WO2016024096A1 - Composés antibactériens - Google Patents

Composés antibactériens Download PDF

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Publication number
WO2016024096A1
WO2016024096A1 PCT/GB2015/052303 GB2015052303W WO2016024096A1 WO 2016024096 A1 WO2016024096 A1 WO 2016024096A1 GB 2015052303 W GB2015052303 W GB 2015052303W WO 2016024096 A1 WO2016024096 A1 WO 2016024096A1
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WIPO (PCT)
Prior art keywords
compound
ethyl
piperidin
amino
independently
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PCT/GB2015/052303
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English (en)
Inventor
Andrew Ratcliffe
Ian Cooper
Mark Pichowicz
Neil STOKES
Cedric Charrier
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Redx Pharma Plc
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Publication date
Priority claimed from GBGB1414205.3A external-priority patent/GB201414205D0/en
Priority claimed from GB201417941A external-priority patent/GB201417941D0/en
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2016024096A1 publication Critical patent/WO2016024096A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • 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.
  • antibiotic resistant Gram-negative strains such as either Escherichia coli NDM-1 (New Delhi metallo- ⁇ -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.
  • CNS central nervous system
  • 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.
  • STI human sexually-transmitted infection
  • 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.
  • 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.
  • TB Another disease in which the development of resistance and multidrug resistance is of particular concern is TB.
  • 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.
  • MDR-TB multidrug-resistant TB
  • 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).
  • XDR-TB extensively drug resistant
  • 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.
  • infections arising from XDR-TB had at that time been identified in 84 different countries.
  • 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.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 is selected from R 2 or R 3
  • R 2 represents the group:
  • X 1 and X 2 are each independently selected from: N and CR 4 ;
  • X 4 is selected from N, NR 2 , NR 3 , CR 2 and CR 4 ; wherein a single one of R 1 and X 4 comprises the group R 2 ; and wherein no more than two of X 1 , X 2 , X 3 and X 4 are N;
  • L 1 is a linker group having the form -(CR 9 R 9 ) r U 1 -U 2 -(CR 9 R 9 )s-U 3 -(CR 9 R 10 ) r ; wherein U 1 , U 2 and U 3 are each independently selected from: a bond, CO, O, S and NR 11 ; wherein r, s, and t are each independently an integer selected from 0, 1 , 2 and 3 and wherein definitions of r, s, t, U 1 , U 2 and U 3 are chosen such that the total length of the linker group is 1 , 2, 3 or 4 atoms;
  • L 2 is 4-, 5-, 6- or 7-membered cycloalkyl ring or a 4-, 5-, 6- or 7- membered heterocycloalkyl ring;
  • L 3 is absent or is -N(R 8 )L 4 -;
  • L 4 is independently selected from -CR 9 R 9 - and a 3-, 4- or 5-membered cycloalkyl ring or a 4- or 5-membered heterocycloalkyl ring;
  • R 3 and R 11 are each independently at each occurrence selected from: H, C 1 -C 4 -alkyl, C 1 -C 4 - haloalkyl, S(O)2-C 1 -C 4 -alkyl and C(O)-C 1 -C 4 -alkyl;
  • R 4 is independently at each occurrence selected from: H, halo, nitro, cyano, NR 6 R 11 , NR 6 S(O) 2 R 6 , NR 6 CONR 6 R 6 , NR 6 C(O)R 6 , NR 6 CO 2 R 6 , OR 6 ; O-aryl, SR 6 , SOR 6 , SO3R 6 , SO2R 6 , SO 2 NR 6 R 6 , CO 2 R 6 , C(O)R 6 , CONR 6 R 6 , aryl, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl;
  • R 5 is absent or is independently selected from: H, C 1 -C 4 -alkyl, and C 1 -C 4 -haloalkyl;
  • R 6 is independently at each occurrence selected from: H , C 1 -C 4 -alkyl, and C 1 -C 4 -haloalkyl;
  • R 7 is a monocyclic aromatic or heteroaromatic ring or R 7 is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic;
  • R 8 is independently selected from: H, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, S(O)2-C 1 -C 4 -alkyl and
  • R 9 is independently at each occurrence selected from: H, Me, and CF3;
  • R 10 is independently at each occurrence selected from: R 9 , OR 6 , CO 2 R 6 and NR 6 R 11 ; wherein each of the aforementioned alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, carbocyclic, heterocycloalkyl, aryl (e.g.
  • linker group L 1 is arranged such that L 2 is attached to the end of linker group L 1 which is defined as (CR 9 R 10 )t.
  • linker group L 1 which is defined as (CR 9 R 9 ) r is attached to the rest of the molecule at the point of contact of the group R 2 .
  • the compound of formula (I) is a compound of formula (II):
  • R 3 , R 7 , A, X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Y 1 , Y 2 , L 1 , L 2 and L 3 are as defined above for formula (I).
  • the compound of formula (I) is a compound of formula (III):
  • R 7 , A, X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Y 1 , Y 2 , L 1 , L 2 and L 3 are as defined above for formula (I) and wherein X 4 is N or CR 4 , R 4 being as defined above for formula (I).
