WO2017046606A1 - Composés antibactériens - Google Patents

Composés antibactériens Download PDF

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Publication number
WO2017046606A1
WO2017046606A1 PCT/GB2016/052899 GB2016052899W WO2017046606A1 WO 2017046606 A1 WO2017046606 A1 WO 2017046606A1 GB 2016052899 W GB2016052899 W GB 2016052899W WO 2017046606 A1 WO2017046606 A1 WO 2017046606A1
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Prior art keywords
methyl
alkyl
compound
cyclopropyl
oxazolo
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PCT/GB2016/052899
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English (en)
Inventor
Anthony Huxley
Ralph KIRK
Gary Noonan
Mario UOSIS-MARTIN
Oliver BARDELL-COX
Neil STOKES
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Redx Pharma Plc
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Priority claimed from GBGB1516613.5A external-priority patent/GB201516613D0/en
Priority claimed from GBGB1613866.1A external-priority patent/GB201613866D0/en
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2017046606A1 publication Critical patent/WO2017046606A1/fr

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    • 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
    • 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
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to antibacterial and antimycobacterial drug compounds containing a tricyclic ring system. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections and to methods of treating bacterial infections. The invention is also directed to antibacterial drug compounds that are capable of treating bacterial infections that are currently hard to treat with existing drug compounds, e.g. those caused by resistant bacterial or mycobacterial strains.
  • antibiotic-resistant Gram-negative strains such as either Escherichia coli NDM-1 (New Delhi metallo ⁇ -lactamase-1) or Klebsiella pneumoniae with the same gene, are also very difficult to treat. Frequently only expensive antibiotics such as vancomycin and colistin are effective against these strains.
  • 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.
  • STI human sexually-transmitted infection
  • N. meningitidis a species of the genus Neisseria that also includes the pathogen N. meningitidis, which is one of the aetiological agents of meningitis.
  • Gonorrhoea is a significant global public health problem.
  • 2008 there were a total of 106 million estimated new cases of N. gonorrhoeae infection (Global Incidence and Prevalence of Selected Curable Sexually Transmitted lnfections-2008, World Health Organization). It is the second most commonly reported infectious disease in the United States. According to the Centers for Disease Control
  • gonorrhoea 2 estimated 820,000 gonococcal infections per year in the United States (Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention).
  • the sulphonamides were the first antibiotics used for the treatment of gonorrhoea, followed by penicillin, tetracycline and spectinomycin.
  • penicillin, tetracycline and spectinomycin In each case the development of resistance to these drugs by N. gonorrhoeae led to their use being discontinued.
  • the fluoroquinolone antibiotics ciprofloxacin and ofloxacin were also historically recommended for the treatment of gonorrhoea.
  • Examples include: i) alterations in the folP gene that encodes the dihydropteroate synthase enzymes that are the target of the sulphonamides; ii) plasmids bearing the ⁇ / ⁇ - ⁇ gene, encoding a TEM-1 - type ⁇ -lactamase; iii) single nucleotide polymorphisms in the tetracycline- and spectinomycin-binding regions of the ribosomal target; and iv) mutations in the gyrA and parC genes that code for subunits of DNA gyrase and topoisomerase IV that are targeted by the fluoroquinolones.
  • tuberculosis A further disease in which the development of resistance and multidrug resistance is of particular concern is tuberculosis (TB). From the 17 th century to the early-20 th century TB was one of the most common causes of death, particularly amongst the urban poor. The development of effective treatments and vaccinations through the middle part of the 20 th century led to a sharp reduction in the number of deaths arising from the disease. TB is usually caused by Mycobacterium tuberculosis. Mycobacteria are aerobic bacteria and, as a result, tuberculosis infections most often develop in the lungs (pulmonary tuberculosis), although this is not always the case. Mycobacteria lack an outer cell membrane and as such they are often classified as Gram-positive bacteria, although they are in many ways atypical.
  • 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.
  • 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
  • the invention provides a compound of formula (I), or a pharmaceutically thereof:
  • X 1 is independently selected from: N and CR 5 ;
  • X 2 is independently selected from: N and CR 6 ;
  • R 1 is independently selected from: H, F, NR 7 R 10 , NR 7 NR 7 R 10 and Ci-C 4 -alkyl;
  • R 2 is Co-Cs-alkylene-R 11 ;
  • R 3 is -W 1 -Co-C3-alkylene-R 12 ; wherein W 1 is selected from a bond, Ci-C3-alkylene, acetylene, -0-, -S(0)y- (wherein y is an integer selected from 0, 1 and 2), -NR 7 -, -NR 7 S(0) 2 - , -S(0) 2 NR 7 -, -C(0)NR 7 , -NR 7 C(0)-, -OC(O)-, -C(0)0-, -OC(0)NR 7 -, -NR 7 C(0)0 and - NR 7 C(0)NR 7 - ; and wherein R 12 is independently selected from phenyl, monocyclic heteroaryl, monocyclic 3-10 heterocycloalkyl, monocyclic C3-Cio-cycloalkyl and a bicyclic group comprising two fused rings each independently selected from phenyl, heteroaryl, 3-7- heterocycloalkyl and C3-C7-cyclo
  • R 4 is independently selected from: d-Cs-alkyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, Ci-Cs-haloalkyI and Co-C3-alkylene-R 14 ; wherein R 14 is selected from C3-C6-cycloalkyl, 3-6-heterocycloalkyl, C3-C6-halocycloalkyl, -phenyl and -heteroaryl;
  • R 5 is independently selected from: H , O-d-Cs-alkyl, halo, d-Cs-alkyl, C 2 -Cs-alkenyl, C 2 -Cs- alkynyl, Ci-Cs-haloalkyl, O-d-Cs-haloalkyl, C3-C6-cycloalkyl, 3-6-heterocycloalkyl, C3-C6- halocycloalkyl; or R 4 and R 5 together form an alkylene or heteroalkylene chain of the form - (CR 7 R 7 )rW 2 -(CR 7 R 7 )s-W 3 -(CR 7 R 7 )t- and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; wherein W 2 and W 3 are each independently selected from: a bond, O, S and NR 15 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of
  • R 3 and R 5 together with the carbons to which they are attached, form a 5-7- heterocycloalkyl ring which is optionally substituted with a single R 11 group and/or from 1 to 5 R 13 groups;
  • R 6 is independently selected from: H , Ci-C 4 -alkyl and halo;
  • R 3 and R 6 together with the carbons to which they are attached, form a 5- 7heterocycloalkyl ring which is optionally substituted with a single R 1 1 group and/or from 1 to 5 R 13 groups;
  • R 7 , R 15 , R 16 and R 23 are independently at each occurrence selected from: H and Ci-C4-alkyl;
  • R 7a is independently selected from: H , halogen and Ci-C4-alkyl;
  • R 8 is independently selected from: R 2 , H , Ci-C4-alkyl, and Ci-C 4 -haloalkyl;
  • R 9 is independently at each occurrence selected from: R 2 , H , halo, nitro, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and Ci-C4-haloalkyl;
  • R 10 is independently at each occurrence selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl,
  • R 1 1 is independently selected from: aryl, C3-C7-cycloalkyl, heteroaryl, 3-12-heterocycloalkyl,
  • R 17 is independently selected from: H, Ci-C4-alkyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-
  • R 18 is independently selected from Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C 7 -cycloalkyl, C(0)R 21 and Ci-C 4 -alkylene-R 20 ;
  • R 19 is independently selected from Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, heteroaryl, 3-12- heterocycloalkyl, C 3 -C 7 -cycloalkyl, aryl, NR 22 R 23 , OR 22 , C(0)OR 22 , C(0)NR 22 R 23 , C1-C3- alkylene-R 24 and Ci-C 3 -alkylene-R 20 ;
  • R 20 is independently aryl, heteroaryl, 3-12-heterocycloalkyl, NR 22 R 23 , OR 22 , C(0)OR 22 , C(0)NR 22 R 23 ;
  • R 21 is independently selected from Ci-C4-alkyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C7- cycloalkyl, NR 22 R 23 , Ci-C 3 -alkylene-R 20 ;
  • R 22 is independently selected from H, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C7-cycloalkyl; or R 22 and R 23 together with the nitrogen atom to which they are attached together form a 5-12-heterocycloalkyl group or heteroaromatic group;
  • R 24 is independently selected from C(0)-Ci-C 3 -alkylene-R 2 ° and S(0) 2 -Ci-C 3 -alkylene-R 20 ; y is independently at each occurrence an integer selected from 1 and 2;
  • R 2 is not selected from:
  • R 25 is independently at each occurrence selected from: H, Ci-C 4 -alkyl, and Ci-C 4 -haloalkyl
  • R 26 is independently at each occurrence selected from: H, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, S(0) 2 -CrC 4 -alkyl, C(0)-Ci-C 4 -alkyl, C(0)-0-Ci-C 4 -alkyl and CH 2 -phenyl.
  • Compounds having a sterically significant group on the 5-membered ring formed by Y 1 , Y 2 , Z 1 , Z 2 and Z 3 are surprisingly potent antibacterial compounds.
