or Ps. aeruginosa, or Staph, aureus infections (orco-infections) in cystic fibrosis (CF), bronchiectasis or COPD patients, as well as co-infections in HIV patients.Competitive advantage of the compounds of the invention

[0436] The compounds may be used as an adjuvant therapy that increases the efficacy of antibiotics, potentially increasing cure rates and improving patient outcomes. This antibiotic potentiator offers a transformative novel strategy to increase antibiotic efficacy and cure the infection using less toxic and shorter treatment regiments. Such an approach may also benefit diabetics, immune-compromised and HIV-infected patients (with weaker immune response), as well as children, for whom lower doses of antibiotics are used.

[0437] In addition, the compounds do not have any pre-existing cross-resistance and are expected to be effective on drug resistant microbes. The absence of human orthologues of MptpB makes it a highly attractive therapeutic target because minimal side effects are expected for the host.

[0438] It is noteworthy that some other small molecule MptpB inhibitors have been previously disclosed. These include oxalylamino-derivatives, salicylic based inhibitors for MptpB, indole salicylic based inhibitors, and very potent oxamic acid inhibitors. Some of these compounds have low molecular weight, nanomolar inhibition with > 1000 fold selectivity and excellent drug like properties, but efficacy in animal models is either not reported or very poor as single agents.Drug development

[0439] It has previously been reported that the isoxazole-based MptpB inhibitor C13 (5-methylisoxazole-3-carboxylic acid) reduced intracellular bacterial load of drug-susceptible and drug-resistant strains of Mtb, despite showing no bactericidal effect on extracellular mycobacterial cultures. Notably, the C13 inhibitor enhanced efficacy of first-line TB drugs, rifampicin and isoniazid, thus resulting in more Mtb intracellular killing in macrophages. In addition, due to its good oral bioavailability and pharmacokinetic profile, C13 was administered as monotherapy in acute and chronic guinea-pig models of infection showing significant reduction on mycobacterial burden and on histopathology, reduced size and number of granulomas. Thus, these findings demonstrated the potential that MptpB inhibitors have in reducing mycobacterial burden and suggested a novel approach to be incorporated into standard of care of TB treatments.

[0440] Optimisation of the lead C13 was undertaken by LifeArc resulting in the synthesis and evaluation of >400 compounds. Through this work is was possible to optimise compounds to low nM in vitro potency vs MptpB, however such compounds tend to have highlipophilicity and poor PK profiles and the optimal region for the series appears to be for compounds with moderate potency but better physical properties.

[0441] In order to address instability in DMSO associated with some of the original isoxazole compounds, alternative cores were investigated. The pyridine compounds of the present invention showed high permeability, displayed excellent in vitro microsomal stability, and have good PK profiles, particularly with respect to lung penetration.

[0442] Compounds of the invention were profiled in a suite of in vitro DMPK assays (LogD, solubility, metabolic stability in human and mouse liver microsomes and PAMPA permeability). They all have good solubility at physiological pH (> 150 pM), but some pyridines are more liphophilic (clogP >5). Permeability for the pyridines is high and microsomal stability was good. Most compounds showed no significant toxicity in hepG2 cell health assay or human macrophages at 10-30 pM. Those that showed toxicity were not pursued. Toxicity was also assessed in macrophages and only compounds with >70% viability were then tested for efficacy in intracellular infections in human THP1 macrophages infected with Mtb H37Rv strain.

[0443] The pyridines were active, and showed better permeability and higher cell activity than C13 with good metabolic stability.

[0444] The pyridine compounds also showed improvement of ADME properties respect to the original isoxazole lead C13, which has demonstrated efficacy in animal models of infection and lead compounds demonstrate similar / improved free-cover in mice. A number of key compounds (with ED50 <20 pM, concentration needed to reduce 50% the bacterial load respect to control) were investigated further in vivo to establish their PK profile, lung distribution and oral bioavailability. 4881 showed high exposure, high distribution to lungs and high oral availability and were selected for preclinical evaluation. Figure 3 shows an overview of the chemical series, physicochemical and in-vitro DMPK profile of the representative compounds tested.In vitro studies

[0445] From the subset of compounds that showed no cytotoxicity in macrophages (tested by the MTT assay) and hepG2 cell health assays, the most promising representatives were tested for cell efficacy in reducing Mtb burden in macrophage infections. Evaluation of the efficacy was done infecting human macrophage cell line THP1 with the laboratory strain of Mtb, H37Rv (see experimental section for details). Bacterial burden was calculated by enumeration of the viable colonies or colony forming units (CFU) after 72hr post infection including control with DMSO. Percentage of viability was calculated relative to the control (RPMI media only) (Figure 3). Infections were done in triplicates and at least 2 independent biological experiments.

