WO2004018462A1 - Derives de quinazolinone - Google Patents

Derives de quinazolinone Download PDF

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WO2004018462A1
WO2004018462A1 PCT/GB2003/003600 GB0303600W WO2004018462A1 WO 2004018462 A1 WO2004018462 A1 WO 2004018462A1 GB 0303600 W GB0303600 W GB 0303600W WO 2004018462 A1 WO2004018462 A1 WO 2004018462A1
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group
alk
optionally substituted
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compounds
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Alan Findlay Haughan
George Martin Buckley
Hazel Joan Dyke
Duncan Robert Hannah
Marianna Dilani Richard
Andrew Sharpe
Sophie Caroline Williams
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Celltech R&D Ltd
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Celltech R&D Ltd
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Priority claimed from GB0303866A external-priority patent/GB0303866D0/en
Priority claimed from GB0312773A external-priority patent/GB0312773D0/en
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Priority to AU2003255803A priority Critical patent/AU2003255803A1/en
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    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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 dinucieotide
  • 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 tetramers 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 Qpin. 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
  • 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. Qpin. 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 6 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 and R 6 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
  • R 4 is a group -(Alk 3 ) p L 2 (Alk 4 ) q R 7 in which p and q, 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
  • certain 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-i-ioalkyl, e.g. C ⁇ _ 6 alkyl, e.g. C 2 - 6 alkenyl or C 2 - ⁇ o alkynyl e.g. C 2 - 6 alkynyl groups.
  • aliphatic groups include optionally substituted straight or branched d- ⁇ 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 ) 4 CH 3 , -(CH 2 ) 5 CH 3 , or C 2-6 alkenyl or C 2 - 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 C 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 Ci -6 alkylene chains such as -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -,-(CH2)2CH2-, -(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 )2CH 2 -, -(CH 2 ) 2 CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH2-, -CH(CH 3 )CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 CH 2 -, -(CH 2 ) CH 2 -, -
  • 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 ) 2 - 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 3 -, -CH 2 L 3 CH 2 CH 2 -, -CH 2 L 3 CH 2 CH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 CH 2 -, -L 3 CH 2 CHCH-, -CHCHCHCH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 CH 2 -, -
  • 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(O) 2 -, -C(O)O-, -OC(O)-, -N(R 8 )- [where R 8 is a hydrogen atom or a straight or branched C ⁇ -6 alkyl group], -N(R 8 )O-, -N(R 8 )N-, -CON(R 8 )-, -OC(O)N(R 8 )-, -CSN(R 8 )-, -N(R 8 )CO-, -N(R 8 )C(O)O-, -N(R 8 )CS-, -S(O) 2 N(R 8 )-, -N(R 8 )
  • cycloaliphatic group includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C 3- ⁇ o ring systems, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbomyl, norbomenyl, 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-i- ⁇ alkyl group (as described herein) where a terminal hydrogen atom is replaced by a C 3- 6 cycloalkyl ring (as described herein). Examples include -(CH2) ⁇ -6-cyclopropyl, -(CH2) ⁇ -6- cyclobutyl, -(CH 2 ) ⁇ -6-cyclopentyl or -(CH 2 ) ⁇ -6-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.
  • L 4 atoms or groups include -O- or -S- atoms or -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -N(R 8 )- [where R 8 is as defined above], -N(R 8 )N(R 8 ), -N(R 8 )O-, -ON(R 8 )-, -CON(R 8 )-, -OC(O)N(R 8 )-, -CSN(R 8 )-, -N(R 8 )CO-, -N(R 8 )C(O)O-, -N
  • heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cydopentanonyl, 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-imidazolinyl imidazolidinyl, 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 described above, include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or d- ⁇ alkyl, e.g. methyl, ethyl, propyi or i-propyl, d- ⁇ alkoxy, e.g. methoxy, ethoxy or propoxy, halod- ⁇ alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, halod- ⁇ alkoxy, e.g.
  • halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, C ⁇ .6alkylthio, 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 C ⁇ -6 alkyl group], -CN, -CO 2 R 10 , -OC(O)R 10 , -NO 2 , -C(0)N(R 1 °) 2 , -C(S)N(R 10 ) 2 , -C(O)R 10 , -C(S)R 10 , -N(R i0 )C(O)R 10 , -N(R
  • R 10 atoms or groups 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, -CO 2 H, -CO 2 R 11 [where R 11 is an optionally substituted d-ealkyl group] e.g. -CO 2 CH 3 or -CO 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 ; C 1-6 alkoxy, e.g. methoxy or ethoxy; halod- ⁇ alkoxy, e.g. trifluoromethoxy or difluoromethoxy; -SH, -S(O)R 11 , e.g. -S(O)CH 3 ; -S(O) 2 R 11 , e.g. -S(0) 2 CH 3 ; C ⁇ alkylthio e.g.
  • R 10 or R 11 When R 10 or R 11 is present as a Ci- ⁇ alkyI group it may be a straight or branched d-6 alkyl group e.g. a C ⁇ -3 alkyl group such as methyl, ethyl or i- 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 d-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 mentioned previously substituted by one, two or three of the halogen atoms as described above. Particular examples of such groups include -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2l -CH 2 F, and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C ⁇ . ⁇ 0 alkoxy for example d -6 alkoxy such as methoxy, ethoxy, n-propoxy, / ' - propoxy and t-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 Ci.ioalkylthio, e.g. C 1-6 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 8 )-, -CSN(R 8 )- or -S(O) 2 N(R 8 )- group, where R 8 is as herein defined.