  • the incorporation of sterically significant groups at this position allows the introduction of oxygen and nitrogen containing groups which might modify the chemical or physical properties of the compounds, e.g. the solubility, lipophilicity, acid/base properties.
  • compounds of the invention can be more stable than similar compounds with smaller groups attached to the 5-membered ring.
  • the compound of formula (I) is a compound of formula (II): (II)
  • ⁇ 1 , ⁇ 2 , ⁇ ⁇ 3 , X 1 , X 2 , R 1 , R 2 , R 3 , R 4 and A are as defined above for formula (I) and wherein Z 2 is N or C.
  • the compound of formula (I) is a compound of formula (III):
  • the compound of formula (I) is a compound of formula (IV):
  • R 1 , R 2 , R 3 , R 4 , R 6 , and X 1 are as defined above for formula (I) and wherein either Z 1 or Z 3 is N and the remaining Z 1 or Z 3 is independently selected from NR 8 , O and S.
  • the compound of formula (I) is a compound of formula
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and A are as defined above for formula (I) and wherein Z 1 is selected from NR 8 , S and O. It may be that R 3 is R 12 .
  • the compound of formula (I) has a structure according to any one or
  • R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , X 1 , X 2 and A are as defined above for formula (I).
  • the compound of formula (I) is a compound of formula (XXXI):
  • R ⁇ R 3 , R 4 , R 22 , R 23 , Z ⁇ Z 2 , Z 3 , Y 1 , Y 2 , X 1 , X 2 and A are as defined above for formula (I); and wherein R 16 is selected from: H and Ci-C4-alkyl; R 27 is independently at each occurrence selected from H and Ci-C4-alkyl; and W 4 is Ci-C3-alkylene.
  • the compound of formula (I) is a compound of formula (XXXII):
  • R 1 , R 3 , R 4 , R 6 , R 22 , R 23 and X 1 are as defined above for formula (I); and wherein R 16 , R 27 and W 4 are as defined above for formula (XXXI); and wherein Z 1 is selected from NR 8 , S and O. It may be that R 3 is R 12 . It may be that Z 1 is selected from S and O. It may be that Z 1 is O.
  • R 1 , R 4 , R 6 , R 12 , R 22 , R 23 and X 1 are as defined above for formula (I); and wherein R 16 , R 27 are as defined above for formula (XXXI); wherein R 28 is independently at each occurrence selected from H, Ci-C4-alkyl and Co-C3-alkylene-R c ; or wherein the two R 28 groups together with the carbon atom to which they are attached form a C3-C7-cycloalkyl ring or a 3-7-heterocycloalkyl ring, wherein R c is independently aryl, heteroaryl, 3-7- heterocycloalkyl, C 3 -C 7 -cycloalkyl, C(0)NR a R a and C(0)OR a ; and wherein Z 1 is selected from NR 8 , S and O. It may be that Z 1 is selected from S and O. It may be that Z 1 is O.
  • R 1 , R 4 , R 6 , R 12 and X 1 are as defined above for formula (I); wherein R 32 is selected from: cyano, C02R a , Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and Ci-C4-haloalkyl; R 33 is selected from H and Ci-C4-alkyl; a1 is an integer selected from 0, 1 , 2, 3 or 4; and Z 1 is selected from NR 8 , S and O. It may be that Z 1 is selected from S and O. It may be that Z 1 is O.
  • the compound of formula (I) is a compound of formula (XXXV): exactly ⁇
  • R 1 , R 4 , R 6 and X 1 are as defined above for formula (I); wherein R 32 , R 33 and a1 are as defined above for formula (XXXIV); and wherein R 34 is independently selected from NR 7 R 10 , halo, cyano, nitro, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, CONR 7 R 7 , Ci-C 4 -alkylene-NR 7 R 10 ; a2 is an integer selected from 0, 1 , 2 and 3; and Z 1 is selected from NR 8 , S and O. It may be that Z 1 is selected from S and O. It may be that Z 1 is O.
  • X 1 may be N. Alternatively, X 1 may be CR 5 .
  • X 2 may be N.
  • X 2 is CR 6 .
  • A may be selected from O or S.
  • A is O.
  • R 1 is independently selected from: H, NR 7 R 10 , and Ci-C 4 -alkyl.
  • R 1 may be H.
  • R 1 may be NR 7 R 10 , e.g. NHR 10 .
  • R 1 may be Ci-C 4 -alkyl, e.g. methyl.
  • R 3 and R 5 together with the carbons to which they are attached, form a 5-7- heterocycloalkyl ring which is optionally substituted with a single R 11 group and/or from 1 to 5 R 13 groups. More typically, however, R 3 and R 5 , together with the carbons to which they resist _
  • R 3 and R 6 together with the carbons to which they are attached, form a 5-7-heterocycloalkyl ring which is optionally substituted with a single R 1 1 group and/or from 1 to 5 R 13 groups. More typically, however, R 3 and R 6 , together with the carbons to which they are attached, do not form a 5-7-heterocycloalkyl ring.
  • R 3 may be independently selected from: H, halo, nitro, cyano, Ci-C4-alkyl and O-C1-C4- alkyl. Thus, R 3 may be independently selected from H and halogen. More typically, however, R 3 is -W 1 -Co-C3-alkylene-R 12 . R 3 may thus be -W1-R 12 . W 1 may be selected from -NR 6 - and -0-. More typically, however, W 1 is a bond. Thus, preferably, R 3 is R 12 .
  • R 12 may be independently selected from: 3-10-heterocycloalkyl, phenyl, and 5, 6- or 9 membered heteroaryl comprising 1 or 2 nitrogen atoms within the ring system; wherein the aryl, heteroaryl or heterocycloalkyl group is optionally substituted with 1 , 2 or 3 R 13 groups.
  • R 12 may be 3-10-heterocycloalkyl. Typically, R 12 will be an N-heterocycloalkyl group.
  • N- heterocycloalkyl groups may be monocyclic or bicyclic and comprise 1 to 3 nitrogen atoms in the heterocyclic ring system and R 12 may be attached to the rest of the molecule via a carbon or a nitrogen in the ring system. It may be that the N-heterocycloalkyl group is attached to the rest of the molecule via the or each nitrogen in the ring system.
  • N R 29 is independently selected from: H , Ci-C4-alkyl.
  • R 29 is independently selected from: H , Ci-C4-alkyl.
  • R 12 may be a monocyclic C3-C7 N-heterocycloalkyl group.
  • R 12 may be a piperazine ring.
  • R 12 may thus be a piperazine ring substituted with a methyl group, e.g. an N-methyl piperazine ring, a 3-methyl piperazine ring, or a 2-methyl piperazine ring.
  • R 12 may be an unsubstituted piperizine group. Any piperazine group will typically be attached to the rest of the molecule via one of the nitrogens in the ring system.
  • R 12 is an azetidine, pyrrolidine or piperidine ring, optionally wherein the ring nitrogen attaches the aziridine, pyrrolidine or piperidine ring to the rest of the compound.
  • R 12 may be an azetidine, pyrrolidine or piperidine ring wherein the ring nitrogen attaches the azetidine, pyrrolidine or piperidine ring to the rest of the compound and which is substituted with a single hydroxyl group.
  • R 12 may be a piperidine ring substituted with a single hydroxyl group, e.g. a 4-hydroxy-piperidine ring.
  • R 12 may be a pyrrolidine substituted with a single hydroxyl group, e.g. a 3-hydroxypyrrolidine.
  • R 12 is a 3-hydroxy aziridine group.
  • R 12 may be a bicylic C7-Cio-N-heterocycloalkyl group. Specific examples of R 12 groups include
  • R 12 may be a bicyclic C7-Cio-N-heterocycloalkyl group.
  • the bicyclic N-heterocycloalkyl group may be attached to the rest of the molecule via either a carbon or a nitrogen in the ring system.
  • R 30 is R 13 ; or wherein two R 30 groups together with the carbon or carbons to which they are attached form a 3-6 membered cycloalkyi, a 3-6 membered heterocycloalkyi ring or a 6-membered aryl or 5- or 6-membered heteroaryl ring. Where two R 30 groups form a heterocycloalkyi ring, that ring will comprise 1 or 2 heteroatoms selected from N, O and S in the ring system.
  • R 30 groups form a cycloalkyi, heterocycloalkyi ring
  • m is an integer independently selected from 0, 1 , 2, 3 and 4. It may be that two 30 groups do not form a cycloalkyi or heterocycloal r
  • R 12 may be . m may be 1. Thus, R 12 may be
  • R 13 may be N R 7 R 10 .
  • Each R 7 and R 10 in R 13 may be H (e.g. R 13 may be N H 2 ).
  • Each R 7 and R 10 in R 12 may independently be C1-C4 alkyl, e.g. each R 7 and R 10 in R 13 may independently be methyl (e.g. R 13 may be NMe 2 ).
  • R 13 may be OR 7 .
  • R 7 may be H and thus, R 13 may be OH .
  • R 13 may be CR 7 R 7 NR 7 R 10 .
