GB2547740A - Antibacterial compounds - Google Patents

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof is provided wherein X1 is selected from N and CR4; X2 is selected from N and CR5; =A is selected from =O, =S, (-F)2, =NR6 and =NOR6; Y1 and Y2 are each independently selected from C and N; Z1, Z2 and Z3 are each independently selected from O, S, S(O)2, S(O), N, NR7, CR8 and C=W, wherein W is selected from O, S or NR6, with the proviso that if none of Z1, Z2 and Z3 is C=W, then the ring formed by Z1, Z2, Z3, Y1 and Y2 contains two endocyclic double bonds and, if one of Z1, Z2 and Z3 is C=W, then the ring formed by Z1, Z2, Z3, Y1 and Y2 contains a single endocyclic double bond; with the further provisos that at least one of Z1, Z2, Z3, Y1 and Y2 is O, S, N or NR7 and that no more than one or Z1, Z2 and Z3 is C=W; R1 and R2 are each independently substituents as herein defined; R3 is as herein defined; R4, R5, R6, R7 and R8 are each independently substituents as herein defined. The compounds of formula (I) are useful as antibacterial and antimycobacterial agents capable of treating bacterial infections which are currently hard to treat with existing drugs e.g. those caused by resistant bacterial or mycobacterial strains.

Description

Antibacterial compounds

This invention relates to antibacterial and antimycobacterial drug compounds containing a tricyclic ring system. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections and to methods of treating bacterial infections. The invention is also directed to antibacterial drug compounds which are capable of treating bacterial infections which are currently hard to treat with existing drug compounds, e.g. those caused by resistant bacterial or mycobacterial strains.

The increasing occurrence of bacterial resistance to antibiotics is viewed by many as being one of the most serious threats to the future health and happiness of mankind. Multidrug resistance has become common among some pathogens, e.g. Staphylococcus aureus, Streptococcus pneumoniae, Clostridium difficile and Pseudomonas aeruginosa. Of these, Staphylococcus aureus, a Gram positive bacterium, is the most concerning due to its potency and its capacity to adapt to environmental conditions. MRSA (methicillin resistant Staphylococcus aureus) is probably the most well known resistant strain and has reached pandemic proportions. Of particular concern is the increasing incidence of ‘community acquired’ infections, i.e. those occurring in subjects with no prior hospital exposure. Many strains of MRSA are also resistant to fluoroquinolone antibiotics, in addition to β-lactam antibiotics such as methicillin.

While less wide-spread, antibiotic resistant Gram negative strains, such as either Escherichia coli NDM-1 (New Delhi metallo-p-lactamase) mutation or Klebsiella pneumoniae with the same mutation, are also very difficult to treat. Frequently only expensive antibiotics such as vancomycin and colistin are effective against these strains.

One specific area were antibacterial resistance is posing a problem is in the treatment of gonorrhoea. Gonorrhoea is a human sexually-transmitted infection (STI) caused by the Gram-negative bacterium Neisseria gonorrhoeae, a species of the genus Neisseria that also includes the pathogen N. meningitidis, which is one of the aetiological agents of meningitis. Gonorrhoea is a significant global public health problem. In 2008 there were a total of 106 million estimated new cases of N. gonorrhoeae infection (Global Incidence and Prevalence of Selected Curable Sexually Transmitted lnfections-2008, World Health Organization). It is the second most commonly reported infectious disease in the United

States. According to the Centers for Disease Control and Prevention (CDC) there are an estimated 820,000 gonococcal infections per year in the United States (Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention. Throughout the twentieth and twenty-first centuries gonorrhoea has been treated with a range of antibiotics. The sulphonamides were the first antibiotics used for the treatment of gonorrhoea, followed by penicillin, tetracycline and spectinomycin. In each case the development of resistance to these drugs by N. gonorrhoeae led to their use being discontinued. The fluoroquinolone antibiotics ciprofloxacin and ofloxacin were also historically recommended for the treatment of gonorrhoea. However, by 2007, fluoroquinolone resistance rates had reached 15% of gonococcal isolates and their use was abandoned. Current treatment recommendations comprise the cephalosporin antibiotics cefixime or ceftriaxone in combination with azithromycin or doxycycline. Resistance to cefixime and ceftriaxone has emerged in recent years. The CDC estimates that approximately 246,000 of the 820,000 gonococcal infections per year in the United States are drug-resistant (Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention). N. gonorrhoeae has evolved diverse molecular resistance mechanisms to overcome the inhibitory effects of antibiotics. Examples include: i) alterations in the folP gene that encodes the dihydropteroate synthase enzymes that are the target of the sulphonamides; ii) plasmids bearing the b/aiEM-i gene, encoding a TEM-1-type β-lactamase; iii) single nucleotide polymorphisms in the tetracycline- and spectinomycin-binding regions of the ribosomal target; and iv) mutations in the gyrA and parC genes that code for subunits of DNA gyrase and topoisomerase IV that are targeted by the fluoroquinolones. A further disease in which the development of resistance and multidrug resistance is of particular concern is TB. From the 17th century to the early-20,h century TB was one of the most common causes of death, particularly amongst the urban poor. The development of effective treatments and vaccinations through the middle part of the 20th century led to a sharp reduction in the number of deaths arising from the disease. TB is usually caused by Mycobacterium tuberculosis. Mycobacteria are aerobic bacteria and, as a result, tuberculosis infections most often develop in the lungs (pulmonary tuberculosis), although this is not always the case. Mycobacteria lack an outer cell membrane and as such they are often classified as Gram-positive bacteria, although they are in many ways atypical. They have a unique cell wall which provides protection against harsh conditions (e.g. acidic, oxidative) but also provides natural protection against many antibiotics. Other antibiotics, such as beta-lactams, are inactive against TB due to the intrinsic activity of the compounds in the mycobacteria. Thus, a drug molecule may have excellent activity against other bacterial strains but no activity against wild-type TB. A number of TB-specific antibiotics have been developed, such as isoniazid, rifampicin, pyrazinamide and ethambutol and these are typically used in combination. Unfortunately, there is now increasing incidence of multidrug-resistant TB (MDR-TB). MDR-TB often arises when a treatment for TB has been interrupted. MDR-TB is the term typically used to refer to TB which has developed a resistance to isoniazid and rifampicin. MDR-TB can also be resistant to fluoroquinolones and also to the so-called ‘second line’ injectable anti-TB drugs: kanamycin, capreomycin and amikacin, with such resistances again commonly developing due to interruptions in treatment regimes. Where a strain of TB is resistant to isoniazid and rifampicin as well as one fluoroquinolone and one of the injectable anti-TB drugs, it is known as extensively drug resistant (XDR-TB). MDR-TB and XDR-TB are often found in those who have been previously treated for TB, but these forms of TB are just as infectious as wild-type TB and the incidence of MDR-TB and XDR-TB around the world is increasing. According to a 2013 World Health Organisation report, infections arising from XDR-TB had at that time been identified in 84 different countries. There have even been some reports of strains of TB which were resistant to all drugs tested against them (so-called ‘totally drug resistant tuberculosis’, TDR-TB). The ‘second line’ anti-TB drugs and other antibiotics typically used to treat resistant infections can have unfavourable side effects.

The fluoroquinolone antibacterial family are synthetic broad-spectrum antibiotics. They were originally introduced to treat Gram negative bacterial infections, but are also used for the treatment of Gram positive strains. One problem with existing fluoroquinolones can be the negative side effects that may sometimes occur as a result of fluoroquinolone use. In general, the common side-effects are mild to moderate but, on occasion, more serious adverse effects occur. Some of the serious side effects that occur, and which occur more commonly with fluoroquinolones than with other antibiotic drug classes, include central nervous system (CNS) toxicity and cardiotoxicity. In cases of acute overdose there may be renal failure and seizure.

In spite of the numerous different antibiotics known in the art for a variety of different infections, there continues to be a need to provide antibiotics that can provide an effective treatment in a reliable manner. In addition, there remains a need for antibiotic drugs which can avoid or reduce the side-effects associated with known antibiotics.

It is an aim of certain embodiments of this invention to provide new antibiotics. In particular, it is an aim of certain embodiments of this invention to provide antibiotics which are active against resistant strains of Gram positive and/or Gram negative bacteria. It is an aim of certain embodiments of this invention to provide compounds which have activity which is comparable to those of existing antibiotics, and ideally which is better. It is an aim of certain embodiments of this invention to provide such activity against wild-type strains at the same time as providing activity against one or more resistant strains.

It is an aim of certain embodiments of this invention to provide antibiotics which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.

It is an aim of certain embodiments of this invention to provide treatment of bacterial infections which is effective in a selective manner at a chosen site of interest. Another aim of certain embodiments of this invention is to provide antibiotics having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide antibiotics in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of the above aims. Compounds of the Invention

In a first aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof:

(I): wherein X1 is independently selected from: N and CR4; X2 is independently selected from: N and CR5; =A is independently selected from: =0, =S, (-F)2, =NR6 and =NOR6; Y1 and Y2 are each independently selected from C and N; Z\ Z2 and Z3 are each independently selected from 0, S, S(0)2, S(0), N, NR7, CR8 and C=W; wherein W is selected from 0, S or NR6; with the proviso that if none of Z\ Z2 and Z3 is C=W, then the ring formed by Z1, Z2, Z3, Y1 and Y2 contains two endocyclic double bonds and, if one of Z\ Z2 and Z3 is C=W, then the ring formed by Z\ Z2, Z3, Y1 and Y2 contains a single endocyclic double bond; with the further provisos that at least one of Z\ Z2, Z3, Y1 and Y2 is O, S, N or NR7 and that no more than one of Z\ Z2 and Z3 is C=W; R1 is independently selected from: H, F, NR6R9, NR6NR6R9 and Ci-C4-alkyl; R2 is independently selected from: CrCs-alkyl, C2-C8-alkenyl, C2-Cs-alkynyl, CrCs-haloalkyl and Co-C3-alkylene-R10; wherein R10 is selected from C3-Cs-cycloalkyl, 3-6-heterocycloalkyl, C3-Ce-halocycloalkyl, phenyl and heteroaryl; R3 is -W1-Co-C3-alkylene-R11; wherein W1 is selected from acetylene, -0-, -S(0)y- (wherein y is an integer selected from 0, 1 and 2), -NR6-, -NR6S(0)2-, -S(0)2NR6-, -C(0)NR6, -NR6C(0)-, -0C(0)-, -C(0)0-, -0C(0)NR6-, -NR6C(0)0, -NR6C(0)NR6- and -C(O)-; and wherein R11 is independently selected from phenyl, monocyclic heteroaryl, monocyclic 3-10-heterocycloalkyl, monocyclic C3-Cio-cycloalkyl and a bicyclic group comprising two fused rings each independently selected from phenyl, heteroaryl, 3-7-heterocycloalkyl and C3-C7-cycloalkyl; wherein R11 is optionally substituted with 1, 2 or 3 R12 groups; wherein R12 is independently at each occurrence selected from: oxo, =NR6, =NOR6, 3-5-heterocycloalkyl, halo, nitro, cyano, NR6R9, NR6S(0)2R6, NR6CONR6R6, NR6C02R6, OR6, SR6, SOR6, SO3R6, S02Rs, S02NR6R6, C02R6, C(0)R6, CONR6R6, C(0)NR6CR6R6C(0)0R6, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, CrC4-alkylene-OR6, Ci-C4-alkylene-NR6R9, and =CR6aCR6R6NR6R9; R4 is independently selected from: H, O-CrCs-alkyl, halo, CrCs-alkyl, C2-C8-alkenyl, C2-Cs-alkynyl, CrCs-haloalkyl, Ο-CrCs-haloalkyl, C3-C6-cycloalkyl, C3-Cs-heterocycloalkyl, C3-C6-halocycloalkyl; or R4 and R2 together form an alkylene or heteroalkylene chain of the form -(CR6R6)rW2-(CR6R6)s-W3-(CR6R6)t- and which is attached at its respective ends to the substitution point for R4 and R2 respectively; wherein W2 and W3 are each independently selected from: a bond, 0, S and NR6; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W2 and W3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms; or R3 and R4, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups; R5 is independently selected from: H, Ci-C4-alkyl and halo; or R3 and R5, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups; R6 is independently at each occurrence selected from: H and CrC4-alkyl; R6a is independently selected from: H, halogen and Ci-C4-alkyl; where the nitrogen to which R7 is attached has a formal double bond to one of its neighbouring atoms in the ring comprising Z1 and Z2, R7 is absent; or, where the nitrogen to which R7 is attached is attached via formal single bonds to both of its neighbouring atoms in the in the ring comprising Z1 and Z2, R7 is independently selected from: H, Ci-C4-alkyl, and CrC4-haloalkyl; R8 may be independently at each occurrence selected from: H, halo, nitro, cyano, NR6R9, NR6S(0)2R6, NR6CONR6R6, NR6C02R6, OR6; SR6, SOR6, SO3R6, S02R6, S02NR6R6 C02R6 C(0)R6, CONR6R6, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, CR6R6OR6, CR6R80C(0)R6and CR6R6NR6R9; R9 is independently at each occurrence selected from: H, CrC4-alkyl, CrC4-haloalkyl, S(0)2-CrC4-alkyl, C(0)-CrC4-alkyl, C(0)-0-CrC4-alkyl and CH2-phenyl; where any of the alkyl, alkylene, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl (e.g. phenyl) or heteroaryl groups mentioned above are optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from: oxo, =NRa, =NORa, halo, nitro, cyano, NRaRa, NRaS(0)2Ra, NRaCONRaRa, NRaC02Ra, ORa; SRa, S(0)Ra, S(0)20Ra, S(0)2Ra, S(0)2NRaRa, C02Ra C(0)Ra, CONRaRa, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 haloalkyl, CRaRaORa, CRaRaNRaRa, CRaRaNRaC(0)Ra and =CRbCRaRaNRaRa; wherein Ra is independently at each occurrence selected from: H and Ci-C4-alkyl; and Rb is independently at each occurrence selected from: H, halogen, Ci-C4-alkyl and C1-C4-haloalkyl; and wherein any alkylene group is optionally substituted with two substituents which together with the carbon atom or carbon atoms to which they are attached form a C3-C7-cycloalkyl ring or a 3-7-heterocycloalkyl ring; wherein any alkylene group is optionally substituted with a single Co-C3-alkylene-Rc group, wherein Rc is independently aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C7-cycloalkyl.

