WO2008040951A1 - Composés - Google Patents

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WO2008040951A1
WO2008040951A1 PCT/GB2007/003719 GB2007003719W WO2008040951A1 WO 2008040951 A1 WO2008040951 A1 WO 2008040951A1 GB 2007003719 W GB2007003719 W GB 2007003719W WO 2008040951 A1 WO2008040951 A1 WO 2008040951A1
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Prior art keywords
optionally substituted
group
alkyl
methyl
amino
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PCT/GB2007/003719
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English (en)
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Jason Grant Kettle
Craig Anthony Roberts
Iain Simpson
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008040951A1 publication Critical patent/WO2008040951A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pyrimidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy and the treating of conditions mediated by polo-like kinases.
  • Cyclin dependent kinase family have long been considered the master regulators of the cell cycle but an increasing number of diverse protein kinases are emerging as critical components of cell cycle progression. Among these are the polo-like kinase family (Plks), serine/threonine kinases that play multiple roles in regulating progress through cell cycle. In man, four distinct family members have been identified. These are Plkl, Plk2 (Snk), Plk3 (Fnk, Prk) and Plk4 (Sak).
  • Plkl The best characterized family member is Plkl which is conserved from yeast to man and has been implicated in numerous mitotic processes including activation of Cdc25C and Cdkl/Cyclin B at the G2-M transition, centrosome maturation, spindle formation and assembly (Glover et al. 1998, Genes Dev. 12:3777-87; Barr et al 2004, Nat. Rev. MoI. Cell Biol 5:429-441). In the later stages of mitosis Plkl is involved in separation of sister chromatids, activation of components of the anaphase-promoting complex and septin regulation during cytokinesis (van Vugt & Medema 2005, Oncogene 24:2844-2859).
  • Plkl is over-expressed in a broad spectrum of cancer types including breast, colorectal, endometrial, oesophageal, ovarian, prostate, pancreatic, non small cell lung cancers and melanomas (Wolf et al. 1997, Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res. Pract. 196:753-759; Takahashi et al. 2003, Cancer Sci. 94:148-152). The expression of Plkl often correlates with poor patient prognosis.
  • Plkl inhibition has been demonstrated in studies employing both antisense oligonucleotides (ASO) and small molecule RNA (siRNA). Reduction in the level of Plkl results in the inhibition of proliferation of tumour cells and loss of cell viability both in vivo and in vitro but does not inhibit proliferation of primary cells (Spankuch-Schmitt et al 2002, Oncogene 21: 3162-3171; Elez et al 2003, Oncogene 22:69-80). Microinjection of anti-Plkl antibodies induced mitotic catastrophe in HeLa tumour cells.
  • ASO antisense oligonucleotides
  • siRNA small molecule RNA
  • Plk3 also appears to play roles in mitosis, like Plkl it has been reported to phosphorylate Cdc25C, regulate microtubule dynamics and is involved in centrosome function. Over-expression of Plk3 has been observed in both breast and ovarian carcinomas, with little or no expression in adjacent normal tissue. Increased protein level was associated with enhanced mitosis and was significantly linked to reduced median survival time of patients (Weichert et al. 2005, Virchows Arch 446: 442-450; Weichert et al. 2004 Br. J.Cancer 90:815-821).
  • PIk family members should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • PIk inhibitors should be useful in the treatment of other disorders associated with uncontrolled cellular proliferation.
  • Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity.
  • WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumoural diseases.
  • tumours The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.
