[go: up one dir, main page]

WO2004022554A1 - Derives de quinazolinone - Google Patents

Derives de quinazolinone Download PDF

Info

Publication number
WO2004022554A1
WO2004022554A1 PCT/GB2003/003878 GB0303878W WO2004022554A1 WO 2004022554 A1 WO2004022554 A1 WO 2004022554A1 GB 0303878 W GB0303878 W GB 0303878W WO 2004022554 A1 WO2004022554 A1 WO 2004022554A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alk
meoh
optionally substituted
dcm
Prior art date
Application number
PCT/GB2003/003878
Other languages
English (en)
Inventor
Alan Findlay Haughan
George Martin Buckley
Natasha Davies
Hazel Joan Dyke
Duncan Robert Hannah
Trevor Morgan
Marianna Dilani Richard
Andrew Sharpe
Sophie Caroline Williams
Original Assignee
Celltech R & D Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0220813A external-priority patent/GB0220813D0/en
Priority claimed from GB0229186A external-priority patent/GB0229186D0/en
Priority claimed from GB0312775A external-priority patent/GB0312775D0/en
Application filed by Celltech R & D Limited filed Critical Celltech R & D Limited
Priority to AU2003263323A priority Critical patent/AU2003263323A1/en
Publication of WO2004022554A1 publication Critical patent/WO2004022554A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to a series of quinazolinones and quinazolinthiones and their derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • IMPDH lnosine-5'-monophosphate dehydrogenase
  • NAD ⁇ -nicotinamide adenine dinucleotide
  • XMP xanthosine-5'-monophosphate
  • Guanine nucleotides are essential to the cell for RNA and DNA synthesis, intermediates in signalling pathways and as energy sources for metabolic pathways.
  • IMPDH is ubiquitous in eukaryotes, bacteria and protozoa (Y. Natsumeda & S.F. Carr, Ann. N.Y. Acad.. 696, pp. 88-93, (1993) ).
  • IMPDH type I and type II form active teframers in solution, with subunit molecular weights of 56 kDa (Y. Yamada et. Al., Biochemistry, 27, pp. 2737-2745, (1988) ). It is thought that type I is the predominant isoform expressed in normal cells, whilst type II is upregulated in neoplastic and replicating cells. Studies have postulated that selective inhibition of type II IMPDH could provide a therapeutic advantage by reducing potential toxicity effects caused by inhibiting the type I isoform (Pankiewicz K.W, Expert Opin. Ther. Patents 11 (7) pp 1161-1170, (2001)).
  • IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
  • MPA Mycophenolic acid
  • Kj 33 nM
  • 9 nM
  • MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen (A.C. Allison et. al., Ann. N. Y. Acad. Sci., 696, 63, (1993) ).
  • Immunosuppressants such as MPA are useful drugs in the treatment of transplant rejection and autoimmune diseases.
  • MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity.
  • Mycophenolate mofetil a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute allograft rejection following kidney transplantation (i.e. renal allograft failure) and heart transplantation.
  • kidney transplantation i.e. renal allograft failure
  • heart transplantation i.e. renal allograft failure
  • Mycophenolate mofetil has also been used for the treatment of rheumatoid arthritis.
  • mycophenolate mofetil has also been described (R. Bentley, Chem. Rev., 100, pp. 3801 -3825, (2000)).
  • Mycophenolate mofetil has also been postulated to be of use for the treatment of atopic dermatitis (Grundmann-Kollman M et al, Archives of Dermatology, 137 (7), pp.
  • Nucleoside analogues such as tiazofurin, ribavirin and mizoribine also inhibit IMPDH (L. Hedstrom, et. al., Biochemistry, 29, pp. 849-854, (1990) ). These nucleoside analogues are competitive inhibitors of IMPDH, but also inhibit other NAD dependant enzymes. This lack of specificity limits the therapeutic application of these compounds. New agents with improved selectivity for IMPDH would represent a significant improvement over these nucleoside analogues.
  • Mizorbine (Bredinin®) has been approved in Japan for multiple indications in transplantation and autoimmune diseases including prevention of rejection after renal transplantation, idiopathic glomerulonephritis, lupus nephritis and rheumatoid arthritis.
  • Vertex has recently disclosed a series of novel IMPDH inhibitors (WO 97/40028), of which VX-497 has been evaluated for the treatment of psoriasis.
  • IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumour cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy (M. Nagai et. al., Cancer Res., 51 , pp. 3886-3890, (1991), Pankiewicz K.W., Exp. Opin. Ther. Patents, 11 , pp. 1161-1170, (2001) ). IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases (C.R. Gregory et. al., Transplantation. 59, pp. 655-61 , (1995); PCT publication WO 94/12184; and PCT publication WO 94/ 01105).
  • IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. (S.F. Carr, J. Biol. Chem., 268, pp. 27286-27290, (1993) ). VX-497 is currently being evaluated for the treatment of hepatitis C in humans. Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.
  • the present inventors disclose a class of substituted quinazolinone and quinazolinthione derivatives having activity as IMPDH inhibitors, and to compositions and methods related thereto.
  • X is an oxygen or sulfur atom
  • R 1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group
  • R 2 is an optionally substituted heteroaromatic group or a -CN group
  • R 3 is a group -(Alk 1 ) m L 1 (Alk 2 ) n R 4 in which m and n, which may be the same or different, is each zero or the integer 1
  • Alk 1 and Alk 2 which may be the same or different, is each an optionally substituted aliphatic or heteroaliphatic chain
  • L 1 is a covalent bond or a linker atom or group
  • R 4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group
  • A is an optionally substituted cycloaliphatic or heterocycloaliphatic group optionally fused to an optionally substituted aryl or heteroaryl group;
  • R 5 which may be attached to any available C or N atom present in the cycloaliphatic or heterocycloaliphatic, or where fused, aryl or heteroaryl group, is a group -(Alk 3 ) t L 2 (Alk 4 ) v R 6 in which t and v, which may be the same or different, is each zero or the integer 1 , Alk 3 and Alk 4 , which may be the same or different, is each an optionally substituted aliphatic or heteroaliphatic chain, L 2 is a covalent bond or a linker atom or group and R 6 is a hydrogen or halogen atom or a -CN group or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates,
  • compounds of formula (1) may exist as geometric isomers (E or Z isomers).
  • the compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers.
  • the invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates.
  • Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
  • Quinazolinones may also exist as tautomers; one possible example is illustrated below:
  • the compounds of the invention may be administered in a pharmaceutically acceptable pro-drug form, for example, as a protected carboxylic acid derivative, e.g. as an acceptable ester.
  • the pro-drugs may be converted in vivo to the active compounds of formula (1), and the invention is intended to extend to such pro-drugs.
  • Such prodrugs are well known in the literature, see for example International Patent Application No. WO 00/23419, Bodor N. (Alfred Benson Symposium, 1982, 17, 156-177), Singh G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).
  • aliphatic group is intended to include optionally substituted straight or branched C ⁇ - ⁇ 0 alkyl, e.g. C ⁇ .Q alkyl, C- 2 - ⁇ oalkenyl e.g. C- 2 - 6 alkenyl or C 2 - 10 alkynyl e.g. C 2 - 6 alkynyl groups.
  • aliphatic groups include optionally substituted straight or branched C ⁇ _ 6 alkyl groups such as -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 )3, -C(CH 3 ) 3 , -(CH 2 ) CH 3 , -(CH 2 ) 5 CH 3 , or C 2 - 6 alkenyl or C - 6 alkynyl groups such as -CHCH 2 , -CHCHCH 3 , -CH 2 CHCH 2 , -CHCHCH 2 CH 3 , -CH 2 CHCHCH 3 , -(CH 2 ) 2 CHCH 2 , -CCH, -CCCH 3 , -CH 2 CCH, -CCCH 2 CH 3
  • More particular examples include optionally substituted d. 4 alkyl groups selected from -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 or -C(CH 3 ) 3 .
  • aliphatic chain is intended to include those alkyl, alkenyl or alkynyl groups as just described where a terminal hydrogen atom is replaced by a covalent bond to give a divalent chain.
  • aliphatic chains include optionally substituted straight or branched C 1 - 6 alkylene chains such as -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -,-(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 -, -CH(CH 3 )(CH 2 ) 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 )2CH2-, -(CH 2 ) 2 CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -(CH 2 )2C(CH 3 )2CH 2 -, -(CH 2 )
  • -(CH 2 ) 2 CCH- chains More particular examples include optionally substituted C 1 - 3 alkylene chains selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 )J ⁇ and -CH 2 CH(CH 3 )- chains.
  • Optional substituents that may be present on the aliphatic groups or chains include those optional substituents mentioned hereinafter.
  • heteroaliphatic chain is intended to include the aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 3 where L 3 is a linker atom or group.
  • L 3 is a linker atom or group.
  • Each L 3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
  • Particular examples include optionally substituted -L 3 CH 2 -, -CH 2 L 3 -, -L 3 CH(CH 3 )-, -CH(CH 3 )L 3 -, -CH 2 L 3 CH 2 -, -L 3 CH 2 CH 2 -, -L 3 CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 L 3 -, -CH 2 CH 2 L -, -CH 2 L CH 2 CH 2 -, -CH 2 L CH 2 CH 2 L -, -(CH 2 )2L CH2-, -(CH 2 )sL CH -, -L 3 (CH 2 ) 2 CH 2 -, -L 3 CH 2 CHCH-, -CHCHCHCH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 CH2-, -(CH 2 ) 3 L 3 CH 2 CH 2 - and -L 3 CH 2 L 3 CH 2 CH 2 - chains.
  • L 3 When L 3 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -C(0)0-, -OC(O)-, -N(R 7 )- [where R 7 is a hydrogen atom or a straight or branched C ⁇ - 6 alkyl group], -N(R 7 )0-, -N(R 7 )N-, -CON(R 7 )-, -OC(0)N(R 7 )-, -CSN(R 7 )-, -N(R 7 )CO-, -N(R 7 )C(O)0-, -N(R 7 )CS-, -S(O) 2 N(R 7 )-, -N(R 7 )S(0) 2 -, -N
  • cycloaliphatic group includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C 3 . ⁇ 0 ring systems, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbomyl, norbornenyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptenyl.