  • 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 C 1-9 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, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazi ⁇ yl, 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 2-6 alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(O)h- [where h is an integer 1 or 2] or -N(R 14 )- groups; R 12a is a halogen atom, or an amino (- NH 2 ), -NHR 13 [where R 13 is the group -(Alk 6 ) ⁇ (R 13a ), in which R 13a is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl, heteroaryl group and Alk 6 , e and f are
  • 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, d-6 alkyl, e.g. methyl, ethyl, /-propyi, haloC 1-6 alkyl, e.g. -CF 3 , haloC 1-6 alkoxy, e.g.
  • R 13 groups include a d-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 Ci ⁇ alkylene chains e.g. methylene, ethylene, propylene, i-propylene or t-butylene.
  • R 13 is most especially a C ⁇ -3 alkyl group.
  • R 14 is particularly hydrogen or methyl.
  • Alk 6 is in particular a C ⁇ -4 alkyl group as defined herein.
  • f is the integer 1 , 2 or 3 Alk 6 is in particular a C ⁇ -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, N-Ci -6 alkylpiperazinyl, especially N-methylpiperazinyl, N-d- 6 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-C 1 - 6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydro
  • 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, C ⁇ -3 alkoxy, especially -OCH 3 , OCF 3 , OCF 2 H, CF 3 , C ⁇ -3 alkylthio, straight or branched C ⁇ -3 alkyl, -CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCHs, CON(CH 3 ) 2 , C0 2 CH 3 , CO 2 CH 2 CH 3 , -CO 2 C(CH 3 )3, or -COCH3, -SO 2 CH 3 , -NHCOCH3, -N(CH 3 )COCH 3 or CO 2 H.
  • two adjacent R 12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C 1-6 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 C 1-6 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. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
  • 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.
  • 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.
  • Particular examples of the group R 4 in compounds of formula (1 ), include -Alk 3 -L 2 -Alk 4 -R 7 , -Alk 3 -L 2 -R 7 , -Alk 3 -R 7 , -L 2 -Alk 4 -R 7 , -L 2 -R 7 or -R 7 wherein Alk 3 , L 2 , Alk 4 and R 7 are as herein defined.
  • 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-6 alkylene chain, most especially a C ⁇ - 3 alkylene chain.
  • Alk 3 and/or Alk 4 is each a -CH 2 -, -(CH 2 ) 2 - or -(CH 2 )3- chain, most especially a -CH - or -(CH2)2- chain.
  • One particular group of compounds of the invention has the formula (1 ) wherein Alk 3 is an optionally substituted C 2 -6alkenylene or C 2 -6 alkynylene chain, especially an ethenylene or ethynylene chain. In one particular group of compounds of the invention Alk 3 is an ethenylene chain.
  • p is zero.
  • p is the integer 1.
  • q in one particular aspect of the invention is zero.
  • 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(O)O-, -OC(O)-, -N(R 8 )- [where R 8 is as defined hereinbefore], -CON(R 8 )-, -CSN(R 8 )-, -N(R 8 )CO-, -N(R 8 )CS-, -S(O) 2 N(R 8 )- or -N(R 8 )S(0) 2 - groups.
  • L 2 More particular examples of L 2 include -O- or -S- atoms or -CO-, -C(O)O-, -CON(R 8 )- or -N(R 8 )CO- groups.
  • R 8 is especially a hydrogen atom or a C 1 - 3 alkyl group, particularly methyl.
  • L 2 in one particular group of compounds of the invention is a covalent bond.
  • R 7 in one particular group of compounds of the invention is a hydrogen atom.
  • R 7 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group especially an optionally substituted C 3 -6 cycloalkyl, 3-10 membered, especially 3-7 membered, saturated monocyclic heterocycloalkyl, phenyl or heteroaromatic group.
  • Particular examples include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C1-6 alkyl piperazinyl, especially V-methyl piperazinyl, ⁇ /-C ⁇ -6 al kyl pyrroli di nyl , especially /V-methylpyrrolidinyl, ⁇ /-C1.6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-
  • More particular examples include optionally substituted cyclohexyl, piperidinyl, tetrahydrofuranyl, phenyl, furyl, thienyl, imidazolyl, N-d -6 alkylimidazolyl, pyridyl, pyridyl-N-oxide, benzofuryl, indolyl or quinolinyl.
  • R 7 Particular values of R 7 include cyclohexyl, piperidin-1-yl, tetrahydrofuran-2-yl, 2,6-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-acetylaminophenyl, 4- acetylaminophenyl, [2,3]methylenedioxyphenyl, fur-2-yl, 5-phenylfur-2-yl, thien-2-yl, 5-methoxycarbonylthien-2-yl, 4-methoxycarbonylthien-2-yl, 1- methylimidazol-2yl, imidazol-2yl, imidazol-4-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-2-yl-N-oxide, pyrid-3-y-N-oxide, pyrid-4-yl-N-oxide
  • One class of compounds of the invention has the formula (1 ) wherein R 4 is the chain -Alk 3 -L 2 -R 7 in which Alk 3 is an optionally substituted aliphatic chain, L 2 is a covalent bond and R 7 is a hydrogen atom.