  • the aim of the present invention is to provide new compounds having an antiproliferative activity. According to a first aspect of the present invention there is provided a compound of formula (I):
  • R 2 represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
  • R 3 represents hydrogen, an optionally substituted Ci-i 2 alkyl group, an optionally substituted C 2 -i 2 alkenyl group, an optionally substituted C 2- i 2 alkynyl group, an optionally substituted C 6- i 4 aryl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted C 3- i 2 cycloalkenyl group, an optionally substituted C 7-12 polycycloalkyl group, an optionally substituted C 7-12 polycycloalkenyl group, an optionally substituted Cs-nspirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 3- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or an optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur, or optionally R 2 and R 3 , together
  • R 4 each independently represent -CN, hydroxy, -NR 6 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C ⁇ alkyloxy group, an optionally substituted
  • C 3-6 cycloalkyloxy group an optionally substituted C 2-5 alkenyloxy group, an optionally substituted C 2-5 alkynyloxy group, an optionally substituted C 1-6 alkythio group, an optionally substituted C 1-6 alkylsulfoxo group or an optionally substituted C 1-6 alkylsulfonyl group, or when p is 2 and when each R 4 is adjacent, both R 4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 or more heteroatoms; p is 0, 1 or 2;
  • R a3 represents H or an optionally substituted C ⁇ alkyl group
  • R b3 represents
  • R a3 and R b3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a3 represents H or an optionally substituted C 1-6 alkyl group
  • R b3 represents
  • R a3 and R b3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a5 represents -L n -R s m ;
  • R a6 represents ⁇ L n -R 5 m ;
  • R a7 represents -L n -R 5 m ;
  • R a8 represents -L n -R 5 m
  • R a9 represents -L n -R 3 m ;
  • L represents a linker selected from optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 6- i 4 aryl, optionally substituted
  • R 5 represents a group selected from among hydrogen, optionally substituted 3- to
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted C 1-4 alkyl group
  • R 8 , R 9 each independently represents hydrogen, an optionally substituted -C 1-6 alkyl, an optionally substituted -Ci. 4 alkyl-C 3-10 cycloalkyl, an optionally substituted
  • Ar represents a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur; or pharmacologically acceptable salts thereof.
  • R 2 represents hydrogen, an optionally substituted Ci -6 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
  • R 3 represents hydrogen, an optionally substituted C 1-12 alkyl group, an optionally substituted C 2- i 2 alkenyl group, an optionally substituted C 2- i 2 alkynyl group, an optionally substituted C 6-14 aryl group, an optionally substituted C 3 -] 2 cycloalkyl group, an optionally substituted C 3- i 2 cycloalkenyl group, an optionally substituted C 7-12 polycycloalkyl group, an optionally substituted C ⁇ .npolycycloalkenyl group, an optionally substituted Cs. ⁇ spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 3- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or an optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur, or optionally R 2 and R 3 ,
  • R a represents H or an optionally substituted Ci -6 alkyl group
  • R b represents H, an optionally substituted Ci_ 6 alkyl group, -L n -R 5 m , or R a and R b together with the nitrogen atom to which they are attached form a 3 ⁇ to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R* 2 represents H or an optionally substituted C ⁇ alkyl group
  • R b2 represents
  • R a3 represents H or an optionally substituted C 1-6 alkyl group
  • R b3 represents -L n -R 5 m , or R a3 and R b3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R a3 represents H or an optionally substituted C 1-6 alkyl group
  • R b3 represents -L n -R 5 m , or R a3 and R b3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R a3 represents H or an optionally substituted C 1-6 alkyl group
  • R b3 represents -L n -R 5 m , or R a3 and R b3 together with the nitrogen atom to which they are attached form a 3- to 7-member
  • R a3 represents H or an optionally substituted C ⁇ aUcyl group
  • R b3 represents -L n -R 5 In , or R a3 and R b3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R a5 represents ⁇ L n -R 5 m
  • R a6 represents -L n -R 5 m ;
  • R represents -L n -R m ;
  • R a8 represents -L n -R 5 m ;
  • R a9 represents -L n -R 5 m ;
  • L represents a linker selected from optionally substituted C 2-1 oalkyl, optionally substituted C 2 . 10 alkenyl, optionally substituted C 6 . 14 aryl, optionally substituted
  • R 5 represents a group selected from among optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 3- to
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted C 1-4 alkyl group
  • R 8 , R 9 each independently represents hydrogen, an optionally substituted -C 1-6 alkyl, an optionally substituted -C 1-4 alkyl-C 3- iocycloalkyl, an optionally substituted
  • alkyl group including alkyl groups that are a part of other groups, unless otherwise stated, includes branched and unbranched alkyl groups with 1 to 12 carbon atoms.
  • Examples of C t - ⁇ alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl groups.
  • propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all the possible isomeric forms.
  • propyl includes the two isomeric groups n-propyl and iso-propyl
  • butyl includes n-butyl, iso-butyl, sec-butyl and tert-butyl
  • pentyl includes iso- pentyl, neopentyl, etc.