  • R 13 may be CMe 2 NR 7 R 10 .
  • R 13 may be CR 7 R 7 NH 2 .
  • R 13 may be CMe 2 NH 2 .
  • m may be 2.
  • Two R 30 groups may form a 3- to 6- membered heterocycloalkyl ring, e.g. a 6-membered heterocycloalkyl ring, e.g. a vicinally fused 6-membered heterocycloalkyl ring.
  • a specific example of a 6-membered heterocycloalkyl ring would be a morpholine ring.
  • the two R 30 groups may also form a 3- to 6- membered cycloalkyi ring, e.g. a 3-membered ring.
  • two R 30 groups may form a vicinally fused 3-membered ring or a spiro fused 3-membered ring. That 3-membered ring (e.g.
  • the 3- membered ring (e.g. that vicinally fused 3-membered ring) may be substituted with an NR 7 R 10 group, e.g. a N H 2 group.
  • R 30 groups In cases in which two R 30 groups form a 3- to 6- membered cycloalkyi or 3- to 6- membered heterocycloalkyl ring, there may be one or more other R 30 groups, e.g. m may be 4. Such additional R 30 groups will generally not form a 3- to 6- membered cycloalkyi or a 3- to 6- membered heterocycloalkyl ring and will thus be R 13 groups.
  • R 13 may be Ci-C 4 -alkyl, e.g. methyl.
  • R 13 may be NR 7 R 10 , e.g. NH 2 .
  • R 12 groups include:
  • R 12 group A specific example of an R 12 group is
  • R 12 is preferably an aryl group, e.g. a phenyl group, or a bicyclic group comprising phenyl ring fused to a ring selected from 3-7-heterocycloalkyl and C3-C7-cycloalkyl. In such bicyclic R 12 groups, the R 12 group will typically be attached to the rest of the molecule through the phenyl ring.
  • R 12 may be a phenyl group.
  • R 12 may be a phenyl group with at least one N R 7 R 10 , CONR 7 R 7 , CR 7 R 7 OR 7 or CR 7 R 7 NR 7 R 10 substituent group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl, e.g. a phenyl group with at least one NR 7 R 10 , CONR 7 R 7 , or CR 7 R 7 NR 7 R 10 group and optionally further substituted with from 1 to 3 halo groups (e.g. fluoro groups).
  • halo groups e.g. fluoro groups
  • R 12 may be a phenyl group with at least one NR 7 R 10 or CR 7 R 7 NR 7 R 10 group and optionally further substituted with from 1-3 groups independently selected from halo, cyano, Ci-C4-haloalkyl and Ci-C4-alkyl, e.g. a phenyl group with at least one N R 7 R 10 or CR 7 R 7 N R 7 R 10 group and rther substituted with from 1-3 halo groups (e.g. fluoro groups).
  • R 12 may be
  • R 34 is independently selected from N R 7 R 10 , halo, cyano, nitro, C1-C4- alkyl, Ci-C 4 -haloalkyl, 7 R 7 , Ci-C 4 -alkylene-N R 7 R 10 ; a2 is an integer selected from 0, 1 ,
  • R 12 may be ; wherein R 35 is independently selected from halo, s, R 12
  • R 12 may be a bicyclic group comprising a phenyl ring fused to a ring selected from 3-7- heterocycloalkyl and C3-C7-cycloalkyl.
  • the R 12 group will typically be attached to the rest of the molecule through the phenyl ring.
  • Compounds having such bicyclic R 12 groups can show reduced inhibition of hERG relative to related compounds. This might be expected to lead to an improved safety profile for the compounds of the invention relative to previously developed compounds.
  • 1 2 may have the structure:
  • ring A is 5- or 6-membered heterocycloalkyi ring or a 5- or 6- membered cycloalkyi ring; and
  • a single one of X 3 , X 4 , X 5 and X 6 is a carbon and is the point of attachment to the ring comprising X 1 and X 2 ; and the remainder of X 3 , X 4 , X 5 and X 6 are independently selected from N and CR 31 ; R 31 is H or is R 13 ; and a is 0, 1 , 2 or 3 provided that X 3 , X 4 , X 5 , X 6 and a are selected such that R 12 contains no more than three R 13 groups.
  • ring A has an NR 7 group, either in the ring or as a substituent.
  • ring A is heterocycloalkyi group comprising an NR 7 group in the ring or that ring A is substituted with at least one R 13 group, that R 13 group comprising NR 7 R 10 .
  • ring A is a 5- or 6-membered heterocycloalkyi ring, e.g. a 5- or 6-membered heterocycloalkyi ring comprising at least one nitrogen atom in the ring.
  • Ring A may be a 6- membered heterocycloalkyi 12 may have the structure: , e.g. .
  • Ring A may be a 6-membered heterocycloalk i ring comprising at least one
  • R 12 may have
  • ring A is a 5-membered cycloalkyl ring or a 5-membered heterocycloalkyi ring. It may be that ring A has an NR 7 group, either in the ring or as a substituent. It may be that either ring A is a 5-membered heterocycloalkyi group comprising an NR 7 group in the ring or that ring A is substituted with at least one R 13 group, that R 13 group comprising NR 7 R 10 .
  • R 12 ma have the structure
  • V 1 is selected from NR 7 and
  • V 1 may be NR 7 .
  • R 7 may be H.
  • V 1 may be CHNR 7 R 10 .
  • R 7 may be H.
  • V 1 may be CH NH 2 .
  • X 4 is a carbon and is the point of attachment of R 12 to the ring comprising X 1 and X 2 .
  • X 3 may be N .
  • X 3 may be CR 31 , e.g. CH .
  • X 5 may be N .
  • X 5 may be CR 31 , e.g. CH .
  • X 6 may be N .
  • X 6 may be CR 31 , e.g. CH . It may be that X 3 , X 5 and X 6 are each CR 31 . Thus, it may be that X 3 , X 5 and X 6 are each CH.
  • R 12 may also be a heteroaryl group.
  • R 12 may be a heteroaryl group comprising at least one nitrogen atom in the ring structure.
  • R 12 may be a heteroaryl group comprising at least one nitrogen atom in the ring system and substituted with at least one NR 7 R 10 , CONR 7 R 7 , or CR 7 R 7 NR 7 R 10 group and optionally further substituted with from 1 to 3 groups independently selected from halo, C1-C4- haloalkyl and Ci-C4-alkyl.
  • R 12 may be a heteroaryl group comprising at least one nitrogen atom in the ring system and substituted with at least one N R 7 R 10 group.
  • R 12 may be a 9-membered bicyclic heteroaryl group.
  • R 12 may be a 9-membered heteroaryl group comprising 1 , 2 or 3 (e.g. 1 or 2) nitrogen atoms in the ring system.
  • R 12 may be an
  • R 12 may be or It may be that R 12 is not a benztriazole.
  • R 12 may comprise a pyridine ring fused to a 5 membered heteroaryl ring, e.g. a 5-membered heteroaryl ring comprising 1 or 2 nitrogen atoms in the ring.
  • exemplary groups include
  • R 12 may be a 6-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system.
  • R 12 may be a group selected from pyridinyl, pyrimidine, pyrazine.
  • R 12 may be substituted with at least one NR 7 R 10 , CONR 7 R 7 , or CR 7 R 7 NR 7 R 10 group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl.
  • R 12 is a 6-membered monocyclic heteroaryl group, it may be substituted with at least one NR 7 R 10 group.
  • R 12 may be an amino-pyridinyl group (e.g. a 6- amino-pyridin-3-yl group) or an amino pyrimidine (e.g. 2-amino-pyrimidin-5-yl group).
  • R 12 may be a 5-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system, e.g. a thiazole or pyrazole.
  • R 12 is selected from phenyl, pyridinyl, pyrimidine, pyrazine, a 9-membered heteroaryl group comprising 1 or 2 nitrogen atoms in the ring system or a bicyclic group comprising phenyl ring fused to a ring selected from 3-7- heterocycloalkyl and C3-C7-cycloalkyl.
  • R 12 is selected from phenyl or 6-membered heteroaryl (e.g. pyridine or pyrimidine) and has an NR 7 R 10 (e.g. an NH2) group situated para to the position at which the R 12 group is attached to the rest of the molecule.
  • phenyl or 6-membered heteroaryl e.g. pyridine or pyrimidine
  • NR 7 R 10 e.g. an NH2
  • R 4 may independently be selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, and Co-C3-alkylene- R 14; wherein R 14 is selected from C3-C6-cycloalkyl, C3-C6-halocycloalkyl, -phenyl and -pyridyl.
  • R 4 is independently selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, and C0-C3- _
  • R 14 is selected from C3-C6-cycloalkyl and C3-C6-halocycloalkyl. It may be that the group Co-C3-alkylene-R 14 is R 14 .
  • R 4 may be selected from Ci-C6-alkyl (e.g. C2-C4-alkyl) and C3-C6-cycloalkyl (e.g. C3-C4-cycloalkyl).
  • R 4 may be selected from C3-C6- cycloalkyl and C3-C6-halocycloalkyl.
  • R 4 may be C3-C6-cycloalkyl.