  • Particular examples include optionally substituted C 3 - 6 cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • Optional substituents present on those groups include those substituents mentioned hereinafter.
  • cycloalkyl-alkyl- group refers to a C ⁇ - 6 alkyl group (as described herein) where a terminal hydrogen atom is replaced by a C 3 . 6 cycloalkyl ring (as described herein). Examples include -(CH 2 ) ⁇ . 6 -cyclopropyl, -(CH 2 ) ⁇ - 6 - cyclobutyl, -(CH 2 ) ⁇ - 6 -cyclopentyl or - ⁇ CH ⁇ -e-cyclohexyl.
  • heterocycloaliphatic group refers to an optionally substituted 3 to 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system containing one, two, three or four L 4 linker atoms or groups.
  • suitable L 4 atoms or groups include -O- or -S- atoms or -C(O)-, -C(0)0-, -OC(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -N(R 7 )- [where R 7 is as defined above], -N(R 7 )N(R 7 ), -N(R 7 )0-, -ON(R 7 )-, -CON(R 7 )-, -OC(0)N(R 7 )-, -CSN(R 7 )-, -N(R 7 )CO-, -N(R 7 )C(0)0-, -N(R 7 )CS-, -S
  • heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e.g. 1 ,3- dioxolanyl, imidazolinyl, e.g.
  • 2-imidazolinyI imidazolidinyl, imidazolidinonyl, imidazolidine-2,4-dionyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g.
  • Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom.
  • Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.
  • the optional substituents which may be present on the aliphatic, cycloaliphatic or heterocycloaliphatic groups include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or Ci- 6 alkyl, e.g. methyl, ethyl, propyl or /-propyl, C ⁇ - 6 alkoxy, e.g. methoxy, ethoxy or propoxy, haloCi-ealkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, haloC ⁇ - 6 alkoxy, e.g.
  • halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, C ⁇ - 6 alkylthio, e.g. methylthio, ethylthio or propylthio, or -(Alk 5 )gR 9 groups in which Alk 5 is a straight or branched C ⁇ - 3 alkylene chain, g is zero or the integer 1 and R 9 is a -OH, -SH, -N(R 10 ) 2 [where R 10 is a hydrogen atom or an optionally substituted Ci- ⁇ alkyl group], -CN, -C0 2 R 10 , -OC(0)R °, -NO 2 , -C(0)N(R 1 °) 2 , -C(S)N(R 1 °) 2 , -C(0)R 10 , -C(S)R 10 , -N(R i o)C(O)R 10 , -N(R 1 °
  • R 9 may also be an -OR 9a group [where R 9a is an optionally substituted C h alky!, phenyl or 5 or 6 membered heteroaryl group]. When two R 10 atoms or groups are present in these substituents these may be the same or different or joined to form a heterocycloaliphatic ring which contains at least one N atom.
  • the aromatic and heteroaromatic groups which may be present in these substituents may optionally be substituted by one, two or three of the R 12 groups described herein.
  • the optional substituents which may be present on aliphatic or heteroaliphatic chains include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, CN, -C0 2 H, -C0 2 R 11 [where R 11 is an optionally substituted Ci-ealkyl group] e.g. -CO 2 CH 3 or -C0 2 C(CH 3 ) 3 ; -CONHR 11 , e.g. -CONHCH 3 ;
  • -CON(R 11 ) 2 e.g. -CON(CH 3 ) 2 ; -COR 11 , e.g. -COCH 3 ; d-ealkoxy, e.g. methoxy or ethoxy; haloC ⁇ - 6 alkoxy, e.g. trifluoromethoxy or difluoromethoxy; -SH, -S(0)R 11 , e.g. -S(0)CH 3 ; -S(0) 2 R 11 , e.g. -S(0) 2 CH 3 ; d. 6 alkylthio e.g. methylthio or ethylthio; amino; -NHR 11 , e.g. -NHCH 3 or -N(R 11 ) 2 , e.g. -N(CH 3 ) 2 groups. Where two R 1 groups are present in any of the above substituents these may be the same or different.
  • R 9a , R 10 or R 11 is present as a straight or branched d. 6 alkyl group it may be a straight or branched C- ⁇ - 6 alkyl group e.g. a d- 3 alkyl group such as methyl, ethyl or /-propyl.
  • Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or Ci- 6 alkoxy e.g. methoxy or ethoxy groups.
  • halogen atom is intended to include fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF 3 , -CCI 3 , -CHF 2) -CHCI 2 , -CH 2 F, and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C ⁇ - 10 alkoxy for example d. 6 alkoxy such as methoxy, ethoxy, ⁇ -propoxy, /- propoxy and f-butoxy.
  • Haloalkoxy as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF 3 , -OCCI 3 , -OCHF 2 , -OCHCI 2 , -OCH 2 F and -OCH 2 CI groups.
  • alkylthio is intended to include straight or branched d_ 10 alkylthio, e.g. d. 6 alkylthio such as methylthio or ethylthio groups.
  • L 1 and L 2 are present in compounds of formula (1) as a linker atom or group they may be any such atom or group as hereinbefore described in relation to L 3 linker atoms and groups.
  • L 1 when present, is a -C(O)-, -C(S)-, -S(O) 2 -, -CON(R 7 )-, -CSN(R 7 )- or -S(0) 2 N(R 7 )- group, where R 7 is as herein defined.
  • L 2 may also be a -C(0)N(R 7 )C(0)-, -C(0)N(R 7 )C(0)0- or -C(0)N(R 7 )0- linker group.
  • aromatic group and "aryl group” are intended to include for example optionally substituted monocyclic ring C 6 - ⁇ 2 aromatic groups, such as phenyl, or bicyclic fused ring C 6 . 12 aromatic groups, such as, 1- or 2-naphthyl groups.
  • heteroaromatic group and “heteroaryl group” are intended to include for example optionally substituted d- 9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof).
  • the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Each of these aromatic or heteroaromatic groups may optionally be substituted by one, two, three or more R 12 atoms or groups as defined below.
  • monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, ⁇ /-C 1 . 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.
  • bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl or phthalazinyl.
  • heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
  • Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R 12 in which R 12 is the group -(Alk 6 ) e (R 12a ) f in which Alk 6 is a straight or branched d- 6 alkylene, C 2 . 6 alkenylene or C 2 .
  • R 12a is a halogen atom, or an amino (- NH 2 ), -NHR 13 [where R 3 is the group -(Alk 6 ) e (R 13a ) f in which R 13a is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl, heteroaryl group and Alk 6 , e and f are as herein defined], -N(R 13 ) 2 , nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-C0 2 H), -CO 2 R 13 , thiol (-SH), -SR 13 , -OR 13 , -COR 13 , -CSR 13 , -S0 3 H,
  • heterocycloaliphatic group optionally containing one or more other -O- or -S- atoms or -N(R 14 )-, -C(O)- or -C(S)- groups], -CONHet i , -CSNHet i , -N(R i4 )S0 2 NHet i , -N(R 14 )CONHet 1 , -N(R i4 )CSNHet 1 , -SO 2 N(R 14 )Het 2 [where Het 2 is an optionally substituted monocyclic C 3 .
  • each may be for example an optionally substituted 2- or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group.
  • Het 2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group.
  • Optional substituents which may be present on -NHet 1 or -Het 2 include those substituents described above in relation to aromatic groups.
  • Particularly useful atoms or groups represented by R 12 include fluorine, chlorine, bromine or iodine, C ⁇ - 6 alkyl, e.g. methyl, ethyl, /-propyl, halod- 6 alkyl, e.g. -CF 3 , halod- 6 alkoxy, e.g.
  • R 13 groups include a Ci-6 alkyl group (where f is zero), or an optionally substituted -(Alk 6 ) e phenyl, -(Alk 6 ) e monocyclic heteroaryl, -(Alk 6 ) e monocyclic heterocycloaliphatic or -(Alk 6 ) e cycloaliphatic.
  • Alk 6 When Alk 6 is present in the above R 12 and R 13 groups it may be for example a methylene, ethylene, n-propylene, /-propylene, n-butylene, /-butylene, s- butylene, f-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(0) 2 - or -N(R 14 )- groups.
  • Particular examples of Alk 6 include C ⁇ - 4 alkylene chains e.g. methylene, ethylene, propylene, i-propylene or t-butylene.
  • R is most especially a Ci- 3 alkyl group.
  • R is particularly hydrogen or methyl.
  • f is zero Alk 6 is in particular a C 1 -4 alkyl group as defined herein.
  • f is the integer 1 , 2 or 3 Alk 6 is in particular a d- 3 alkylene chain.
  • aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups which may be present in the group -R 12a or -R 13a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-d- 6 alkylpiperazinyl, especially /V-methylpiperazinyl, ⁇ /-C ⁇ - 6 alkylpyrrolidinyl, especially ⁇ /-methylpyrrolidinyl, ⁇ /-d- 6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofurany
  • Optional substituents which may in particular be present on the aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups represented by -R 12a or -R 13a include one, two, three or more atoms or groups selected from fluorine, chlorine, d- 3 alkoxy, especially -OCH 3 , OCF 3 , OCF 2 H, CF 3 , C1-3 alkylthio, straight or branched d-3 alkyl, -CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , C0 2 CH 3 , C0 2 CH 2 CH 3 , -C0 2 C(CH3) 3) or -COCH3, -SO 2 CH 3 , -NHCOCH3, -N(CH 3 )COCH 3 or C0 2 H.
  • two adjacent R 12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a d. 6 alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 . 6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • a cyclic ether e.g. a d. 6 alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 . 6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • R 12 substituents are present, these need not necessarily be the same atoms and/or groups.
  • the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
  • the presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed.
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulfonates, e.g. methanesulfonates, ethanesulfonates, or isothionates, arylsulfonates, e.g. p-toluenesulfonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • alkylsulfonates e.g. methanesulfonates, ethanesulfonates, or isothionates
  • arylsulfonates e.g. p-toluenesulfonates
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • X is an O atom.
  • Examples of cycloaliphatic groups which may represent R 1 include C 3 - 6 cycloalkyl groups, such as those described previously.
  • Examples of cycloalkyl-alkyl- groups which may represent R 1 include C ⁇ - 3 alkyl groups (as described herein) where a terminal hydrogen atom is replaced by a C 3 - 6 cycloalkyl ring (as described herein), for example, cyclopropylCH 2 -.
  • R 1 in compounds of formula (1), is in particular a C ⁇ - 6 alkyl group. Especially preferred is when R 1 is a -3 alkyl group. Most especially preferred is when R 1 is a methyl group.
  • R 1 is a haloalkyl group, especially a CHF 2 or CH 2 F group.
  • a particularly preferred group of compounds of the invention has the formula (1) wherein R 2 is an optionally substituted monocyclic heteroaromatic group, especially a five-membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Particular preferred heteroaromatic groups which may represent R 2 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, ⁇ /-d. 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or pyrazolyl.