  • alkyl bridge includes branched and unbranched alkyl bridging groups with 1 to 5 carbon atoms, for example methylene, ethylene, propylene, butylene and pentylene bridges. Unless otherwise stated, the terms propylene, butylene and pentylene include all the possible isomeric forms. In the aforementioned alkyl bridges, 1 or 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulfur.
  • alkenyl groups includes branched and unbranched alkylene groups with 2 to 10 carbon atoms comprising at least one carbon-carbon double bond.
  • Examples of C 2-10 alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl groups.
  • propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl also include all the possible isomeric forms.
  • butenyl includes 1 -butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1 -propenyl, 1 -methyl-2 -propenyl, 2-methyl- 1 -propenyl, 2-methyl-2 -propenyl and 1 -ethyl- 1 -ethenyl.
  • alkynyl groups includes branched and unbranched alkynyl groups with 2 to 10 carbon atoms comprising at least one triple bond.
  • Examples of C 2-10 alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl groups.
  • propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl also include all the possible isomeric forms.
  • butynyl includes 1 -butynyl, 2-butynyl, 3 -butynyl and l-methyl-2-propynyl.
  • aryl includes aromatic ring systems with 6 to 14 carbon atoms, said aromatic ring systems comprising one or more rings having from 6 to 14 ring atoms wherein at least one ring is aromatic.
  • C 6-14 aryl groups include phenyl (C 6 ), indenyl (Cg), naphthyl (Cio), fluorenyl (C 13 ), anthracyl (Ci 4 ), and phenanthryl (Ci 4 ).
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • aryl groups may be substituted by the following substituents groups: OH; NO 2 ; CN; NH 2 ; halogen, for example fluorine or chlorine; optionally substituted Ci-ioalkyl, for example methyl, ethyl, propyl or CF 3 ; optionally substituted -OCi -3 alkyl, for example -OMe, -OEt, OCHF 2 , or OCF 3 ; optionally substituted -NHC 1-3 alkyl, for example NHMe, NHEt, NHiPr; optionally substituted -N(C 1-3 alkyl) 2 , for example NMe 2 , NEt 2 , NMeEt; -COOH, -COO-C 1-4 alkyl, for example -COOMe or -COOEt, or -CONH 2 .
  • substituents groups OH; NO 2 ; CN; NH 2 ; halogen, for example fluorine or chlorine; optional
  • heteroaryl comprising 1 or 2 nitrogen atoms includes heteroaromatic ring systems with 5 to 14 ring atoms, said heteroaromatic ring systems comprising one or more rings having from 5 to 14 ring atoms wherein at least one ring is aromatic and wherein one or two of the ring atoms are replaced by nitrogen atoms the remaining ring atoms being carbon atoms.
  • heteroaryl groups wherein up to two carbon atoms are replaced by one or two nitrogen atoms comprising one ring include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl and pyrimidinyl groups.
  • heteroaryl rings may optionally also be anellated by a further ring, for example a benzene ring.
  • heteroaryl groups wherein up to two carbon atoms are replaced by one or two nitrogen atoms comprising two rings include indolyl, benzimidazolyl, quinolinyl, isoquinolinyl and quinazolinyl.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • heteroaryl groups may be substituted by the following substituents groups: F; Cl; Br; OH; OMe; Me; Et; CN; NH 2 ; CONH 2 ; optionally substituted phenyl; and optionally substituted heteroaryl, for example optionally substituted pyridyl.
  • cycloalkyl groups includes cycloalkyl groups comprising 1 ring with 3 to 12 carbon atoms.
  • Examples of C 3- i 2 cycoalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • C 3 .i 2 cycloakenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl groups.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • heterocycloalkyl and heterocycloakenyl include 3- to 12-membered, for example 5-, 6- or 7-membered heterocycles, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Heterocycloalkyl denotes a saturated heterocycle
  • heterocycloakenyl denotes an unsaturated heterocycle.
  • heterocycloalkyl or heterocycloakenyl groups examples include tetrahydrofuran, tetrahydrofuranone, g ⁇ mr ⁇ -butyrolactone, alpha-pyran, g ⁇ mm ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiopliene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole, and pyrazolidine.
  • heterocycloalkyl or heterocycloakenyl groups may optionally be replaced by other substituent groups.