  • the compound of formula (I) is a compound of formula (IV):
  • the compound of formula (I) is a compound of formula (V):
  • R 4 , R 7 , X 1 , X 2 , X 3 , L 1 , L 2 and L 3 are as defined above for formula (I) and wherein X 4 is N or CR 4 .
  • the compound of formula (I) is a compound of formula (VI):
  • R 4 , R 7 , L 1 , L 2 and L 3 are as defined above for formula (I).
  • the compound of formula (I) is a compound of formula
  • the compound of formula (I) is a compound of formula (VIII):
  • R 1 , R 4 , A, X 1 , X 2 , X 3 , and X 4 are as defined above for formula (I).
  • the compound of formula (I) has a structure according to any more of formulae (IX) to (XXXXVII):
  • R 1 , R 4 , R 5 , A, X 1 , X 2 , X 3 , X 4 and W are as defined above for formula (I) and wherein R 5 is independently selected from: H, C 1 -C 4 -alkyl, and C 1 -C 4 -haloalkyl.
  • the compound may thus be a compound of formula (XXIV).
  • the compound of formula (I) is a compound of formula (XXXXXVIII):
  • R 4 , R 7 , X 1 , X 2 , X 3 , L 1 , L 2 and L 3 are as defined above for formula (I) and wherein X 4 is N or CR 4 .
  • the compound of formula (I) is a compound of formula (XXXXXIX):
  • R 4a is selected from H, F, NR 6 R 11 , OR 6 , O-aryl and SR 6 ;
  • W 1 is N or CR 13 ;
  • R 12 is independently at each occurrence selected from: halo, nitro, cyano, NR a R a , NR a S(O)2R a , NR a CONR a R a , NR a C(O)R a , NR a CO 2 R a , OR a ;
  • SR a S(O)R a , S(O) 2 OR a , S(O) 2 R a , S(O) 2 NR a R a , CO 2 R a C(O)R a , CONR a R a , C 1 -C 4 -
  • the compound of formula (I) is selected from a compound of formula (XXXXX) and a compound of formula (XXXXXI):
  • X 4 is selected from N, NR 3 , CR 2 and CR 4 . It may be that X 4 is selected from N, NR 3 and CR 4
  • bond between X 3 and X 4 is a double bond;
  • X 1 , X 2 and X 3 are each independently selected from: N and CR 4 ; and X 4 is selected from N, CR 2 and CR 4 .
  • R 1 is R 3 and X 4 is CR 2 .
  • R 1 may be H or C 1 -C 4 -alkyl.
  • R 1 is R 2 and X 4 is selected from N or CR 4 .
  • X 1 , X 2 , X 3 and X 4 are N. It may be that a single one of X 1 , X 2 , X 3 and X 4 is N. It may be that X 1 is N .
  • X 1 , X 2 , X 3 and X 4 is CR 4a wherein R 4a is selected from H, CN, halo, NR 6 R 11 , OR 6 , O-aryl, SR 6 , e.g. selected from halo, CN, NR 6 R 11 , OR 6 ; O-aryl, SR 6 . It may be that R 4a is selected from H, CN, F and OR 6 . It may be that a single one of X 1 , X 2 , X 3 and X 4 is CR 4a . It may be that R 4a is OR 6 . 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.
  • X 1 , X 2 and X 4 are each CH.
  • X 3 is CR 4a , wherein R 4a is selected from H, halo, CN, NR 6 R 11 , OR 6 , O-aryl and SR 6 .
  • R 4a may be selected from: F, CN, NR 6 R 11 , OR 6 ; O-aryl and SR 6 .
  • R 4a may be selected from: NR 6 R 11 , OR 6 ; O-aryl and SR 6 . It may be that R 4a is selected from H, F, CN and OR 6 .
  • R 4a may be selected from F, CN and OR 6 , e.g. from F and OR 6 . It may be that R 4a is OR 6 .
  • R 4a is 0-C 1 -C 4 -alkyl, e.g. OMe. In other preferred embodiments, R 4a is halo, e.g. F. Alternatively, X 3 may be CH.
  • R 3 is selected from H and C 1 -C 4 -alkyl. Thus, R 3 may be selected from H and methyl.
  • U 1 is CO
  • U 2 is preferably independently selected from: a bond, O, S and NR 11 , e.g. U 2 is independently selected from NR 11 or O.
  • U 1 is preferably independently selected from: a bond, O, S and NR 11 , e.g. U 1 is independently selected from NR 11 or O.
  • U 1 and U 2 are CO and the other is O.
  • Such compounds 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.
  • L 1 is an alkylene chain of the form -(CR 9 R 9 ) r (CR 9 R 10 ) r .
  • L 2 is a heterocycloalkyl ring having a nitrogen atom in the ring, and where L 1 is attached to L 2 through that nitrogen atom, it is preferable that t is absent, e.g. it is preferable that L 1 is a linker group of the form -(CR 9 R 9 ) r U 1 -U 2 -(CR 9 R 9 ) s - wherein s is an integer selected from 1 , 2 and 3.
  • L 1 may be a linker group of the form -(CR 9 R 9 ) S -.
  • R 1 is R 2
  • r is preferably an integer selected from 1 , 2 or 3.
  • t is 1 and R 10 is OR 6 (e.g. OH). It may be that t is 2 and R 10 is at each occurrence OR 6 (e.g. OH). It may be that t is 1 and R 10 is NR 6 R 11 , (e.g. NH 2 ).