[0446] Tracking the plC50 observed on the target, compound 4881 showed the highest efficacy in macrophages (Figure 3).In Vivo studies

[0447] Following the in vitro and PK studies, compound 4881 was selected to test efficacy in vivo in both guinea pig models of chronic tuberculosis infection and in mouse models of M. avium infection. Studies were conducted by the UK Health Security Agency at Porton Down.Evaluation of a MptpB inhibitor compound in rodent models of tuberculosis disease

[0448] The work consisted of three separate studies. The first two studies examined the tolerability of a MptpB inhibitor compound in both mice and guinea pigs in preparation for use in efficacy studies. The third study evaluated the efficacy of compound 4881 in the guinea pig model of chronic tuberculosis disease.Drug tolerability analyses

[0449] All tissues were scored by an experienced veterinary pathologist using the following grading system: 0=unremarkable, 1=minimal, 2=mild, 3=moderate, and 4=severe.Mouse tolerability study

[0450] No remarkable findings were observed during the week of treatment in the brain, eye, salivary gland, lymph node, lung, spleen, kidney, heart, reproductive tract, pancreas, or gastro-intestinal tract, following treatment with compound 4881 . Scores of 1 or 2 were observed in all mice. These results are expected. The liver lesions are normally minimal to mild and related to physiological glycogen storage (Table 6). This finding is typical in rodents and has no pathological significance, in relation to drug treatment. No clinical signs of drug intolerance were observed during the study.Table 6. Pathology score attributed to Liver determined at necropsyGuinea pig tolerability study

[0451] No remarkable findings were observed during the week of treatment in the brain, eye, salivary gland, lymph node, lung, spleen, kidney, heart, reproductive tract, pancreas, or gastro-intestinal tract, following treatment with compound 4881. Scores of 0 to 3 were observed in all guinea pigs. These results are expected. The liver lesions are typicallyminimal to mild and related to physiological glycogen storage (Table 7). This finding is typical in rodents and has no pathological significance, in relation to drug treatment. No clinical signs of drug intolerance were observed during the study.Table 7. Pathology score attributed to Liver determined at necropsyEfficacy study challenge dose confirmation

[0452] Confirmation of the delivered dose for the guinea pig efficacy study was obtained by measurement of the mean number of viable bacteria in the lungs of a group of 4 animals at one day post-challenge. The estimated target dose was 20-50 CFU and the confirmed dose post-challenge was ~39 CFU and deemed an acceptable challenge dose for this study.Clinical monitoring - Guinea pig efficacy study

[0453] The weights of the guinea pigs in each group were measured and monitored over the duration of the study (Figure 4), as was their physical condition (Figure 5). Any animals reaching their humane endpoint (20% loss of maximal body weight, and / or a clinical signs score of over 4) were killed and samples collected for analyses.

[0454] No animals in any of the groups reached their humane endpoint prior to the end of the study. No significant changes in weight gain were observed in the group treated with compound 4881. Animals treated with rifampicin demonstrated a cessation in weight gain during the treatment period, which was not observed with compound 4881.Efficacy study - Bacterial load profiles

[0455] Figure 6 shows the bacterial load in tissues following challenge, and after four weeks’ drug treatment during the chronic phase of M. tuberculosis disease. As expected, bacterial burden following challenge increased in both lung and spleen in the untreated groups. Compound 4881 gave significantly reduced bacterial load compared to the untreated control group in the lung only (P=0.0196). Rifampicin treatment reduced bacterial load in both lung (P=0.0022) and spleen (P=0.0022) compared to the untreated control group.Histopathology Analysis

[0456] Figure 7 depicts the histopathology score of each animal in each treatment group in both lungs (7A) and spleen (7B). Histopathology scores are attributed from a combination of numbers of lesions, lesion size and presence of caseated and calcified lesions.Compound 4881 and Rifampicin significantly improved pathology following treatment compared to the untreated control group.

[0457] The percentage area of lesions within both lung (Figure 7C) and spleen (Figure 7D) was measured using image analyses software of the entire tissue sections. Treatment with compound 4881 gave a significantly reduced area of lesions in the lung and a reduced area of lesions in the spleen. Rifampicin also reduced lesions area in both lung and spleen.

