WO2017046605A1 - Composés antibactériens - Google Patents

Composés antibactériens Download PDF

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Publication number
WO2017046605A1
WO2017046605A1 PCT/GB2016/052898 GB2016052898W WO2017046605A1 WO 2017046605 A1 WO2017046605 A1 WO 2017046605A1 GB 2016052898 W GB2016052898 W GB 2016052898W WO 2017046605 A1 WO2017046605 A1 WO 2017046605A1
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compound
alkyl
ring
independently
alkylene
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PCT/GB2016/052898
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English (en)
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Anthony Huxley
Ralph KIRK
Andrew Ratcliffe
David LYTH
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Redx Pharma Plc
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Publication of WO2017046605A1 publication Critical patent/WO2017046605A1/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
    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • This invention relates to antibacterial and anti-mycobacterial 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
  • 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 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.
  • a strain of TB is resistant to isoniazid and rifampicin as well as one fluoroquinolone and one of the injectable anti-TB drugs, it is known as extensively drug resistant (XDR-TB).
  • MDR-TB and XDR-TB are often found in those who have been previously treated for TB, but these forms of TB are just as infectious as wild- type TB and the incidence of MDR-TB and XDR-TB around the world is increasing.
  • 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
  • SUBSTITUTE SHEET RULE 26 certain embodiments of this invention to provide compounds that have activity that is comparable to those of existing antibiotics, and ideally that is better. It is an aim of certain embodiments of this invention to provide such activity against wild-type strains at the same time as providing activity against one or more resistant strains.
  • the invention provides a compound of formula (I), or a pharmaceutically
  • ring A is 5- or 6- membered heterocycloalkyl ring or a 5- or 6- membered cycloalkyl ring;
  • X 1 is independently selected from: N and CR 5 ;
  • X 2 is independently selected from: N and CR 6 ;
  • 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 7 ;
  • R 1 is independently selected from: H, F, NR 8 R 1 1 , NR 8 NR 8 R 1 1 and Ci-C 4 -alkyl;
  • R 2 is independently selected from: d-Cs-alkyl, d-Cs-alkenyl, d-Cs-alkynyl, d-Cs-haloalkyl, and Co-C3-alkylene-R 12 ; wherein R 12 is independently selected from: C3-C6-cycloalkyl, 3-6- heterocycloalkyl, C3-C6-halocycloalkyl, phenyl and heteroaryl;
  • R 4 is absent or is C 0 -C 3 -alkylene-NR 13 R 14 ;
  • ring A is a 5- or 6-membered heterocycloalkyl ring comprising at least one nitrogen atom in the ring, the or each nitrogen atom will be an NR 14 group;
  • R 5 is independently selected from: H, O-d-Ce-alkyl, halo, d-Cs-alkyl, C 2 -Cs-alkenyl, C 2 -Cs- alkynyl, d-Cs-haloalkyl, O-d-Cs-haloalkyl, d-ds-cycloalkyl, C3-C6-heterocycloalkyl, C3-C6- halocycloalkyl; or R 2 and R 5 together form an alkylene or heteroalkylene chain of the form - (CR 8 R 8 )rW 1 -(CR 8 R 8 )s-W 2 -(CR 8 R 8 )t- and which is attached at its respective ends to the substitution point for R 2 and R 5 respectively; wherein W 1 and W 2 are each independently selected from: a bond, O, S and N R 15 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein
  • R 6 is independently selected from: H, Ci-C 4 -alkyl and halo;
  • R 7 is independently at each occurrence selected from: H, halo, nitro, cyano, NR 8 R 8 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C0 2 R 8 , OR 8 ; SR 8 , SOR 8 , S(0) 2 OR 8 , S(0) 2 R 8 , S(0) 2 NR 8 R 8 , C0 2 R 8 , C(0)R 8 , C0NR 8 R 8 , d-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, d-C 4 -haloalkyl, d-C 4 - alkylene-OR 8 and d-C 4 -alkylene-NR 8 R 1 1 ;
  • R 8 , R 13 , R 15 , R 16 and R 21 are independently at each occurrence selected from: H and d-C 4 - alkyl;
  • R 9 is independently selected from: H, Ci-C4-alkyl, and Ci-C4-haloalkyl;
  • R 10 may be independently at each occurrence selected from: H, halo, nitro, cyano, NR 16 R 17 , NR 16 S(0) 2 R 16 , NR 16 CONR 16 R 16 , NR 16 C0 2 R 16 , OR 16 ; SR 16 , SOR 16 , S0 3 R 16 , S0 2 R 16 , S0 2 NR 16 R 16 C0 2 R 16 C(0)R 16 , CONR 16 R 16 , Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 - haloalkyl, CR 16 R 16 OR 16 , CR 16 R 16 OC(0)R 16 and CR 16 R 16 NR 16 R 17 ;
  • R 11 and R 17 are each independently at each occurrence selected from: H, Ci-C 4 -alkyl, S(0) 2 -
  • Ci-C -alkyl C(0)-Ci-C -alkyl, C(0)-0-Ci-C -alkyl, CH 2 -aryl and CH 2 -heteroaryl;
  • R 14 is independently selected from H, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C 3 -C 7 -cycloalkyl, C(S)R 18 , C(0)R 18 , C(NH)R 18 , S(0) 2 R 18 and
  • Ci-C 4 -alkylene-R 19 Ci-C 4 -alkylene-R 19 ;
  • R 18 is Co-C 4 -alkylene-R 19 ;
  • R 19 is independently aryl, heteroaryl, 3 -i 2 -heterocycloalkyl, NR 20 R 21 , OR 20 , C(0)OR 20 , C(O)NR 20 R 21 ;
  • R 20 is independently selected from H, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, aryl, heteroaryl, 3-7-heterocycloalkyl, C3-C 7 -cycloalkyl; or R 20 and R 21 together with the nitrogen atom to which they are attached together form a ⁇ -heterocyclic or heteroaromatic group; a is an integer independently selected from 0, 1 , 2 and 3; and
  • ula (I) is a compound of formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 6 , X 1 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , a and ring A are as defined above for formula (I). It may be that Z 1 , Z 2 and Z 3 are selected such that the 5-membered ring which comprises Z 1 , Z 2 and Z 3 is an oxazole, thiazole, isoxazole or thioxazole ring.