  • R 2 is an oxazolyl group.
  • R 2 is an oxazol-5-yl group.
  • R 3 in compounds of formula (1), include - Alk 1 -L 1 -Alk 2 -R 4 , -Alk 1 -L 1 -R 4 , -Alk 1 -R 4 , -L 1 -Alk 2 -R 4 , -L 1 -R 4 or -R 4 wherein Alk 1 , L 1 , Alk 2 and R 4 are as herein defined.
  • R 3 is the group -Alk 1 - L 1 -R 4 .
  • Alk 1 and Alk 2 when present in compounds of formula (1), may be the same or different and is each preferably an optionally substituted aliphatic chain, in particular a d- ⁇ alkylene chain, especially an optionally substituted -CH 2 -, - CH2CH2-, -CH2CH2CH2-, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )- chain, most especially a d-3 alkylene chain such as -CH 2 -, -CH 2 CH 2 - or -CH2CH2CH2- chain.
  • a d- ⁇ alkylene chain especially an optionally substituted -CH 2 -, - CH2CH2-, -CH2CH2CH2-, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )- chain, most especially a d-3 alkylene chain such as -CH 2 -, -CH 2 CH 2 - or -CH2CH2CH2- chain.
  • L 1 when present in compounds of formula (1), include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -C(0)0-, -OC(O)-, -N(R 7 )- [where R 7 is as defined hereinbefore], -CON(R 7 )-, -CSN(R 7 )-, -N(R 7 )CO-, - N(R 7 )CS-, -S(0) 2 N(R 7 )- or -N(R 7 )S(0) 2 - groups.
  • R 7 is especially a hydrogen atom or a C 1 -3 alkyl group, particularly methyl.
  • L 1 in one particular group of compounds of the invention is a covalent bond.
  • One particular class of compounds of the invention has the formula (1) wherein R 3 is the chain -Alk 1 -L 1 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a covalent bond and R 4 is a hydrogen atom.
  • R 3 is especially a straight or branched Ci-ealkyl group, particularly -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 or -C(CH 3 ) 3 .
  • R 3 is preferably a methyl or ethyl group, most especially a methyl group.
  • Another class of compounds of the invention has the formula (1) wherein R 3 is a hydrogen atom.
  • R 3 is a hydrogen atom or a Ci- 6 alkyl group, particularly methyl.
  • A is an optionally substituted, optionally fused C 3 - 6 cycloaliphatic group or 3 to 6 membered saturated monocyclic hydrocarbon ring system containing one or two L 4 linker atoms or groups.
  • L 4 atoms or groups include -O- or -S- atoms or -C(O)-, -C(S)-, -S(0) 2 -, -N(R 7 )- [where R 7 is as defined above], - CON(R 7 )-, -CSN(R 7 )-, -N(R 7 )CO-, -N(R )CS-, -S(0) 2 N(R 7 ), -N(R 7 )S(O) 2 -, groups.
  • group A include optionally substituted cyclopentyl, cyclopentenyl, cyclohexyl, cyclopentanonyl, cyclohexanonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g.
  • group A include optionally substituted cyclopentyl, cyclohexyl, cyclopentanonyl, cyclohexanonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, /V-C 1 -6 alkylpyrrolidinyl or ⁇ /-C ⁇ - 6 alkylpiperidinyl.
  • A is in particular an optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, ⁇ /-C 1 - 6 alkylpyrrolidinyl, especially ⁇ /-methylpyrrolidinyl, or ⁇ /-C 1 -6 alkylpiperidinyl, especially ⁇ /-methylpiperidinyl group.
  • A is an optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, tetrahydrothiophenyl or tetrahydrothiophenyl 1 ,1-dioxide group.
  • Typical examples of A include optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3-yl, pyrrolidin-2-on-3-yl, piperidin-4-yl, tetrahydrothiophen-3-yl or tetrahydrothiophen-3-yl 1 ,1 -dioxide group.
  • One particular class of compounds of the invention has the formula (1) wherein A is an optionally substituted cycloaliphatic or heterocycloaliphatic group fused to an optionally substituted aryl or heteroaryl group.
  • aryl or heteroaryl groups which may be fused to the group A include optionally substituted monocyclic C 6 - ⁇ 2 aromatic groups, such as phenyl or optionally substituted monocyclic C ⁇ .
  • 9 heteroaromatic groups especially 5 or 6 membered heteroaromatic groups, containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms as defined hereinbefore.
  • aryl or heteroaryl groups which may be fused to the group A include optionally substituted phenyl, pyrrolyl, furyl, thienyl, imidazolyl, ⁇ /-C ⁇ . 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or pyridyl- ⁇ /-oxide.
  • More particular examples include optionally substituted imidazolyl, ⁇ /-C ⁇ _ 6 alkylimidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or pyridyl-N-oxide.
  • A is an optionally substituted cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, N-C ⁇ . 6 alkylpyrrolidinyl, especially /V-methylpyrrolidinyl, group fused to an optionally substituted imidazolyl, ⁇ /-C ⁇ - 6 alkylimidazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or pyridyl- ⁇ /-oxide group.
  • A forms an optionally substituted indanyl group.
  • A may also in particular be an optionally substituted 5,6-dihydro-4H-cyclopenta[b]thiophenyl or tetrahydronaphthyl group.
  • Typical examples of A include indan-1-yl, indan- 2-yl, 5-nitroindan-2-yl, 5-aminoindan-2-yl, 5-terf-butoxycarbonylaminoindan-2- yl, 5,6-dihydro-4H-cyclopenta[b] thiophen-5-yl or 1 ,2,3,4-tetrahydronaphth-2-yl groups.
  • Particular examples of the group R 5 in compounds of formula (1), include -Alk 3 -L 2 -Alk 4 -R 6 , -Alk 3 -L 2 -R 6 , -Alk 3 -R 6 , -L 2 -Alk 4 -R 6 , -L 2 -R 6 or -R 6 wherein Alk 3 , L 2 , Alk 4 and R 6 are as herein defined.
  • t is zero. In another particular embodiment of the invention t is the integer 1.
  • v in one particular aspect of the invention is zero. In another embodiment v is the integer 1.
  • Alk 3 and Alk 4 when present in compounds of formula (1), may be the same or different and is each preferably an optionally substituted aliphatic chain, in particular a d- ⁇ alkylene chain, most especially a C ⁇ - 3 alkylene chain.
  • Alk 3 in one particular group of compounds of the invention is a -CH 2 - chain.
  • Alk 4 in compounds of the invention include -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -CH 2 C(CH 3 ) 2 CH 2 - or
  • Optional substituents which may in particular be present on Alk 3 and/ or Alk 4 include -CN, -C0 2 H, -C0 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , Ci-ealkoxy, particularly methoxy or ethoxy; haloC ⁇ - 6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(0) 2 R 11 , amino, -NHR 11 or-N(R 11 ) 2 , groups.
  • R 11 is in particular a C 1 -3 alkyl group.
  • L 2 when present in compounds of formula (1), include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -C(0)0-, -OC(O)-, -N(R 7 )- [where R 7 is as defined hereinbefore], -CON(R 7 )-, -CSN(R 7 )-, -N(R 7 )CO-, -N(R 7 )CS-, -S(0) 2 N(R 7 )- or -N(R 7 )S(0) 2 - groups.
  • L 2 may also, in particular, be a -N(R 7 )C(0)0-, -C(0)N(R 7 )C(0)- or -C(0)N(R 7 )0- group.
  • R 7 is especially a hydrogen atom or a C 1 - 3 alkyl group, particularly methyl.
  • L 2 examples include -C(O)-, -S(0) 2 -, -C(0)0-, -CON(H)-, -CON(CH 3 )-, -CON(CH 2 CH 3 )-, -CON(CH(CH 3 ) 2 )-, -N(H)CO-, -N(H)C(0)0-, -C(0)N(H)C(0)- or -C(0)N(CH 3 )0-.
  • L 2 in one particular group of compounds of the invention is a covalent bond.
  • R 6 in compounds of formula (1) is in particular a hydrogen or halogen atom or an optionally substituted C 3 -6 cycloalkyl, 5 to 7 membered heterocycloalkyl, phenyl or a 5 to 10 membered heteroaryl group.
  • R 6 examples include hydrogen or fluorine or optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C1-6 alkylpiperazinyl, especially ⁇ /-methylpiperazinyl, ⁇ /-C 1 -6 alkylpyrrolidinyl, especially /V-methylpyrrolidinyl, ⁇ /-C 1 -6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imi
  • More particular examples include optionally substituted cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, isoxazolyl, pyridyl, pyrimidinyl, benzofuryl or benzothienyl.
  • R 6 examples include hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, 1-(te/f-butoxycarbonyl)piperidin-4- yl, 1-acetylpiperidin-4-yl, 4-(4-chlorophenoxy)piperidin-1-yl, 4- trifluoromethylpiperidin-1 -yl, 4-(2-fluorophenyl)piperidin-1 -yl, 4-(pyridyl-4- oxy)piperidin-1-yl, 4-(benzofur-2-yl)piperidin-1-yl, 4-methylpiperazin-1 -yl, 4- (terf-butoxycarbonyl)piperazin-l -yl, morphoIin-1 -yl, tetrahydropyran-4-yl, phenyl, 3-aminophenyl, 3-amino
  • R 5 is the chain -Alk 3 -L 2 -R 6 in which Alk 3 is an optionally substituted aliphatic chain, L 2 is a covalent bond and R 6 is a hydrogen atom.
  • Alk 3 in compounds of this type is preferably a straight or branched Ci- 6 alkylene chain as herein defined, especially -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 - or -CH 2 C(CH 3 )2-.
  • Optional substituents present on these chains include those as herein defined for Alk 3 substituents, especially -CN, -C0 2 H, -C0 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , Ci- 6 alkoxy, particularly methoxy or ethoxy; haloC ⁇ - 6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(0)R 11 , -S(0) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 groups.
  • R 11 is in particular a Ci_ 3 alkyl group.
  • Alk 1 is a -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - chain substituted with a -NH(CH 3 ), -N(CH 3 ) 2 , -CN, -CO 2 H, -C0 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , -CONH 2 , -CONHCH 3 or -CON(CH 3 ) 2 group.
  • Typical examples of R 5 in compounds of this type include methyl, -(CH 2 ) 2 C(CH 3 ) 3 , -CH 2 CO t Bu or - CH 2 CON(CH 3 ) 2 .
  • R 5 is the chain -Alk 3 -L 2 -R 6 in which Alk 3 is an optionally substituted aliphatic chain, L 2 is a covalent bond or a linker atom or group and R 6 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group especially an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 3 in compounds of this type is in particular an optionally substituted Ci- 6 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or - CH 2 CH 2 CH 2 -.
  • R 6 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • Particular R 6 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C 1 - 6 alkylpiperazinyl, especially N- methylpiperazinyl, ⁇ /-C1- 6 alkylpyrrolidinyl, especially /V-methylpyrrolidinyl, N- C 1 - 6 alkylpiperidinyl, especially /V-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyr
  • R 5 in compounds of this type includes -CH 2 phenyl.
  • R 5 is the chain -L 2 -(Alk 4 ) v -R 6 in which L 2 is a linker atom or group, Alk 4 is an optionally substituted aliphatic or heteroaliphatic chain, v is zero or the integer 1 and R 6 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, as defined herein.