[0458] Compound 4881 and Rifampicin reduced the group average number of necrotic lesions in the lung (Figure 7E).Statistics SummaryBacteriologyTable 8. Statistical summary of Log w CFU / ml dataHistopathology

[0459] The histopathology data presented in Figure 7 was further analysed for statistical significance, with P-values from each treatment compared to the untreated group (Table 9).Table 9. Statistical summary of histopathology data

[0460] Compound 4881 demonstrated superior tolerability in both balb / c mice and Dunkin-Hartley guinea pigs. This test drug compound when given during the chronic phase of M. tuberculosis infection showed no inhibition of animal weight gain during treatment as observed with rifampicin.

[0461] Compound 4881 gave significant protection in the lung as determined by a reduction in both bacterial load and disease severity measured using histology score and percentage lesion area.

[0462] Rifampicin demonstrated significant protection in both lung and spleen as determined by both bacterial load and histopathology readouts.Evaluation of the efficacy of a MptpB inhibitor compound in the UKHSA mouse model of M. avium infection

[0463] The study evaluated the efficacy of a MptpB inhibitor compound in the UKHSA mouse model of Mycobacterium avium (M. avium) infection.Efficacy study challenge dose confirmation

[0464] Confirmation of the delivered dose for the mouse efficacy study was obtained by the measurement of the mean number of viable bacteria in the lungs of group 1 animals (n=6) at one day post-challenge. The estimated target aerosol dose was 3-4 x 104 CFU. The confirmed dose at day 1 post-challenge was an average of ~3.6 x 104 CFU, and deemed an acceptable challenge dose for this study.Clinical monitoring

[0465] The weights of the mice in each group were measured and monitored over the duration of the study (Figure 8), as well as their physical condition (Figure 9). Any animals displaying clinical signs above 4 were monitored under health surveillance. Physical conditions beyond 4, along with a 20% loss of maximal body weight were considered to have reached their humane end point. Under these circumstances, animals were culled, and samples collected for analyses.

[0466] Animal 87365 (group 8 - clarithromycin) was removed from study at day 39 post-challenge due to its clinical signs score increasing from 5 at day 34 post-challenge to 7 by day 39 post challenge, as well as showing continued weight loss from day 28 postchallenge. Necropsy results suggested the animal welfare was due to disease progression rather than drug toxicity. The samples from this animal were not included in the final data analyses.

[0467] Animals treated with the test compound group gave a trend of slight weight loss at the start of drug treatment, and regained weight by increasing again after 3-4 weeks of thetreatment regimen (Figure 8A). Untreated and clarithromycin treated animals did not show any significant signs of weight loss (Figures 8B and 8C), with the exception of animal 87365 within the clarithromycin group.

[0468] Within the group given compound 4881 , 2 animals displayed only transient symptoms of ruffled fur and / or laboured breathing and had completely recovered after 24-48 hours (day 35-36 post-infection). Only 1 animal within the clarithromycin treatment group displayed symptoms attributed to M. avium disease progression. Due to the advancement of these symptoms, the animal had reached its humane end point and was removed from study at 39 days post-infection.Efficacy study - Bacterial load profiles

[0469] Following 4 weeks of drug treatment during M. avium infection, bacterial burden was significantly reduced in the lungs of all animals within the two treatment groups when compared with the untreated control group, as shown in Figure 10. Bacterial burden within the lungs of animals treated with compound 4881 was significantly reduced, (P = 0.030), when compared with the untreated control group. Clarithromycin treated animals also gave a reduced bacterial burden within the lung when compared with untreated group (P = 0.002).

[0470] No significant decrease in bacterial burden was observed in the spleens of mice treated with compound 4881 , when compared to the untreated control group (P = 0.937) (Figure 10). Clarithromycin treated animals gave a significant reduction in bacterial burden when compared to the untreated control group (P = 0.002).Statistics summaryBacteriology

[0471] The bacteriological data presented in Figure 10 was analysed for statistical significance. Test for P-values from each treatment compared to the untreated group (Table 10).Table 10. Statistical summary of Log w CFU / ml data. Statistical analysis shows multiple t tests with post-hoc Mann-Whitney test (P values: ns=>0.05, *=<0.01, ***=<0.005).

[0472] Compound 4881 significantly reduced bacterial burden in the lungs of mice following infection with M. avium, compared to the untreated control group. Animals receivingcompound 4881 by the oral route gave very mild transient weight loss during the first 3-4 weeks of treatment followed by a return to normal weight gain kinetics thereafter.