  • the compound of formula (I) is a compound of formula (III):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , X 3 , X 4 , X 5 , X 6 , ring A and a are as defined above for formula (I) and wherein Z 1 is selected from S and O.
  • the compound of formula (I) is a compound of formula (IV):
  • the compound of formula (I) is a compound of formula
  • (I) is a compound of formula (VI):
  • R ⁇ R 2 , R 3 , R 6 , Z ⁇ Z 2 , Z 3 , X 1 , X 3 , X 4 , X 5 and X 6 are as defined above for formula (I); and wherein V 1 and b are as defined above for formula (V). It may be that X 3 , X 4 , X 5 and X 6 are each CR 7 . It may be that Z 1 , Z 2 and Z 3 are selected such that the 5-membered ring which comprises Z 1 , Z 2 and Z 3 is an oxazole, thiazole, isoxazole or thioxazole ring.
  • the compound of formula (I) is a compound of formula (VII):
  • the compound of formula (I) has a structure according to any
  • R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , W, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , ring A, A and a are as defined above for formula (I) .
  • X 1 may be N .
  • X 1 may be CR 5 .
  • X 2 may be N .
  • X 2 is CR 6 .
  • R 1 is independently selected from: H , N R 8 R 1 1 , and Ci-C4-alkyl.
  • R 1 may be H .
  • R 1 may be N R 8 R 1 1 , e.g. N H R 1 1 .
  • R 1 may be CrC 4 -alkyl, e.g. methyl.
  • R 2 may be selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, and Co-C3-alkylene-R 12 ; wherein R 12 is selected from: C3-C6-cycloalkyl and C3-C6-halocycloalkyl.
  • R 2 may be selected from: C1-C6 alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl and C3-C6-halocycloalkyl.
  • R 2 may be selected from: Ci-C6-alkyl, Co-C3-alkylene-R 12 ; wherein R 12 is C3-C6-cycloalkyl.
  • R 2 may be selected from: Ci-C6-haloalkyl, and Co-C3-alkylene-R 12 ; wherein R 12 is C3-C6-halocycloalkyl.
  • R 2 may be selected from: Ci-C6-alkyl (e.g. C2-C 4 -alkyl) and C3-C6-cycloalkyl (e.g. C3-C 4 - cycloalkyl).
  • R 2 may be selected from C3-C6-cycloalkyl and C3-C6-halocycloalkyl.
  • R 2 may be C3-C6-cycloalkyl.
  • R 2 is ethyl. In certain other particular
  • R 2 is cyclopropyl.
  • R 2 may be Co-C3-alkylene-R 12 wherein R 12 is C3-C6 cycloalkyl.
  • R 3 may be selected from oxo, Ci-C4-alkyl and NR 8 R 11 wherein Ci-C4-alkyl is optionally substituted by C0 2 R a .
  • 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 5 may be C1-C4 alkyl, e.g. Me.
  • R 6 is F and R 5 is H. It may be that R 6 is H and R 5 is Ci-C 4 -alkyl, (e.g. Me). It may be that R 6 is F and R 5 is CI.
  • R 2 and R 5 together form an alkylene or heteroalkylene chain of the form -(CR ⁇ W ⁇ CR ⁇ W CR ⁇ and which is attached at its respective ends to the substitution point for R 2 and R 5 respectively; wherein W 1 and W 2 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 1 and W 2 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms.
  • r, s, t, W 1 and W 2 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 1 is O.
  • R 2 and R 5 may together form an alkylene or heteroalkylene chain of the form -W 1 -(CR 8 R 8 ) S -.
  • W 1 is attached to the rest of the molecule at the substitution point for R 5 and the CR 8 R 8 at the opposite end of the chain to W 1 is attached to the rest of the molecule at the substitution point for R 2 .
  • s is 2.
  • W 1 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 2 and R 5 may together form an alkylene or heteroalkylene chain of the form -0-(CR 8 R 8 )2- and which is attached at its respective ends to the substitution point for R 2 and R 5 respectively.
  • R 5 is Me and R 2 is cyclopropyl.
  • R 6 may be independently selected from: H and F.
  • R 6 may be H.
  • R 6 may be halo, e.g. F.
  • ring A has an NR 14 group, either in the ring or as a substituent.
  • ring A is heterocycloalkyi group comprising an NR 14 group in the ring or that ring A is substituted with an R 4 group, R 4 being Co-C3-alkylene-NR 13 R 14 .
  • 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 ring.
  • Ring A may be a 6-membered heterocycloalkyi ring comprising two heteroatoms in the ring. attached, may have the structure:
  • Ring A may be a 6-membered heterocycloalkyi ring comprising at least one nitrogen atom in is attached, may have the structure:
  • ring A is a heterocyclic ring comprising two heteroatoms in the ring, it may be that at least one of the two heteroatoms is a nitrogen. It may be that ring A is a 6-membered ring comprising a carbamate group, the N and O of the carbamate being in the ring. s attached, may have the structure:
  • R 24 is selected from H, Ci-
  • ring A together with the ring to which it is attached, may have
  • R 14 may be H.