  • R 4 is ethyl.
  • R 4 is cyclopropyl.
  • the alkyl, haloalkyl, alkylene, cycloalkyl and halocycloalkyl groups in R 4 may be unsubstituted.
  • R 5 may be independently selected from: H, 0-Ci-C4-alkyl, halo, Ci-C4-alkyl, Ci-C4-haloalkyl and 0-Ci-C4-haloalkyl.
  • R 5 is independently selected from: 0-Ci-C4-alkyl, C1-C4- alkyl, Ci-C4-haloalkyl and 0-Ci-C4-haloalkyl.
  • R 5 may be H.
  • R 5 may be CI or F.
  • R 5 may be methyl.
  • R 5 may be OMe.
  • R 6 is F and R 5 is H. It may be that R 6 is H and R 5 is C1-C4 alkyl, (e.g. Me). It may be that R 6 is F and R 5 is CI.
  • R 4 and R 5 together form an alkylene or heteroalkylene chain of the form -(CR 7 R 7 ) r -W 2 -(CR 7 R 7 ) s -W 3 -(CR 7 R 7 ) t - and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; wherein W 2 and W 3 are each independently selected from: a bond, O, S and NR 15 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W 2 and W 3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms.
  • r, s, t, W 2 and W 3 are chosen such that the total length of the alkylene or heteroalkylene chain is 3 atoms. It may be that r is 0 and W 2 is O.
  • R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form -W 2 -(CR 7 R 7 ) S - .
  • W 2 is attached to the rest of the molecule at the substitution point for R 5 and the CR 7 R 7 at the opposite end of the chain to W 2 is attached to the rest of the molecule at the substitution point for R 4 .
  • s is 2.
  • W 2 is O.
  • R 5 is independently selected from: CI, 0-Ci-C4-alkyl, Ci-C4-alkyl, C1-C4- haloalkyl and 0-Ci-C4-haloalkyl; or R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form -0-(CR 7 R 7 )2- and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively.
  • R 5 is Me and R 4 is cyclopropyl.
  • R 6 may be H.
  • R 6 may be F. It may be that A is O;
  • R 1 is independently selected from: H, NR 7 R 10 , and Ci-C 4 -alkyl;
  • X 1 is CR 5 ;
  • X 2 is CR 6 ;
  • R 4 is independently selected from: Ci-Ce-alkyl, Ci-Ce-haloalkyl, and C0-C3- alkylene-R 14 ; wherein R 14 is selected from C3-C6-cycloalkyl and C3-C6-halocycloalkyl and
  • R 5 is independently selected from: CI, 0-Ci-C 4 alkyl, Ci-C 4 alkyl, Ci-C 4 -haloalkyl and 0-Ci-C 4 - haloalkyl; or R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form - 0-(CR 7 R 7 )2- and which is attached at its respective ends to the substitution point
  • R 1 is H. It may also be that R 5 is Ci-C 4 -alkyl.
  • R 3 may be selected from phenyl, 6- or 9-membered heteroaryl comprising at least one nitrogen and a bicyclic group comprising a phenyl ring fused to a ring selected from 3-7- heterocycloalkyl and C3-C7-cycloalkyl.
  • Y 1 and Y 2 are both C.
  • Y 1 and Y 2 are not both N .
  • Z 1 , Z 2 and Z 3 are each be independently selected from O, S, S(O), NR 8 and CR 9 ;
  • Z 2 is independently selected from O, S, S(O), N R 8 and CR 9 and the ring formed by Y 1 , Y 2 , Z ⁇ Z 2 , Z 3 contains two endocyclic double bonds; and with the further proviso that at least one of Z ⁇ Z 2 and Z 3 is O, S or NR 8 .
  • Z 1 , Z 2 and Z 3 are each independently selected from O, S, N R 8 and CR 9 .
  • 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, N R 8 and CR 9 ; 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 ⁇ Z 2 , Z 3 , Y 1 and Y 2 is O, S, N or NR 8 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, pyrazole or pyrole 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, pyrazole or pyrole ring in which 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 8 and the remaining two of Z 1 , Z 2 and Z 3 are each CR 9 .
  • 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 Z 2 and Z 3 is independently CR 9 and the remaining two of Z 1 , Z 2 and Z 3 are selected from O, S and N R 8 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an oxazole, thiazole, isoxazole or isothiazole ring.
  • the remaining Z 1 , Z 2 or Z 3 is selected from O and S.
  • W is preferably O.
  • R 2 is connected to the ring formed by Y 1 , Y 2 , Z 1 , Z 2 and Z 3 at Z 2 .
  • Z 2 is either NR 2 or CR 2 .
  • Z 2 is CR 2 .
  • A is O; R 1 is H; X 1 is CR 5 ; X 2 is CR 6 ; R 3 is selected from phenyl, 6- or 9- membered heteroaryl comprising at least one nitrogen and a bicyclic group comprising a phenyl ring fused to a ring selected from 3-7-heterocycloalkyl and C3-C7-cycloalkyl; R 4 is independently selected from Ci-C4-alkyl, Ci-C4-haloalkyl, cyclopropyl and halocyclopropyl and R 5 is independently selected from: 0-Ci-C4 alkyl, C1-C4 alkyl; or R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form -0-(CR 7 R 7 )2- and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; both Y 1 and Y 2 are C and Z 1 and Z 3 are selected from O, S and N ;
  • R 2 comprises at least one oxygen atom. It may be that R 2 comprises at least one nitrogen atom. Preferably R 2 comprises at least one oxygen atom and at least one nitrogen atom.
  • R 2 may be Ci-C 3 -alkylene-R 1 1 .
  • R 2 may be Ci-alkylene-R 1 1 .
  • R 2 may be -C(0)R 1 1 .
  • R 2 may be C(R 27 R 27 )R 1 1 , wherein R 27 is independently at each occurrence selected from H and C1-C4 alkyl.
  • R 2 may be CH 2 R 1 1 .
  • R 1 1 may be NR 16 R 17 .
  • R 2 may be NR 16 R 17 .
  • R 16 may be Ci-C 4 -alkyl, e.g. methyl.
  • R 16 and R 17 together with the nitrogen to which they are attached may together form a 5-12- heterocycloalkyl or heteroaromatic group.
  • R 2 may be NR 16 R 17 in which R 16 and R 17 form a 5-i2heterocycloalkyl group which is optionally substituted.
  • R 16 and R 17 may form a 5-7heterocycloalkyl group which is optionally substituted.
  • R 17 may be C(0)R 19 .
  • R 19 may be Ci-C 3 -alkylene-R 20 , e.g. Ci-alkylene-R 20 .
  • R 19 may be -W 4 -R 20 where -W 4 - is Ci-C 3 -alkylene, e.g. Ci-alkylene.
  • R 20 may be NR 22 R 23 .
  • R 22 and R 23 may each be selected from H and Ci-C4-alkyl.
  • R 22 and R 23 may both be H. These embodiments are particularly preferred where R 2 is C(R 27 R 27 )R 11 .
  • -W 4 - may be -CR 28 R 28 -, where R 28 is independently at each occurrence selected from H, Ci-C4-alkyl, and Ci-C4alkylene-R c , or wherein the two R 28 groups together with the carbon atom to which they are attached form a C3-C7-cycloalkyl ring or a 3-7-heterocycloalkyl ring. It may be that R 28 is Ci-C4-alkylene-R c at no more than one occurrence.
  • R 2 may be -CR 27 R 27 N(R 16 )C(0)CR 28 R 28 NR 22 R 23 .
  • R 27 is independently at each occurrence selected from H and Ci-C4-alkyl.
  • R 27 is at each occurrence H.
  • R 16 is H.
  • R 22 and R 23 are each H.
  • R 2 may be -CH 2 NHC(0)CR 28 R 28 NH 2 .
  • R 28 is independently at each occurrence selected from H, Ci-C4-alkyl, and Ci-C4-alkylene-R c , or the two R 28 groups together with the carbon atom to which they are attached form a C3-C7-cycloalkyl ring or a 3- 7-heterocycloalkyl ring.
  • R 2 groups include:
  • R 2 may be -CR 27 R 27 N(R 16 )C(0)R 19 where R 19 is a 3-7-heterocycloalkyl group.
  • R 2 may be -CH2NHC(0)R 19 where R 19 is a 3-7-heterocycloalkyl group.
  • the heterocycloalkyi group may comprise at least one nitrogen atom in the ring.
  • R 2 groups include:
  • R 11 may be a 3-12-heterocycloalkyl group or a heteroaryl group.
  • R 2 may be a 3-12- heterocycloalkyl group or a heteroaryl group.
  • R 11 may be a 3-7-heterocycloalkyl group.
  • R 2 may be a 3-7-heterocycloalkyl group.
  • R 11 may be a 3-7-heterocycloalkyl group comprising nitrogen in the heterocycloalkyi ring.
  • R 2 may be a 3-7-heterocycloalkyl group comprising nitrogen in the heterocycloalkyi ring.
  • R 11 may be a 6-membered heterocycloalkyi group.
