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WO2015114317A1 - 5h-isothiazolo[4,5-c]pyridine-3,4-dione ou 5h-pyrazolo[4,3-c]pyridine-3,4-dione en tant que composés antibactériens - Google Patents

5h-isothiazolo[4,5-c]pyridine-3,4-dione ou 5h-pyrazolo[4,3-c]pyridine-3,4-dione en tant que composés antibactériens Download PDF

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Publication number
WO2015114317A1
WO2015114317A1 PCT/GB2015/050182 GB2015050182W WO2015114317A1 WO 2015114317 A1 WO2015114317 A1 WO 2015114317A1 GB 2015050182 W GB2015050182 W GB 2015050182W WO 2015114317 A1 WO2015114317 A1 WO 2015114317A1
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compound
alkyl
independently
formula
group
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Inventor
Andrew Ratcliffe
Ian Cooper
David MCGARRY
Mark Pichowicz
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Redx Pharma Ltd
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Redx Pharma Ltd
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Priority claimed from GB201401407A external-priority patent/GB201401407D0/en
Priority claimed from GB201417939A external-priority patent/GB201417939D0/en
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Publication of WO2015114317A1 publication Critical patent/WO2015114317A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • This invention relates to antibacterial drug compounds containing a fused isothiazolinone or pyrazolone ring and related compounds. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections and in methods of treating bacterial infections. Many of the antibacterial drug compounds contain a isothiazolinone or pyrazolone ring fused to a pyridone ring. The compounds have broad spectrum antibacterial activity but are particularly effective against Gram negative strains.
  • antibiotic resistant Gram negative strains such as either Escherichia coli NDM-1 (New Delhi metallo ⁇ -lactamase) mutation or Klebsiella pneumoniae with the same mutation, are also very difficult to treat. Frequently only expensive, last resort antibiotics such as vancomycin and colistin are effective against these strains.
  • the fluoroquinolone antibacterial family are synthetic broad-spectrum antibiotics. They were originally introduced to treat Gram negative bacterial infections, but are also used for the treatment of Gram positive strains.
  • One problem with existing fluoroquinolones can be the negative side effects that may sometimes occur as a result of fluoroquinolone use. In general, the common side-effects are mild to moderate but, on occasion, more serious adverse effects occur.
  • Some of the serious side effects that occur, and which occur more commonly with fluoroquinolones than with other antibiotic drug classes, include central nervous system (CNS) toxicity and cardiotoxicity. In cases of acute overdose there may be renal failure and seizure.
  • CNS central nervous system
  • Fluoroquinolone antibiotics have been developed which contain a isothiazolinone fused to the quinolone core (WO2005/019228; WO2006/118605; WO2007/014308; WO2008/0364240). Such compounds have however been shown to exhibit some cytotoxicity in human cell lines (Kim et al; J. Med. Chem.; 2011, 54, 3268-3282).
  • Related antibiotic compounds containing an isothiazolinone ring fused to a 4-pyrone ring are disclosed in JP 3068175.
  • the invention provides a compound of formula (I), or a pharmaceutically thereof:
  • A is independently selected from: aryl, heteroaryl and C3-Cio-heterocycloalkyl;
  • X is independently selected from: S, SO, S0 2 , O, NR 4 ;
  • R 1 is independently selected from: H, halogen, cyano, NR 5 R 5 ; OR 6 ; C1-C6 alkyl, C1-C6 haloalkyi, -(CZ 2 ) n -C3-C6 cycloalkyl, -(CZ 2 ) n -C3-C6 halocycloalkyl; -(CZ 2 ) n -phenyl; -(CZ 2 ) n - heteroaryl, C 2 -C6 alkenyl and C 2 -C6 alkynyl;
  • R 2 and R 4 are each independently selected from: H; C1-C6 alkyl, C1-C6 haloalkyi, -(CZ 2 ) n -C3- C6 cycloalkyl, -(CZ 2 ) n -C3-C6 halocycloalkyl and -(CZ 2 ) n -phenyl;
  • R 3 is independently selected from the group consisting of: H, -(CZ 2 ) n -C3-Cio heterocycloalkyl, -(CZ 2 ) n -phenyl, -(CZ 2 ) n -heteroaryl, -(CZ 2 ) n -C 3 -Cio cycloalkyl, -(CZ 2 ) n -NR 5 R 5 ;
  • R 5 is independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyi, S(0) 2 - C1-C4 alkyl and C(0)-Ci-C 4 alkyl;
  • R 6 is independently at each occurrence selected from H, C1-C4 alkyl, and C1-C4 haloalkyi;
  • Z is independently at each occurrence selected from H, Me, CF3 or F; and n is an integer independently selected at each occurrence from 0, 1 , 2 and 3; and wherein each of the aforementioned aryl, heteroaryl, C3-C10 heterocycloalkyl or C3-C10 cycloalkyl groups are monocyclic or bicyclic; and each of the aforementioned alkyl, haloalkyi, cycloalkyi, halocycloalkyi, heterocycloalkyi, aryl (e.g.
  • A may be substituted with a substituent as recited above, even when R 3 is H.
  • the compound of formula (I) or formula (la) is a compound of formula (II)
  • R 1 , R 2 , R 3 and A are as defined for formula (I) above or formula (la) below.