  • Alk 3 in compounds of this type is preferably a straight or branched d-6 alkylene chain as herein defined, especially -CH 2 -, -CH 2 CH2-, -(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, -CO 2 H, -CO 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , d-e alkoxy, particularly methoxy or ethoxy; halod- ⁇ alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)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.
  • 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.
  • Alk 3 is a -CH 2 - or -(CH 2 ) 2 - chain substituted with a -OCOCH 3 , -OH, -SCH 3 , -OCH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 3 , -CONHCH 3 , -CN or -NHCO 2 l Bu group or a -CHCH- chain substituted with a -C0 2 CH 3 , -CO2H or -CN group.
  • R 4 is the chain -Alk 3 -L 2 -R 7 in which Alk 3 is an optionally substituted aliphatic chain, L 2 is a covalent bond or a linker atom or group and R 7 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group especially an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 3 is an optionally substituted d-6 alkylene chain, especially -CH2-, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • R 7 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic or bicyclic heteroaromatic group.
  • Particular R 7 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrol idinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, A/-Ci- 6 alkylpiperazinyl, especially N- methyl piperazinyl, / -C ⁇ .6 alkylpyrrolidinyl, especially /-methylpyrrolidinyl, N- Ci-6 alkylpiperidinyl, especially ⁇ /-methyl piperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-d.
  • R 7 is a morpholinyl, thiomorpholinyl, pyrrolidinyl, N- methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, piperazinyl, N- methyl piperazinyl, imidazolyl, phenyl, pyridyl, pyrimidinyl or pyrazolyl group.
  • One particular group of compounds of this type has the formula (1) wherein Alk 3 is a -CH 2 - or -(CH 2 ) 2 - chain and L 2 is a covalent bond or a -O-, -S- or -NHCO- linker atom or group.
  • R 7 is in particular a phenyl, 4-chlorophenyl, 2- acetylaminophenyl, tetrahydrofuran-2-yl or piperidin-1-yl group.
  • Alk 3 is an optionally substituted C 2- 6 alkenylene chain, especially -CHCH- or C 2- 6 alkynylene chain, especially -CC-.
  • L 2 in one embodiment is preferably a covalent bond.
  • L 2 in another embodiment is a -CO- or -CON(CH 3 )- group.
  • R 7 is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or heteroaromatic group.
  • Particular R 7 groups include optionally substituted furyl, thienyl or phenyl.
  • Other particular examples include optionally substituted piperidinyl, pyridyl, imidazolyl, indolyl, benzofuryl or quinolinyl.
  • R 4 is the chain -L 2 -(Alk 4 ) q -R 7 in which L 2 is a linker atom or group, Alk 4 is an optionally substituted aliphatic or heteroaliphatic chain, q is zero or the integer 1 and R 7 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 4 in compounds of this type is preferably an optionally substituted straight or branched C1-6 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 and R 7 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 8 )-, -C(O)-, -C(S)-, -S(O) 2 -, -C(0)O-, -OC(O)-, -CON(R 8 )- -CSN(R 8 )-, -N(R 8 )CO- or -N(R 8 )CS-, [where R 8 is especially a hydrogen atom or a methyl group] and Alk 4 is most preferably an optionally substituted C1-3 alkylene chain, especially -CH2-, CH 2 CH2- or -CH 2 CH 2 CH 2 -.
  • 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 , particularly methoxy or ethoxy; halod- ⁇ alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(O) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 , groups.
  • R 11 is in particular a d- 3 alkyl group.
  • L 2 is a linker atom or group, most especially a -CONH- group, q is zero and R 7 is an optionally substituted C3-6 cycloalkyl, 3-7 membered saturated monocyclic heterocycloalkyl, phenyl or heteroaromatic group, most especially a phenyl group.
  • R 4 is the group R 7 .
  • R 7 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 or bicyclic heteroaromatic group.
  • R 4 is an optionally substituted phenyl or heteroaromatic group, typically phenyl, fur-2-yl, benzofur-2-yl, 7-methoxybenzofur-2-yl, 5-chlorobenzofur-2-yl and quinolin-2- yi.
  • R 4 is the chain -Alk 3 -L 2 -Alk 4 - R 7 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 7 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • R 4 is a d- 6 alkyl group, especially a C 1 - 3 alkyl group, most especially a methyl group.
  • R 5 in compounds of this type is in particular a hydrogen atom or a C1-6 alkyl group.
  • R 5 in compounds of formula (1 ) is in particular a hydrogen atom or a C ⁇ - 3 alkyl group, especially methyl.
  • R 5 is also in particular a -CF 3 group.
  • R 4 in one particular group of compounds of formula (1 ), is a hydrogen atom then R 5 is other than a hydrogen atom.
  • 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 d- 6 alkyl group. Especially preferred is when R 1 is a C 1 - 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, N-d.
  • R 2 is an oxazolyl group. Most especially preferred is where R 2 is an oxazol-5-yl group.
  • R 3 in compounds of formula (1), include - Alk 1 -L 1 -Alk 2 -R 6 , -Alk 1 -L 1 -R 6 , -Alk 1 -R 6 , -L 1 -Alk 2 -R 6 , -L 1 -R 6 or -R 6 wherein Alk 1 , L 1 , Alk 2 and R 6 are as herein defined.
  • One particular group of compounds of the invention has the formula (1 ) wherein R 3 is the group -Alk 1 - L 1 -R 6 .