  • polycycloalkyl includes cycloalkyl groups comprising 3 to 12 carbon atoms and comprising 2 or more rings.
  • examples of polycycloalkyl groups include optionally substituted, bi-, tri-, tetra- or pentacyclic cycloalkyl groups, for example pinane, 2,2,2-octane, 2,2,1 -heptane or adamantane.
  • polycycloalkenyl unless otherwise stated, includes cycloalkenyl groups comprising 7 to 12 carbon atoms and comprising 2 or more rings wherein at least one ring comprises a carbon-carbon double bond.
  • polycycloalkenyl groups are optionally bridged and/or substituted bi-, tri-, tetra- or pentacyclic cycloalkenyl groups, for example bicycloalkenyl or tricycloalkenyl groups having at least one double bond, such as norbornene.
  • spirocycloalkyl unless otherwise stated, includes spirocycloalkyl groups comprising 5 to 12 carbon atoms and comprising 2 or more rings wherein two rings are joined at a spiro carbon centre. Examples of spirocycloalkyl groups include spiro[4.4]nonyl and spiro[3.4]octyl.
  • 5- or 6-membered aromatic or heteroaromatic ring optionally comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which one or more ring atoms is optionally a heteroatom selected from nitrogen, oxygen or sulfur, with the remaining ring atoms being carbon.
  • Examples of a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur include furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl thiazolyl, thienyl and triazolyl rings.
  • 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms includes optionally substituted C 3-6 cylcoalkyl and optionally substituted C 3 . 6 cylcoalkenyl groups, and optionally substituted 3- to 6-membered heterocylcoalkyl and optionally substituted 3- to 6-membered heterocylcoalkenyl groups each with 1 or 2 heteroatoms.
  • 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms includes optionally substituted 3- to 7-membered heterocylcoalkyl and optionally substituted 3- to 7-membered heterocylcoalkenyl groups each with 1 or 2 heteroatoms
  • halogen includes fluorine, chlorine, bromine or iodine.
  • alkyloxy (-OR wherein R is an alkyl), alkenyloxy (-OR wherein R is an alkenyl), alkynyloxy (-OR wherein R is an alkynyl) and cycloalkyloxy (-OR wherein R is a cycloalkyl) denote an -OR group wherein the respective alkyl, alkenyl, alkynyl or cycloalkyl group is as hereinbefore described above.
  • alkyl-aryl refers to an alkyl group with an aryl substituent.
  • -alkyl-cycloalkyl refers to an alkyl group with a cycloalkyl substituent.
  • -aryl-alkyl refers to an aryl group with an alkyl substituent.
  • R 3 represents a substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or a substituted 3- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, one or more substituents may be present and are as defined above for R 8 .
  • R 5 represents a substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpliolinyl, sulfonylmorpholinyl, thiomorpholinyl, or azacycloheptyl
  • one or more substituents may be present and are as defined above for R 8 .
  • R 5 represents a substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, or azacycloheptyl
  • one or more substituents may be present and are as defined above for R .
  • R 1 to R 9 All the groups mentioned in the definition of R 1 to R 9 , R a to R a6 , and R b to R b3 may optionally be branched and/or substituted.