  • Alk 4 in compounds of this class is preferably an optionally substituted straight or branched C ⁇ - 6 alkylene chain as defined herein or a -CH 2 L 3 - [where L 3 is as defined herein], -CH(CH 3 )L 3 -, -CH 2 L 3 CH 2 -, -CH(CH 3 )CH 2 L 3 -, -CH 2 CH 2 L 3 -, -CH 2 L 3 CH 2 CH 2 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 - or -(CH 2 ) 3 L 3 - chain, most especially a C ⁇ - 6 alkylene chain.
  • R 6 is preferably a hydrogen atom or an optionally substituted C 3 . 6 cycloalkyl, 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • L 2 is in particular -0-, -N(R 7 )-, -C(O)-, -C(S)- , -S(0)sr.
  • Alk 4 is most preferably an optionally substituted C ⁇ - 3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • L 2 is a -C(O)-, -C(0)O-, -S(0) 2 -, -CON(R 7 ), -N(R 7 )C(0)0- or -C(0)N(R 7 )CO- group.
  • Optional substituents which may in particular be present on Alk 4 include -CN, -CO 2 H, -CO 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , d- 6 alkoxy, particularly methoxy or ethoxy; haloC ⁇ - 6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(0) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 , groups.
  • R 11 is in particular a d- 3 alkyl group.
  • R 5 is the group R 6 .
  • R 6 is in particular a halogen atom a -CN group or an optionally substituted C 3 - 6 cycloalkyl, 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • a typical example of R 6 in compounds of this type includes pyrid-2-yl.
  • R 5 is the chain -Alk 3 -L 2 -Alk 4 - R 6 in which Alk 3 is an optionally substituted aliphatic chain, L 2 is a linker atom or group, Alk 4 is an optionally substituted aliphatic or heteroaliphatic chain and R 6 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • R 5 is a C 1 - 6 alkyl group, especially a C ⁇ - 3 alkyl group, most especially a methyl group.
  • Another particular group of compounds of the invention has the formula (1) wherein R 5 is a hydrogen atom.
  • One group of cycloaliphatic or heterocycloaliphatic substituents which may be present on the groups A, R 4 or R 6 , are one, two, three or more groups selected from C1- 3 alkoxy, OCF 3 , OCF 2 H, CF 3 , - 3 alkylthio, optionally substituted straight or branched C ⁇ - 3 alkyl (wherein the optional alkyl substituent is in particular an optionally substituted phenyl or monocyclic heteroaromatic group), optionally substituted phenyl or monocyclic heteroaromatic group, - CN, NHCHs, N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , C0 2 CH 3 , C0 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , or -COCH 3 , -NHCOCH3, -N(CH 3 )COCH 3 or C0 2 H.
  • substituents which may in particular be present on R 6 , include te/ -butoxycarbonyl, optionally substituted phenoxy e.g. 4-chlorophenoxy, pyridyloxy e.g. pyrid-4-yloxy.
  • One group of aromatic or heteroaromatic substituents which may be present on the groups R 4 or R 6 , or the aryl or heteroaryl group optionally fused to the group A, are one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched C ⁇ - 6 alkyl, optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH3, CON(CH 3 ) 2 , C0 2 CH 3 , C0 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , or -COCH3, -NHCOCH3, -N(CH 3 )COCH 3 , -SCH 3 , -S0 2 CH 3 or C0 2 H.
  • One particular class of compounds of the invention has the formula (1a):
  • A is an optionally substituted cyclopentyl ring fused to a group Cy in which Cy is an optionally substituted phenyl or monocyclic d-gheteroaromatic group, especially a 5 or 6 membered heteroaromatic group, containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms as defined hereinbefore; T is a carbon or nitrogen atom; R 1 , R 2 , R 3 , R 5 and X are as defined and further defined for compounds of formula
  • Another particular class of compounds of the invention has the formula (1 b): in which A is an optionally substituted pyrrolidinyl ring; R 1 , R 2 , R 3 , R 5 and X are as defined and further defined for compounds of formula (1).
  • R 5 is a group -L 2 -(Alk 4 ) v - R 6 in which L 2 is a linker atom or group, Alk 4 is an optionally substituted aliphatic or heteroaliphatic chain, v is zero or the integer 1 and R 6 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, as defined herein.
  • Alk 4 in compounds of this type is preferably an optionally substituted straight or branched Ci- 6 alkylene chain as defined herein or a -CH 2 L 3 - [where L 3 is as defined herein], -CH(CH 3 )L 3 -, -CH 2 L 3 CH 2 -, -CH(CH 3 )CH 2 L 3 -, -CH 2 CH 2 L 3 -, -CH 2 L 3 CH 2 CH 2 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 - or -(CH 2 ) 3 L 3 - chain, most especially a Ci- 6 alkylene chain.
  • R 6 is preferably a hydrogen atom or an optionally substituted C 3 - ⁇ cycloalkyl, 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • L 2 is in particular -C(O)-, -C(S)-, -S(0) 2 -, - C(0)0-, -CON(R 7 )- or -CSN(R 7 )- [where R 7 is especially a hydrogen atom or a methyl group] and Alk 4 is most preferably an optionally substituted C ⁇ - 3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • L 2 is a -C(O)-, -C(O)O-, -S(O) 2 -, -CON(R 7 ), -N(R 7 )C(0)0- or -C(0)N(R 7 )CO- group.
  • Optional substituents which may in particular be present on Alk 4 include -CN, -C0 2 H, -C0 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , d- 6 alkoxy, particularly methoxy or ethoxy; haloC ⁇ - 6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(0)R 11 , -S(O) 2 R 11 , amino, -NHR 11 or-N(R 11 ) 2 , groups.
  • R 11 is in particular a C ⁇ - 3 alkyl group.
  • L 2 is a linker group selected from -C(O)-, -C(S)-, -S(O) 2 -, especially -C(O)-, v is zero and R 6 is an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic group which contains one or more N atoms or groups, wherein the heterocycloaliphatic group is attached to the group L 2 through any available N atom.
  • R 6 groups of this type include optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, piperazinyl, ⁇ /-C ⁇ - 6 alkylpiperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl or oxazolidinyl, especially optionally substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • a further particular class of compounds of the invention has the formula (1c):
  • R 15 is a group selected from -CN, -CO 2 R 10a [where R 10a is a hydrogen atom or a Ci-ealkyl group], -AlkOR 10a [where Alk is a C ⁇ . 3 alkylene chain], - NR 10a COR 16 [where R 16 is a Ci-ealkyl group], -NR 0a SO 2 R 16 , -S0 2 R 16 , -COR 16 , -CONR 17 R 18 [where R 17 and R 18 , which may be the same or different, is each a hydrogen atom or a C ⁇ .
  • R 17 and R 18 may join together to form a 4 to 6 membered heterocycloalkyl group], -NR 17 R 18 , -S0 2 NR 17 R 18 , Ci-ealkyl, haloC ⁇ - 6 alkyl or 5 or 6 membered heteroaryl group.
  • R 15 in one particular group of compounds of formula (1c) is selected from -CN, -CO 2 R 10a , -AlkOR 10a , -NR 10a COR 16 , -CONR 17 R 18 , -NR 17 R 18 , or optionally substituted Ci-ealkyl or 5 or 6 membered heteroaryl group.
  • R 15 is selected from -CN, -CO 2 R 10a , -AlkOR 10a , -CONR 17 R 18 , or a 5 or 6 membered heteroaryl group.
  • R 15 is a -CO 2 R 10a or -CONR 17 R 18 group.
  • Particular d-6 alkyl groups which may represent the groups R 10a , R 16 , R 17 or R 18 in compounds of formula (1c), include methyl, ethyl, propyl or isopropyl.
  • Alk in compounds of formula (1c) is preferably a C ⁇ . 3 alkylene chain, especially methylene or ethylene.
  • heterocycloalkyl groups which may represent NR 17 R 18 , include 4 - 6 membered heterocycloalkyl groups selected from azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, piperazinyl, ⁇ /-C 1 -6 alkylpiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, most particularly pyrrolidinyl.
  • heteroaryl groups which may represent R 15 include optionally substituted 5 membered groups selected from pyrrolyl, furyl, thienyl, imidazolyl, ⁇ /-C ⁇ _ 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl, especially 3-methyl oxadiazolyl.
  • Typical examples of the group R 15 include -C0 2 CH 3 , -C0 2 CH(CH 3 ) 2 , -CO 2 H, CON(CH 3 ) 2 , -C(O)pyrrolidin-1-yl or 3-methyloxadiazolyl.
  • R 5 in compounds of formula (1c) include H, -C0 2 CH 3 , -CO2CH2CH3, -C0 2 CH(CH 3 ) 2 , -C0 2 C(CH 3 )3, -C(0)fur-2-yl, -C(0)piperidin-1- yl, -CON(CH 3 )phenyl or -C(0)N(CH 3 )OCH 3 .
  • Compounds of formula (1) are potent inhibitors of IMPDH.
  • the ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
  • IMPDH-associated disorders refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monphosphate dehydrogenase, EC1.1.1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause(s) of that disorder or disease. There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme.
  • IMPDH inosine monphosphate dehydrogenase
  • IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, lupus, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumors, T-cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases.
  • Use of the compounds of the present invention is exemplified by, but is not limited to, treating a range of disorders such as: treatment of transplant rejection (e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • transplant rejection e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus), pyoderma gangrenum, lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis, eczema, dermatitis, dermatomyosis, atopic dermatitis; multiple sclerosis, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as
  • IMPDH is also known to be present in bacteria and thus may regulate bacterial growth.
  • the IMPDH-inhibitor compounds of the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
  • the compounds of the present invention are useful for the treatment of the afore mentioned exemplary disorders irrespective of their etiology, for example, for the treatment of lupus, psoriasis, inflammatory bowl disease, multiple sclerosis, atopic dermatitis, transplant rejection or rheumatoid arthritis.
  • the compounds of the present invention are of particular use for the treatment of DNA or RNA viral replication diseases, such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • viruses such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • HIV human immundeficiency virus
  • influenza influenza
  • cancer and tumour disorders such as solid tumors, lymphoma, leukemia and other forms of cancer.
  • the compounds of formula (1) can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