  • 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 C ⁇ _6 alkylene chain, especially an optionally substituted -CH 2 -, - CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )- chain, most especially a C ⁇ - 3 alkylene chain such as -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - chain.
  • m is zero.
  • n is the integer 1.
  • n in one particular aspect of the invention is zero.
  • 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(O)O-, -OC(O)-, -N(R 8 )- [where R 8 is as defined hereinbefore], -CON(R 8 )-, -CSN(R 8 )-, -N(R 8 )CO-, - N(R 8 )CS-, -S(0) 2 N(R 8 )- or -N(R 8 )S(O) 2 - groups.
  • R 8 is especially a hydrogen atom or a C ⁇ -3 alkyl group, particularly methyl.
  • L 1 in one particular group of compounds of the invention is a covalent bond.
  • R 6 is a hydrogen atom.
  • R 6 is an optionally substituted C 3- 6 cycloalkyl, 3-7 membered saturated monocyclic heterocycloalkyl, phenyl or heteroaromatic group as described herein for R 7 .
  • Typical examples of R 6 include morpholin-1-yl, pyrid-4yl and imidazol-1-yl.
  • R 3 is the chain -Alk 1 -L 1 -R 6 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a covalent bond and R 6 is a hydrogen atom.
  • R 3 is especially a straight or branched d-6 alkyl 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 -CH 3 group.
  • Alk 1 is a substituted aliphatic chain
  • L 1 is a covalent bond
  • R 6 is a hydrogen atom.
  • Alk 1 in compounds of this type is preferably a straight or branched d-6 alkylene chain as herein defined, especially -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH2-, -(CH 2 ) 3 CH2- or -CH 2 C(CH 3 ) 2 -.
  • Substituents present on these chains include those as herein defined for Alk 1 substituents, especially -CN, -CO2H, -CO2R 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.
  • 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, -CO 2 CH 3 , -C0 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , -CONH 2 , -CONHCHs or -CON(CH 3 ) 2 group.
  • R 3 is the chain -Alk 1 -L 1 -R 6 in which Alk 1 is an optionally substituted aliphatic chain, L 1 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 1 in compounds of this type is in particular an optionally substituted C ⁇ -6 alkylene chain, especially -CH 2 -, CH 2 CH2- or - CH2CH 2 CH2-.
  • 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, N-d-6 alkylpiperazinyl, especially N- methylpiperazinyl, N-C1-6 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N- C1-6 alkylpiperidinyl, especially N-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazo
  • R 6 is a morpholinyl, thiomorpholinyl, pyrrolidinyl, N- methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, piperazinyl, N- methyl piperazinyl, imidazolyl, pyridyl, pyrimidinyl or pyrazolyl group.
  • One particular group of compounds of this class are those wherein L 1 is a covalent bond.
  • R 3 is a - (CH 2 ) 2 morpholin-1-yl, -(CH 2 ) 2 Pyrid-4-yl and -(CH2) 2 ⁇ midazol-1-yl group.
  • R 3 in another class of compounds of formula (1 ) is the chain -L 1 -R 6 in which L 1 is a linker group and R 6 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • L 1 in compounds of this type is especially a -C(O)-, -C(S)- or -S(O)2 group.
  • R 6 is an optionally substituted phenyl or monocyclic heteroaromatic group.
  • R 6 is in particular an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group.
  • R 3 is the chain -Alk 1 -L 1 -Alk 2 - R 6 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a linker atom or group, Alk 2 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.
  • Alk 1 in compounds of this type is preferably an optionally substituted straight or branched C1-6 alkylene chain such as herein defined, especially optionally substituted -CH2-, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 - or -CH 2 C(CH 3 ) 2 -;
  • Alk 2 is preferably an optionally substituted straight or branched C ⁇ .
  • R 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 -, -CH2CH2L 3 -, -CH 2 L 3 CH 2 CH2-, -(CH 2 )2L 3 CH 2 -, -(CH 2 ) 3 L 3 CH - or -(CH 2 ) 3 L 3 - chain and R 6 is preferably a hydrogen atom or an optionally substituted Qj-6 cycloalkyl, 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • Alk 1 is most especially a C ⁇ -3 alkylene chain, particularly -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 ;
  • L 1 is in particular -0-, -N(R 8 )-, - CON(R 8 )- or -N(R 8 )CO- [where R 8 is especially a hydrogen atom or a methyl group] and
  • Alk 2 is most preferably an optionally substituted C ⁇ -3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH2CH2CH2-.
  • Optional substituents which may in particular be present on Alk 2 include -CN, -C0 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(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.
  • a further class of compounds of the invention has the formula (1 ) wherein R 3 is the group R 6 .
  • R 6 is in particular an optionally substituted C 3- 6 cycloalkyl, 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • R 3 is a hydrogen atom or a C h alky! group, especially a C ⁇ -3 alkyl group, most especially a methyl group.
  • One group of cycloaliphatic or heterocycloaliphatic substituents which may be present on the groups R 6 or R 7 , are one, two, three or more groups selected from C ⁇ -3 alkoxy, OCF 3 , OCF 2 H, CF 3 , C ⁇ -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), -CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CO 2 CH 3 , CO 2 CH 2 CH 3 , -CO 2 C(CH 3 )3, or -COCH 3> -NHCOCH3, -N(CH 3 )COCH 3 or CO 2 H.