  • R 24 may be selected from H and Ci-C4-alkyl.
  • R 24 may be selected from H and Me.
  • R 24 may be at each occurrence Me.
  • ring A is a 5-membered cycloalkyi ring or a 5-membered heterocycloalkyi ring. It may be that ring A has an NR 14 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 14 group in the ring or that ring A is substituted with an R 4 group, R 4 being Co-C3-alkylene-NR 13 R 14 .
  • ring A, togeth it is attached may have the structure:
  • V 1 is selected from NR 14 and
  • R 23 is independently selected from H, C0 2 R 8 , C(0)R 8 , CONR 8 R 8 , Ci- C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C -alkynyl, Ci-C -haloalkyl, Ci-C -alkylene-OR 8 , Ci-C -alkylene- NR 8 R 11 ; and wherein b is an integer selected from 0, 1 and 2. a may be 0. Thus, b may be 0.
  • V 1 may be NR 14 .
  • V 1 may be CR 23 NR 13 R 14 .
  • R 13 may be H.
  • R 23 may be selected from H and C0 2 R 8 .
  • R 14 may be
  • R 14 may be selected from C(S)R 18 , C(0)R 18 , C(NH)R 18 , S(0) 2 R 18 and Ci-C 4 -alkylene-R 19 .
  • X 4 is a carbon and is the point of attachment to the ring comprising X 1 and X 2 .
  • X 3 may be N.
  • X 3 may be CR 7 , e.g. CR 7a ; wherein R 7a is independently at each occurrence selected from: H, halo, nitro, cyano, NR 8 R 8 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C0 2 R 8 , OR 8 ;
  • SUBSTITUTE SHEET RULE 26 SR 8 , SOR 8 , S(0) 2 OR 8 , S(0) 2 R 8 , S(0) 2 NR 8 R 8 , C0 2 R 8 , C(0)R 8 , CONR 8 R 8 , Ci-C 4 -alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl, CR 8 R 8 OR 8 and CR 8 R 8 NR 8 R 11 . It may be that R 7a is selected from: H, halo or Ci-C 4 -alkyl. It may be that R 7a is H. It may be that R 7a is selected from: halo or Ci-C 4 -alkyl.
  • X 5 may be N.
  • X 5 may be CR 7 , e.g. CR 7b ; wherein R 7b is independently at each occurrence selected from: H, halo, nitro, cyano, NR 8 R 8 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C0 2 R 8 , OR 8 ; SR 8 , SOR 8 , S(0) 2 OR 8 , S(0) 2 R 8 , S(0) 2 NR 8 R 8 , C0 2 R 8 , C(0)R 8 , CONR 8 R 8 , Ci-C 4 -alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl, CR 8 R 8 OR 8 and CR 8 R 8 NR 8 R 11 .
  • R 7b is selected from: H, halo or Ci-C 4 -alkyl. It may be that R 7b is
  • X 6 may be N.
  • X 6 may be CR 7 , e.g. CR 7c ; wherein R 7c is independently at each occurrence selected from: H, halo, nitro, cyano, NR 8 R 8 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C0 2 R 8 , OR 8 ; SR 8 , SOR 8 , S(0) 2 OR 8 , S(0) 2 R 8 , S(0) 2 NR 8 R 8 , C0 2 R 8 , C(0)R 8 , CONR 8 R 8 , d-C 4 -alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl, CR 8 R 8 OR 8 and CR 8 R 8 NR 8 R 11 . It may be that R 7c is selected from: H, halo or Ci-C 4 -alkyl. It may be that R
  • R 7 is independently selected from: H, halo or Ci-C 4 -alkyl. It may be that R 7 is at each occurrence H.
  • X 3 , X 5 and X 6 are each CR 7 .
  • X 3 , X 5 and X 6 are each CH.
  • A is O; R 1 is independently selected from: H, NR 8 R 11 , and Ci-C -alkyl; X 1 is CR 5 ; X 2 is CR 6 ; R 2 is independently selected from Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, -(CR 8 R 8 ) n - C3-C6-cycloalkyl and -(CR 8 R 8 ) n -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 2 and R 5 may together form an alkylene or heteroalkylene chain of the form -0-(CR 8 R 8 ) 2 - and which is attached at its respective ends to the substitution point for R 2 and R 5 respectively. Furthermore, it may be that R 1
  • SUBSTITUTE SHEET RULE 26 It may be that Y 1 and Y 2 are both C. Preferably, Y 1 and Y 2 are not both N.
  • Z 1 and Z 3 may each be independently selected from O, S, S(O), NR 9 and CR 10 ;
  • Z 1 , Z 2 and Z 3 are each independently selected from O, S, N R 9 and CR 10 .
  • Y 1 and Y 2 are each independently selected from C and N;
  • Z Z 2 and Z 3 are each independently selected from O, S, NR 9 and CR 10 ; with the proviso that the ring formed by Z 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 9 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, tetrazole, 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 Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, tetrazole, 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 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 9 and the remaining two of Z Z 2 and Z 3 are each CR 10 .
  • Z 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 10 and the remaining two of Z 1 , Z 2 and Z 3 are selected from O, S and NR 9 .
  • Z Z 2 , Z 3 , Y 1 and Y 2 together form a oxazole, thiazole, isoxazole or isothiazole ring.
  • the remaining Z 1 , Z 2 or Z 3 is selected from O and S.