  • R 9 is at each occurrence H.
  • the total length of the -L 1 - linker group (i.e. the number of atoms in a continuous chain between L 2 and the point of contact of R 2 to the rest of the molecule) is 2 or 3 atoms, e.g. the total length of the linker group is 2 atoms.
  • L 1 examples include -CH 2 CH 2 -, -CH 2 CH 2 CH 2 , -CH 2 CH(NH 2 )-, -CH(OH)CH(OH)-, CH 2 CH(OH) and -CH(OH)CH 2 CH 2 -.
  • L 1 may also be -CO 2 CH 2 -.
  • L 2 may be a saturated 5-, 6- or 7- membered monocyclic cycloalkyl or heterocycloakyl ring.
  • L 2 is preferably a saturated 6-membered monocyclic cycloalkyl or heterocycloakyl ring.
  • the groups L 1 and N(R 7 )L 3 R 8 are preferably attached to L 2 para to each other, i.e. the 6- membered monocyclic cycloalkyl or heterocycloakyl ring is 1 , 4-substituted with respect to the groups L 1 and N(R 7 )L 3 R 8 .
  • L 2 may therefore be a cyclohexyl ring.
  • L 2 may also be a tetrahydropyran ring.
  • L 2 may also be a piperidine ring. Where L 2 is a piperidine ring, it may be linked to L 1 through the nitrogen in the piperidine ring. If this is not the case, the nitrogen in the piperidine ring will take the form NR 11 group. Thus, L 2 may take the form:
  • W 1 is N or CR 13 ;
  • W 1 is N. If this is the case it is preferable that L 1 is a linker group of the form - (CR 9 R 9 ) ⁇ U 1 -U 2 -(CR 9 R 9 )s- wherein s is an integer selected from 1 , 2 and 3.
  • W 1 is CR 13 .
  • R 13 is H.
  • L 2 groups include:
  • L 2 is a saturated 7-, 8- or 9- membered bicyclic cycloalkyl or heterocyclic ring.
  • L 2 and R 8 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, L 1 is preferably attached to the piperidine ring at the 4-position relative to the piperidine nitrogen.
  • the group -L 2 NR 8 - may take the form:
  • L 3 may be absent.
  • R 2 may be
  • L 3 may be -N(R 8 )L 4 -.
  • R 2 may be
  • L 4 is preferably -CR 9 R 9 - and most preferably is -CH 2 -.
  • L 4 may be a 3-, 4- or 5- membered cycloalkyl ring, e.g. a 4-membered cycloalkyl ring.
  • Y 1 and Y 2 are both C.
  • Y 1 and Y 2 are not both N.
  • Z 1 and Z 3 may each be independently selected from O, S, S(O), NR 5 and CR 4 ;
  • 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.
  • Z 1 , Z 2 and Z 3 are each independently selected from O, S, NR 5 and CR 4 .
  • Y 1 and Y 2 are each independently selected from C and N;
  • Z 1 , Z 2 and Z 3 are each independently selected from O, S, NR 5 and CR 4 ; with the proviso that the ring formed by Z 1 , Z 2 , Z 3 , Y 1 and Y 2 contains two endocyclic double bonds; and with the further proviso that at least one of Z 1 , Z 2 , Z 3 , Y 1 and Y 2 is O, S, N or NR 5 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, triazole, tetrazole, pyrazole or pyrrole ring. It may be that one of Y 1 and Y 2 is N and the other is C. Thus, it may be that Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, triazole, tetrazole, pyrazole or pyrrole ring in which a single one of Y 1 and Y 2 is N. It may be that Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an triazole or tetrazole.
  • Y 1 and Y 2 may be N and the other is C.
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a triazole or tetrazole ring in which a single one of Y 1 and Y 2 is N. It may be that Y 1 is N. It may be that Y 2 is N .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a thiophene, furan, or pyrrole ring.
  • a single one of Z 1 , Z 2 and Z 3 is independently selected from O, S and NR 5 and the remaining two of Z 1 , Z 2 and Z 3 are each CR 4 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a pyrazole, oxazole, imidazole, thiazole, isoxazole or isothiazole ring.
  • a single one of Z 1 , Z 2 and Z 3 is independently CR 4 and the remaining two of Z 1 , Z 2 and Z 3 are selected from O, S and NR 5 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a oxazole, thiazole, isoxazole, furan, thiophene or isothiazole ring.
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a oxazole, thiazole, isoxazole or isothiazole ring.
  • the remaining Z 1 , Z 2 or Z 3 is selected from O and S.
  • Z 1 , Z- or Z- is O.
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a oxazole or isoxazole ring.
  • a single one of X 1 , X 2 , X 3 and X 4 is N, e.g. it may be that X 1 is N.
  • the remainder of X 1 , X 2 , X 3 and X 4 (e.g. X 2 , X 3 and X 4 ) may be CR 4 .
  • Y 1 and Y 2 are each C; Z 1 is CR 4 (e.g. CH); Z 2 is selected from O, S and N R 5 ; and Z 3 is N.
  • Z 1 is CR 4 (e.g. CH); Z 2 is selected from O, S and N R 5 ; and Z 3 is N.
  • Z 2 is selected from O and S.