  • R 2 represents hydrogen or an optionally substituted Ci -6 alkyl group
  • R 3 represents hydrogen, an optionally substituted C 1-12 alkyl group, an optionally substituted C 2- i 2 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C 6- i 4 aryl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted C 3 .]2cycloalkenyl group, an optionally substituted
  • C 7- i 2 polycycloalkyl group an optionally substituted C 7- i 2 polycycloalkenyl group, an optionally substituted Cs- ⁇ spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 3- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms or an optionally substituted 5- or 6-membered heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur, or
  • R 2 and R 3 together represent a saturated or unsaturated C 3-4 alkyl bridge optionally comprising 1 heteroatom;
  • R 4 each independently represent -CN, hydroxy, -NR 6 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted C 3-6 cycloalkyloxy group, an optionally substituted C 2- salkenyloxy group, an optionally substituted C 2-5 alkynyloxy group, an optionally substituted Ci -6 alkythio group, an optionally substituted Ci- ⁇ alkylsulfoxo group or an optionally substituted Ci- ⁇ alkylsulfonyl group, or when p is 2 and when each R is adjacent, both R 4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 or more heteroatoms; p is 0, 1
  • R 5 represents a group selected from among optionally substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR 8 R 9 ;
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted C 1-4 alkyl group;
  • R 8 , R 9 each independently represents hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted -C 1-4 alkyl-C 3-1 ocycloalkyl, an optionally substituted -C 3-10 cycloalkyl, an optionally substituted -C ⁇ -uaryl, an optionally substituted -Ci -4 alkyl-C 6-14
  • R 2 represents hydrogen or an optionally substituted C 1-6 alkyl group
  • R 3 represents hydrogen, an optionally substituted Q. ⁇ alkyl group, an optionally substituted C 2- i 2 alkenyl group, an optionally substituted C 2- j 2 alkynyl group, an optionally substituted C 6-1 4aryl group, an optionally substituted C 3- i 2 cycloalkyl group, an optionally substituted C 3- i 2 cycloalkenyl group, an optionally substituted
  • C 7-12 polycycloalkyl group an optionally substituted C 7- i 2 polycycloalkenyl group, an optionally substituted C5-i 2 spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 3- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms or an optionally substituted 5- or 6-membered heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur, or
  • R 2 and R 3 together represent a saturated or unsaturated C 3-4 alkyl bridge optionally comprising 1 heteroatom;
  • R 4 each independently represent -CN, hydroxy, -NR 6 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted C 3-6 cycloalkyloxy group, an optionally substituted C 2-5 alkenyloxy group, an optionally substituted C 2- salkynyloxy group, an optionally substituted C 1-6 alkythio group, an optionally substituted C 1-6 alkylsulfoxo group or an optionally substituted C 1-6 alkylsulfony 1 group; p is 0, 1 or 2;
  • L represents a linker selected from optionally substituted C 2 -ioalkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 6 . 14 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted optionally substituted C 3- i 2 cycloalkyl, and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2; R 5 represents a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR 8 R 9 ;
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted Ci- 4 alkyl group
  • R 8 , R 9 each independently represents hydrogen, an optionally substituted Ci -6 alkyl, an optionally substituted -Ci -4 alkyl-C 3- i 0 cycloalkyl, an optionally substituted -Q.iocycloalkyl, an optionally substituted -C 6- i 4 aryl, an optionally substituted -Ci- 4 alkyl-C 6- j 4 aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted an optionally substituted -C 6 - 14 arylcarbonyl, an optionally substituted an optionally substituted -C ⁇ - ⁇ arylmethyloxycarbonyl, an optionally substituted -C ⁇ -warylsulfonyl, an optionally substituted -C 1-4 alkylsul
  • R 2 represents hydrogen or an optionally substituted C 1-6 alkyl group
  • R 3 represents hydrogen, an optionally substituted C].i 2 alkyl group, an optionally substituted C 2-12 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C ⁇ - ⁇ aryl group, an optionally substituted C 3 .i 2 cycloalkyl group, an optionally substituted C 3- i 2 cycloalkenyl group, an optionally substituted C 7- i 2 polycycloalkyl group, an optionally substituted C ⁇ npolycycloalkenyl group, an optionally substituted Cs-nspirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 3- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms or an optionally substituted 5- or 6-membered heteroaryl ring comprising
  • heteroatoms each independently selected from nitrogen, oxygen or sulphur, or
  • R 2 and R 3 together represent a saturated or unsaturated C 3 . 4 alkyl bridge optionally comprising 1 heteroatom;
  • R 4a , R 4b and R 4c each independently represent hydrogen, -CN, hydroxy, -NR 6 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted C 3-6 cycloalkyloxy group, an optionally substituted
  • R 5 represents a group selected from among optionally substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR 8 R 9 ;
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted C 1-4 alkyl group
  • R 8 , R 9 each independently represents hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted -Cj -4 alkyl-C3-jocycloalkyl, an optionally substituted
  • the ring Ar represents a phenyl, pyridinyl or isoxazolyl ring. In one embodiment, for compounds of the first and second aspect of the present invention, the ring Ar represents a phenyl ring.
  • the group R 1 represents hydrogen or a methyl or ethyl group.
  • the group R 1 represents a methyl group.
  • the group R 2 represents hydrogen or a C 1-6 alkyl group optionally substituted by one or more substituents selected from Ci_3alkyloxy, Ci -3 alky lthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di- (C 1-3 alkyl)amino.