  • therapeutic or prophylactic agents such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions of this invention comprise a compound formula (1) or a salt thereof; an additional agent selected from an immunosuppressant, an anticancer agent, an anti-viral agent, anti-inflammatory agent, anti-fungal agent, anti-vascular hyperproliferation agent or an antibiotic agent; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, OKT3, ATAG, interferon and mizoribine.
  • Additional anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres.
  • Additional anti-viral agents include, but are not limited to, Cytovene, Ganiclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT and acyclovir.
  • Additional anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, and rapamycin.
  • HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, and rapamycin.
  • the above other therapeutic agents when employed
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen- free water, before use.
  • the compounds of formula (1 ) may be coated on particles such as microscopic gold particles.
  • the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • the compounds of formula (1) may be formulated as a suppository.
  • These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature.
  • suitable non-irritating excipient include for example cocoa butter and polyethylene glycols.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.
  • R 1 , R 2 , R 3 , R 4 and R 5 when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated.
  • reactive functional groups for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, (1999) and the examples herein].
  • deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. It will be appreciated that the syntheses described herein for the preparation of compounds of formula (1) also apply to the compounds of formulae (1a), (1b) and (1c), unless otherwise stated.
  • Amines of general formula (ii) may be prepared in a variety of ways.
  • the amine of formula (ii) where R 1 is a methyl group and R 2 is an oxazole group may be prepared using methods known in the literature (CAS 198821-79-3).
  • a suitable leaving group e.g. trifluoromethylsulfonyloxy (OTf) and -NRR' is a nitro group or an amine group (which may be suitably protected)
  • OTf trifluoromethylsulfonyloxy
  • -NRR' is a nitro group or an amine group (which may be suitably protected)
  • OTf trifluoromethylsulfonyloxy
  • -NRR' is a nitro group or an amine group (which may be suitably protected)
  • R 2 -W where W is as described below
  • -NRR' when -NRR' is a nitro group this may be reduced to an amine using standard techniques such as those methods as described hereinafter, or when -NRR' is a protected amine the protecting group may be removed using standard methodology, for example a carbamate protecting group e.g. tert-butoxycarbonyl may be removed under acidic conditions e.g. trifluoroacetic acid.
  • a carbamate protecting group e.g. tert-butoxycarbonyl may be removed under acidic conditions e.g. trifluoroacetic acid.
  • the various R 2 -W derivatives are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compounds of formula (iii) are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compound of formula (iii) may be prepared by alkylation of the phenol precursor of (iii) using standard techniques.
  • R 2 is a CN group amines of formula (ii) may be prepared from 2-hydroxy-4-nitrobenzonitrile (iiia) (CAS 39835-14-8) as shown in the general Scheme B below:
  • a phenol of formula (iiia) may be alkylated using conditions known to those skilled in the art, typically using an alkyl halide e.g. iodoethane and sodium hydride in ⁇ /, ⁇ /-dimethylformamide, to give an ether of formula (iiib).
  • alkyl halide e.g. iodoethane and sodium hydride in ⁇ /, ⁇ /-dimethylformamide
  • R 1 Me (CAS 101084-96-2)
  • the compound of formula (iiib) may then be reduced to give the desired amine of formula (ii) using standard methods, for example hydrogenolysis using palladium catalysis.
  • the amine of formula (ii) may then be converted to an amino acid of general formula (iv) using a two-step process as shown in Scheme C.
  • an amine of formula (ii) may be treated with a halogen source such as bromine or a halosuccinimide e.g. chloro or bromosuccinimide.
  • a halogen source such as bromine or a halosuccinimide e.g. chloro or bromosuccinimide.
  • the reaction may be performed in a solvent such as acetonitrile or an ether e.g. a cyclic ether such as tetrahydrofuran at a temperature from about 0° to 30°.
  • bromine is used as halogen source the reaction may optionally be performed in the presence of added base such as an amine e.g. triethylamine.
  • the intermediate thus formed may be converted into a carboxylic acid of formula (iv) using methods known to those skilled in the art.
  • the halogenated intermediate may be treated with carbon monoxide under pressure in the presence of a catalyst e.g. a palladium catalyst such as dichlorobis(triphenylphosphene)palladium(ll) in for example water and an appropriate solvent e.g ⁇ /, ⁇ /-dimethylformamide or tetrahydrofuran. It may be appropriate to carry out the reaction at an elevated temperature, such as 90- 100°C.
  • a catalyst e.g. a palladium catalyst such as dichlorobis(triphenylphosphene)palladium(ll) in for example water and an appropriate solvent e.g ⁇ /, ⁇ /-dimethylformamide or tetrahydrofuran.
  • a catalyst e.g. a palladium catalyst such as dichlorobis(triphenylphosphene)palladium(ll) in for example water and an appropriate solvent e.g ⁇ /, ⁇ /-dimethylformamide or tetrahydrofur
  • quinazolinones of formula (1) may be prepared by reacting an amine of formula (vi) with a carbonyl compound of formula (vii).
  • quinazolinones of formula (1) may be prepared using the general route as shown in Scheme D:
  • amino acids of formula (iv) may be reacted with amines of formula (v) using coupling reaction conditions familiar to those skilled in the art to give amides (vi).
  • an acid of formula (iv) may be activated in situ using for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), advantageously in the presence of a catalyst such as a ⁇ /-hydroxy compound, e.g. /V-hydroxybenzotriazole, using suitable conditions, e.g. in ⁇ /, ⁇ /-dimethylformamide, prior to the subsequent addition of an amine of formula (v).
  • a base such as an amine base e.g.
  • triethylamine or diisopropylethylamine may also be employed in the reaction.
  • acids of formula (iv) may be reacted with oxalyl chloride in an inert solvent (such as dichloromethane) to give an intermediate acid chloride, which may or may not be isolated, but which in turn is reacted with an amine of formula (v) at a suitable temperature such as room temperature to give the amide (vi).
  • the reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or ⁇ /-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide at for example ambient temperature.
  • a base such as a hydride, e.g. sodium hydride or an amine, e
  • Amines of formula (v) may be commercially available, known compounds in the literature or may be prepared using methods known to those skilled in the art. Formation of quinazolinones of formula (1) may be achieved by condensation of amino amides (vi) with aldehydes or ketones of formula (vii) typically using acid, e.g p-toluenesulfonic acid, catalysed conditions similar to those employed by Bhavani and Reddy (Org. Prep. Proced. Int. 1992, 24, 1) or Sharma and Kaur (Synthesis 1989, 9, 677) or Takai et al (Chem. Pharm. Bull. 1985, 33, 1116).
  • the acid used as a catalyst may be hydrochloric acid (Klemm et al; J.
  • the reaction may be performed in a sealed tube, for example, using microwaves as an energy source or under vacuum.
  • Suitable solvents for use in this reaction include halogenated hydrocarbons, e.g. dichloromethane or dichloroethane, amides, e.g. dimethylformamide, ethers such as cyclic ethers e.g. 1-4-dioxane, alcohols e.g. ethanol or esters e.g. isopropylacetate.
  • Drying agents such as magnesium sulfate or molecular sieves may be added or the reaction may be performed using Dean Stark conditions.
  • the reaction may be achieved at a range of temperatures e.g. from room temperature to reflux.
  • Carbonyl compounds of formula (vii) are either commercially available or may be prepared using methods known to those skilled in the art. Alternatively a carbonyl compound protected as an acetal may be used in the condensation reaction rather than the carbonyl compound itself. Such compounds are either commercially available or prepared using methods previously reported in the literature.
  • ketones of formula (vii) may be prepared from appropriate ketones of formula (vii), e.g. 4-hydroxyproline, using standard methodology known to those skilled in the art, such as those methods as described in the examples hereinafter.
  • standard manipulations may afford ketones of formula (vii) as enatiomerically pure compounds. Cyclisation of these ketones with amino amides of formula (vi) may thus afford two out of four possible diastereomers of quinazolinones of formula (1c).
  • the diastereomers thus formed may be separated using methods known to those skilled in the art, such as by column chromatography and/or preparative HPLC.
  • a thiation reagent such as Lawesson's Reagent or P 2 S 5
  • an anhydrous solvent for example a cyclic ether such as tetrahydrofuran, or toluene at an elevated temperature such as the reflux temperature (see for example Tetrahedron 1985, 41 , 5061).
  • compounds of formula (1) or any preceding intermediates may be further derivatised by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions.
  • Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of any of formula (1) or any preceding intermediates where appropriate functional groups exist in these compounds.
  • ester groups may be converted to the corresponding acid [- CO 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the ester.
  • Acid- or base- catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • an organic or inorganic acid e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • an acid [-C0 2 H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.
  • -OH groups may be generated from the corresponding ester or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride in e.g. tetrahydrofuran or sodium borohydride in an alcohol e.g. methanol.
  • an alcohol may be prepared by reduction of the corresponding acid [-C0 2 H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon e.g. dichloromethane to yield the corresponding chloride.