  • R 2 ⁇ may be a 6-membered heterocycloalkyi group.
  • R 11 may be a 5-membered heterocycloalkyi group.
  • R 2 may be a 5-membered heterocycloalkyi group.
  • the heterocycloalkyi group may comprise at least one nitrogen atom in the ring. Where the heterocycloalkyi group comprises a nitrogen atom in the ring it may be that the nitrogen atom or one of the nitrogen atoms is the point of connection of R 11 or R 2 to the rest of the molecule. Alternatively, it may be that a carbon atom is the point of connection of R 11 or R 2 to the rest of the molecule.
  • R 1 1 may be a morpholinyl group.
  • R 2 may be a morpholinyl group.
  • R 11 may be
  • R 32 is selected from: cyano, C02R a , Ci-C4-alkyl, C2-C4-alkenyl,
  • R 33 is selected from H and Ci-C4-alkyl; a1 is an integer selected from 0, 1 , 2, 3 or 4. It may be that a1 is 0. It may thus, it may
  • R 11 is , e.g. .
  • R 2 may be wherein R is selected from: cyano, C02R a , Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4- haloalkyl; R 33 is selected from H and Ci-C4-alkyl; a1 is an integer selected from 0, 1 , 2, 3 or It may be that a1 is 0. It may be that R 33 is H. Thus, it may be that R 2 is wherein R is selected from: cyano, C02R a , Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4- haloalkyl; R 33 is selected from H and Ci-C4-alkyl; a1 is an integer selected from 0, 1 , 2, 3 or It may be that a1 is 0. It may be that R 33 is H. Thus, it may be that R
  • R 19 may be a 3-12-heterocycloalkyl group or a heteroaryl group.
  • R 19 may be a 3-12- heterocycloalkyl group optionally substituted with an C02R a group and/or from 0-3 C1-C4- alkyl groups.
  • the compound of formula (I) may be any one of Examples 1 to 106 below.
  • the compound of formula (I) may be selected from:
  • the invention includes compounds as described in the following numbered paragraphs: la (I), or a pharmaceutically acceptable salt or N-oxide thereof:
  • X 1 is independently selected from: N and CR 5 ;
  • X 2 is independently selected from: N and CR 6 ;
  • R 1 is independently selected from: H, F, NR 7 R 10 , NR 7 NR 7 R 10 and Ci-C 4 -alkyl;
  • R 2 is Co-Cs-alkylene-R 11 ;
  • R 3 is independently selected from: H, halo, nitro, cyano, Ci-C 4 -alkyl, 0-Ci-C 4 -alkyl and -W 1 -Co- C3-alkylene-R 12 ; wherein W 1 is selected from a bond, Ci-C3-alkylene, acetylene, -0-, -S(OV (wherein y is an integer selected from 0, 1 and 2), -NR 7 -, -NR 7 S(0) 2 -, -S(0) 2 NR 7 -, -C(0)NR 7 , - NR 7 C(0)-, -OC(O)-, -C(0)0-, -OC(0)NR 7 -, -NR 7 C(0)0 and -NR 7 C(0)NR 7 - ; and wherein R 12 is independently selected from phenyl, monocyclic heteroaryl, monocyclic 3-10 heterocycloalkyl, monocyclic C3-Cio-cycloalkyl and a bicyclic
  • R 4 is independently selected from: d-Cs-alkyl, d-Cs-alkenyl, d-Cs-alkynyl, d-Cs-haloalkyl and Co-C3-alkylene-R 14 ; wherein R 14 is selected from C3-C6-cycloalkyl, 3-6-heterocycloalkyl, C3-C6- halocycloalkyl, -phenyl and -heteroaryl;
  • R 5 is independently selected from: H, O-d-Cs-alkyl, halo, Ci-Cs-alkyl, d-Cs-alkenyl, d-Cs- alkynyl, d-Cs-haloalkyl, O-d-Cs-haloalkyl, C3-C6-cycloalkyl, 3-6-heterocycloalkyl, d-d- halocycloalkyl; or R 4 and R 5 together form an alkylene or heteroalkylene chain of the form - and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; wherein W 2 and W 3 are each independently selected from: a bond, O, S and NR 15 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W 2 and W 3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4
  • R 3 and R 5 together with the carbons to which they are attached, form a 5-7-heterocycloalkyl ring which is optionally substituted with a single R 11 group and/or from 1 to 5 R 13 groups;
  • R 6 is independently selected from: H, d-d-alkyl and halo
  • R 3 and R 6 together with the carbons to which they are attached, form a 5-7heterocycloalkyl ring which is optionally substituted with a single R 11 group and/or from 1 to 5 R 13 groups;
  • R 7 , R 15 , R 16 and R 23 are independently at each occurrence selected from: H and d-d-alkyl; R 7a is independently selected from: H, halogen and d-d-alkyl;
  • R 8 is independently selected from: R 2 , H, d-d-alkyl, and d-d-haloalkyl;
  • R 9 is independently at each occurrence selected from: R 2 , H, halo, nitro, cyano, d-d-alkyl, d- d-alkenyl, d-d-alkynyl and d-d-haloalkyl;
  • R 10 is independently at each occurrence selected from: H, d-d-alkyl, d-d-haloalkyl, S(0)2-Ci- C 4 -alkyl, C(0)-Ci-C 4 -alkyl, C(0)-0-Ci-C 4 -alkyl and CH 2 -phenyl;
  • R 11 is independently selected from: aryl, C3-C7-cycloalkyl, heteroaryl, 3-12-heterocycloalkyl, CN, NR 16 R 17 , OR 18 , SR 18 , C(0)R 19 , S(0) y R 19 (wherein y is 1 or 2) and S(0)(NR 7 )R 19 ;
  • R 17 is independently selected from: H, Ci-C 4 -alkyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C7- cycloalkyl, C(0)R 19 , C(S)R 19 , C(NR 6 )R 19 ; S(0) 2 R 19 ; d-C 3 -alkylene-R 20 ; or R 16 and R 17 , together with the nitrogen to which they are attached together form a 5-12-heterocycloalkyl group or a heteroaromatic group;
  • R 18 is independently selected from Ci-C 4 -alkyl, d-C 4 -alkenyl, d-C 4 -alkynyl, aryl, heteroaryl, 3-7- heterocycloalkyl, d-d-cycloalkyl, C(0)R 21 and Ci-C 4 -alkylene-R 20 ; _
  • R 19 is independently selected from Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, heteroaryl, 3-12- heterocycloalkyl, C 3 -C 7 -cycloalkyl, aryl, NR 22 R 23 , OR 22 , C(0)OR 22 , C(0)NR 22 R 23 , Ci-C 3 -alkylene- R 24 and Ci-C 3 -alkylene-R 20 ;
  • R 20 is independently aryl, heteroaryl, 3-12-heterocycloalkyl, NR 22 R 23 , OR 22 , C(0)OR 22 , C(0)NR 22 R 23 ;
  • R 21 is independently selected from Ci-C4-alkyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C7- cycloalkyl, NR 22 R 23 , Ci-C 3 -alkylene-R 20 ;
  • R 22 is independently selected from H, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, aryl, heteroaryl, 3- 7 -heterocycloalkyl, C3-C 7 -cycloalkyl; or R 22 and R 23 together with the nitrogen atom to which they are attached together form a 5-12-heterocycloalkyl group or heteroaromatic group;
  • R 24 is independently selected from C(0)-Ci-C 3 -alkylene-R 2 ° and S(0) 2 -Ci-C 3 -alkylene-R 20 ;
  • y is independently at each occurrence an integer selected from 1 and 2;
  • R 25 is independently at each occurrence selected from: H, Ci-C4-alkyl, and Ci-C4-haloalkyl;
  • R 26 is independently at each occurrence selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, S(0)2-Ci-
  • Z 1 is selected from S and O.
  • R 5 is independently selected from: H, O-C1-C4 alkyl, halo, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl and O-C1-C4 haloalkyl.
  • R 4 is independently selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, and Co-C3-alkylene-R 14 ; wherein R 14 is selected from: C3-C6- cycloalkyl and C3-C6-halocycloalkyl.
  • R 4 and R 5 together form an alkylene or heteroalkylene chain of the form -(CR 7 R 7 ) r W 2 -(CR 7 R 7 ) s -W 3 -(CR 7 R 7 )r and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; wherein W 2 and W 3 are each independently selected from: a bond, O, S and NR 15 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W 2 and W 3 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms.
  • R 6 is independently selected from: H and F.
  • R 12 is a phenyl group with at least one NR 7 R 10 , CONR 7 R 7 , CR 7 R 7 OR 7 or CR 7 R 7 NR 7 R 10 substituent group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl.
  • R 12 is a 9-membered heteroaryl group comprising 1 , 2 or 3 nitrogen atoms in the ring system. paragraph 12, wherein R 12 may have the structure:
  • ring A is 5- or 6-membered heterocydoalkyi ring or a 5- or 6- membered cycloalkyi ring;
  • a single one of X 3 , X 4 , X 5 and X 6 is a carbon and is the point of attachment of the ring comprising X 3 , X 4 , X 5 and X 6 to the ring comprising X 1 and X 2 ; and the remainder of X 3 , X 4 , X 5 and X 6 are independently selected from N and CR 31 ; R 31 is H or is R 13 ; and a is 0, 1 , 2 or 3 provided that X 3 , X 4 , X 5 , X 6 and a are selected such that R 12 contains no more than three R 13 groups.