  • the group R 2 represents hydrogen or a methyl or ethyl group. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the group R 2 represents a methyl or ethyl group.
  • the group R 2 represents an ethyl group.
  • R 3 represents hydrogen; a Ci-i 2 alkyl, for example ethyl, propyl, butyl, pentyl or hexyl, optionally substituted by one or more substituents selected from Ci -3 alkyloxy, Ci. 3 alky.thi0, C 1-3 alkyl-S(O) 2 , Ci. 3 alkylamino and di-(Ci.
  • alkyI)amino a C 2-12 alkenyl, for example C 5-7 alkenyl, optionally substituted by one or more substituents selected from C ⁇ alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C ⁇ -3 alkylamino and di-(C 1-3 alkyl)amino; C 2 .
  • alkynyl for example C 5-7 alkynyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C ⁇ alkylthio, Ci -3 alkyl-S(O) 2 , C ⁇ alkylamino and di-(Ci -3 alkyl)amino; a C 6 .i 4 aryl, for example phenyl, optionally substituted by one or more substituents selected from C ⁇ alkyloxy, Ci. 3 alkylthio, Ci.
  • R 3 represents cyclopentyl
  • R 2 and R 3 together represent a saturated or unsaturated C 3 -C 4 alkyl bridge optionally comprising 1 heteroatom selected from oxygen or nitrogen.
  • R 4 represents a group selected from among -CN; hydroxyl; -NR 6 R 7 ; halogen, for example chlorine or fluorine; C 1-6 alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from halogen, Ci -3 alkyloxy, C ⁇ alkylthio, Ci_ 3 alkyl-S(O) 2 , Ci -3 alkylamino and di-(C 1-3 alkyl)amino; C 2-6 alkenyl, for example ethenyl or propenyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, Ci
  • C ⁇ alkyloxy for example methoxy, ethoxy or propargyloxy, optionally substituted by one or more substituents selected from halogen, Ci -3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C ⁇ alkylamino and di-(Ci -3 alkyl)amino; C 2-5 alkenyloxy optionally substituted by one or more substituents selected from Ci- 3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , Ci -3 alkylamino and di-(C 1-3 alkyl)amino; C 2-5 alkynyloxy optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkylthio, Ci -3 alkyl-S(O) 2 , Ci- 3 alkylamino and di-(C 1-3 alkyl)amino;
  • C 1-6 alkylsulfoxo optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1 _ 3 alkyl)amino and C 1-6 alkylsulfonyl optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C ⁇ alkylthio, Ci-3alkyl-S(O) 2 , Ci -3 alkylamino and di-(Ci -3 alkyl)amino.
  • R 4 represents a group selected from among -CN, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, /-propyl, t-butyl, trifluoromethyl, methoxy, trifluoromethyloxy, difluoromethyloxy, methylthio, trifluoromethylthio, difluoromethylthio, ethoxy, propyloxy, i- propyloxy,
  • R 4 represents a group selected from among -CN; hydroxyl; -NR 6 R 7 ; halogen, for example chlorine or fluorine; C 1-6 alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from Ci -3 alkyl- S(O) 2 , C]_ 3 alkylamino and di-(C 1-3 alkyl)amino; C 2-6 alkenyl, for example ethenyl or propenyl, optionally substituted by one or more substituents selected from C ⁇ alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , Ci.
  • halogen for example chlorine or fluorine
  • C 1-6 alkyl for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from Ci -3 alkyl- S(O) 2 , C]_ 3 alkylamino and di-(C
  • C 2-6 alkynyl for example ethynyl, propynyl or butynyl, optionally substituted by one or more substituents selected from Ci -3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , d ⁇ alkylamino and di-(Ci -3 alkyl)amino
  • C 1-5 alkyloxy for example methoxy, ethoxy or propargyloxy, optionally substituted by one or more substituents selected from C ⁇ alkyloxy, C 1 .
  • R 4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine.
  • R 4 represents methoxy, methyl, ethoxy, ethyl, chlorine or fluorine.
  • R 4 represents methoxy. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1 , R 4 represents methyl.
  • R 4 represents ethoxy
  • R 4 represents ethyl. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R 4 represents propargyloxy.