  • a base e.g. triethylamine may also
  • alcohol or phenol groups may be converted to ether groups groups by coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine
  • an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • ether groups may be prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkylhalide.
  • Aldehyde or ketone groups may be obtained by oxidation of a corresponding alcohol using well known conditions.
  • an oxidising agent such as a periodinane e.g. Dess Martin
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane.
  • An alternative oxidation may be suitably activating dimethyl sulfoxide using for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the addition of an amine base, such as triethylamine.
  • Suitable conditions for this reaction may be using an appropriate solvent, for example, a halogenated hydrocarbon, e.g. dichloromethane at -78°C followed by subsequent warming to room temperature.
  • primary amine (-NH 2 ) or secondary amine (-NH-) groups may be alkylated using a reductive alkylation process employing an aldehyde or ketone and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a halogenated hydrocarbon e.g. dichloromethane
  • an alcohol e.g. ethanol
  • amine [-NH 2 ] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
  • a nitro [-N0 2 ] group may be reduced to an amine [-NH 2 ], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol
  • an acid such as hydrochloric acid
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic ether, e.g. tetrahydrofuran, at a temperature from -78°C to the reflux temperature.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Compounds possessing a urea linker may be prepared by reaction of an isocyanate with an amine in the presence of a base e.g. triethylamine or DIPEA in a suitable solvent such as dichloromethane.
  • Isocyanates may be prepared by reaction of an amine with phosgene or triphosgene in the presence of a base e.g. triethylamine in a suitable solvent such as dichloromethane.
  • Compounds possessing an amide linker may be prepared by reaction of an amine with an activated acid using standard methods known to those skilled in the art.
  • acids may be activated in situ using for example a diimide such as EDC, advantageously in the presence of a catalyst such as a ⁇ /-hydroxy compound, e.g. ⁇ /-hydroxybenzotriazole, using suitable conditions, e.g. in ⁇ /, ⁇ /-dimethylformamide, prior to the subsequent addition of an amine.
  • a base such as an amine base e.g. triethylamine or diisopropylethylamine may also be employed in the reaction.
  • Alternative activated acids which may be used, include acid chlorides, chloroformates or anhydrides.
  • Aromatic halogen substituents in the compounds may be subjected to halogen- metal exchange by treatment with a base, for example a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example, a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using dimethylformamide as the electrophile
  • a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • Aromatic halogen substituents may also be subjected to palladium
  • sulfur atoms in the compounds may be oxidised to the corresponding sulfoxide or sulfone using an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
  • an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid
  • an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane
  • N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid
  • an elevated temperature for example around 70°C to 80°C
  • a peracid such as peracetic acid in a solvent, e.g. dichloromethane
  • Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base or acid in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures. Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
  • a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures.
  • Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
  • diastereomeric derivatives e.g. salts
  • a mixture of enantiomers of formula (1) e.g. a racemate
  • an appropriate chiral compound e.g. a chiral base
  • the diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Varian Gradient HPLC system consisting of Varian 9012/9050/9100 Modules and Waters fraction collector.
  • MPLC medium pressure liquid chromatography
  • so-Propyl-(4f?)-4-hvdroxy-D-prolinate hydrochloride To a suspension of c/s-4-hydroxy-D-proline (1.0g) in dry iso-propanol (25ml) under nitrogen cooled to 0°C was added dropwise thionyl chloride (0.8ml). The reaction mixture was heated at 100°C for 6 hours. The mixture was concentrated in vacuo to afford the title compound as a white solid (1.6g, quantitative).
  • Examples 2-6 were prepared in a similar manner to the method of Example
  • Example 9 ferf-Butvi y'-methoxy-e'-d ⁇ -oxazol-S-yl '-oxo-S' ⁇ '-dihvdro-yRT'H- spirorpyrrolidine-3.2'-quinazolinel-1 -carboxylate
  • Example 12 (246mg) and palladium on carbon were combined in EtOH (15ml) and stirred under hydrogen gas for 48 hours. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo. The resulting residue was dissolved in DCM (30ml) and washed with aqueous 1 M HCI (2x15ml). The aqueous layers were collected and extracted with DCM (3x30ml). The combined organic layers were dried over MgS0 4 , filtered and the solvent removed in vacuo. The resulting residue was purified by column chromatography on silica eluting with 50-100% EtOAc/heptane to yield the title compound as a yellow solid (12.9 mg, 56%).
  • Examples 14-15 were prepared in a similar manner to the method of example 12:-
  • Example 15 To a solution of Example 15 in methanol (10ml) was added a solution of oxone ® in H 2 O (5ml) and the reaction mixture stirred at room temperature for 18 hours. The solvent was removed in vacuo. The residue was purified by triturating with H 2 0 and washing with Et 2 0 followed by further trituration with MeOH/DCM to yield the title compound as an off-white solid (26mg, 24%).
  • Example 8 (0.20g), DCM (10ml) and HCI (2M in Et 2 0, 30ml) were stirred at room temperature for 1 hour. The reaction mixture was filtered and the solid dried in vacuo to yield the title compound as a solid (206mg, quantitative). TLC R f 0.13 (10% MeOH/DCM). LCMS 315 [M+H] + , RT 1.33 mins.
  • Example 24 was prepared in a similar manner to the method of Example 23:- Example 24.
  • Examples 26 - 42 were prepared in a similar manner to the method of Example 25:- Example 26.
  • Example 21 From Example 21 (50mg) and tetrahydropyran-4-carboxylic acid (19mg). The residue was purified by column chromatography on silica eluting with 4-7% MeOH/DCM to yield the title compound as a solid (35mg, 57%). TLC R f 0.46 (10% MeOH/DCM). LCMS 427 [M+H] + , RT 2.21 mins.
  • Example 21 From Example 21 (50mg) and isonicotinic acid (18mg). The aqueous phases were re-extracted with DCM (3x50ml) after first basifying the acidic layer. The organic layers were combined, dried over MgS0 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 6-10% MeOH/DCM to yield the title compound as a solid (35mg, 58%). TLC R f 0.54 (10% MeOH/DCM). LCMS 420 [M+H] + , RT 1.91 mins.
  • Example 21 From Example 21 (50mg) and 2-furoic acid (15mg). The residue was purified using an MPLC Retrieve eluting with 5% MeOH/DCM to yield the title compound as a solid (23mg, 43%). TLC R f 0.51 (10% MeOH/DCM). LCMS 409 [M+ T, RT 2.37 mins.
  • Example 21a 120mg and 2-furoic acid (36mg). The residue was purified by column chromatography on silica eluting with 0-5% MeOH/DCM to yield the title compound as a solid (35mg, 26%). TLC R f 0.2 (5% MeOH/DCM). LCMS 409 [M+H] + , RT 2.42 mins.
  • Example 21 From Example 21 (50mg) and ⁇ /-methylpyrrole-2-carboxylic acid (16mg). The residue was purified by preparative HPLC (Method A) to yield the title compound as a solid (7mg, 13%). LCMS 422 [M+H] + , RT 2.58 mins.
  • Example 21 From Example 21 (50mg) and 1 -methyl- 7r7-imidazole-2-carboxylic acid (49mg) The residue was purified by column chromatography on silica eluting with 5%MeOH/DCM to yield the title compound as an off-white solid (35.9mg, 66%). TLC R f 0.08 (5% MeOH/DCM). LCMS 423 [M+H] + , RT 2.14 mins.
  • Example 21 From Example 21 (50mg) and 1 benzothiophene-3-carboxylic acid (23mg). The residue was dissolved in DCM (10ml) and washed with water (3x10ml). The organic phase was separated, dried over MgS0 , filtered and concentrated in vacuo to give a residue that was purified by column chromatography on silica eluting with 4%MeOH/DCM to yield the title compound as a solid (16mg, 26%). TLC R f 0.19 (5% MeOH/DCM). LCMS 475 [M+H] + , RT 2.97 mins.
  • Examples 45-46 were prepared in a similar manner to the method of Example 44:-
  • Example 21a (40mg), 1-piperidinecarbonyl chloride (0.013ml), DCM (20ml) and DIPEA (0.037ml) were combined under a nitrogen atmosphere and stirred at room temperature for 1.5 hours. The mixture was taken up in EtOAc (100ml) and washed with 1 M HCI (30ml) and saturated aqueous Na 2 C0 3 (30ml). The organic layer was separated, dried over MgS0 4 , filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica eluting with 0-8% MeOH/DCM followed by preparative HPLC (Method A) to give the title compound as a solid (11 mg, 25%).
  • Example 47 was prepared in a similar manner to the method of example 46a:-
  • Example 21 50mg
  • phenyl chloroformate 0.018ml
  • DMF 10ml
  • TEA 0.1 ml
  • Example 21 (75mg) and TEA (0.09ml) in THF (5ml) at 0°C, was added 1-bromopinacolone (0.04ml). The reaction mixture was stirred for 18 hours with slow warming to room temperature.
  • Examples 56-58 were prepared in a similar manner to the method of example 55:-
  • Example 21 From Example 21 (50mg) and 4-morpholine carbonyl chloride (0.02ml). The residue was purified by column chromatography on silica eluting with 3- 5%MeOH/DCM to yield the title compound as a solid (20.6 mg, 37%). TLC R f 0.44 (10% MeOH/DCM). LCMS 428 [M+H] + , RT 2.22 mins.
  • Examples 63-83 were prepared in a similar manner to the method of example 62:- Example 63.
  • Example 21 From Example 21 (50mg) and ⁇ /-benzylmethylamine (0.017ml). Purification by column chromatography on silica eluting with 5% MeOH/DCM followed by trituration in DCM/pentane afforded the title compound as an off-white solid (31 mg, 52%). TLC R f 0.52 (10%MeOH/DCM). LCMS 462 [M+H] + , RT 2.94 mins.
  • Example 21 From Example 21 (100mg) and f-butyl-1-piperazine (48.4mg). Purification by column chromatography on silica eluting with 5% MeOH/DCM and trituration with DCM/pentane yielded the title compound as a yellow solid (34.5mg, 25%). TLC R f 0.59 (10% MeOH/DCM). LCMS 527 [M+H] + , RT 3.01 mins.