  • the compound of formula (I) or formula (la) is a compound of formula (III)
  • the compound of formula (I) or formula (la) is a compound of formula (IV) or a pharmaceutically acceptable salt or N-oxide thereof: NH
  • R x is a group selected from 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 , SOR a , S0 3 R a , S0 2 R a , S0 2 NR a R a , C0 2 R a C(0)R a , CONR a R a , C1-C4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 haloalkyl and CR b R b NR a R a ; and p is an integer
  • Y ⁇ Y 2 , Y 3 or Y 4 is carbon
  • the carbon will be substituted with either H or an R x group.
  • at least 1 of Y 1 , Y 2 , Y 3 and Y 4 is nitrogen and p is 0.
  • Y 1 , Y 2 , Y 3 and Y 4 are each carbon.
  • R 3 is preferably an N-heterocycloalkyl group which is attached to the rest of the molecule via the or one nitrogen in the heterocycloalkyl ring system.
  • the compound of formula (I) is a compound of formula (V) or a or N-oxide thereof:
  • R 1 , R 2 and R 3 are as defined for formula (I) above; wherein R 12 is independently selected from H, Ci-C 4 alkyl and Ci-C 4 haloalkyl; and optionally wherein X is S.
  • the compound of formula (I) is a compound of formula (VI) or a pharmaceutically acceptable salt or N-oxide thereof:
  • X, R 1 and R 2 are as defined for formula (I) above; Y 1 , Y 2 , Y 3 , Y 4 , R x and p are as defined above for formula (IV); and wherein R 9 is independently selected from H, C1-C4 alkyl and C1-C4 haloalkyl; R 10 is selected from H, C1-C4 alkyl and C1-C4 haloalkyl; R 11 is selected from H, F, C1-C4 alkyl and C1-C4 haloalkyl; or where R 10 and R 11 together with the atoms to which they are attached form a 5- or 6- membered cycloalkyi or heterocycloalkyi ring; and p is an integer from 1 to 4; optionally wherein X is S.
  • Y 1 , Y 2 , Y 3 and Y 4 are each carbon.
  • the compound of formula (I) is a compound of formula (VII) or a or N-oxide thereof:
  • the compound of formula (I) is a compound of formula (VIII) or a pharmaceutically acceptable salt or N-oxide thereof:
  • Y 1 , Y 2 , Y 3 and Y 4 are each carbon, p may be 0.
  • the compound of formula (I) is a compound of formula (IX) or a pharmaceutically acceptable salt or N-oxide thereof:
  • X, R 1 , R 2 and R a are as defined for formula (I) above; Y 1 , Y 2 , Y 3 , Y 4 , R x and p are as defined above for formula (IV); and wherein R 7 is as defined above for formula (VIII); optionally wherein X is S.
  • Y 1 , Y 2 , Y 3 and Y 4 are each carbon, p may be 0.
  • A-R 3 is preferably
  • A is phenyl
  • it may be para-substituted, i.e. the R 3 group may be in a para position relative to the rest of the molecule.
  • A is independently from para- substituted phenyl, heteroaryl and C3-Cio-heterocycloalkyl.
  • A is a six-membered monocyclic heteroaryl group, it may be para-substituted, i.e. the R 3 group may be in a para position relative to the rest of the molecule.
  • A is independently from para-substituted phenyl, para-substituted 6-membered monocyclic heteroaryl, 5-membered monocyclic heteroaryl, bicyclic heteroaryl and C3-Cio-heterocycloalkyl;
  • A may also be heteroaryl.
  • A may be thiophene.
  • A is heteroaryl it may be that A is a heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system.
  • A might be a monocyclic heteroaryl group, e.g. a monocyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system.
  • A may also be a bicyclic heteroaryl group, e.g. a bicyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system.
  • A may be an five-membered monocyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system, e.g.
  • A may be an six-membered monocyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system, e.g. pyridyl, pyrimidyl, pyrazinyl or pyridazinyl (any of which may be unsubstituted or may be substituted as described herein for heteroaromatic groups).
  • A may be para-substituted, i.e. the R 3 group may be in a para position relative to the rest of the molecule.
  • A-R 3 may be wherein Y 1 , Y 2 , Y 3 and Y 4 are each selected from carbon or nitrogen;
  • R x is a group selected from halo, nitro, cyano, NR a R a , NR a S(0)2R a , NR a CONR a R a , NR a C0 2 R a , OR a ;
  • SR a SOR a , S0 3 R a , S0 2 R a , S0 2 NR a R a , C0 2 R a C(0)R a , CONR a R a , C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and CR b R b NR a R a ; and
  • p is an integer from 1 to 4; provided that no more than two of Y 1 , Y 2 ,
  • Y 1 , Y 2 , Y 3 or Y 4 is carbon
  • the carbon will be substituted with either H or an R x group.
  • Y 1 , Y 2 , Y 3 and Y 4 are each carbon at leas 1 , Y 2 , Y 3 and Y 4 is nitrogen and p is 0.
  • p is 0.
  • Y 2 , Y 3 and Y 4 are each CH or N; provided that at least 1 of Y ⁇ Y 2 , Y 3 and Y 4 is N.
  • Y 1 , Y 2 , Y 3 and Y 4 may be N but it also possible that exactly two of Y 1 , Y 2 , Y and Y 4 are N.
  • A may be pyridyl (which may be unsubstituted or may be substituted as described herein for
  • A-R 3 may be or -R 3 may
  • R 3 is preferably not H.
  • A may also be a ten-membered bicyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system, e.g. quinoline or isoquinoline (any of which may be unsubstituted or may be substituted as described herein for heteroaromatic groups).