  • Z 2 is O.
  • a single one of X 1 , X 2 , X 3 and X 4 is N, e.g. it may be that X 1 is N.
  • the remainder of X 1 , X 2 , X 3 and X 4 may be CR 4 .
  • R 3 is selected from H and C 1 -C 4 -alkyl.
  • R 3 may be selected from H and methyl.
  • R 4 may be independently at each occurrence selected from: H, halo, nitro, cyano, SOR 6 , SO 3 R 6 , SO2R 6 , SO 2 NR 6 R 6 CO 2 R 6 C(O)R 6 , CONR 6 R 6 , C 1 -C 4 -alkyl, C 2 -C 4 -alkynyl, C 2 -C 4 - alkenyl and C 1 -C 4 -haloalkyl.
  • R 4 may be independently at each occurrence selected from: halo, nitro, cyano, SOR 6 , SO3R 6 , SO2R 6 , SO 2 NR 6 R 6 CO 2 R 6 C(O)R 6 , CONR 6 R 6 , C 1 -C 4 -alkyl, C 2 -C 4 -alkynyl, C 2 -C 4 -alkenyl and C 1 -C 4 -haloalkyl.
  • R 4 may be independently at each occurrence selected from: H, halo, nitro, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C1-C4- haloalkyl.
  • R 4 may be independently at each occurrence selected from: halo, nitro, C1-C4- alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl.
  • R 4 may be independently at each occurrence selected from: H, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl.
  • R 4 may at all occurrences be H.
  • R 4 group which forms part of Z 1 , Z 2 or Z 3 is an R 4b group, wherein R 4b is independently at each occurrence selected from: H, halo, nitro, cyano, C2-alkynyl, CO 2 H, C(O)H, and CONH 2 .
  • R 4b may be at each occurrence independently selected from: H, halo, nitro, cyano, C 2 -alkynyl.
  • R 4b may be at each occurrence independently selected from: H and halo.
  • R 4b may at all occurrences be H.
  • R 5 is attached to a nitrogen which forms a double bond to a neighbouring atom in the ring formed by Z 1 , Z 2 , Z 3 , Y 1 and Y 2 , R 5 is absent. Where R 5 is attached to a nitrogen which forms only single bonds to the neighbouring atoms in the ring formed by Z 1 , Z 2 , Z 3 , Y 1 and Y 2 , R 5 is not absent.
  • R 5 may be H.
  • R 5 may be C 1 -C 4 -alkyl, e.g. methyl.
  • R 6 is H. It may be that at all occurrences R 6 is H.
  • R 7 may be a monocyclic aryl group.
  • R 7 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 a R a , NR a S(O) 2 R a , NR a CONR a R a , NR a CO 2 R a , NR a C(O)R a , OR a ; SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 R a C(O)R a , CONR a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -
  • R 7 may be a phenyl group which is substituted by 1 to 3 substituents independently at each occurrence selected from F, nitro, C 1 -C 4 -alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl.
  • R 7 groups include 2,5-difluorophen-1-yl and 3-nitro-4-methylphen-1-yl.
  • R 7 is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic.
  • R 7 may take the form:
  • V 1 , V 2 and V 3 are each independently selected from: N and CR 4 ; with the proviso that no more than two of V 1 , V 2 and V 3 are N; and wherein the ring B is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyl or heterocycloalkyl ring.
  • R 7 takes the form:
  • V 4 and V 5 are each independently selected from O, S and NR a ;
  • V 1 , V 2 , V 3 , V 4 , V 5 , R 14 and m are selected such that the number of substituent groups off the R 7 bicycle does not exceed 5.
  • V 1 , V 2 and V 3 are each independently selected from: N and CH; with the proviso that no more than two of V 1 , V 2 and V 3 are N. It may be that a single one of V 1 , V 2 and V 3 is N.
  • V 3 is CR 4 (e.g. CH).
  • V 1 is N and V 2 is CR 4 (e.g. CH).
  • V 2 is N and V 1 is CR 4 (e.g. CH).
  • V 1 and V 2 are each N.
  • V 4 is O.
  • both V 4 and V 5 are O.
  • V 4 is O and V 5 is S.
  • V 4 is O and V 5 is NR a (e.g. NH).
  • V 4 can also be S. Thus, it may be that V 4 is S and V 5 is NR a (e.g. NH).
  • V 5 is NR a (e.g. NH).
  • NR a e.g. NH
  • m may be 1.
  • m is 2.
  • V 4 is O, V 5 is O, m is 2 and R 14 is in all instances H.
  • V 4 is O, V 5 is S, m is 2 and R 14 is in all instances H.
  • R 7 may also take the form , wherein V 6 is independently selected from N and CR 4 (e.g. CH); V 7 is independently selected from NR a , S and O; and R 15 is independently at each occurrence selected from: halo, nitro, cyano, NR a R a , NR a S(O) 2 R a , NR a C(O)R a , NR a CONR a R a , NR a CO 2 R a , NR a C(O)R a , OR a ; SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 R a C(O)R a , CONR a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -hal
  • R 15 may be independently at each occurrence selected from F, CN, OR a , nitro, C 1 -C 4 -alkyl, C2- C4-alkenyl, C ⁇ C ⁇ -alkynyl and C 1 -C 4 -haloalkyl.