  • Example 74 (484mg), LiOH.H 2 0 (161 mg), THF (18ml), MeOH (9ml) and water (9ml) were combined and stirred at room temperature for 18 hours. The solvents were removed in vacuo and the residue triturated with 2N HCI to afford the title compound as a yellow solid (420mg). TLC R f 0.17 (EtOAc). LCMS 492 [M+Hf, RT 2.39 mins.
  • Example 21 (35mg), 2-chloropyridine, DBN (0.045ml) and DMF (3ml) were combined and heated to 120°C for 1.5 hours in a microwave reactor. The solvents were then removed in vacuo and the residue purified by preparative HPLC (Method A) to give the title compound as a glass (3mg). LCMS 392 [M+Hf, RT 1.57 mins.
  • Examples 87 - 90 were prepared in a similar manner to the method of example 86:- Example 87.
  • Example 21a From Example 21a (80mg) and ⁇ /,0-dimethylhydroxylamine hydrochloride (22mg) using diisopropylethylamine (141 mg). The residue was by preparative HPLC (Method A) to yield the title compound as a white solid (27.7mg, 32%). TLC R f 0.37 (5% MeOH/DCM). LCMS 402 [M+Hf, RT 2.37 mins.
  • Example 21a From Example 21a (50mg) and ⁇ /,/V,/V'-trimethylethylenediamine (13mg). The residue was purified by column chromatography on silica eluting with DCM/MeOH/c.NH 4 OH (90:9:1) to give the title compound as a pale green glass (3.2mg, 6%). TLC R f 0.32 (9% MeOH/DCM + trace c.NH OH). LCMS 443 [M+Hf, RT 1.50 mins.
  • Example 21a From Example 21a (50mg) and ⁇ /-[2-(methylamino)ethyl]acetamide (CAS 4814-81-7) (15mg). The residue was purified by preparative HPLC (Method B) to give the title compound (19mg, 32%). TLC R f 0.45 (10% MeOH/DCM). LCMS 457 [M+Hf, RT 2.01 mins.
  • Example 100 1 -Benzyl-7'-methoxy-3'-methyl-6'-(1 -3-oxazol-5-yl )- 7 ⁇ .2H- spirorpyrrolidine-3,2'-quinazoline1-2,4'(3 ? H)-dione
  • sodium hydride 11mg
  • the solution was stirred under nitrogen for 90 mins at which point benzylbromide (0.03ml) was added.
  • the solution was stirred for 18 hours.
  • the solvents were removed in vacuo and the product purified by preparative HPLC (Method A) to give the title compound as a beige solid (11 mg, 10%).
  • Examples 102, 103 and 104 describe the preparation of three out of the four diastereomers of 1-terf-butyl 5-methyl 7'-methoxy-3'-methyl-6'-(1 ,3-oxazol-5- yl)-4'-oxo-3',4'-dihydro- 1H, 7'H-spiro[pyrrolidine-3,2'-quinazoline]-1 ,5- dicarboxylate.
  • Example 102. 1-ferf-Butyl 5-methyl 7'-methoxy-3'-methyl-6'-(1 ,3-oxazol-5-v ⁇ -4'-oxo- 3 , .4 , -dihvdro-7H,7 ? H-spirorpyrrolidine-3,2'-quinazoline1-1 ,5-dicarboxylate (Diastereomer 1 )
  • Diastereomer 1 was separated into its component diastereomers by preparative HPLC (Method A) to afford Diastereomer 1 as a cream solid (197mg). TLC R f 0.29 (EtOAc). LCMS 473 [M+Hf, RT 3.25 mins.
  • Examples 107 and 108 describe the preparation of two out of the four diastereomers of tert-butyl 7'-methoxy-3'-methyl-5-(3-methyl-1 ,2,4-oxadiazol- 5-yl)-6'-(1 ,3-oxazol-5-yl)-4'-oxo-3',4'-dihydro- 1H, 7'/-/-spiro[pyrrolidine-3,2'- quinazoline]-1 -carboxylate.
  • Diastereomer 1 as a white solid (4.8mg, 9%). TLC R f 0.29 (EtOAc). LCMS 498 [M+Hf, RT 3.28 mins.
  • Example 106 To a stirring solution of Example 106 (44mg), HBTU (36mg), and DIPEA (0.09ml) in DMF (2ml) was added pyrrolidine (0.02ml). The reaction mixture was stirred at room temperature for 18 hours concentrated in vacuo and the residue purified by column chromatography on silica eluting with 2% MeOH/DCM, to yield the title compound as a single diastereomer as a solid 18mg (37%). TLC R f 0.24 (2%MeOH/DCM). LCMS 512 [M+Hf, RT 3.14 mins.
  • Example 106 To a stirring solution of Example 106 (70mg), EDC (29mg), HOBt (21 mg) and TEA (0.06ml) in DCM (5ml), was added dimethylamine hydrochloride (25mg). The mixture was stirred at room temperature overnight. More dimethylamine hydrochloride (25mg) and TEA (0.03ml) were added to the reaction mixture, which was left to stir at room temperature overnight. DMAP (1 mg) was added to the reaction mixture, which was left to stir at room temperature overnight. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica eluting with 4%MeOH/DCM to yield the title compound as a single diastereomer as a white solid 5.3mg (7%).
  • Example 111 To a solution of Example 111 (49mg) in DCM (5ml), stirring under nitrogen at 0°C was added TEA (0.05ml) followed by ethylchloroformate (0.013ml). The mixture was allowed to warm slowly to room temperature. The reaction mixture was diluted with water ((20ml) and extracted into DCM (3x50ml). The organic layers were combined, dried over MgS0 , filtered and concentrated in vacuo. Purification by column chromatography on silica eluting with 2% MeOH/DCM afforded the title compound as a single diastereomer as an off- white solid (35.7mg, 67%). HPLC RT 2.77 mins.
  • Example 114 was prepared in a similar manner to the method of Example
  • Example 114 1 -/so-Propyl 5-methyl 7'-methoxy-3'-methyl-6'-(1 ,3-oxazol-5-yl )-4'-oxo- 3 , .4'-dihvdro-7tf, 7 ? H-spirorpyrrolidine-3.2'-quinazoline1-1 ,5-dicarboxylate From Example 111 (50mg) and /so-propylchloroformate. The residue was purified by column chromatography on silica eluting with 2% MeOH/DCM to yield the title compound as a single diastereomer as a yellow solid, (41.7mg, 62%). HPLC RT 2.99 mins.
  • Example 111 To a suspension of Example 111 (65mg) in dry DCM (10ml) under N 2 cooled to 0°C was added dropwise 1-piperidinecarbonyl chloride (0.024ml) followed by TEA (0.05ml), again dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica eluting with 5% MeOH/DCM to afford the title compound as a single diastereomer as a pale yellow solid (50mg, 65%). LCMS 484 [M+Hf, RT 2.85 mins.
  • Example 117 was prepared in a similar manner to the method of Example
  • Methyl 7 -methoxy-1-f ⁇ methoxy(methyl)amino ⁇ carbonyl)-3 , -methyl-6 , - (1.3-oxazol-5-vn-4'-oxo-3'.4'-dihvdro-7 , H-spirorpyrrolidine-3.2'- quinazolinel-5-carboxylate
  • Example 111 From Example 111 (50mg) and ⁇ /,0-dimethylhydroxylamine hydrochloride (14mg). Purification by column chromatography on silica eluting with 2% MeOH/DCM afforded the title compound as a brown solid, 14.4mg (21 %). HPLC RT 2.53 minutes. LCMS 460 [M+H]+, RT 2.57 minutes.
  • Example 118 describes the preparation of a mixture of two out of the four diastereomers of 1 -tert-butyl 5-methyl 7'-methoxy-6'-(1 ,3-oxazol-5-yl)-4'-oxo- 3',4'-dihydro- 1H, 7'H-spiro[pyrrolidine-3,2'-quinazoline]-1 ,5-dicarboxylate, and was prepared in a similar manner to the method of example 104:- Example 118.
  • IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the coenzyme.
  • IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 2OO I containing IMPDH (2 ⁇ g), NAD (100 ⁇ M), IMP (100 /M), 1% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. Fluorescence (excitation 340nm / emission 465nm) was read continuously at 25°C for 30 minutes. From this data, initial rates (i.e. change in fluorescence intensity per minute) were calculated.
  • test compounds were prepared at an initial concentration of 1.0mM in 100% DMSO, then diluted in assay buffer to 0.2mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 20-fold into the assay, to allow testing across the range 0.3nM to 10 /M.
  • PBMC Proliferation Assay Peripheral blood mononuclear cells were isolated from freshly taken human blood using standard procedures. Cells were plated out in RPMI medium containing 5% human serum in the presence and absence of inhibitor. PHA (25 ⁇ l of 30 ⁇ g/ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C0 2 for 48 hours. O. ⁇ Ci of tritiated thymidine was added to each well and the plates were incubated for a further 18 hours. The contents of the plate were transferred to a filter plate and the cells washed with saline. The plates were dried, microscintillation fluid was added to each well and the plate was counted on a scintillation counter. IC50 values were calculated by plotting inhibitor concentration versus %inhibition.
  • the assay described above can be carried out using anti-CD3 (40 ⁇ l of 3750ng/ml concentration to each well) stimulation instead of PHA.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (1), dans laquelle X représente un atome d'oxygène ou de soufre ; R1 représente un groupe aliphatique, cycloaliphatique ou cycloalkyl-alkyle ; R2 représente un groupe hétéroaromatique éventuellement substitué ou un groupe CN ; R3 représente un groupe -(Alk1)mL1(AIk2)nR4 dans lequel m et n, égaux ou différents, représentent chacun zéro ou le nombre entier 1, Alk1 et AIk2, égaux ou différents, représentent chacun une chaîne aliphatique or hétéroaliphatique éventuellement substituée, L1 représente une liaison covalente ou un atome ou un groupe de liaison et R4 représente un atome d'hydrogène ou un groupe cycloaliphatique, hétérocycloaliphatique, aromatique ou hétéroaromatique éventuellement substitué ; A représente un groupe cycloaliphatique ou hétérocycloaliphatique éventuellement substitué et éventuellement fusionné à un groupe aryle ou hétéroaryle éventuellement substitué ; R5, qui peut être lié à n'importe quel atome C ou N disponible présent dans le groupe cycloaliphatique ou hétérocycloaliphatique, ou là ou il est fusionné, dans le groupe aryle ou hétéroaryle, représente un groupe -(AIk3)tL2(AIk4)vR6 dans lequel t et v, égaux ou différents, représentent chacun zéro ou le nombre entier 1, Alk3 et AIk4, égaux ou différents, représente chacun une chaîne aliphatique ou hétéroaliphatique éventuellement substituée, L2 représente une liaison covalente ou un atome ou un groupe de liaison et R6 représente un atome hydrogène ou halogène ou un groupe -CN ou un groupe cycloaliphatique, hétérocycloaliphatique, aromatique ou hétéroaromatique éventuellement substitué. L'invention concerne également des sels, des solvates, des hydrates, des tautomères, des isomères ou des N-oxydes de ces composés. Lesdits composés sont des inhibiteurs potentiels de IMPDH.
PCT/GB2003/003878 2002-09-07 2003-09-05 Derives de quinazolinone WO2004022554A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003263323A AU2003263323A1 (en) 2002-09-07 2003-09-05 Quinazolinone derivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0220813.0 2002-09-07
GB0220813A GB0220813D0 (en) 2002-09-07 2002-09-07 Chemical compounds
GB0229186A GB0229186D0 (en) 2002-12-14 2002-12-14 Chemical compounds
GB0229186.2 2002-12-14
GB0312775A GB0312775D0 (en) 2003-06-04 2003-06-04 Chemical compounds
GB0312775.0 2003-06-04