  • R 2 is C(R 27 R 27 )R 11 , wherein R 27 is independently at each occurrence selected from H and C1-C4 alkyl.
  • R 17 is C(0)R 19 ; and R 19 is -W 4 -R 20 where -W 4 - is Ci-C3-alkylene.
  • R 20 is NR 22 R 23 and R 22 and R 23 are each be selected from H and Ci-C4-alkyl.
  • a pharmaceutical formulation comprising a compound of any one of paragraphs 1 to 20 and a pharmaceutically acceptable excipient.
  • 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.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • 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 monovalent radical which is a linear or branched hydrocarbon chain.
  • Ci-C6-alkyl may refer to methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, te/f-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 .
  • alkylene refers to a divalent radical which is a linear hydrocarbon chain.
  • Ci-C3-alkylene may refer to -CH2-, -CH2CH2-, or -CH2CH2CH2- or substituted equivalents thereof.
  • the alkylene 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 .
  • a Co-alkylene is a bond.
  • the Co-C m -alkylene could be either a bond or a Ci-C, alkylene.
  • Acetylene refers to the following divalent group:
  • 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.
  • Ci-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
  • 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.
  • C3-C6-cycloalkyl may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be fluorine, OR a or NHR a . _
  • 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.
  • 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 Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • 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
  • 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,
  • heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones.
  • the heteroaryl system itself may be substituted with other groups.
  • the heteroaryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each heteroaryl group independently may be Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • m -nheterocycloalkyl may refer to an m-n membered monocyclic or bicyclic saturated or partially saturated groups comprising 1 or 2 heteroatoms independently selected from 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. the rings are linked to each other two non-adjacent carbon or nitrogen atoms.
  • the heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be fluorine, OR a or NHR a
  • the aryl and heteroaryl groups are optionally substituted with 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR a R a , NR a S(0) 2 R a , NR a CONR a R a , NR a C0 2 R a , OR a ; SR a , S(0)R a , S(0) 2 OR a , S(0) 2 R a , S(0) 2 NR a R a , C0 2 R a C(0)R a , CONR a R a , Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, CrC 4 -haloalkyl, CR a ROR a , CR a R a NR a R a , and CR a R a NR a C(0)R a
  • the compound of formula (I) is an N-oxide
  • it will typically be a pyridine N-oxide, i.e. where the compound of formula (I) comprises a pyridine ring, the nitrogen of that pyridine may be N + -0 " .
  • the compound of the invention is not an N- oxide.
  • the present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXV) 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 11 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 0, 17 0 and 18 0, 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. one or more strains of bacteria that are resistant to one or more approved antibiotics.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-positive bacteria.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram- negative bacteria.
  • the compounds and formulations of the present invention can be used to treat both Gram- positive and Gram-negative bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staphylococcus aureus).
  • the compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, Escherichia coli, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, Helicobacter pylori, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo.
  • the compounds and formulations of the invention may be used to treat infections caused by bacteria that are in the form of a biofilm.
  • compounds of the invention may be used for the prevention and treatment of biofilm infections.
  • Prevention includes prophylaxis, e.g. before or after surgery, and pre-emptive treatment. Treatment covers both empiric therapy, where a biofilm infection is diagnosed but the specific microbial cause is unknown, and definitive therapy based on clinical diagnosis and known aetiology.
  • Antibiotic compounds may be used systemicaHy (oral, intravenous) or topically for the prevention and treatment of biofilm infection.
  • antibiotic compounds may be used to coat the surfaces of objects, e.g. implantable medical devices, to reduce biofilm formation.
  • Antibiotic compounds may be used in the prevention and treatment of biofi!ms on natural or artificial surfaces within the mammalian host body.
  • natural surface biofilm infections are chronic otitis media, chronic sinusitis, dental plaques, endocarditis, cystic fibrosis, urinary tract infection, osteomyelitis and chronic wounds.
  • Artificial surfaces include implantable medical devices such as catheters, cardiac devices and orthopaedic devices.
  • catheters include intravascular catheters (arterial catheters, venous catheters, etc.), dialysis catheters and urethral catheters.
  • Cardiac devices include stents, heart valves, pacemakers, and vascular grafts.
  • orthopaedic devices include joint replacements (knee, hip, etc.), spinal disc replacements, orthopaedic pins, plates, screws and rods.
  • implantable medical devices include endotracheal tubes, nasogastric feeding tubes, gastric feeding tubes, bone grafts, vascular grafts, ureter renal biliary stents, gastric bypass balloons, insulin pumps, neurostimuiators, soft tissue silicone implants, intrauterine contraceptive devices, cochlear implants and voice restoration devices.
  • the term 'resistant' is intended to refer to strains of bacteria that have shown non- susceptibility to one or more known antibacterial drug.
  • a non-susceptible strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a higher number than for corresponding susceptible strains.
  • it may refer to strains that are non-susceptible to ⁇ -lactam antibiotics, strains that are non-susceptible to one or more fluoroquinolones and/or strains that are non-susceptible to one or more other antibiotics (i.e. antibiotics other than ⁇ -lactams and fluoroquinolones).
  • the term 'resistant' may refer to one in which the MIC of a given compound or class of compounds for that strain has shifted to a significantly higher number than for corresponding susceptible strains.
  • a bacterial strain might be said to be resistant to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic failure.
  • the 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.
  • the bacterial strain e.g. the MRSA strain
  • 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 that are resistant to one or more antibiotics, e.g. one or more approved antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-positive bacteria that are resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may _. ⁇
  • the compounds of the invention may be particularly effective at treating infections caused by MRSA and/or methicillin-resistant S. epidermidis.
  • the compounds of the invention may be particularly effective at treating infections caused by strains of Staphylococcus aureus and/or S. epidermidis that are resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by MRSA and/or methicillin-resistant S. epidermidis that is also resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria that are resistant to one or more antibiotics, e.g. one or more approved antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria which are resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp.
  • pathogens are all fastidious Gram-negative organisms.
  • a fastidious bacterium is one having a complex nutritional requirement, i.e. one that will only grow when specific nutrients are included in the culture medium.
  • 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 that can be treated include secondary infections that 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 that is resistant to at least one approved antibacterial drug, e.g. at least one approved ⁇ -lactam drug.
  • the compounds of the invention can be used to treat or prevent mycobacterial infections, e.g. mycobacterial infections caused by strains of mycobacteria that are resistant to approved mycobacterials. Thus, they can be used to treat TB or leprosy.
  • the compounds may be used to treat resistant strains of TB, e.g. MDR-TB (i.e. TB infections caused by strains that are resistant to isoniazid and rifampicin), XDR-TB (i.e. TB infections caused by strains that are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin) and/or TDR-TB (i.e. TB infections caused by strains that have proved resistant to every drug tested against it with the exception of a compound of the invention).
  • MDR-TB i.e. TB infections caused by strains that are resistant to isoniazid and rifampicin
  • the compounds of the invention can be used to treat infections caused by obligate anaeoric bacteria, e.g. resistant strains of obligate anaerobic bacteria.
  • the bacterial infection may be caused by a bacterium selected from: Bacteroides spp., Bifidobacterium spp. Clostridium spp., Eubacterium spp., Finegoldia spp., Fusobacterium spp., Parvimonas spp., Peptoniphilus spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Propionibacterium spp. and Veillonella spp.
  • the bacterial infection may be caused by a bacterium selected from: Bacteroides spp., Bifidobacterium spp. Clostridium spp., Eubacterium spp., Fusobacterium spp., Parvimonas spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Propionibacterium spp. and Veillonella spp.
  • Bacteroides spp. Bacteroides spp., Bifidobacterium spp. Clostridium spp., Eubacterium spp., Fusobacterium spp., Parvimonas spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Propionibacterium spp. and Veillonella spp.
  • the bacterial infection may be caused by a bacterium selected from: Bacteroides spp., Clostridium spp., Finegoldia spp., Parvimonas spp., Peptoniphilus spp., Peptostreptococcus spp., Prevotella spp. and Propionibacterium spp.
  • the bacterial infection may be caused by a bacterium selected from: Bacteroides spp., Clostridium spp., Peptostreptococcus spp., Prevotella spp. and Propionibacterium spp.
  • the infection may be caused, at least in part by, Clostridium spp.
  • the bacterial infection may be caused, at least in part, by Clostridium difficile.
  • the compounds of the invention may be used to treat Clostridium difficile associated disease (CDAD).
  • CDAD Clostridium difficile associated disease
  • the compounds may be used to treat Clostridia spp., e.g. Clostridium difficile, including those resistant to other approved antibiotics.