  • R 10 may be independently at each occurrence selected from: H, halo, nitro, cyano, S(0)R 16 , S(0) 2 OR 16 , S(0) 2 R 16 , S(0) 2 NR 16 R 16 C0 2 R 16 , C(0)R 16 , CONR 16 R 16 , d-C 4 -alkyl, C 2 -C 4 -
  • R 10 may be independently at each occurrence selected from: halo, nitro, cyano, S(0)R 16 , S(0)20R 16 , S(0) 2 R 16 , S(0) 2 NR 16 R 16 C0 2 R 16 , C(0)R 16 , CONR 16 R 16 , d-C 4 -alkyl, C 2 -C 4 -alkynyl, C 2 -C 4 - alkenyl, Ci-C 4 -haloalkyl, CR 16 R 16 OR 16 and CR 16 R 16 NR 16 R 17 .
  • R 10 may be independently at each occurrence selected from: H, halo, nitro, Ci-C 4 -alkyl, C2-C 4 -alkenyl, C2-C 4 -alkynyl, Ci- C 4 -haloalkyl.
  • R 10 may be independently at each occurrence selected from: halo, nitro, Ci-C 4 - alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl CR 16 R 16 OR 16 and CR 16 R 16 NR 16 R 17 .
  • R 10 may be independently at each occurrence selected from: Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 - alkynyl, Ci-C 4 -haloalkyl CR 16 R 16 OR 16 and CR 16 R 16 NR 16 R 17 .
  • R 10 may be independently at each occurrence selected from: H, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl, Q R 16 R 16 0 R16 and CR 6 R 16 NR 6 R 17 .
  • R 10 may be independently at each occurrence selected from: H, Ci-C 4 -alkyl, CR 16 R 16 OR 16 and CR 16 R 16 NR 16 R 17 .
  • R 10 may be independently selected from CR 16 R 16 OR 16 and CR 16 R 16 NR 16 R 17 .
  • R 10 may be CR 16 R 16 NR 16 R 17 .
  • R 10 may be H or Ci- C 4 -alkyl.
  • W is preferably O.
  • R 20 and R 21 together with the nitrogen to which they are attached form a heteroaromatic ring
  • the ring is selected such that the nitrogen atom to which R 20 and R 21 are attached is formally sp 3 hybridised and forms a single bond to each of the neighbouring atoms in the heteroaromatic ring system.
  • R 20 and R 21 may be that
  • heteroaromatic group selected from pyrrole, pyrazole, imidazole, tetrazole or triazole.
  • the compound of formula (I) may be a compound selected from:
  • tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism
  • 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 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 N R a R 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 m - alkylene.
  • 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, flouromethyl, trifluoromethyl, chloroethyl e.g. 1- chloroethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
  • a haloalkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one fluorine 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 (e.g. cis or trans).
  • the double bond may be at any chemically 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 in each alkenyl group independently may be fluorine, OR a or NR a R 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 in each alkynyl group independently may be fluorine, OR a or NR a R 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 and 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 .
  • Vnheterocycloalkyl may refer to a m to n membered monocyclic or bicyclic saturated or partially saturated group 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.
  • An N- heterocycloalkyl group is a heterocycloalkyl group comprises at least one nitrogen atom in the ring system.
  • 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.
  • heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each heterocycloalkyl group may independently be fluorine, OR a or NHR a .
  • Aryl groups have from 6 to 20 carbon atoms as appropriate to satisfy valency requirements.
  • Aryl groups satisfy the Huckel rule.
  • Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted naphthalenyl groups or optionally substituted anthracenyl groups. Equally, aryl groups may include non-aromatic carbocyclic portions.
  • a 5-membered heteroaromatic ring may be an aromatic ring with 1-4 (e.g.1-3) heteroatoms selected from O, S and N in the ring system, e.g. pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, triazole or tetrazole.
  • 1-4 e.g.1-3
  • heteroatoms selected from O, S and N in the ring system, e.g. pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, triazole or tetrazole.
  • the ring contains a nitrogen in the ring system
  • that nitrogen may be attached via a double bond to one of the neighbouring atoms, in which case the nitrogen will be unsubstituted or it may be attached via a single bond to both of the neighbouring atoms, in which case the nitrogen will be substituted with an R 11 group.
  • Heteroaryl groups may be 5- or 6-membered heteroaryl groups. Heteroaryl groups may be selected from: 5-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 heteroatoms selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-2 nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms.
  • heteroaryl groups may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • 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
  • An endocyclic double bond is formed between two atoms which both form part of a ring.
  • An exocyclic double bond is formed between one atom which forms part of a ring and one atom which does not form part of the ring.
  • the compound of formula (I) is an N-oxide
  • it will typically be a pyridine N-oxide, i.e. the nitrogen of the pyridine may be N + -0 " .
  • the compound of the invention is not an N-oxide.
  • the present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXXIV) 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 ore more strains of bacteria which 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-positive bacteria.
  • SUBSTITUTE SHEET RULE 26 can be used to treat bacterial infections caused by one or more resistant strains of Gram- negative bacteria.
  • the compounds and formulations of the present invention can be used to treat both Gram- positive and Gram-negative bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staphylococcus aureus).
  • the compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, Escherichia coli, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, Helicobacter pylori, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo.
  • the compounds and formulations of the invention may be used to treat infections caused by bacteria which are in the form of a biofilm.
  • the term 'resistant' is intended to refer to strains of bacteria that have shown 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 (e.g. the MRSA strain) be resistant to one or more fluoroquinolone antibiotics, e.g. one or more antibiotics selected from levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin.
  • the bacterial strain may (e.g.
  • the 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 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 which are resistant to one or more antibiotics, e.g. one or more approved antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria which are resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp.
  • pathogens are all fastidious Gram-negative organisms.
  • a fastidious bacterium is one having a complex nutritional requirement, i.e. one which will only grow when specific nutrients are included in the culture medium.