  • This form of R 7 is particularly preferred where L 3 is absent.
  • V 6 , V 7 , and R 15 are selected such that the number of substituent groups off the R 7 bicycle does not exceed 5.
  • An exemplary R 7 group is
  • R 8 is selected from H or C 1 -C 4 -alkyl. Even more preferably, R 8 is H. Preferably, R 9 is at all occurrences H.
  • R 10 is independently at each occurrence selected from: H, OR 6 , CO 2 R 6 and NR 6 R 11 . It may be that R 10 is independently selected from OR 6 and NR 6 R 11 . Preferably, R 10 is independently selected from OH and NH 2 .
  • R 11 is selected from H and C 1 -C 4 -alkyl.
  • R 11 is at each occurrence selected from H and C 1 -C 4 -alkyl.
  • R 11 may be H.
  • R 11 may be C 1 -C 4 -alkyl, e.g. methyl. It may be that at all occurrences, R 11 is H.
  • W is preferably O.
  • the compound may be any one or more compound(s) selected from those tested in
  • the compound may be any one or more compound(s) selected from:
  • 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;
  • 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 " .
  • 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:
  • R 1 is selected from R 2 or R 3 ;
  • R 2 represents the group: are each independently selected from: N and CR 4 ;
  • X 4 is selected from N, CR 2 and CR 4 ; wherein only one of R 1 and X 4 contains the group R 2 ; and wherein no more than two of X 1 , X 2 , X 3 and X 4 are N;
  • Y 1 and Y 2 are each independently selected from C and N;
  • the compound may be a compound of formula (lb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • 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.
  • 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.
  • 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 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.
  • chromatography typically HPLC
  • 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.
  • racemic compounds such as 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).
  • C m -C n refers to a group with m to n carbon atoms.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • C 1 -C 6 -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 .
  • 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.
  • C 1 -C 6 -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.
  • a halo alkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom.
  • 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.
  • 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 .
  • 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.
  • 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 .
  • cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 6 -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 .
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • heteromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ 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).
  • aryl refers to an aromatic hydrocarbon ring system.
  • the ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • 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 C 1 -C 4 -alkyl, C 1 -C 4 -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.
  • aryl groups may include non-aromatic carbocyclic portions.
  • An aromatic ring is a phenyl ring.
  • heteroaryl may refer to any aromatic (i.e. a ring system containing (4n + 2) ⁇ - electrons or n- electrons in the ⁇ -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).
  • 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.
  • 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 C 1 -C 4 -alkyl, C 1 -C 4 -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.
  • heteroaryl groups and heteroaromatic rings may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine.
  • 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).
  • 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.
  • 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.
  • 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 .
  • 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 a R a , N R a S(O) 2 R a , NR a CON R a R a , NR a CO 2 R a , NR a C(O)R a , OR a ; SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 R a C(O)R a , CON R a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 - C4-haloalkyl and CR a R a N R a R a ; wherein R a is independently at each occurrence selected from H
  • the present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXXXI) 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.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H , carbon, such as 1 1 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, 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. 2 H, 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.
  • 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.
  • each of the compounds of the present invention may be used as a medicament.
  • compound as defined above for the treatment of bacterial infections 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ -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 ⁇ -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 bacterial 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.
  • fluoroquinolone antibiotics e.g. one or more antibiotics selected from
  • 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).
  • 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.
  • 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.
  • a strain selected from: Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp.
  • a fastidious bacterium is one having a complex nutritional requirement, i.e.
  • 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 ⁇ -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 ⁇ -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.
  • mycobacterial infections e.g. mycobacterial infections caused by resistant strains of mycobacteria.
  • they can be used to treat TB or leprosy.
  • the mycobacterial infection is caused by M. tuberculosis.
  • 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 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
  • 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.
  • 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.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Suitable base salts are formed from bases which form non-toxic salts.
  • bases 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.
  • 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.
  • 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.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/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.
  • 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.
  • active compounds e.g. antifungal compounds, oncology compounds
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • Examples of other bacterial compounds which could be administered with the compounds of the invention are penems, carbapenems, fluoroquinolones, ⁇ -lactams, vancomycin, erythromycin or any other known antibiotic drug molecule.
  • 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.
  • 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).
  • oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules
  • 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
  • a compound with an in vitro MIC of, for example, 16-64 ⁇ g/mL may still provide an effective treatment against certain bacterial infections.
  • 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.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a method of treating a bacterial infection comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention.
  • 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.
  • a compound for use in the preparation of a medicament may be for use in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • 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.
  • 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.).
  • 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.
  • the animals may be rats, badgers, deer, foxes, wolves, mice, kangaroos and monkeys and other apes.
  • 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.
  • 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.
  • typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal.
  • the range is 0.1 to 10 mg per kg.
  • 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.
  • the compounds 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.
  • Certain compounds of the invention are of particular use in the treatment of mastitis.
  • 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).
  • 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:
  • DIPEA diisopropylethylamine
  • DMAP N, N- dimethylaminopyridine
  • DMSO dimethyl sulfoxide
  • DPPA Diphenylphosphoryl azide
  • HATU 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate
  • T3P propylphosphonic anhydride
  • TFA trifluoroacetic acid
  • 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 Cs 2 CO 3 , and Pd catalyst, such as palladium(ll)dichloride dichloromethane, in a solvent, such as a mixture of toluene and H 2 O.