[0473] Clarithromycin treated animals gave a significant reduction in bacterial load in both lung and spleen, compared with the untreated animals. No deviations from expected weight gain kinetics were observed in clarithromycin treated animals.Results and discussion - part BDetermination of intracellular efficacy of 4881 in infected THP-1 macrophages

[0474] The drug efficacy of 4881 was tested against various pathogens in the intracellular compartment. The tumour macrophage-derived cell line THP-1 was used. The THP-1 cells are grown in RPMI medium in 75-cm2flasks. RPMI media was supplemented with 100 mM sodium pyruvate, 200 mM L-glutamine, 3.7 g of sodium bicarbonate per litre, and 10% foetal calf serum without any antibiotics.

[0475] After counting the macrophages in a hemacytometer, viability was determined by trypan blue exclusion, and the macrophages (2-5 X 105macrophages / mL) were seeded in 24-well plates with complete RPMI. The THP-1 cells were induced by 50nM phorbol 12- myristate 13-acetate (PMA) to achieve macrophage differentiated phenotypes and incubated at 37°C / 48-72hr / 5% CO2 atmosphere.

[0476] After 48hr of activation, the THP-1 macrophages were infected with the pathogen (see Table 12) at a multiplicity of infection (MOI) of 1 :1. The macrophage infection was allowed to take place for 2 h at 37°C with 5% CO2. The media containing the pathogen were discarded, macrophage monolayers were washed twice with phosphate-buffered saline (+Ca2++ Mg2+) to remove the free bacteria and replenished with fresh complete RPMI.

[0477] To remove the extracellular bacteria, Amikacin treatment (25ug / mL) was given to the cells for 1 h and washed to remove the drug. The infected cells were treated with the compound at concentrations of 80, 40, 20, 10, 5, and 0 pM (DMSO < 1 %, master stock of 10mM). Sets of triplicate wells were lysed (0.05% SDS) at specific timepoints and enumerated to estimate the numbers of intracellular pathogens postinfection.

[0478] CFU were sampled for kinetic studies at O-hr, 6-hr, 24-hr for Mabs and O-hr, 3- hr, 6-hr for Abau. The lysates were serially diluted and plated onto Middlebrook 7H11 agar plates for Mabs and MHA plates for Abau for enumeration of the bacteria after compound treatment. Plates were read after 4 days for Abau and after 7 days for Mabs.Table 11 - test compoundsTable 12 - pathogens and strains used in the assay

[0479] The intracellular efficacy of 4881 against A. baumannii in activated THP-1 macrophages is shown in figures 11 and 12.

[0480] The intracellular efficacy of 4881 against M. abscessus ATCC 19977 in activated THP-1 macrophages is shown in figure 13.In vivo efficacy testing of 4881

[0481] A study was carried out to evaluate the efficacy of one anti-virulence compound as a combination therapy with standard of care treatment in the LIKHSA mouse model of Mycobacterium avium (M. avium) infection.

[0482] The study was conducted according to UK Home Office Legislation for animal experimentation under a Project Licence (P9EFCFD9C) that was approved by a local animal welfare and ethical review body (AWERB) at UKHSA Porton.

[0483] Seventy-two adult female Balb / c mice aged six to eight weeks, free from pathogen-specific infection, were purchased from an approved supplier (Envigo, UK) and used in this study.

[0484] Group sizes for the efficacy study were determined by statistical power calculations (Minitab version 16) performed on previous data with the aim to reliably detect a difference between the mean colony forming units (CFU) per mL of homogenised tissue of 1.0 log (standard deviation (SD): 0.61 ; confidence: 95%; power: 80).

[0485] Individual mice were randomly assigned to groups and were subcutaneously administered RFID microchips to uniquely identify each animal and enable blinding of the analyses wherever possible. Throughout the study, the animals were housed in the Biological Services Group (BSG) facility and had free access to food and water. The rooms meet the Home Office guidelines for environmental control. The health and welfare of each animal was monitored and assessed regularly.Method

[0486] Mice were infected via the aerosol route with M. avium strain Chester (NCTC 13034 / ATCC 25291) at a targeted inhaled retained dose of ~1x104CFU per animal. All micewere challenged at day 0. Aerosol challenge was performed within ACDP containment level 2 facilities. The animals were challenged using a contained Henderson apparatus in conjunction with an AeroMP control unit (Williams et al, Clark et al, Hartings et al). Fine particle aerosols of M. avium with a mean diameter of 2 pm, were generated in a Collison nebuliser and delivered directly to the snout of each animal. The AeroMP is a platform system designed to manage the aerosol generation, characterisation and sampling processes via a dashboard software laptop system. The aerosol management platform controls, monitors, and records all relevant parameters during an aerosol procedure including air flow rate, temperature, and relative humidity (Hartings et al). The bacterial suspension, stored at -80°C, was thawed and diluted in sterile Phosphate Buffer Saline (PBS) (Severn Biotech Ltd 20-74-10) to achieve a target concentration of 2 x 107CFU / mL, which was placed in the Collison nebuliser. Based upon historical data this concentration will result in an estimated retained, inhaled dose of approximately ~1 x 104CFU to the lungs of each animal. The nebuliser suspension of M. avium was plated onto Middlebrook 7H11 OADC selective agar to evaluate retrospectively that the expected concentration had been achieved. A sample was taken during the exposure period to determine the concentration of bacteria in the aerosol. Three mice were culled at one-day post infection to determine the inhaled and retained M. avium dose.