  • the compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains which are category A pathogens as identified by the US government (e.g. those which cause anthrax, plague etc.) and/or they may be strains which are category B pathogens as identified by the US government (e.g. those which cause Glanders disease, mellioidosis etc).
  • 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 compounds of the present invention may also be used in treating other conditions treatable by eliminating or reducing a bacterial infection. In this case they will act in a secondary manner alongside for example a chemotherapeutic agent used in the treatment of cancer.
  • the compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, 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. Also included are acid
  • 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. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( 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 or with antibiotic potentiators, such as efflux pump inhibitors.
  • active compounds e.g. antifungal compounds, oncology compounds
  • antibiotic potentiators such as efflux pump inhibitors.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • BOP benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
  • DMSO dimethyl sulfoxide
  • dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
  • EA ethyl acetate
  • FBS Foetal Bovine Serum
  • Fmoc fluorenylmethylcarbonate
  • HATU 1-[bis(dimethylamino)methylene]-1 /-/-
  • I PA Isopropanol MCPBA - metachloroperoxybenzoic acid
  • TBHP te/f-Butyl hydroperoxide
  • TFA trifluoroacetic acid
  • Certain compounds of the invention may be made according to or analogously to the synthetic Schemes A-AB. Throughout Schemes A-AB, W represents a halogen. Certain compounds of the invention can be made according to or analogously to the methods described in examples 1 to 43. Certain compounds of the invention can be made analogously to the methods described in PCT/GB2015/051 107 (WO2015/155549).
  • Amine (1) can be converted into a-keto-amide (2) using chloral hydrate (e.g. in the presence of HCI and Na2S0 4 in H2O followed by NH2OH.HCI).
  • a-Keto-amide can subsequently alkylated with R 4 W in the presence of a base (e.g. K2CO3 optionally with heating) to form a-keto-amide (3).
  • a-Keto-amide (3) can alternatively be made from amine (4) via a reaction with oxalyl chloride (e.g. in DCM optionally with heating) followed by a ring closing Friedel-Crafts reaction (e.g. with AlC optionally at 0°C).
  • Key intermediate (5) can be obtained from amide (3) by reaction with H2O2 and aq. NaOH (e.g. at room temperature).
  • the amide can be made for example by treatment with thionyl chloride and DMF in THF (optionally with heating) to form the acid chloride and subsequent reaction with ammonia gas (e.g. in THF at 0°C) and the dehydration can be achieved by treating the amide with P2O5 (optionally at room temperature initially and then heating to 75°C).
  • Carbamate formation e.g. using CIC(0)OEt with NaHCC>3 in 2-butanone
  • Cyclisation with a hydrazide (7a) e.g.
  • Acid amine (5) can be converted into diamine (10) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by 3 ⁇ 4uOH and treating the product with TFA).
  • a condensation reaction e.g. using EtOH as a solvent optionally with heating
  • an appropriate a-ester-aldehyde e.g. EtOaCCHO
  • Triazole (12) can be prepared from intermediate (1 1) by reacting with H2O2 and aq. NaOH and then with POC in DCM followed by hydrazine displacement of the resultant halide (e.g. in EtOH).
  • the resultant hydrazide product can be converted into triazole (12) by reaction with orthoester (11 a) (e.g. by heating in an inert solvent, such as toluene).
  • Triazole (12) can then be converted into 1 ,2,4-triazole (13) (a subset of compounds of formula (I)).
  • R 3 aryl or heteroaryl
  • this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Intermediate (5) can be acetylated (e.g. with AcCI, EhN optionally in dioxane at room temperature).
  • Acid (14) can be converted into amine (15) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by 3 ⁇ 4uOH and treating the product with TFA).
  • Diazotisation reaction e.g. with HCI and NaNC>2 optionally in EtOH at 0- 5 °C
  • reaction with ethyl-2-chloroacetoacetate e.g. in the presence of NaOAc
  • hydrazonoyl hydrochloride (16) which on treatment with an oxime (16a) (e.g.
  • Addition of ethyldiazoacetate (e.g. with Et2NH and EtOH) to intermediate (3) can provide alcohol (21) which, upon treatment with a Lewis acid and 'BuOH (e.g. BF3.0Et2 in acetonitrile and 3 ⁇ 4uOH optionally at room temperature) can ring open to form alkyne (22).
  • a Lewis acid and 'BuOH e.g. BF3.0Et2 in acetonitrile and 3 ⁇ 4uOH optionally at room temperature
  • 1 ,3-dipolar cycloaddition with a substituted azide (22a) e.g. with heating in toluene
  • triazole (23) can cyclise to form tricycle (24).
  • Tricycle (24) can then finally be converted into 1 ,2,3- triazole (25) (a subset of compounds of formula (XXVIII)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Reaction of urea with intermediate (5) can provide bicycle (26).
  • Treatment with Lawesson's reagent e.g. in dioxane
  • subsequent methylation e.g. by heating with Mel in acetone
  • thiane 28
  • Displacement of the SMe group with hydrazide e.g. by heating in EtOH
  • hydrazide 219
  • an orthoester 11 a
  • an inert solvent such as toluene
  • Triazole (30) can then be converted into 1 ,2,4-triazole (31) (a subset of compounds of formula (I)).
  • R 3 aryl or heteroaryl
  • this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Amine (32) can be obtained from intermediate (4).
  • R 3 aryl or heteroaryl
  • this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Bromination e.g. using B3 ⁇ 4 in CH3COOH and sodium acetate optionally at room temperature
  • bromide (33) can provide bromide (33).
  • Subsequent acylation with an appropriate acylating agent (33a) e.g. the acid chloride, exemplary conditions being with ⁇ optionally in THF with heating
  • amide (34) amide
  • a intramolecular cross- coupling reaction e.g. using CU2O, 4,7-dimethoxy-1 , 10-phenanthroline, CS2CO3, PEG, n- PrCN, ⁇
  • imidazole (35) a subset of compounds of formula (I)
  • Intermediate (10) can be converted into chloride (37) by treatment with oxalyl chloride (e.g. in DCM at room temperature) followed by treatment with POC (optionally with heat).
  • Chloride displacement with an amino ⁇ -ketone (37a) can provide ketone (38) which in the presence of acid (e.g. tosic acid in isopropyl alcohol) can cyclise to form imidazole (39).
  • Imidazole (39) can then be converted into imidazole (40) (a subset of compounds of formula (XV)).
  • Intermediate (5) can be converted to enol (41) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl nitroacetate (e,g. heating with EtzN in THF).
  • Enol (41) can be converted into diamine (44) by chlorination (e.g. by heating with POCb) followed by displacement of the resultant chlorine with a protected amine (e.g. 4-methoxybenzylamine optionally in DMF at room temperature).
  • Reduction of the nitro group e.g. by heating with NaHSC in EtOH and H2O
  • alkylation with R 8 W e.g.
  • Intermediate (5) can be converted into bicycle (47) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl 2-(benzyloxy)acetate (e.g. by heating with EtzN in THF).
  • phosgene e.g. in THF at room temperature
  • ethyl 2-(benzyloxy)acetate e.g. by heating with EtzN in THF.
  • a similar chlorination, amination, deprotection sequence to that used in Scheme I above can generate amine (49).
  • the benzyl protecting group of amine (49) can be removed (e.g. using Pd/C and H2 in MeOH at room temperature) to provide aminoenol (50) which can be converted into the oxazole (51) by reaction with an orthoester (11 a) (e.g. by heating in an inert solvent, such as toluene).
  • Oxazole (51) can be converted into oxazole (52) (a subset of compounds of formula (XI)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Boc protection of amine (33) can provide carbamate (59).
  • a sequential palladium coupling of intermediate (59) to bis(pinacolato)diboron e.g. using Pd(dppf)Cl2 and KOAc in 1 ,4 dioxane at 80°C
  • a substituted Boc-protected 4-bromo-1 H-pyrazole-5- carboxylic acid ethyl ester 60a
  • Boc deprotection e.g.
  • Intermediate (5) can be converted into ⁇ -ketoamide (64) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl 3-(benzyloxy)propanoate (e.g with heating in DMF following deprotonation of ethyl 3-(benzyloxy)propanoate with NaH).
  • ⁇ -Ketoamide (64) can be converted into ⁇ -ketoamide (65).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Removal of the benzyl protecting group e.g. using Pd/C and H2 optionally in MeOH at room temperature
  • oxidation e.g. using Dess-Martin Periodinane in DCM at room temperature
  • sequential addition of a nucleophile, such as R 9 MgBr e.g. in THF
  • R 9 MgBr e.g. in THF
  • Example 3 step (a) can be converted into a substituted oxazole (70) by treating with an orthoester (1 1 a) (e.g. by heating in an inert solvent, such as toluene). This then can be converted into a substituted oxazole (71) (a subset of compounds of formulae (VII) ).
  • R 3 aryl or heteroaryl
  • this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Amide coupling of an N-Boc protected amino acid (73) with compound (72) may give amide (74) which can be converted into oxazole (75).
  • R 3 aryl or heteroaryl
  • this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Standard Boc deprotection conditions e.g. with TFA in CH2CI2 at room temperature
  • (75) can deliver (76) (a subset of compounds of formula (XXXI)).
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Intermediate (4) can be converted into iodide (99) (e.g. by treating with iodine and NaHC03 optionally in EtOAc at room temperature).
  • Acylation with an acid chloride (100) e.g. using ⁇ in THF at room temperature
  • amide (101) which, following an intramolecular Heck reaction (e.g. by heating amide (101) with Pd(PP i3) 4 and EtzN in acetonitrile) can give tricycle (102).
  • Tricycle (102) can be converted into tricycle (103) (e.g.
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3- C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Reaction of fluoride (108) with NHR 4 can provide amine (109) (e.g by heating in DMSO).
  • amine (109) e.g by heating in DMSO
  • Acylation of amine (109) with acyl chloride (1 10) e.g. using EtzN in THF at room temperature
  • amide (1 1 1) which upon deprotection (e.g. using TFA in DCM at room temperature) can give pyrrole (1 12).
  • An addition-elimination cyclisation reaction e.g. by heating pyrrole (1 12) with K2CO3 in DMSO
  • Tricycle (1 13) can be converted into tricycle (1 14) by reduction of the nitro group (e.g.
  • Cio heterocycloalkyl this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Amide (1 17) can, for example, be converted to thioamide (1 18) by heating with P2S5 in pyridine.
  • Amide (1 17) can, for example, be converted to amidine (1 19) by heating with POC and heating the product with the primary amine NH2R 7 .
  • Amide (1 17) can, for example, be converted to oxime (120) by heating with POC and heating the product with the O-substituted hydroxylamine NH2OR 6 .
  • NMR spectra were obtained on a Bruker AV1 500 using a 5 mm QNP probe (Method A) or Bruker AVI 11 400 Nanobay using a 5 mm BBFO with z-gradients (Method B).
  • MS was carried out on a Waters ZQ MS (Method A and B) or ACQ-SQD2#LCA081 (Method C) using H 2 0 and ACN (0.1-0.05% formic acid - high pH; 0.05% ammonia - low pH). Wavelengths were 254 and 210 nm.
  • Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) Waters 2767 Sample Manager (Method B) using H 2 0 and ACN (0.1-0.05% formic acid high pH; 0.05% ammonia - low pH)
  • Preparative HPLC was performed using column: XBridgeTM prep C18 5 ⁇ OBD 19 mm. Flow rate: 20 mL/min.
  • Oxalyl chloride (30 ⁇ _, 0.31 mmol) was added to a stirred solution of monoethyl malonic acid (40 ⁇ _, 0.30 mmol) in dry DCM (2 mL) under N 2 at 0°C. DMF (1 drop) was added and the solution was stirred for 1 h at 0°C.
  • the reaction mixture was diluted with DCM (20 mL) and washed with 1 N HCI (20 mL) then H2O (2 x 20 mL).
  • the organic phase was then passed through a phase separator and concentrated in vacuo to give the crude product.
  • the crude product was purified by column chromatography using 100% EtOAc as the eluent.
  • the product containing fractions were combined and concentrated to give ethyl 3-[(7-bromo-5- cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl)methylamino]-3-oxo-propanoate (60 mg, 56 % yield) as a yellow oil.
  • the crude reaction product was purified by reverse phase column chromatography using a gradient of 20-60 % ACN in H 2 0 as the eluent to give 2-[[7-(4-amino-2,5-difluoro-phenyl)-5- cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl]methylamino]-2-oxo-acetic acid (8 mg, 16 % yield) as a white solid.
  • the reaction was left to stir for 1 h at -78°C, then 7 h at 0°C.
  • the reaction was then separated between DCM (20 mL) and H2O (20 mL).
  • the organic layer was then washed with H2O (3 x 20 mL), dried with MgSCU, filtered and concentrated under reduced pressure.
  • the crude reaction product was purified by column chromatography using a gradient of 0-80 % EtOAc in DCM as the eluent.
  • the crude reaction product was purified by flash silica chromatography using a gradient of 0-5 % methanolic ammonia (1 N) in DCM as eluent. The solvent was removed from fractions containing the desired product to afford methyl (2S)-1- [(7-bromo-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl)methyl]pyrrolidine-2- carboxylate (20 mg, 64 % yield) as a pale brown solid.
  • Example 36 1 -rr7-(4-amino-2,5-difluoro-phenyl)-5-cvclopropyl-6-methyl-4-oxo- oxazolor4,5-c1quinolin-2-yl1methyllpiperazine-2-carboxylate; triethylammonium
  • the aq. layer was neutralized to pH 7 using 1 M HCI, and was then extracted with DCM (3 x 5 mL). The combined organic layers were dried using a hydrophobic frit and the solvent removed in vacuo to give the desired product as a white solid, which was used immediately in the next step.
  • the reaction mixture was diluted with DCM (10 mL) and washed with sat. aq. NaHC0 3 (10 mL) and brine (10 mL).
  • the organic layer was dried using a hydrophobic frit, and the solvent removed in vacuo.
  • the resulting residue was purified by flash chromatography using a gradient of 0-10% MeOH in DCM. The fractions containing the desired product were collected and concentrated in vacuo.

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Abstract

La présente invention concerne des composés médicamenteux antibactériens et antimycobactériens de formule (I). L'invention concerne également des formulations pharmaceutiques de composés médicamenteux antibactériens de formule (I). L'invention concerne également des utilisations des dérivés dans le traitement d'infections bactériennes et des méthodes de traitement d'infections bactériennes. Les composés sont particulièrement utiles pour le traitement d'infections bactériennes ayant développé une résistance à d'autres composés médicamenteux, par exemple des souches résistantes de S. aureus.
PCT/GB2016/052899 2015-09-18 2016-09-16 Composés antibactériens WO2017046606A1 (fr)

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GBGB1516613.5A GB201516613D0 (en) 2015-09-18 2015-09-18 Antibacterial compounds
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GBGB1613866.1A GB201613866D0 (en) 2016-08-12 2016-08-12 Antibacterial compounds

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Citations (10)

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Publication number Priority date Publication date Assignee Title
JP2006045118A (ja) * 2004-08-04 2006-02-16 Mochida Pharmaceut Co Ltd 新規ピラゾロキノロン誘導体
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
CN103012397A (zh) * 2011-09-26 2013-04-03 赛诺菲 吡唑并喹啉酮衍生物、其制备方法及其治疗用途
US20130143907A1 (en) * 2011-10-07 2013-06-06 Eisai R&D Management Co., Ltd. Pyrazoloquinoline derivatives
EP2615096A1 (fr) * 2010-09-07 2013-07-17 Astellas Pharma Inc. Composé quinoxaline
US20140275023A1 (en) * 2013-03-12 2014-09-18 Arqule, Inc. Substituted Tricyclic Pyrazolo-Pyrimidine Compounds
WO2014154586A1 (fr) * 2013-03-25 2014-10-02 Sanofi Dérivés de pyrazolonaphthyridinone servant d'inhibiteurs de metap2 (methionine aminopeptidase de type-2)
CA2904820A1 (fr) * 2013-04-05 2014-10-09 Eisai R&D Management Co., Ltd. Compose de pyridinylpyrazoloquinoline
WO2015155549A1 (fr) * 2014-04-10 2015-10-15 Redx Pharma Plc Composés antibactériens
WO2016024096A1 (fr) * 2014-08-11 2016-02-18 Redx Pharma Plc Composés antibactériens

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006045118A (ja) * 2004-08-04 2006-02-16 Mochida Pharmaceut Co Ltd 新規ピラゾロキノロン誘導体
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
EP2615096A1 (fr) * 2010-09-07 2013-07-17 Astellas Pharma Inc. Composé quinoxaline
CN103012397A (zh) * 2011-09-26 2013-04-03 赛诺菲 吡唑并喹啉酮衍生物、其制备方法及其治疗用途
US20130143907A1 (en) * 2011-10-07 2013-06-06 Eisai R&D Management Co., Ltd. Pyrazoloquinoline derivatives
US20140275023A1 (en) * 2013-03-12 2014-09-18 Arqule, Inc. Substituted Tricyclic Pyrazolo-Pyrimidine Compounds
WO2014154586A1 (fr) * 2013-03-25 2014-10-02 Sanofi Dérivés de pyrazolonaphthyridinone servant d'inhibiteurs de metap2 (methionine aminopeptidase de type-2)
CA2904820A1 (fr) * 2013-04-05 2014-10-09 Eisai R&D Management Co., Ltd. Compose de pyridinylpyrazoloquinoline
WO2015155549A1 (fr) * 2014-04-10 2015-10-15 Redx Pharma Plc Composés antibactériens
WO2016024096A1 (fr) * 2014-08-11 2016-02-18 Redx Pharma Plc Composés antibactériens

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DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 3 April 2013 (2013-04-03), "Pyrazolo-quinolinone derivatives, and their preparation method and the therapeutic application thereof Pyrazoloquinolinone derivatives, preparation thereof and therapeutic use thereof", XP002763169, retrieved from STN Database accession no. 2013:530177 *

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