  • a base such as Cs 2 CO 3
  • Pd catalyst such as palladium(ll)dichloride dichloromethane
  • 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.
  • 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 Cs 2 CO 3 , and Pd catalyst, such as palladium(ll)dichloride dichloromethane, in a solvent, such as a mixture of toluene and H 2 O, 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 H 2 in the presence of a Pd/C catalyst in 55
  • 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 K 2 CO 3 , 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.
  • 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 K 2 CO 3 , with optional heating.
  • 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 K 2 CO 3 , with optional heating. Removal of the nitrogen PG in
  • (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 K 2 CO 3 , with optional heating.
  • 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.
  • a Pd catalyst/phosphine ligand combination such as bis(tri-tert- butylphosphine)palladium(O)
  • Alkene (19) can be converted to aldehyde (20) by treatment with osmium tetroxide and sodium periodate in a solvent, such as a mixture of H 2 O 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 H 2 in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature.
  • a solvent such as THF
  • 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 K 2 CO 3 , with optional heating.
  • Bromide (18) can be converted to acid (27) by first forming the Grignard with Mg activated by 1 ,2-dibromoethane and Me 3 SiCI in a solvent, such as THF, at a temperature from room temperature to 100°C, followed by quenching with CO 2 .
  • Coupling of the acid (27) to alcohol (28), where PG represents a nitrogen protecting group, such as BOC or Bn, can be effected with PPh 3 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 H 2 in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (30) can be converted to
  • 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 K 2 CO 3 , 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 H 2 O 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 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
  • 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 H 2 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 K 2 CO 3 , with optional heating.
  • Ring opening of epoxide (40) (prepared as described in Scheme K) by tricycle (33) using a base, such as K 2 CO 3 or Cs 2 CO 3 , 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 PPh 3 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 PPh 3 in a solvent, such as a mixture of H 2 O in THF, at room temperature.
  • a solvent such as a mixture of H 2 O in THF
  • 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 Et 3 N, in a solvent, such as THF, at a temperature of 0°C, followed by treatment with NaBH 4 in a solvent, such as a mixture of H 2 O in THF, at a temperature from 5°C to room temperature. Oxidation of the hydroxyl to an aldehyde (e.g.
  • PG is a Bn then by the action of H 2 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 K 2 CO 3 , with optional heating.
  • Ring opening of epoxide (47) (prepared as described in Scheme K) by tricycle (33) using a base, such as K 2 CO 3 or Cs 2 CO 3 , in a solvent, such as DMF, at a temperature from 70°C to 150°C can provide hydroxy (49).
  • a base such as K 2 CO 3 or Cs 2 CO 3
  • a solvent such as DMF
  • 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 H 2 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.
  • a solvent such as THF
  • 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 K 2 CO 3 , with optional heating.
  • 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.
  • a halogenated solvent such as 1 ,2-dichloroethane
  • Et 3 N a halogenated solvent
  • EtOH ethyl nitroacetate
  • the nitro 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.
  • the nitro can be reduced to the amine using sodium hydrosulphite in the presence of NaOH and H 2 O at room temperature.
  • Oxazole ring formation to (54) can be achieved by acylation of amine (58) with R 4 COCI in the presence of a base, such as Et 3 N, in a solvent, such as THF, followed by heating in a high boiling solvent.
  • Amine (66) can be converted into iodide (67) (e.g. by treating with iodine and NaHCO 3 in a solvent, such as EtOAc, at room temperature).
  • a solvent such as EtOAc
  • Acylation with an acid chloride (68) e.g. using Et 3 N in THF at room temperature
  • amide (69) which following an intramolecular Heck reaction (e.g. by heating amide (69) with Pd(PPh 3 )4 and NEt 3 in acetonitrile) can give tricycle (65).
  • amide (84) 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 K 2 CO 3 , in a solvent, such as DMF, at a temperature from 100°C to 150°C) to provide pyrazole (82).
  • a base such as K 2 CO 3
  • Benzoxazine-2,4-dione (56) (prepared as described in Scheme N) can be converted into ⁇ - ketoamide (99) by reaction with ethyl 3-(benzyloxy)propanoate (98) (e.g. with heating in DMF following deprotonation of (98) with NaH).
  • 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 H 2 in an alcoholic solvent, such as EtOH, at room temperature
  • oxidation of (100) e.g. using Dess-Martin Periodinane in a solvent, such as DCM, at room temperature
  • (101) Treatment of (101) with hydrazine (102) (e.g.
  • 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
  • nitro e.g. by use of H 2 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).
  • Oxazole ring formation to (111) can be achieved by acylation of amine alcohol (115) with R 4 COCI in the presence of a base, such as Et 3 N, in a solvent, such as THF, followed by heating in a high boiling solvent.
  • the hydroxyl in (57) (prepared as described in Scheme N) can be converted to chloro (1 18) (e.g. by heating with POCl 2 ).
  • Displacement of the resultant chlorine with a protected amine e.g. para-methoxybenzylamine in a solvent, such as DMF, at room temperature
  • deprotecting the amine in the case of para-methoxybenzylamine this can be achieved using TFA in DCM at room temperature
  • 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.