  • One group of aromatic or heteroaromatic substituents which may be present on the groups R 6 or R 7 , are one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched d-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) -CONHCH 3 , -CON(CH 3 ) 2 , -CO 2 CH 3 , -C0 2 CH 2 CH 3 , -CO 2 C(CH 3 )3, or -COCH3, -NHCOCH3, -N(CH3)COCH 3 , -SCH 3 , -S0 2 CH 3 or CO H. More particular examples include fluorine, chlorine, methyl, methoxy,
  • One particularly preferred group of compounds of the invention has the formula (2):
  • R 1 , R 2 , R 4 , R 5 and X are as defined and further defined herein;
  • R 3a is a hydrogen atom or a d- 6 alkyl group; and the salts, solvates, hydrates, tautomers, isomers or N-oxides thereof.
  • R 3a in compounds of this type is in particular a hydrogen atom or a d-3 alkyl group, especially a methyl or ethyl group, most especially a methyl group.
  • One particular group of compounds of the invention has the formulae (1 ) or (2) wherein R 5 is a hydrogen atom or d-6 alkyl group, especially C ⁇ -3 alkyl, most especially methyl and R 4 is the group -(Alk 3 ) p L 2 (Alk 4 ) q R 7 .
  • Another particularly preferred group of compounds of the invention has the formula (3):
  • R 1 , R 2 , R 3 , R 5 and X are as defined herein;
  • R 7a is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein for R 7 ; and the salts, solvates, hydrates, tautomers, isomers or N-oxides thereof.
  • R 7a present in compounds of formula (3) include optionally substituted cyclohexyl, phenyl, furyl, thienyl, pyridyl, pyridyl- N-oxide, imidazolyl, benzofuryl and quinolinyl.
  • Typical values for R 7a include cyclohexyl, phenyl, 2,6-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4- methoxyphenyl, 4-acetylaminophenyl, 5-phenylfur-2-yl,
  • Particularly useful compounds of the invention include: 2-(2-furan-2-yl-vinyl)-7-methoxy-2,3-dimethyl-6-oxazol-5-yl-2,3-dihydro-7r7- quinazolin-4-one; 7-methoxy-2,3-dimethyl-6-oxazol-5-yl-2-(2-thiophen-2-yl-vinyl)-2,3-dihydro- H-quinazolin-4-one; 7-methoxy-2,3-dimethyl-6-oxazol-5-yl-2-styryl-2,3-dihydro-1H-quinazolin-4- one;
  • 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.
  • the compounds of the invention may be used in the treatment of IMPDH- associated disorders.
  • the invention extends to such a use and in general to the use of the compounds of formula (1 ) for the manufacture of a medicament for treating such diseases and disorders.
  • 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
  • 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.
  • DNA or RNA viral replication diseases such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • the compounds of the present invention are of particular use for the treatment of 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.
  • 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 anti- cancer 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, cydosporin 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, cydosporin 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.
  • 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. Such materials 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.
  • 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, Greene, 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 applies to the compounds of formulae (2) and (3), 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).
  • the resulting coupled product may require further manipulation, depending on the nature of the -NRR' group, in order to obtain an amine of formula (ii).
  • a carbamate protecting group e.g. terf-butoxycarbonyl may be removed under acidic conditions e.g. trifluoroacetic acid.
  • R 2 -W derivatives are either commercially available or may be prepared using methods known to those skilled in the art.
  • 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 No. 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 No. 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.
  • 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°.
  • 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
  • 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 reduced pressure in the presence of a catalyst e.g. a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(ll) in for example water and an appropriate solvent e.g A/, ⁇ /-dimethylformamide or tetrahydrofuran. It may be appropriate to carry out the reaction at an elevated temperature, such as 90- 100°C. 1 ) Halogenation 2) Carbonylation
  • 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, advantageously in the presence of a catalyst such as a N- hydroxy compound, e.g. ⁇ /-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 N-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.g
  • 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 Bonala et al (J. Med. Chem. 1968, 11 , 1136), Bonala et al (J. Med. Chem. 1968, 11, 1136), Gould et al (Tetrahedron, 1991 , 47, 7209) or Larsen et al (J. Med. Chem. 2001 , 44, 1217).
  • acid e.g p-toluenesulfonic acid
  • the acid used as a catalyst may be hydrochloric acid (Klemm et al; J. Heterocycl. Chem. 1998, 35, 1269), trichloroacetic acid (Yamato et al; Chem. Pharm. Bull. 1981 , 29, 3124) or a Lewis acid such as zinc chloride (Yamato et al; Chem. Pharm. Bull. 1981 , 29, 3124) or cerium chloride or borontrifluoride diethyl etherate, or acetic acid.
  • 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.
  • a thiation reagent such as Lawesson's Reagent or P 2 Ss
  • 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 ).
  • (viii) may be prepared using the methodology described herein for the preparation of compounds of formula (1 ).
  • the phosphonate may then be reacted with an aldehyde of formula OHCL 2 (Alk ) q R 7 in the presence of a base e.g. potassium hydroxide in a suitable solvent such as an alcohol e.g. ethanol to give a compound of formula (1 ) wherein Alk 3 is a -CHCH-chain.
  • 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.
  • 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 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 or sodium borohydride in a solvent such as tetrahydrofuran.
  • a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as tetrahydrofuran.
