WO2009034386A1 - Dérivés de l'adénine et de la 8-aza-adénine et leurs utilisations - Google Patents

Dérivés de l'adénine et de la 8-aza-adénine et leurs utilisations Download PDF

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WO2009034386A1
WO2009034386A1 PCT/GB2008/050812 GB2008050812W WO2009034386A1 WO 2009034386 A1 WO2009034386 A1 WO 2009034386A1 GB 2008050812 W GB2008050812 W GB 2008050812W WO 2009034386 A1 WO2009034386 A1 WO 2009034386A1
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Prior art keywords
purin
amine
butoxy
ylethyl
morpholin
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PCT/GB2008/050812
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English (en)
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Gloria Breault
Charles Joseph Eyermann
Bolin Geng
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009034386A1 publication Critical patent/WO2009034386A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel derivatives of adenine and 8-aza-adeninine, their pharmaceutical compositions and methods of use.
  • the present invention relates to the use of derivatives of adenine and 8-aza-adeninine for treatment and prevention of various diseases caused by bacteria, for example, Enterococcus faecalis or Enterococcus faecium infection.
  • Most bacteria utilize a cell wall comprised of crosslinked peptidoglycan units to maintain shape and resist high osmotic pressure potentials.
  • Bacterial cell wall biosynthesis is a validated target for antimicrobial activity; cephalosphorins, penicillins and glycopeptides are antimicrobial agents, which block cell wall biosynthesis (Walsh, C, Molecular mechanisms that confer antibacterial resistance. Nature, 2000, 406: p. 775-781).
  • Cell wall biosynthesis requires the enzyme Murl, a glutamate racemase, and therefore this enzyme is essential for bacterial viability (Doublet, P., et al., The murl gene of Escherichia coli is an essential gene that encodes a glutamate racemase activity.
  • the present invention describes novel derivatives of adenine and 8-aza-adeninine, which inhibit bacterial Murl, e.g., E.faecalis Murl or E. faecium Murl, and compositions of such compounds and methods of use.
  • the compounds disclosed herein represent a valuable contribution to the development of therapies directed to diseases resulting from bacterial infection, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections or, for example, E.faecalis, or E.faecium infection.
  • the compounds are of particular interest to treat infections that are resistant to conventional antibiotics, such as penicillin and cephalosporin.
  • the invention relates to compounds represented by formula (I):
  • X 2 is -O-, -S-, or -NR a -, wherein R a is hydrogen or a
  • Ri is a C 3 _i 4 carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H- pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1-benzothiophenyl, furanyl, thiazolyl, isoxazolyl, or oxetanyl, wherein the carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H-pyrazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran,
  • R 5 , R5 and R 7 are independently selected from the group consisting of a halo, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i4carbocycle, heterocycle, C 3-14 carbocycleC 1-6 alkyl, heterocycleC 1-6 alkyl, C 1-6 haloalkyl, -ORn, -SRn, - NR 12 R 13 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 12 R 13 , -NR 11 C(O)R 11 , -OC(O)R 11 , -NR 11 C(O)OR 11 , -OC(O)NR 12 R 13 , -NR 11 C(O)NR 12 R 13 , -NR 11 C(O)NR 12 R 13 , -NR 11 C(NR 14 )NR 12 R 13 , -S(O) p R ⁇ ,
  • R 8 , R 9 , or R 17 are independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-1 4carbocycle, heterocycle, C 3- 14 carbocycleC 1-6 alkyl, heterocycleC 1-6 alkyl, C 1-6 haloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NRi 2 Rn, -S(O)pRn,and -S(O) p NRi 2 Ri3, wherein if R 8 , R 9 or R n is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally substituted on one or more carbon atoms with one or more Ri 5 ; and wherein if R 8 , R 9 or Rn is a heterocycle or a heterocyclealkyl that comprises
  • Rio is hydrogen, a Ci -6 alkyl, a heterocycleCi -6 alkyl, -NRi 2 Rn, -C(O)Rn, -C(O)ORn, -C(O)NRi 2 R n , -NRnC(O)Rn, -OC(O)Rn, -NRnC(O)ORn, -OC(O)NRi 2 Ri 3 , - NRnC(NRi 4 )NRi 2 Ri 3 , -S(O) p Rn, -NRnS(0) p Rn, and -S(O) p NRi 2 Ri 3 ;
  • R 16 for each occurrence, is independently selected from the group consisting of Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 carbocycle, heterocycle, C 3-14 carbocycleC 1-6 alkyl, heterocycleCi-ealkyl, Ci -6 haloalkyl, -C(O)Ri 8 , -C(O)ORi 8 , -C(O)NRi 9 R 20 , -S(O) p Ri 8 , and -
  • Ri 8 for each occurrence, is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 carbocycle, heterocycle, C 3- i4carbocycleCi. 6 alkyl, heterocycleC 1-6 alkyl;
  • Ri 9 and R 20 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 carbocycle, heterocycle, C 3-
  • Ri is not an unsubstituted phenyl, unsubstituted biphenyl, an unsubstituted cyclopropyl, or 3-cyclopentyloxy-4-methoxyphenyl; when Ri is 4-chlorophenyl, 4-fiuorophenyl, cyclohexyl, or furanyl, R 2 is not unsubstituted naphthyl or unsubstituted cyclopentyl; when Ri is morpholinyl, one of R 3 and R 4 are not 4-aminobenzyl or phenylethyl; when X 2 is -NR a -, R 2 is a C 1-6 alkyl which is optionally substituted with on one or more carbon atom with one or more R 6 , and Ri is not 4-aminophenyl, 2-chlorophenyl, 4- methylphenyl, 3-(methoxycarbonylmethyl)-phenyl, 2-fluorophenyl, or 2,6-
  • Ri when -X 2 -R 2 is methylsulfanyl, Ri is not 4-methylphenyl, 2-methoxyphenyl, or 2- fluorophenyl; when -X2-R2 is an unsubstituted n-butyloxy , Ri is not 3-(2-methoxy-2-oxoethyl)- phenyl, 3-cyanomethyl-phenyl, 3-chloromethyl-phenyl, 3-hydroxymethyl-phenyl, 4- benzyloxyphenyl, 3-cyanomethyl-4-fluoro-phenyl, 3-chloromethyl-4-fluoro-phenyl, 3- hydroxymethyl-4-fluoro-phenyl, 3-methoxycarbonyl-4-fluoro-phenyl, 2-methoxy-5- cyanomethyl-phenyl, 2-methoxy-5 -chloromethyl-phenyl, 2-methoxy-5 -hydroxymethyl- phenyl, 2-methoxy-5-methoxycarbonyl-phenyl,
  • X 3 , R 2 , R3, and R4 are defined as above, and wherein: X 4 is -O- or -S-; R22 is a C3-6alkyl which is optionally substituted on one or more carbon atom with one or more substituents selected from the group consisting of halo, nitro, cyano, -ORn, -SRn, - NRi 2 R n , -C(O)Rn, -C(O)ORn, -C(O)NRi 2 R n , -NRnC(O)Rn, -OC(O)Rn, -NRnC(O)ORn, -OC(O)NRi 2 Ri 3 , -NRnC(O)NRi 2 Ri3, -NRnC(NRi 4 )NRi 2 Ri 3 , -S(O) p Rn, -NRnS(0) p
  • one or both of the following provisos apply: when both R 3 and R 4 are hydrogen, R 2 and R 22 are not both n-hexyl or both n-propyl, or R 22 is not n-propyl and R 2 is not methyl; and when R 2 is methyl, R 3 and R 4 taken together with the nitrogen atom to which they are attached are not a substituted or unsubstituted piperazino.
  • Compounds represented by formula (I) or (II) have bacterial, e.g., E.faecalis Murl, or E.faecium Murl, inhibitory activity and are accordingly useful for their treatment and prophylaxis of various diseases caused by bacteria expressing Murl, for example E.faecalis or E.faecium infection, and thus in methods of treatment or prophylaxis for humans and animals.
  • the invention also relates to processes for the manufacture of compounds represented by formula (I) or (II), to pharmaceutical compositions containing compounds represented by formula (I) or (II), and to their use in the manufacture of medicaments for use in the treatment and prophylaxis of various diseases caused by bacterial infection, e.g., E.faecalis ox E.faecium infection, in a warm-blooded animal such as man.
  • bacterial infection e.g., E.faecalis ox E.faecium infection
  • the term “carbocycle” refers to a monocyclic or polycyclic, saturated, partially saturated or unsaturated ring system having 3 to 14 ring atoms, wherein all the ring atoms are carbon atoms. Carbocyclic ring systems can be unsubstituted or substituted with one or more independently selected substituents. Carbocyclic ring systems include aryl, cycloalkenyl, and cycloalkyl ring systems.
  • the term “C3_i4carbocycle” refers to a carbocycle having from 3 to 14 ring carbon atoms.
  • aryl means a monocyclic or poly cyclic-aromatic ring system.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fiuorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • An aryl group can be unsubstituted or substituted with one or more independently selected substituents.
  • C ⁇ - ⁇ aryl refers to an aryl group having from 6 to 14 ring carbon atoms.
  • the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms.
  • cycloalkyl means a saturated, mono- or polycyclic alkyl radical typically having from 3 to 14 carbon atoms.
  • Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly, decahydronaphthyl, octahydropentalene, bicycle[l.l.l]pentanyl, and the like.
  • Cycloalkyl groups can be unsubstituted or substituted with one or more independently selected substituents.
  • the term "C 3 -i 4 cycloalkyl” refers to a cycloalkyl group having from 3 to 14 ring carbon atoms.
  • cycloalkenyl means a cyclic non-aromatic alkenyl radical having at least one carbon-carbon double bond in the cyclic system and typically having from 5 to 14 carbon atoms.
  • Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl and the like.
  • Cycloalkenyl groups can be unsubstituted or substituted with one or more independently selected substituents.
  • C 3 -i 4 Cycloalkenyl refers to a cycloalkenyl group having from 3 to 14 ring carbon atoms.
  • alkyl means a saturated straight chain or branched non- cyclic hydrocarbon typically having from 1 to 10 carbon atoms, preferably 1-6 carbon atoms.
  • saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3- dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylp
  • alkenyl means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms, preferably 2-6 carbon atom, and having at least one carbon-carbon double bond.
  • Representative straight chain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1- butenyl, l-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3- nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like.
  • Alkenyl groups can be unsubstituted or substituted with one or more independently selected substituents on the saturated or unsaturated portion of the akenyl group.
  • C 2 - 6 alkenyl refers to an alkenyl group having from 2 to 6 carbon atoms.
  • alkynyl means a straight chain or branched, hydrocarbonon radical typically having from 2 to 10 carbon atoms, preferably 2-6 carbon atoms, and having at lease one carbon-carbon triple bond.
  • Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1- butynyl, 4-pentynyl-l-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1- octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 2-decy
  • alkylene refers to an alkyl group that has two points of attachment to two moieties (e.g., -CH 2 -, -CH 2 CH 2 -, etc.). Alkylene groups may be unsubstituted or substituted with one or more independently selected substituents.
  • Ci_6alkylene refers to an alkylene group having from 1 to 6 carbon atoms.
  • An alkylene group is also referred to herein as a divalent alkyl group.
  • divalent Ci- 6 alkenyl refers to a divalent alkenyl group having from 1 to 6 carbon atoms.
  • divalent Ci- 6 alkynyl refers to a divalent alkynyl group having from 1 to 6 carbon atoms.
  • Carbocyclealkyl refers to a carbocycle group that is attached to another moiety via an alkylene linker.
  • Cs- ⁇ carbocycleCi-ealkyl refers to a C3_i4carbocycle group that is attached to another moiety via a linker.
  • Carbocyclealkyl groups can be unsubstituted or substituted on the alkyl or carbocycle portion with one or more independently selected substituents.
  • Representative carbocyclealkyl groups include benzyl, cyclopropylmethyl, phenylethyl, 2-(naphth-l-yl)-propyl, 2-(fluoren-9-yl)- ethyl, 3-cyclohexyl-propyl, and the like.
  • arylalkyl refers to an aryl group that is attached to another moiety via an alkylene linker.
  • Ce- ⁇ arylCi-ealkyl refers to a C ⁇ - ⁇ aryl group that is attached to another moiety via a Ci-6alkylene linker.
  • Arylalkyl groups can be unsubstituted or substituted with one or more independently selected substituents.
  • Representative arylalkyl groups include benzyl, phenylethyl, 2-(naphth-l-yl)-propyl, 2-(fluoren-9-yl)-ethyl, and the like.
  • heterocycle refers to a monocyclic or polycyclic heterocyclic ring having 3- to 14- ring members which is either a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring.
  • a 3-membered heterocycle can contain up to 3 heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 to about 8 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the heterocycle may be attached to another moiety via a nitrogen or carbon atom.
  • heterocycle encompasses heteroaryl rings, heterocycloalkenyl rings, and heterocycloalkyl rings.
  • heteroaryl means a monocyclic or polycyclic aromatic ring system having carbon atom ring members and one or more heteroatom ring members selected from oxygen, sulfur or nitrogen.
  • a heteroaryl ring has from 5 to about 14 ring members in which at least 1 ring member is a heteroatom selected from oxygen, sulfur and nitrogen.
  • the heteroaryl ring is a 5 or 6 membered ring and may contain from 1 to about 4 heteroatoms.
  • the heteroaryl ring has a 7 to 14 ring members and may contain from 1 to about 7 heteroatoms.
  • heteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl
  • heterocycloalkyl refers to a saturated, monocyclic or polycyclic ring system having carbon atom ring members and one or more heteroatom ring members selected from oxygen, sulfur or nitrogen. Heterocycloalkyl groups may be optionally substituted on a carbon or a nitrogen ring atom with one or more independently selected substituents.
  • a heterocycloalkyl has from 3 to 14 ring members.
  • heterocycloalkyl groups include morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • heterocycloalkenyl refers to a partially unsaturated, non-aromatic, monocyclic or polycyclic ring system having carbon atom ring members and one or more heteroatom ring members selected from oxygen, sulfur or nitrogen. Heterocycloalkenyl groups may be optionally substituted on a carbon or a nitrogen ring atom with one or more independently selected substituents. A heterocycloalkenyl has from 3 to 14 ring members. Representative heterocycloalkenyl groups include 4H-pyranyl, tetrahydropyridinyl, dihydropyridinyl, and the like.
  • heterocyclealkyl group refers to a heterocycle that is attached to another moiety via an alkylene linker.
  • heterocycleCi- 6 alkyl refers to a heterocycle group that is attached to another moiety via an alkylene having from 1 to 6 carbon atoms.
  • Heterocyclealkyl groups can be unsubstituted or substituted on the heterocycle or alkyl portion with one or more independently selected substituents.
  • alkoxy refers to an alkyl group which is linked to another moiety though an oxygen atom.
  • Ci-6alkoxy refers to an alkoxy group that has from 1 to 6 carbon atoms. Alkoxy groups can be substituted or unsubstituted with one or more independently selected substituents.
  • alkylsulfanyl refers to an alkyl group which is linked to another moiety though a divalent sulfur atom.
  • Ci- 6 alkylsulfanyl refers to an alkylsulfanyl group that has from 1 to 6 carbon atoms.
  • Alkylsulfanyl groups can be substituted or unsubstituted with one or more independently selected substituents.
  • arylsulfanyl refers to an aryl group which is linked to another moiety though a divalent sulfur atom.
  • Ce- ⁇ arylsulfanyl refers to an arylsulfanyl group that has from 6-14 ring carbon atoms.
  • Arylsulfanyl groups can be substituted or unsubstituted with one or more independently selected substituents.
  • amino refers to -NH 2 .
  • alkylamino refers to an amino group in which one hydrogen atom attached to the nitrogen has been replaced by an alkyl group.
  • Ci.6alkylamino refers to an alkylamino group in which the alkyl portion has from 1 to 6 carbon atoms.
  • dialkylamino refers to an amino group in which two hydrogen atoms attached to the nitrogen have been replaced by alkyl groups, in which the alkyl groups can be the same or different.
  • 6dialkylamino refers to a dialkylamino group in which each alkyl group, independently, has from 1 to 6 carbon atoms.
  • Alkylamino groups and dialkylamino groups can be substituted or unsubstituted with one or more independently selected substituents.
  • halogen or “halo” means fluoro, chloro, bromo, or iodo.
  • haloalkyl means an alkyl group in which one or more -H is replaced with a halo group.
  • Ci -6 IIaIo alkyl refers to a haloalkyl that has 1-6 carbon atoms.
  • Representative haloalkyl groups include -CF 3 , -CHF 2 , -CCl 3 , -CH 2 CH 2 Br, - CH 2 CH(CH 2 CH 2 Br)CH 3 , -CHICH 3 , and the like.
  • hydroxyalkyl means an alkyl group in which one or more - H is replaced with an -OH group.
  • Ci- 6 hydroxyalkyl refers to a hydroxyalkyl that has 1-6 carbon atoms.
  • Representative hydroxyalkyl groups include -CH 2 OH, -CH(OH) 2 , - CH 2 CH 2 OH, -CH 2 CH(CH 2 CH 2 OH)CH 3 , -CH(OH)CH 3 , and the like.
  • lower refers to a group having up to four carbon atoms.
  • a “lower alkyl” refers to an alkyl radical having from 1 to 4 carbon atoms
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
  • a lower alkoxy or a lower alkylsulfanyl refers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms. Lower substituents are typically preferred.
  • compound(s) of this invention refers to a compound of formula (I) or (II), or any exemplified compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • displaceable group refers to a group which can be displaced by a nucleophile under the reaction condition specified. Skilled artisan can select displaceable groups which can be displaced by a particular nucleophile under particular reaction conditions. Preferred displaceable groups are halo groups.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, but they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formulas (I) or (II), or any of the exemplified compounds disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of formulas (I) or (II), or any of the exemplified compounds disclosed herein that comprise -NO, -NO 2 , -ONO, or -ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949- 982 (Manfred E. Wolff ed., 5.sup.th ed), the entire teachings of which are incorporated herein by reference.
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, CC- amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocycle amines, and polyether amines.
  • a biohydrolyzable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include d-ealkoxymethyl esters for example methoxymethyl, d-ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyCi.
  • alkyl esters for example l-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci- 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • a biohydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and CC -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and CC -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydro lyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and ⁇ /-(dialkylaminoethyl)-7V-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.
  • the term "pharmaceutically acceptable salt,” is a salt formed from an acid and a basic group of a compound of the invention.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis- (2-)-
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butyl
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of the invention having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • solvate is a solvate formed from the association of one or more solvent molecules to one or more molecules of a compound of a compound of the invention.
  • solvate includes hydrates (e.g., hemi- hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • Some compounds of the invention may have chiral centres and/or geometric isomeric centres (e.g., E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess E.faecalis Murl or E. faecium Murl inhibitory activity.
  • the invention relates to any and all tautomeric forms of the compounds of the invention that possess E.faecalis Murl or E. faecium Murl inhibitory activity.
  • a "subject,” as used herein, refers to a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a Murl enzyme for cell wall biosynthesis, such as E.faecalis and E. faecium infections.
  • Treating a subject with a disease caused by a bacterial infection includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.
  • preventing a bacterial infection refers to the reduction in the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.
  • the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the present invention provides a compound of formula (I):
  • X 2 is -O-, -S-, or -NR a -, wherein R a is hydrogen or a
  • Ri is a C 3 _i 4 carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H- pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1-benzothiophenyl, furanyl, thiazolyl, isoxazolyl, or oxetanyl, wherein the carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H-pyrazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran,
  • R 5 , R5 and R 7 are independently selected from the group consisting of a halo, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i4carbocycle, heterocycle, C 3-14 carbocycleC 1-6 alkyl, heterocycleC 1-6 alkyl, C 1-6 haloalkyl, -ORn, -SRn, - NR 12 R 13 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 12 R 13 , -NR 11 C(O)R 11 , -OC(O)R 11 , -NR 11 C(O)OR 11 , -OC(O)NR 12 R 13 , -NR 11 C(O)NR 12 R 13 , -NR 11 C(O)NR 12 R 13 , -NR 11 C(NR 14 )NR 12 R 13 , -S(0) p R ⁇ , -
  • R 9 , or R 17 are independently selected from the group consisting of C 1-6 alkyl, C 2- 6alkenyl, C 2- 6alkynyl, C 3-1 4carbocycle, heterocycle, C 3- 14 carbocycleC 1-6 alkyl, heterocycleC 1-6 alkyl, C 1-6 haloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 12 R 13 , -S(O)pR ⁇ ,and -S(O) P NR 12 R 13 , wherein if R 8 , R 9 or R 17 is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally substituted on one or more carbon atoms with one or more R 15 ; and wherein if R 8 , R 9 or R 17 is a heterocycle or a heterocyclealkyl that comprises one
  • R 10 is hydrogen, a C 1-6 alkyl, a heterocycleC 1-6 alkyl, -NR 12 R 13 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 12 R 13 , -NR 11 C(O)R 11 , -OC(O)R 11 , -NR 11 C(O)OR 11 , -OC(O)NR 12 R 13 , - NR 11 C(NR 14 )NR 12 R 13 , -S(O) p R ⁇ , -NR 11 S(O) P R 11 , and -S(O) P NR 12 R 13 ;
  • R 11 for each occurrence, is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2- 6alkenyl, C 2- 6alkynyl, C 3-1 4carbocycle, heterocycle, C 3-14 Ca ⁇ OCyCIeC 1- ⁇ alkyl, heterocycleC ⁇ ealkyl, wherein
  • Ri5 for each occurrence, is independently selected from the group consisting of halo, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3_i4carbocycle, heterocycle, C 3-
  • Ri 4 and R 2 are independently selected from the group consisting of hydrogen, a C 1-6 alkyl, nitro, cyano, amino, alkylamino, dialkylamino, or hydroxy;
  • R 16 for each occurrence, is independently selected from the group consisting of Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i4carbocycle, heterocycle, C 3-14 carbocycleC 1-6 alkyl, heterocycleCi -6 alkyl, Ci -6 haloalkyl, -C(O)Ri 8 , -C(O)ORi 8 , -C(O)NRi 9 R 20 , -S(O) p Ri 8 , and - Ri 8 , for each occurrence, is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i4carbocycle, heterocycle, C 3- i4carbocycleCi_ 6 alkyl, heterocycleC 1-6 alkyl; R 19 and R20, for each occurrence, are independently selected from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 - 6
  • Ri is not an unsubstituted phenyl, unsubstituted biphenyl, an unsubstituted cyclopropyl, or 3-cyclopentyloxy-4-methoxyphenyl; when Ri is 4-chlorophenyl, 4-fiuorophenyl, cyclohexyl, or furanyl, R 2 is not unsubstituted naphthyl or unsubstituted cyclopentyl; when Ri is morpholinyl, one of R 3 and R 4 are not 4-aminobenzyl or phenylethyl; when X2 is -NR a -, R2 is a which is optionally substituted with on one or more carbon atom with one or more R 6 , and Ri is not 4-aminophenyl, 2-chlorophenyl, 4- methylphenyl, 3-(methoxycarbonylmethyl)-phenyl, 2-fluorophenyl, or 2,6-difiuoroph
  • Ri when -X 2 -R 2 is methylsulfanyl, Ri is not 4-methylphenyl, 2-methoxyphenyl, or 2- fluorophenyl; when -X2-R2 is an unsubstituted n-butyloxy , Ri is not 3-(2-methoxy-2-oxoethyl)- phenyl, 3-cyanomethyl-phenyl, 3-chloromethyl-phenyl, 3-hydroxymethyl-phenyl, 4- benzyloxyphenyl, 3-cyanomethyl-4-fluoro-phenyl, 3-chloromethyl-4-fluoro-phenyl, 3- hydroxymethyl-4-fluoro-phenyl, 3-methoxycarbonyl-4-fluoro-phenyl, 2-methoxy-5- cyanomethyl-phenyl, 2-methoxy-5 -chloromethyl-phenyl, 2-methoxy-5 -hydroxymethyl- phenyl, 2-methoxy-5-methoxycarbonyl-phenyl,
  • R22 is a C 3- 6alkyl which is optionally substituted on one or more carbon atom with one or more substituents selected from the group consisting of halo, nitro, cyano, -ORn, -SRn, - NR 12 R 13 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 12 R 13 , -NR 11 C(O)R 11 , -OC(O)R 11 , -NR 11 C(O)OR 11 , -OC(O)NR 12 R 13 , -NR 11 C(O)NR 12 R 13 , -NR 11 C(NR 14 )NR 12 R 13 , -S(O) p R ⁇ , -NR n S(0) p Rn, and -S(O) P NR 12 R 13 ; wherein R 11 , Ri 2 , Ri 3 , RH, and p are defined as above.
  • one or both of the following provisos apply: when both R 3 and R 4 are hydrogen, R 2 and R 22 are not both n-hexyl or both n-propyl, or R 22 is not n-propyl and R 2 is not methyl; and when R 2 is methyl, R 3 and R 4 taken together with the nitrogen atom to which they are attached are not a substituted or unsubstituted piperazino.
  • Ri is a C 3- i4carbocycle which is optionally substituted on one or more carbon atoms with one or more independently selected R 5 .
  • Ri is phenyl which is optionally substituted with one or more independently selected R 5 .
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N- methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fi
  • Ri is morpholinyl which is optionally substituted on one or more carbon atom with one or more independently selected R 5 , and wherein if the morpholinyl comprises -NH-, it may be optionally substituted on the nitrogen atom with Rn.
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2- (N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fi
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, Rn is selected from the group consisting of C 1-4 alkyl, benzyl, acetyl, C i- 4 alkoxycarbonyl, carbamoyl,
  • Ri is benzodioxinyl or benzodioxolyl, which can be optionally substituted on one or more carbon atom with one or more independently selected R 5 .
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2- (N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfon
  • Ri is quinolinyl which is optionally substituted with one or more independently selected R 5 and which is optionally substituted on the nitrogen atom with an oxo.
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l- yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole- 5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, amino sulfonyl, 4-
  • Xi is -CH 2 -.
  • Xi is - C(O)CH 2 -, -CH 2 C(O)-, -C(O)-, -CH(OH)CH 2 -, or -CH 2 CH 2 -.
  • X 2 is -0-.
  • X 2 is -S-.
  • X 2 is -NR a -.
  • R a is H.
  • R a is a Ci- 6 alkyl.
  • R a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
  • R 22 is an unsubstituted C3.6alkyl group.
  • R 22 is propyl, butyl, 2,3-dihydroxy-propyl, 3-cycanopropyl, 2-methyl-propyl, 3-phenoxy-2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-3-methoxy-propyl, 4,4,4-trifluoro-butyl, 2- hydroxybutyl, 2-ethyl-butyl, 4-cyanobutyl, or isopentyl.
  • X4 is -0-.
  • X4 is -S-.
  • R 2 is Ci- 6alkyl which is optionally substituted on one or more carbon atoms with one or more R 6 .
  • R 2 is a Ci_ 6 alkyl selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopentyl, and 2-methylbutyl, wherein the Ci- 6alkyl may be optionally substituted on one or more carbon atom with one or more R 6 .
  • R 6 for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N,N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • R 2 is a C 3 _ 6 Cycloalkyl which may be optionally substituted on one or more carbon atom with one or more R 6 .
  • R 2 is cyclopentyl or cyclohexyl which may be optionally substituted on one or more carbon atom with one or more R 6 .
  • R 6 for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, ⁇ /, ⁇ /-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • R 2 is decahydronaphthalenyl, phenyl, but-2-en-l-yl, pent-2-yn-l-yl, but-2-yn-l-yl, or phenyl, each of which may be optionally substituted on one or more carbon atom with one or more R 6 .
  • R 6 for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N, N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • R 2 is piperidinyl which may be optionally substituted on one or more carbon atom with one or more R 6 , and wherein if the piperidinyl group comprises -NH-, it may be substituted with Rs.
  • R 6 for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N, N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • Rs is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, acetyl, or methylsulfonyl.
  • R 4 are both hydrogen.
  • one of R 3 or R 4 is hydrogen and the other is methyl, n-butyl, morpholinoethyl, (furan-3-yl)-methyl, (5- methyl-furan-2-yl)-methyl, benzyl, 2,6-difluourobenzyl, cyclopropyl, 2-phenyl-cyclopropyl, or benzoimidazol-2-yl.
  • R 3 or R 4 are both methyl. In another embodiment of the compounds represented by formula (I) or (II), R 3 and R 4 together with the nitrogen atom to which they are attached form morpholino.
  • X 3 is CRio.
  • Rio is H.
  • Rio is selected from the group consisting of 2-piperizino-ethylamino, 2-(4-methyl-piperazino)- ethylamino, 2-morpholino-ethylamino, 2-hydroxyethylamino, 2-(diethylamino)-ethylamino, morpholino, piperazine, methyl, carboxy, and ethoxycarbonyl.
  • X 3 is N.
  • Ri is phenyl which is optionally substituted with from one to three independently selected R 5 ;
  • R 2 is a Ci- 6alkyl which is optionally substituted with from one to three independently selected R 6 ; and
  • Xi is -CH 2 -.
  • R5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent- 2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fiuor
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, R 2 is unsubstituted. In another aspect of this embodiment, R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N,N- dime thy lamino, acetamido, fiuoro, hydroxy, phenyl, and methylsulfonyl.
  • Ri is phenyl which is optionally substituted with from one to three independently selected R 5 ;
  • R 2 is a C 1-6 alkyl which is optionally substituted with from one to three independently selected R 6 ;
  • Xi is - CH 2 -; and
  • R 3 and R 4 are both hydrogen.
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N- methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorine
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, R 2 is unsubstituted. In another aspect of this embodiment, R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • Ri is phenyl which is optionally substituted with from one to three independently selected R 5 ;
  • R 2 is a Ci -6 alkyl which is optionally substituted with from one to three independently selected R 6 ;
  • Xi is - CH 2 -; and one of R 3 or R 4 is hydrogen and the other is 2-morpholinoethyl.
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l- yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole- 5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4- chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluoroph
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, R 2 is unsubstituted. In another aspect of this embodiment, R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • Ri is phenyl which is optionally substituted with from one to three independently selected R 5 ;
  • R 2 is a Ci -6 alkyl which is optionally substituted with from one to three independently selected R 6 ;
  • Xi is - CH 2 -;
  • R 3 and R 4 are both hydrogen; and
  • X 3 is CH.
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2- (N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyl, 2- methoxy
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, R 2 is unsubstituted. In another aspect of this embodiment, R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • Ri is phenyl which is optionally substituted with from one to three independently selected R 5 ;
  • R 2 is a Ci -6 alkyl which is optionally substituted with from one to three independently selected R 6 ;
  • Xi is - CH 2 -;
  • R 3 and R 4 are both hydrogen; and
  • X 3 is CR 10 , wherein Rio is -NRi 2 Ri 3 .
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2- carboxyphenyl, tetrazole-5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophen
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, R 2 is unsubstituted. In another aspect of this embodiment, R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N, N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • -NRi 2 Ri 3 is selected from the group consisting of 2-piperizino-ethylamino, 2-(4-methyl-piperazino)-ethylamino, 2-morpholino-ethylamino, 2-hydroxyethylamino, 2- (diethylamino)-ethylamino, morpholino, and piperazine.
  • Ri is phenyl which is optionally substituted with from one to three independently selected R 5 ;
  • R 2 is a C 3- ⁇ cycloalkyl which is optionally substituted with from one to three independently selected R 6 ; and
  • Xi is -CH 2 -.
  • R 2 is a cyclopentyl or cyclohexyl which is optionally substituted with one or more independently selected R 6 .
  • R 5 for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l- yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole- 5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, amino sulfonyl, 4- chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluor
  • Ri has one R 5 substituent. In another aspect of this embodiment, Ri has two independently selected R 5 substituents. In another aspect of this embodiment, Ri has three independently selected R 5 substituents. In another aspect of this embodiment, R 2 is unsubstituted. In another aspect of this embodiment, R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • R 2 is a Ci- 6alkyl which is optionally substituted with from one to three independently selected R 6 ;
  • X 3 is CH; and
  • R 3 and R 4 are both hydrogen.
  • R 2 is unsubstituted.
  • R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • R 2 is a Ci- 6alkyl which is optionally substituted with from one to three independently selected R 6 ; X 3 is CH; and one of R 3 or R 4 is hydrogen and the other is 2-morpholinoethyl. In one aspect of this embodiment, R 2 is unsubstituted.
  • R 2 is substituted with from one to three R 6 which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, ⁇ /, ⁇ /-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • R 6 are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, ⁇ /, ⁇ /-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.
  • the invention provides compounds selected from the group consisting of:
  • the present invention provides a process for preparing a compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • An adenine derivative, represented by formula (I) or (II) in which X 2 or X 4 , respectively, is -S- can be prepared by reacting a 4,6-diaminopyrimidine-2-thiol with an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl that has a displaceable group, such as a halo, in the presence of a base, such as NaOH, KOH or LiOH and a polar solvent, such as an alcohol, to form intermediate (i).
  • Intermediate (i) is then converted to a nitroso compound by reacting it with sodium nitrite in the presence of acetic acid and water to form intermediate (ii).
  • Intermediate (ii) is hydrogenated using platinum(IV)oxide and H 2 gas to convert the nitroso group to an amine group, forming intermediate (iii). Typically, this reaction is carried out in an alcoholic solvent such as ethanol. Intermediate (iii) is converted to a purine by refiuxing it in formamide to form intermediate (iv). Intermediate (iv) can be reacted in the presence of a carbonate, such as cesium carbonate or MP carbonateTM, with an alkyl, a carbocyclealkyl, or a heterocyclealkyl that comprises a displaceable group to form a compound of formula (I) or (II) (see Scheme A).
  • a carbonate such as cesium carbonate or MP carbonateTM
  • X for each occurrence, is an independently selected displaceable group such as a halo.
  • compounds of the invention represented by formula (I) or (II) can be prepared by heating 2,6-dichloro-9H-purine with aqueous ammonia or with a primary or secondary amine to form intermediate (vi).
  • the chloro substituent of intermediate (vi) can then be displaced by a thiol substituent of an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl in the presence of cesium carbonate and heat to form a compound of intermediate (vii).
  • the chloro group of intermediate (vi) can be displaced by a hydroxy substituent or an amine substituent of an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl in the presence of a strong base, such as NaOH, and heat to form intermediate (viii) (see Scheme B).
  • Intermediate (vii) or (viii) can be reacted in the presence of a carbonate, such as cesium carbonate or MP carbonateTM, with an alkyl, a carbocyclealkyl, or a heterocyclealkyl that comprises a displaceable group to form a compound of formula (I) or (II), as shown in Scheme A.
  • a carbonate such as cesium carbonate or MP carbonateTM
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifiuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifiuoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • Other suitable protecting groups for an alcohol include alkyl silyl group such as trimethylsilyl or t-butyl-dimethylsilyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • Alkylsilyl groups may be removed by treatment with a fluoride such as tetra-n- butylammonium fluoride or by treatment with an acid such as aqueous HCl.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • the compounds defined in the present invention have Murl inhibitory activity and are useful for treating or preventing bacterial infection. These properties may be assessed, for example, using the procedure described in Example 221. LGDH Coupled Enzyme Assay
  • the pellet was then dissolved in 9mL of Buffer A.
  • the 5mL sample was applied at a flow rate of l.OmL/min to a 32OmL Sephacryl S-200 (HR 26/60) (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A.
  • the fractions containing Murl were pooled and dialyzed against IL Storage buffer (1OmM Tris/HCl, pH 7.5, 0.ImM EGTA, 15OmM NaCl, ImM TCEP, 5mM DL-GIu, 50% Glycerol).
  • the protein was characterized by SDS-
  • E.faecalis reactions were incubated at rt for 60min and S.aureus reactions were incubated at rt for 120min before reactions were quenched by addition of 50 ⁇ L 1.5% acetic acid (final concentration was 0.5%). Quenched plates were centrifuged at rt for 30min at
  • Assay artifacts due to insoluble compounds under assay conditions were assessed using nephelometry to measure turbidity.
  • the compounds of the invention described herein have a measured IC50 in this assay against at least one isozyme of Murl (e.g., E.faecalis Murl, E.faecium Murl or S. aureus Murl) of ⁇ 400 ⁇ M or the compounds inhibit the glutamate racemase reaction by >20% at the limit of their solubility in the assay medium.
  • Solubility is determined under assay conditions using a nephelometer to detect a change in turbidity as the concentration of compound increases. The limit of solubility is defined as the maximum concentration before a detectable increase in turbidity is measured.
  • the compounds defined in the present invention are effective anti-bacterial agents which property is believed to arise from their Murl inhibitory properties. Accordingly the compounds of the present invention are expected to be useful for treating or preventing diseases or medical conditions resulting in whole or in part from an infection caused by bacteria expressing Murl.
  • an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Bacteroides spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Burkholderia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Campylobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydophila spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Clostridium spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Escherichia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Gardnerella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Helicobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Klebsiella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Legionella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Moraxella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Morganella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycoplasma spp.
  • an "infection” or “bacterial infection” refers to an infection caused by Neisseria spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Proteus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Pseudomonas spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Serratia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by
  • an “infection” or “bacterial infection” refers to an infection caused by Strep toccocus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Stenotrophomonas spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Ureaplasma spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by aerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by obligate anaerobes.
  • an “infection” or “bacterial infection” refers to an infection caused by facultative anaerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram-positive bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram-negative bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram- variable bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by atypical respiratory pathogens.
  • an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter baumanii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter haemolyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter junii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter johnsonii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter Iwoffi.
  • an “infection” or “bacterial infection” refers to an infection caused by B 'acteroides bivius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by B acteroides fragilis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Burkholderia cepacia. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia pneumoniae.
  • an “infection” or “bacterial infection” refers to an infection caused by Chlamydia urealyticus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydophila pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Clostridium difficili. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus faecalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by an infection caused by
  • an "infection” or “bacterial infection” refers to an infection caused by Escherichia coli. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus par ainfluenzae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus influenzae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Helicobacter pylori.
  • an “infection” or “bacterial infection” refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Legionella pneumophila. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Methicillin-resistant Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Methicillin-susceptible Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Moraxella catarrhalis.
  • an “infection” or “bacterial infection” refers to an infection caused by Morganella morganii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Neisseria gonorrhoeae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Penicillin- resistant Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae.
  • an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus anaerobius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus asaccharolyticus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus prevotii.
  • an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus vaginalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Proteus mirabilis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Pseudomonas aeruginosa. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Quino lone-Resistant Staphylococcus aureus.
  • an “infection” or “bacterial infection” refers to an infection caused by Quino lone-Resistant Staphylococcus epidermis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella typhi. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella enteritidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella typhimurium.
  • an “infection” or “bacterial infection” refers to an infection caused by Serratia marcescens. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus saprophyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptoccocus agalactiae.
  • an “infection” or “bacterial infection” refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptococcus pyogenes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Stenotrophomonas maltophilia. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Ureaplasma urealyticum. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Enter ococcus faecium.
  • an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Enterococcus faecalis . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Staphylococcus epidermis.
  • infection or “bacterial infection” refers to a gynecological infection. In one aspect of the invention “infection” or “bacterial infection” refers to a respiratory tract infection (RTI). In one aspect of the invention “infection” or “bacterial infection” refers to a sexually transmitted disease. In one aspect of the invention “infection” or “bacterial infection” refers to a urinary tract infection. In one aspect of the invention “infection” or “bacterial infection” refers to acute exacerbation of chronic bronchitis (ACEB). In one aspect of the invention “infection” or “bacterial infection” refers to acute otitis media. In one aspect of the invention “infection” or “bacterial infection” refers to acute sinusitis.
  • RTI respiratory tract infection
  • infection or “bacterial infection” refers to a sexually transmitted disease.
  • infection or “bacterial infection” refers to a urinary tract infection.
  • infection or “infection” or “bacterial infection” refers to acute exacerbation of chronic bronchi
  • infection refers to an infection caused by drug resistant bacteria. In one aspect of the invention “infection” or “bacterial infection” refers to catheter-related sepsis. In one aspect of the invention “infection” or “bacterial infection” refers to chancroid. In one aspect of the invention “infection” or “bacterial infection” refers to chlamydia. In one aspect of the invention “infection” or “bacterial infection” refers to community-acquired pneumonia (CAP). In one aspect of the invention “infection” or “bacterial infection” refers to complicated skin and skin structure infection. In one aspect of the invention “infection” or “bacterial infection” refers to uncomplicated skin and skin structure infection.
  • CAP community-acquired pneumonia
  • infection or “bacterial infection” refers to endocarditis. In one aspect of the invention “infection” or “bacterial infection” refers to febrile neutropenia. In one aspect of the invention “infection” or “bacterial infection” refers to gonococcal cervicitis. In one aspect of the invention “infection” or “bacterial infection” refers to gonococcal urethritis. In one aspect of the invention “infection” or “bacterial infection” refers to hospital-acquired pneumonia (HAP). In one aspect of the invention “infection” or “bacterial infection” refers to osteomyelitis. In one aspect of the invention “infection” or “bacterial infection” refers to sepsis.
  • HAP hospital-acquired pneumonia
  • infection refers to syphilis.
  • the invention provides a method of treatment or prophylaxis of bacterial infection, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections for example, E.faecalis or E.faecium infection, e.g treatment or prophylaxis of antibiotic resistant infection, or in treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection, in a patient in need of such treatment or prophylaxis, comprising administering to the patient an effective amount of a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore
  • a bacterial Murl inhibitory effect e.g., a E.faecalis or E.faecium Murl inhibitory effect in a warm-blooded animal such as man.
  • a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment or prophylaxis of bacterial infection e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or E.faecium infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.
  • bacterial infection e.g., infection by Murl expressing bacteria
  • a method for producing a bacterial Murl inhibitory effect e.g., a E.faecalis or E.faecium inhibitory effect, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined above.
  • a method for producing an antibacterial effect in a warm-blooded animal which comprises administering to said animal an effective amount of a compound of formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined above.
  • a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore for use in the treatment or prophylaxis of bacterial infection e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or E.
  • faecium infection for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.
  • Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofioxacin; ⁇ -lactams e.g. penicillins e.g.
  • amoxicillin or piperacillin cephalosporins e.g. ceftriaxone or ceftazidime
  • carbapenems e.g. meropenem or imipenem etc
  • aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones
  • anti-infective agents for example, an antifungal triazole e.g. or amphotericin
  • biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors.
  • a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • a chemotherapeutic agent selected from: i) one or more
  • a pharmaceutical composition which comprises a compound of formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvates, or prodrugs thereof, as defined hereinbefore, in association with a pharmaceutically-acceptable diluent or carrier.
  • a pharmaceutical composition which comprises a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a Murl inhibitory effect, e.g., a E.faecalis or E.faecium Murl inhibitory effect in a warm-blooded animal such as man.
  • a Murl inhibitory effect e.g., a E.faecalis or E.faecium Murl inhibitory effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an antibacterial effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment or prophylaxis of bacterial infection, e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or E.faecium infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl /?-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexito
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidants such as ascorbic acid); colouring agents; flavouring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin.
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
  • the compounds of formula (I) or (II) and pharmaceutically acceptable salts, solvates or prodrugs thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of Murl in bacteria, e.g., E.faecalis or E. faecium Murl, in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • temperatures are given in degrees Celsius ( 0 C); operations that were carried out at room or ambient temperature (“rt") were at a temperature in the range of 18-25°C;
  • organic solutions were dried over anhydrous sodium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60 0 C;
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulphoxide (DMSOd 6 ) as solvent unless otherwise indicated;
  • HATU O-(7-Azabenzotriazol- 1 -yl)- ⁇ WN ',N '-tetramethyluronium hexafluorophosphate; THF tetrahydrofuran; DMF 7V,7V-dimethylformamide;
  • ISCO refers to normal phase flash column chromatography using 12 g and 40 g pre-packed silica gel cartridges used according to the manufacturers instruction obtained from ISCO, Inc, 4700 superior street Lincoln, NE, USA.;
  • Glass HPLC refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in water/MeCN with 0.1% TFA as mobile phase, obtained
  • Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psig) and temperatures to 80 0 C.
  • the title compound was prepared by treating a solution of 6-amino-8-bromo-9-(2,6- difluorobenzyl)-9H-purin-2-ol (2.5g, 7.02 mmol) [Intermediate 31] in DMF (5OmL) with 1- bromobutane (2.25mL, 20.95mmol) and K2CO3 (5.8g, 42mmol). The reaction mixture was heated at 45 0 C overnight. The reaction was concentrated at reduced pressure, diluted with water (25mL) neutralized with NaHSO 4 (10% solution) and extracted with EtOAc. Organic extracts were dried over MgSO 4 and evaporated.
  • Example 134 l-[6-amino-2-fbutylthio)-9H-purin-9-yll-2-(2.,6-difluorophenyl)ethanol
  • the titled compound was obtained by demethylation of 2-(butylthio)-9-(2-methoxy-5- 5 nitrobenzyl)-9H-purin-6-amine (Example 7) (30.5mg, 0.0786mmol) with boron tribromide solution in dichloromethane (IM, 3mL, 3mmol) in dichloromethane (6mL) at 50°C for 24h as monitored by LC-MS.
  • the reaction was quenched with water at room temperature and extracted with dichloromethane. After drying (MgSO 4 ) and removal of solvent, the desired product was purified by reverse phase HPLC (acetonitrile/Water/TFA). Yield, 5%.
  • Examples 138 and 139 4-f ⁇ 2-butoxy-6-[f2-morpholin-4-ylethyl)aminol-l-oxido-9H- purin-9-vU methvDbenzamide and 4-( ⁇ 2-butoxy-6- [(2-morpholin-4-ylethyl)aminol -9H- 15 purin-9-yl ⁇ methyl)benzamide
  • the titled compound was prepared by oxidizing 4-( ⁇ 2-butoxy-6-[(2-morpholin-4- ylethyl)amino]-9H-purin-9-yl ⁇ methyl)benzonitrile (Example 83) (2.Og, 4.60mmol) with hydrogen peroxide (1OmL, 30% solution) in presence of IM NaOH (1OmL) in ethanol (5mL) at 0°C for Ih. The reaction was quenched with Na 2 S 2 O 3 . After removing water and ethanol from the aqueous phase, the mixture was purified by reverse phase HPLC (NH40 Ac/Water). Two products were isolated.
  • the first peak of 17mg was assigned as 4-( ⁇ 2-butoxy-6-[(2- morpholin-4-ylethyl)amino]-l-oxido-9H-purin-9-yl ⁇ methyl)benzamide (Example 138) and The second peak of 1.3 mg as 4-( ⁇ 2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl ⁇ methyl)benzamide (Example 139)
  • Example 138 MS (ES): 470(MH + ) for C 23 H 3 IN 7 O 4 1 H NMR (CDSOD-D 1 ) ⁇ : 0.75 (t, 3H); 1.42(m, 2H); 1.64(m, 2H); 3.10(m, 2H); 3.50(m, 6H); 4.2(m, 3H); 4.25 (t, 2H); 5.25(s, 2H); 7.25(d, 2H); 7.76(d, 2H); 7.82(s, IH)
  • Example 139 MS (ES): 454(MH + ) for C 23 H 3 iN 7 O 4 1 H NMR (CD30D-D £ ) ⁇ : 0.85 (t, 3H); 1.38(m, 2H); 1.65(m, 2H); 2.45(s, br, 4H); 2.55(t, 2H); 3.60(m, 6H); 4.25 (t, 2H); 5.29(s, 2H); 7.30(d, 2H); 7.76(d, 2H); 7.85 (s, IH)
  • the titled compound was prepared by reacting 4-( ⁇ 2-butoxy-6-[(2-morpholin-4- ylethyl)amino]-9H-purin-9-yl ⁇ methyl)benzonitrile (Example 83) (280mg, 0.64mmol) with methyl magnesium bromide (3M solution in diethyl ether, 0.56mL, 1.68mmol) in diethyl ether (1OmL) at -78 0 C. The reaction was allowed to warm to rt. The reaction was quenched with ammonium chloride and extracted with ethyl acetate.
  • Example 142 2-butoxy-9-(2.,6-difluorobenzyl)-A /8 -(2-morpholin-4-ylethyl)-9H-purine-
  • the title compound was prepared from Intermediate 53 as follows: 8-bromo-2- butoxy-9-(2,6-difluorobenzyl)-9H-purin-6-amine (lOOmg, 0.24mmol) was added to 4-(2- aminoethyl)morpholine (ImL, 7.63mmol). The reaction was heated to 17O 0 C for 1800s using microwave irradiation. The reaction mixture was concentrated at reduced pressure. The product was purified by reverse phase chromatography [5-95 % CH3CN/H2 ⁇ /O.l% TFA] to give the title compound as a TFA salt.
  • Table 5 The Examples in Table 5 were prepared as described for Example 142 using the appropriate amines
  • Example 150 2-butoxy-A / -f2,6-difluorobenzyl)-9-f2-morpholin-4-ylethyl)-9H-purin-6- amine
  • the title compound was prepared from 2-chloro-7V-(2,6-difiuorobenzyl)-9-(2- morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 41) as follows: A solution of 2- chloro- ⁇ /-(2,6-difluorobenzyl)-9-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 4I)(1.26g, 3.09mmol) in n-butanol (7.5mL) was treated with sodium hydroxide pellets (l.Og, 25mmol). The reaction was heated at 12O 0 C for 1800s using microwave irradiation.
  • Table 6 The Examples in Table 6 were prepared as described for Example 152 using the appropriate alkylating agent and Intermediate 17 as starting material.
  • Example 177 4- ⁇ [2-butoxy-9- ⁇ -morpholin-4-ylethyl)-9H-purin-6- yll ami noj meth v Dbenzenesu lfonam ide
  • Example 178 4-f ⁇ 2-butoxy-6-2-morpholin-4-ylethyl)aminol-9H-purin-9-yl ⁇ methyl)-3- methoxybenzoic acid
  • Table 7 The Examples in Table 7 were prepared as described for Example 179 using the appropriate alkylating agent and Intermediate 17 as starting material.
  • Example 209 9-[2-fluoro-6-fpent-2-vn-l-yloxy)benzyll-A / -(2-morpholin-4-ylethyl)-2- (pent-2-vn-l-yloxy)-9H-purin-6-amine
  • Table 8 Compounds in Table 8 were prepared as for Example 209 using the appropriate alcohol and the starting material as shown.
  • Example 217 ethyl 2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8- carboxylate
  • Example 220 To a solution of 4-( ⁇ 2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl ⁇ methyl)benzonitrile (Example 83) (95mg, 0.218mmol) in THF (4 ml) was added a solution of lithium aluminum hydride(0.436 ml, 0.436mmol) at room temperature. The reaction was completed in 2 hrs. The reaction was quenched by slow addition of methanol. After removing THF and methanol, the residue was extracted with ethyl acetate and washed with water. The aqueous phase was evaporated to obtain the crude product. The product was purified by reverse phase HPLC (Acetonitrile/Water /TFA). The product (80mg, 84% yield) was obtained as and oil. MS (ES): 440(MH + ) for C 23 H 33 N 7 O 2
  • Example 221 LGDH Coupled Enzyme Assay Compounds were tested for inhibition of glutamate racemase using a coupled enzyme assay as previously described (Lundqvist et al, "Exploitation of structural and regulatory diversity in glutamate racemases” Nature, 2007, in press).
  • Assays were performed in 96-well polystyrene flat-bottom black plates (FLUOTRAC 200) in 102 ⁇ l reactions containing 2 ⁇ l compound dissolved in dimethylsulfoxide, 85 ⁇ l Enzyme Working Solution (final concentrations were 100 mM Tris pH 8.0, 0.03 % PEG 8000, 0.03 mg/mL bovine serum albumin, 15 LVmL L-glutamate dehydrogenase (LGDH), 5 mM dithiothreitol, 10 mM NAD + and either 80 nM E.faecalis Murl or 100 nM E.faecium Murl or 1 uM S. aureus Murl) and 15 ⁇ l 6.67 mM D-glutamate to initiate the reaction (final concentration was 1 mM).
  • the proteins of interest were prepared as follows: E. faecalis Murl and S. aureus Murl were cloned into pET28b expression vector to allow expression of N-terminal histidine tagged protein. Each vector was co-transformed with a groESL expression vector (to facilitate proper folding) into E. coli strain BL21(DE3). Cultures were grown in LB medium containing lOug/ml tetracycline and 50ug/ml kanamycin to mid- log phase. Induction was carried out overnight at room temperature in the presence of 50OuM IPTG and ImM D/L Glutamate.
  • E. faecium Murl was cloned into a modified pET28b expression vector.
  • This protein is contains an N-terminal histidine tag and was expressed in E. coli strain BL21(DE3) as follows: the culture was grown to mid-log phase in LB medium containing 25ug/ml kanamycin, then induced with 40OuM IPTG for 2 hours at 37C.
  • aureus Murl was carried out as follows.
  • the frozen cell paste was resuspended in 50 ml of Lysis Buffer [20 mM Tris/HCl, pH 7.5, 5 mM DL-Glutamate, 1 EDTA-free protease inhibitor cocktail tablet (Roche Molecular Biochemical)].
  • Cells were disrupted by French press at 18,000 psi twice at 4 0 C, and the crude extract was centrifuged at 20,000 rpm (45Ti rotor, Bechman) for 30 minutes at 4 0 C.
  • the supernatant was loaded at a flow rate of 2.0 ml/min onto a 5 ml HiTrap Ni 2+ chelating column (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A (20 mM Tris/HCl, pH 7.5, 5 mM DL-GIu). The column was then washed with Buffer A, and the protein was eluted by a linear gradient from 0 to 0.5 M Imidazole in Buffer A. Fractions containing Murl were pooled, and solid (0.4 g/ml) was added to precipitate all the proteins and mixed on ice for 1 hour.
  • the sample was centrifuged at 25,000 rpm for 30 min at 4 0 C (45Ti rotor, Beckman); the pellet was then dissolved in 9 ml of Buffer A.
  • the 5 ml sample was applied at a flow rate of 1.0 ml/min to a 320 ml Sephacryl S-200 (HR 26/60) (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A.
  • the fractions containing Murl were pooled and dialyzed against 1 L Storage buffer (10 mM Tris/HCl, pH 7.5, 0.1 mM EGTA, 150 mM NaCl, 1 mM TCEP, 5 mM DL-GIu, 50% Glycerol).
  • the protein was characterized by SDS-PAGE analysis and analytical LC-MS and judged to be at 95% purity.
  • the protein was stored at -2O 0 C.
  • the assay reactions were incubated at room temperature for 60 minutes. Plates were read using a Tecan Ultra plate reader (excitation wavelength 340 nm, emission wavelength 465 nm). Data were reported as the difference between the fluorescence reads at 60 and 0 minutes.
  • Compound potency was based on IC50 measurements determined from reactions performed in the presence often different compound concentrations. Assay artifacts due to insoluble compounds under assay conditions were assessed using nephelometry to measure turbidity. The limit of compound solubility was defined as the maximum concentration before a detectable increase in turbidity was observed by nephelometry.
  • the compounds of the invention described herein have a measured IC50 in this assay against at least one isozyme of Murl (e.g., E. faecalis Murl, E. faecium Murl or S. aureus Murl) of ⁇ 400 ⁇ M or the compounds inhibit the glutamate racemase reaction by >20% at the limit of their solubility in the assay medium.
  • Murl e.g., E. faecalis Murl, E. faecium Murl or S. aureus Murl

Abstract

L'invention porte sur des composés chimiques ou leurs sels pharmacocompatibles de formule (I): présentant une activité inhibitrice du Mur1 bactérien, et donc utiles pour le traitement et la prophylaxie des infections bactériennes, par exemple par le E.faecalis ou le E. faeciuminfection. L'invention porte également sur des méthodes de traitement de l'homme ou de l'animal. Elle porte en outre: sur des procédés de fabrication desdits composés, sur des préparations pharmaceutiques les contenant, et sur leur utilisation pour la fabrication de médicaments utilisables pour le traitement et la prévention de différentes maladies bactériennes des animaux à sang chaud tels que l'homme.
PCT/GB2008/050812 2007-09-13 2008-09-10 Dérivés de l'adénine et de la 8-aza-adénine et leurs utilisations WO2009034386A1 (fr)

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