  • Neisseria gonorrhoeae requires, amongst other supplements, iron,
  • Pathogenic Neisseria species include Neisseria gonorrhoeae (the pathogen responsible for gonorrhoea) and Neisseria meningitidis (one of the pathogens responsible for bacterial meningitis).
  • Infections which can be treated include secondary infections which can arise from lack of treatment of a primary Neisseria gonorrhoeae infection.
  • Exemplary secondary infections include urethritis, dysuria, epididymitis, pelvic inflammatory disease, cervicitis and endometritis and also systemic gonococcal infections (e.g. those manifesting as arthritis, endocarditis or meningitis).
  • the gonorrhoea infection may be one caused by a strain of Neisseria gonorrhoeae which is resistant to at least one approved antibacterial drug, e.g. at least one approved ⁇ -lactam drug.
  • the compounds of the invention can be used to treat or prevent mycobacterial infections, e.g. mycobacterial infections caused by strains of mycobacteria which are resistant to approved mycobacterials. Thus, they can be used to treat TB or leprosy.
  • the compounds may be used to treat resistant strains of TB, e.g. MDR-TB (i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin), XDR-TB (i.e. TB infections caused by strains which are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin) and/or TDR-TB (i.e. TB infections caused by strains which have proved resistant to every drug tested against it with the exception of a compound of the invention).
  • MDR-TB i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin
  • the compound of the invention can be used to treat infections caused by obligate anaerobic bacteria, e.g. resistant strains of obligate anaerobic bacteria.
  • the compounds may be used to treat Clostridia spp., e.g. Clostridium difficile, including those resistant to other approved antibiotics.
  • the compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains which are category A pathogens as identified by the US government (e.g. those which cause anthrax, plague etc.) and/or they may be strains which are category B pathogens as identified by the US government (e.g. those which cause Glanders disease, mellioidosis etc). In a specific embodiment, the compounds and formulations of the present invention can be used to treat or to prevent infections caused by Gram-positive bacterial strains associated with biowarfare (e.g. anthrax). More particularly, the compounds and
  • SUBSTITUTE SHEET RULE 26 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.
  • 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
  • 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
  • SUBSTITUTE SHEET RULE 26 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.
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • 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 2 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).
  • Acid amine (5) can be converted into diamine (6) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by 'BuOH and treating the product with TFA).
  • a condensation reaction e.g. using EtOH as a solvent optionally with heating
  • an appropriate a-ester-aldehyde e.g. EtC ⁇ CCHO
  • Tetrazole formation can be effected by reaction with H2O2 and aq. NaOH and then by POC in DCM (optionally at a temperature of from 0°C to 45°C) followed by azide displacement of the resultant halide (e.g.
  • tetrazole (8) can be converted into tetrazole (9) (a subset of compounds of formula (XXXXVI)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • 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 formic hydrazide e.g.
  • Triazole (14) can be prepared from intermediate (7) by reaction with H2O2 and aq. NaOH and then with POCb in DCM (optionally at a temperature from 0°C to 45°C) followed by hydrazine displacement of the resultant halide (e.g. in EtOH).
  • the resultant hydrazide product can be converted into triazole (14) by reaction with triethylorthoformate.
  • Triazole (14) can then be converted into 1 ,2,4-triazole (15) (a subset of compounds of formula (XXXXXI)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (5) can be acetylated (e.g. with AcCI, EtsN optionally in dioxane at room temperature).
  • Acid (16) can be converted into amine (17) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by 'BuOH and treating the product with TFA).
  • Diazotisation reaction e.g. with HCI and NaNC>2 optionally in EtOH at 0- 5°C
  • reaction with ethyl-2-chloroacetoacetate e.g. in the presence of NaOAc
  • treatment of the product with NH3 (g) e.g. in THF
  • NH3 e.g. in THF
  • SUBSTITUTE SHEET RULE 26 CIC(0)C02Et (e.g. in Et20 at room temperature) can then be used to generate compound (19) which upon heating can cyclise to form triazole (20). Decarboxylation and deacetylation (e.g. by heating with NaOH in EtOH) can produce triazole (21). Triazole (21) can then be converted into 1 ,2,4-triazole (22) (a subset of compounds of formula (XXXXXII)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Addition of ethyldiazoacetate (e.g. with Et2NH and EtOH) to intermediate (3) can provide alcohol (23) which, upon treatment with a Lewis acid and t-BuOH (e.g. BF3.0Et2 in acetonitrile and t-BuOH optionally at room temperature) can ring open to form alkyne (24).
  • a Lewis acid and t-BuOH e.g. BF3.0Et2 in acetonitrile and t-BuOH optionally at room temperature
  • 1 ,3-Dipolar cycloaddition with an azide e.g. with heating in toluene
  • triazole (25) can cyclise to form tricycle (26).
  • Tricycle (26) can then finally be converted into 1 ,2,3-triazole (27) (a subset of compounds of formula (XXXXXIII)). This can be achieved by cross coupling with arylB(OH) 2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Reaction of urea with intermediate (5) can provide bicycle (28).
  • Treatment with Lawesson's reagent e.g. in dioxane
  • subsequent methylation e.g. by heating with Mel in acetone
  • thiane e.g. by heating with Mel in acetone
  • Displacement of the SMe group with hydrazide e.g. by heating in EtOH
  • hydrazide (31) which, upon reaction with triethylorthoformate (e.g. with TFA) can give triazole (32).