  • an alcohol may be prepared ,by reduction of the corresponding acid [-CO 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 [-CHO] 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 [-NO 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 an ether, e.g. a cyclic ether such as 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
  • Alkyl groups may be prepared by reduction of a corresponding alkyne or alkene group, 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.
  • 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.
  • 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 or a peroxy acid e.g. 3- chloroperoxybenzoic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • 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.
  • diastereomeric derivatives e.g. salts
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers of formula (1 ) e.g. a racemate, and 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.
  • Gilson 215 liquid handler setup Column: Luna C18(2) 100x21 mm, 5 ⁇ M particle size Prep column.
  • CDCI 3 Chloroform-d; DCE - Dichloroethane;
  • Examples 2-6 were prepared in a similar manner to the method in Example 1 :-
  • Example 8 7-Methoxy-2.3-dimethyl-2-(2-methylsulfanyl-ethyl)-6- oxazol-5-yl-2.3-dihvdro-7r7-quinazolin-4-one From Intermediate 2 (50mg) and 4-(methylthio)-2-butanone (0.07ml). Purification by preparative HPLC (Method A) afforded the title compound (13mg, 18%). LCMS 348 [M+H] + , RT 2.84 mins.
  • Example 9 7-Methoxy-2-methoxymethyl-2.3-dimethyl-6-oxazol-5- yl-2,3-dihvdro-7/-/-quinazolin-4-one From Intermediate 2 (50mg) and methoxyacetone (0.06ml). Purification by preparative HPLC (Method A) afforded the title compound (7mg, 10%). LCMS 318 [M+H] + , RT 2.45 mins.
  • Example 12 was prepared in a similar manner to the method in Example 11 :- Example 12. 7-Methoxy-3-methyl-6-oxazol-5-yl-4-oxo-1.2.3.4- tetrahvdro-quinazoline-2-carboxylic acid ethyl ester
  • Example 13 7-Methoxy-3-methyl-6-oxazol-5-yl-4-oxo-1.2.3.4- tetrahvdro-quinazoline-2-carboxylic acid
  • glyoxylic acid monohydrate 36.8mg
  • MgS0 50mg
  • PTSA catalytic
  • the reaction mixture was heated at reflux for 4 hours, allowed to cool, filtered and concentrated in vacuo. Water (10ml) was added and the mixture acidified with 2 ⁇ 7 hydrochloric acid. The solid formed was filtered off and dried in vacuo to afford the title compound as a pale orange solid (36.6mg, 30%).
  • Example 23 2-(2-Furan-2-yl-vinyl -methoxy-2.3-dimethyl-6- oxazol-5-yl-2,3-dihydro-7H-quinazolin-4-one.
  • (enantiomer 1) Racemic Example 22 (40mg) was separated using CHIRALPAK AD 250 * 4.6mm 10 ⁇ m column eluting with ethanol + 0.1 % DEA to afford enantiomer 1 as an off-white solid (17mg).
  • LCMS 366 [M+H] + RT 3.05 mins.
  • Example 24 2-(2-Furan-2-yl-vinyl)-7-methoxy-2.3-dimethyl-6- oxazol-5-yl-2,3-dihydro-7H-quinazolin-4-one.
  • (enantiomer 2) Racemic Example 22 (40mg) was separated using CHIRALPAK AD 250*4.6mm 10 ⁇ m column eluting with ethanol + 0.1 % DEA to afford enantiomer 2 as an off-white solid (19mg).
  • Example 25 7-Methoxy-2.3-dimethyl-6-oxazol-5-yl-2-styryl-2.3- dihvdro-1H-quinazolin-4-one
  • a solution of Intermediate 2 (50mg), frar ⁇ S-4-phenyl-3-buten-2-one (100mg) and PTSA (1mg) in DMF (2ml) was heated in a sealed tube in a microwave reactor to 170°C for 30 mins. After cooling, the mixture was concentrated in vacuo and the residue purified by preparative HPLC (Method A) to yield the title compound as an off-white solid (19mg, 25%).
  • Examples 34-35 were prepared in a similar manner to the method in Example
  • Example 34 2-(4-Chloro-phenylsulfanylmethyl)-7-methoxy-2.3- dimethyl-6-oxazol-5-yl-2,3-dihydro-7H-quinazolin-4- one From Intermediate 2 (50mg) and (4-chlorophenylthio)propan-2-one (2ml). Purification by preparative HPLC (Method A) afforded the title compound as an off-white solid (7mg, 8%). LCMS 430 [M+H] ⁇ RT 3.41 mins.
  • Example 25 A solution of Example 25 (10mg) in EtOH (10ml) was treated with 10% palladium on carbon (catalytic) and stirred under an atmosphere of hydrogen gas at atmospheric pressure for 3 hours. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by preparative TLC eluting with 75% EtOAc/hexane to furnish the title compound as a white solid (7mg, 70%). LCMS 378 [M+H] + , RT 3.33 mins.
  • Example 38 was prepared in a similar manner to the method in Example 37:- Example 38. 7-Methoxy-2.3-dimethyl-6-oxazol-5-yl-2- tetrahvdrofuranylethyl-2.3-dihvdro-f - -quinazolin-4- one From Example 22 (50mg). Purification by preparative HPLC (Method A) afforded the title compound as an off-white solid (13mg, 25%). LCMS 372 [M+H] ⁇ RT 2.70mins.