  • the nitro can be reduced to the amine using sodium hydrosulphite in the presence of NaOH and H 2 O at room temperature.
  • Imidazole ring formation to (121) can be achieved by treatment with R 4 COOH in the presence of T3P and a base, such as Et 3 N, in a solvent, such as DMF, at a temperature from 80°C to 100°C.
  • R 4 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 converted to (116) and (1 17) by reaction with R 5 -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.
  • 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 Et 3 N, in a solvent, such as DMF, at room temperature
  • a base such as Et 3 N
  • Oxidation of the triple bond to the dicarbonyl (126) can be achieved with KMnCU (e.g. in the presence of MgSO 4 and a base, such as NaHCO 3 , in a solvent, such as H 2 O, at room temperature).
  • Treatment of (126) with NH4OH in the presence of R 4 CHO can provide imidazole (127).
  • Nitro reduction to give amine (128) can be effected using sodium hydrosulphite in the presence of NaOH and H 2 O at room temperature.
  • Reaction of amine (128) with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide tricycle (122).
  • 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
  • Treatment with iodomethane in the presence of a base e.g. use of NaOMe, in a solvent, such as MeOH, at room temperature
  • a base such as pyridine
  • Displacement of the resultant chlorine with a protected amine e.g. para- methoxybenzylamine in a solvent, such as DMF, at room temperature
  • deprotecting the amine in the case of para-methoxybenzylamine this can be achieved using TFA in DCM at room temperature
  • 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
  • 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 H 2 O/MeOH, at a temperature from 80°C to 100°C).
  • 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 R 4 COCI, 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).
  • 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).
  • 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 R 4 COCI, 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).
  • 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 H 2 O/MeOH, at a temperature from 80°C to 100°C).
  • Carbamate (146) can be prepared from amine (145) by reaction with ethyl chloroformate in the presence of a base, such as NaHCO 3 , 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).
  • 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).
  • 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.
  • Standard amide coupling reagents such as DCC in a solvent, such as DCM
  • DMAP in the presence of DMAP.
  • Treatment of (161) with an azide, such as NaN 3 in the presence of Cul, in a solvent, such as DMSO, at a temperature from 50°C to 100°C, can form tricycle (159).
  • alkyne (164) Treatment of iodo (123) with alkyne (164) under Pd coupling (e.g. use of Pd(PPh3)2Cl 2 and Cul in the presence of a base, such as Et 3 N, in a solvent, such as DMF, at room temperature) can provide alkyne (165).
  • a base such as Et 3 N
  • a solvent such as DMF
  • benzyl azide e.g. with heating in toluene at a temperature from 50°C to 80°C
  • triazole e.g. with heating in toluene at a temperature from 50°C to 80°C
  • 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.
  • Intermediate (168) can be converted to (162) and (163) by reaction with R 5 -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 K 2 CO 3 or NaH, with optional heating.
  • Silver mediated Pd catalyst CH arylation of (123) with isothiazole (170) (e.g. using AgF and Pd(PPh 3 ) 2 CI 2 and PPh 3 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/H 2 O, with optional heating, to give tricycle (172).
  • 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.
  • Displacement of the chlorine in (113) (prepared as described in Scheme X) with NHR 5 (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 H 2 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).
  • Benzylation of the NH in benzoxazine-2,4-dione (56) can be effected with BnBr in the presence of a base, such as K 2 CO 3 , in a solvent such as DMF, with optional heating.
  • a base such as K 2 CO 3
  • a solvent such as DMF
  • Treatment of (181) with Et 3 N, 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 H 2 O 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.
  • R 5 H.
  • Oxazolidone (184) can be converted to (185) by reaction with R 5 -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 H 2 in an alcohol, such as EtOH, at room temperature
  • 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.
  • 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 NHR 5 (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 H 2 O 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 R 5 -LG, where LG represents a leaving group, such as halide or tosyl group.
  • reaction can be performed in a solvent, such as DMF or MeOH, in the presence of a base, such as K 2 CO 3 or NaH, with optional heating.
  • a base such as K 2 CO 3 or NaH
  • Hydrogenation of (191) e.g. using Pd/C and H 2 in an alcohol, such as EtOH, at room temperature
  • 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 converted to (194) by reaction with R 5 -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 K 2 CO 3 or NaH, with optional heating.
  • the hydroxyl in (203) can be converted to chloro (204) (e.g. by heating with POCI 3 ).
  • Displacement of the chlorine in (204) with NHR 5 e.g. in a solvent, such as DMF, at room temperature
  • NHR 5 e.g. in a solvent, such as DMF, at room temperature
  • a Pummerer rearrangement of the methyl sulphoxide using trifluoroacetic anhydride in a solvent, such as DCM, followed by treatment with a base, such as Et 3 N 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).
  • Amide (33) can, for example, be converted to thioamide (207) by heating with P2S5 in pryridine.
  • Amide (33) can, for example, be converted to amidinine (208) by heating with POCI3 and heating the product with the primary amine NH 2 R 6 .
  • Amide (33) can, for example, be converted to oxime (209) by heating with POCI3 and heating the product with the O-substituted hydroxylamine NH 2 OR 6 .
  • Compounds of formula I where one of X 1 , X 2 , X 3 or X 4 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 CH 2 CI2, at a temperature from 0°C to room temperature.
  • 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 H 2 O and ACN (0.1 % formic acid - acidic pH; 0.1 % ammonia - basic pH). Wavelengths were 254 and 210 nM.
  • Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) or Waters 2767 Sample Manager (Method B) using H 2 O and ACN (0.1-% formic acid - acidic pH; 0.1 % ammonia - basic pH).
  • 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. NaHCO 3 solution (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organics were washed with brine (50 ml_), dried over MgSO 4 and concentrated in vacuo.
  • 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.
  • 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.
  • 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.
  • reaction mixture was diluted with saturated aq. NaHCO 3 solution (5 ml_) and extracted with EtOAc (3 x 5 ml_). The combined organics were washed with brine (5 ml_), dried over MgSO 4 and concentrated in vacuo to give a yellow oil.
  • 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.
  • 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 .
  • 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
  • step (a) 7-fluoro-5-(2- ⁇ 4-[( ⁇ 3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl ⁇ methyl)amino]piperidin-
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • reaction mixture was treated with H 2 O (50 ml_) and extracted with EtOAc (3 x 25 ml_). The combined organics were washed with H 2 O (2 x 50 ml_), brine (50 ml_), dried over MgSO 4 and concentrated in vacuo.
  • reaction mixture was filtered and the filtrate loaded onto a Redisep C18 silica cartridge and eluted with 5% to 95% ACN in H 2 O/0.1 % NH 3 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.
  • MICs Minimum Inhibitory Concentrations 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 ⁇ g/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.
  • E. coli ATCC BAA-2452 E. coli NCTC 13476
  • E. coli MG1655 E. coli MG1655
  • 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.
  • 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 ⁇ g/mL.
  • Stock solutions of compounds were made in DMSO at 12800 ⁇ g/mL.
  • 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 ⁇ where compounds were soluble in DMSO at 10 mM.
  • Microbial growth was measured by OD590 and fluorescence (Ex 560/Em 590) using a BioTekTM 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).
  • the antimicrobial activity of compounds against M. tuberculosis H37Rv grown under hypoxic conditions was assessed using the low oxygen recovery assay (LORA).
  • LORA low oxygen recovery assay
  • 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.
  • NTP stage 2 non-replicating state
  • 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.
  • THP-1 cells 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 ⁇ 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.
  • 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 ⁇ _ of Alamar blue to 100 ⁇ _ 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).
  • an MIC (in ⁇ / ⁇ .) 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.
  • MRSE methicillin-resistant S. epidermidis
  • Compound A shows good activity against MRSE.
  • the compound's activity against MRSE is broadly the same as its activity against wild-type S. epidermidis.
  • CIP ciprofloxacin
  • LEV levofloxacin
  • CIP ciprofloxacin
  • LEV levofloxacin
  • 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.
  • a MIC (in ⁇ g/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.
  • a MIC (in ⁇ g/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.
  • HepG2 ATCC HB-8065 Human hepatic cell line
  • 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.
  • MEM minimal essential medium
  • FBS FBS
  • 1 mM sodium pyruvate a final concentration of 10% FBS and 1 mM sodium pyruvate.
  • DM EM Dulbecco's minimum essential media
  • the tested compounds show low toxicities against human hepatic cell lines.
  • 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.
  • 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.

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Abstract

La présente invention concerne des composés médicamenteux antibactériens contenant un système cyclique tricyclique. L'invention concerne également des formulations pharmaceutiques de composés médicamenteux antibactériens. L'invention concerne aussi des utilisations des dérivés dans le traitement d'infections bactériennes et dans des méthodes de traitement d'infections bactériennes. L'invention concerne en outre des composés médicamenteux antibactériens qui peuvent traiter des infections bactériennes actuellement difficiles à traiter à l'aide de composés médicamenteux existants.
PCT/GB2015/052303 2014-08-11 2015-08-10 Composés antibactériens WO2016024096A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017046606A1 (fr) * 2015-09-18 2017-03-23 Redx Pharma Plc Composés antibactériens
WO2017046603A1 (fr) * 2015-09-18 2017-03-23 Redx Pharma Plc Composés antibactériens et nouvelles utilisations de ceux-ci

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5683998A (en) * 1991-04-23 1997-11-04 Toray Industries, Inc. Tricyclic triazolo derivatives, processes for producing the same and the uses of the same
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
WO2012078633A2 (fr) * 2010-12-07 2012-06-14 Philadelphia Health And Education Corporation, D/B/A Drexel University College Of Medicene Méthodes d'inhibition de la métastase d'un cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5683998A (en) * 1991-04-23 1997-11-04 Toray Industries, Inc. Tricyclic triazolo derivatives, processes for producing the same and the uses of the same
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
WO2012078633A2 (fr) * 2010-12-07 2012-06-14 Philadelphia Health And Education Corporation, D/B/A Drexel University College Of Medicene Méthodes d'inhibition de la métastase d'un cancer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017046606A1 (fr) * 2015-09-18 2017-03-23 Redx Pharma Plc Composés antibactériens
WO2017046603A1 (fr) * 2015-09-18 2017-03-23 Redx Pharma Plc Composés antibactériens et nouvelles utilisations de ceux-ci

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