[0487] Four weeks following infection, groups of mice were treated once daily via the oral gavage for a total of six weeks, with pre-determined combinations of either 4881 , Clarithromycin (CLR) (Merck C9742), Rifampicin (RIF) (Merck R3501) and / or Ethambutol (EMB) (Merck E4630), as show in figure 14. All drugs given to mice were formulated with carrier solution comprising of 50% DMSO + 50% HP-b-CD (180 mg / mL in PBS).Necropsy

[0488] At day 1 post-challenge, 3 animals from group 12 were killed via cervical dislocation. The lungs were aseptically removed for bacterial load analysis and these samples were processed on the day of necropsy.

[0489] At day 28 post-challenge, the remaining 3 animals from group 12 were killed via cervical dislocation, and the lungs aseptically removed. These samples were processed on the day of necropsy to determine the bacterial load at the beginning of the treatment regime.

[0490] Final necropsies were performed at day 70 on all remaining animals.

[0491] Lungs and spleen were aseptically removed, placed into pre-weighed Precellys tubes, weighed and stored at -20°C prior to being processed to determine bacterial burden.Bacterial load assay

[0492] Whole lungs from day 1 post-challenge were homogenized in 1 mL sterile phosphate buffered saline (PBS), and the homogenate was serially diluted in sterile PBS andplated onto Middlebrook 7H11 OADC selective agar supplemented with adult bovine serum (10% v / v), Fungizone (50mg / L), polymixin B (200,000iu / L), trimethoprim lactate (0.001 % v / v, amoxacillin (100mg / L) and lysed ovine blood (5% v / v).

[0493] The remaining lung and spleen samples were thawed, homogenized in 1 mL PBS, serially diluted in PBS and 100 pL of each dilution plated, in duplicate onto Middlebrook 7H11 OADC selective agar.

[0494] All agar plates containing tissue homogenates were bagged, sealed, and incubated at 37°C for up to 4 weeks. Following incubation, colonies were enumerated to determine the CFU per plate, and from this, the concentration of bacilli per mL of each sample was calculated. Bacterial load data (except for day 1 tissues) were expressed as Log CFLI / mL.

[0495] Efficacy of the combination therapies were measured by a reduction in bacterial burden and pathology, compared to positive and negative control groups, during M. avium disease in mice. The results are shown in figure 15.

[0496] In both the lung and spleen, a significant decrease in bacterial burden was observed when 4881 (20mg / kg) was given to mice in combination with Clarithromycin (100mg / kg) and Rifampicin (10mg / kg), compared with Clarithromycin and Rifampicin in combination alone (i.e. , without 4881).

[0497] In the lung, higher bacterial load was observed in groups given 4881 alone at concentrations of both 50mg / kg and 20mg / kg compared to the carrier only group. All other combination treatment groups had lower bacterial burden compared to the carrier only group.Clinical monitoring

[0498] The body weight of the mice in each group described in figure 14 were measured, recorded and monitored over the duration of the study, as was their physical condition. Any animals displaying clinical signs above 4 (see Table 5) were monitored more frequently. Physical conditions beyond 4, along with a 20% loss of maximal body weight were considered to have reached their humane end point. Under these circumstances, animals were culled, and tissues taken for histopathology analysis.

[0499] All animals followed a normal weight gain trend until aerosol challenge with M. avium, at which point many animals expressed a transient mild reduction in body weight, but recovered one week post-infection. Post-challenge the mice continued to gain weight until the beginning of the treatment phase, with no clinical signs being observed during this time (see figure 16). Throughout the treatment phase animals weight began to plateaux. During the treatment phase, eight animals were observed to display clinical signs (see figure 17). Six animals reached their humane endpoint before the end of the study. Clinical andhistopathology analyses of these animals suggest these were in relation to the oral gavage procedure rather than due to specific treatment or infection.Histopathology analysis

[0500] Area of lesions within the lung and spleen were measured as a percentage of the total tissue section using image analysis. The highest level of lesions within the lung were observed in the carrier only group. The majority of the remaining treatment groups provided minimal to no lesion areas of disease within the lungs.