  • Example 2 A solution of Example 2 (50mg), and 2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4- diphosphetane-2,4-disulfide (70mg) in toluene (1 ml) was heated to reflux for 2 hours under nitrogen. The reaction mixture was purified by column chromatography on silica eluting with 50% EtOAc/hexane to yield the title compound as a yellow solid (21.1 mg, 40%). TLC R f 0.56 (EtOAc). LCMS 304 [M+H] ⁇ RT 2.93 mins.
  • Examples 42-52 were prepared in a similar manner to the method in Example 41 :-
  • Example 42 2-(2-Cvclohexyl-vinyl)-7-methoxy-2.3-dimethyl-6- oxazol-5-yl-2.3-dihydro-7 ' rY-q ⁇ inazoline-4-one From Intermediate 2 (50mg), and 4-cyclohexyl-but-3-en-one (CAS 7152-32-1) (31 mg). The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method A) to yield the title compound as an off-white solid (8 mg, 10%). LCMS 381[M+H] ⁇ RT 4.17 mins.
  • Example 43 7-Methoxy-2.3-dimethyl-6-oxazol-5-yl-(2-pyridin-3-yl- vinyl)-2,3-dihvdro-7H-quinazoline-4-one From Intermediate 2 (100mg), and 4-pyridin-3-yl-but-3-en-2-one (CAS 28447- 16-7) (100mg).
  • the reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method B) to yield the title compound as an off-white solid (37 mg, 25%).
  • Example 47 7-Methoxy-2.3-dimethyl-2-r2-(1 -methyl-1 H-imidazol-2- yl-vinv ⁇ -6-oxazol-5-yl-2.3-dihvdro-7H-quinazoline-4- one
  • Example 54 was prepared in a similar manner to the method in Example 53:- Example 54. 2-(2-(4-methoxyphenyl)-vinyl)-2-yl-7-methoxy-2.3- dimethyl-6-oxazol-5-yl-2,3-dihydro-7H-quinazolin-4- one
  • Example 55 7-Methoxy-2.3-dimethyl-6-oxazol-5-yl-4-oxo-1.2.3.4- tetrahvdroquinazoline-2-carboxylic acid ethyl ester
  • Ethyl pyruvate (0.52 ml) and Intermediate 2 (1.10 g) were dissolved in ethanol (40 ml), treated with concentrated hydrochloric acid (5 drops) and heated to reflux under a calcium chloride guard tube. After 90 hours, the reaction was cooled and concentrated in vacuo. The residue was dissolved in EtOAc (50ml) and washed with 50% saturated NaHCOs/water (30ml), water (20ml) and saturated brine (20ml).
  • Example 57 was prepared in a similar manner to the method in Example 56:- Example 57. 7-Methoxy-2.3-dimethyl-6-oxazol-5-yl-4-oxo-1,2.3.4- tetrahvdro-quinazolin-2-vD-acrylonitrile. A mixture of Intermediate 2 (390mg), 4-oxo-pent-2-enenitrile (CAS 55728-58- 0) (220mg) and PTSA (catalytic) in isopropyl acetate (20ml) was heated to 100°C using Dean-Stark apparatus for 3 hours.
  • Intermediate 2 390mg
  • 4-oxo-pent-2-enenitrile CAS 55728-58- 0
  • PTSA catalytic
  • Example 61 2-Ethvnyl-7-methoxy-2.3-dimethyl-6-oxazol-5-yl-2.3- dihvdro-7rY-quinazolin-4-one
  • An ice-cold solution of Intermediate 9 (0.983 g) in THF (40 ml) was treated dropwise with a solution of tetrabutylammonium fluoride (1 M in THF, 2.79 ml) and the reaction stirred in the ice-bath for 1 hour.
  • Acetic acid (0.25ml) was added and the mixture stirred in the ice-bath for 15 minutes, then at room temperature for 15 minutes.
  • the mixture was concentrated in vacuo and the solid residue triturated with saturated NaHCO 3 and water.
  • Example 63 was prepared in a similar manner to the method in Example 62:- Example 63. ⁇ /-r2-(7-methoxy-2.3-dimethyl-6-oxazol-5-yl-4-oxo- 1.2.3.4-tetrahydroquinazolin-2-yl)ethvnbenzamide
  • Examples 66-67 were prepared in a similar manner to the method in Example
  • Example 70 was prepared in a similar manner to the method in Example 69:- Example 70. 7-Methoxy-2.3-dimethyl-2-r(E)-2-(1-methyl-1 H-indol-3- yl)-vinvn-6-oxazol-5-vn-2.3-dihvdro-1H-quinazolin-4- one
  • Example 71 7-Methoxy-2.3-dimethyl-6-oxazol-5-yl-2-r(E)-2-(1-oxy- pyridin-2-yl ⁇ -vinv ⁇ -2.3-dihvdro-1H-quinazolin-4-one
  • DCM dimethylethyl-N-(2-aminoethyl)
  • 3-chloroperoxybenzoic acid 134mg
  • the reaction mixture was diluted with DCM (50ml) and washed with saturated aqueous Na 2 CO 3 (25ml). The organic layer was separated, dried over MgSO , filtered and the solvent removed in vacuo.
  • Example 72 (20mg), HBTU (21 mg), DMF (2ml) and piperidine (3 drops) were combined and stirred at room temperature for 24 hours. The reaction was concentrated in vacuo and the resulting residue purified by preparative HPLC (Method A) to give the title compound as a tan glass (3.5mg, 15%). LCMS 411 [M+H] + , RT 2.52 mins.