  • A may also be a nine-membered bicyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system, e.g. indolyl, benzimidazolyl, benzothiazole, benzoxazole or indazolyl (any of which may be unsubstituted or may be substituted as described herein for heteroaromatic groups).
  • A-R 3 may be indolyl or indazolyl. Where A is a nine-membered bicyclic heteroaryl group, A-R 3 may be attached to the rest of the molecule via the six-membered ring of A or via the five membered ring of A.
  • R 3 may be attached to A via the six-membered ring of A or via the five membered ring of A.
  • A-R 3 is attached to the rest of the molecule via the six- membered ring of A and, where present, R 3 is attac membered ring of
  • A-R 3 may e.g. , wherein Y 5 is independently selected from nitrogen and carbon and R 12 is independently selected from H,
  • R 3 may be H (or, where the compound is a compound of formula la, absent).
  • X is S. It may be, however, that X is O or NH.
  • R 1 may independently be selected from: C1-C6 alkyl, C1-C6 haloalkyl, -(CZ2) n -C3-C6 cycloalkyl, -(CZ2) n -C3-C6 halocycloalkyl; -(CZ2) n -phenyl; C2-C6 alkenyl and C2-C6 alkynyl.
  • R 1 may independently selected from C1-C6 alkyl, C1-C6 haloalkyl, -(CZ2) n -C3-C6 cycloalkyl and -(CZ2) n -C3-C6 halocycloalkyl.
  • R 1 may be selected from C1-C6 alkyl and - (CH2)n-C3-C6 cycloalkyl, wherein n is an integer selected from 0, 1 , 2 and 3.
  • R 1 may be selected from C1-C6 haloalkyl and -(CZ2) n -C3-C6 halocycloalkyl, wherein n is an integer selected from 0, 1 , 2 and 3.
  • R 1 may be selected from C1-C6 alkyl (e.g. C2-C4 alkyl) and C3-C6 cycloalkyl (e.g. C3-C4 cycloalkyl).
  • R 1 may be selected from C1-C4 alkyl and cyclopropyl.
  • R 1 is ethyl.
  • R 1 is cyclopropyl.
  • R 2 may independently be selected from H, C1-C6 alkyl, C1-C6 haloalkyl, -(CZ2) n -C3-C6 cycloalkyl and -(CZ2) n -C3-C6 halocycloalkyl.
  • R 2 may be selected from H, and C1-C6 alkyl.
  • R 2 is H.
  • R 2 is methyl.
  • R 3 may be H (or, where the compound is a compound of formula la, absent). Typically, however, where A is aryl (e.g. phenyl), R 3 will not be H (or, where the compound is a compound of formula la and A is aryl, R 3 will not be absent).
  • A is aryl (e.g. phenyl)
  • R 3 will not be H (or, where the compound is a compound of formula la and A is aryl, R 3 will not be absent).
  • R 3 is preferably an N-heterocycloalkyl group which is attached to the rest of the molecule via the or one nitrogen in the heterocycloalkyi ring system.
  • R 3 may be -(CZ2) n -C3-Cio heterocycloalkyi, e.g. C3-C10 heterocycloalkyi.
  • R 3 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 3 may be attached to the rest of the molecule via a carbon or one nitrogen in the ring system. It may be that the N-heterocycloalkyl group is attached to the rest of the molecule via the or one nitrogen in the ring system.
  • any nitrogen in the ring system which is not at a bridgehead or is not the point of attachment of R 3 to the rest of the molecule will be an NR 12 group.
  • R 3 may be a monocyclic C3-C7 N-heterocycloalkyl group.
  • R 3 may be a piperazine ring.
  • R 3 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 3 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 3 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 3 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 3 may be a piperidine ring substituted with a single hydroxyl group, e.g. a 4- hydroxy-piperidine ring.
  • R 3 may be a pyrrolidine substituted with a single hydroxyl group, e.g. a 3-hydroxypyrrolidine.
  • R 3 is a 3-hydroxy azridine group.
  • R 3 may be a bicylic C 7 -C 10 N- heterocycloalkyl group.
  • R 3 may be a bicyclic C7-C10 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 7 groups form a heterocycloalkyi ring
  • that ring will comprise 1 or 2 heteroatoms selected from N, O and S in the ring system.
  • two R 7 groups form a cycloalkyl or heterocycloalkyi ring
  • m is an integer independently selected from 0, 1 , 2, 3 and 4. These embodiments are particularly preferred when A is phenyl or a 6-membered heteroaryl group. m may be an integer independently selected from 1 , 2, 3 and 4.
  • tw 7 groups do not form a cycloalkyl or heterocycloalkyl ring.
  • R 3 may be 1.
  • R 7 may be NR a R a .
  • Each R a in R 7 may be H (e.g. R 7 may be NH 2 ).
  • Each R a in R 7 may independently be Ci-C 4 alkyl, e.g. each R a in R 7 may independently be methyl (e.g. R 7 may be NMe 2 ).
  • R a may at one occurrence be H and at the other occurrence be Ci-C 4 alkyl (e.g. R 7 may be NHMe).
  • R 7 may be OR a .
  • R a may be H and, thus, R 7 may be OH.
  • R 7 may be CR b R b NR a R a .
  • Each R b in R 7 may independently be C1-C4 alkyl, e.g. each R b in R 7 may independently be methyl (e.g. R 7 may be CMe 2 NR a R a ).
  • Each R a in R 7 may be H (e.g. R 7 may be CR b R b NH 2 ).