[0501] Ziehl-Nelsen (ZN) staining used to identify the presence of mycobacteria in lung and spleen tissues followed the same pattern of expression as that of the % lesion area, with little to no mycobacteria present in all combination regimen groups.Luminex analysis

[0502] Luminex analysis was performed on sera samples from all animals following six weeks of daily oral gavage. Sera was analysed using a Bio-Rad Pro Mouse Cytokine 23- Plex Assay in 384-well format at 1X concentration on an I ntelliflex analyser. An outline of the cytokine / chemokines analysed in this assay is shown in Table 13. The data was quality checked by removing any replicates which contained less than 20 beads prior to graphical representation.Table 13: cytokines / chemokines assayed within BioPlex panel

[0503] To assess systemic immune responses following treatment of M. avium infection in mice, cytokine and chemokine levels were measured in sera from blood taken at final necropsy.

[0504] As shown in the heatmap (see figure 19), mice receiving the carrier only exhibited elevated levels of multiple pro-inflammatory cytokines and chemokines (KC, RANTES), the anti-inflammatory cytokine IL-10, and Th2-associated cytokines (IL-4, IL-5, IL- 9). This systemic cytokine signature is consistent with uncontrolled infection and immune dysregulation (Sakai et al).

[0505] Treatment with 4881 at 50 mg / kg alone reduced bacterial burden and selectively suppressed RANTES and I L-12p40 relative to the carrier group, suggesting modest immunomodulatory activity (Shi et al). When delivered as a 20 mg / kg dose the effects of 4881 were variable but were enhanced when used in combination with standard of care therapies.

[0506] When comparing standard of care regimens without 4881 (20mg / kg) to the carrier group, modest reductions in systemic cytokines were observed. For example, CLR alone reduced KC and increased IL-4 and IL-5, consistent with a partial Th2 shift (Romagnani et al). CLR+RIF and CLR+EMB groups exhibited broader suppression of pro-inflammatory cytokines but retained elevated IL-5 and IL-9 levels, suggesting incomplete resolution of adaptive immune activation (O’Garra et al).

[0507] In contrast, addition of 4881 (20 mg) to the standard of care regimens significantly enhanced systemic cytokine modulation. The CLR+4881 group reduced KC and IL-5 compared to carrier and CLR alone. Similarly, the CLR+RIF+4881 group exhibited marked reductions in KC, IL-5, IL-9, and IL-12p40 relative to both the carrier and CLR+RIF groups. The most pronounced effect was observed in the CLR+RIF+EMB+4881 group, which demonstrated broad suppression of pro-inflammatory (KC, RANTES, MIP-1 P), antiinflammatory (IL-10), and adaptive (IL-5, IL-9) cytokines compared to carrier and to CLR+RIF+EMB alone.Antifungal analysis

[0508] To test the efficacy of the compounds of the invention against A. fumigatus, the inventors leveraged powerful in vitro infection technologies developed by the Bertuzzi laboratory to measure the effect of known antimicrobials in modulating intracellular killing within host cells. The Bertuzzi laboratory has previously developed a novel genetically engineered dual-fluorescent reporter A. fumigatus strain allowing the inventors to quantify, in a high-throughput manner, uptake and intracellular killing by host cells. This fluorescent strain was used for infection of immortalised human alveolar epithelial cells (A549 cells) in the presence and absence of a compound of the invention (4881) and a known antifungal (voriconazole), as positive controls for intracellular killing (see figure 21). Infections werecarried out for 3 hrs, followed by washes to remove extracellular fungus and 3 hrs incubation with the drugs as indicated. 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Claims

CLAIMS1. A compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, having the structural Formula (I), shown below:wherein:R1 is selected from: -[CH2]n-C(O)OH; integer n is 0, 1 or 2;R2 is selected from hydrogen, halo, hydroxy, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1- 3C)haloalkoxy, (1-3C)hydroxyalkyl or (1-3C)hydroxyalkoxy;R3 is selected from hydrogen, hydroxy, halo, (1-6C)alkyl, (1-6C)alkoxy, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkylene, (3-8C)cycloalkoxy, (3-8C)cycloalkyl(1-2C)alkylene-O-, wherein any alkyl, alkoxy or alkylene group is optionally substituted by one or more substituent groups independently selected from hydroxy, halo, (1-3C)alkoxy, (1- 3C)haloalkoxy, or amino; wherein any cycloalkyl or cycloalkoxy group is optionally substituted by one or more substituent groups independently selected from hydroxy, halo, (1-3C)alkoxy, amino, (1- 3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl or (1- 3C)hydroxyalkoxy;R4 is selected from hydrogen, halo, hydroxy, (1 -3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1- 3C)haloalkoxy;Ring A is a phenyl ring or a 5- or 6-membered heteroaryl ring; integer m is 0, 1 or 2; each R5 group present is independently selected from hydroxy, halo, cyano, or a group of the formula:-Y R5-QR5 wherein:YR5is absent or O, S, SO, SO2, N(R5a), C(O), C(O)O, OC(O), C(O)N(R5a), N(R5a)C(O), N(R5a)C(O)N(R5b), N(R5a)C(O)O, OC(O)N(R5a), S(O)2N(R5a), N(Rsa)SO2, or C(O)N(Rsa)SO2, wherein Rsaand Rsb are each independently selected from hydrogen or (1 -2C)alkyl; andQRS is hydrogen, (1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkylene, heterocyclyl or heterocyclyl(1-3C)alkylene; wherein QRS is optionally further substituted by one or more substituent groups independently selected from oxo, (1-2C)alkyl, (1-2C)alkoxy, halo, cyano, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl or amino;L is a covalent bond, -C(RL)2-, or -C(RL)2-C(RL)2-, wherein each R present is independently selected from hydrogen or methyl;Bi is selected from CH, C-Re or N;B2is selected from CH, C-R? or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH, C-Rg or N;Bs is selected from CH, C-R10 or N; with the proviso that only one, two or three of Bi , B2, B3, B4 and Bs may be N; and wherein Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-LI-Y-L2-Q wherein:Li is absent or (1-2C)alkylene optionally substituted by one or more substituents selected from methyl or oxo;Y is absent or O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), N(Ra)C(O)O, OC(O)N(Ra), C(=NRy)N(Ra), N(Ra)C(=NRy), N(Ra)C(=NRy)N(Rb), S(O)2N(Ra), N(Ra)SO2, or C(O)N(Ra)SO2, wherein Raand Rb are each independently selected from hydrogen or (1- 4C)alkyl and Ryis selected from hydrogen, (1 -4C)alkyl, nitro or cyano;L2is absent or (1-4C)alkylene optionally substituted by one or more substituents selected from methyl or oxo; andQ is hydrogen, (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, cyano, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)PRc(where p is 0,1 or 2), SC>2N(Rd)Rc, N(Rd)SC>2Rc,or (CH2)qNRcRd (where q is 1 , 2 or 3); wherein Rc, Rd and Reare each independently selected from hydrogen, (1 -6C)alkyl, (3- 6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; and wherein Rg and R are each independently selected from halo, hydroxy, (1- 3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl or (1- 3C)hydroxyalkoxy.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ri is -[CH2]-C(O)OH or Ri is -C(O)OH.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2 is selected from hydrogen, fluoro, chloro, hydroxy, (1- 2C)alkyl, (1-2C)alkoxy, (1-2C)fluoroalkyl, (1-2C)fluoroalkoxy, (1-2C)hydroxyalkyl or (1- 2C)hydroxyalkoxy.

4. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2 is hydrogen.

5. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R3 is selected from hydrogen, hydroxy, fluoro, chloro, (1-6C)alkyl, or (3-8C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy or (1-2C)fluoroalkoxy; and wherein any cycloalkyl group is optionally substituted by one or more substituent groups independently selected from hydroxy, fluoro, chloro, (1-2C)alkoxy, amino, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)fluoroalkyl, or (1-2C)fluoroalkoxy.

6. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R3 is selected from hydroxy, fluoro, chloro, (1-6C)alkyl, or (3-6C)cycloalkyl, wherein any alkyl group is optionally substituted by one or more fluoro.

7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R3 is selected from methyl, isopropyl, 2- methylpropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl.

8. The compound according to any one of the preceding claims, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, wherein R4 is selected from hydrogen, fluoro, chloro, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy.

9. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ring A is a phenyl ring or a 5- or 6- membered heteroaryl ring comprising one or two heteroatoms selected from N, O or S.

10. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein integer m is 0 or 1.

11. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R5 group present is independently selected from hydroxy, halo, cyano or a group of the formula:-Y R5-QR5 wherein:YR5is absent or O, SO2, N(R5a), C(O), C(O)N(R5a), N(R5a)C(O), S(O)2N(R5a) or N(R5a)SC>2, wherein Rsa is selected from hydrogen or (1 -2C)alkyl; andQRS is hydrogen, (1 -4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkylene, 4-to 6-membered heterocyclyl, or [4-to 6-membered heterocyclyl](1- 2C)alkylene; wherein QRS is optionally further substituted by one or more halo atoms.

12. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each Rs group present is independently selected from fluoro, chloro, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)fluoroalkyl, or (1- 2C)fluoroalkoxy.

13. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is selected from a covalent bond or - CH2-.

14. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:Bi is selected from CH, C-Re or N;B2is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH or C-Rg;Bs is selected from CH or C-R10; with the proviso that only one or two of Bi , B2 or B3 may be N.

15. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:Bi is selected from CH, C-Re or N;B2 is selected from CH, C-R7 or N;B3 is selected from CH, C-Rs or N;B4 is selected from CH;B5 is selected from CH; with the proviso that only one or two of Bi , B2 or B3 may be N.

16. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, S, SO, SO2, N(Ra), C(O), C(O)N(Ra), N(Ra)C(O), S(O)2N(Ra) or N(Ra)SO2, wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, phenyl, (3- 6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, NRcRd, ORC, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)PRC(where p is 0, 1 or 2), SO2N(Rd)Rc, or N(Rd)SO2Rc, wherein Rcand Rd are each independently selected from hydrogen or (1 -2C)alkyl.

17. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, phenyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, or (1-2C)haloalkoxy.

18. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Re, R7 and Rs are each independently selected from halo, cyano or a group of the formula:-L1-Y-L2-Q wherein:Li is absent or (1-2C)alkylene;Y is absent or O, C(O)N(Ra) or N(Ra)C(O), wherein Raand Rb are each independently selected from hydrogen or (1 -2C)alkyl;L2 is absent or (1-3C)alkylene; andQ is hydrogen, (1-4C)alkyl, or 5- or 6-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, cyano, (1-2C)haloalkyl, or (1-2C)haloalkoxy.

19. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Rg and R10 are each independently selected from halo, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1- 2C)hydroxyalkyl or (1-2C)hydroxyalkoxy.

20. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Rg and R10 are each independently selected from halo, hydroxy, (1-2C)haloalkyl, (1-2C)haloalkoxy.

21. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from: 5-Methyl-3-[3-(4-tetrahydropyran-4-ylphenyl)phenyl]pyridine-2-carboxylic acid;3-[3-[3-(trifluoromethyl)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3-[3-(trifluoromethyl)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3-[2-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-Cyclopentyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-isopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-cyclopropyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl] pyridine-2-carboxylic acid; 5-isobutyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-cyclobutyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;3-[3-[3-(Trifluoromethoxy)phenyl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxylic acid; 5-Chloro-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]pyridine-2-carboxylic acid;5-methyl-3-[3'-(trifluoromethyl)-3-biphenylyl]-2-pyridinecarboxylic acid;3-(3'-chloro-4'-morpholino-3-biphenylyl)-5-cyclopropyl-2-pyridinecarboxylic acid;5-cyclobutyl-3-(3'-trifluoromethoxy-3-biphenylyl)-2-pyridinecarboxylic acid;3-(4'-hydroxy-3-biphenylyl)-5-isopropyl-2-pyridinecarboxylic acid; and 5-isopropyl-3-(4'-methoxy-3-biphenylyl)-2-pyridinecarboxylic acid.

22. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

23. A compound according to any one of claims 1-21 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 22 for use in therapy.

24. A compound according to any one of claims 1-21 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 22:(i) for use in the treatment or prevention of a microbial disease in which the inhibition of MptpB is beneficial;(ii) for use in the treatment or prevention of a microbial disease in which the activity of MptpB is implicated;(iii) for use in the treatment or prevention of a microbial infection;(iv) for use in the treatment or prevention of a mycobacterium infection;(v) for use in the treatment or prevention of a Mycobacterium tuberculosis infection or a non- tuberculous mycobacterium infection;(vi) for use in the treatment or prevention of a pulmonary tuberculosis or non-tuberculous pulmonary disease;(vii) for use in the treatment or prevention of a Mycobacterium tuberculosis infection;(viii) for use in the treatment or prevention of a multidrug resistant Mycobacterium tuberculosis infection;(ix) for use in the treatment or prevention of an extremely drug resistant Mycobacterium tuberculosis infection;(x) for use in the treatment or prevention of an inflammatory disease I disorder;(xi) for use in the treatment or prevention of a fungal disease I disorder I infection (i.e., mycosis).

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