  • 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 200 ⁇ l 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 I .OmM 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.
  • the functional effect of the compounds of the invention may be demonstrated using the following assay: PBMC Proliferation Assay Peripheral blood mononudear 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
  • 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.
  • IC 50 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.
  • Compounds of the invention such as compounds of the Examples generally inhibit IMPDH enzymes with IC50 values of 5 ⁇ M or below.

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Abstract

L'invention concerne un composé de formule (1) dans laquelle X désigne oxygène ou atome de soufre ; R1 désigne groupe aliphatique, cycloaliphatique ou cycloalkyl-alkyle; R2 désigne groupe hétéroaromatique éventuellement substitué ou groupe -CN; R3 désigne groupe -(Alk1)mL1(Alk2)nR6 où m et n, qui peuvent être identiques ou différents, désignent chacun 0 ou l'entier 1, Alk1 et Alk2, qui peuvent être identiques ou différents, désignent chacun une chaîne aliphatique ou hétéroaliphatique éventuellement substituée. L1 désigne une liaison covalente ou atome liant ou groupe et R6 désigne atome d'hydrogène ou groupe cycloaliphatique, hétérocycloaliphatique, aromatique ou hétéroaromatique éventuellement substitué ; R4 désigne groupe -(Alk3)pL2(Alk4)qR7 où p et q qui peuvent être identiques ou différents, désignent chacun 0 ou l'entier 1, Alk3 et Alk4, qui peuvent être identiques ou différents, désignent chacun une chaîne aliphatique ou hétéroaliphatique éventuellement substituée, L2 désigne une liaison covalente ou atome liant ou groupe R7 désigne hydrogène ou atome d'halogène, ou groupe -CN ou groupe cycloaliphatique, hétérocycloaliphatique, aromatique ou hétéroaromatique éventuellement substitué; R5 désigne atome d'hydrogène ou groupe aliphatique éventuellement substitué ; et leurs sels, solvates, hydrates, tautomères, isomères ou N-oxydes. Les composés de la présente invention sont de puissants inhibiteurs de IMPDH.
PCT/GB2003/003600 2002-08-23 2003-08-18 Derives de quinazolinone Ceased WO2004018462A1 (fr)

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GB0303866A GB0303866D0 (en) 2003-02-20 2003-02-20 Chemical compounds
GB0303866.8 2003-02-20
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014014814A1 (fr) * 2012-07-16 2014-01-23 Brown University Composés destinés au traitement et à la prévention d'infections
US20150173359A1 (en) * 2010-09-03 2015-06-25 Bayer Intellectual Property Gmbh Substituted fused pyrimidinones and dihydropyrimidinones
EP3659592A4 (fr) * 2017-07-27 2021-05-26 Korpharm Co., Ltd. Nouveau dérivé de benzylidène-acétone et son utilisation
EP3638235A4 (fr) * 2017-06-14 2021-06-09 Trevena, Inc. Composés pour moduler l'activité de s1p1 et leurs procédés d'utilisation
US11884655B2 (en) 2019-11-19 2024-01-30 Trevena, Inc. Compounds and methods of preparing compounds S1P1 modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026197A1 (fr) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Nouveaux inhibiteurs de l'enzyme impdh
WO2001081340A2 (fr) * 2000-04-24 2001-11-01 Bristol-Myers Squibb Company Heterocycles utiles en tant qu'inhibiteurs de l'enzyme impdh

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026197A1 (fr) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Nouveaux inhibiteurs de l'enzyme impdh
WO2001081340A2 (fr) * 2000-04-24 2001-11-01 Bristol-Myers Squibb Company Heterocycles utiles en tant qu'inhibiteurs de l'enzyme impdh

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150173359A1 (en) * 2010-09-03 2015-06-25 Bayer Intellectual Property Gmbh Substituted fused pyrimidinones and dihydropyrimidinones
WO2014014814A1 (fr) * 2012-07-16 2014-01-23 Brown University Composés destinés au traitement et à la prévention d'infections
US20150166517A1 (en) * 2012-07-16 2015-06-18 Brown University Compounds for the treatment and prevention of infections
US9695156B2 (en) 2012-07-16 2017-07-04 Brown University Compounds for the treatment and prevention of infections
EP3638235A4 (fr) * 2017-06-14 2021-06-09 Trevena, Inc. Composés pour moduler l'activité de s1p1 et leurs procédés d'utilisation
IL271149B1 (en) * 2017-06-14 2024-01-01 Trevena Inc Compounds for modulating s1p1 activity and methods of using the same
AU2018282747B2 (en) * 2017-06-14 2024-01-18 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
IL271149B2 (en) * 2017-06-14 2024-05-01 Trevena Inc Compounds for modulating s1p1 activity and methods of using the same
EP3659592A4 (fr) * 2017-07-27 2021-05-26 Korpharm Co., Ltd. Nouveau dérivé de benzylidène-acétone et son utilisation
US11629121B2 (en) 2017-07-27 2023-04-18 Korpharm Co., Ltd. Benzylideneacetone derivative and use thereof
US11884655B2 (en) 2019-11-19 2024-01-30 Trevena, Inc. Compounds and methods of preparing compounds S1P1 modulators

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