  • R 7 may be CMe 2 NH 2 .
  • each R b in R 7 may independently be H (i.e. R 7 may be CH 2 NR a R a ). It may be that R a in R 7 is at one instance H and the other instance Ci-C 4 alkyl, e.g. methyl.
  • Two R 7 groups may form a 3-6 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 7 groups may also form a 3-6 membered cycloalkyi ring, e.g. a 3-membered ring.
  • two R 7 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
  • R 7 groups may form a 3 to 6-membered cycloalkyi or 3 to 6-membered heterocycloalkyl ring
  • R 7 groups e.g. m may be 4.
  • Such additional R 7 groups will generally not form a 3 to 6-membered cycloalkyi or a 3 to 6- membered heterocycloalkyl ring.
  • R 7 may be Ci-C 4 alkyl, e.g. methyl.
  • R 7 may be NR a R a , e.g. NH 2 .
  • R 3 may be wherein R 9 is independently selected from H, Ci-C 4 alkyl and
  • Ci-C 4 haloalkyl is selected from H, Ci-C 4 alkyl and Ci-C 4 haloalkyl; R 11 is selected from H, F, Ci-C 4 alkyl and Ci-C 4 haloalkyl; or where R 10 and R 11 together with the atoms to which they are attached form a 5- or 6- membered cycloalkyi or heterocycloalkyl ring. This is particularly preferred when A is phenyl.
  • R 3 is or comprises a NR 8 R 8 group, wherein R 8 is independently H or Ci-C 4 alkyl.
  • R 3 may be comprise an NH2 group or an ⁇ 2 group.
  • R 7 is present at least once and in that at least one occurrence represents NR a R a wherein R a is independently H or Ci-C 4 alkyl.
  • R 3 is NR 5 R 5 , wherein R 5 is independently H or Ci-C 4 alkyl.
  • R 3 may be a cyclopropyl group substituted with a NH2 group.
  • R 3 may be an aryl group, e.g. a phenyl group.
  • R 3 may be a phenyl group with at least one NR A R A or CR B R B NR A R A group and optionally further substituted with from 1 -3 groups independently selected from halo, C 1 -C4 haloalkyl and C 1 -C4 alkyl, e.g. a phenyl group with at least one NR A R A or CR B R B NR A R A group and optionally further substituted with from 1 -3 halo groups (e.g. fluoro groups).
  • R 3 may be a group selected
  • R 3 may also be a heteroaryl group.
  • R 3 may be a heteroaryl group comprising at least one nitrogen atom in the ring structure.
  • R 3 may be a 9- membered bicyclic heteroaryl group comprising nitrogen atoms in the ring
  • R 3 may be R 3 may be a 6-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system, e.g. a pyridinyl group, e.g. a 6-amino-pyridin-3-yl group.
  • R 3 may be -(CZ 2 ) N -NR 5 R 5
  • R 3 may be NR 5 R 5 .
  • R 3 may be CH 2 NR 5 R 5 .
  • Each R 5 in R 3 may independently be C 1 -C4 alkyl, e.g. each R 5 in R 3 may independently be methyl (e.g. R 3 may be ⁇ 2).
  • one R 5 in R 3 may be H and the other may be C 1 -C 4 alkyl which may be substituted, e.g. substituted with an OR A group.
  • R 3 would be CH 2 NHCH 2 CH 2 OMe.
  • n is always 0.
  • X is preferably independently selected from S, O, NR 4 .
  • X may be independently selected from S and NR 4 .
  • X may be S.
  • X may be NR 4 .
  • R 4 is preferably selected from H and C 1 -C4 alkyl. In a particular embodiment, R 4 is H. In another particular embodiment, R 4 is Me.
  • X is selected from S, O, NR 4 , R 2 and R 4 are each independently selected from H and Ci-C4alkyl, A is phenyl or 6 membered heteroaryl, R 3 is a monocyclic or bicyclic N-heterocycloalkyl group which is attached to the rest of the molecule via the or one nitrogen in the ring system; and R 1 is selected from C 1 -C4 alkyl and cyclopropyl. Particularly preferred are embodiments in which X is S.
  • X is selected from S, O, NR 4 , R 2 and R 4 are each independently selected from H and C 1 -C4 alkyl, A is a nine-membered bicyclic heteroaryl group which comprises at least one nitrogen atom in the heteroaromatic ring system, R 3 is H; and R 1 is selected from C1-C4 alkyl and cyclopropyl.
  • the compound of formula (I) may be a compound selected from:
  • the compound may be a compound selected from the compounds for which the biological data is provided in Examples 21 and/or 22 below or a pharmaceutically acceptable salt or N- oxide thereof.
  • the compound may be a compound selected from:
  • the compound may be a compound of formula (la), or a pharmaceutically acceptable salt thereof:
  • A is independently aryl, heteroaryl or C3-Cio-heterocycloalkyl;
  • X is independently selected from S, SO, SO2, O, NR 4 ;
  • R 1 is independently selected from: H, halogen, cyano, NR 5 R 5 ; OR 6 ;
  • R 2 and R 4 are each independently selected from H; C1-C6 alkyl, C1-C6 haloalkyi, -(CZ2) n -C3-C6 cycloalky
  • I e invention is a method of making a compound of formula (X),
  • A is independently aryl or heteroaryl
  • X is independently selected from S, SO, S0 2 , O, NR 4 ;
  • R 1 is independently selected from: H, halogen, cyano, NR 5 R 5 ; OR 6 ; C1-C6 alkyl, C1-C6 haloalkyl, -(CZ 2 )n-C3-Ce cycloalkyl, -(CZ 2 )n-C3-Ce halocycloalkyl; -(CZ 2 ) n -phenyl; -(CZ 2 ) n - heteroaryl, C 2 -C6 alkenyl and C 2 -C6 alkynyl;
  • R 2 and R 4 are each independently selected from H; C1-C6 alkyl, C1-C6 haloalkyl, -(CZ 2 ) n -C3- C6 cycloalkyl, -(CZ 2 ) n -C3-C6 halocycloalkyl and -(CZ 2 ) n -phenyl;
  • R 3 is independently selected from the group consisting of: heterocycloalkyl, phenyl, heteroaryl, cycloalkyl, -NR 5 R 5 ; wherein the heterocycloalkyl group comprises at least one nitrogen in the ring and wherein the heterocyclolkyi group is linked to A (or L 2 ) through a nitrogen atom;
  • R 5 is independently at each occurrence selected from H, Ci-C 4 alkyl, Ci-C 4 haloalkyl, S(0) 2 - C1-C4 alkyl and C(0)-Ci-C 4 alkyl;
  • R 6 is independently at each occurrence selected from H, C1-C4 alkyl, and C1-C4 haloalkyl;
  • Z is independently at each occurrence selected from H, Me, CF3 or F; and n is an integer independently selected at each occurrence from 0, 1 , 2 and 3; and wherein each of the aforementioned aryl, heteroaryl, C3-C10 heterocycloalkyl or C3-C10 cycloalkyl groups are monocyclic or bicyclic; and each of the aforementioned alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl (e.g.
  • L 1 is independently selected from halogen, boronic acid and boronate ester; wherein P 1 and P 2 are each independently selected from: substituted or unsubstituted benzyl group; Ci-C 4 alkyl or substituted or unsubstituted benzyl carbonate group; or SiR 9 3, wherein R 9 is independently selected from phenyl or Ci-C 4 alkyl;
  • L 2 is independently selected from: H, halogen, boronic acid and boronate ester; in the presence of a catalyst to provide a compound of formula Xllla (where R 2 for the compound of formula X is H) or formula Xlllb (where R 2 for the compound of formula X is not H).
  • the catalyst comprises palladium.
  • L 1 is halogen. It may be that P 1 and P 2 are the same.
  • P 1 and P 2 are both SiR 9 3, e.g. Si('Pr)3. The inventors have surprisingly found that the most efficient and consistent coupling reactions are obtained when both P 1 and P 2 are triisopropylsilyl.
  • R 2 is H, i.e. it may be that the method comprises reacting a compound of formula XIa with a compound of formula XII in the presence of a catalyst to provide a compound of formula Xllla
  • the compounds of formulae Xllla or Xlllb can be converted to the compound of formula X using an ion exchange column. Alternatively, this can be achieved by treating the compound of formula formulae Xllla or Xlllb withTBAF
  • the compound of formula XII is a compound of formula XIV:
  • the method may also comprise the step of converting a compound of formula XV into a compound of formula Xla (where R 2 for the compound of formula X is H) or formula Xlb (where R 2 for the compound of formula X is not H):
  • 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.
  • Compounds of the invention may be depicted throughout this specification as containing a ring with the re:
  • both tautomeric forms form part of the present invention and the disclosure of this specification.
  • the compounds of the invention may in actuality exist entirely in the tautomeric form depicted throughout this specification, as the alternative tautomeric form described in this paragraph or as a mixture of the two tautomeric forms.
  • the existence of the compound in a one form or the other (or, where in a mixture of forms, the distribution of that mixture) may depend on the environment that the compound is in or it may be energetically preferred irrespective of the environment.
  • One tautomer may be more active than the other and, where this is the case, it will not necessarily be the most energetically favourable form (although it may be), and it will not necessary be the form depicted in this specification (although it may be).
  • 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 to 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).
  • 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.
  • aryl groups may include non-aromatic carbocyclic portions.
  • 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.
  • Cycloalkyl groups may be saturated or partially unsaturated. They may be a monocyclic ring or a bicyclic ring system.
  • a haloalkyi group is an alkyl group substituted with at least one halogen substituent, e.g. at least one fluorine substituent.
  • a halocycloalkyl group is a cycloalkyl group substituted with at least one halogen substituent, e.g. at least one fluorine substituent.
  • An alkyl group may be a straight chain alkyl group or it may be a branched chanin alkyl group.
  • a C 4 -alkyl group may be n-butyl, isobutyl or t-butyl.
  • 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 , SOR a , S0 3 R a , S0 2 R a , S0 2 NR a R a , C0 2 R a C(0)R a , CONR a R a , C1-C4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 haloalkyi and CR b R b NR a R a ; wherein R a is independently at each occurrence selected from H, Ci-C 4 alkyl and Ci-C 4 haloalkyi;
  • a heterocycloalkyl group is a saturated or partially saturated ring or bicyclic ring system comprising 1 , 2 or 3 heteroatoms independently selected from O, S and N (in other words from 1 , 2 or 3 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.
  • a heterocycloalkyl group is described as a C 4 heterocycloalkyl group it is intended to mean that the ring system comprises 4 carbon atoms (e.g. a morpholine).
  • a pyrrolidine group is a 5-membered heterocycloalkyl group comprising one nitrogen and four carbon atoms in the ring. It is thus a C 4 heterocycloalkyl group.
  • monocylclic heterocycloalkyl groups include: piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine.
  • Cycloalkyl groups may be saturated or partially unsaturated. They may be a monocyclic ring or a bicyclic ring system.
  • a haloalkyi group is an alkyl group substituted with at least one halogen substituent, e.g. at least one fluorine substituent.
  • a halocycloalkyl group is a cycloalkyl group substituted with at least one halogen substituent, e.g. at least one fluorine substituent.
  • An alkyl group may be a straight chain alkyl group or it may be a branched chanin alkyl group.
  • a C 4 -alkyl group may be n-butyl, isobutyl or t-butyl.
  • the present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (IX) (including formula (la)) 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.
  • isotopically-labelled compounds for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • 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.
  • 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, MRSA, impetigo, tuberculosis, meningitis, abdominal infection, bacteraemia, septicaemia, leprosy and sexually transmitted bacterial infections (e.g.
  • the compounds of the invention can be used to treat infections caused by a resistant strain of bacteria. In a further embodiment, the compounds can be used to treat infections caused by a resistant strain of Gram positive bacteria and/or resistant strains of Gram negative bacteria.
  • the compounds and formulations of the invention may be used to treat infections caused by bacteria which are in the form of a biofilm.
  • resistant strains is intended to mean strains of bacteria which have shown resistance to one or more known antibacterial drug. For example, it may refer to strains which are resistant to methicillin, strains that are resistant to other ⁇ -lactam antibiotics and/or strains that are resistant to fluoroquinolones.
  • a resistant strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a significantly higher number than for the parent (susceptible) strain.
  • the compounds of the invention may be particularly effective at treating infections caused by fluoroquinolone resistant strains of Staphylococcus aureus.
  • 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, parastic infections and/or viral infections.
  • the compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.
  • 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 formic, 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
  • Compounds of the invention may exist in a single crystal form or in a mixtures 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) and, in particular, with other antibacterial compounds.
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • 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 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 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 by inhalation (i.e. in
  • a compound with an in vitro MIC of, for example, 16-64 ug/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.
  • 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. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • 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.
  • 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 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 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.
  • Ketone (1) can be converted to imine (2) by reaction with an excess of tert-butyl amine in the presence of a Lewis acid, such as titanium tetrachloride, or a dehydrating agent, such as para-toluenesulphonic acid, in a solvent, such as DCM.
  • Imine (2) can be converted to hydroxyl 2-pyridones (3) by reaction with CH(C02Et)3, in a high boiling solvent, such as diphenyl ether, at temperatures from 130°C to 230°C.
  • Conversion of the OH in (3) to CI in (4) can be accomplished using a chlorinating agent, such as oxalyl chloride, either neat or in a solvent, such as DCM.
  • thiol (5) Treatment of chloride (4) with potassium thioacetate in a solvent, such as DMF, at temperatures from 0°C to room temperature can deliver thiol (5).
  • Thiol (5) may also be accessed from chloride (4) via reaction with sodium hydrosulphide hydrate in a solvent, such as DMF, at temperatures from 20°C to 50°C.
  • Reaction of thiol (5) with hydroxylamine-O-sulphonic acid in the presence of a base, such as NaHCC or potassium phosphate tribasic, in a solvent, such as a mixture of THF and H2O, can provide isothiazolone (6).
  • Ketone (1) can be prepared as described in Scheme B:
  • Carboxylic acid (7) can be converted to Weinreb amide (8) by treatment with an activating agent, such as thionyl chloride, in a solvent, such as DCM, with heating optional, followed by ⁇ , ⁇ -dimethylhydroxylamine, in the presence of a base, such as pyridine, at a temperature from 0°C to 20°C.
  • Ketone (1) can be formed from reaction of Weinreb amide (8) with metallated species AM (9) (where M represents a metal, such as lithium or magnesium). The reaction can be carried out in a solvent, such as THF, at temperatures from -60°C to 20°C.
  • Ketone (1) can also be formed from reaction of nitrile (10) with Grignard MgCH2Ri . The reaction can be carried out in a solvent, such as diethyl ether, at temperatures from 0°C to 35°C.
  • Isothiazolone (11) (prepared by adaptation of the route described in Scheme A) can be converted to (12) on treatment with triisopropylsilyl tnfluoromethanesulphonate in the presence of a base, such as 2,6-lutidine, in a solvent, such as DCM, at room temperature.
  • a base such as 2,6-lutidine
  • TIPS protected (12) can be treated with amine (13) (where R represents H, C1-C4 alkyl, Ci- C 4 haloalkyl or the R groups can be taken together with the nitrogen of attachment to form a C3-C10 heterocycle optionally substituted with R 7 ) in the presence of a Pd(0) catalyst, such as bis(dibenzylideneacetone)palladium(0), a suitable phosphine ligand, such as 2-(di-tert- butylphosphino)biphenyl, and a suitable base, such as sodium t-butoxide or lithium bis(trimethylsilyl)amide, in a solvent, such as toluene or dioxane, at a temperature from 50°C to 100°C to provide amine (14).
  • Amine (14) can also be obtained directly from (11) without the need for protected intermediate (12).
  • Isothiazolone (11) (prepared by adaptation of the route described in Scheme A) can be converted to (15) (where R3 represents an aryl or heteroaryl group, optionally substituted) through cross coupling with arylB(OH)2 or heteroaryl B(OH)2 using standard Suzuki coupling conditions of a Pd catalyst, such as Pd(PP i3) 4 , in the presence of a base, such as NaHCC or K2CO3, in a solvent, such as DMF or THF, at temperatures from 20°C to 100°C.
  • a Pd catalyst such as Pd(PP i3) 4
  • Chloride (4) (prepared as described in Scheme A) can be converted to the isoxazolone (16) by reaction with hydroxyurea in the presence of a base, such as 1 ,8- diazabicyclo[5,4,0]undec-7-ene (DBU), in an alcoholic solvent, such as CH3OH, at room temperature.
  • a base such as 1 ,8- diazabicyclo[5,4,0]undec-7-ene (DBU)
  • DBU 1 ,8- diazabicyclo[5,4,0]undec-7-ene
  • Chloride (4) (prepared as described in Scheme A) can be converted to the pyrazolone (20) by reaction with NH2NHR4 in a high boiling solvent, such as NMP, at temperatures from 100°C to 200°C.
  • a high boiling solvent such as NMP
  • Chloride (4) (prepared as described in Scheme A) can be alkylated with R2LG (where LG represents a leaving group, such as halide or tosyl group).
  • the reaction can be carried out with a base, such as NaH, in a solvent, such as DMF, at temperatures from 0°C to 20°C.
  • Pyridone (24) can be transformed to isothiazolone (25), isoxazolone (26) and pyrazolone (27) by following Scheme A, E and F respectively.
  • Isothiazolone (25) can be converted to sulphoxide (37) by reaction with an oxidising agent, such as mCPBA, in a solvent, such as DCM, at temperatures from 0°C to 20°C.
  • an oxidising agent such as mCPBA
  • a solvent such as DCM
  • PMB protected (39) can be treated with amine (13) (where R represents H, C1-C4 alkyl, C1-C4 haloalkyi or the R groups can be taken together with the nitrogen of attachment to form a C3-C10 heterocycle optionally substituted with R 7 ) in the presence of a Pd(0) catalyst, such as bis(dibenzylideneacetone)palladium(0), a suitable phosphine ligand, such as 2-(di-tert-butylphosphino)biphenyl, and a suitable base, such as sodium t-butoxide or CS2CO3, in a solvent, such as toluene or dioxane, at a temperature from 50°C to 100°C to provide amine (40).
  • a Pd(0) catalyst such as bis(dibenzylideneacetone)palladium(0)
  • a suitable phosphine ligand such as 2-(di-tert-butylphosphino)
  • Deprotection of the remaining PMB group can be effected with HCI in a solvent, such as dioxane, at room temperature.
  • Conversion of the OH in (41) to CI in (42) can be accomplished using a chlorinating agent, such as oxalyl chloride, either neat or in a solvent, such as DCM.
  • Pyridone (42) can be converted to (43), where PG* represents an O- linked protecting group, such as DMB.
  • the reaction can be carried out under Mitsunobu conditions using 2,4-dimethoxybenzyl alcohol in the presence of PP and DIAD in a solvent, such as THF, at temperatures from 0°C to 20°C.
  • DMB protected chloride (43) Treatment of DMB protected chloride (43) with potassium thioacetate in a solvent, such as DMF, at temperatures from 0°C to room temperature can deliver DMB protected thiol (44).
  • Thiol (44) may also be accessed from DMB protected chloride (43) via reaction with sodium hydrosulphide hydrate in a solvent, such as DMF, at temperatures from 20°C to 50°C.
  • Reaction of DMB protected thiol (44) with hydroxylamine-O-sulphonic acid in the presence of a base, such as NaHC03 or potassium phosphate tribasic, in a solvent, such as a mixture of THF and H2O, can provide DMB protected isothiazolone (45).
  • Removal of the DMB group to yield (14) can be effected with neat trifluoromethanesulphonic acid at room temperature.
  • NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A). MS was carried out on a Waters ZQ MS (Method A, B and 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).
  • Method A Column: XBridgeTM prep C18 5 ⁇ OBD 19 x 100 mm. Flow rate: 20 mL/min.
  • Method B Column: XBridgeTM prep C18 5 ⁇ OBD 19 x 100 mm. Flow rate: 20 mL/min.
  • Example 1 -6-[4-[3-(Dimethylamino)pyrrolidin-1-yl]phenyl]-7-ethyl-5H-isothiazolo[4,5- clpyridine-3,4-dione 1e
  • the aqueous extractions were combined and acidified dropwise with HCI (37%) to pH 1.
  • the aqueous fraction was extracted with DCM (3 x 50 mL).
  • the organic layers were combined, dried over Na2S0 4 and concentrated in vacuo to give ethyl 6-(4-chlorophenyl)-5- ethyl-2-oxo-4-sulfanyl-1 H-pyridine-3-carboxylate 1c as a brown solid.
  • the crude solid was used immediately to avoid degradation.
  • the vessel was sealed and purged with alternative applications of vacuum and N2, then N,N-dimethylpyrrolidin-3-amine (0.1 ml_, 0.8 mmol) and toluene (0.5 ml_) was added.
  • the vessel was heated, with stirring, to 100°C in an oil bath overnight.
  • the reaction was cooled to room temperature and further small spatula tips of catalyst and ligand were added.
  • the reaction was resealed, purged with alternative applications of vacuum and N2 and heated, with stirring, to 100°C in an oil bath overnight.
  • the reaction mixture was cooled to room temperature and loaded in MeOH onto a pre- equilibrated SCX ion exchange column.
  • test solutions for compound 2b used in Examples 21 and 22 were prepared by dissolving the formate salt in the appropriate solvent.
  • reaction mixture was evaporated to dryness under reduced pressure and the crude product was purified by flash chromatography using petroleum ether (40-60) in EtOAc (0-20% gradient) to furnish ethyl-6-(4-chlorophenyl)-5-ethyl-2,4-bis[(4-methoxyphenyl)methoxy]pyridine-3-carboxylate 7a (420 mg, 50%) as a pale yellow oil.
  • test solutions for compound 7d used in Examples 21 and 22 were prepared by dissolving the diformate salt in the appropriate solvent.
  • MICs Minimum Inhibitory Concentrations versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Ninth Edition. CLSI document M07-A9, 2012).
  • the broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.25-128 ⁇ g/mL and a maximum final concentration of 1 % DMSO.
  • the bacterial strains tested include the gram-positive strain Staphylococcus aureus ATCC 29213 and the Gram- negative strains Escherichia coli ATCC 25922, Acinetobacter baumannii NCTC 13420, Enterobacter cloacae NCTC 13406, Haemophilus influenzae ATCC 49247, Klebsiella pneumoniae ATCC 700603, Klebsiella pneumoniae NCTC 13443, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa NCTC 13437, Neisseria gonorrhoeae ATCC 49226 and Neisseria meningitidis ATCC 13090.
  • the tested compounds of the invention thus show good activity against a range of bacterial pathogens, including some strains which have shown resistance to known antibacterial drug molecules.
  • the compounds show good activity against both Gram-positive bacteria (e.g. S. aureus) and Gram-negative bacteria (e.g. P. aeruginosa).
  • 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% foetal bovine serum (FBS) and 1 mM sodium pyruvate.
  • MEM minimal essential medium
  • FBS foetal bovine serum
  • DMEM Dulbecco's minimum essential media
  • A represents a concentration of 1 ⁇ g/mL or lower; B represents a concentration of from 1.1 to 8 ⁇ g/mL; C represents a concentration of from 9 ⁇ g/mL to 127 ⁇ g/mL; and D represents a concentration of 128 ⁇ g/mL or higher.
  • a known isothiazolinone antibacterial compound has an IC50 of 16 ⁇ g/mL (compound 4 of Kim et al; J. Med. Chem.; 2011, 54, 3268-3282).
  • the tested compounds of the invention therefore demonstrate a very favourable cytotoxicity profile.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne des composés de médicament antibactériens de formule (I) contenant un cycle isothiazolinone ou pyrazolone condensé et des composés associés. L'invention concerne également des formulations pharmaceutiques de composés de médicament antibactériens. L'invention concerne également des utilisations des dérivés dans le traitement d'infections bactériennes et dans des méthodes de traitement d'infections bactériennes. De nombreux composés de médicament antibactériens contiennent un cycle isothiazolinone ou pyrazolone condensé sur un cycle pyridone. Les composés présentent une activité antibactérienne à large spectre mais sont particulièrement efficaces contre les souches à Gram négatif. X étant choisi parmi S, SO, SO2, O et NR4.
PCT/GB2015/050182 2014-01-28 2015-01-27 5h-isothiazolo[4,5-c]pyridine-3,4-dione ou 5h-pyrazolo[4,3-c]pyridine-3,4-dione en tant que composés antibactériens Ceased WO2015114317A1 (fr)

Applications Claiming Priority (4)

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GB201401407A GB201401407D0 (en) 2014-01-28 2014-01-28 Antibacterial Compounds
GB1401407.0 2014-01-28
GB201417939A GB201417939D0 (en) 2014-10-10 2014-10-10 Antibacterial compounds
GB1417939.4 2014-10-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105175321A (zh) * 2015-08-10 2015-12-23 上海瑞博化学有限公司 2-氨基-5-羟基吡啶的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04198185A (ja) * 1990-11-28 1992-07-17 Dainippon Pharmaceut Co Ltd イソチアゾロ〔５，４―ｂ〕ピリジン誘導体
WO2007014308A1 (fr) * 2005-07-27 2007-02-01 Achillion Pharmaceuticals, Inc. 8-methoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones et composes afferents, comme agents anti-infectieux
WO2007137255A2 (fr) * 2006-05-22 2007-11-29 Thioredoxin Systems Ab Inhibiteurs de thioredoxine reductase bacterienne et procédés d'utilisation afférents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04198185A (ja) * 1990-11-28 1992-07-17 Dainippon Pharmaceut Co Ltd イソチアゾロ〔５，４―ｂ〕ピリジン誘導体
WO2007014308A1 (fr) * 2005-07-27 2007-02-01 Achillion Pharmaceuticals, Inc. 8-methoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones et composes afferents, comme agents anti-infectieux
WO2007137255A2 (fr) * 2006-05-22 2007-11-29 Thioredoxin Systems Ab Inhibiteurs de thioredoxine reductase bacterienne et procédés d'utilisation afférents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HA YOUNG KIM ET AL: "Exploration of the Activity of 7-Pyrrolidino-8-methoxyisothiazoloquinolones against Methicillin-Resistant Staphylococcus aureus (MRSA)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 9, 12 May 2011 (2011-05-12), pages 3268 - 3282, XP055169387, ISSN: 0022-2623, DOI: 10.1021/jm101604v *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105175321A (zh) * 2015-08-10 2015-12-23 上海瑞博化学有限公司 2-氨基-5-羟基吡啶的合成方法

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