  • Triazole (32) can then be converted into 1 ,2,4-triazole (33) (a subset of compounds of formula (XXXXIX)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (31) can be converted into tetrazole (34) (e.g. using NaNC>2 and HCI optionally in ethanol at 0-5 °C). Tetrazole (34) can then be converted into tetrazole (35) (a subset of compounds of formula (XXXXVII)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Amine (40) can be obtained from intermediate (4). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions. Bromination (e.g. using Br2 in acetic acid and sodium acetate optionally at room temperature) can provide bromide (41). Subsequent acylation with an appropriate acylating agent (e.g. an acid chloride, exemplary conditions being with EtsN optionally in THF with heating) can provide amide (42). Finally a intramolecular cross-coupling reaction (e.g. using CU2O, 4,7- dimethoxy-1 , 10-phenanthroline, CS2CO3, PEG, n-PrCN, ⁇ ) can provide imidazole (43) (a subset of compounds of formula (XXI)).
  • Bromination e.g. using Br2 in acetic acid and sodium acetate optionally at room temperature
  • an appropriate acylating agent e.g. an acid chloride, exemplary conditions
  • Intermediate (6) can be converted into chloride (45) by treatment with oxalyl chloride (e.g. in DCM at room temperature) followed by treatment with POC (optionally with heat).
  • Chloride displacement with aminoacetaldehyde diethyl acetal can provide acetal (46) which in the presence of acid (e.g. tosic acid in isopropyl alcohol) can cyclise to form imidazole (47).
  • Imidazole (47) can then be converted into imidazole (48) (a subset of compounds of formula (XXXI)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (5) can be converted to enol (49) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl nitroacetate (e,g. heating with EtsN in THF).
  • Enol (49) can be converted into enamine (51) by chlorination (e.g. by heating with POC ), displacement of the resultant chlorine with a protected amine (e.g. 4-methoxybenzylamine optionally in DMF at room temperature) and then deprotecting the amine (in the case of 4- methoxybenzylamine this can be achieved using TFA, e.g. in DCM at room temperature).
  • Reduction of the nitro group e.g.
  • Imidazole (53) can be converted into imidazole (54) (a subset of compounds of formula (IX)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (5) can be converted into bicycle (55) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl 2-(benzyloxy)acetate (e.g. by heating with EtsN in THF).
  • phosgene e.g. in THF at room temperature
  • ethyl 2-(benzyloxy)acetate e.g. by heating with EtsN in THF.
  • a similar chlorination, amination, deprotection sequence to that used in Scheme K above can generate amine (57).
  • the benzyl protecting group of amine (57) can be removed (e.g. using Pd/C and H2 in MeOH at room temperature) to provide aminoenol (58) which can be converted into the oxazole (59) by reaction with triethylorthoformate (e.g. by heating with triethylorthoformate).
  • Oxazole (59) can be converted into oxazole (60) (
  • a sequential palladium coupling of intermediate (41) to bis(pinacolato)diboron e.g. using Pd(dppf)Cl2 and KOAc in 1 ,4 dioxane at 80°C
  • an appropriately substituted 1- benzyl-5-bromopyrazole e.g. using Pd(dppf)Cl2 and CS2CO3 in a 10: 1 dioxane: H2O mixture at 70°C
  • pyrazole (62) Removal of the benzyl protecting group (e.g. using Pd/C and H2 in MeOH at room temperature) and subsequent reaction with phosgene (e.g. in THF at room temperature) or an equivalent reagent can provide pyrazole (64) (a subset of compounds of formula (XXXII)).
  • Reaction of intermediate (41) with an appropriate acylating agent e.g. 2H-pyrazole-3- carboxylic acid, exemplary conditions being to do so by heating with propylphosphonic anhydride and diisopropylamine in THF
  • an appropriate acylating agent e.g. 2H-pyrazole-3- carboxylic acid, exemplary conditions being to do so by heating with propylphosphonic anhydride and diisopropylamine in THF
  • amide (65) which can undergo an intramolecular cross-coupling reaction (e.g. using CU2O, 4,7-dimethoxy-1 , 10-phenanthroline, CS2CO3, PEG, n-PrCN, ⁇ ) to provide pyrazole (66) (a subset of compounds of formula (XXIX)).
  • Boc protection of amine (41) can provide carbamate (67).
  • Boc deprotection e.g. using TFA in DCM at room temperature
  • ester hydrolysis e.g.
  • Intermediate (5) can be converted into ⁇ -ketoamide (72) by reaction with phosgene (e,g, in THF at room temperature) followed by ethyl 3-(benzyloxy)propanoate (e.g with heating in DMF following deprotonation of ethyl 3-(benzyloxy)propanoate with NaH).
  • ⁇ -Ketoamide (72) can be converted into ⁇ -ketoamide (73). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions. Removal of the benzyl protecting group (e.g. using Pd/C and H2 optionally in MeOH at room temperature) followed by oxidation (e.g. using Dess-Martin Periodinane optionally in DCM at room temperature) can provide aldehyde (75). Treatment of aldehyde (75) with hydrazine (e.g. as
  • SUBSTITUTE SHEET RULE 26 hydrazine hydrate in THF in the presence of acetic acid can provide pyrazole (76) (a subset of compounds of formula (XXVIII)).
  • Intermediate (5) can be converted into oxazole (77) by treating with triphosgene (e.g. in THF at room temperature) and reacting the product with ethyl isocyanate (e.g. by heating in the presence of EtsN in THF). Cyclisation (e.g. by heating with NaH in DMF) can provide oxazole (78) which can be converted into oxazole (79) (a subset of compounds of formula (III)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • triphosgene e.g. in THF at room temperature
  • ethyl isocyanate e.g. by heating in the presence of EtsN in THF
  • Cyclisation e.g. by heating with NaH in DMF
  • This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (4) can be converted into iodide (83) (e.g. by treating with iodine and NaHCC>3 optionally in EtOAc at room temperature).
  • Acylation with an acid chloride (84) e.g. using EtsN in THF at room temperature
  • amide (85) which, following an intramolecular Heck reaction (e.g. by heating amide (85) with Pd(PP i3) 4 and EtsN in acetonitrile) can give tricycle (86).
  • Tricycle (86) can be converted into tricycle (87) (e.g.
  • amide (89) Acylation of iodide (83) with an appropriately substituted acyl chloride (88) (e.g. using EtsN in THF at room temperature) can provide amide (89) which, following an intramolecular Heck reaction (e.g. by heating amide (89) with Pd(PPhs) 4 and EtsN in acetonitrile) can give tricycle (90).
  • Tricycle (90) can be converted into tricycle (91) (a subset of compounds of formula (XXXXIV)). This can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Reaction of fluoride (92) with NHR 2 can provide amine (93) (e.g by heating in DMSO).
  • Acylation of amine (93) with an appropriately substituted acyl chloride (94) e.g. using EtsN in THF at room temperature
  • amide (95) which upon deprotection (e.g. using TFA in DCM at room temperature) can give pyrrole (96).
  • An addition-elimination cyclisation reaction e.g. by heating pyrrole (96) with K2CO3 in DMSO
  • Tricycle (97) can be converted into tricycle (98) by reduction of the nitro group (e.g.
  • Amide (36) can, for example, be converted to thioamide (37) by heating with P2S5 in pyridine.
  • Amide (36) can, for example, be converted to amidine (38) by heating with POCb and heating the product with the primary amine N H2R 8 .
  • Amide (36) can, for example, be converted to oxime (39) by heating with POCb and heating the product with the O-substituted hydroxylamine NH2OR 8 .
  • SUBSTITUTE SHEET RULE 26 cooled to room temperature and allowed to stir at room temperature overnight. It was then diluted with H2O (10 mL) and acidified with 6M aq. HCI. The aq. layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with aq. NaHCC>3 (10 mL) and brine (10 mL), dried over Na2S0 4 , filtered and the solvent removed under vacuo to give N-(7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-2-oxo-3-quinolyl)acetamide (101 mg, 43 %) as a brown oil. The product was used in the next step without further purification.
  • Glacial acetic acid (1.0 mL, 17.47 mmol) and TFA (1.0 mL, 13.07 mmol) were added to N-(7- bromo-1-cyclopropyl-4-hydroxy-8-methyl-2-oxo-3-quinolyl)acetamide (101 mg, 0.29 mmol) in a microwave vial.
  • the solution was then irradiated with microwaves at 200°C for 20 min, allowed to cool and solvent removed under vacuo.
  • EtOAc (20 mL) and the solution washed with aq. NaHCC>3 (5 mL) followed by brine (5 mL). The organic layer was then dried over Na2S0 4 , filtered and the solvent removed under vacuo.
  • reaction solution was then irradiated with microwaves at 60°C for 30 min.
  • the solution was diluted with MeOH, filtered, dry-loaded onto silica and purified by flash chromatography using a gradient of 0-10% MeOH in DCM.
  • the fractions containing the required product were then concentrated in vacuo to give 5-cyclopropyl-2,6-dimethyl-7-(1 , 2,3,4- tetrahydroisoquinolin-6-yl)oxazolo[4,5-c]-quinolin-4-one (2 mg, 3 %) as a pale yellow solid.
  • step (a) Prepared using method described in Example 7, step (a) and ethyl 3-bromopropanoate to give ethyl 3-(5-bromo-2,3-dihydro-1 H-isoindol-2-yl)propanoate.
  • step (b) Prepared using method described in Example 4, step (b) with tert-butyl 5-[(2S)-2-methyl-15-oxo-4, 11 -dioxa-1 , 13-diazatetracyclo[7.6.1.0 5 , l6 .0 l0 , l4 ]hexadeca-5(16),6, 8, 10(14), 12-pentaen-6-yl]-2,3-dihydro-1 H-isoindole-2-carboxylate.
  • Example 12 7-(2-amino-2,3-dihydro-1 H-inden-5-yl)-5-cvclopropyl-8-fluoro-oxazolor4,5- clquinolin-4-one
  • Example 13 7-(2-amino-2,3-dihvdro-1 H-inden-5-yl)-5-cvclopropyl-8-fluoro-2-methyl- oxazolor4,5-c1quinolin-4-one
  • Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '- biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) (10% mmol) was used as catalyst and .2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10% mmol) as ligand. Column chromatography was carried out, eluting with 0-20% MeOH in DCM.
  • Example 15 (2S)-2-methyl-6-r(1 R)-1 -methyl-2,3-dihvdro-1 H-isoindol-5-vn-4,11-dioxa- 1 ,13-diazatetracvclor7.6.1.0 5 , l6 .0 1 °, l4 1hexadeca-5(16),6,8,10(14),12-pentaen-15-one
  • Example 17 7-(2-amino-2,3-dihydro-1 H-inden-5-yl)-2-(aminomethyl)-5-cvclopropyl-6- methyl-oxazolor4,5-c1quinolin-4-one
  • reaction mixture was concentrated then purified by column chromatography, eluting with 0-80% EtOAc in petroleum ether (40-60) to give tert-butyl N-( ⁇ 7-bromo-5-cyclopropyl-6- methyl-4-oxo-[1 ,3]oxazolo[4,5-c]quinolin-2-yl ⁇ methyl)carbamate (1.0 g, 74 % yield) as a pale solid.
  • step (b) tert-butyl N-( ⁇ 7-bromo-5- cyclopropyl-6-methyl-4-oxo-[1 ,3]oxazolo[4,5-c]quinolin-2-yl ⁇ methyl)carbamate (step (b) above).
  • Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino- 1 , 1 '-biphenyl)]palladium(ll) (10% mmol) was used as catalyst and .2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10% mmol) as ligand.
  • Example 18 2-(aminomethyl)-5-cvclopropyl-6-methyl-7-r(1 S)-1 -methyl-2,3-dihydro-1 H- isoindol-5-yl1-oxazolor4,5-c1quinolin-4-one
  • Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll) (10% mmol) was used as catalyst and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (10% mmol) as ligand.
  • step (a) Prepared using method described in Example 4, step (a) with the solution being initially irradiated for 90 min and then a further 90 min using 5-cyclopropyl-6-methyl-7-(tetramethyl- 1 ,3,2-dioxaborolan-2yl)-oxazolo[4,5-c]quinolin-4-one (Intermediate D) and 5-bromo-2,3- dihydro-1 H-isoindol-1-one.
  • Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '- biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) (10% mmol) was used as catalyst and .2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10% mmol) as ligand. Column chromatography was carried out, eluting with 0-20% MeOH in DCM.
  • Example 21 6- ⁇ 5-cvclopropyl-6-methyl-4-oxo-oxazolor4,5-c1quinolin-7-yl)-4,4- dimethyl-2,4-dihvdro-1 H-3,1-benzoxazin-2-one
  • Example 22 6-(5-cyclopropyl-1 ,6-dimethyl-4-oxo-imidazor4,5-c1quinolin-7-yl)-4,4- dimethyl-1 H-3,1 -benzoxazin-2-one
  • 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) or 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 x 100 mm. Flow rate: 20 mL/min.
  • MICs Minimum Inhibitory Concentrations versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Ninth Edition. CLSI document M07-A9, 2012).
  • the broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.001-128 ⁇ g/mL and a maximum final concentration of 1 % DMSO.
  • the bacterial strains tested include Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Staphylococcus epidermidis ATCC 12228, Streptococcus pneumoniae ATCC 49619, Haemophilus influenzae ATCC 49247 and a panel of methicillin-resistant S. aureus strains including S. aureus NRS482, S. aureus NRS271 , S. aureus VRS8 and S. aureus ATCC 43300 (Table 1).
  • Strains are grown in cation- adjusted Muller-Hinton broth (supplemented with 2% w/v NaCI in the case of MRSA strains or supplemented with 5% blood in the case of S. pneumoniae) or in haemophilus test medium broth.
  • the MIC is determined as the lowest concentration of compound that inhibits growth following a 16-20 h incubation period. The data reported correspond to the modes of three independent experiments.
  • a MIC (in ⁇ g/mL) of less than 1 is assigned the letter A; a MIC of from 1 to 10 is assigned the letter B; a MIC of from 10 to 100 is assigned the letter C; and a MIC of over 100 is assigned the letter D.
  • MSSA methicillin-susceptible Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • FQ fluoroquinolone
  • LZD linezolid
  • VAN vancomycin
  • certain compounds of the invention including compounds 4, 5, 6, 7, 1 1 , 14, 15 and 19-22 exhibit good activity against all S. aureus strains tested including those which are resistant to fluoroquinolone antibiotics and other antibiotics.
  • compounds 5, 15 and 20-22 exhibit excellent activity against all S. aureus strains which are resistant to fluoroquinolone antibiotics and other antibiotics.
  • Compounds 4, 5, 6, 1 1 , 14, 15 and 19-22 also exhibit good activity against the other Gram-positive and Gram-negative strains tested.
  • HepG2 ATCC HB-8065 Human hepatic cell line
  • HepG2 cells are seeded at 20,000 cells/well in 96-well microtitre plates in minimal essential medium (MEM) supplemented with a final concentration of 10 % FBS and 1 mM sodium pyruvate.
  • MEM minimal essential medium
  • DMEM Dulbecco's minimum essential media
  • an IC50 (in ⁇ g/mL) of less than 10 is assigned the letter C; an IC50 of from 10 to 100 is assigned the letter B; and an IC50 of over 100 is assigned the letter A

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Abstract

La présente invention concerne des composés médicamenteux antibactériens et anti-mycobactériens 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. L'invention concerne en outre des composés médicamenteux antibactériens de formule (I) qui sont aptes à traiter des infections bactériennes actuellement difficiles à traiter avec les composés médicamenteux existants, par exemple celles provoquées par des souches bactériennes ou mycobactériennes résistantes.
PCT/GB2016/052898 2015-09-18 2016-09-16 Composés antibactériens WO2017046605A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106957255A (zh) * 2017-03-28 2017-07-18 上海馨远医药科技有限公司 一种(R)‑N‑Boc‑5‑溴‑1‑甲基异吲哚啉及其制备方法和应用
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0882725A1 (fr) * 1996-02-09 1998-12-09 Toyama Chemical Co., Ltd. Derives de l'acide quinolonecarboxylique et leurs sels
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
WO2013153394A1 (fr) * 2012-04-11 2013-10-17 Redx Pharma Limited Quinolonones ayant des propriétés antibactériennes
WO2015155549A1 (fr) * 2014-04-10 2015-10-15 Redx Pharma Plc Composés antibactériens

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0882725A1 (fr) * 1996-02-09 1998-12-09 Toyama Chemical Co., Ltd. Derives de l'acide quinolonecarboxylique et leurs sels
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
WO2013153394A1 (fr) * 2012-04-11 2013-10-17 Redx Pharma Limited Quinolonones ayant des propriétés antibactériennes
WO2015155549A1 (fr) * 2014-04-10 2015-10-15 Redx Pharma Plc Composés antibactériens

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
CN106957255A (zh) * 2017-03-28 2017-07-18 上海馨远医药科技有限公司 一种(R)‑N‑Boc‑5‑溴‑1‑甲基异吲哚啉及其制备方法和应用
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof

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