In an embodiment, the compound of formula (I) is a compound of formula (II):

wherein R1, R2, R3, R5, X1, Z1, Z2 and Z3 are as defined above for formula (I).

In an embodiment, the compound of formula (I) is a compound of formula (III):

(HI) wherein R1, R2, R3, R8, X1, X2 and A are as defined above for formula (I) and wherein Z1 is selected from O and S. It may be that Z1 is O.

In an embodiment, the compound of formula (I) is a compound of formula (IV):

(IV) wherein R1, R2, R3, R5, R8 and X1 are as defined above for formula (I); and wherein Z1 is selected from 0 and S. It may be that Z1 is 0.

In an embodiment, the compound of formula (I) has a structure according to any one or more of formulae (V) to (XXXXXIII):

wherein R1, R2, R3, R7, R8, , W, X1, X2 and A are as defined above for formula (I).

In an embodiment, the compound of formula (I) is a compound of formula (XXXXXIV):

(XXXXXIV) wherein R1, R2, R5, R8, R11, X1 and W1 are as defined above for formula (I) and wherein Z1 is selected from O and S.

In an embodiment, the compound of formula (I) is a compound of formula (XXXXXV):

(XXXXXV) wherein R1, R2, R8, R11, R12 and X1 are as defined above for formula (I) ; and wherein Z1 is selected from O and S; wherein ring A is a 5-7-heterocycloalkyl ring; a is an integer selected from 0 and 1; and b is an integer selected from 0, 1, 2, 3, 4 and 5.

In an embodiment, the compound of formula (I) is a compound of formula (XXXXXVI):

(XXXXXVI) wherein R1, R2, R8, R11, R12 and X2 are as defined above for formula (I); and wherein Z1 is selected from O and S; wherein ring B is a 5-7-heterocycloalkyl ring; c is an integer selected from 0 and 1; and d is an integer selected from 0, 1, 2, 3, 4 and 5.

The following statements apply to compounds of any of formulae (I) to (XXXXXVI). These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may (where chemically allowable) be combined with the features described in one or more other statements below. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the statements below which describe a feature of that compound, expressed at any level of generality, may be combined so as to represent subject matter which is contemplated as forming part of the disclosure of this invention in this specification. X1 may be N. Alternatively, X1 may be CR4. X2 may be N. Preferably, X2 is CR5. A may be selected from O or S. Preferably, A is O.

Preferably, R1 is independently selected from: H, NR6R9, and CrC4-alkyl. Thus, R1 may be H. R1 may be NR6R9, e.g. NHR9. R1 may be CrC4-alkyl, e.g. methyl. R5 may be independently selected from: H, Ci-C4-alkyl and halo. Thus, R5 may be H. Likewise, R5 may be F.

It may be that R3 and R4, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups.

Likewise, it may be that R3 and R5, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups.

It may be that R3 is -W1-Co-C3-alkylene-R11. It may be that R3 is -W1-Ci-alkylene-R11. It may be that R3 is -W1- R11. It may be that W1 is selected from: -0-, -S- and -NR6, e.g. -NH-. It may be that W1 is -NR6-, e.g. NH.

It may be that R11 is independently selected from: 3-10-heterocycloalkyl, phenyl, and 5, 6- or 9 membered heteroaryl comprising 1 or 2 nitrogen atoms within the ring system; wherein the aryl, heteroaryl or heterocycloalkyl group is optionally substituted with 1, 2 or 3 R12 groups. R11 may be 3-ioheterocycloalkyl. Typically, R11 will be an N-heterocycloalkyl group. N-heterocycloalkyl groups may be monocyclic or bicyclic and comprise 1 to 3 nitrogen atoms in the heterocyclic ring system and R11 may be attached to the rest of the molecule via a carbon or a nitrogen in the ring system. It may be that the N-heterocycloalkyl group is attached to the rest of the molecule via the or each nitrogen in the ring system. Any nitrogen in the ring system which is not at a bridgehead or is not the point of attachment of R11 to the rest of the molecule will be NR13; wherein R13 is independently selected from: H, CrC4-alkyl. Unless otherwise stated, any N-heterocycloalkyl group mentioned as a possibility for R11 may be unsubstituted or may be substituted with 1 to 3 R12 groups selected from oxo, =NOR6, NR6R9, OR6, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CR6R6NR6R9 and =CR6CR6R6NR6R9. R11 may be a monocyclic C3-C7-N-heterocycloalkyl group. Thus, R11 may be a piperazine ring. R11 may thus be a piperazine ring substituted with a methyl group, e.g. an N-methyl piperazine ring, a 3-methyl piperazine ring, ora 2-methyl piperazine ring. Alternatively, R11 may be an unsubstituted piperizine group. Any piperazine group will typically be attached to the rest of the molecule via one of the nitrogens in the ring system. Possibly, R11 is an azetidine, pyrrolidine or piperidine ring, optionally wherein the ring nitrogen attaches the aziridine, pyrrolidine or piperidine ring to the rest of the compound. R11 may be an azetidine, pyrrolidine or piperidine ring wherein the ring nitrogen attaches the azetidine, pyrrolidine or piperidine ring to the rest of the compound and which is substituted with a single hydroxyl group. R11 may be a piperidine ring substituted with a single hydroxyl group, e.g. a 4-hydroxy-piperidine ring. R11 may be a pyrrolidine substituted with a single hydroxyl group, e.g. a 3-hydroxypyrrolidine. R11 is a 3-hydroxy aziridine group. R11 may be a bicylic C7-Cio-N-heterocycloalkyl group. Specific examples of R11 groups include:

Further examples

include: R11 may be a bicyclic C7-Cio-N-heterocycloalkyl group. The bicyclic N-heterocycloalkyl group may be attached to the rest of the molecule via either a carbon or a nitrogen in the ring system.

Preferably, R11 is

wherein R14 is R12; or wherein two R14 groups together with the carbon or carbons to which they are attached form a 3-to 6- membered cycloalkyl, a 3- to 6- membered heterocycloalkyl ring, , a 6-membered aryl or 5- or 6- membered heteroaryl ring. Where two R14 groups form a heterocycloalkyl ring, that ring will comprise 1 or 2 heteroatoms selected from N, O and S in the ring system. Where two R14 groups form a cycloalkyl or heterocycloalkyl ring, that ring may be substituted with one or two R12 groups; wherein R12 is independently selected from oxo, =NOR6, NR6R9, OR6, CrC4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CR6R6NR6R9 and =CR6CR6R6NR6R9. m is an integer independently selected from 0, 1, 2, 3 and 4.

It may be that two R14 groups do not form a cycloalkyl or heterocycloalkyl ring. In other words R11 may be

m may be 1. Thus, R11 may be

R12 may be NR6R9. Each R6 and R9 in R12 may be H (e.g. R12 may be NH2). Each R6 and R9 in R12 may independently be C1-C4 alkyl, e.g. each R6 and R9 in R12 may independently be methyl (e.g. R12 may be NMe2). R12 may be OR6. R6 may be H and thus, R12 may be OH. R12 may be CR6R6NR6R9. R12 may be CMe2NR6R9. R12 may be CR6R6NH2. R12 may be CMe2NH2. m may be 2. In one particular example where m is 2, R12 may at one instance be =NOR6 (e.g. =NOMe), and at the other instance be CR6R6NR6R9(e.g. CH2NR6R9 orCH2NH2).

Two R14 groups may form a 3- to 6- membered heterocycloalkyl ring, e.g. a 6-membered heterocycloalkyl ring, e.g. a vicinally fused 6-membered heterocycloalkyl ring. A specific example of a 6-membered heterocycloalkyl ring would be a morpholine ring. The two R14 groups may also form a 3- to 6- membered cycloalkyl ring, e.g. a 3-membered ring. Thus, two R14 groups may form a vicinally fused 3-membered ring or a spiro fused 3-membered ring. That 3-membered ring (e.g. that vicinally fused 3-membered ring) may be substituted with one or two R12 groups independently selected from oxo, =NOR6, NR6R9, OR6, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CR6R6NR6R9 and =CR6CR6R6NR6R9. Thus, the 3-membered ring (e.g. that vicinally fused 3-membered ring) may be substituted with an NR6R9 group, e.g. a NH2 group.

In cases in which two R14 groups form a 3- to 6- membered cycloalkyl or 3- to 6- membered heterocycloalkyl ring, there may be one or more other R14 groups, e.g. m may be 4. Such additional R14 groups will generally not form a 3- to 6- membered cycloalkyl or a 3- to 6-membered heterocycloalkyl ring and will thus be R12 groups. R12 may be CrC4-alkyl, e.g. methyl. R12 may be NR6R9, e.g. NH2.

Specific examples of R11 groups include:

R11 may be Cs-Cs-cycloalkyl group. Typically, where R11 is a Cs-Ce-cycloalkyl group, it is substituted with at least one group selected from NR6R9, OR6, CrC4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CR6R6NR6R9 and =CR6aCR6R6NR6R9. Specifically, R11 may be a cyclopropyl group substituted with a NH2 group. A specific example of an R11 group is R11 may be an aryl group, e.g. a phenyl group. R11 may be a phenyl group with at least one NR6R9, CONR6R6 , CR6R6OR6 or CR6R6NR6R9 group and optionally further substituted with from 1 to 3 groups independently selected from halo, CrC4-haloalkyl and Ci-C4-alkyl, e.g. a phenyl group with at least one NR6R9, CONR6R6, or CR6R6NR6R9 group and optionally further substituted with from 1 to 3 halo groups (e.g. fluoro groups). Thus, R11 may be a phenyl group with at least one NR6R9 or CR6R6NR6R9 group and optionally further substituted with from 1-3 groups independently selected from halo, CrC4-haloalkyl and C1-C4-alkyl, e.g. a phenyl group with at least one NR6R9 or CR6R6NR6R9 group and optionally further substituted with from 1-3 halo groups (e.g. fluoro groups). In particular embodiments, R11 may be a group selected from:

R11 may have the structure:

j wherein ring C is 5- or 6- membered heterocycloalkyl ring or a 5- or 6- membered cycloalkyl ring; and wherein a single one of X3, X4, X5 and X6 is a carbon and is the point of attachment to the ring comprising X1 and X2; and the remainder of X3, X4, X5 and X6 are independently selected from N and CR15; R15 is H or is R12; and e is an integer selected from 0, 1, 2 or 3 provided that X3, X4, X5, X6 and a are selected such that R11 contains no more than three R12 groups.

It may be that ring C has an NR6 group, either in the ring or as a substituent. Thus, it may be that either ring C is heterocycloalkyl group comprising an NR6 group in the ring or that ring C is substituted with at least one R12 group, that R12 group comprising NR6R9.

It may be that ring C is a 5- or 6-membered heterocycloalkyl ring, e.g. a 5- or 6-membered heterocycloalkyl ring comprising at least one nitrogen atom in the ring. Ring C may be a 6-membered heterocycloalkyl ring. Thus, R11 may have the structure:

Ring C may be a 6-membered heterocycloalkyl ring comprising at least one nitrogen atom in the ring. Thus, R11 may have the structure:

It may be that ring C is a 5-membered cycloalkyl ring or a 5-membered heterocycloalkyl ring. It may be that ring C has an NR6 group, either in the ring or as a substituent. It may be that either ring C is a 5-membered heterocycloalkyl group comprising an NR6 group in the ring or that ring C is substituted with at least one R12 group, that R12 group comprising NR6R9.

It may be that R11 may have the structure:

wherein V1 is selected from NR6 and CHNR6R9; and wherein f is an integer selected from 0, 1 and 2. e may be 0. Thus, f may be 0. V1 may be NR6. R6maybeH. V1 may be CHNR6R9. R6 may be Η. V1 may be CHNH2.

Preferably, X4 is a carbon and is the point of attachment of R11 to the ring comprising X1 and X2. X3 may be N. X3 may be CR15, e.g. CH. X5 may be N. X3 may be CR15, e.g. CH. X6 may be N. X3 may be CR15, e.g. CH. It may be that X3, X5 and X6 are each CR15. Thus, it may be that X3, X5 and X6 are each CH. R11 may also be a heteroaryl group. R11 may be a heteroaryl group comprising at least one nitrogen atom in the ring structure. R11 may be a heteroaryl group comprising at least one nitrogen atom in the ring system and substituted with at least one NR6R9, CONR6R6, or CR6R6NR6R9 group and optionally further substituted with from 1 to 3 groups independently selected from halo, CrC4-haloalkyl and

CrC4-alkyl. R11 may be a heteroaryl group comprising at least one nitrogen atom in the ring system and substituted with at least one NR6R9 group.

Exemplary R11 groups include:

R11 may be a 9-membered bicyclic heteroaryl group. R11 may be a 9-membered heteroaryl group comprising 1, 2 or 3 (e.g. 1 or 2) nitrogen atoms in the ring system. R11 may be an indazole group, e.g. R11 may be

R11 may be a benzimiazole, e.g. R11 may be

R11 may be a benzoxadiazole, e.g. R11 may be

R11 may be indole, e.g. R11 may be

It may be that R11 is not a benztriazole. R11 may comprise a pyridine ring fused to a 5 membered heteroaryl ring, e.g. a 5-membered heteroaryl ring comprising 1 or 2 nitrogen atoms in the ring. Thus, further exemplary R11 groups include

and

R11 may be a 6-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system. Thus R11 may be a group selected from pyridinyl, pyrimidine, pyrazine. Where R11 is a 6-membered monocyclic heteroaryl group, it may be substituted with at least one NR6R9, CONR6R6, or CR6R6NR6R9 group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl. Where R11 is a 6-membered monocyclic heteroaryl group, it may be substituted with at least one NR6R9 group. Thus, R11 may be an amino-pyridinyl group (e.g.a 6-amino-pyridin-3-yl group) or an amino pyrimidine (e.g. 2-amino-pyrimidin-5-yl group). R11 may be a 5-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system, e.g. a thiazole or pyrazole.

In certain preferred embodiments, R11 is selected from phenyl, pyridinyl, pyrimidine, pyrazine, a 9-membered heteroaryl group comprising 1 or 2 nitrogen atoms in the ring system or a bicyclic group comprising phenyl ring fused to a ring selected from 3-7 heterocycloalkyl and C3-C7 cycloalkyl.

In certain preferred embodiments, R11 is selected from phenyl or 6-membered heteroaryl (e.g. pyridine or pyrimidine) and has an NR6R9 (e.g. an NH2) group situated para to the position at which the R11 group is attached to the rest of the molecule. R2 may independently be selected from: Ci-C6-alkyl, CrC6-haloalkyl, and Co-C3-alkylene-R10; wherein R10 is selected from C3-C6-cycloalkyl, Cs-Ce-halocycloalkyl, phenyl and pyridyl. Preferably, R2 is independently selected from: Ci-Ce-alkyl, CrCe-haloalkyl, and C0-C3-alkylene-R10; wherein R10 is selected from C3-C6-cycloalkyl and C3-Ce-halocycloalkyl. It may be that the group Co-C3-alkylene-R10 is R10. Thus, R2 may be selected from Ci-Ce-alkyl (e.g. C2-C4-alkyl) and C3-Ce-cycloalkyl (e.g. C3-C4-cycloalkyl). R2 may be selected from C3-C6-cycloalkyl and C3-C6-halocycloalkyl. R2 may be C3-C6-cycloalkyl. In certain particular embodiments, R2 is ethyl. In certain other particular embodiments, R2 is cyclopropyl. The alkyl, haloalkyl, alkylene, cycloalkyl and halocycloalkyl groups in R2 may be unsubstituted. R4 may be independently selected from: H, 0-CrC4-alkyl, halo, Ci-C4-alkyl, Ci-C4-haloalkyl and 0-CrC4-haloalkyl. Preferably, R4 is independently selected from: 0-Ci-C4-alkyl, Ci-C4-alkyl, CrC4-haloalkyl and 0-CrC4-haloalkyl. R4 may be H. R4 may be Cl or F. R4 may be methyl. R4 may be OMe.

It may be that R5 is F and R4 is H. It may be that R5 is H and R4 is CrC4 alkyl, (e.g. Me). It may be that R5 is F and R4 is Cl.

In a preferred alternative, R4 and R2 together form an alkylene or heteroalkylene chain of the form -(CR6R6)rW2-(CR6R6)s-W3-(CR6R6)t- and which is attached at its respective ends to the substitution point for R4 and R2 respectively; wherein W2 and W3 are each independently selected from: a bond, O, S and NR6; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W2 and W3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms. It may be that r, s, t, W2 and W3 are chosen such that the total length of the alkylene or heteroalkylene chain is 3 atoms. It may be that r is 0 and W2 is O. Preferably, R4 and R2 may together form an alkylene or heteroalkylene chain of the form -W2-(CR6R6)S-. For the absence of doubt, W2 is attached to the rest of the molecule at the substitution point for R4 and the CR6R6 at the opposite end of the chain to W2 is attached to the rest of the molecule at the substitution point for R2. Preferably, s is 2. Preferably, W2 is 0.

Thus, preferably, R4 is independently selected from: Cl, 0-Ci-C4-alkyl, CrC4-alkyl, C1-C4-haloalkyl and 0-CrC4-haloalkyl; or R2 and R4 may together form an alkylene or heteroalkylene chain of the form -0-(CR6R6)2- and which is attached at its respective ends to the substitution point for R4 and R2 respectively.

In certain preferred embodiments, R4 is Me and R2 is cyclopropyl.

It may be that A is O; R1 is independently selected from: H, NR6R9, and Ci-C4-alkyl; X1 is CR4; X2 is CR5; R2 is independently selected from: CrC6-alkyl, Ci-Ce-haloalkyl, and C0-C3-alkylene-R10; wherein R10 is selected from Cs-Ce-cycloalkyl and Cs-Ce-halocycloalkyl; and R4 is independently selected from: Cl, 0-CrC4-alkyl, CrC4-alkyl, Ci-C4-haloalkyl and O-C1-C4 haloalkyl; or R2 and R4 may together form an alkylene or heteroalkylene chain of the form -0-(CR8R8)2- and which is attached at its respective ends to the substitution point for R4 and R5 respectively. Furthermore, it may be that R1 is H. It may also be that R4 is CrC4-alkyl. R3 may be -W1-Co-C3-alkylene-R11, wherein R11 is selected from phenyl, 6- or 9- membered heteroaryl comprising at least one nitrogen and a bicyclic group comprising a phenyl ring fused to a ring selected from 3-7-heterocycloalkyl and C3-C7-cycloalkyl.

It may be that Y1 and Y2 are both C. Preferably, Y1 and Y2 are not both N.

It may be that no more than one of Z1, Z2 and Z3 is selected from N or NR7.Thus, Z1 and Z3 may each be independently selected from 0, S, S(0), NR7 and CR8; Z2 is independently selected from 0, S, S(0), NR7, CR8 and C=W. It may be that Z2 is C=W, e.g. C=0.

It may be that Z1,Z2 and Z3 are each independently selected from O, S, NR7 and CR8. Thus, it may be that Y1 and Y2 are each independently selected from C and N; Z1, Z2 and Z3 are each independently selected from 0, S, NR7 and CR8; with the proviso that the ring formed by Z1, Z2, Z3, Y1 and Y2 contains two endocyclic double bonds; and with the further proviso that at least one of Z\ Z2, Z3, Y1 and Y2 is 0, S, N or NR7.

It may be that Z\ Z2, Z3, Y1 and Y2 together form an imidazole, tetrazole, pyrazole or pyrole ring. It may be that one of Y1 and Y2 is N and the other is C. Thus, it may be that Z\ Z2, Z3, Y1 and Y2 together form an imidazole, tetrazole, pyrazole or pyrole ring in which one of Y1 andY2isN. It may be that Y1 is N. It may be that Y2 is N.

It may be that Z1, Z2, Z3, Y1 and Y2 together form a thiophene, furan, or pyrrole ring. Thus, it may be that a single one of Z\ Z2 and Z3 is independently selected from 0, S and NR11 and the remaining two of Z\ Z2 and Z3 are each CR8.

It may be that Z1, Z2, Z3, Y1 and Y2 together form a pyrazole, oxazole, imidazole, thiazole, isoxazole or isothiazole ring. Thus, it may be that a single one of Z\ Z2 and Z3 is independently CR8 and the remaining two of Z\ Z2 and Z3 are selected from 0, S and NR2

It may be that Z1, Z2, Z3, Y1 and Y2 together form a oxazole, thiazole, isoxazole or isothiazole ring. Thus, it may be that both Y1 and Y2 are C and Z1, Z2 and Z3 are selected from CR8, 0, S and N; wherein a single one of Z\ Z2 and Z3 is N and that N must form part of a C=N endocyclic double bond; and wherein a single one of Z1, Z2 and Z3 is CR8. For the absence of doubt, the remaining Z1, Z2 or Z3 is selected from 0 and S. R8 may be independently at each occurrence selected from: H, halo, nitro, cyano, S(0)R6, S(0)20R6, S(0)2R6, S(0)2NR6R6 C02R6 C(0)R6, CONR6R6, CrC4-alkyl, C2-C4-alkynyl, C2-C4-alkenyl, CrC4-haloalkyl, CR6R6OR6 and CR6R6NR6R9. R8 may be independently at each occurrence selected from: halo, nitro, cyano, S(0)R6, S(0)20R6, S(0)2R6, S(0)2NR6R6 C02R6, C(0)R6, CONR6R6, CrC4-alkyl, C2-C4-alkynyl, C2-C4-alkenyl, Ci-C4-haloalkyl, CR6R6OR6 and CR6R6NR6R9. R8 may be independently at each occurrence selected from: H, halo, nitro, CrC4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CrC4-haloalkyl. R8 may be independently at each occurrence selected from: halo, nitro, CrC4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CrC4-haloalkyl CR8R8OR8 and CR8R8NR8R9. R8 may be independently at each occurrence selected from: CrC4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CrC4-haloalkyl CR6RsOR6 and CR6R6NR6R9. R8 may be independently at each occurrence selected from: H. Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CrC4-haloalkyl, CR6R6OR6 and CR6R6NR6R9. R8 may be independently at each occurrence selected from: H. CrC4-alkyl, CR6R6OR6 and CR6R8NR6R9. R8 may be independently selected from CR6R6OR6 and CR6R6NR6R9. R12 may be CR6R6NR6R9.

Where present, W is preferably O.

It may be that A is O; R1 is Η; X1 is CR4; X2 is CR5; R3 may be -W1-Co-C3-alkylene-R11, wherein R11 is selected from phenyl, 6- or 9-membered heteroaryl comprising at least one nitrogen and a bicyclic group comprising a phenyl ring fused to a ring selected from 3-7 heterocycloalkyl and C3-C7-cycloalkyl; R2 is independently selected from CrC4-alkyl, Ci-C4-haloalkyl, cyclopropyl and halocyclopropyl and R4 is independently selected from: 0-Ci-C4-alkyl, CrC4-alkyl; or R2 and R4 may together form an alkylene or heteroalkylene chain of the form -0-(CR6R6)2- and which is attached at its respective ends to the substitution point for R2 and R4 respectively; both Y1 and Y2 are C and Z1, Z2 and Z3 are selected from CR8, 0, S and N; wherein a single one of Z\ Z2 and Z3 is N and that N must form part of a C=N endocyclic double bond; wherein a single one of Z1, Z2 and Z3 is CR8 and wherein R8 is independently at each occurrence selected from: H. Ci-C4-alkyl, CR6R6OR6 and CR6R6NR6R9

The compound of formula (I) may be any one of Examples 1 to 7 below.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or Z/E) isomers are possible. Specifically, the oxime groups present in certain compounds of the invention may be present as the E-oxime, as the Z-oxime or as a mixture of both in any proportion. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Where structurally isomeric forms of a compound are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety.

Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted into the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).

It follows that a single compound may exhibit more than one type of isomerism.

The term Cm-Cn refers to a group with m to n carbon atoms.

The term “alkyl” refers to a monovalent radical which is a linear or branched hydrocarbon chain. For example, Ci-Ce-alkyl may refer to methyl, ethyl, η-propyl, /so-propyl, /7-butyl, sec-butyl, ferf-butyl, /7-pentyl and /7-hexyl. The alkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, ORa or NHRa.

The term “alkylene” refers to a divalent radical which is a linear hydrocarbon chain. For example, Ci-C3-alkylene may refer to -CH2-, -CH2CH2-, or -CH2CH2CH2- or substituted equivalents thereof. Thus, the alkylene groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, ORa or NHRa. For the absence of doubt a Co-alkylene is a bond. Thus, where a group comprises a Co-Cm-alkylene, the Co-Cm-alkylene could be either a bond or a Ci-Cm-alkylene.

Acetylene refers to the following divalent group:

The term “haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C6 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2.2.2- trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1.2.2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A halo alkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom.

The term “alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkenyl” may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be fluorine, ORa or NHRa.

The term “alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond. The triple bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkynyl” may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be fluorine, ORa or NHRa.

The term “cycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, “C3-C6-cycloalkyl” may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be fluorine, ORa or NHRa.

The term “aromatic” when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane.

The term “aryl” refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π system are in the same plane. For example, the “aryl” may be phenyl and naphthyl. The aryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each aryl group independently may be Ci-C4-alkyl, CrC4-haloalkyl, cyano, halogen, ORa or NHRa.

The term “heteroaryl” may refer to any aromatic (i.e. a ring system containing (4n + 2) tt-electrons or n- electrons in the π-system) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from 0, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from 0, 5 and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine. Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones. The heteroaryl system itself may be substituted with other groups. The heteroaryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each heteroaryl group independently may be Ci-C4-alkyl, CrC4-haloalkyl, cyano, halogen, 0Ra or NHRa.

The term “m-nheterocycloalkyl” may refer to an m-n membered monocyclic or bicyclic saturated or partially saturated groups comprising 1 or 2 heteroatoms independently selected from 0, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from 0, S and N). By partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to monocyclic rings with from 5 to 8 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahyd ropy ran, dihydropyran, dioxane, azepine. Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may be share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms. The heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be fluorine, 0Ra or NHRa.

The aryl and heteroaryl groups are optionally substituted with 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NRaRa, NRaS(0)2Ra, NRaCONRaRa, NRaC02Ra, 0Ra; SRa, S(0)Ra, S(0)20Ra, S(0)2Ra, S(0)2NRaRa, C02Ra C(0)Ra, CONRaRa, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CrC4-haloalkyl, CRaRaORa, CRaRaNRaRa, and CRaRaNRaC(0)Ra; wherein Ra is independently at each occurrence selected from: H and CrC4-alkyl.

Where the compound of formula (I) is an N-oxide, it will typically be a pyridine N-oxide, i.e. where the compound of formula (I) comprises a pyridine ring, the nitrogen of that pyridine may be N+-0\ Alternatively, it may be that the compound of the invention is not an N-oxide.

The present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXXXVI) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150,170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.

Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

Medical uses, methods of treatment and pharmaceutical formulations

Each of the compounds of the present invention may be used as a medicament. Thus, in another aspect of the invention, there is provided compound as defined above for the treatment of bacterial infections.

The compounds and formulations of the present invention may be used in the treatment of a wide range of bacterial infections. In some embodiments, the compounds can be used to treat bacterial infections caused by one or more resistant strains of bacteria, e.g. one ore more strains of bacteria which are resistant to one or more approved antibiotics. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram positive bacteria. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram negative bacteria.

The compounds and formulations of the present invention can be used to treat both Gram positive and Gram negative bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staphylococcus aureus). The compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, Escherichia coli, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, Helicobacter pylori, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo.

The compounds and formulations of the invention may be used to treat infections caused by bacteria which are in the form of a biofilm.

The term ‘resistant’ is intended to refer to strains of bacteria that have shown nonsusceptibility to one or more known antibacterial drug. A non-susceptible strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a higher number than for corresponding susceptible strains. For example, it may refer to strains that are non-susceptible to β-lactam antibiotics, strains that are non-susceptible to one or more fluoroquinolones and/or strains that are non-susceptible to one or more other antibiotics (i.e. antibiotics other than β-lactams and fluoroquinolones).

In certain embodiments, the term ‘resistant’ may refer to one in which the MIC of a given compound or class of compounds for that strain has shifted to a significantly higher number than for corresponding susceptible strains. A bacterial strain might be said to be resistant to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic failure.

The term ‘approved’ is intended to mean that the drug in question had been approved by either the US FDA or the EMA on the 1 August 2015.

The bacterial strain may (e.g. the MRSA strain) be resistant to one or more fluoroquinolone antibiotics, e.g. one or more antibiotics selected from levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin. The bacterial strain may (e.g. the MRSA strain) be resistant to one or more approved fluoroquinolone antibiotics

The compounds of the invention may be particularly effective at treating infections caused by Gram positive bacteria. The compounds of the invention may be particularly effective at treating infections caused by Gram positive bacteria which are resistant to one or more antibiotics, e.g. one or more approved antibiotics. The compounds of the invention may be particularly effective at treating infections caused by Gram positive bacteria which are resistant to one or more fluoroquinolone antibiotics. The compounds of the invention may be particularly effective at treating infections caused by MRSA and/or methicillin-resistant S. epidermidis. The compounds of the invention may be particularly effective at treating infections caused by strains of Staphylococcus aureus and/or S. epidermidis which are resistant to one or more fluoroquinolone antibiotics. The compounds of the invention may be particularly effective at treating infections caused by MRSA and/or methicillin-resistant S. epidermidis that is also resistant to one or more fluoroquinolone antibiotics.

The compounds of the invention may be particularly effective at treating infections caused by Gram negative bacteria. The compounds of the invention may be particularly effective at treating infections caused by Gram negative bacteria which are resistant to one or more antibiotics, e.g. one or more approved antibiotics. The compounds of the invention may be particularly effective at treating infections caused by Gram negative bacteria which are resistant to one or more fluoroquinolone antibiotics.

The compounds of the invention may be particularly effective at treating infections caused by Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp.. These pathogens are all fastidious

Gram-negative organisms. A fastidious bacterium is one having a complex nutritional requirement, i.e. one which will only grow when specific nutrients are included in the culture medium. As an example Neisseria gonorrhoeae requires, amongst other supplements, iron, several amino acids, cofactors and vitamins in order to grow. Members of the fastidious Gram-negative bacteria group often share common antibiotic susceptibility profiles.

Pathogenic Neisseria species include Neisseria gonorrhoeae (the pathogen responsible for gonorrhoea) and Neisseria meningitidis (one of the pathogens responsible for bacterial meningitis). Infections which can be treated include secondary infections which can arise from lack of treatment of a primary Neisseria gonorrhoeae infection. Exemplary secondary infections include urethritis, dysuria, epididymitis, pelvic inflammatory disease, cervicitis and endometritis and also systemic gonococcal infections (e.g. those manifesting as arthritis, endocarditis or meningitis). The gonorrhoea infection may be one caused by a strain of Neisseria gonorrhoeae which is resistant to at least one approved antibacterial drug, e.g. at least one approved β-lactam drug.

The compounds of the invention can be used to treat or prevent mycobacterial infections, e.g. mycobacterial infections caused by strains of mycobacteria which are resistant to approved mycobacterials. Thus, they can be used to treat TB or leprosy. The compounds may be used to treat resistant strains of TB, e.g. MDR-TB (i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin), XDR-TB (i.e. TB infections caused by strains which are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin) and/or TDR-TB (i.e. TB infections caused by strains which have proved resistant to every drug tested against it with the exception of a compound of the invention).

The compound of the invention can be used to treat infections caused by obligate anaeoric bacteria, e.g. resistant strains of obligate anaerobic bacteria. The compounds may be used to treat Clostridia spp., e.g. Clostridium difficile, including those resistant to other approved antibiotics.

The compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains which are category A pathogens as identified by the US government (e.g. those which cause anthrax, plague etc.) and/or they may be strains which are category B pathogens as identified by the US government (e.g. those which cause Glanders disease, mellioidosis etc). In a specific embodiment, the compounds and formulations of the present invention can be used to treat or to prevent infections caused by Gram positive bacterial strains associated with biowarfare (e.g. anthrax). More particularly, the compounds and formulations may be used to treat category A and/or category B pathogens as defined by the US government on 1st Jan 2014.

The compounds of the present invention may also be used in treating other conditions treatable by eliminating or reducing a bacterial infection. In this case they will act in a secondary manner alongside for example a chemotherapeutic agent used in the treatment of cancer.

The compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parastic infections and/or viral infections.

The compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.

The compounds of the invention may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxy maleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg). A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", Μ. E. Aulton, Churchill Livingstone, 1988.

The compounds of the invention may be administered in combination with other active compounds (e.g. antifungal compounds, oncology compounds) and, in particular, with other antibacterial compounds or with antibiotic potentiators, such as efflux pump inhibitors. The compound of the invention and the other active (e.g. the other antibacterial compound) may be administered in different pharmaceutical formulations either simultaneously or sequentially with the other active. Alternatively, the compound of the invention and the other active (e.g. the other antibacterial compound) may form part of the same pharmaceutical formulation.

Examples of other bacterial compounds which could be administered with the compounds of the invention are penems, carbapenems, fluoroquinolones, β-lactams, vancomycin, erythromycin or any other known antibiotic drug molecule.

Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.

The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or by inhalation (i.e. in the form of an aerosol or by nebulisation).

If administered topically, high-dosages of the compounds of the invention can be administered. Thus, a compound with an in vitro MIC of, for example, 16-64 pg/mL may still provide an effective treatment against certain bacterial infections.

For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of the invention 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

Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

In another aspect the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient. The formulation may further comprise one or more other antibiotics, e.g. one or more fluoroquinolone antibiotics. Illustrative fluoroquinolone antibiotics include levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin.

In another aspect of the invention is provided a method of treating a bacterial infection, the method comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention.

In an aspect of the invention is provided a compound of the invention for medical use. The compound may be used in the treatment of any of the diseases, infections and indications mentioned in this specification.

In yet another aspect of the invention is provided a compound for use in the preparation of a medicament. The medicament may be for use in the treatment of any of the diseases, infections and indications mentioned in this specification.

Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, means “including but not limited to”, and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Synthesis

The skilled man will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions), "March's Advanced Organic Chemistry -Reactions, Mechanisms and Structure”, MB Smith, J. March, Wiley, (5th edition or later) “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection / deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.

Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.

Throughout this specification these abbreviations have the following meanings: ACN = acetonitrile aq. = Aqueous DCM = dichloromethane DMF = N, /V-dimethylformamide DMSO = dimethyl sulfoxide dppf = 1,1'-Bis(diphenylphosphino)ferrocene

EtOAc = ethyl acetate FBS = Foetal Bovine Serum HEPES = 4-(2-Hydroxyethyl)-1-piperazineethanesulponic acid IPA = Isopropanol NMP = N-Methyl-2-pyrrolidone TFA = trifluoroacetic acid THF = tetrahydrofuran

Certain compounds of the invention may be made according to or analogously to the synthetic Schemes A-X. Throughout Schemes A-X, W represents a halogen. Certain compounds of the invention can be made according to or analogously to the methods described in examples 1 to 6. Certain compounds of the invention can be made analogously to the methods described in PCT/GB2015/051107 (unpublished at time of filing).

Certain compounds of formula (XXXXV) can be made via Schemes A and B:

Scheme A

Amine (1) can be converted into α-keto-amide (2) using chloral hydrate (e.g. in the presence of HCI and Na2S04 in water followed by NH2OH.HCI). α-Keto-amide can subsequently alkylated with R2W in the presence of a base (e.g. K2CO3 optionally with heating) to form α-keto-amide (3). α-Keto-amide (3) can alternatively be made from amine (4) via a reaction with oxalyl chloride (e.g. in DCM optionally with heating) followed by a ring closing Friedel-Crafts reaction (e.g. with AICI3 optionally at 0°C). Key intermediate (5) can be obtained from amide (3) by reaction with H2O2 and aq. NaOH (e.g. at room temperature).

Scheme B

Acid amine (5) can be converted into diamine (6) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by ‘BuOH and treating the product with TFA). A condensation reaction (e.g. using EtOH as a solvent optionally with heating) with an appropriate α-ester-aldehyde (e.g. EtC>2CCHO) can provide bicycle (7). Tetrazole formation can be effected by reaction with H2O2 and aq. NaOH and then by POCI3 in DCM (optionally at a temperature of from 0°C to 45°C) followed by azide displacement of the resultant halide (e.g. with NaN3 in acetonitrile optionally at room temperature). Finally, tetrazole (8) can be converted into tetrazole (9) (a subset of compounds of formula (XXXXV)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXVII) can be made via Scheme C:

Scheme C

The synthesis again starts with acid amine (5) which is initially converted into the nitrile via dehydration of the corresponding unsubstituted amide. The amide can be made for example by treatment with thionyl chloride and DMF in THF (optionally with heating) to form the acid chloride and subsequent reaction with ammonia gas (e.g. in THF at 0°C) and the dehydration can be achieved by treating the amide with P2O5 (optionally at room temperature initially and then heating to 75°C). Carbamate formation (e.g. using CIC(0)0Et with NaHCOs in 2-butanone) provides carbamate (11). Cyclisation with formic hydrazide (e.g. in DMF with heating) provides 1,2,4-triazole (12) which can finally be converted into triazole (13) (a subset of compounds of formula (XXXXVII)). Where W1 is -Ο-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXX) can be made via Scheme D:

Scheme D

Triazole (14) can be prepared from intermediate (7) by reaction with H2O2 and aq. NaOH and then with POCI3 in DCM (optionally at a temperature of from 0°C to 45°C) followed by hydrazine displacement of the resultant halide (e.g. in ethanol). The resultant hydrazide product can be converted into triazole (14) by reaction with triethylorthoformate. Triazole (14) can then be converted into 1,2,4-triazole (15) (a subset of compounds of formula (XXXXX)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXXI) can be made via Scheme E:

Scheme E

Intermediate (5) can be acetylated (e.g. with AcCI, Et3N optionally in dioxane at room temperature). Acid (16) can be converted into amine (17) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by *BuOH and treating the product with TFA). Diazotisation reaction (e.g. with HCI and NaNC>2 optionally in EtOH at 0-5°C) followed by reaction with ethyl-2-chloroacetoacetate (e.g. in the presence of NaOAc) and treatment of the product with NH3 (g) (e.g. in THF) can provide compound (18). CIC(0)C02Et (e.g. in Et20 at room temperature) can then be used to generate compound (19) which upon heating can cyclise to form triazole (20). Decarboxylation and deacetylation (e.g. by heating with NaOH in EtOH) can produce triazole (21). Triazole (21) can then be converted into 1,2,4-triazole (22) (a subset of compounds of formula (XXXXXI)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXXII) can be made via Scheme F:

Scheme F

Addition of ethyldiazoacetate (e.g. with Et2NH and EtOH) to intermediate (3) can provide alcohol (23) which, upon treatment with a Lewis acid and t-BuOH (e.g. BF3.OEt2 in acetonitrile and t-BuOH optionally at room temperature) can ring open to form alkyne (24). 1.3- dipolar cycloaddition with an appropriately substituted azide (e.g. with heating in toluene) can provide triazole (25). Upon carbamate removal (e.g. with TFA) and heating triazole (25) can cyclise to form tricycle (26). Tricycle (26) can then finally be converted into 1.2.3- triazole (27) (a subset of compounds of formula (XXXXXII)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXVIII) can be made via Scheme G:

Scheme G

Reaction of urea with intermediate (5) (e.g. by heating in a high-boiling solvent such as DMSO) can provide bicycle (28). Treatment with Lawesson’s reagent (e.g. in dioxane) and subsequent methylation (e.g. by heating with Mel in acetone) can provide thiane (30). Displacement of the SMe group with hydrazide (e.g. by heating in EtOH) can produce hydrazide (31) which, upon reaction with triethylorthoformate (e.g. with TFA) can give triazole (32). Triazole (32) can then be converted into 1,2,4-triazole (33) (a subset of compounds of formula (XXXXVIII)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXVI) can be made via Scheme H:

Scheme H

Intermediate (31) can be converted into tetrazole (34) (e.g. using NaN02 and HCI optionally in EtOH at 0-5 °C). Tetrazole (34) can then be converted into tetrazole (35) (a subset of compounds of formula (XXXXVI)). Where W1 is -0-, -S- or-NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXIX) can be made via Scheme I:

Scheme I

Amine (40) can be obtained from intermediate (4). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions. Bromination (e.g. using Br2 in acetic acid and sodium acetate optionally at room temperature) can provide bromide (41). Subsequent acylation with an appropriate acylating agent (e.g. an acid chloride, exemplary conditions being with EtsN optionally in THF with heating) can provide amide (42). Finally a intramolecular cross-coupling reaction (e.g. using CU2O, 4,7-dimethoxy-1,10-phenanthroline, CS2CO3, PEG, n-PrCN, Δ) can provide imidazole (43) (a subset of compounds of formula (XXIX)).

Certain compounds of formula (XXX) can be made via Scheme J

Scheme J

Intermediate (6) can be converted into chloride (45) by treatment with oxalyl chloride (e.g. in DCM at room temperature) followed by treatment with POCb (optionally with heat). Chloride displacement with aminoacetaldehyde diethyl acetal can provide acetal (46) which in the presence of acid (e.g. tosic acid in isopropyl alcohol) can cyclise to form imidazole (47). Imidazole (47) can then be converted into imidazole (48) (a subset of compounds of formula (XXX)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (VIII) can be made via Scheme K:

Scheme K

Intermediate (5) can be converted to enol (49) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl nitroacetate (e,g. heating with EbN in THF). Enol (49) can be converted into enamine (51) by chlorination (e.g. by heating with POCb), displacement of the resultant chlorine with a protected amine (e.g. 4-methoxybenzylamine optionally in DMF at room temperature) and then deprotecting the amine (in the case of 4-methoxybenzylamine this can be achieved using TFA, e.g. in DCM at room temperature). Reduction of the nitro group (e.g. by heating with NaHSOs in EtOH and H2O) can provide the diamine (52) which can be converted into the imidazole (53) by reaction with triethylorthoformate (e.g. by heating with triethylorthoformate). Imidazole (53) can be converted into imidazole (54) (a subset of compounds of formula (VIII)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (IX) can be made via Scheme L:

Scheme L

Intermediate (5) can be converted into bicycle (55) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl 2-(benzyloxy)acetate (e.g. by heating with EtjN in THF). A similar chlorination, amination, deprotection sequence to that used in Scheme K above can generate amine (57). The benzyl protecting group of amine (57) can be removed (e.g. using Pd/C and H2 in MeOH at room temperature) to provide aminoenol (58) which can be converted into the oxazole (59) by reaction with triethylorthoformate (e.g. by heating with triethylorthoformate). Oxazole (59) can be converted into oxazole (60) (a subset of compounds of formula (IX)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXI) can be made via Scheme M:

Scheme M A sequential palladium coupling of intermediate (41) to bis(pinacolato)diboron (e.g. using Pd(dppf)Cl2 and KOAc in 1,4 dioxane at 80°C) and then to an appropriately substituted 1-benzyl-5-bromopyrazole (e.g. using Pd(dppf)CI2 and Cs2COz in a 10:1 dioxane:H20 mixture at 70°C) provides pyrazole (62). Removal of the benzyl protecting group (e.g. using Pd/C and H2 in MeOH at room temperature) and subsequent reaction with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide pyrazole (64) (a subset of compounds of formula (XXXI)).

Certain compounds of formula (XXVIII) can be made via Scheme N:

Scheme N

Reaction of intermediate (41) with an appropriate acylating agent (e.g. 2H-pyrazole-3-carboxylic acid, exemplary conditions being to do so by heating with propylphosphonic anhydride and diisopropylamine in THF) can provide amide (65) which can undergo an intramolecular cross-coupling reaction (e.g. using CU2O, 4,7-dimethoxy-1,10-phenanthroline, CS2CO3, PEG, n-PrCN, Δ) to provide pyrazole (66) (a subset of compounds of formula (XXVIII)).

Certain compounds of formula (XVIII) can be made via Scheme O:

Scheme 0

Boc protection of amine (41) can provide carbamate (67). A sequential palladium coupling of intermediate (67) to bis(pinacolato)diboron (e.g. using Pd(dppf)Cl2 and KOAc in 1,4 dioxane at 80°C) and then to an appropriately substituted Boc-protected 4-bromo-1H-pyrazole-5-carboxylic acid methyl ester (e.g. using Pd(dppf)Cl2 and CS2CO3 in a 10:1 dioxane:H20 mixture at 70°C) provides pyrazole (69). Boc deprotection (e.g. using TFA in DCM at room temperature) followed by ester hydrolysis (e.g. using aq. NaOH in EtOH) and lactam formation (e.g. by heating with propylphosphonic anhydride and diisopropylamine in THF) can provide pyrazole (71) (a subset of compounds of formula (XVIII)).

Certain compounds of formula (XXIV) can be made via Scheme P:

Scheme P

Intermediate (5) can be converted into β-ketoamide (72) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl 3-(benzyloxy)propanoate (e.g. with heating in DMF following deprotonation of ethyl 3-(benzyloxy)propanoate with NaH). β-Ketoamide (72) can be converted into β-ketoamide (73). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions. Removal of the benzyl protecting group (e.g. using Pd/C and H2 optionally in MeOH at room temperature) followed by oxidation (e.g. using Dess-Martin Periodinane optionally in DCM at room temperature) can provide aldehyde (75). Treatment of aldehyde (75) with hydrazine (e.g. as hydrazine hydrate in THF in the presence of acetic acid) can provide pyrazole (76) (a subset of compounds of formula (XXIV)).

Certain compounds of formula (III) can be made via Scheme Q:

Scheme Q

Intermediate (5) can be converted into oxazole (77) by treating with triphosgene (e.g. in THF at room temperature) and reacting the product with ethyl isocyanate (e.g. by heating in the presence of EtsN in THF). Cyclisation (e.g. by heating with NaH in DMF) can provide oxazole (78) which can be converted into oxazole (79) (a subset of compounds of formula (III). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (III) can be made via Scheme R:

Scheme R

Coupling of intermediate (68) with 5-ethyl-5-iodothiazole-4-carboxylate (e.g. using Pd(dppf)Cl2 and Cs2COz in a 10:1 dioxane:H20 mixture at 70°C provides thiazole (80). Boc deprotection (e.g. using TFA in DCM at room temperature) followed cyclisation (e.g. by heating with NaH in DMF) can provide thiazole (82) (a subset of compounds of formula (III)).

Certain compounds of the following formulae (XVI), (XXI), (XXII), (XXVI), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI) and (XXXXII) can be made via Scheme S:

Scheme S

Intermediate (4) can be converted into iodide (83) (e.g. by treating with iodine and NaHCCh optionally in EtOAc at room temperature). Acylation with an acid chloride (84) (e.g. using ΕΐβΝ in THF at room temperature) can provide amide (85) which, following an intramolecular Heck reaction (e.g. by heating amide (85) with Pd(PPh3)4 and ΕΐβΝ in acetonitrile) can give tricycle (86). Tricycle (86) can be converted into tricycle (87) (e.g. compounds of formulae (XVI), (XXI), (XXII), (XXVI), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI) and (XXXXII)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXIII) can be made via Scheme T:

Scheme T

Acylation of iodide (83) with acyl chloride (88) (e.g. using ΕΐβΝ in THF at room temperature) can provide amide (89) which, following an intramolecular Heck reaction (e.g. by heating amide (89) with Pd(PPh3)4 and EtsN in acetonitrile) can give tricycle (90). Tricycle (90) can be converted into tricycle (91) (a subset of compounds of formula (XXXXIII)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

Certain compounds of formula (XXXXIV) can be made via Scheme U:

Scheme U

Reaction of fluoride (92) with NHR2 can provide amine (93) (e.g by heating in DMSO). Acylation of amine (93) with acyl chloride (94) (e.g. using Et3N in THF at room temperature) can provide amide (95) which upon deprotection (e.g. using TFA in DCM at room temperature) can give pyrrole (96). An addition-elimination cyclisation reaction (e.g. by heating pyrrole (96) with K2C03 in DMSO) can furnish tricycle (97). Tricycle (97) can be converted into tricycle (98) by reduction of the nitro group (e.g. using Pd/C and H2 optionally in MeOH at room temperature) followed by halogen replacement of the amine. Where W is F this can be achieved using NaN02, HCI, HBF4 at -5°C to 0°C; where W is Br this can be achieved by heating amine (98) with HBr in H20 and then reacting with CuBr and NaN02, again heated in H20; and where W is Cl this can be achieved by heating amine (98) with HCI in H20 and then reacting with CuCI and NaN02, again heated in H20. Tricycle (99) can be converted into tricycle (100) (a subset of compounds of formula (XXXXIV)). Where W1 is -0-, -S- or -NR6-, for example, this can be achieved by nucleophilic displacement of W using standard conditions.

All of the above Schemes A-U provide compounds of the invention in which A is O. Such compounds (i.e. compounds of formula (36)) can be converted into compounds in which A is S, =NR6 and =NOR6 according to Schemes V, W and X.

(36) (37)

Scheme V

Amide (36) can, for example, be converted to thioamide (37) by heating with P2S5 in pyridine.

(38) (36)

Scheme W

Amide (36) can, for example, be converted to amidine (38) by heating with POCb and heating the product with the primary amine NH2R6.

(36) (39)

Scheme X

Amide (36) can, for example, be converted to oxime (39) by heating with POCb and heating the product with the O-substituted hydroxylamine NH2OR6.

Experimental Analytical Methods NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A) or Bruker AVIII 400 Nanobay using a 5 mm BBFQ with z-gradients (Method B). MS was carried out on a Waters ZQ MS (Method A and B) or ACQ-SQD2#LCA081 (Method C) using H20 and ACN (0.1-0.05% formic acid - high pH; 0.05% ammonia - low pH). Wavelengths were 254 and 210 nm.

Method A

Column: Gemini NX C18, 5 pm, 50 x 2 mm. Column flow rate was 1 mL/min. Injection volume 10 pL

Method B

Column: Waters XBridge C18, 5 pm, 50 x 2.1 mm. Flow rate: 0.8 mL/min. Injection volume 10 pL

Method C

Column: ACQUITY UPLC® BEH C18, 1.7 pm, 50 x 2.1 mm. Flow rate: 0.6 mL/min. Injection volume 2 μΙ_.

Method D

Column: YMC-Triart C18, 5 pm, 50 x 2 mm. Flow rate: 0.8 mL/min. Injection volume 5 pL.

Method E

Column YMC Triart-C18, 5 pm, 50 x 2 mm. Flow rate: 0.8 mL/min. Injection volume 5 pL Mobile Phase A H20,

B ACN

C 1 % formic in 50% H20 / 50% ACN

Method F (Basic pH)

Column: YMC-Triart C18, 5 pm, 50 x 2 mm,. Flow rate: 0.8 mL/min. Injection volume: 5 pL.

Mobile Phase A H2O

B ACN C 50% H20 / 50% ACN + 1.0% ammonia

Method G (Basic pH)

Column YMC Triart-C18, 5 pm, 50 x 2 mm. Flow rate: 0.8 mL/min. Injection volume: 10 pL Mobile Phase A H2O

B ACN C 50% H20 / 50% ACN + 1.0% NH3

Preparative Methods

Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) or Waters 2767 Sample Manager (Method B) using H20 and ACN (0.1-0.05% formic acid -high pH; 0.05% ammonia - low pH).

Preparative HPLC was performed using column: XBridge™ prep C18 5 pm OBD 19 x 100 mm. Flow rate: 20 mL/min.

Method A

Waters 3100 Mass detector using H20 and ACN + formic acid (0.05%-0.1%)

Method B

Waters 2767 Sample Manager (0.05% NH3)

Intermediate 1 - 5-cvclopropvl-7.8-difluoro-2-methvl-oxazolor4,5-c1quinolin-4-one (a) 2,4,5-trifluorobenzoyl chloride

A suspension of 2,4,5-trifluorobenzoic acid (5 g, 28.4 mmol) in DCM (60 mL) was cooled to 0°C. Oxalyl chloride (3.72 mL, 42.59 mmol) was added followed by 3 drops of DMF and the reaction allowed to warm to room temperature. Effervescence commenced on warming.

The mixture was stirred at room temperature for 2 h then evaporated (co-evaporated from DCM x 3) and used without further purification. (b) ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate

Ethyl isocyanoacetate (3.72 g, 31.23 mmol) in THF (30 ml_) was cooled to 0°C. EbN (11.81 ml_, 85.19 mmol) was added drop wise followed by the addition of 2,4,5-trifluorobenzoyl chloride (5.52 g, 28.4 mmol) in THF (30 ml_) over 5 min. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM (100 ml_) and washed with saturated aq. NaHC03 (3 x 50 mL) and brine (50 ml_). The organic phase was separated, dried over Na2SC>4, filtered and solvent removed in vacuo to give a brown solid. Purification by flash chromatography eluting with 0-80% EtOAc in petroleum ether (40-60) gave ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (3.7 g, 48% yield) as a cream solid. LC-MS (Method C) 272.0 [M+H]+; RT 1.97 min (c) ethyl (Z)-2-amino-3-hydroxy-3-(2,4,5-trifluorophenyl)prop-2-enoate

A solution of ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (2.70 g, 9.96 mmol) in 1,4-dioxane (50 mL) was treated with 1M aq. HCI (50 mL). After stirring for 72 h at room temperature the solvent was removed in vacuo to give ethyl (Z)-2-amino-3-hydroxy-3-(2,4,5-trifluorophenyl)prop-2-enoate as a yellow oily solid (2.60 g) which was used without further purification. LC-MS (Method C) 262.0 [M+H]+; RT 0.72 min (d) ethyl 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate

A mixture of ethyl (Z)-2-amino-3-hydroxy-3-(2,4,5-trifluorophenyl)prop-2-enoate (2.60 g, 9.95 mmol) and trimethyl orthoacetate (25 ml_, 24.98 mmol) was heated under reflux at 110°C for 2 h. After consumption of starting material (monitored by LCMS) the mixture was concentrated in vacuo to give ethyl 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (2.82 g) which was used without further purification. LC-MS (Method C) 286.1 [M+H]+; RT 1.70 min (e) 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylic acid

A solution of ethyl 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (2.82 g, 9.9 mmol) in 1,4-dioxane (60 mL) was treated with 1M aq. LiOH (59.4 mL) and stirred at room temperature overnight. The mixture was evaporated to a minimum, partitioned with EtOAc (50 ml_) and H2O (80 ml_) and the aq. washed with EtOAc (2 x 50 ml_). The aq. was acidified with 1M aq. HCI (80 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylic acid (2.50 g, 98 % yield) as a cream solid. LC-MS (Method C) 258.0 [M+H]+; RT 1.41 min (f) 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carbonyl chloride

A suspension of 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylic acid (2.50 g, 9.72 mmol) in DCM (75 ml_) was treated with oxalyl chloride (1.27 mL, 14.58 mmol) and cat. DMF (1 drop) and stirred at room temperature for 1 h under N2. The mixture was then evaporated and co-evaporated from DCM (3 x) to give a yellow powder, which was used immediately in step (g). (g) N-cyclopropyl-2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxamide

A solution of 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carbonyl chloride (2.68 g, 9.72 mmol) in DCM (75 mL) was treated with cyclopropylamine (1.41 mL, 20.42 mmol) and stirred at room temperature overnight. The mixture was then diluted with DCM (50 mL) and washed with saturated aq. NaHC03 (3 x 30 mL) and brine (30 mL). The organic phase was separated, dried over Na2S04, filtered and solvent removed in vacuo to give N-cyclopropyl-2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxamide (2.30 g, 79 % yield) as a pale solid. LC-MS (Method C) 297.1 [M+H]+; RT 1.62 min (h) 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one

A solution of N-cyclopropyl-2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxamide (500 mg, 1.69 mmol) and 18-crown-6 (446 mg, 1.69 mmol) in DMSO (10 mL) was heated at 140°C for 50 min. On cooling the reaction was diluted with EtOAc (100 mL) and washed 5 x with H20 followed by brine (30 mL). The organic phase was dried over Na2S04, filtered and the solvent removed in vacuo. The resulting residue was purified by flash chromatography eluting with 0-100% EtOAc in heptane to give 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (300 mg, 64 % yield) as a pale brown powder. LC-MS (Method C) 277.1 [M+H]+; RT 1.53 min

Intermediate 2 - 5-cvclopropvl-6.7.8-trifluoro-2-methvl-oxazolor4.5-c1auinolin-4-one

5-Cyclopropyl-6,7,8-trifluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one was prepared analogously to steps (a) to (h) described above in relation to Intermediate 1, but using 2,3,4,5-tetrafluorobenzoic acid as a starting material. LC-MS (Method D) 295.0 [M+H]+; RT 2.59 min

Intermediate 3 - 7-chloro-5-cvclopropvl-8-fluoro-oxazolor4,5-c11.8-naphthvridin-4-one

7-Chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]1,8-naphthyridin-4-one was prepared analogously to steps (a) to (h) described above in relation to Intermediate 1, but using 2,6-dichloro-5-fluoronicotinic acid as a starting material.

Example 1 - 6-chloro-5-cvclopropvl-8-fluoro-2-methvl-7-rt1-methvl-4-piperidvHaminol-oxazolor4.5-clquinolin-4-one (a) 5-cyclopropyl-8-fluoro-2-methyl-7-[(1-methyl-4-piperidyl)amino]oxazolo[4,5-c]quinolin-4-one

Prepared using Intermediate 1 and 1-methylpiperidin-4-amine and the procedure described in Example 4, step (a). (b) 6-chloro-5-cyclopropyl-8-fluoro-2-methyl-7-[(1-methyl-4-piperidyl)amino]oxazolo[4,5-c]quinolin-4-one

A solution of 5-cyclopropyl-8-fluoro-2-methyl-7-[(1-methyl-4-piperidyl)amino]oxazolo[4,5-c]quinolin-4-one (33 mg, 0.09 mmol) in DCM (0.5 mL) was added to a solution of 1,3-dichloro-5,5-dimethylhydantoin (26 mg, 0.13 mmol) in DCM (0.5 mL) and the resulting mixture allowed to stir at room temperature for 1 h. The solution was then diluted with DCM (5 mL) and washed with aq. NaHSCh (0.5 g in 5 mL) and then with saturated aq. NaHCC>3 (5 mL). The organic layer was dried by using a hydrophobic frit and the solvent removed in vacuo. The resulting residue was purified by flash chromatography using a gradient of 0-10% MeOH in DCM to give 6-chloro-5-cyclopropyl-8-fluoro-2-methyl-7-[(1-methyl-4-piperidyl)amino]oxazolo[4,5-c]quinolin-4-one (4.6 mg, 12.6 % yield) as a yellow solid. 1H NMR (Method A) (CDCh): δ 7.37 (d, J= 11.6 Hz, 1H), 4.49 (d, J= 9.1 Hz, 1H), 3.80-3.65 (m, 2H), 2.83 (d, J= 12.1 Hz, 2H), 2.62 (s, 3H), 2.33 (s, 3H), 2.19 (t, J= 11.2 Hz, 2H), 2.05 (dd, J= 12.6, 3.2 Hz, 2H), 1.61 (q, J= 10.2, 9.8 Hz, 2H), 1.25 (m, 2H), 0.59 - 0.52 (m, 2H); LC-MS (Method D ) 405.0/407.0 [M+H]+; RT 1.61 min

Example_2_-_17-cvclopropvl-8-fluoro-6.13-dimethvl-3.12-dioxa-6.14.17- triazatetracvclor8.7.0.02.7.011 ,l5lheptadeca-1,7,9,11(15), 13-pentaen-16-one (a) 5-cyclopropyl-6,8-difluoro-7-[2-hydroxyethyl(methyl)amino]-2-methyl-oxazolo[4,5-c]quinolin-4-one

To a solution of 5-cyclopropyl-6,7,8-trifluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (Intermediate 2) (109 mg, 0.37 mmol) in DMSO (2 ml_) was added n-methylethanolamine (0.06 mL, 0.74 mmol) and Ν,Ν-Diisopropylethylamine (0.39 mL, 2.22 mmol). The reaction mixture was heated to 120°C for 4 h. Additional n-methylethanolamine (0.03 mL, 0.37 mmol) was added and the solution left to stir at 120°C overnight. The solution was then diluted with EtOAc (10 mL) and extracted with H2O (5 x 10 mL) followed by 0.5M HCI (10 mL). The HCI layer was neutralised to pH7 and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated aq. NaHCOs (10 mL) followed by brine (10 mL). The H2O extract was saturated with solid NaCI and further extracted with DCM (2x10 mL). The combined organic layers were dried over MgS04, filtered and the solvent removed under vacuum. The resulting residue was purified by flash chromatography using a gradient of 0-10% MeOH in DCM to give 5-cyclopropyl-6,8-difluoro-7-[2-hydroxyethyl(methyl)amino]-2-methyl-oxazolo[4,5-c]quinolin-4-one (106.1 mg, 82 % yield) as a black oil. 1H NMR (Method A) (CDCh): δ 7.32 (dd, J= 10.0, 1.9 Hz, 1H), 3.73 (t, J= 5.3 Hz, 2H), 3.49 (m, 1H), 3.36 (t, J= 5.3 Hz, 2H), 2.98 (t, J= 1.5 Hz, 3H), 2.66 (s, 3H), 2.62 (s, 1H), 1.27 (m, 2H), 0.73 (m, 2H); LC-MS (Method D) 350.1 [M+H]+; RT 2.09 min (b) 17-cyclopropyl-8-fluoro-6,13-dimethyl-3,12-dioxa-6,14,17- triazatetracyclo[8.7.0.02,7.011,l5]heptadeca-1,7,9,11(15),13-pentaen-16-one

To a solution of 5-cyclopropyl-6,8-difluoro-7-[2-hydroxyethyl(methyl)amino]-2-methyl-oxazolo[4,5-c]quinolin-4-one (42 mg, 0.11 mmol) in DMF (0.5 mL) was added potassium phosphate tribasic (76 mg, 0.35 mmol) and the reaction heated to 120°C for 1.5 h using a microwave reactor. The solution was diluted with H20 (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (MgSCU) and the solvent removed in vacuo. The resulting residue was purified by flash chromatography using a gradient of 0-10% MeOH in DCM. This was further purified by flash chromatography using a gradient of 0-100% EtOAc in petroleum ether (40-60) to give 17-cyclopropyl-8-fluoro-6,13-dimethyl-3,12-dioxa-6,14,17-triazatetracyclo[8.7.0.02,7.011,l5]heptadeca-1,7,9,11 (15), 13-pentaen-16-one (1.0 mg, 2.7 % yield) as an orange solid. 1H NMR (Method A) (CDCh): δ 7.05 (d, J= 1.8 Hz, 1H), 4.24 - 4.18 (m, 2H), 3.51 - 3.45 (m, 1H), 3.34-3.30 (m, 2H), 3.10 (d, J= 2.9 Hz, 3H), 2.62 (s, 3H), 1.24 (m, 2H), 0.74 (m, 2H); LC-MS (Method D) 330.0 [M+H]+; RT 2.41 min

Example 3 - 6-chloro-5-cvclopropvl-8-fluoro-2-methvl-7-(4-piperidvlamino)oxazolor4.5-clauinolin-4-one (a) terf-butyl-4-[(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7- yl)amino]piperidine-1-carboxylate

A DMSO (2 mL) suspension containing 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (Intermediate 1) (152 mg, 0.55 mmol), Ν,Ν-Diisopropylethylamine (1.42 mL, 8.15 mmol) and 4-amino-1-Boc-piperidine (1.11 g, 5.57 mmol) was irradiated in a microwave reactor at 140°C for 5 h. The resulting mixture was diluted with EtOAc (30 mL) and washed with H20 (3 x 40 mL), 0.5M HCI (40 mL), dried over anhydrous MgS04, filtered and concentrated with Et20 evaporations to give a brown solid (156 mg). Purification using normal phase chromatography (0-100% EtOAc in petroleum ether (40-60)) afforded a light brown solid of ferf-butyl 4-[(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)amino]piperidine-1-carboxylate (69 mg, 27.5 %). 1H NMR (Method A) (CDCb): δ 7.41 (d, J = 10.80 Hz, 1H), 7.14 (d, J = 7.28 Hz, 1H), 4.26 (dd, J = 3.50, 7.78 Hz, 1H), 4.09 (d, J = 13.75 Hz, 2H), 3.57 (d, J = 7.39 Hz, 1H), 3.04 (s, 1H), 3.02 - 2.91 (m, 2H), 2.62 (s, 3H), 2.13 (dd, J = 3.80, 12.76 Hz, 2H), 1.53 - 1.31 (m, 11H), 1.00 - 0.86 (m, 3H); LC-MS (Method F) 457.5 [M+H]+; RT 3.05 min (b) ferf-butyl 4-[(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)amino]piperidine-1-carboxylate

To a solution of ferf-butyl 4-[(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)amino]piperidine-1-carboxylate (33 mg, 0.07 mmol) in DCM (2.5 mL) was added 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (29 mg, 0.15 mmol). Stirring was continued for 30 min and the reaction quenched with 1M NaHSOs (6 mL). Saturated aq. Na2CC>3 (10 mL) and DCM (10 mL) was added and the mixture passed through a phase separator cartridge. The DCM phase when concentrated down gave ferf-butyl 4-[(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)amino]piperidine-1-carboxylate (31 mg, 87.3 % yield). LC-MS (Method F) 491.5 [M+H]+; RT 3.34 min (c) 6-chloro-5-cyclopropyl-8-fluoro-2-methyl-7-(4-piperidylamino)oxazolo[4,5-c]quinolin-4-one

A solution of ferf-butyl 4-[(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)amino]piperidine-1-carboxylate (54 mg, 0.11 mmol) in DCM (6 ml_) was treated with TFA (0.9 ml_, 11.7 mmol). After 30 min saturated aq. Na2CC>3 was added until the mixture was at pH 8. DCM was added and the mixture passed through a phase separator cartridge. The concentrated DCM phase was purified using normal phase chromatography (eluting with 0-100% EtOAc in petroleum ether (40-60) and 0-10% MeOH in DCM) to give 6-chloro-5-cyclopropyl-8-fluoro-2-methyl-7-(4-piperidylamino)oxazolo[4,5-c]quinolin-4-one (6 mg, 14 % yield). 1H NMR (Method A) (CDCh): δ 7.37 (d, J = 11.46 Hz, 1H), 4.50 (d, J = 9.15 Hz, 1H), 3.81 (d, J= 10.49 Hz, 1H), 3.76-3.62 (m, 1H), 3.13 (dt, J= 3.80, 12.72 Hz, 2H), 2.71 (m, 2H), 2.63 (s, 3H), 2.05 (d, J = 12.55 Hz, 2H), 1.40 (q, J = 8.37, 9.23 Hz, 2H), 1.31 - 1.20 (m, 4H), 0.86 (d, J= 14.40 Hz, 1H), 0.61 - 0.51 (m, 2H); LC-MS (Method G) 391.4 [M+H]+; RT 6.25 min

Example 4 - 6-chloro-5-cvclopropvl-8-fluoro-2-methvl-7-r(2-oxooxazolidin-4-vl)methvl-amino1oxazolor4.5-c1quinolin-4-on (a) ferf-butyl N-[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)azetidin-3-yl]carbamate

A DMSO (2.3 ml_) suspension containing 3-N-Boc-amino-azetidine (433 mg, 2.5 mmol), 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (Intermediate 1) (150 mg, 0.54 mmol) and Ν,Ν-diisopropylethylamine (0.66 ml_, 3.8 mmol) was irradiated at 140°C for 3 h. EtOAc (25 ml_) was added and the suspension washed with H20 (4 x 25 ml_), brine (25 ml_), dried over anhydrous MgS04 and concentrated. Purification using normal phase chromatography (eluting with 0-100% EtOAc in petroleum ether (40-60)) gave tert-butyl N-[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)azetidin-3-yljcarbamate (120 mg, 53.3 % yield) as a green solid. 1H NMR (Method A) (CDCb): δ 7.36 (d, J = 11.45 Hz, 1H), 6.81 (d, J = 7.69 Hz, 1H), 4.64 (s, 1H), 4.45 (td, J = 2.31, 7.85 Hz, 2H), 3.95 - 3.86 (m, 2H), 3.48 (q, J = 6.99 Hz, 1H), 2.93 (tt, J = 4.05, 6.83 Hz, 1H), 2.62 (s, 3H), 1.47 (s, 9H), 1.37 (m, 2H), 0.99 - 0.84 (m, 2H); LC-MS (Method F) 429.5 [M+H]+; RT 2.9 min (b) ferf-butyl N-[1-(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)azetidin-3-yl]carbamate

To a solution of ferf-butyl N-[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)azetidin-3-yl]carbamate (120 mg, 0.28 mmol) in DCM (10 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (110 mg, 0.56 mmol). After 30 min 1M NaHSOj (12 mL) was added. The mixture was diluted with DCM (30 mL) and saturated aq. Na2CC>3 (30 mL). The DCM phase was isolated by passing through a phase separator cartridge. Concentration gave a dark yellow solid of tert-butyl N-[1-(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)azetidin-3-yl]carbamate (88 mg, 67.9 % yield). 1H NMR (Method A) (CDCb): δ 7.28 (d, J= 12.45 Hz, 1H), 4.78 (td, J= 3.46, 8.45 Hz, 2H), 4.26-4.17 (m, 2H), 3.68 (tt, J = 4.13, 6.98 Hz, 1H), 2.62 (s, 3H), 1.47 (s, 10H), 1.28-1.23 (m, 3H), 0.61 - 0.52 (m, 2H); LC-MS (Method F) 463.4 [M+H]+; RT 3.03 min (c) 6-chloro-5-cyclopropyl-8-fluoro-2-methyl-7-[(2-oxooxazolidin-4-yl)methylamino]oxazolo[4,5-c]quinolin-4-one

A solution of terf-butyl N-[1-(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)azetidin-3-yl]carbamate (105 mg, 0.23 mmol) in DCM (8 mL) was treated with TFA (1 mL, 13 mmol). After 40 min saturated aq. NaHCOs was added until pH 8. The mixture was then passed through a phase separator. The concentrated DCM phase gave a pale yellow solid. Trituration in MeOH followed by filtration gave a white solid, which on drying yielded 6-chloro-5-cyclopropyl-8-fluoro-2-methyl-7-[(2-oxooxazolidin-4- yl)methylamino]oxazolo[4,5-c]quinolin-4-on (8 mg, 8.7 % yield). 1H NMR (Method A) (DMSO-de): δ 7.80 (s, 1H), 7.61 (d, J = 12.37 Hz, 1H), 5.98 (s, 1H), 4.36 (t, J = 8.50 Hz, 1H), 4.26 (dd, J = 4.67, 8.71 Hz, 1H), 3.99 (t, J = 6.69 Hz, 1H), 3.56 (ddd, J = 5.11, 8.29, 16.79 Hz, 2H), 3.45 (ddt, J = 3.72, 7.29, 14.03 Hz, 1H), 2.60 (s, 3H), 1.19 - 1.09 (m, 2H), 0.47 (q, J = 4.27 Hz, 2H); LC-MS (Method G) 407.3 [M+H]+; RT 5.48 min

Example 5 - 7-(4-aminophenoxv)-5-cvclopropvl-8-fluoro-oxazolor4.5-c1H.81-naphthvridin-4-one (a) 7-(4-aminophenoxy)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one

To a microwave vial was added 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (Intermediate 3) (100 mg, 0.36 mmol), 4-aminophenol (47 mg, 0.43 mmol), CS2CO3 (233 mg, 0.72 mmol) and DMSO (2 mL) and the reaction mixture was heated to 60°C, under conventional heating, overnight. EtOAc (10 mL) was added to the crude reaction mixture together with H2O (10 mL) and the layers were separated. The organic layer was then washed with H20 (2x10 mL), dried over MgSCU, filtered and the solvent was removed under reduced pressure to leave the crude reaction product. The crude product was purified by flash silica chromatography using 0-2.5% MeOH in DCM as eluent. The solvent was then removed from fractions containing the desired product to give a sample (39 mg), which was further purified by dissolution in DCM (15 mL) and washing with NaOH (2x10 mL). The organic layer was then dried over MgSCU, filtered and the solvent was removed under reduced pressure to give 7-(4-aminophenoxy)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (34 mg, 27 % yield) as an off-white solid. 1H NMR (Method A) (CDCh): δ 8.07 (s, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.11 - 6.98 (m, 2H), 6.81 - 6.69 (m, 2H), 3.70 (s, 2H), 2.75 - 2.63 (m, 1H), 1.01 - 0.91 (m, 2H), 0.75 - 0.63 (m, 2H); LCMS (Method E) 353.4 [M+H]+; RT 4.43 min

Example 6 - AM5-cvclopropvl-6-methvl-4-oxo-thiazolor4.5-c!quinolin-7-vl}-1H-pvrazole-3-carboxamide.

To a solution of 7-amino-5-cyclopropyl-6-methyl-thiazolo[4,5-c]quinolin-4-one (240 mg, 0.88 mmol) (which can be prepared as described in patent WO2015/155549, Example 108, steps (a)-(e)) in dry DMF (10 mL) 1/-/-pyrazole-3-carboxylic acid (99 mg, 0.88 mmol), N,N-diisopropylethylamine (0.31 mL, 1.77 mmol) and HATU (370 mg, 0.97 mmol) were added and the reaction mixture was allowed to stir at room temperature for 96 h. After which time, the reaction mixture was diluted with H20 (20 mL) and extracted with DCM (2 x 20 mL). The combined organics layers were washed with brine (20 mL) and dried over MgS04 before concentration to dryness under reduced pressure. The crude product was then purified by Prep HPLC in basic buffers (H2O/ACN/0.1% ammonia) to give the titled compound (13 mg, 4% yield) as a cream solid. 1H NMR (Method A) (DMSO-cfe): δ ppm 9.23 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 6.85 (d, J= 2.0 Hz, 1H), 3.65-3.59 (m, 1H), 3.50-3.15 (br s, 2H + H20), 2.56 (s, 3H), 1.19 - 1.14 (m, 2H), 0.51 - 0.47 (m, 2H); LC-MS (Method C) 366.4 [M+H]+; RT 1.77 min.

Example 7 - Antibacterial susceptibility testing

Minimum Inhibitory Concentrations (MICs) versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Ninth Edition. CLSI document M07-A9, 2012). The broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.001-128 pg/mL and a maximum final concentration of 1 % DMSO. The bacterial strains tested include Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213 and Streptococcus pneumoniae ATCC 49619 (Table 1). Strains are grown in cation-adjusted Muller-Hinton broth (supplemented with 5% blood in the case of S. pneumoniae). The MIC is determined as the lowest concentration of compound that inhibits growth following a 16-20 h incubation period. The data reported correspond to the modes of three independent experiments.

In Table 1 a MIC (in pg/mL) of less than 1 is assigned the letter A; a MIC of from 1 to 10 is assigned the letter B; a MIC of from 10 to 100 is assigned the letter C; and a MIC of over 100 is assigned the letter D.

Claims (28)

1. Claims

   1. A compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof:

   (i); wherein X1 is independently selected from: N and CR4; X2 is independently selected from: N and CR5; =A is independently selected from: =0, =S, (-F)2, =NR6 and =NOR6; Y1 and Y2 are each independently selected from C and N; Z1, Z2 and Z3 are each independently selected from 0, S, S(0)2, S(0), N, NR7, CR8 and C=W; wherein W is selected from 0, S or NR6; with the proviso that if none of Z1, Z2 and Z3 is C=W, then the ring formed by Z\ Z2, Z3, Y1 and Y2 contains two endocyclic double bonds and, if one of Z1, Z2 and Z3 is C=W, then the ring formed by Z1, Z2, Z3, Y1 and Y2 contains a single endocyclic double bond; with the further provisos that at least one of Z1, Z2, Z3, Y1 and Y2 is 0, S, N or NR7 and that no more than one of Z1, Z2 and Z3 is C=W; R1 is independently selected from: H, F, NR6R9, NR6NR6R9 and CrC4-alkyl; R2 is independently selected from: Ci-Ce-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, CrCe-haloalkyl and Co-C3-alkylene-R10; wherein R10 is selected from C3-C6-cycloalkyl, 3-6-heterocycloalkyl, Cs-Ce-halocycloalkyl, phenyl and heteroaryl; R3 is -W1-Co-C3-alkylene-R11; wherein W1 is selected from acetylene, -0-, -S(0)y (wherein y is an integer selected from 0, 1 and 2), -NR6-, -NR6S(0)2-, -S(0)2NR6-, -C(0)NR6, -NR6C(0)-, -0C(0)-, -C(0)0-, -0C(0)NR6-, -NR6C(0)0, -NR6C(0)NR6- and -C(0)-; and wherein R11 is independently selected from phenyl, monocyclic heteroaryl, monocyclic 3-10-heterocycloalkyl, monocyclic C3-Cio-cycloalkyl and a bicyclic group comprising two fused rings each independently selected from phenyl, heteroaryl, 3-7-heterocycloalkyl and C3-C7-cycloalkyl; wherein R11 is optionally substituted with 1, 2 or 3 R12 groups; wherein R12 is independently at each occurrence selected from: oxo, =NR6, =NOR6, 3-5-heterocycloalkyl, halo, nitro, cyano, NR6R9, NR6S(0)2R6, NR6CONR6R6, NR6C02R6, OR6, SR6, SOR6, SO3R6, SO2R6, S02NR6R6, CO2R6, C(0)R6, CONR6R6, C(0)NR6CR6R6C(0)0R6, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, Ci-C4-alkylene-OR6, Ci-C4-alkylene-NR6R9, and =CR6aCR6R6NR6R9; R4 is independently selected from: H, O-CrCe-alkyl, halo, CrCe-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Ci-Ce-haloalkyl, O-Ci-Ce-haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-heterocycloalkyl, C3-C6-halocycloalkyl; or R4 and R2 together form an alkylene or heteroalkylene chain of the form -(CR6R6)r-W2-(CR6R6)s-W3-(CR6R6)t- and which is attached at its respective ends to the substitution point for R4 and R2 respectively; wherein W2 and W3 are each independently selected from: a bond, O, S and NR6; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W2 and W3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms; or R3 and R4, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups; R5 is independently selected from: H, CrC4-alkyl and halo; or R3 and R5, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups; R6 is independently at each occurrence selected from: H and CrC4-alkyl; R6a is independently selected from: H, halogen and CrC4-alkyl; where the nitrogen to which R7 is attached has a formal double bond to one of its neighbouring atoms in the ring comprising Z1 and Z2, R7 is absent; or, where the nitrogen to which R7 is attached is attached via formal single bonds to both of its neighbouring atoms in the in the ring comprising Z1 and Z2, R7 is independently selected from: H, Ci-C4-alkyl, and CrC4-haloalkyl; R8 may be independently at each occurrence selected from: H, halo, nitro, cyano, NR6R9, NR6S(0)2R6, NR6CONR6R6, NR6C02R6, OR6; SR6, SOR6, SO3R6, SO2R6, S02NR6R6 CO2R6 C(0)R6, CONR6R6, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, CR6R6OR6, CR6R60C(0)R6 and CR6R6NR6R9; R9 is independently at each occurrence selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, S(0)2-Ci-C4-alkyl, C(0)-Ci-C4-alkyl, C(0)-0-CrC4-alkyl and CH2-phenyl; where any of the alkyl, alkylene, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl (e.g. phenyl) or heteroaryl groups mentioned above are optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from: oxo, =NRa, =NORa, halo, nitro, cyano, NRaRa, NRaS(0)2Ra, NRaCONRaRa, NRaC02Ra, ORa; SRa, S(0)Ra, S(0)20Ra, S(0)2Ra, S(0)2NRaRa, C02Ra C(0)Ra, CONRaRa, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 haloalkyl, CRaRORa, CRaRaNRaRa, CRaRaNRaC(0)Ra and =CRbCRaRaNRaRa; wherein Ra is independently at each occurrence selected from: H and CrC4-alkyl; and Rb is independently at each occurrence selected from: H, halogen, CrC4-alkyl and C1-C4-haloalkyl; and wherein any alkylene group is optionally substituted with two substituents which together with the carbon atom or carbon atoms to which they are attached form a C3-Cycycloalkyl ring or a 3-7-heterocycloalkyl ring; wherein any alkylene group is optionally substituted with a single Co-C3-alkylene-Rc group, wherein Rc is independently aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C7-cycloalkyl.
2. 2. A compound of claim 1, wherein the compound of formula (I) is a compound of formula (III):

   (III) wherein Z1 is selected from O and S.
3. 3. A compound of claim 2, wherein Z1 is O.
4. 4. A compound of any preceding claim, wherein =A is =0.
5. 5. A compound of any preceding claim, wherein R1 is H.
6. 6. A compound of any preceding claim, wherein X1 is CR4.
7. 7. A compound of any preceding claim, wherein X2 is CR5.
8. 8. A compound of claim 6, wherein R5 is selected from H and F.
9. 9. A compound of any one of claims 1 to 8, wherein R3 is -W1-Co-C3-alkylene-R11.
10. 10. A compound of claim 9, wherein W1 is selected from -0-, -S- and-NR6-.
11. 11. A compound of any preceding claim, wherein R4 is independently selected from: H, 0-CrC4-alkyl, halo, CrC4-alkyl, CrC4-haloalkyl and 0-CrC4-haloalkyl.
12. 12. A compound of any preceding claim, wherein R2 is independently selected from: C1-C6-alkyl, Ci-C6-haloalkyl, and Co-C3-alkylene-R10; wherein R10 is selected from C3-C6-cycloalkyl and C3-C6-halocycloalkyl.
13. 13. A compound of any one of claims 1 to 7, 11 and 12, wherein R3 and R5, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups.
14. 14. A compound of any one of claims 1 to 8 and 12, wherein R3 and R4, together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R11 group and/or from 1 to 5 R12 groups.
15. 15. A compound of any one of claims 1 to 10, wherein R4 and R2 together form an alkylene or heteroalkylene chain of the form -(CR6R6)r-W2-(CR6R6)s-W3-(CR6R6)t- and which is attached at its respective ends to the substitution point for R4 and R2 respectively; wherein W2 and W3 are each independently selected from: a bond, O, S and NR6; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W2 and W3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms.
16. 16. A compound of any preceding claim, wherein R11 is a phenyl group with at least one NR6R9, CONR6R6 , CR6R6OR6 or CR6R6NR6R9 group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and C1-C4-alkyl,
17. 17. A compound of any one of claims 1 to 15, wherein R11 is a heteroaryl group comprising at least one nitrogen atom in the ring structure.
18. 18. A compound of any one of claims 1 to 17, for use as a medicament.
19. 19. A compound of any one of claims 1 to 17, for use in treating a bacterial or mycobacterial infection.
20. 20. A compound of any one of claims 1 to 17, for the use of claim 19, wherein the infection is a bacterial infection is caused by Gram negative bacteria.
21. 21. A compound of any one of claims 1 to 17, for the use of claim 20, wherein the bacterial infection is caused by a bacterial strain selected from Haemophilus spp., Moraxella spp., Legionella spp. and Neisseria spp.
22. 22. A compound of any one of claims 1 to 17, for the use of claim 21, wherein the bacterial infection is gonorrhoea.
23. 23. A compound of any one of claims 1 to 17, for the use of claim 19, wherein the infection is a bacterial infection caused by Gram positive bacteria.
24. 24. A compound of any one of claims 1 to 17, for the use of claim 23, wherein the bacterial infection is caused by methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis.
25. 25. A compound of any one of claims 1 to 17, for the use of any one of claims 16 to 24, wherein the bacterial infection is caused by a bacterial strain which is resistant to one or more fluoroquinolone antibiotics.
26. 26. A compound of any one of claims 1 to 17, for the use of claim 16, wherein the infection is a mycobacterial infection.
27. 27. A compound of any one of claims 1 to 17, for the use of claim 25, wherein the mycobacterial infection is TB.
28. 25. A pharmaceutical formulation comprising a compound of any one of claims 1 to 17 and a pharmaceutically acceptable excipient.