Publications (1)

Publication Number Publication Date
WO2004022554A1 true WO2004022554A1 (fr) 2004-03-18

Family

ID=31982029

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2003/003878 WO2004022554A1 (fr) 2002-09-07 2003-09-05 Derives de quinazolinone

Country Status (2)

Country Link
AU (1) AU2003263323A1 (fr)
WO (1) WO2004022554A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7009049B2 (en) 2002-02-15 2006-03-07 Cytokinetics, Inc. Syntheses of quinazolinones
US7038048B2 (en) 2002-05-23 2006-05-02 Cytokinetics, Inc. 3H-pyridopyrimidin-4-one compounds, compositions, and methods of their use
US7041676B2 (en) 2002-06-14 2006-05-09 Cytokinetics, Inc. Compounds, compositions, and methods
US7166595B2 (en) 2002-05-09 2007-01-23 Cytokinetics, Inc. Compounds, methods and compositions
US7211580B2 (en) 2002-07-23 2007-05-01 Cytokinetics, Incorporated Compounds, compositions, and methods
US7214800B2 (en) 2002-05-09 2007-05-08 Cytokinetics, Inc. Compounds, compositions, and methods
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US7294634B2 (en) 1999-10-27 2007-11-13 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
JP2008504278A (ja) * 2004-06-24 2008-02-14 インサイト・コーポレイション アミド化合物およびその医薬としての使用
WO2008102749A1 (fr) * 2007-02-20 2008-08-28 Takeda Pharmaceutical Company Limited Composé hétérocyclique
US7439254B2 (en) 2003-12-08 2008-10-21 Cytokinetics, Inc. Compounds, compositions, and methods
US7557115B2 (en) 2002-09-30 2009-07-07 Cytokinetics, Inc. Compounds, compositions, and methods
US7776874B2 (en) 2004-05-07 2010-08-17 Incyte Corporation Amido compounds and their use as pharmaceuticals
US8288417B2 (en) 2004-06-24 2012-10-16 Incyte Corporation N-substituted piperidines and their use as pharmaceuticals
WO2014117920A1 (fr) 2013-02-04 2014-08-07 Merck Patent Gmbh Dérivés spiro-quinazolinone utiles pour le traitement de troubles et de maladies neurologiques
CN110831593A (zh) * 2017-06-14 2020-02-21 特维娜有限公司 用于调节s1p1活性的化合物及其使用方法
US11884655B2 (en) 2019-11-19 2024-01-30 Trevena, Inc. Compounds and methods of preparing compounds S1P1 modulators
WO2025036472A1 (fr) * 2023-08-16 2025-02-20 Pharmaengine, Inc. Inhibiteur de prmt5 mta-coopératif spirocyclique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014686A1 (fr) * 1995-10-17 1997-04-24 Astra Pharmaceuticals Limited Composes de quinazoline, a activite pharmaceutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014686A1 (fr) * 1995-10-17 1997-04-24 Astra Pharmaceuticals Limited Composes de quinazoline, a activite pharmaceutique

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US7589098B2 (en) 1999-10-27 2009-09-15 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7294634B2 (en) 1999-10-27 2007-11-13 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7009049B2 (en) 2002-02-15 2006-03-07 Cytokinetics, Inc. Syntheses of quinazolinones
US7161002B2 (en) 2002-02-15 2007-01-09 Cytokinetics, Inc. Syntheses of quinazolinones
US7166595B2 (en) 2002-05-09 2007-01-23 Cytokinetics, Inc. Compounds, methods and compositions
US7214800B2 (en) 2002-05-09 2007-05-08 Cytokinetics, Inc. Compounds, compositions, and methods
US7528137B2 (en) 2002-05-09 2009-05-05 Cytokinetics, Inc. Compounds, compositions, and methods
US7332498B2 (en) 2002-05-23 2008-02-19 Cytokinetics, Inc. Modulation of KSP kinesin activity with heterocyclic-fused pyrimidinone derivatives
US7038048B2 (en) 2002-05-23 2006-05-02 Cytokinetics, Inc. 3H-pyridopyrimidin-4-one compounds, compositions, and methods of their use
US7041676B2 (en) 2002-06-14 2006-05-09 Cytokinetics, Inc. Compounds, compositions, and methods
US7211580B2 (en) 2002-07-23 2007-05-01 Cytokinetics, Incorporated Compounds, compositions, and methods
US7557115B2 (en) 2002-09-30 2009-07-07 Cytokinetics, Inc. Compounds, compositions, and methods
US7439254B2 (en) 2003-12-08 2008-10-21 Cytokinetics, Inc. Compounds, compositions, and methods
US7776874B2 (en) 2004-05-07 2010-08-17 Incyte Corporation Amido compounds and their use as pharmaceuticals
US9670154B2 (en) 2004-05-07 2017-06-06 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
US8058288B2 (en) 2004-05-07 2011-11-15 Incyte Corporation Amido compounds and their use as pharmaceuticals
US9126927B2 (en) 2004-05-07 2015-09-08 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
US9957229B2 (en) 2004-05-07 2018-05-01 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
JP2008504278A (ja) * 2004-06-24 2008-02-14 インサイト・コーポレイション アミド化合物およびその医薬としての使用
US8288417B2 (en) 2004-06-24 2012-10-16 Incyte Corporation N-substituted piperidines and their use as pharmaceuticals
WO2008102749A1 (fr) * 2007-02-20 2008-08-28 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2014117920A1 (fr) 2013-02-04 2014-08-07 Merck Patent Gmbh Dérivés spiro-quinazolinone utiles pour le traitement de troubles et de maladies neurologiques
JP2016506939A (ja) * 2013-02-04 2016-03-07 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 神経学的疾患および状態の処置に有用なスピロ−キナゾリノン誘導体
US9708321B2 (en) 2013-02-04 2017-07-18 Merck Patent Gmbh Spiro-quinazolinone derivatives and their use as positive allosteric modulators of mGluR4
CN104955826A (zh) * 2013-02-04 2015-09-30 默克专利股份公司 可用于治疗神经学疾病和病症的螺-喹唑酮衍生物
AU2014211728B2 (en) * 2013-02-04 2018-05-17 Merck Patent Gmbh Spiro-quinazolinone derivatives useful for the treatment of neurological diseases and conditions
CN104955826B (zh) * 2013-02-04 2019-05-31 默克专利股份公司 可用于治疗神经学疾病和病症的螺-喹唑酮衍生物
CN110831593A (zh) * 2017-06-14 2020-02-21 特维娜有限公司 用于调节s1p1活性的化合物及其使用方法
US20210188826A1 (en) * 2017-06-14 2021-06-24 Trevena, Inc. Compounds for modulating s1p1 activity and methods of using the same
US11912693B2 (en) * 2017-06-14 2024-02-27 Trevena, Inc. Compounds for modulating S1P1 activity and methods of using the same
US11884655B2 (en) 2019-11-19 2024-01-30 Trevena, Inc. Compounds and methods of preparing compounds S1P1 modulators
WO2025036472A1 (fr) * 2023-08-16 2025-02-20 Pharmaengine, Inc. Inhibiteur de prmt5 mta-coopératif spirocyclique

Also Published As

Publication number Publication date
AU2003263323A1 (en) 2004-03-29

Similar Documents

Publication Publication Date Title
JP7280928B2 (ja) 脱ユビキチン化酵素（ｄｕｂ）阻害剤としてのスピロ縮合ピロリジン誘導体
US12157733B2 (en) Aminotriazolopyridines as kinase inhibitors
KR102449652B1 (ko) Rock의 억제제로서의 스피로-융합 시클릭 우레아
JP5651692B2 (ja) 縮合アミノジヒドロ−オキサジン誘導体
US9546153B2 (en) Bicyclic heterocycle substituted pyridyl compounds useful as kinase modulators
EP3692028B1 (fr) Inhibition de la peptidase 30 spécifique de l'ubiquitine
EP1268412B1 (fr) D riv s de bicyxloalkyle pontage substitution sulphonamido
WO2004022554A1 (fr) Derives de quinazolinone
EP3548468B1 (fr) Inhibiteurs de rho kinase tricyclique
IL275058B1 (en) Sulphonyl urea derivatives as nlrp3 inflammasome modulators
WO2003053958A1 (fr) Derives de quinazolinedione
US20080280925A1 (en) Amines as Small Molecule Inhibitors
JP2019508467A (ja) 癌治療用の２−シアノイソインドリン誘導体
AU2013341200A1 (en) Heteroaryl substituted pyridyl compounds useful as kinase modulators
US10301306B2 (en) Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
JP2012533602A (ja) 縮合アミノジヒドロピリミドン誘導体
KR20100103702A (ko) 축합 아미노디하이드로 티아진 유도체
EA036965B1 (ru) Ингибиторы деацетилаз гистонов и композиции и способы их применения
WO2016124129A1 (fr) Composés diaza-benzofluoranthrène
WO2003035066A1 (fr) Derives de 2-aminoquinolone utilises en tant qu'inhibiteurs de l'impdh
TWI308568B (en) Chemokine receptor antagonists and methods of use therefor
WO2004018462A1 (fr) Derives de quinazolinone
EP4516793A1 (fr) Dérivé d'azaindane de pipéridine carboxamide, son procédé de préparation et son utilisation
WO2003087071A1 (fr) Derives de sulfamide
JP2024529445A (ja) 例えば糖尿病の治療のための細胞外ニコチンアミドホスホリボシルトランスフェラーゼ（ｅｎａｍｐｔ）のモジュレーターとしての６－置換ナフタレン－１，３－ジスルホン酸誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP