WO2016024096A1

WO2016024096A1 - Antibacterial compounds

Info

Publication number: WO2016024096A1
Application number: PCT/GB2015/052303
Authority: WO
Inventors: Andrew Ratcliffe; Ian Cooper; Mark Pichowicz; Neil STOKES; Cedric Charrier
Original assignee: Redx Pharma Ltd
Current assignee: Redx Pharma Ltd
Priority date: 2014-08-11
Filing date: 2015-08-10
Publication date: 2016-02-18
Anticipated expiration: 2017-02-11

Abstract

This invention relates to antibacterial 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 in 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.

Description

Antibacterial compounds

This invention relates to antibacterial 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 in 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. Such infections are frequently referred to as resistant 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 group of resistant strains 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. While less widespread, antibiotic resistant Gram-negative strains, such as either Escherichia coli NDM-1 (New Delhi metallo-β-lactamase) or Klebsiella pneumoniae NDM-1 , are also very difficult to treat. Frequently only expensive antibiotics such as vancomycin and colistin are effective against these strains.

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 addition, an increasing number of strains of MRSA are also resistant to fluoroquinolone antibiotics, in addition to β-lactam antibiotics such as methicillin. 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. Untreated infection can result in a range of clinical complications including urethritis, dysuria, epididymitis, pelvic inflammatory disease, cervicitis, endometritis and even infertility and ectopic pregnancy. In rare cases, gonorrhoea can also spread to the blood to cause disseminated gonococcal infection that can manifest as arthritis, endocarditis or meningitis. Human immunodeficiency virus (HIV) is more readily-transmitted in individuals co-infected with gonorrhoea. 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).

Another disease in which the development of resistance and multidrug resistance is of particular concern is TB. From the 17^th century to the early-20^th 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 20^th 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.

Bacterial resistance is also becoming a problem in the treatment of animals. Antibacterials find widespread use in industrial farming, e.g. to prevent mastitis in dairy cattle, where they are often used prophylactically. Such widespread prophylactic use has led to the build-up of resistance in certain bacterial strains which are particularly relevant to animal health.

In spite of the numerous different antibiotics known in the art for a variety of different infections, there continues to be a need for 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 compounds which exhibit a smaller reduction in activity against resistant strains compared to wild-type strains than prior art compounds do. It may be that certain compounds of the invention are less active than prior art compounds but there is a benefit associated with having a more consistent activity against a range of 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:

wherein R¹ is selected from R² or R³

R² represents the group:

X¹ and X² are each independently selected from: N and CR⁴; X³ is independently selected from: N, C=0 and CR⁴; X⁴ is selected from N, NR², NR³, CR² and CR⁴; wherein a single one of R¹ and X⁴ comprises the group R²; and wherein no more than two of X¹ , X², X³ and X⁴ are N;

the bond between X³ and X⁴ is a single bond or a double bond; wherein when X⁴ is NR² or NR³, the bond between X³ and X⁴ is a single bond and X³ is C=0; and when X⁴ is selected from N, CR² and CR⁴ the bond between X³ and X⁴ is a double bond and X³ is selected from N and CR⁴;

Y¹ and Y² are each independently selected from C and N; Z¹ , Z² and Z³ are each independently selected from O, S, S(O), NR⁵, CR⁴ and C=W; wherein W is selected from O, S or NR⁶; wherein when 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 when 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; and with the further provisos that at least one of Z¹ , Z², Z³, Y¹ and Y² is O, S, N or NR⁵ and that no more than one of Z¹ , Z² and Z³ is C=W;

=A is independently selected from: =0, =S, =NR⁶ and =NOR⁶;

L¹ is a linker group having the form -(CR⁹R⁹)_rU¹-U²-(CR⁹R⁹)s-U³-(CR⁹R¹⁰)_r; wherein U¹ , U² and U³ are each independently selected from: a bond, CO, O, S and NR¹¹ ; wherein r, s, and t are each independently an integer selected from 0, 1 , 2 and 3 and wherein definitions of r, s, t, U¹ , U² and U³ are chosen such that the total length of the linker group is 1 , 2, 3 or 4 atoms;

L² is 4-, 5-, 6- or 7-membered cycloalkyl ring or a 4-, 5-, 6- or 7- membered heterocycloalkyl ring;

L³ is absent or is -N(R⁸)L⁴-;

L⁴ is independently selected from -CR⁹R⁹- and a 3-, 4- or 5-membered cycloalkyl ring or a 4- or 5-membered heterocycloalkyl ring;

R³ and R¹¹ are each independently at each occurrence selected from: H, C₁-C₄-alkyl, C₁-C₄- haloalkyl, S(O)2-C₁-C₄-alkyl and C(O)-C₁-C₄-alkyl;

R⁴ is independently at each occurrence selected from: H, halo, nitro, cyano, NR⁶R¹¹ , NR⁶S(O)₂R⁶, NR⁶CONR⁶R⁶, NR⁶C(O)R⁶, NR⁶CO₂R⁶, OR⁶; O-aryl, SR⁶, SOR⁶, SO3R⁶, SO2R⁶, SO₂NR⁶R⁶, CO₂R⁶, C(O)R⁶, CONR⁶R⁶, aryl, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl;

R⁵ is absent or is independently selected from: H, C₁-C₄-alkyl, and C₁-C₄-haloalkyl;

R⁶ is independently at each occurrence selected from: H , C₁-C₄-alkyl, and C₁-C₄-haloalkyl;

R⁷ is a monocyclic aromatic or heteroaromatic ring or R⁷ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic;

R⁸ is independently selected from: H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, S(O)2-C₁-C₄-alkyl and

C(O)-C₁-C₄-alkyl; or L² and R⁸ together with the nitrogen to which they are attached together form a saturated 5-, 6- or 7- membered monocyclic heterocycloalkyl ring or a saturated 7-,

8- or 9- membered bicyclic heterocycloalkyl ring system;

R⁹ is independently at each occurrence selected from: H, Me, and CF3;

R¹⁰ is independently at each occurrence selected from: R⁹, OR⁶, CO₂R⁶ and NR⁶R¹¹ ; wherein each of the aforementioned alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, carbocyclic, heterocycloalkyl, aryl (e.g. phenyl) and heteroaryl groups and aromatic and heteroaromatic rings is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: =0, =S, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aC(O)R^a, NR^aCONR^aR^a, NR^aCO₂R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, CR^aR^aNR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl; wherein R^a is independently at each occurrence selected from H, C₁-C₄-alkyl and C₁-C₄-haloalkyl;

For the absence of doubt, the linker group L¹ is arranged such that L² is attached to the end of linker group L¹ which is defined as (CR⁹R¹⁰)t. Thus, the end of linker group L¹ which is defined as (CR⁹R⁹)_r is attached to the rest of the molecule at the point of contact of the group R².

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

wherein R³, R⁷, A, X¹ , X², X³, Z¹ , Z² , Z³, Y¹ , Y², L¹, L² and L³ are as defined above for formula (I).

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

wherein R⁷, A, X¹ , X², X³, Z¹ , Z², Z³, Y¹ , Y², L¹, L² and L³ are as defined above for formula (I) and wherein X⁴ is N or CR⁴, R⁴ being as defined above for formula (I).

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

wherein R³, R⁴, R⁷, X¹ , X², X³, L¹ , L² and L³ are as defined above for formula (I). In an embodiment, the compound of formula (I) is a compound of formula (V):

wherein R⁴, R⁷, X¹ , X², X³, L¹, L² and L³ are as defined above for formula (I) and wherein X⁴ is N or CR⁴.

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

wherein R⁴, R⁷, L¹ , L² and L³ are as defined above for formula (I).

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

wherein R³, R⁴, R⁷, L¹ , L² and L³ are as defined above for formula (I). In an embodiment, the compound of formula (I) is a compound of formula (VIII):

wherein R¹, R⁴, A, X¹ , X², X³, and X⁴ are as defined above for formula (I).

In an embodiment, the compound of formula (I) has a structure according to any more of formulae (IX) to (XXXXXVII):

wherein R¹, R⁴, R⁵, A, X¹ , X², X³, X⁴ and W are as defined above for formula (I) and wherein R⁵ is independently selected from: H, C₁-C₄-alkyl, and C₁-C₄-haloalkyl. The compound may thus be a compound of formula (XXIV).

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

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

wherein Z\ Z², Z³, Y¹ , Y², L⁴, R⁸, R⁹, R¹⁰ are as described above for compounds of formula (I); R^4a is selected from H, F, NR⁶R¹¹ , OR⁶, O-aryl and SR⁶; W¹ is N or CR¹³; R¹² is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)2R^a, NR^aCONR^aR^a, NR^aC(O)R^a, NR^aCO₂R^a, OR^a; SR^a, S(O)R^a, S(O)₂OR^a, S(O)₂R^a, S(O)₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, and C₁-C₄-haloalkyl; or any two R¹² groups which are attached to the same carbon form a group selected from: =0, =S, =NR^a and =NOR^a; R¹³ is independently selected from H and R¹²; and n is an integer selected from 0, 1 , 2, 3 and 4; V¹ , V² and V³ are each independently selected from: N and CR⁴; with the proviso that no more than two of V¹ , V² and V³ are N; and wherein the ring B is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyl or heterocycloalkyl ring. It may be that both Y¹ and Y² are C, a single one of Z¹ , Z² and Z³ is N and that N must form part of a C=N endocyclic double bond; a single one of Z¹ , Z² and Z³ is CR⁴ and the remaining Z¹ , Z² or Z³ is selected from O and S.

In an embodiment, the compound of formula (I) is selected from a compound of formula (XXXXXX) and a compound of formula (XXXXXXI):

wherein L⁴, R⁴, R⁸, R⁹, R¹⁰ are as described above for compounds of formula (I); and wherein R^4a, W¹ , R¹², n, V¹ , V² and V³ are as described above for compounds of formula (XXXXXIX).

The following statements apply to compounds of any of formulae (I) to (XXXXXXI). 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.

It may be that X⁴ is selected from N, NR³, CR² and CR⁴. It may be that X⁴ is selected from N, NR³ and CR⁴

It may be that the bond between X³ and X⁴ is a double bond; X¹ , X² and X³ are each independently selected from: N and CR⁴; and X⁴ is selected from N, CR² and CR⁴.

It may be that R¹ is R³ and X⁴ is CR². R¹ may be H or C₁-C₄-alkyl. Alternatively, it may be that R¹ is R² and X⁴ is selected from N or CR⁴.

It may be that none of X¹ , X², X³ and X⁴ is N. It may be that a single one of X¹ , X², X³ and X⁴ is N. It may be that X¹ is N .

It may be that at least one of X¹ , X², X³ and X⁴ is CR^4a wherein R^4a is selected from H, CN, halo, NR⁶R¹¹ , OR⁶, O-aryl, SR⁶, e.g. selected from halo, CN, NR⁶R¹¹ , OR⁶; O-aryl, SR⁶. It may be that R^4a is selected from H, CN, F and OR⁶. It may be that a single one of X¹ , X², X³ and X⁴ is CR^4a. It may be that R^4a is OR⁶. In some preferred embodiments, R^4a is O-C1-C4- alkyl, e.g. OMe. In other preferred embodiments, R^4a is halo, e.g. F.

It may be that X¹ , X² and X⁴ are each CH.

It may be that X³ is CR^4a, wherein R^4a is selected from H, halo, CN, NR⁶R¹¹ , OR⁶, O-aryl and SR⁶. R^4a may be selected from: F, CN, NR⁶R¹¹ , OR⁶; O-aryl and SR⁶. R^4a may be selected from: NR⁶R¹¹ , OR⁶; O-aryl and SR⁶. It may be that R^4a is selected from H, F, CN and OR⁶. R^4a may be selected from F, CN and OR⁶, e.g. from F and OR⁶. It may be that R^4a is OR⁶. In some preferred embodiments, R^4a is 0-C₁-C₄-alkyl, e.g. OMe. In other preferred embodiments, R^4a is halo, e.g. F. Alternatively, X³ may be CH.

It may be that X³ is C=0 and X⁴ is NR². It may be that X³ is C=0 and X⁴ is NR³. Preferably, R³ is selected from H and C₁-C₄-alkyl. Thus, R³ may be selected from H and methyl.

It may be that =A is selected from =0 and =S. Preferably, Where U¹ is CO, U² is preferably independently selected from: a bond, O, S and NR¹¹ , e.g. U² is independently selected from NR¹¹ or O. Likewise, where U² is CO, U¹ is preferably independently selected from: a bond, O, S and NR¹¹ , e.g. U¹ is independently selected from NR¹¹ or O.

L¹ may be a linker group of the form -C(=O)U²-(CR⁹R⁹)s(CR⁹R¹⁰)r, wherein U² is independently selected from: a bond, O, S and NR¹¹ , e.g. wherein U² is independently selected from NR¹¹ or O. In particular, L₁ may be a linker group of the form -C(=0)0- (CR⁹R⁹)s(CR⁹R¹⁰)r, e.g. -C(=0)0-(CR⁹R⁹)_s

It may be that one of U¹ and U² is CO and the other is O. Such compounds, including the examples of such compounds mentioned in the previous paragraph, may find particular use in the treatment of mastitis in domestic animals, e.g. by direct application (either topical or by injection) to the udder of a subject.

Preferably, L¹ is an alkylene chain of the form -(CR⁹R⁹)_r(CR⁹R¹⁰)_r.

Where L² is a heterocycloalkyl ring having a nitrogen atom in the ring, and where L¹ is attached to L² through that nitrogen atom, it is preferable that t is absent, e.g. it is preferable that L¹ is a linker group of the form -(CR⁹R⁹)_rU¹-U²-(CR⁹R⁹)_s- wherein s is an integer selected from 1 , 2 and 3. Thus, L¹ may be a linker group of the form -(CR⁹R⁹)_S-.

When R¹ is R², r is preferably an integer selected from 1 , 2 or 3.

It may be that t is 1 and R¹⁰ is OR⁶ (e.g. OH). It may be that t is 2 and R¹⁰ is at each occurrence OR⁶ (e.g. OH). It may be that t is 1 and R¹⁰ is NR⁶R¹¹ , (e.g. NH₂).

Preferably, R⁹ is at each occurrence H.

It may be that the total length of the -L¹- linker group (i.e. the number of atoms in a continuous chain between L² and the point of contact of R² to the rest of the molecule) is 2 or 3 atoms, e.g. the total length of the linker group is 2 atoms.

Specific examples of L¹ include -CH₂CH₂-, -CH₂CH₂CH₂, -CH₂CH(NH₂)-, -CH(OH)CH(OH)-, CH₂CH(OH) and -CH(OH)CH₂CH₂-. L¹ may also be -CO₂CH₂-. L² may be a saturated 5-, 6- or 7- membered monocyclic cycloalkyl or heterocycloakyl ring. L² is preferably a saturated 6-membered monocyclic cycloalkyl or heterocycloakyl ring. The groups L¹ and N(R⁷)L³R⁸ are preferably attached to L² para to each other, i.e. the 6- membered monocyclic cycloalkyl or heterocycloakyl ring is 1 , 4-substituted with respect to the groups L¹ and N(R⁷)L³R⁸.

L² may therefore be a cyclohexyl ring. L² may also be a tetrahydropyran ring. L² may also be a piperidine ring. Where L² is a piperidine ring, it may be linked to L¹ through the nitrogen in the piperidine ring. If this is not the case, the nitrogen in the piperidine ring will take the form NR¹¹ group. Thus, L² may take the form:

wherein W¹ is N or CR¹³; R¹² is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aCONR^aR^a, NR^aC(O)R^a, NR^aCO₂R^a, OR^a; SR^a, S(O)R^a, S(O)₂OR^a, S(O)₂R^a, S(O)₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄ alkenyl, C4-alkynyl, and C₁-C₄-haloalkyl; or any two R¹² groups which are attached to the same carbon form a group selected from: =0, =S, =N R^a and =NOR^a; R¹³ is independently selected from H and R¹²; and n is an integer selected from 0, 1 , 2, 3 and 4. For the absence of doubt, the group W¹ is the point of connection of the group L² to the linker group L¹.

It may be that W¹ is N. If this is the case it is preferable that L¹ is a linker group of the form - (CR⁹R⁹)_гU¹-U²-(CR⁹R⁹)s- wherein s is an integer selected from 1 , 2 and 3.

Alternatively, it may be that W¹ is CR¹³. Preferably R¹³ is H.

Specific examples of L² groups include:

It may be that L² is a saturated 7-, 8- or 9- membered bicyclic cycloalkyl or heterocyclic ring. Thus in any of formulae (I) to (XXXXXVIII), L² may be selected from a saturated 4-, 5-, 6- or 7- membered monocyclic cycloalkyl or heterocyclic ring and a saturated 7-, 8- or 9- membered bicyclic cycloalkyl or heterocyclic ring system. This might particularly apply where R¹ is R³ and X⁴ is CR². It might particularly apply where Z² is C=W, e.g. C=0. It might also apply where one of U¹ and U² is CO and the other is O.

A specific example of an L² group would be:

It may be that L² and R⁸ together with the nitrogen to which they are attached together form a saturated 5-, 6- or 7- membered monocyclic heterocycloalkyl ring, e.g. a piperidine ring. If so, L¹ is preferably attached to the piperidine ring at the 4-position relative to the piperidine nitrogen.

Thus, the group -L²NR⁸- may take the form:

wherein R¹² is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aCONR^aR^a, NR^aCO₂R^a, NR^aC(O)R^a, OR^a; SR^a, S(O)R^a, S(O)₂OR^a, S(O)₂R^a, S(O)₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄- haloalkyl; or any two R¹² groups which are attached to the same carbon form a group selected from: =0, =S, =NR^a and =NOR^a; and n is an integer selected from 0, 1 , 2, 3 and 4.

A specific example of an L² group would be:

Thus, -L¹-L²- may take the form:

L³ may be absent. Thus, R² may be

Alternatively, L³ may be -N(R⁸)L⁴-. Thus, R² may be

L⁴ is preferably -CR⁹R⁹- and most preferably is -CH₂-. Alternatively, L⁴ may be a 3-, 4- or 5- membered cycloalkyl ring, e.g. a 4-membered cycloalkyl ring.

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

Thus, Z¹ and Z³ may each be independently selected from O, S, S(O), NR⁵and CR⁴; Z² is independently selected from O, S, S(O), NR⁵, CR⁴ and C=W; wherein W is selected from O, S or NR⁶; with the proviso that if Z² is not C=W, then the ring formed by Y¹ , Y², Z¹ , Z², Z³ contains two endocyclic double bonds and if Z² is C=W, the bond between Y¹ and Y² (which may both be C) is a double bond; and with the further proviso that at least one of Z¹ , Z² and Z³ is O, S or NR⁵.

It may be that Z² is C=W, e.g. C=0. Where Z² is C=W, e.g. C=0 it is typically the case that Y¹ and Y² are both C. Thus the compound may be a compound of one or more of formulae (XIV), (XV), (XVI), (XVII), (XVIII) or (XXXXXVII), e.g. a compound of formula (XIV), (XV), (XVI), (XVII), (XVIII) or (XXXXXVII) in which W is O. Compounds in which Z² is C=W, e.g. C=0 may find particular use in the treatment of mastitis in domestic animals, e.g. by direct application (either topical or by injection) to the udder of a subject.

It may be that Z¹, Z² and Z³ are each independently selected from O, S, NR⁵ and CR⁴. 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 O, S, NR⁵ and CR⁴; 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 Z¹ , Z², Z³, Y¹ and Y² is O, S, N or NR⁵.

It may be that Z¹ , Z², Z³, Y¹ and Y² together form an imidazole, triazole, tetrazole, pyrazole or pyrrole ring. It may be that one of Y¹ and Y² is N and the other is C. Thus, it may be that Z¹ , Z², Z³, Y¹ and Y² together form an imidazole, triazole, tetrazole, pyrazole or pyrrole ring in which a single one of Y¹ and Y² is N. It may be that Z¹ , Z², Z³, Y¹ and Y² together form an triazole or tetrazole. It may be that one of Y¹ and Y² is N and the other is C. Thus, it may be that Z¹ , Z², Z³, Y¹ and Y² together form a triazole or tetrazole ring in which a single one of Y¹ and Y² is N. 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 Z¹ , Z² and Z³ is independently selected from O, S and NR⁵ and the remaining two of Z¹ , Z² and Z³ are each CR⁴.

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 Z¹ , Z² and Z³ is independently CR⁴ and the remaining two of Z¹ , Z² and Z³ are selected from O, S and NR⁵.

It may be that Z¹ , Z² , Z³, Y¹ and Y² together form a oxazole, thiazole, isoxazole, furan, thiophene or isothiazole ring. Thus, it may be that both Y¹ and Y² are C and Z¹ , Z² and Z³ are selected from CR⁴, O, S and N, wherein if one of Z¹ , Z² and Z³ are N, that N must form part of a C=N endocyclic double bond.

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 CR⁴, O, S and N; wherein a single one of Z¹ , 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 CR⁴. For the absence of doubt, the remaining Z¹ , Z² or Z³ is selected from O and S. It may be that the remaining Z¹ , Z- or Z- is O. Thus it may be that Z¹ , Z² , Z³, Y¹ and Y² together form a oxazole or isoxazole ring. In these embodiments, it may be that a single one of X¹ , X², X³ and X⁴ is N, e.g. it may be that X¹ is N. The remainder of X¹ , X², X³ and X⁴ (e.g. X², X³ and X⁴) may be CR⁴.

In certain preferred embodiments, Y¹ and Y² are each C; Z¹ is CR⁴ (e.g. CH); Z² is selected from O, S and N R⁵; and Z³ is N. For the absence of doubt, the two endocyclic double bonds are situated between Z¹ and Y¹ and between Z³ and Y². It may be that Z² is selected from O and S. It may be that Z² is O. In these embodiments, it may be that a single one of X¹ , X², X³ and X⁴ is N, e.g. it may be that X¹ is N. The remainder of X¹ , X², X³ and X⁴ (e.g. X², X³ and X⁴) may be CR⁴.

Preferably, R³ is selected from H and C₁-C₄-alkyl. Thus, R³ may be selected from H and methyl. R⁴ may be independently at each occurrence selected from: H, halo, nitro, cyano, SOR⁶, SO₃R⁶, SO2R⁶, SO₂NR⁶R⁶ CO₂R⁶ C(O)R⁶, CONR⁶R⁶, C₁-C₄-alkyl, C₂-C₄-alkynyl, C₂-C₄- alkenyl and C₁-C₄-haloalkyl. R⁴ may be independently at each occurrence selected from: halo, nitro, cyano, SOR⁶, SO3R⁶, SO2R⁶, SO₂NR⁶R⁶ CO₂R⁶ C(O)R⁶, CONR⁶R⁶, C₁-C₄-alkyl, C₂-C₄-alkynyl, C₂-C₄-alkenyl and C₁-C₄-haloalkyl. R⁴ may be independently at each occurrence selected from: H, halo, nitro, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C1-C4- haloalkyl. R⁴ may be independently at each occurrence selected from: halo, nitro, C1-C4- alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl. R⁴ may be independently at each occurrence selected from: H, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl. R⁴ may at all occurrences be H.

It may be that any R⁴ group which forms part of Z¹ , Z² or Z³ is an R^4b group, wherein R^4b is independently at each occurrence selected from: H, halo, nitro, cyano, C2-alkynyl, CO₂H, C(O)H, and CONH₂. Thus, R^4b may be at each occurrence independently selected from: H, halo, nitro, cyano, C²-alkynyl. R^4b may be at each occurrence independently selected from: H and halo. R^4b may at all occurrences be H.

Where R⁵ is attached to a nitrogen which forms a double bond to a neighbouring atom in the ring formed by Z¹ , Z², Z³, Y¹ and Y², R⁵ is absent. Where R⁵ is attached to a nitrogen which forms only single bonds to the neighbouring atoms in the ring formed by Z¹ , Z², Z³, Y¹ and Y², R⁵ is not absent. R⁵ may be H. Alternatively, R⁵ may be C₁-C₄-alkyl, e.g. methyl.

It may be that at any specific occurrence R⁶ is H. It may be that at all occurrences R⁶ is H.

R⁷ may be a monocyclic aryl group. Thus, R⁷ may be a phenyl group. Said phenyl group may be unsubstituted or it may be substituted with from 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aCONR^aR^a, NR^aCO₂R^a, NR^aC(O)R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁- C4-haloalkyl, and CR^aR^aNR^aR^a. R⁷ may be a phenyl group which is substituted by 1 to 3 substituents independently at each occurrence selected from F, nitro, C₁-C₄-alkyl, C₂-C₄- alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl.

.Exemplary R⁷ groups include 2,5-difluorophen-1-yl and 3-nitro-4-methylphen-1-yl. Preferably, R⁷ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic. Thus, R⁷ may take the form:

wherein V¹ , V² and V³ are each independently selected from: N and CR⁴; with the proviso that no more than two of V¹ , V² and V³ are N; and wherein the ring B is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyl or heterocycloalkyl ring.

Preferably, R⁷ takes the form:

wherein V⁴ and V⁵ are each independently selected from O, S and NR^a; R¹⁴ is independently at each occurrence selected from: H, fluoro, cyano, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl; or any two R¹⁴ groups which are attached to the same carbon together form a group selected from: =0, =S, =NR^a and =NOR^a; and m is an integer selected from 1 and 2. For the absence of doubt, V¹ , V², V³, V⁴, V⁵, R¹⁴ and m are selected such that the number of substituent groups off the R⁷ bicycle does not exceed 5.

It may be that V¹ , V² and V³ are each independently selected from: N and CH; with the proviso that no more than two of V¹ , V² and V³ are N. It may be that a single one of V¹ , V² and V³ is N. Preferably, V³ is CR⁴ (e.g. CH). Thus, it may be that V¹ is N and V² is CR⁴ (e.g. CH). Alternatively, it may be that V² is N and V¹ is CR⁴ (e.g. CH). In a further alternative, it may be that V¹ and V² are each N. R¹⁴ may be independently at each occurrence selected from: H, fluoro, cyano, C02R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl; or any two R¹⁴ groups which are attached to the same carbon together form a group selected from: =0, =S, =NR^a and =NOR^a. Preferably R¹⁴ is independently at each occurrence selected from H, F, C₁-C₄-alkyl or C₁-C₄-haloalkyl; or any two R¹⁴ groups which are attached to the same carbon together form a =0 group. Preferably R¹⁴ is independently at each occurrence selected from: H, C₁-C₄-alkyl or C₁-C₄-haloalkyl; or any two R¹⁴ groups which are attached to the same carbon together form a =0 group.

In a preferred embodiment, V⁴ is O. Thus, it may be that both V⁴ and V⁵ are O. It may be that V⁴ is O and V⁵ is S. It may be that V⁴ is O and V⁵ is NR^a (e.g. NH).

V⁴ can also be S. Thus, it may be that V⁴ is S and V⁵ is NR^a (e.g. NH).

It may be that V⁵ is NR^a (e.g. NH). In this case it is preferable that the -CR¹⁴R¹⁴- group attached to said V⁵ is C=0. m may be 1. Preferably, m is 2.

In a specific embodiment, V⁴ is O, V⁵ is O, m is 2 and R¹⁴ is in all instances H. In another specific embodiment, V⁴ is O, V⁵ is S, m is 2 and R¹⁴ is in all instances H. In yet another specific embodiment, V⁴ is O, V⁵ is NH, m is 2, the -CR¹⁴R¹⁴- group attached to V⁵ is C=0 and the -CR¹⁴R¹⁴- group attached to V⁴ is CH₂.

.Exemplary R⁷ groups include:

R⁷ may also take the form

, wherein V⁶ is independently selected from N and CR⁴ (e.g. CH); V⁷ is independently selected from NR^a, S and O; and R¹⁵ is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aC(O)R^a, NR^aCONR^aR^a, NR^aCO₂R^a, NR^aC(O)R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, and CR^aR^aNR^aR^a. R¹⁵ may be independently at each occurrence selected from F, CN, OR^a, nitro, C₁-C₄-alkyl, C2- C4-alkenyl, C^C^-alkynyl and C₁-C₄-haloalkyl. This form of R⁷ is particularly preferred where L³ is absent. For the absence of doubt, V⁶, V⁷, and R¹⁵ are selected such that the number of substituent groups off the R⁷ bicycle does not exceed 5.

An exemplary R⁷ group is

Preferably, R⁸ is selected from H or C₁-C₄-alkyl. Even more preferably, R⁸ is H. Preferably, R⁹ is at all occurrences H.

It may be that R¹⁰ is independently at each occurrence selected from: H, OR⁶, CO₂R⁶ and NR⁶R¹¹. It may be that R¹⁰ is independently selected from OR⁶ and NR⁶R¹¹. Preferably, R¹⁰ is independently selected from OH and NH₂.

At any given occurrence, it may be that R¹¹ is selected from H and C₁-C₄-alkyl. Preferably, R¹¹ is at each occurrence selected from H and C₁-C₄-alkyl. Thus, at any specific occurrence R¹¹ may be H. Alternatively, at any specific occurrence R¹¹ may be C₁-C₄-alkyl, e.g. methyl. It may be that at all occurrences, R¹¹ is H.

Where present, W is preferably O. The compound may be any one or more compound(s) selected from those tested in

.Examples 24 and/or 25 below, or a pharmaceutically acceptable salt or N-oxide thereof. Thus, the compound may be any one or more compound(s) selected from:

5- {2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmettiyl}amino)piperidin-1-yl]ethylM

[1 ,3]oxazolo[4,5-c]quinolin-4-one A;

6- ({[1-(2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5-yl}ethyl)piperidin-4-yl]amino}methyl)- 3,4-dihydro-2H-1 ,4-benzoxazin-3-one B;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-7-methoxy- 4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one C;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-7-fluoro- 4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one D;

7- methoxy-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin- 1-yl}ethyl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one E;

7-fluoro-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one F;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)- 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one G;

Example 8 - 5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}- 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one H;

7-fluoro-5-{2-[4-({2H,3H,4H-pyrano[2,3-c]pyridin-6-ylmethyl}amino)piperidin-1-yl]ethyl}- 4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one I;

7-methoxy-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin- 1-yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one J;

7-fluoro-5-(2-{4-[({7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}methyl)amino]piperidin-1- yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one K;

7-fluoro-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one L;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-7-fluoro- 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one M ; 5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}am

4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one N;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}m^

4H,5H-[1 ,2]oxazolo[3,4-c]1 ,5-naphthyridin-6-one O;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-yl}methyl)amino]piperidin-1 -yl}ethyl}-5H,6H- [1 ,2]oxazolo[3,4-c]1 ,5-naphthyridin-6-one P;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)^ 4H,5H-[1 ,2,4]triazolo[4,3-a]quinoxalin-4-one Q;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)- 4H,5H-[1 ,2,3,4]tetrazolo[1 ,5-a]quinoxalin-4-one R;

5- {2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-yl}methyl)amino]piperidin-1 -yl}ethyl}-4H,5H- [1 ,2,3,4]tetrazolo[1 ,5-a]quinoxalin-4-one S;

6- (2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)- 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5-one T;

6-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-yl}methyl)amino]piperidin-1 -yl}ethyl}-5H,6H- [1 ,2,4]triazolo[1 ,5-c]quinoxalin-5-one U;

8-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)- 3,5,6,8, 10-pentaazatricyclo[7.4.0.0 ²'⁶]trideca-1 (9),2,4, 10.12-pentaen-7-one V; and

5-{2-hydroxy-2-[trans-4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}methyl)amino]cyclohexyl]ethyl}-7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one W; or a pharmaceutically acceptable salt or N-oxide thereof

Where the compound of the invention is an N-oxide, it will typically be a pyridine N-oxide, i.e. where the compound of the invention comprises a pyridine ring (which may form part of a bicyclic or tricyclic ring system), 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 compound may be a compound of formula (la), or a pharmaceutically acceptable salt thereof:

wherein R¹ is selected from R² or R³; R² represents the group:

are each independently selected from: N and CR⁴; X⁴ is selected from N, CR² and CR⁴; wherein only one of R¹ and X⁴ contains the group R²; and wherein no more than two of X¹, X², X³ and X⁴ are N; Y¹ and Y² are each independently selected from C and N; Z¹, Z² and Z³ are each independently selected from O, S, S(O), NR⁵, CR⁴ and C=W; wherein W is selected from O, S or NR⁶; wherein when 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 when 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; and wherein at least one of Z¹, Z², Z³, Y¹ and Y² is O, S, N or NR⁵; =A is independently selected from: =0, =S, =NR⁶ and =NOR⁶; L¹ is a linker group having the form -(CR⁹R⁹)_rU¹-U²-(CR⁹R⁹)s-U³-(CR⁹R¹⁰)_r; wherein U¹, U² and U³ are each independently selected from: a bond, CO, O, S and NR¹¹; wherein r, s, and t are each independently an integer selected from 0, 1 , 2 and 3 and wherein definitions of r, s, t, U¹ , U² and U³ are chosen such that the total length of the linker group is 1 , 2, 3 or 4 atoms; L² is a saturated monocyclic 4-, 5-, 6- or 7- membered cycloalkyl or heterocyclic ring; L³ is absent or is -N(R⁸)L⁴-; L⁴ is independently selected from -CR⁹R⁹- and a 3-, 4- or 5- membered cycloalkyl or heterocycloalkyl ring; R³ and R¹¹ are each independently at each occurrence selected from: H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, S(O)2-C₁-C₄-alkyl and C(O)-C₁-C₄-alkyl; R⁴ is independently at each occurrence selected from: H, halo, nitro, cyano, NR⁶R¹¹ , NR⁶S(O)2R⁶, NR⁶CONR⁶R⁶, NR⁶C(O)R⁶, NR⁶CO₂R⁶, OR⁶; O-aryl, SR⁶, SOR⁶, SO₃R⁶, SO₂R⁶, SO₂NR⁶R⁶, CO₂R⁶, C(O)R⁶, CONR⁶R⁶, aryl, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄- haloalkyl; R⁵ is absent or is independently selected from: H, C₁-C₄-alkyl, and C₁-C₄-haloalkyl; R⁶ is independently at each occurrence selected from: H, C₁-C₄-alkyl, and C₁-C₄-haloalkyl; R⁷ is a monocyclic aromatic or heteroaromatic ring or R⁷ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic; R⁸ is independently selected from: H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, S(O)2-C₁-C₄-alkyl and C(O)-C₁-C₄-alkyl; or L² and R⁸ together with the nitrogen to which they are attached together form a saturated 5-, 6- or 7- membered monocyclic heterocycloalkyl ring or a saturated 7-, 8- or 9- membered bicyclic heterocycloalkyl ring system; R⁹ is independently at each occurrence selected from: H, Me, CF3 and F; R¹⁰ is independently at each occurrence selected from: R⁹, OR⁶, CO₂R⁶ and NR¹¹ R¹¹ ; wherein each of the aforementioned alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, carbocyclic, halocycloalkyl, heterocyclic, aryl (e.g. phenyl) and heteroaryl groups and aromatic and heteroaromatic rings is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aC(O)R^a, NR^aCONR^aR^a, NR^aCO₂R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, CR^bR^bNR^aR^a, C₁-C₄-alkyl, C₂-C₄- alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl; wherein R^a is independently at each occurrence selected from H, C₁-C₄-alkyl and C₁-C₄-haloalkyl; and R^b is independently at each occurrence selected from H, halogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl.

The compound may be a compound of formula (lb), or a pharmaceutically acceptable salt or N-oxide thereof:

independently selected from: N, C=0 and CR⁴; X⁴ is selected from N, NR², NR³, CR² and CR⁴; wherein only one of R¹ and X⁴ comprises the group R²; and wherein no more than two of X¹ , X², X³ and X⁴ are N; the bond between X³ and X⁴ is a single bond or a double bond; wherein when X⁴ is NR² or NR³, the bond between X³ and X⁴ is a single bond and X³ is C=0; and when X⁴ is selected from N, CR² and CR⁴ the bond between X³ and X⁴ is a double bond and X³ is selected from N and CR⁴; Y¹ and Y² are each independently selected from C and N; Z¹, Z² and Z³ are each independently selected from O, S, S(O), NR⁵, CR⁴ and C=W; wherein W is selected from O, S or NR⁶; wherein when 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 when 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; and wherein at least one of Z¹ , Z², Z³, Y¹ and Y² is O, S, N or NR⁵; =A is independently selected from: =0, =S, =NR⁶ and =NOR⁶; L¹ is a linker group having the form -(CR⁹R⁹)_rU¹-U²-(CR⁹R⁹)s-U³-(CR⁹R¹⁰)_r; wherein U¹ , U² and U³ are each independently selected from: a bond, CO, O, S and NR¹¹ ; wherein r, s, and t are each independently an integer selected from 0, 1 , 2 and 3 and wherein definitions of r, s, t, U¹ , U² and U³ are chosen such that the total length of the linker group is 1 , 2, 3 or 4 atoms; L² is a saturated monocyclic 4-, 5-, 6- or 7- membered cycloalkyl or heterocyclic ring; L³ is absent or is -N(R⁸)L⁴-; L⁴ is independently selected from -CR⁹R⁹- and a 3-, 4- or 5- membered cycloalkyl or heterocycloalkyl ring; R³ and R¹¹ are each independently at each occurrence selected from: H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, S(O)2-C₁-C₄ alkyl and C(O)-C₁-C₄-alkyl; R⁴ is independently at each occurrence selected from: H, halo, nitro, cyano, NR⁶R¹¹ , NR⁶S(O)2R⁶, NR⁶CONR⁶R⁶, NR⁶C(O)R⁶, NR⁶CO₂R⁶, OR⁶; O-aryl, SR⁶, SOR⁶, SO₃R⁶, SO₂R⁶, SO₂NR⁶R⁶ CO₂R⁶, C(O)R⁶, CONR⁶R⁶, aryl, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄- haloalkyl; R⁵ is absent or is independently selected from: H, C₁-C₄-alkyl, and C₁-C₄- haloalkyl; R⁶ is independently at each occurrence selected from: H, C₁-C₄-alkyl, and C₁-C₄- haloalkyl; R⁷ is a monocyclic aromatic or heteroaromatic ring or R⁷ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic; R⁸ is independently selected from: H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, S(O)2- C₁-C₄-alkyl and C(O)-C₁-C₄-alkyl; or L² and R⁸ together with the nitrogen to which they are attached together form a saturated 5-, 6- or 7- membered monocyclic heterocycloalkyl ring or a saturated 7-, 8- or 9- membered bicyclic heterocycloalkyl ring system; R⁹ is independently at each occurrence selected from: H, Me, CF3 and F; R¹⁰ is independently at each occurrence selected from: R⁹, OR⁶, CO₂R⁶ and NR¹¹ R¹¹ ; wherein each of the aforementioned alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, carbocyclic, halocycloalkyl, heterocyclic, aryl (e.g. phenyl) and heteroaryl groups and aromatic and heteroaromatic rings is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aC(O)R^a, NR^aCONR^aR^a, NR^aCO₂R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, CR^bR^bNR^aR^a, C₁-C₄-alkyl, C^-CU-alkenyl, C^-CU-alkynyl and C₁-C₄-haloalkyl; wherein R^a is independently at each occurrence selected from H, C₁-C₄ alkyl and C₁-C₄ haloalkyl; and R^b is independently at each occurrence selected from H, halogen, C₁-C₄ alkyl and C₁-C₄ haloalkyl.

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 I- 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 C_m-C_n refers to a group with m to n carbon atoms.

The term "alkyl" refers to a linear or branched hydrocarbon chain. For example, C₁-C₆-alkyl may refer to methyl, ethyl, n-propyl, /^'so-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n- hexyl. The alkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, OR^a or NHR^a.

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, OR^a or NHR^a.

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, OR^a or NHR^a.

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, OR^a or NHR^a.

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 "heteroaromatic" 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 ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring or ring system are selected from O, S and N).

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 C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano, halogen, OR^a or NHR^a.

Aryl groups may have from 6 to 20 carbon atoms as appropriate to satisfy valency requirements. Aryl groups comprise aromatic rings, i.e. rings which satisfy the Huckel rule. Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted naphthalenyl groups or optionally substituted anthracenyl groups. Equally, aryl groups may include non-aromatic carbocyclic portions. An aromatic ring is a phenyl ring.

The term "heteroaryl" may refer to any aromatic (i.e. a ring system containing (4n + 2) ττ- electrons or n- electrons in the ττ-system) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, 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 O, S 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 C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano, halogen, OR^a or NHR^a.

Heteroaryl groups may mean a 5- or 6-membered heteroaryl group. They may therefore comprise a 5- or 6- membered heteroaromatic ring, i.e. a 5- or 6- membered ring which satisfies the Huckel rule and comprises a heteroatom. Heteroaryl groups may be selected from: 5-membered heteroaryl groups in which the heteroaromatic ring is includes 1-4 heteroatoms selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring includes 1-2 nitrogen atoms. Specifically, heteroaryl groups and heteroaromatic rings may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine.

The term "y-membered heterocycloalkyl" may refer to a y-membered monocyclic or bicyclic saturated or partially saturated groups comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, 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, tetrahydropyran, 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, OR^a or N H R^a.

An 'endocyclic' double bond is one where both of the atoms between which the double bond is formed are in the ring or ring system in which the atoms are situated.

A carbocyclic group consists of one or more rings which are entirely formed from carbon atoms. A carbocylic group can be a mono- or bicyclic cycloalkyl group, or it can comprise at least one phenyl ring.

A heterocyclic group consists of one or more rings wherein the ring system includes at least one heteroatom. A heterocyclic group comprises at least one heteroaryl or heterocycloalkyl rings. A heterocycloalkyl ring may be a saturated ring comprising at least one heteroatom selected from O, S and N .

Where a ring system is described as being a x-membered bicyclic group, that is intended to mean that the skeleton of the bicyclic ring system is formed from x atoms (i.e. the total number of atoms across the two rings of the bicycle is x).

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, N R^aR^a, N R^aS(O)₂R^a, NR^aCON R^aR^a, NR^aCO₂R^a, NR^aC(O)R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CON R^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁- C4-haloalkyl and CR^aR^aN R^aR^a; wherein R^a is independently at each occurrence selected from H , C₁-C₄-alkyl and C₁-C₄-haloalkyl.

The present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXXXXI) 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 ^{1 1} C, 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 ¹⁵O, ¹⁷O and ¹⁸O, 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, ¹⁵O 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.

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 a strain which is resistant to at least one approved antibiotic drug. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-positive bacteria e.g a strain which is resistant to at least one approved antibiotic drug. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-negative bacteria, e.g a strain which is resistant to at least one approved antibiotic drug. 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 strains' is intended to mean strains of bacteria which have shown resistance to one or more known antibacterial drug. For example, it may refer to strains which are resistant to methicillin, strains that are resistant to one or more other β-lactam antibiotics, strains that are resistant to one or more fluoroquinolones and/or strains that are resistant to one or more other antibiotics (i.e. antibiotics other than β-lactams and fluoroquinolones). A resistant strain is 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 the parent (susceptible) strain.

The term 'approved drug' is intended to mean that the drug is one which had been approved by the US FDA or the EMA prior to 1 August 2014.

The bacterial strain (e.g. the MRSA strain or E. Coli strain) may 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 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 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 fluoroquinolone antibiotics.

The compounds of the invention may be particularly effective at treating infections caused by aerobic bacteria, e.g. S. Aureus. The compounds of the invention may be particularly effective at treating infections caused by anaerobic bacteria, e.g. a Clostridium spp such as Clostridium difficile.

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 1^st Jan 2014.

[0001] The bacterial infection may be caused by a strain selected from: Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp. Like Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp. are 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 by the compounds and methods of the invention include gonorrhoea. 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 known antibacterial drug, e.g. at least one β-lactam drug. The gonorrhoea infection may be one caused by a strain of Neisseria gonorrhoeae which is resistant to at least one approved drug. The at least one drug may be an antibiotic drug, e.g. one that is approved for use in treating one of the fastidious Gram negative species mentioned in this specification. It may be approved for use in treating gonorrhoea. The approved drug may be a β-lactam drug. Further infections which can be treated by the compounds and methods of the invention include bacterial meningitis and Neisseria meningitidis infections of other parts of the human or animal body.

The compounds of the invention can be used to treat or prevent mycobacterial infections, e.g. mycobacterial infections caused by resistant strains of mycobacteria. Thus, for example, they can be used to treat TB or leprosy. Thus, it may be that the mycobacterial infection is caused by M. tuberculosis. It may also be that the mycobacterial infection is caused by a mycobacterium selected from: M. avium complex, M. abscessus, M. leprae, M. bovis, M. kansasii, M. chelonae, M. africanum, M. canetti and M. microti. 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 mycobacterium is caused by a mycobacterial strain which is resistant to at least one approved antimycobacterial compound. The at least one approved antimycobacterial compound may be selected from: rifampicin, isoniazid, kanamycin, capreomycin, amikacin and a fluoroquinolone. The at least one approved antimycobacterial compound may be selected from: rifampicin, moxifloxacin, isoniazid, ciprofloxacin and levofloxacin. The compounds of the invention may be used to treat non- replicating TB.

The compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parasitic 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, hydroxymaleic, 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. Suitable base salts are formed from bases which form non-toxic salts. .Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. 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 (μg/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", M. 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. 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 μg/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 the 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.

Medical uses The compounds of the present invention can be used in the treatment of the human body.

The compounds of the invention may be for use in treating human 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, tuberculosis, tonsillitis, Escherichia coli, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, abdominal infection, bacteraemia, septicaemia, sexually transmitted bacterial infection (e.g. gonorrhoea, Chlamydia), bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, Helicobacter pylori, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo.

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.

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.

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.

Veterinary uses

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. The livestock may be mammal (excluding humans) e.g. cows, pigs, goats, sheep, llamas, alpacas, camels and rabbits. The livestock may be birds (e.g. chickens, turkeys, ducks, geese etc.). Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc. The veterinary use may be to treat wild populations of animals in order to prevent the spread of disease to humans or to commercial animals. In this case, the animals may be rats, badgers, deer, foxes, wolves, mice, kangaroos and monkeys and other apes.

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

In another aspect the present invention provides a veterinary formulation comprising a compound of the invention and a veterinarily acceptable excipient.

The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice. The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg. In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

As an alternative, when treating animals the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.

The following table provides an illustrative example of the diseases and corresponding bacterial pathogens which can be treated with antibiotics such as those of the invention within the field of animal health.

Diseases and Bacterial Pathogens Animal Species Affected

Certain compounds of the invention are of particular use in the treatment of mastitis. In this regard, a particularly preferred method of administration is by injection into the udder of a subject (e.g. a cow, a goat, a pig or sheep).

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:

Ac = acetyl ACN = acetonitrile

aq. = aqueous Bn = benzyl

BOC = tert-butyloxycarbonyl DCC = N, N'-dicyclohexylcarbodiimide

DCM = Dichloromethane DEAD = Diethylazodicarboxylate

DIPEA = diisopropylethylamine DMAP = N, N- dimethylaminopyridine

DME - dimethoxyethane DMF = N, N-dimethylformamide

DMSO = dimethyl sulfoxide DPPA = Diphenylphosphoryl azide

HATU = 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate

mCPBA = meta-chloroperbenzoic acid NMP = N- methylpyrrolidinone

PMB = para-methoxybenzyl RaNi = Raney Nickel™ (a nickel sponge)

T3P = propylphosphonic anhydride TFA = trifluoroacetic acid

THF = tetrahydrofuran

Compounds of formula (II) can be made by Scheme A:

Scheme A

Bromide (1) can be converted into (3) by reaction with the trifluoroborate salts of (2). The reaction can be performed in the presence of a base, such as Cs₂CO₃, and Pd catalyst, such as palladium(ll)dichloride dichloromethane, in a solvent, such as a mixture of toluene and H₂O.

Trifluoroborate salts of (2) can be prepared by Scheme B using the method of Marder et al (JOC, 2012, 77, 10399) and involving the reaction of bromide (4) with bis(pinacolato)diboron, LiOMe, triphenylphosphine polymer bound and Cul in DMF at room temperature, followed by aq. KHF2 in THF at room temperature.

Scheme B

A subset of compounds of formula (II) can be made by Scheme C:

Scheme C

Bromide (1) can be converted into (6) by reaction with the trifluoroborate salts of (5), where PG represents a nitrogen protecting group, such as BOC or Bn. The reaction can be performed in the presence of a base, such as Cs₂CO₃, and Pd catalyst, such as palladium(ll)dichloride dichloromethane, in a solvent, such as a mixture of toluene and H₂O, at a temperature from 70°C to 100°C. Removal of the nitrogen PG in (6) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in 55

an alcoholic solvent, such as EtOH, at room temperature. Compound (7) can be converted to (9) by coupling with (8), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

Trifluoroborate salts of (5) can be prepared by Scheme D using the method of Marder et al (JOC, 2012, 77, 10399) and involving the reaction of bromide (10) with bis(pinacolato)diboron, LiOMe, triphenylphosphine polymer bound and Cul in DMF at room temperature, followed by aq. KHF2 in THF at room temperature.

Scheme D

Compounds of formula (III) can be made by Scheme E:

Tricycle (1 1) can be converted into (13) by reaction with (12), where LG represents a leaving group, such as a halide or tosyl group, The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

A subset of compounds of formula (III) can be made by Scheme F:

Scheme F

Tricycle (11) can be converted into (15) by reaction with (14), where LG represents a leaving group, such as a halide or tosyl group, and PG represents a nitrogen protecting group, such as BOC or Bn. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating. Removal of the nitrogen PG in

(15) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Compound

(16) can be converted to (17) by coupling with (8), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

A subset of compounds of formula (II) can be made by Scheme G:

Scheme G

Bromide (18) can be converted to alkene (19) by reaction with allyltributylstannane in the presence of a Pd catalyst/phosphine ligand combination, such as bis(tri-tert- butylphosphine)palladium(O), in a solvent, such as 1 ,4-dioxane, with optional heating. Alkene (19) can be converted to aldehyde (20) by treatment with osmium tetroxide and sodium periodate in a solvent, such as a mixture of H₂O in THF, at room temperature. Reductive amination of (20) with amine (21), where PG represents a nitrogen protecting group, such as BOC or Bn, can be effected by first heating in a solvent, such as THF, at a temperature of 50°C to 80°C, in the presence of 4A sieves, followed by treatment with sodium triacetoxyborohydride. Removal of the nitrogen PG in (22) to give amine (23) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (23) can be converted to (25) (a subset of compounds of formula II) by heating with aldehyde (24) in a solvent, such as THF, at a temperature of 50°C to 80°C, in the presence of 4A sieves, followed by treatment with sodium triacetoxyborohydride. Amine (23) can be converted to (26) (another subset of compounds of formula II) by coupling with (8), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

A further subset of compounds of formula (II) can be made by Scheme H:

Scheme H

Bromide (18) can be converted to acid (27) by first forming the Grignard with Mg activated by 1 ,2-dibromoethane and Me₃SiCI in a solvent, such as THF, at a temperature from room temperature to 100°C, followed by quenching with CO₂. Coupling of the acid (27) to alcohol (28), where PG represents a nitrogen protecting group, such as BOC or Bn, can be effected with PPh₃ and DEAD in a solvent, such as toluene, at a temperature from 0°C to room temperature. Removal of the nitrogen PG in ester (29) to give amine (30) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (30) can be converted to

(31) (a yet further subset of compounds of formula II) by heating with aldehyde (24) in a solvent, such as THF, at a temperature from 50°C to 80°C, in the presence of 4A sieves, followed by treatment with sodium triacetoxyborohydride. Amine (30) can be converted to

(32) (a further subset of compounds of formula II) by coupling with (8), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

A subset of compounds of formula (III) can be made by Scheme I:

Scheme I

Pyridone (33) can be converted to alkene (34) by reaction with allyl bromide in a solvent, such as DMF, in the presence of a base, such as K₂CO₃, at a temperature from 100°C to 150°C. Alkene (34) can be converted to aldehyde (35) by treatment with osmium tetroxide and sodium periodate in a solvent, such as a mixture of H₂O in THF, at a temperature from 0°C to room temperature. Reductive amination of aldehyde (35) with amine (21), where PG represents a nitrogen protecting group, such as BOC or Bn, can be effected by first heating in a solvent, such as THF, at a temperature of 50°C to 80°C, in the presence of 4A sieves, followed by treatment with sodium triacetoxyborohydride. Removal of the nitrogen PG in

(36) to give amine (37) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (37) can be converted to (38) (a subset of compounds of formula III) by heating with aldehyde (24) in a solvent, such as THF, at a temperature from 50°C to 80°C, in the presence of 4A sieves, followed by treatment with sodium triacetoxyborohydride. Amine

(37) can be converted to (39) (another subset of compounds of formula III) by coupling with (8), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

A further subset of compounds of formula (III) can be made by Scheme J:

Ring opening of epoxide (40) (prepared as described in Scheme K) by tricycle (33) using a base, such as K₂CO₃ or Cs₂CO₃, in a solvent, such as DMF, at a temperature from 70°C to 150°C can provide hydroxy (41) (a subset of compounds of formula (III)). Conversion of the hydroxyl in (41) to the corresponding azide (42) can be accomplished under Mitsunobu reaction conditions using DPPA, DEAD and PPh₃ in a solvent, such as THF, at a temperature from 0°C to room temperature. Azide (42) can be converted to amine (43) (another subset of compounds of formula (III)) by reduction. The reaction can be performed using PPh₃ in a solvent, such as a mixture of H₂O in THF, at room temperature. Alternatively, the reaction can be performed by hydrogenation in the presence of Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature.

Epoxide (40) can be made by Scheme K:

Carboxylic acid (44), where PG represents a nitrogen protecting group, such as BOC or Bn, can be converted to hydroxy (45) by reaction with ethyl chloroformate in the presence of a base, such as Et₃N, in a solvent, such as THF, at a temperature of 0°C, followed by treatment with NaBH₄ in a solvent, such as a mixture of H₂O in THF, at a temperature from 5°C to room temperature. Oxidation of the hydroxyl to an aldehyde (e.g. using Dess-Martin Periodinane in a solvent, such as DCM, at room temperature) followed by a Wittig reaction using Ph₂PCH₃ (prepared in situ from the action of dimsyl sodium in DMSO on methyltriphenylphosphonium bromide) in a solvent, such as DMSO, at a room temperature, can provide alkene (46). Expoxidation of the alkene to (47) can be effected with mCPBA in a solvent, such as DCM, at a temperature from 0°C to room temperature. Removal of the nitrogen PG in (47) to give amine (48) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (48) can be converted to (40) by coupling with (8), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

A further subset of compounds of formula (III) can be made by Scheme L:

Ring opening of epoxide (47) (prepared as described in Scheme K) by tricycle (33) using a base, such as K₂CO₃ or Cs₂CO₃, in a solvent, such as DMF, at a temperature from 70°C to 150°C can provide hydroxy (49). Removal of the nitrogen PG in (49) to give amine (50) can be performed under standard conditions. If the PG is a BOC then by the action of TFA in DCM at room temperature. If the PG is a Bn then by the action of H₂ in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (50) can be converted to (51) (a subset of compounds of formula III) by heating with aldehyde (24) in a solvent, such as THF, at a temperature from 50°C to 80°C, in the presence of 4A sieves, followed by treatment with sodium triacetoxyborohydride.

Bromide (18) can be made by Scheme M :

Scheme M

Pyridone (52) can be converted to bromide (18) with (53), where LG represents a leaving group, such as halide or tosyl group. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K₂CO₃, with optional heating.

Certain compounds of formula (IV), (V), (VI), (VII), (VIII) and (XXXXXXI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (54), which can be made by Scheme N:

Scheme N

Carboxylic acid (55) can be converted into benzoxazine-2,4-dione (56) by reaction with triphosgene in a halogenated solvent, such as 1 ,2-dichloroethane, at a temperature from room temperature to 75°C. Treatment of (56) with Et₃N, followed by heating with ethyl nitroacetate in a solvent, such as THF, can provide the nitro (57), which can be reduced to the amine (58) by hydrogenation in the presence of Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Alternatively, the nitro can be reduced to the amine using sodium hydrosulphite in the presence of NaOH and H₂O at room temperature. Oxazole ring formation to (54) can be achieved by acylation of amine (58) with R⁴COCI in the presence of a base, such as Et₃N, in a solvent, such as THF, followed by heating in a high boiling solvent. A subset of oxazole pyridones (54), where R⁴ = H can be formed from (58) by treatment with triethyl orthoformate at a temperature from 80°C to 110°C. Alternatively, oxazole pyridones (54), where R⁴ = H, can be directly formed from (56) by treatment with the anion of ethyl isocyanoacetate (formed from NaH in DMF at room temperature) in DMF at a temperature from 80°C to 110°C.

Certain compounds of formula (IX) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (59), which can be made by Scheme O:

Scheme O

Pd coupling of amine (60) to iodothiazole (61) (e.g. using Pd(dppf)Cl2 and Cs₂CO₃ in a 10: 1 dioxane:H₂O mixture at 70 °C) provides thiazole (62). Cyclisation (e.g. by heating with NaH in DMF) can provide thiazole (59).

Replacement of (61) in Scheme O with halothiazole (63) (where X = CI, Br, I) can provide thiazole (64), which can be used in Schemes A, C, E, F, G, H, I, J and L to provide certain compounds of formula (XIII).

Certain compounds of formula (XIX), (XXIV), (XXV), (XXIX), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), (XXXXIII), (XXXXIV), (XXXXV) and (XXXXXX) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (65), which can be made by Scheme P:

Scheme P

Amine (66) can be converted into iodide (67) (e.g. by treating with iodine and NaHCO₃ in a solvent, such as EtOAc, at room temperature). Acylation with an acid chloride (68) (e.g. using Et₃N in THF at room temperature) can provide amide (69), which following an intramolecular Heck reaction (e.g. by heating amide (69) with Pd(PPh₃)4 and NEt₃ in acetonitrile) can give tricycle (65).

Certain compounds of formula (XXXXVI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (70), which can be made by Scheme Q:

Scheme Q

Acylation of iodide (67) (prepared as described in Scheme P) with acyl chloride (71) (e.g. using Et₃N in THF at room temperature) can provide amide (72), which following an intramolecular Heck reaction (e.g. by heating amide (72) with Pd(PPh₃)4 and NEt₃ in acetonitrile) can give tricycle (70). Certain compounds of formula (XXXXVII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (73), which can be made by Scheme R:

Scheme R

Acylation of amine (74) with acyl chloride (75), where PG represents a nitrogen protecting group, such as PMB, (e.g. using Et₃N in THF at room temperature) can provide amide (76). Removal of the nitrogen PG in (76) to give pyrrole (77) can be performed under standard conditions. In the case of PMB use of TFA in DCM at room temperature. An addition- elimination cyclisation reaction (e.g. by heating pyrrole (77) with K₂CO₃ in DMSO) can furnish tricycle (73).

Certain compounds of formula (XXXIV) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (78), which can be made by Scheme S:

Scheme S

Pd coupling of boronate (60) to 1-benzyl-5-bromopyrazole (79) (e.g. using Pd(dppf)Cl2 and Cs₂CO₃ in a 10:1 dioxane:H₂O mixture at 70°C) provides pyrazole (80). Subsequent debenylation of the product (e.g. using Pd/C and H₂ in an alcoholic solvent, such as EtOH, at room temperature) provides amine (81). Reaction of amine (81) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (78).

Certain compounds of formula (XXXI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (82), which can be made by Scheme T:

Scheme T

Acylation of amine (74) with pyrazole acid (83) (e.g. use of DIPEA and HATU in a solvent, such as DCM, at room temperature) by can provide amide (84), which can undergo an intramolecular ring closing reaction (e.g. by treatment with a base, such as K₂CO₃, in a solvent, such as DMF, at a temperature from 100°C to 150°C) to provide pyrazole (82).

Replacement of (83) in Scheme T with imidazole acid (85) can provide imidazole (86), which can be used in Schemes A, C, E, F, G, H, I, J and L to provide certain compounds of formula (XXXII).

Certain compounds of formula (XXI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (87), which can be made by Scheme U:

Scheme U Pd coupling of boronate (60) to bromopyrazole (88) (e.g. using Pd(dppf)Cl2 and Cs₂CO₃ in a 10: 1 dioxane:H₂O mixture at 70°C) can provide pyrazole (89). Ester hydrolysis (e.g. using aq. NaOH in ethanol with optional heating) followed by lactam formation (e.g. by heating with propylphosphonic anhydride and diisopropylamine in THF) can provide pyrazole (87).

Replacement of (88) in Scheme U with bromopyrazole (90) can provide pyrazole (91), which can be used in Schemes A, C, E, F, G, H, I, J and L to provide certain compounds of formula (XXII).

Replacement of (88) in Scheme U with bromoisothiazole (92) can provide isothiazole (93), which can be used in Schemes A, C, E, F, G, H, I, J and L to provide certain compounds of formula (XXIII).

Replacement of (88) in Scheme U with bromoisothiazole (94) can provide isothiazole (95), which can be used in Schemes A, C, E, F, G, H, I, J and L to provide certain compounds of formula (XX).

Certain compounds of formula (XXX) and (XXVII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediates (96) and (97) respectively, which can be made by Scheme V:

Benzoxazine-2,4-dione (56) (prepared as described in Scheme N) can be converted into β- ketoamide (99) by reaction with ethyl 3-(benzyloxy)propanoate (98) (e.g. with heating in DMF following deprotonation of (98) with NaH). Removal of the benzyl protecting group (e.g. using Pd/C and H₂ in an alcoholic solvent, such as EtOH, at room temperature) followed by oxidation of (100) (e.g. using Dess-Martin Periodinane in a solvent, such as DCM, at room temperature) can provide (101). Treatment of (101) with hydrazine (102) (e.g. in the presence of a solvent, such as THF, in the presence of acetic acid) can provide pyrazoles (96) and (97). Certain compounds of formula (XXXIII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (103), which can be made by Scheme W:

Displacement of the chloride in (104) by treatment with 4-methoxybenzylamine (e.g. in an alcohol, such as isopropanol, at temperature from 80°C to 100°C) can provide nitro (105), which can be reduced to amine (106) (e.g. by use of H₂ in the presence of RaNi in a solvent, such as THF, at room temperature). Amine (106) can be converted to dione (107) by heating in diethyloxalate, which on treatment with POCI3 (e.g. in the presence of a base, such as DIPEA, in a solvent, such as DMF, at a temperature from 80°C to 100°C) can provide chloride (108). Chloride displacement with aminoacetal (109) can provide acetal (110), which in the presence of an acid (e.g. TFA in DCM) can cyclise with PMB deprotection to form imidazole (103).

Certain compounds of formula (XII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (111), which can be made by Scheme X:

Treatment of (56) (prepared as described in Scheme N) with Et₃N, followed by heating with ethyl 2-(benzyloxy)acetate in a solvent, such as THF, can provide the hydroxy (112), which can be converted to the chloro (113) (e.g. by heating with POCl₃). Displacement of the resultant chlorine with a protected amine (e.g. para-methoxybenzylamine in a solvent, such as DMF, at room temperature) and then deprotecting the amine (in the case para- methoxybenzylamine this can be achieved using TFA e.g. in DCM at room temperature) can provide amine (114). The alcohol benzyl protecting group of amine (114) can be removed (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) to provide amino alcohol (115). Oxazole ring formation to (111) can be achieved by acylation of amine alcohol (115) with R⁴COCI in the presence of a base, such as Et₃N, in a solvent, such as THF, followed by heating in a high boiling solvent. A subset of oxazole pyridones (11 1), where R⁴ = H can be formed from (115) by treatment with triethyl orthoformate at a temperature from 80°C to 1 10°C.

Certain compounds of formula (X) and (XI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (116) and (117) respectively, which can be made by Scheme Y:

The hydroxyl in (57) (prepared as described in Scheme N) can be converted to chloro (1 18) (e.g. by heating with POCl₂). Displacement of the resultant chlorine with a protected amine (e.g. para-methoxybenzylamine in a solvent, such as DMF, at room temperature) and then deprotecting the amine (in the case of para-methoxybenzylamine this can be achieved using TFA in DCM at room temperature) can provide nitro amine (1 19). The nitro in (1 19) can be reduced to amine (120) by hydrogenation in the presence of Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Alternatively, the nitro can be reduced to the amine using sodium hydrosulphite in the presence of NaOH and H₂O at room temperature. Imidazole ring formation to (121) can be achieved by treatment with R⁴COOH in the presence of T3P and a base, such as Et₃N, in a solvent, such as DMF, at a temperature from 80°C to 100°C. In the case of R⁴ = H imidazole ring closure can be affected by treatment with triethyl orthoformate at a temperature from 80°C to 1 10°C. Intermediate (121) can be used in Schemes A, C, E, F, G, H, I, J and L to deliver compounds of formula (X) and (XI) where R⁵ = H. Intermediate (121) can be converted to (116) and (1 17) by reaction with R⁵-LG, where LG represents a leaving group, such as halide or tosyl group. The reaction can be performed in a solvent, such as DMF or MeOH, in the presence of a base, such as K2C03 or NaH, with optional heating.

Certain compounds of formula (XXXV) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (122), which can be made by Scheme Z:

Scheme Z

Treatment of iodo (123) with alkyne (124) under Pd coupling (e.g. use of Pd(PPh3)2Cl2 and Cul in the presence of a base, such as Et₃N, in a solvent, such as DMF, at room temperature) can provide alkyne (125). Oxidation of the triple bond to the dicarbonyl (126) can be achieved with KMnCU (e.g. in the presence of MgSO₄ and a base, such as NaHCO₃, in a solvent, such as H₂O, at room temperature). Treatment of (126) with NH4OH in the presence of R⁴CHO can provide imidazole (127). Nitro reduction to give amine (128) can be effected using sodium hydrosulphite in the presence of NaOH and H₂O at room temperature. Reaction of amine (128) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (122).

Certain compounds of formula (XXXVI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (129), which can be made by Scheme A1 :

Scheme A1

Carboxylic acid (55) can be treated with ethoxycarbonyl isothiocyanate in a solvent, such as ACN, at a temperature of 80°C to form (130), which on treatment with AC2O at a temperature of 60°C can cyclise to (131). Hydrolysis using a base (e.g. use of NaOMe, in a solvent, such as ACN/THF, at a temperature from 60°C to 80°C) can form (132). Treatment with iodomethane in the presence of a base (e.g. use of NaOMe, in a solvent, such as MeOH, at room temperature) can deliver (133), which on treatment with POCI3 (e.g. in the presence of a base, such as pyridine, at a temperature from 80°C to 110°C) can form the chloride (134). Displacement of the resultant chlorine with a protected amine (e.g. para- methoxybenzylamine in a solvent, such as DMF, at room temperature) and then deprotecting the amine (in the case of para-methoxybenzylamine this can be achieved using TFA in DCM at room temperature) can provide amine (135), which on reaction with (136), where LG represents a leaving group, such as halide or tosyl, in a solvent, such as 1 ,4-dioxane, at a temperature from 70°C to 100°C, can form (137). Removal of the SMe and formation of (129) can be effected by treatment with a base (e.g. use of KOH in a solvent, such as H₂O/MeOH, at a temperature from 80°C to 100°C).

Certain compounds of formula (XXXXXIII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (138), which can be made by Scheme B1 :

Scheme B1

Chlorine displacement in (108) (prepared as described in Scheme W) with hydrazine (e.g. in a solvent, such as EtOH, with optional heating) can form (139), which on treatment with R⁴COCI, in the presence of a base, such as pyridine, with optional heating, followed by heating the resultant product in the presence of polyphosphoric acid, at a temperature from 100°C to 150°C can give triazole (140). In the case of R⁴ = H ring closure to the triazole from (139) can be effected by treatment with triethyl orthoformate at a temperature from 80°C to 110°C. Removal of the PMB protecting group to give (138) can be effected with TFA (e.g. in a solvent, such as DCM, at room temperature).

Certain compounds of formula (XXXXXI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (141), which can be made by Scheme C1 :

Scheme C1

Chlorine displacement in (134) (prepared as described in Scheme A1) with hydrazine (e.g. in a solvent, such as EtOH, with optional heating) can form (142), which on treatment with R⁴COCI, in the presence of a base, such as pyridine, with optional heating, followed by heating the resultant product in the presence of polyphosphoric acid, at a temperature from 100°C to 150°C can give triazole (143). In the case of R⁴ = H ring closure to the triazole from (143) can be effected by treatment with triethyl orthoformate at a temperature from 80°C to 110°C. Removal of the SMe and formation of (141) can be effected by treatment with a base (e.g. use of KOH in a solvent, such as H₂O/MeOH, at a temperature from 80°C to 100°C).

Certain compounds of formula (XXXXX) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (144), which can be made by Scheme D1 :

Carbamate (146) can be prepared from amine (145) by reaction with ethyl chloroformate in the presence of a base, such as NaHCO₃, in a solvent, such as butanone. Treatment of (146) with hydrazide (147) in a solvent, such as NMP, at a temperature from 120°C to 180°C can give tricycle (144).

Certain compounds of formula (XXXXXIV) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (148), which can be made by Scheme E1 :

NH

Treatment of amine (149) with NaNO₂/H₂O in the presence of 6N HCI at a temperature from 0°C to 5°C, followed by treatment with SnCl₂ in the presence of concentrated HCI at a temperature from 0°C to 5°C can give hydrazine (150). Formation of (152) can be effected by treatment of (150) with (151) in the presence of a base, such as pyridine. Acylation of the amine in (152) with ethyl 2-(chlorocarbonyl)actetate in a solvent, such as Et₃O , can give (153), which on heating in a solvent, such as NMP, at a temperature between 120°C to 180°C can cyclise to form triazole (154). Nitro reduction of (154) followed by concomitant ring closure can be effected with Fe in the presence of AcOH, at a temperature of 60°C to 100°C to give tricycle (148).

Certain compounds of formula (XXXXIX) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (155), which can be made by Scheme F1 :

( )

Tetrazole (156) can be prepared from cyanide (145) by reaction with NalsU in the presence of NH4CI, in a solvent, such as NMP, at a temperature from 30°C to 100°C. Treatment of amine (156) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (155).

Certain compounds of formula (XXXXVIII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (157), which can be made by Scheme G1 :

Treatment of (139) (prepared as described in Scheme B1) with NaNO₂/H₂O in the presence of 6N HCI at a temperature of 0°C to 5°C, can provide tetrazole (158). Removal of the PMB protecting group to give tricycle (157) can be effected with TFA (e.g. in a solvent, such as DCM, at room temperature). Certain compounds of formula (XXXXXII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (159), which can be made by Scheme H1 :

Amide coupling between amine (67) (prepared as described in Scheme P) and carboxylic acid (160) can be effected by standard amide coupling reagents, such as DCC in a solvent, such as DCM, in the presence of DMAP. Treatment of (161) with an azide, such as NaN₃, in the presence of Cul, in a solvent, such as DMSO, at a temperature from 50°C to 100°C, can form tricycle (159).

Certain compounds of formula (XXXXXV) and (XXXXXVI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (162) and (163) respectively, which can be made by Scheme 11 :

Treatment of iodo (123) with alkyne (164) under Pd coupling (e.g. use of Pd(PPh3)2Cl₂ and Cul in the presence of a base, such as Et₃N, in a solvent, such as DMF, at room temperature) can provide alkyne (165). 1.3-Dipolar cycloaddition with benzyl azide (e.g. with heating in toluene at a temperature from 50°C to 80°C) can provide triazole (166). Nitro reduction of (166) followed by concomitant ring closure can be effected with Zn in the presence of AcOH, with optional heating, to give tricycle (167). The benzyl protecting group of triazole (167) can be removed (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) to provide (168). Intermediate (168) can be used in Schemes A, C, E, F, G, H, I, J and L to deliver compounds of formula (XXXXXV) and (XXXXXVI) where R⁵ = H. Intermediate (168) can be converted to (162) and (163) by reaction with R⁵-LG, where LG represents a leaving group, such as halide or tosyl group. The reaction can be performed in a solvent, such as DMF or MeOH, in the presence of a base, such as K₂CO₃ or NaH, with optional heating.

Certain compounds of formula (XXVIII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (169) which can be made by Scheme J1 :

Silver mediated Pd catalyst CH arylation of (123) with isothiazole (170) (e.g. using AgF and Pd(PPh₃)₂CI₂ and PPh₃ in a solvent, such as ACN, at a temperature from 50°C to 80°C) can provide (171). Nitro reduction of (171), followed by concomitant ring closure can be effected with Fe in the presence of HCI, in a solvent mixture of EtOH/H₂O, with optional heating, to give tricycle (172). Treatment of bromide (172) under Suzuki coupling conditions with R⁴B(OH)2 in the presence of a Pd catalyst, such as [1 , 1 '-bis(diphenylphosphino)-ferrocene]- dichloropalladium(ll), in the presence of a base, such as NaHCO₃, in a solvent mixture of DME/H₂O, at a temperature from 50°C to 80°C, can provide (169). Alternatively, intermediate (169) can be accessed by treatment of bromide (172) with (n-Bu)3SnR⁴ in the presence of a Pd catalyst, such as Pd(PPh₃)₄, in a solvent, such as toluene, from a temperature of 80°C to 120°C. Hydrogenation of (172) (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) can provide intermediate (169) where R⁴ = H.

Certain compounds of formula (XXVI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (173) which can be made by Scheme K1 :

Carboxylic acid (55) can be converted to primary carboxamide (174) using standard amide coupling procedures, such as DCC in the presence of benzotriazole, in a solvent, such as DCM, followed by treatment with NH4OH in a solvent, such as THF. Further amide coupling of the amine (174) and carboxylic acid (160) can be effected by standard amide coupling reagents, such as DCC in a solvent, such as DCM, in the presence of DMAP. Treatment of (175) with chlorocarbonylsulphenyl chloride in a solvent, such as THF, at a temperature from 40°C to 65°C can form cycloadduct (176), which on heating in a high boiling solvent, such as xylene, can form tricycle (173).

Certain compounds of formula (XIV) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (177) which can be made by Scheme L1 :

Displacement of the chlorine in (113) (prepared as described in Scheme X) with NHR⁵ (e.g. in a solvent, such as DMF, at room temperature) can provide amine (178). The alcohol benzyl protecting group of amine (178) can be removed (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) to provide amino alcohol (179). Treatment of amino alcohol (179) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (177).

Certain compounds of formula (XVII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (180) which can be made by Scheme M 1 :

Benzylation of the NH in benzoxazine-2,4-dione (56) (prepared as described in Scheme N) can be effected with BnBr in the presence of a base, such as K₂CO₃, in a solvent such as DMF, with optional heating. Treatment of (181) with Et₃N, followed by heating with ethyl nitroacetate in a solvent, such as THF, can provide the nitro (182), which can be reduced to the amine (183) using sodium hydrosulphite in the presence of NaOH and H₂O at room temperature. Treatment of amino alcohol (183) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (184). Hydrogenation of (84) (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) can provide intermediate (180) where R⁵ = H. Oxazolidone (184) can be converted to (185) by reaction with R⁵-LG, where LG represents a leaving group, such as halide or tosyl group. The reaction can be performed in a solvent, such as DMF or MeOH, in the presence of a base, such as K2C03 or NaH, with optional heating. Hydrogenation of (185) (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) can provide intermediate (180). The PMB group can be considered an alternative PG for the NH in benzoxazine-2,4-dione (56), where deprotection at the appropriate stage can be achieved using TFA in DCM at room temperature.

Certain compounds of formula (XVI) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (186) which can be made by Scheme N1 :

The hydroxyl in (182) (prepared as described in Scheme M1) can be converted to chloro (187) (e.g. by heating with POCI3). Displacement of the chlorine in (187) with NHR⁵ (e.g. in a solvent, such as DMF, at room temperature) can provide amine nitro (188). The nitro can be reduced to the diamine (189) using sodium hydrosulphite in the presence of NaOH and H₂O at room temperature. Treatment of the diamine (189) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (190). The cyclic urea (190) can be converted to (191) by reaction with R⁵-LG, where LG represents a leaving group, such as halide or tosyl group. The reaction can be performed in a solvent, such as DMF or MeOH, in the presence of a base, such as K₂CO₃ or NaH, with optional heating. Hydrogenation of (191) (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) can provide intermediate (186). Intermediate (186) where R⁵ = H can be made by treatment of diamine (120) (prepared as described in Scheme Y) with phosgene (e.g. in THF at room temperature) or an equivalent reagent.

Certain compounds of formula (XXXXXVII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (192) which can be made by Scheme 01 :

Hydrogenation of (112) (prepared as described in Scheme X) (e.g. using Pd/C and H₂ in an alcohol, such as EtOH, at room temperature) can provide diol (193), which on treatment with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (192).

Certain compounds of formula (XVIII) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (194) which can be made by Scheme P1 :

Displacement of the chlorine in (1 18) (prepared as described in Scheme Y) with thiourea (e.g. heating neat at 170°C to 190°C, followed by treatment with EtOH and NaOH) can provide nitro thiol (195). The nitro can be reduced to the amino thiol (196) using Zn dust in the presence of concentrated HCI and AcOH, with optional heating, which on treatment with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (197). Intermediate (197) can be used in Schemes A, C, E, F, G, H, I, J and L to deliver compounds of formula (XVIII) where R⁵ = H. Intermediate (197) can be converted to (194) by reaction with R⁵-LG, where LG represents a leaving group, such as halide or tosyl group. The reaction can be performed in a solvent, such as DMF or MeOH, in the presence of a base, such as K₂CO₃ or NaH, with optional heating.

Certain compounds of formula (XV) can be made as described by Schemes A, C, E, F, G, H, I, J and L using intermediate (198) which can be made by Scheme Q1 :

Acylation of amine (199) with ethyl chloroformate (e.g. using Et₃N in THF at room temperature) can give carbamate (200). Bromination of (200) with Br2 in a solvent, such as CHCl₂ can give bromide (201). The bromide can be displaced with sodium methanethiolate in a solvent, such as MeOH, followed by mCPBA oxidation of the methyl sulphide (e.g. in a solvent, such as DCM, at a temperature from 0°C to room temperature) to give methyl sulphoxide (202). Ring closure of (202) to (203) can be effected by a base, such as NaH, in a solvent, such as THF, with optional heating. The hydroxyl in (203) can be converted to chloro (204) (e.g. by heating with POCI₃). Displacement of the chlorine in (204) with NHR⁵ (e.g. in a solvent, such as DMF, at room temperature) can provide amine (205). A Pummerer rearrangement of the methyl sulphoxide using trifluoroacetic anhydride in a solvent, such as DCM, followed by treatment with a base, such as Et₃N in a solvent, such as MeOH, can give amino thiol (206), which on treatment with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (198).

All of the above Schemes N to Q1 provide compounds of the invention in which A is O. Such compounds can be converted into compounds in which A is =S, =NR⁶ and =NOR⁶ according to Schemes R1 , S1 and T1 , which can be used to provide compounds of the invention where A is S, =NR⁶ and =NOR⁶

Amide (33) can, for example, be converted to thioamide (207) by heating with P2S5 in pryridine.

S S1

Amide (33) can, for example, be converted to amidinine (208) by heating with POCI3 and heating the product with the primary amine NH₂R⁶.

S T1

Amide (33) can, for example, be converted to oxime (209) by heating with POCI3 and heating the product with the O-substituted hydroxylamine NH₂OR⁶. Compounds of formula I where one of X¹ , X², X³ or X⁴ represents an N-oxide can be made by oxidation of the corresponding pyridine substrate. The reaction can be effected using standard oxidising reagents, such as mCPBA, in a solvent, such as CH₂CI2, at a temperature from 0°C to room temperature.

Compounds of formula I where X⁴ represents an N-oxide and X³ represents a CH can be converted to compounds of formula I where X⁴ represents a NH and X³ represents a C=0. The reaction can be effected using neat AC2O at a temperature of 140°C.

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, B, C and D) using H₂O and ACN (0.1 % formic acid - acidic pH; 0.1 % ammonia - basic pH). Wavelengths were 254 and 210 nM.

Method A

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

Method B

Column: Waters XBridge C 18, 5μηι, 50 x 2.1 mm. Flow rate: 0.8 mL/min. Injection volume 10 μΙ_

Method C

Column: YMC-Triart C18 50 x 2 mm, 5 uM. Flow rate: 0.8 mUmin. Injection volume 5 μΙ_.

Method D

Column: YMC-Triart C18 50 x 2 mm, 5 uM. Flow rate: 0.8 mUmin. Injection volume 5-10 μΙ_

Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) or Waters 2767 Sample Manager (Method B) using H₂O and ACN (0.1-% formic acid - acidic pH; 0.1 % ammonia - basic pH).

Method A Column: XBridge™ prep C18 5 μΜ OBD 19 x 100 mm. Flow rate: 20 mUmin. Method B

Column: XBridge™ prep C18 5 μΜ OBD 19 x 100 mm. Flow rate: 20 mUmin.

Example 1 - 5-{2-[4-({2H,3H-[1,4]dioxinor2,3-c]pyridin-7-ylmethyl}amino )piperidin-1 - yl]ethyl}-4H,5H-[1,3]oxazolor4,5-c]quinolin-4-one A

(a) 4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one

To a mixture of NaH (60% dispersion in mineral oil) (882 mg, 22.07 mmol) in anhydrous DMF (10 ml_) at room temperature under N2 was added ethyl isocyanoacetate (2.41 ml_, 22.07 mmol) dropwise and the resulting mixture was left to stir for 30 min. To the resulting mixture was added 2,4-dihydro-1 H-3,1-benzoxazine-2,4-dione (3 g, 18.39 mmol) and the reaction heated to 100°C for 3 h. The reaction was allowed to cool to room temperature, quenched with saturated aq. NH4CI solution (50 ml_) and poured into H₂O (150 ml_). The precipitate was filtered off and washed with diethyl ether to give 4H,5H-[1 ,3]oxazolo[4,5- c]quinolin-4-one (1.20 g, 35% yield) as a brown solid.

LC-MS (Method A acidic) 187.3 [M+H]⁺; RT 1.21 min

(b) 5-(prop-2-en-1-yl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one

A mixture of 4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one (500 mg, 7.69 mmol), allyl bromide (0.28 ml_, 3.22 mmol) and K₂CO₃ (482 mg, 3.49 mmol) in anhydrous DMF (4 ml_) was heated in a microwave (Biotage Initiator) at 150°C for 30 min. The reaction was diluted with saturated aq. NH4CI (50 ml_) and then extracted with EtOAc (3 x 50 ml_). The combined organics were washed with H₂O (50 ml_), brine (50 ml_), dried over MgSO₄ and concentrated in vacuo. The crude product was purified by flash chromatography eluting with petroleum ether (40/60) to EtOAc to afford 5-(prop-2-en-1-yl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one (363 mg, 60% yield) as an ochre solid.

LC-MS (Method A acidic) 227.4 [M+H]⁺; RT 1.59 min

(c) 2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5-yl}acetaldehyde

Osmium tetroxide (4 % in H₂O) (0.1 ml_, 0.02 mmol) was added to a solution of 5-(prop-2- en-1-yl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one (100 mg, 0.44 mmol) and sodium periodate (236 mg, 1.11 mmol) in THF (4 ml_) and H₂O (3.5 ml_) under N2. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction was diluted with brine (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organics were dried over MgSO₄ and concentrated in vacuo. The crude was purified by flash chromatography eluting with petroleum ether (40/60) to EtOAc to afford 2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5- yl}acetaldehyde (86 mg, 85% yield) as a cream solid.

LC-MS (Method A acidic) 229.4 [M+H]⁺; RT 1.16 min

(d) tert-butyl N-[1-(2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5-yl]ethyl}piperidin-4- yl]carbamate

A mixture of 2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5-yl}acetaldehyde (85 mg, 0.37 mmol) and tert-butyl N-(piperidin-4-yl)carbamate (82 mg, 0.41 mmol) in anhydrous THF (5 ml_) with 4A molecular sieves was heated at 75°C for 3 h. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (236 mg, 1 .12 mmol) was added and stirred at room temperature for a further 2 h. The reaction mixture was diluted with saturated aq. NaHCO₃ solution (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organics were washed with brine (50 ml_), dried over MgSO₄ and concentrated in vacuo to afford tert-butyl N-[1 -(2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5- yl]ethyl}piperidin-4-yl]carbamate (132 mg, 86% yield) as a cream solid. The product was used without further purification.

LC-MS (Method A acidic) 413.4 [M+H]⁺; RT 2.19 min

(e) 5-{2-[4-({2H ,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-4H,5H- [1 ,3]oxazolo[4,5-c]quinolin-4-one A

A mixture of tert-butyl N-[1 -(2-{4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5-yl]ethyl}piperidin-4- yl]carbamate (105 mg, 0.25 mmol) and trifluoroacetic acid (2.5 ml_, 32.65 mmol) in DCM (2.5 ml_) was stirred at room temperature for 2 h. The reaction mixture solvent was removed under vacuo and the residue dissolved in MeOH and passed through a Silicycle Si- carbonate column. The eluent fractions were combined and solvent removed under vacuo to afford crude 5-[2-(4-aminopiperidin-1-yl)ethyl]-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one.

A mixture of the crude 5-[2-(4-aminopiperidin-1 -yl)ethyl]-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4- one and 2H,3H-[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (synthesised as described in WO2004058144, Example 2(c)) (59 mg, 0.36 mmol) in anhydrous THF (5 ml_) with 4A molecular sieves was heated at 75°C for 3 h. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (207 mg, 0.98 mmol) was added and stirred at room temperature for a further 2 h. The reaction mixture was diluted with saturated aq. NaHCO₃ solution (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organics were washed with brine (50 ml_), dried over MgSO₄ and concentrated in vacuo. The crude was purified by flash chromatography eluting with DCM to 15% MeOH/1 % NH₃/DCM to afford 5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl}amino)piperidin-1-yl]ethyl}-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one A (20 mg, 17% yield) as a beige solid.

1 H NMR (Method A) (CDCI₃): δ ppm 8.10 (m, 2H), 7.98 (d, J = 8.0 Hz, 1 H), 7.63 (m, 2H), 7.35 (m, 1 H), 6.82 (s, 1 H), 4.56 (t, J = 7.3 Hz, 2H), 4.32 (m, 2H), 4.27 (m, 2H), 3.80 (s, 2H), 3.02 (m, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.53 (m, 1 H), 2.21 (t, J = 1 1.5 Hz, 2H), 1.92 (d, J = 12.8 Hz, 2H), 1.47 (m, 2H); LC-MS (Method A acidic) 462.4 [M+H]⁺; RT 1.76 min

Example 2 - 6-({[i -(2-{4-oxo-4H,5H-[1 ,3]oxazolor4,5-c]quinolin-5-yl}ethyl)piperidin-4- vnamino }methyl)-3,4-dihydro-2H-1 ,4-benzoxazin-3-one B

To a solution of 5-[2-(4-aminopiperidin-1-yl)ethyl]-4H ,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (e)) (28 mg, 0.09 mmol) in THF (5 ml_) and MeOH (0.5 ml_) was added EtaN (0.020 ml_, 0.15 mmol) and 3-oxo-4/-/-1 ,4-benzoxazine-6- carbaldehyde (26 mg, 0.15 mmol) and the mixture was heated at 65°C for 90 min. After cooling to 0°C, sodium borohydride (6 mg, 0.16 mmol) was added and the mixture was stirred for a further 45 min. The mixture was poured into H₂O (20 ml_) and extracted with DCM (2 x 10 ml_). The combined organics were washed with H₂O (10 ml_), brine (10 ml_), dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by preperative TLC (DCM/MeOH 9:1) to furnish 6-({[1-(2-{4-oxo-4H ,5H-[1 ,3]oxazolo[4,5- c]quinolin-5-yl}ethyl)piperidin-4-yl]amino}methyl)-3,4-dihydro-2H-1 ,4-benzoxazin-3-one B (3.8 mg, 5% yield) as a pale yellow soild.

¹ H NMR (Method A) (CDCI₃) 8.14 (s, 1 H), 8.01 (dd, J = 7.9, 1.3 Hz, 1 H), 7.60-7.68 (m 2H), 7.38 (m, 1 H), 6.92 (br. s, 3H) , 4.57-4.61 (m, 4H), 3.77 (s, 2H), 3.08 (m, 2H), 2.75 (br. t, J = 7.4 Hz, 2H), 2.61 (m, 1 H), 2.25 (br. t, J = 10.8 Hz, 2H), 1.95 (br. d, J = 12.5 Hz, 2H), 1.45- 1.57 (m, 2H); LC-MS (Method B acidic) 474.5 [M+H]⁺, RT 1.92 min

Example 3 - 5-{2-[4-({2H,3H-[1,4]dioxinor2,3-c]pyridin-7-ylmethyl}amino )piperidin-1 - yl]ethyl}-7-methoxy-4H,5H-[1,3]oxazolo[4,5-c]quinolin-4-one C

Following the procedures of Example 1 (a)-(e) but using 7-methoxy-2,4-dihydro-1 H-3,1- benzoxazine-2,4-dione in step (a) 5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl}amino)piperidin-1-yl]ethyl}-7-rnethoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one C was synthesised as a white solid.

1 H NMR (Method A) (CD₃OD): δ ppm 8.34 (s, 1 H), 7.93 (s, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.09 (d, J = 2.2 Hz, 1 H), 6.99 (dd, J = 8.8, 2.1 Hz, 1 H), 6.87 (s, 1 H), 4.48 (t, J = 7.4 Hz, 2H), 4.28-4.26 (m, 2H), 4.22-4.19 (m, 2H), 3.88 (s, 3H), 3.77 (s, 2H), 3.03 (d, J = 11.5 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.56 (m, 1 H), 2.16-2.06 (m, 2H), 1.89 (d, J = 12.2 Hz, 2H), 1.43 (m, 3H); LC-MS (Method B acidic) 492.5 [M+H]⁺; RT 1.95 min

Example 4 - 5-{2-[4-({2H,3H-n.4]dioxinor2,3-c]pyridin-7-ylmethyl)amino )piperidin-1 - yl]ethyl}-7-fluoro-4H,5H-[1,3]oxazolor4,5-c]quinolin-4-one D

Following the procedures of [Example 1 (a)-(e) but using 7-fluoro-2,4-dihydro-1 H-3,1- benzoxazine-2,4-dione in step (a) 5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl}amino)piperidin-1-yl]ethyl}-7-meth^ D was synthesised as a white solid.

1 H NMR (Method A) (CD₃OD): δ ppm 8.42 (s, 1 H), 8.01 (dd, J = 8.8, 6.1 Hz, 1 H), 7.90 (s, 1 H), 7.50 (dd, J = 1 1.7, 2.2 Hz, 1 H), 7.18-7.13 (m, 1 H), 6.86 (s, 1 H), 4.46 (t, J = 7.4 Hz, 2H), 4.28-4.25 (m, 2H), 4.23-4.16 (m, 2H), 3.66 (s, 2H), 2.98 (d, J = 1 1.6 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 2.41 (td, J = 10.8, 5.5 Hz, 1 H), 2.08 (td, J = 12.1 , 2.2 Hz, 2H), 1.84 (d, J = 12.6 Hz 2H), 1.36 (m, 2H); LC-MS (Method B acidic) 480.5 [M+H]⁺; RT 1.81 min

Example 5 - 7-methoxy-5-{2-[4-[({3-oxo-2H,3H,4H-pyridor3,2-b][1.4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1,3]oxazolor4,5-c]quinolin-4-one E

Following the procedures of Example 1 (a)-(e) but using 7-methoxy-2,4-dihydro-1 H-3,1- benzoxazine-2,4-dione in step (a) and 3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazine-6- carbaldehyde in step (e) 7-methoxy-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}rnethyl)arnino]piperidin-1-yl}ethyl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one E was synthesised as a white solid.

1 H NMR (Method A) (CDCI₃): δ ppm 8.03 (s, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 7.10 (s, 1 H), 7.00-6.90 (m, 2H), 4.63 (s, 2H), 4.54 (t, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 2H), 3.06 (d, J = 11.3 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.59-2.54 (m, 1 H), 2.24 (t, J = 1 1.1 Hz, 2H), 1.94 (d, J = 12.6 Hz 2H), 1.55-1.47 (m, 2H); LC-MS (Method B acidic) 505.9 [M+H]⁺; RT 1.71 min

Example 6 - 7-fluoro-5-(2-{4-[({3-oxo-2H,3H,4H-pyridor3,2-b][1.4]oxazin-6- yl)methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1,3]oxazolor4,5-c]quinolin-4-one F

Following the procedures of [Example 1 (a)-(e) but using 7-fluoro-2,4-dihydro-1 H-3,1- benzoxazine-2,4-dione in step (a) and 3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazine-6- carbaldehyde in step (e) 7-fluoro-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one F was synthesised as a white solid.

1 H NMR (Method A) (CD₃OD): δ ppm 8.42 (s, 1 H), 8.00 (dd, J = 8.8, 6.1 Hz, 1 H), 7.49 (dd, J = 1 1.7, 2.2 Hz, 1 H), 7.20-7.10 (m, 2H), 6.87 (d, J = 8.0 Hz, 1 H), 4.53 (s, 2H), 4.46 (t, J = 7.3 Hz, 2H), 3.70 (s, 2H), 3.00 (d, J = 1 1.6 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H), 2.47 (m, 1 H). 2.09 (td, J = 11.9, 2.4 Hz, 2H), 1.86 (d, J = 12.7 Hz, 2H), 1.38 (qd, J = 12.1 , 3.7 Hz, 2H); LC-MS (Method B acidic) 493.4 [M+H]⁺; RT 2.05 min

Example 7 - 5-(2-{4-[({3-oxo-2H.3H.4H-pyridor3.2-b][1.4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1 ,2]oxazolor3,4-c]quinolin-4-one G

(a) dimethyl[(E)-2-(2-nitrophenyl)ethenyl]amine

A mixture of N,N-dimethylfonmamide dimethyl acetal (0.73 ml_, 5.5 mmol) and 1-methyl-2- nitrobenzene (0.43 ml_, 3.65 mmol) in DMF (2 ml_) under N2 was heated in a microwave (Biotage Initiator) at 100°C for 3 h. The reaction mixture was partitioned between Et₂O and H₂O. The aq. was washed with Et₂O (4 x 30 ml_) and the organics were combined, dried over MgSO₄ and concentrated in vacuo to give the product as a dark red oil, which was used without further purification.

LC-MS (Method B acidic) 193.4 [M+H]⁺; RT 2.62 min

(b) ethyl 4-(2-nitrophenyl)-1 ,2-oxazole-3-carboxylate

To dimethyl[(E)-2-(2-nitrophenyl)ethenyl]amine (617 mg, 3.21 mmol) in THF (10 mL) was added Et₃N (0.71 mL, 5.09 mmol). To the reaction mixture was added very slowly a solution of ethyl (2Z)-2-chloro-2-(hydroxyimino)acetate (0.71 mL, 4.86 mmol) in THF (10 mL) in the dark. The reaction mixture was stirred at room temperature in the dark for 4 h, then concentrated in vacuo. The residue was dissolved in EtOH (10 mL), concentrated HCI (2 mL) added and the mixture heated to 50°C overnight. The reaction was concentrated in vacuo and poured onto saturated aq. NaHCO₃ solution (20 mL) and extracted with DCM (3 x 10 mL). The combined organics were dried over MgSO₄, concentrated in vacuo and the crude product purified by flash chromatography eluting with 40% DCM in petroleum ether (40/60) to petroleum ether (40/60) to afford ethyl 4-(2-nitrophenyl)-1 ,2-oxazole-3-carboxylate (746 mg, 89% yield) as an orange oil.

LC-MS (Method B acidic) 263.3 [M+H]⁺; RT 2.35 min

(c) 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one

Ethyl 4-(2-nitrophenyl)-1 ,2-oxazole-3-carboxylate (886 mg, 3.38 mmol) and sodium hydrosulfite (1.18 g, 6.76 mmol) were dissolved in EtOH (3 ml_) and H₂O (2 ml_). The mixture was refluxed overnight then concentrated in vacuo. The residue was suspended in saturated aq. NaHCO₃ solution and extracted with DCM (2 x 10 ml_). A white solid precipitated during the extraction, which was suspended in DCM/MeOH/EtOAc and the resulting slurry was filtered. The filtrate was combined with the organic extractions and further extractions of the aq. were performed with DCM then with EtOAc. The organic extracts were combined, dried over MgSO₄ then concentrated in vacuo. The crude product was purified by flash chromatography eluting with DCM to 20% MeOH in DCM to give 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one (220 mg, 35 % yield) as a white solid.

LC-MS (Method B acidic) 187.3 [M+H]⁺; RT 1.52 min

(d) tert-butyl N-[1-(2-hydroxyethyl)piperidine-4-yl]carbamate

In a microwave vial tert-butyl N-(piperidin-4-yl)carbamate (498 mg, 2.49 mmol), 2- bromoethanol (0.18 ml_, 2.54 mmol) and Et₃N (0.38 ml_, 2.73 mmol) were dissolved in ACN (2 ml_). The tube was sealed and heated on a hot plate at 50°C overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc and washed with saturated aq. NaHC03 solution. The aq. was back-extracted with EtOAc and the combined organics were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by flash chromatography eluting with DCM to 20% MeOH in DCM to give tert-butyl N-[1-(2- hydroxyethyl)piperidine-4-yl]carbamate (415 mg, 68% yield) as a colourless oil.

(e) tert-butyl N-[1-(2-{4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5-yl}ethyl)piperidin-4- yl]carbamate

A mixture of tert-butyl N-[1-(2-hydroxyethyl)piperidine-4-yl]carbamate (400 mg, 1.64 mmol) and EtaN (0.32 ml_, 2.29 mmol) in DCM (5 ml_) was treated at 0°C with methanesulfonyl chloride (0.15 ml_, 1.96 mmol) and the mixture left to stir for 45 min in an ice bath. Potassium phosphate buffer solution (1 M, 5 ml_) was added to the reaction mixture and the DCM was removed in vacuo. The residue was extracted with ice cold EtOAc (3 x 10 ml_). The combined organics were dried over MgSO₄ and concentrated in vacuo to yield tert-butyl N-{1-[2-(methanesulphonyloxy)ethyl]piperidin-4-yl}carbamate (531 mg, 100% yield) as a white solid, which was used directly in the next step.

A solution of 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one (165 mg, 0.89 mmol) in DMF (5 ml_) was treated at 0°C with NaH (37 mg, 0.93 mmol). The mixture was stirred for 40 min at room temperature, then tert-butyl N-{1-[2-(methanesulphonyloxy)ethyl]piperidin-4-yl}carbamate (531 mg, 1.65 mmol) in DMF (5 ml_) was added dropwise over 20 min. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to remove the DMF and the residue was dissolved in EtOAc. The organic layer was washed with saturated aq. NaHCO₃ solution and the aqueous was back extracted with EtOAc. The combined organics were dried over MgSO₄ and concentrated in vacuo to give a crude residue. The residue was dissolved in MeOH and loaded onto a pre-equilibriated SCX column, washing with MeOH then eluting with MeOH/Nh₃. The elution was concentrated in vacuo to give tert-butyl N-[1-(2-{4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5-yl}ethyl)piperidin- 4-yl]carbamate (141 mg, 39% yield) as a brown solid.

LC-MS (Method B acidic) 413.5 [M+H]⁺; RT 1.53 min

(f) 5-[2-(4-aminopiperidin-1-yl)ethyl]-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one

A solution of tert-butyl N-[1-(2-{4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5-yl}ethyl)piperidin- 4-yl]carbamate (126 mg, 0.31 mmol) in DCM (10 ml_) was treated with 4 M HCI in dioxane (0.5 ml_, 2 mmol). The reaction was stirred at room temperature for 1 h, then neutralised with saturated aq. NaHCO₃ solution and loaded directly onto a pre-equilibriated SCX column, washing with MeOH, then eluting with MeOH/Nh₃. The elution was concentrated in vacuo to give 5-[2-(4-aminopiperidin-1-yl)ethyl]-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one (93 mg, 98% yield).

LC-MS (Method B acidic) 313.5 [M+H]⁺; RT 0.88 min

(g) 5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one G

A mixture of 5-[2-(4-aminopiperidin-1-yl)ethyl]-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one (50 mg, 0.16 mmol) and 3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde (33 mg, 0.19 mmol) in a solvent mixture of DCM (1 ml_) and THF (2ml_) over molecular sieves (4A) was stirred at room temperature for 5 min. Sodium triacetoxyborohydride (44 mg, 0.21 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated aq. NaHCO₃ solution (5 ml_) and extracted with EtOAc (3 x 5 ml_). The combined organics were washed with brine (5 ml_), dried over MgSO₄ and concentrated in vacuo to give a yellow oil. The oil was dissolved in DCM and purified by flash chromatography eluting with DCM to 20% MeOH in DCM to afford 5-(2-{4-[({3-oxo- 2H,3H,4H^yrido[3,2-b][1,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H- [1,2]oxazolo[3,4-c]quinolin-4-one (27 mg, 36% yield) as a white solid.

1H NMR (Method A) (CDCI3): δ ppm 9.18 (s, 1H), 7.79 (d, J = 1.4 Hz, 1H), 7.56-7.44 (m, 2H), 7.33-7.24 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 4.51 (t, J = 7.5 Hz, 2H), 3.85 (s, 2H), 3.10 (d, J = 11.6 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.67-2.58 (m, 1H). 2.26 (t, J = 9.5 Hz, 2H), 1.98 (d, J = 12.5 Hz, 2H), 1.62-1.50 (m, 2H); LC-MS (Method B acidic) 475.5 [M+H]⁺; RT 0.90 min

Example 8 - 5-{2-r4-({2H.3H-[1.4]dioxinor2.3-c]Pyridin-7-ylmethyl}amino)piperidin-1- yl1ethyl}-4H.5H-[1.21oxazolor3.4-clauinolin-4-one H

Following the procedures of Example 7 but using 2H,3H-[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde in step (g) 5-{2-[4-({2H,3H-[1,4]dioxino[2,3-c]pyridin-7- ylmethyl}amino)piperidin-1-yl]ethyl}-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one H was synthesised as a white solid.

1H NMR (Method A) (CDCI3): δ ppm 9.20 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H) 7.54-7.49 (m, 2H), 7.33-7.25 (m, 1H), 6.82 (s, 1H), 4.51 (br t, J = 6.0 Hz, 2H), 4.36-4.30 (m, 2H), 4.30-4.25 (m, 2H), 3.85 (s, 2H), 3.07 (d, J = 11.0 Hz, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.67- 2.62 (m, 1H), 2.35-2.21 (br s, 2H), 2.01-1.96 (d, J = 10.5 Hz, 2H). 1.58 (q, J = 12.0 Hz, 2H); LC-MS (Method B acidic) 462.5 [M+H]⁺; RT 0.98 min

Example 9 - 7-fluoro-5-{2-r4-({2H.3H.4H-pyranor2.3-c]Pyridin-6- ylmethyltomino)piperidin-1-yl]ethyl}-4H.5H-[1,3]oxazolor4.5-c]quinolin-4-one I

Following the procedures of [Example 1 (a)-(e) but using 7-fluoro-2,4-dihydro-1 H-3,1- benzoxazine-2,4-dione in step (a) and 2H,3H.4H-pyran[2,3-c]pyridine-6-carbaldehyde in step (e) 7-fluoro-5-{2-[4-({2H,3H,4H-pyrano[2,3-c]pyridin-6-ylmethyl}arnino)pipehdin-1- yl]ethyl}-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one I was synthesised as a yellow solid.

1 H NMR (Method A) (CD₃OD): δ ppm 8.42 (s, 1 H), 8.01 (dd, J = 8.8, 6.1 Hz, 1 H), 7.85 (s, 1 H), 7.50 (dd, J = 1 1.8, 2.2 Hz, 1 H), 7.16 (td, J = 8.5, 2.3 Hz, 1 H), 7.04 (s, 1 H), 4.47 (t, J = 7.3 Hz, 2H), 4.16-4.09 (m, 2H), 3.69 (s, 2H), 2.99 (m, 2H), 2.72 (t, J = 6.5 Hz, 2H), 2.59 (t, J = 7.3 Hz, 2H). 2.48-2.38 (m, 1 H), 2.09 (m, 2H), 1.98-1.87 (m, 2H), 1.85 (d, J = 13 Hz, 2H), 1.44-1.30 (m, 2H); LC-MS (Method C acidic) 478.5 [M+H]⁺; RT 1.16 min

Example 10 - 7-methoxy-5-(2-f4-[({3-oxo-2H.3H.4H-pyridor3.2-b][1.4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1,21oxazolor3,4-c]quinolin-4-one J

Following the procedures of Example 7 but using 4-methoxy-1-methyl-2-nitrobenzene in step (a) 7-methoxy-5-(2-(4-r((3-oxo-2H,3H,4H-pvridor3,2-biri.41oxazin-6- yl}methyl)arnino]piperidin-1-yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one J was synthesised as a yellow solid. 1 H NMR (Method A) (CD₃OD): δ ppm 9.45 (s, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 6.95-6.80 (m, 3H), 4.51 (s, 2H), 4.34 (t, J = 7.0 Hz, 2H), 3.80 (s, 3H), 3.70 (s, 2H), 2.99 (m, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.47 (m, 1 H), 2.07 (m, 2H), 1.86 (m, 2H), 1.39 (m, 2H); LC-MS (Method C basic) 505.5 [M+H]⁺; RT 2.37 min

Example 11 - 7-fluoro-5-{2-[4-r({7-oxo-6H.7H.8H-pyrimidor5.4-b][1.4]oxazin-2- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1,21oxazolor3,4-c]quinolin-4-one K

Following the procedures of Example 7 but using 4-fluoro-1-methyl-2-nitrobenzene in step (a) and using 7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazine-2-carbaldehyde in step (g) 7- fluoro-5-(2-{4-[({7-oxo-6H7H,8H-pyrimido[5,4-b][1 ,4loxazin-2-yl}methyl)aminolpiperidin-1- yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one K was synthesised as an off white solid .

1 H NMR (Method A) (DMSO-d₆): δ ppm 10.04 (s, 1 H), 8.21 (s, 1 H), 8.12 (dd, J = 8.7, 6.3 Hz, 1 H), 7.46 (dd, J = 12.1 , 2.5 Hz, 1 H), 7.23 (td, J = 8.5, 2.4 Hz, 1 H), 4.70 (s, 2H), 4.37 (t, J = 6.9 Hz, 2H), 3.74 (s, 2H), 2.90 (d, J = 10.8 Hz, 2H), 2.57 (dd, J = 12.8, 5.9 Hz, 2H), 2.43 (dq, J = 8.4, 4.1 , 3.1 Hz, 2H), 2.07 (t, J = 10.4 Hz, 2H), 1.77 (d, J = 12.2 Hz, 2H), 1.25 (t, J = 1 1.4 Hz, 2H); LC-MS (Method D basic) 494.5 [M+H]+; RT 4.63 min

Example 12 -7-fluoro-5-{2-[4-[({3-oxo-2H.3H.4H-pyridor3.2-b][1.4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1,21oxazolor3,4-c]quinolin-4-one L

Following the procedures of Example 7 but using 4-fluoro-1-methyl-2-nitrobenzene in step (a) 7-fluoro-5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-

1-yl}ethyl)-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one L was synthesised as a yellow solid.

1 H NMR (Method A) (CD₃OD): δ ppm 9.55 (s, 1 H), 7.90 (dd, J = 8.6, 6.2 Hz, 1 H), 7.27 (dd, J = 1 1.6, 2.3 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 6.99 (td, J = 8.6, 2.3 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 4.51 (s, 2H), 4.35 (s, 2H), 4.35 (t, J = 7.0 Hz, 2H), 3.00 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.46 (m, 1 H), 2.07 (m, 2H), 1.85 (m, 2H), 1.36 (m, 2H); LC-MS (Method D acidic) 493.4 [M+H]⁺; RT 4.01 min

Example 13 - 5-{2-r4-({2H,3H-[1,4]dioxinor2,3-c]pyridin-7-ylmethyl}amino)piperidin-1- yl]ethylV7-fluoro-4H,5H-[1 ,2]oxazolor3,4-c]quinolin-4-one M

Following the procedures of Example 7 but using 4-fluoro-1-methyl-2-nitrobenzene in step (a) and using 2H,3H-[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde in step (g) 5-{2-[4-({2H,3H- [1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}arnino)pipehdin-1-yl]ethyl}-7-fluoro-4H,5H- [1 ,2]oxazolo[3,4-c]quinolin-4-one M was synthesised as a white solid. 1 H NMR (Method A) (CD₃OD): δ ppm 9.55 (s, 1 H), 7.99 (m, 2H), 7.27 (dd, J = 11.6, 2.3 Hz, 1 H), 6.99 (td, J = 8.3, 2.3 Hz, 1 H), 6.84 (s, 1 H), 4.34 (t, J = 7.0 Hz, 2H), 4.29-4.16 (m, 4H), 3.71 (bs, 2H), 3.00 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.49 (m, 1 H), 2.09 (t, J = 11.9 Hz, 2H), 1.91-1.77 (m, 2H), 1.45-1.30 (m, 2H); LC-MS (Method D acidic) 480.4 [M+H]+; RT 3.92 min

Example 14 - 5-{2-r4-({2H,3H-[1,4]dioxinor2,3-c]pyridin-7-ylmethyl}amino)piperidin-1- yl]ethyl}-7-methoxy-4H,5H-[1 ,2]oxazolor3,4-c]quinolin-4-one N

Following the procedures of Example 7 but using 4-methoxy-1-methyl-2-nitrobenzene in step (a) and using 2H,3H-[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde in step (g) 5-{2-[4- ({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-7-methoxy-4H,5H- [1 ,2]oxazolo[3,4-c]quinolin-4-one_N was synthesised as a white solid.

1 H NMR (Method A) (CD₃OD): δ ppm 9.55 (s, 1 H), 7.99 (s, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 6.88-7.01 (m, 3H), 4.47-4.26 (m, 6H), 3.90 (s, 3H), 3.77 (s, 2H), 3.10 (m, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.54 (m, 1 H), 2.18 (m, 2H), 1.90 (m, 2H), 1.48 (m, 2H); LC-MS (Method C basic) 492.53 [M+H]+; RT 2.43 min

Example 15 - 5-{2-[4-[({3-oxo-2H.3H.4H-pyridor3.2-b][1.4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1 ,2]oxazolor3,4-c]1 ,5-naphthyridin-6-one

O

Following the procedures of Example 7 but using 2-methyl-3-nitro-pyridine in step (a) 5-(2- {4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H- [1,2]oxazolo[3,4-c]1,5-naphthyridin-6-one O was synthesised as an off white solid.

1H NMR (Method A) (DMSO-d₆): δ ppm 11.07 (s, 1H), 10.15 (s, 1H), 8.51 (dd, J = 4.6, 1.2 Hz, 1H), 7.99 (dd, J = 8.7, 1.3 Hz, 1H), 7.58 (dd, J = 8.7, 4.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.00 (d, J= 8.1 Hz, 1H), 4.60 (s, 2H), 4.37 (t, J = 7.0 Hz, 2H), 4.00 (br. s, 1H), 3.67 (s, 2H), 2.90 (d, J= 11.3 Hz, 2H), 2.57 (t, J= 6.9 Hz, 2H), 2.43-2.34 (m, 1H), 2.07 (td, J= 11.4, 2.5 Hz, 2H), 1.96 (br. s, 1H), 1.82-1.73 (m, 2H), 1.29-1.18 (m, 2H); LCMS (Method D basic) 476.4 [M+H]⁺; RT 5.59 min

Example 16 - 5-{2-[4-({2H,3H-[1.4]dioxinor2,3-c]pyridin-7-ylmethyl}amino)piperidin-1- yl]ethyl}-5H,6H-[1,2]oxazolor3,4-c]1,5-naphthyridin-6-one P

Following the procedures of Example 7 but using 2-methyl-3-nitro-pyridine in step (a) and using 2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde in step (g) 5-{2-[4-({2H,3H- [1,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-5H,6H-[1,2]oxazolo[3,4-c]1,5- naphthyridin-6-one P was synthesised as an off white solid. 1H NMR (Method A) (CD3OD): δ ppm 9.63 (s, 1H), 8.37 (dd, J = 4.6, 1.2 Hz, 1 H), 7.95-7.86 (m, 2H), 7.46 (dd, J = 8.7, 4.7 Hz, 1 H), 6.83 (s, 1H), 4.37 (t, J = 7.2 Hz, 2H), 4.28-4.22 (m, 2H), 4.22-4.15 (m, 2H), 3.64 (s, 2H), 2.95 (dd, J = 10.2, 5.6 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.39 (tt, J = 10.7, 4.0 Hz, 1H), 2.06 (td, J = 11.7, 2.5 Hz, 2H), 1.86-1.76 (m, 2H), 1.40-1.25 (m, 2H); LC-MS (Method D basic) 463.4 [M+H]⁺; RT 5.74 min

Example 17 - 5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3.2-b][1,4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1,2.4]triazolor4.3-a]quinoxalin-4-one Q

H

Following steps (e) to (g) of Example 7, but using 4H,5H-[1,2,4]triazolo[4,3-a]quinoxalin-4- one (prepared as described in European Journal of Medicinal Chemistry, 2013, 69, 115-124) in step (e) 5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-4H,5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-one_Q was synthesised as an off white solid.

1H NMR (Method A) (CD3OD): δ ppm 9.61 (s, 1 H), 8.07 (dd, J = 8.2, 1.4 Hz, 1H), 7.60 (dd, J = 8.6, 1.3 Hz, 1 H), 7.52 (ddd, J = 8.6, 7.4, 1.3 Hz, 1H), 7.35 (ddd, J = 8.3, 7.2, 1.2 Hz, 1 H), 7.21-7.11 (m, 1H), 6.88 (d, J = 8.0 Hz, 1 H), 4.53 (d, J = 1.5 Hz, 2H), 4.45 (t, J = 6.9 Hz, 2H), 3.78 (s, 2H), 3.08-2.99 (m, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.62-2.53 (m, 1H), 2.09 (td, J = 11.7, 2.3 Hz, 2H), 1.88 (d, J = 12.6 Hz, 2H), 1.45-1.34 (m, 2H); LC-MS (Method C acidic) 475.4 [M+H]⁺; RT 0.86 min

Example 18 - 5-{2-[4-[({3-oxo-2H.3H.4H-pyridor3.2-b][1.4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-4H,5H-[1.2,3,4]tetrazolori.5-a]quinoxalin-4-one R

Following steps (e) to (g) of Example 7, but using 4H,5H-[1,2,3,4]tetrazolo[1,5-a]quinoxalin- 4-one (prepared as described in Organic Chemistry: An Indian Journal, 2009, 5, 348-356) in step (e) 5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-4H,5H-[1,2,3,4]tetrazolo[1,5-a]quinoxalin-4-one R was synthesised as a white solid.

1H NMR (Method A) (DMSO-d₆): δ ppm 11.12 (s, 1H), 8.39 (dd, J= 8.3, 1.4 Hz, 1H), 7.82 (dd, J = 8.7, 1.2 Hz, 1H), 7.75 (ddd, J = 8.6, 7.2, 1.5 Hz, 1H), 7.55 (dd, J = 15.4, 1.1 Hz, 1H), 7.29 (d, J= 8.1 Hz, 1H), 7.02 (d, J= 8.1 Hz, 1H), 4.60 (s, 2H), 4.43 (t, J =7.2 Hz, 2H), 3.69 (s, 2H), 2.98-2.89 (m, 2H), 2.65-2.53 (m, 2H), 2.49-2.35 (m, 1H), 2.09 (td, J= 11.4, 2.5 Hz, 2H), 2.05-1.95 (m, 1H), 1.79 (d, J= 11.8 Hz, 2H), 1.32-1.23 (m, J= 11.5 Hz, 2H); LC- MS (Method D basic) 476.5 [M+H]⁺; RT 5.79 min

Example 19 - 5-{2-[4-({2H,3H-[1,4]dioxinor2,3-c]pyridin-7-ylmethyl}amino)piperidin-1- yl]ethyl}-4H.5lH-[.2.3.4]tetrazolo[1.5-a]quinoxalin-4-oneS

Following steps (e) to (g) of Example 7, but using 4H,5H-[1,2,3,4]tetrazolo[1,5-a]quinoxalin- 4-one (prepared as described in Organic Chemistry: An Indian Journal, 2009, 5, 348-356) in step (e) and using 2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde in step (g) 5-{2-[4- ({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmeth^

[1 ,2,3,4]tetrazolo[1 ,5-a]quinoxalin-4-one S was synthesised as an off white solid.

1 H NMR (Method A) (DMSO-d₆): δ ppm 8.38 (dd, J = 8.1 , 1.4 Hz, 1 H), 8.01 (s, 1 H), 7.82 (dd, J = 8.6, 1.3 Hz, 1 H), 7.75 (ddd, J = 8.6, 7.3, 1.5 Hz, 1 H), 7.55 (ddd, J = 8.2, 7.2, 1.1 Hz, 1 H), 6.94 (s, 1 H), 4.43 (t, J = 7.2 Hz, 2H), 4.37-4.31 (m, 2H), 4.31-4.24 (m, 2H), 3.70 (s, 2H), 2.93 (d, J = 10.9 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.09 (td, J = 11.3, 2.4 Hz, 2H), 1.84- 1.76 (m, 2H), 1.43-1.06 (m, 3H); LC-MS (Method D basic) 463.5 [M+H]⁺; RT 5.73 min.

Example 20 - 6-(2-{4-[({3-oxo-2H,3H,4H-pyridor3,2-b][1,4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-5H,6H-[1.2,4]triazolori .5-c]quinazolin-5-one T

(a) 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5-one

A mixture of ethyl N-(2-cyanophenyl)carbamate (3.75 g, 19.7 mmol) and formic hydrazide (1.18g, 19.7 mmol) in NMP (7 ml_) was heated at 160°C for 3 h. The reaction mixture was allowed to cool to room temperature and H₂O (50 ml_) added followed by pouring the mixture on to ice. The resulting precipitate was collected and washed with Et₂O to afford 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5-one (2.08 g), which was used without further purification.

1 H NMR (Method A) (DMSO-d₆): δ ppm 12.37 (s, 1 H), 8.57 (s, 1 H), 8.22 (dd, J = 7.8, 1.5 Hz, 1 H), 7.76 (ddd, J = 8.6, 7.4, 1.6 Hz, 1 H), 7.56-7.41 (m, 2H); LC-MS (Method C basic) 187.4 [M+H]+; RT 1.07 min

(b) 6-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5-one T

Following steps (e) to (g) of [Example 7, but using 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5- one (prepared as described in Example 20 step (a)) in step (e)_6-(2-{4-[({3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)-5H,6H-[1 ,2,4]triazolo[1 ,5- c]quinazolin-5-one_T was synthesised as an off white solid.

1 H NMR (Method A) (DMSO-d₆): δ ppm 11.14 (s, 1 H), 8.53 (s, 1 H), 8.27 (dd, J = 7.9, 1.6 Hz, 1 H), 7.81 (ddd, J = 8.7, 7.1 , 1.7 Hz, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 4.60 (s, 2H), 4.42 (t, J = 7.0 Hz, 2H), 3.71 (s, 2H), 2.92 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 2.07 (t, J = 11.1 Hz, 2H), 1.79 (d, J = 12.1 Hz, 2H), 1.25 (m, 2H); LC-MS (Method C basic) 475.5 [M+H]+; RT 1.83 mm

Example 21 - 6-{2-r4-({2H,3H-[1.4]dioxinor2,3-c]pyridin-7-ylmethyl}amino)piperidin-1- vl]ethyl}-5H,6H-[1,2,4]triazolo[1,5-c]quinoxalin-5-one U

Following steps (e) to (g) of Example 7, but using 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5- one (prepared as described in Example 20 step (a)) in step (e) and using 2H,3H- [1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde in step (g) 6-{2-[4-({2H,3H-[1 ,4]dioxino[2,3- c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-5H,6H-[1 ,2,4]triazolo[1 ,5-c]quino^ U was synthesised as a white solid

1 H NMR (Method A) (DMSO-d₆): δ ppm 8.57 (s, 1 H), 8.27 (dd, J = 7.9, 1.7 Hz, 1 H), 7.99 (s, 1 H), 7.81 (ddd, J = 8.8, 7.1 , 1.7 Hz, 1 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 1 H), 6.92 (s, 1 H), 4.42 (t, J = 6.9 Hz, 2H), 4.29 (ddd, J = 24.6, 5.8, 3.0 Hz, 4H), 3.67 (s, 2H), 2.90 (d, J = 1 1.1 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.38 (m, 1 H), 2.11-2.00 (m, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.25 (t, J = 11.0 Hz, 2H); LC-MS (Method C basic) 475.5 [M+H]+; RT 1.85 mm.

Example 22 - 8-(2-{4-r({3-oxo-2H.3H.4H-pyridor3.2-b][1,4]oxazin-6- yl}methyl)amino]piperidin-1-yl}ethyl)-3,5,6,8,10-pentaazatricvclor7.4.0.0 ^2,6]trideca- 1 (9),2,4,10.12-pentaen-7-one V

(a) 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5-one

Following Example 20 but using N-(3-cyanopyridin-2-yl)carbamate in step (a) 3,5,6,8, 10- pentaazatricyclo[7.4.0.0 ²'⁶]trideca-1 (9),2,4, 10.12-pentaen-7-one was synthesised as an orange solid.

LC-MS (Method C, acidic) 188.4 [M+H]⁺; RT 1.12 min

(b) 8-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-3,5,6,8, 10-pentaazatricyclo[7.4.0.0 ²'⁶]trideca-1 (9), 2, 4, 10.12-pentaen-7-one V

Following steps (e) to (g) of Example 7, but using 3,5,6,8, 10-pentaazatricyclo[7.4.0.0 2,6]trideca-1 (9),2,4, 10.12-pentaen-7-one (prepared as described in Example 22 step (a)) in step (e) 8-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1- yl}ethyl)-3,5,6,8, 10-pentaazatricyclo[7.4.0.0 ^{2 (5}]trideca-1 (9),2,4, 10.12-pentaen-7-one V was synthesised as a colourless solid.

¹ H NMR (Method A) (CDCI₃): δ ppm 8.73 (dd, J = 4.8, 1.9 Hz, 1 H), 8.64 (dd, J = 7.8, 1.8 Hz, 1 H), 8.34 (s, 1 H), 7.39 (dd, J = 7.8, 4.7 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 4.76 (t, J = 6.7 Hz, 2H), 4.61 (s, 2H), 3.80 (s, 2H), 3.07 (dd, J = 10.0, 5.4 Hz, 2H), 2.81 (t, J = 6.7 Hz, 2H), 2.54 (tt, J = 10.5, 4.0 Hz, 1 H), 2.15 (td, J = 1 1.5, 2.5 Hz, 3H), 1.87 (d, J = 12.5 Hz, 2H), 1.47-1.31 (m, 2H), 1.25 (d, J = 2.9 Hz, 1 H); LC-MS (method C basic) 476.5 [M+H]⁺; RT 1.74 min

Example 23 - 5-{2-hvdroxy-2-rtrans-4-r({3-oxo-2H.3H.4H-pyridor3.2-b][1.4]oxazin-6- yl}methyl)amino]cvclohexynethyl}-7-methoxy-4H,5H-[1,3]oxazolor4,5-c]quinolin-4-one

W

(a) trans 4-ethenylcyclohexan-1 -amine

A solution of tert-butyl N-(trans-4-ethenylcyclohexyl)carbamate (2.87 g, 12.7 mmol) in DCM at room temperature was treated with 4 M HCI in dioxane (20 ml_). After stirring for 90 min excess volatiles were removed and the resulting residue azeotroped with Et₂O to give trans 4-ethenylcyclohexan-1 -amine (2.13 g) as a white solid, isolated as its hydrochloride salt.

1 H NMR (Method A) (DMSO-d₆): δ ppm 7.95 (s, 2H), 5.67 (ddd, J = 17.1 , 10.4, 6.4 Hz, 1 H), 5.07-4.65 (m, 2H), 2.83 (tt, J = 1 1.8, 3.9 Hz, 1 H), 1.99-1.75 (m, 3H), 1.75-1.58 (m, 2H), 1.27 (qd, J = 12.6, 3.5 Hz, 2H), 1.18-0.91 (m, 2H)

(b) benzyl N-(trans-4-ethenylcyclohexyl)carbamate

To a suspension of the hydrochloride salt of trans 4-ethenylcyclohexan-1 -amine (190 mg, 1.18 mmol) and Et₃N (0.57 ml_, 4.11 mmol) in DCM (5 ml_) was added benzyl chloroformate (0.4 ml_, 2.8 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. DCM was added and the organics washed with aq. 2 M HCI, followed by saturated aq. NaHCO₃ and brine. The DCM phase was dried through a phase separator cartridge and concentrated in vacuo. The crude was purified by flash chromatography eluting with petroleum ether (40/60) to 30% EtOAc in petroleum ether (40/60) to give benzyl N-(trans-4- ethenylcyclohexyl)carbamate (60 mg, 19% yield) as a white greasy solid.

1 H NMR (Method A) (CDCI₃): δ ppm 7.36 (d, J = 4.4 Hz, 4H), 7.33-7.28 (m, 1 H), 5.75 (ddd, J = 17.1 , 10.5, 6.5 Hz, 1 H), 5.09 (s, 2H), 5.00-4.87 (m, 2H), 4.56 (s, 1 H), 3.45 (s, 1 H), 2.05 (d, J = 11.3 Hz, 2H), 1.96-1.83 (m, 1 H), 1.79 (d, J = 12.7 Hz, 2H), 1.29-1.09 (m, 4H)

(c) benzyl N-(trans-4-(oxiran-2-yl)cyclohexyl)carbamate

To a solution of benzyl N-(trans-4-ethenylcyclohexyl)carbamate (599 mg, 2.31 mmol) in DCM (30 ml_) at 0°C was added mCPBA (1.06 g, 4.62 mmol). After stirring for 20 min the reaction mixture was allowed to warm to room temperature and stirred for a further 2 h. A further portion of mCPBA (1.80 g, 10.4 mmol) was added and stirring continued for a further 1.5 h. The reaction mixture was diluted with DCM (300 ml_) and treated with aq. sodium thiosulphate (10% V/V, 50 ml_). After stirring for 10 min the layers were separated and the aq. layer further extracted with DCM (2 x 200 ml_). The combined organics were washed with saturated aq. Na₂C0₃ (2 x 200 ml_), brine (300 ml_), dried over MgSO₄ and concentrated in vacuo to give benzyl N-(trans-4-(oxiran-2-yl)cyclohexyl)carbamate (615 mg, 97% yield) as a white solid.

1 H NMR (Method A) (CDCI₃): δ ppm 7.35 (d, J = 4.1 Hz, 4H), 7.31 (m, 1 H), 5.09 (s, 2H), 4.56 (s, 1 H), 3.46 (s, 1 H), 2.71 (dq, J = 6.8, 4.0 Hz, 2H), 2.51 (dd, J = 4.7, 2.9 Hz, 1 H), 2.12- 2.02 (m, 2H), 1.96 (dt, J = 12.9, 3.1 Hz, 1 H), 1.75 (dq, J = 12.3, 3.1 Hz, 1 H), 1.32-1.04 (m, 5H)

(d) benzyl N-[trans-4-(1-hydroxy-2-{7-methoxy-4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5- yl}ethyl)cyclohexyl]carbamate

To a suspension of 7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one (240 mg, 1.1 1 mmol) (prepared following the procedure of [Example 1 step (a) but using 7-methoxy-2,4- dihydro-1 H-3, 1-benzoxazine-2,4-dione) and benzyl N-(trans-4-(oxiran-2- yl)cyclohexyl)carbamate (900 mg, 3.27 mmol) in DMF (25 ml_) was added Cs₂CO₃ (720 mg, 1.33 mmol). The resulting reaction mixture was heated at 100°C for 6 h and allowed to cool to room temperature. The reaction mixture was treated with H₂O (50 ml_) and extracted with EtOAc (3 x 25 ml_). The combined organics were washed with H₂O (2 x 50 ml_), brine (50 ml_), dried over MgSO₄ and concentrated in vacuo. The crude was purified by flash chromatography eluting with 0-100% EtOAc in petroleum ether (40/60) to give benzyl N- [trans-4-(1-hydroxy-2-{7-methoxy-4-oxo-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-5- yl}ethyl)cyclohexyl]carbamate (68 mg, 1 1 %) as a white solid.

1 H NMR (Method A) (CDCI₃): δ ppm 8.05 (s, 1 H), 7.92 (d, J = 8.6 Hz, 1 H), 7.40-7.29 (m, 5H), 7.02-6.93 (m, 2H), 5.10 (s, 2H), 4.75 (dd, J = 14.9, 9.9 Hz, 1 H), 4.61 (s, 1 H), 4.25 (d, J = 14.9 Hz, 1 H), 3.93 (s, 3H), 3.88 (m, 1 H), 3.52 (m, 1 H), 3.02-2.93 (m, 1 H), 2.14 (t, J = 14.9 Hz, 3H), 1.97 (s, 1 H), 1.62 (m, 2H),1.43 (s, 2H), 1.30-1.17 (m, 1 H); LC-MS (method B acidic) 476.5 [M+H]+; RT 1.74 min 5-{2-hydroxy-2-[trans-4-aminocyclohexyl]ethyl}-7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-

A solution of benzyl N-[trans-4-(1-hydroxy-2-{7-methoxy-4-oxo-4H,5H-[1 ,3]oxazolo[4,5- c]quinolin-5-yl}ethyl)cyclohexyl]carbamate (68 mg, 0.14 mmol) in MeOH (10 ml_) was hydrogenated under H₂ (1 atm) over Pd/C (82 mg). After stirring at room temperature for 4 h the reaction mixture was filtered through celite, which was washed with MeOH and DCM. The combined filtrates were concentrated in vacuo to give 5-{2-hydroxy-2-[trans-4- aminocyclohexyl]ethyl}-7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one (37 mg, 75% yield) as a light brown solid, which was used without further purification.

LC-MS (method B acidic) 358.44 [M+H]+; RT 1.27 min

(f) 5-{2-hydroxy-2-[trans-4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}methyl)amino]cyclohexyl]ethyl}-7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one W

A solution of 5-{2-hydroxy-2-[trans-4-aminocyclohexyl]ethyl}-7-methoxy-4H,5H- [1 ,3]oxazolo[4,5-c]quinolin-4-one (50 mg, 0.12 mmol) and 3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazine-6-carbaldehyde (23.3 mg, 0.13 mmol) in a mixture of MeOH (1 ml_) and DMF (1 ml_) was stirred over 3A molecular sieves at room temperature for 30 min. Sodium triacetoxyborohydride (62 mg, 0.29 mmol) was added and the reaction mixture stirred for 17 h. The MeOH was removed in vacuo and the reaction mixture treated with a further quantity of sodium triacetoxyborohydride (25 mg, 0.12 mmol). After stirring for a further 90 min an aq. solution of NH₄OH (3 drops) was added. The reaction mixture was filtered and the filtrate loaded onto a Redisep C18 silica cartridge and eluted with 5% to 95% ACN in H₂O/0.1 % NH₃ to give 5-{2-hydroxy-2-[trans-4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}methyl)amino]cyclohexyl]ethyl}-7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one W (2 mg, 3% yield) as an off white solid.

1 H NMR (Method A) (DMSO-d₆): δ 11.04 (s, 1 H), 8.72 (s, 1 H), 7.91 (d, J = 8.7 Hz, 1 H), 7.35-7.19 (m, 2H), 7.09-6.99 (m, 2H), 4.67 (d, J = 5.7 Hz, 1 H), 4.61 (s, 2H), 4.46 (d, J = 14.4 Hz, 1 H), 4.25 (m, 1 H), 3.91 (s, 3H), 3.71 (s, 2H), 3.70 (m, 1 H), 2.34 (m, 1 H), 1.97 (m, 4H), 1.73 (d, J = 12.6 Hz, 1 H), 1.42 (m, 1 H), 1.22 (m, 2H), 1.04 (m, 2H); LC-MS (Method D basic) 520.5 [M+H]+; RT 5.65 min

Example 24 - 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 0.25-128 μg/mL and a maximum final concentration of 1 % DMSO. The bacterial strains tested include the Gram-positive strains Staphylococcus aureus ATCC 29213, Staphylococcus aureus NRS1 , Staphylococcus aureus NRS74, Staphylococcus aureus NRS482, Staphylococcus epidermidis ATCC 12228, Staphylococcus epidermidis NRS101 , Streptococcus pneumoniae ATCC 49619, Streptococcus uberis DSM 20569, Enterococcus faecalis ATCC 29212, Enterococcus faecium ATCC 19434, the fluoroquinolone-resistant Enterococcus faecium ATCC 700221 and the Gram negative strains Acinetobacter baumannii NCTC 13420, Acinetobacter baumannii ATCC 19606, Enterobacter cloacae NCTC 13406, Escherichia coli ATCC 25922, E. coli ATCC BAA-2452, E. coli NCTC 13476, E. coli MG1655 and the gyrase A mutants E. coli MG1655 S83L and E. coli MG1655 D87G derived from the isogenic parent strain E. coli MG1655, four fluoroquinolone-resistant E. coli clinical isolates: CH440, CH460, CH418, CH448, Haemophilus influenzae ATCC 49247, Klebsiella pneumoniae ATCC 700603, Klebsiella pneumoniae NCTC 13443, Mycobacterium smegmatis ATCC 19420, Neisseria gonorrhoeae ATCC 49226, Neisseria meningitidis ATCC 13090, Pseudomonas aeruginosa ATCC 27853, Serratia marcescens ATCC 13880, Stenotrophomonas maltophilia ATCC 13637. Additionally, two fluoroquinolone-resistant mutant strains of each S. aureus ATCC 29213 and E. coli ATCC 25922 were generated in- house using a serial passage method with ciprofloxacin at sub-inhibitory concentrations. These strains are referred to as S. aureus SACPX1-SP25 and SACPX1-SP28 and E. coli ECCPX1-SP22 and ECCPX1-SP25.

Strains are grown in cation-adjusted Muller-Hinton broth (supplemented with 2% w/v NaCI in the case of methicillin-resistant S. aureus strains) or on Muller-Hinton agar at 37°C in an ambient atmosphere. 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 and is reported in Tables 1-3.

The antimicrobial susceptibility profile of Clostridium difficile was determined by estimating MIC using the agar dilution method according to the guidelines of the CLSI criteria for anaerobes (Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Eighth Edition. CLSI document M11-A8, 2012). Stock solutions of vancomycin and ciprofloxacin were made in water at 5120 μg/mL. Stock solutions of compounds were made in DMSO at 12800 μg/mL. Compounds were diluted to 100 fold the test range concentrations in DMSO and 400 μΙ of the 100X solutions were added to 39.6 mL of Brucella blood agar supplemented with haemin and vitamin K1. Isolates were sub-cultured twice on Brucella blood agar plates at 35°C for 48 h in an anaerobic cabinet. Colonies were resuspended in Brucella broth to a turbidity of 0.5 Mc Fariand and 100 of the suspension was transferred to a 96-well plate. The antibacterial agent containing plates were inoculated with 1 μί of bacterial suspension using a Masturi® Dot inoculator. Plates were incubated at 35°C for 48 h in anaerobic conditions and MIC were read visually following CLSI guidelines. The MIC was defined as the lowest concentration of antimicrobial agent that inhibited visible growth.

The antimicrobial activity of compounds against M. tuberculosis H37Rv grown under aerobic conditions was assessed by measuring bacterial growth after 5 days in the presence of test compounds. Compounds were prepared as 20-point two-fold serial dilutions in DMSO and diluted into 7H9-Tw-OADC medium in 96-well plates with a final DMSO concentration of 2%. The highest concentration of compound was 200 μΜ where compounds were soluble in DMSO at 10 mM. Microbial growth was measured by OD590 and fluorescence (Ex 560/Em 590) using a BioTek™ Synergy 4 plate reader. To determine the MIC, the dose response curve was plotted as % growth and fitted to the Gompertz model using GraphPad Prism 5. The MIC was defined as the minimum concentration at which growth was completely inhibited and was calculated from the inflection point of the fitted curve to the lower asymptote (zero growth).

The strains tested include M. tuberculosis H37Rv, two isoniazid resistant strains, INH-R1 (derived from M. tuberculosis H37Rv KatG mutant, Y155 truncation) and INH-R2 (strain ATCC 35822), two rifampicin resistant strains, RIF-R1 (derived from H37Rv, RpoB S522L mutant) and RIF-R2 (strain ATCC 35828) and a fluoroquinolone resistant strain, FQ-R1 derived from H37Rv (GyrB D94N mutant).

Antimicrobial activity under low oxygen conditions

The antimicrobial activity of compounds against M. tuberculosis H37Rv grown under hypoxic conditions was assessed using the low oxygen recovery assay (LORA). Bacteria were first adapted to low oxygen conditions and then exposed to compounds under hypoxia. The method used was as described above for aerobic conditions with the following modifications: M. tuberculosis constitutively expressing the luxABCDE operon was inoculated into DTA medium in gas-impermeable glass tubes and incubated for 18 days to generate hypoxic conditions (Wayne model of hypoxia). At this point, bacteria are in a non-replicating state (NRP stage 2) induced by oxygen depletion. Oxygen-deprived bacteria were inoculated into compound assay plates and incubated under anaerobic conditions for 10 days followed by incubation under aerobic conditions (outgrowth) for 28h. Growth was measured by luminescence. Oxygen-deprived bacteria were also inoculated into compound assay plates and incubated under aerobic conditions for 5 days.

Intracellular activity assay

The activity of compounds against intracellular bacteria was determined by measuring viability in infected THP-1 cells (macrophage-like cells) after 3 days in the presence of test compounds. Compounds were prepared as 10-point three-fold serial dilutions in DMSO. The highest concentration of compound tested was 50 μΜ where compounds were soluble in DMSO at 10 mM. THP-1 cells were cultured in complete RPMI medium and differentiated into macrophage-like cells using 80 nM PMA overnight at 37°C, 5% C02. THP-1 cells were infected with a luminescent strain of H37Rv (which constitutively expresses luxABCDE) at a multiplicity of infection of 1 and incubated overnight at 37°C, 5% C02. Infected cells were recovered using Accutase/EDTA solution, washed twice with PBS to remove extracellular bacteria and seeded into assay pates. Compound dilutions were added to a final DMSO concentration of 0.5%. Assay plates were incubated for 72 h at 37°C, 5% C02. Relative luminescent units (RLU) were measured using a Biotek Synergy 2 plate reader. The dose response curve was fitted using the Levenberg-Marquardt algorithm. The IC50 was defined as the compound concentrations that produced 50% inhibition of microbial growth.

Antimicrobial activity against other mycobacteria

The activity of compounds against Mycobacterium abscessus subsp. bollettii 103 and Mycobacterium avium subsp. avium 2285 was assessed under aerobic conditions by determining the MIC as described previously and with the following modifications:

M. abscessus plates were inoculated and incubated for 3 days at 37°C; growth was measured by OD590. The dose response curve was plotted as % growth and fitted to the Gompertz model and the MIC was defined as the minimum concentration at which growth was completely inhibited and was calculated from the inflection point of the fitted curve to the lower asymptote (zero growth).

M. avium plates were inoculated and incubated for 5 days at 37°C and Alamar blue was added to each well (10 μΙ_ of Alamar blue to 100 μΙ_ culture) and incubated for a further 24 h at 37°C. Plates were visually inspected and the colour recorded for each well. MIC was defined as the lowest concentration at which no metabolic activity was seen (blue well).

The results are shown in Table 6.

In Tables 1 , 2 and 3 an MIC (in μς/Γηί.) of less or equal to 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.

All compounds tested show activity against both Gram-negative and Gram-positive bacteria. Compounds E, F, G and J in particular, exhibited excellent activity against both Gram- negative and Gram-positive bacteria. Compounds A, C, E, F, G and J exhibited excellent activity against all strains of S. aureus tested, including those which are resistant to fluoroquinolone antibiotics and other antibiotics. Compound B also showed significant activity against all strains tested. Compounds E, F, G, J, L, M, N and O exhibited excellent activity against all strains of E. coli tested, including fluoroquinolone-resistant strains. Compounds E, F, G, J, L, M and N also showed significant activity against clinical isolates.

Table 3 - Potency of reference compounds and test compound A against methicillin- resistant Staphylococcus epidermidis strain

MRSE = methicillin-resistant S. epidermidis

Compound A shows good activity against MRSE. Notably, the compound's activity against MRSE is broadly the same as its activity against wild-type S. epidermidis.

Table 4 - Fold increase in MIC against fluoroquinolone-resistant single point mutant Escherichia coli strains (MG1655 S83L and MG1655 D87G) compared to the isogenic parent strain E. coli MG1655.

CIP = ciprofloxacin; LEV = levofloxacin

¹ : S83L mutation on DNA gyrase subunit GyrA

²: D87G mutation on DNA gyrase subunit GyrA

Compounds A-0 showed no significant loss of activity against the E. coli MG1655 mutant strains.

Table 5 - Fold increase in MIC against fluoroquinolone-resistant multiple points mutant Escherichia coli strains (ECCPX1 -SP22 and ECCPX1 -SP25) compared to the isogenic parent strain E. coli ATCC 25922.

CIP = ciprofloxacin; LEV = levofloxacin

¹ : double mutation on DNA gyrase subunit GyrA: S83L and D87G

²: triple mutation on DNA gyrase subunit GyrA: S83L and D87G, and on DNA topoisomerase IV subunit ParC: E84K

Thus, compounds B, C, D, E, F, J, and O showed an eight-fold increase in MIC against both FQR mutant strains compared to the wild-type parent strain E. coli ATCC 25922 and were less susceptible to the gyrase S83L and D87G mutations than the fluoroquinolone antibiotics. Compound N showed a four-fold increase in MIC against both FQR mutant strains compared to the wild-type parent strain E. coli ATCC 25922 and was less susceptible to the gyrase S83L and D87G mutations than the fluoroquinolone antibiotics and the other compounds tested.

Table 6 - MIC against mycobacterial strains. CIP: ciprofloxacin, NOV: Novobiocin, RIF: rifampicin, MXF: moxifloxacin.

In Table 6 a MIC (in μg/mL) of less than or equal to 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.

Compound F showed excellent activity against M. smegmatis ATCC 19420 and against the virulent strain M. tuberculosis H37Rv in aerobic conditions. Compound F also showed excellent activity against intracellular bacteria and retained good activity against M. tuberculosis strains resistant isoniazid (INH-R), rifampicin (RIF-R) and fluoroquinolone (FQ- R). Compound F also showed good activity against non-tuberculosis strains such as M. avium and M. abscessus.

Table 7 - MIC against Clostridium difficile strains. CIP: ciprofloxacin, VAN: vancom cin

In Table 7 a MIC (in μg/mL) of less than or equal to 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.

Compound N showed excellent activity against all C. difficile strains tested, including ciprofloxacin-resistant strains.

Example 25 - Human cell viability assay

Compounds are assessed for potential non-specific cytotoxic effects against a human hepatic cell line (HepG2 ATCC HB-8065). HepG2 cells are seeded at 20,000 cells/well in 96-well microtitre plates in minimal essential medium (MEM) supplemented with a final concentration of 10% FBS and 1 mM sodium pyruvate. After 24 h compound dilutions are prepared in Dulbecco's minimum essential media (DM EM) supplemented with final concentrations of 0.001 % FBS, 0.3% bovine albumin and 0.02% HEPES and added to cells. Compounds are tested in two-fold serial dilutions over a final concentration range of 1-128 μg/mL in a final DMSO concentration of 1 % vol/vol. Chlorpromazine is used as a positive control. Cells are incubated with compound at 37°C and 5% CO₂ for a further 24 h, after which time the CellTiter-Glo reagent (Promega) is added. Luminescence is measured on a BMG Omega plate reader. Data are analysed using GraphPad Prism software to determine the concentration of compound that inhibits cell viability by fifty percent (IC50). The results are provided in Table 8.

In Table 8, an IC50 (in μg/mL) of less than 1 is assigned the letter D; an IC50 of from 1 to 10 is assigned the letter C; an IC50 of from 10 to 100 is assigned the letter B; and an IC50 of over 100 is assigned the letter A. Table 8 - ICso values against HepG2 cell line

Thus, the tested compounds show low toxicities against human hepatic cell lines. In particular, compound A showed no detectable toxicity against human hepatic cell lines. Compound A therefore shows an excellent therapeutic benefit relative to its hepatic toxicity as expressed by the ratio of hepatic toxicity. In particular, compounds A, C, D, F, O, R, S, T and U showed no detectable toxicity against the tested human hepatic cell lines. These compounds therefore show an excellent therapeutic benefit relative to their hepatic toxicities. Compounds E, G, H, I, J and N also demonstrate an acceptable level of hepatic toxicity relative to therapeutic activity. This indicates that these compounds have the potential to have an excellent therapeutic benefit relative to their hepatic toxicity.

Claims

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

wherein R¹ is selected from R² or R³

R² represents the group:

Y¹ and Y² are each independently selected from C and N; Z¹, Z² and Z³ are each independently selected from O, S, S(O), NR⁵, CR⁴ and C=W; wherein W is selected from O, S or NR⁶; wherein when 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 when 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; and with the further provisos that at least one of Z¹ , Z², Z³, Y¹ and Y² is O, S, N or NR⁵ and that no more than one of Z¹ , Z² and Z³ is C=W;

=A is independently selected from: =0, =S, =NR⁶ and =NOR⁶;

L¹ is a linker group having the form -(CR⁹R⁹)_гU¹-U²-(CR⁹R⁹)s-U³-(CR⁹R¹⁰)_r; wherein U¹ , U² and U³ are each independently selected from: a bond, CO, O, S and NR¹¹ ; wherein r, s, and t are each independently an integer selected from 0, 1 , 2 and 3 and wherein definitions of r, s, t, U¹ , U² and U³ are chosen such that the total length of the linker group is 1 , 2, 3 or 4 atoms;

L² is 4-, 5-, 6- or 7-membered cycloalkyl ring or a 4-, 5-, 6- or 7- membered heterocycloalkyl ring; L³ is absent or is -N(R⁸)L⁴-;

R⁴ is independently at each occurrence selected from: H, halo, nitro, cyano, NR⁶R¹¹ , NR⁶S(O)₂R⁶, NR⁶CONR⁶R⁶, NR⁶C(O)R⁶, NR⁶CO₂R⁶, OR⁶; O-aryl, SR⁶, SOR⁶, SO3R⁶, SO2R⁶, SO₂NR⁶R⁶ CO₂R⁶, C(O)R⁶, CONR⁶R⁶, aryl, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl;

R⁶ is independently at each occurrence selected from: H, C₁-C₄-alkyl, and C₁-C₄-haloalkyl; R⁷ is a monocyclic aromatic or heteroaromatic ring or R⁷ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic; R⁸ is independently selected from: H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, S(O)2-C₁-C₄-alkyl and C(O)-C₁-C₄-alkyl; or L² and R⁸ together with the nitrogen to which they are attached together form a saturated 5-, 6- or 7- membered monocyclic heterocycloalkyl ring or a saturated 7-, 8- or 9- membered bicyclic heterocycloalkyl ring system;

R⁹ is independently at each occurrence selected from: H, Me, and CF3 ;

R¹⁰ is independently at each occurrence selected from: R⁹, OR⁶, CO₂R⁶ and NR⁶R¹¹ ;

wherein each of the aforementioned alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, carbocyclic, heterocycloalkyl, aryl (e.g. phenyl) and heteroaryl groups and aromatic and heteroaromatic rings is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: =0, =S, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aC(O)R^a, NR^aCONR^aR^a, NR^aCO₂R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, CR^aR^aNR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl; wherein R^a is independently at each occurrence selected from H, C₁-C₄ alkyl and C₁-C₄-haloalkyl.

2. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III):

wherein X⁴ is N or CR⁴.

3. A compound of claim 1 or claim 2, wherein both Y¹ and Y² are C, a single one of Z¹ , Z² and Z³ is N and that N must form part of a C=N endocyclic double bond; a single one of Z¹ , Z² and Z³ is CR⁴ and the remaining Z¹ , Z² or Z³ is selected from O and S.

4. A compound of claim 1 , wherein the compound of formula (I) has a structure selected from any one or more of formulae (VIII) and (IX) to (XXXXXVII):

wherein R⁵ is independently selected from: H, C₁-C₄-alkyl, and C₁-C₄-haloalkyl.

5. A compound of any one of claims 1 to 4, wherein X¹ , X² and X⁴ are each CH.

6. A compound of any one of claims 1 to 4, wherein X¹ is N and wherein X² and X⁴ are each CH.

7. A compound of any one of claims 1 to 6, wherein X³ is CR^4a, wherein R^4a is selected from halo, CN, NR⁶R¹¹ , OR⁶, O-aryl, SR⁶.

8. A compound of any one of claims 1 to 7, wherein -L¹-L²- takes the form:

wherein R¹² is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aCONR^aR^a, NR^aC(O)R^a, NR^aCO₂R^a, OR^a; SR^a, S(O)R^a, S(O)₂OR^a, S(O)₂R^a, S(O)₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, and C₁-C₄- haloalkyl; or any two R¹² groups which are attached to the same carbon form a group selected from: =0, =S, =NR^a and =NOR^a; and n is an integer selected from 0, 1 , 2, 3 and 4.

A compound of any of claims 1 to 7, wherein -L¹-L²- takes the form:

A compound of any of claims 1 to 7, wherein -L¹-L²- takes the form:

wherein W¹ is N or CR¹³; R¹² is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aCONR^aR^a, NR^aC(O)R^a, NR^aCO₂R^a, OR^a; SR^a, S(O)R^a, S(O)₂OR^a, S(O)₂R^a, S(O)₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C4-alkynyl, and C₁-C₄-haloalkyl; or any two R¹² groups which are attached to the same carbon form a group selected from: =0, =S, =N R^a and =NOR^a; R¹³ is independently selected from H and R¹²; and n is an integer selected from 0, 1 , 2, 3 and 4.

11. A compound of any of claims 1 to 7, wherein -L¹-L²-N(R⁸)- takes the form:

12. A compound of any of claims 1 to 10, wherein L³ is -N(R⁸)L⁴-.

13. A compound of any one of claims 1 to 12, wherein L⁴ is -CR⁹R⁹-.

14. A compound of any of claims 1 to 10, wherein L³ is absent.

15. A compound of any one of claims 1 to 14, wherein R⁷ is a phenyl group which is unsubstituted or substituted with from 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aCONR^aR^a, NR^aCO₂R^a, NR^aC(O)R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄- haloalkyl, and CR^aR^aNR^aR^a.

16. A compound of any one of claims 1 to 14, wherein R⁷ takes the form: wherein V¹ , V² and V³ are each independently selected from: N and CR⁴; with the proviso that no more than two of V¹ , V² and V³ are N; and wherein the ring B is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyl or heterocycloalkyl ring.

17. A compound of any one of claims 1 to 14, wherein R⁷ may also take the form

wherein V⁶ is independently selected from N and CR⁴; V⁷ is independently selected from NR¹¹ , S and O; and R¹⁵ is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(O)₂R^a, NR^aC(O)R^a, NR^aCONR^aR^a, NR^aCO₂R^a, NR^aC(O)R^a, OR^a; SR^a, SOR^a, SO₃R^a, SO₂R^a, SO₂NR^aR^a, CO₂R^a C(O)R^a, CONR^aR^a, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, and CR^aR^aNR^aR^a. R¹⁵ may be independently at each occurrence selected from F, CN, OR^a, nitro, C₁-C₄-alkyl, C2- C4-alkenyl, C₂-C₄-alkynyl and C₁-C₄-haloalkyl.

18. A compound of claim 1 , wherein the compound is a compound selected from:

5- {2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-4H,5H

[1 ,3]oxazolo[4,5-c]quinolin-4-one A;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl)- 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one G; Example 8 - 5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}- 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one H;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}- 4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one M;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-7-m

4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one N;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl) 4H,5H-[1 ,2]oxazolo[3,4-c]1 ,5-naphthyridin-6-one O;

5-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-4H,6h- [1 ,2]oxazolo[3,4-c]1 ,5-naphthyridin-6-one P;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl) 4H,5H-[1 ,2,4]triazolo[4,3-a]quinoxalin-4-one Q;

5-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl) 4H,5H-[1 ,2,3,4]tetrazolo[1 ,5-a]quinoxalin-4-one R;

5- {2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-4H,5h- [1 ,2,3,4]tetrazolo[1 ,5-a]quinoxalin-4-one S;

6- (2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}methyl)amino]piperidin-1-yl}ethyl) 5H,6H-[1 ,2,4]triazolo[1 ,5-c]quinazolin-5-one T;

6-{2-[4-({2H,3H-[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)piperidin-1-yl]ethyl}-5H,6h- 8-(2-{4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin^

3,5,6,8, 10-pentaazatricyclo[7.4.0.0 ^{2 ,6}]trideca-1 (9),2,4, 10.12-pentaen-7-one V; and

5-{2-hydroxy-2-[trans-4-[({3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}methyl)amino]cyclohexyl]ethyl}-7-methoxy-4H,5H-[1 ,3]oxazolo[4,5-c]quinolin-4-one W; or a pharmaceutically acceptable salt or N-oxide thereof.

19. A compound of any one of claims 1 to 18, for medical use.

20. A compound of any one of claims 1 to 18, for veterinary use.

21. A compound of any one of claims 1 to 18, for use in treating a bacterial or mycobacterial infection.

22. A compound of any one of claims 1 to 18, for the use of claim 21 , wherein the infection is caused by a Gram-positive bacteria.

23. A compound of any one of claims 1 to 18, for the use of claim 21 , wherein the infection is caused by a Gram-negative bacteria.

24. A compound of any one of claims 1 to 18, for the use of any one of claims 21 to 22, wherein the infection which is caused by a bacterial strain which is resistant to at least one approved antibacterial drug.

25. A compound of any one of claims 1 to 18, for the use of claim 24, wherein the strain is resistant to at least one fluoroquinolone antibacterial drug.

26. A compound of any one of claims 1 to 18, for the use of any one of claims 21 to 25, wherein the infection which is caused by an anaerobic bacteria.

28. A compound of any one of claims 1 to 18, for the use of claim 21 , wherein the infection is caused by mycobacteria.

29. A compound of any one of claims 1 to 18, for the use of claim 28, wherein the infection which is caused by a mycobacterial strain which is resistant to at least one approved antimycobacterial drug.