  • R 4 represents chlorine. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R 4 represents fluorine.
  • each R may be the same or different and selected from methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine or fluorine.
  • p 2 and when each R 4 is adjacent, both R 4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 or more heteroatoms.
  • the heteroatoms are selected from oxygen, sulphur or nitrogen.
  • both R 4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 to 2 heteroatoms.
  • R 4a and R 4b together with the carbon ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 or more heteroatoms.
  • the heteroatoms are selected from oxygen, sulphur or nitrogen.
  • R 4b and R 4c are hydrogen and R 4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine.
  • R 4b and R 4c are hydrogen and R 4a represents methoxy, methyl, ethoxy, chlorine or fluorine.
  • R and R c are hydrogen and R 4a represents methoxy.
  • R 4b and R 4c are hydrogen and R 4a represents methyl.
  • R 4b and R 4c are hydrogen and R 4a represents ethoxy.
  • R 4b and R 4c are hydrogen and R 4a represents chlorine.
  • R 4 and R c are hydrogen and R 4a represents fluorine.
  • R 4b is hydrogen and R a and R 4Q may be the same or different and selected from methoxy, chlorine or fluorine.
  • R 4b is hydrogen and R 4a and R 4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine.
  • R 4b is hydrogen
  • R 4c is fluorine
  • R 4a is selected from methoxy, chlorine or fluorine.
  • R 4c is hydrogen and R 4a and R 4b together form a OCH 2 O bridge.
  • L represents a linker selected from among Ct.ioalkyl, for example methyl, ethyl, propyl, butyl or pentyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, Ci -3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; C 2-1 oalkenyl, optionally substituted by one or more substituents selected from C ⁇ alkyloxy, Ci -3 alky lthio,
  • Ci- 3 alkyl-S(O) 2 Ci_ 3 alkylamino and di-(Ci. 3 alkyl)amino; C 6- i 4 aryl, for example phenyl, optionally substituted by one or more substituents selected from
  • Ci -3 alkyl-S(O) 2 Cj -3 alkylamino and di-(Ci -3 alkyl)amino; -C 2-4 alkyl-C 6-14 aryl optionally substituted by one or more substituents selected from Cj -3 alkyloxy, Ci -3 alkyl-
  • L represents a linker selected from among C 2 _i O alkyl, for example ethyl, propyl, butyl or pentyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci- 3 alkylthio, Ci -3 alkyl-S(O)2, Ci -3 alkylamino and di-(C 1-3 alkyl)amino; C 2- ioalkenyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkylthio, Ci- 3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; C 6- i 4 aryl, for example phenyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S
  • L represents an optionally substituted C 1-10 alkyl or C 3-12 cycloalkyl linker.
  • L represents an optionally substituted a C 2-10 alkyl linker.
  • L represents -C(CHb) 2 -CH 2 -, -CH 2 -C(CH 3 ) 2 -CH 2 - or a cyclohexyl linker.
  • L represents -C(CH 3 ) 2 -CH 2 - or -CH 2 -C(CH 3 ) 2 -CH 2 -.
  • L represents a cyclohexyl linker.
  • n is 0. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, m is 1.
  • R 5 represents a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR 8 R 9 .
  • R 5 represents a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -NR 8 R 9 and azacycloheptyl wherein each morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -NR 8 R 9 and azacycloheptyl is optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted granatanyl, optionally substituted oxogranatanyl -NR 8 R 9 and optionally substituted azacycloheptyl wherein each morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulphoxomorpholinyl, s
  • R 5 represents piperidinyl, morpholinyl, pyrrolidinyl, sulfoxomorpholinyl, piperazinyl, thiomorpholinyl or tropenyl each optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents hydrogen, -NR 8 R 9 or a piperidinyl, morpholinyl, pyrrolidinyl, sulphoxomorpholiny, piperazinyl, thiomorpholinyl, tropenyl, granatanyl, oxogranatanyl or azacycloheptyl each optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents piperidinyl optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents piperidinyl which is bound to L by carbon and optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents piperidinyl which is bound to L by carbon and substituted on nitrogen by R 8 .
  • R 5 represents pyrrolidinyl optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents pyrrolidinyl which is bound to L by carbon and optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents pyrrolidinyl which is bound to L by carbon and substituted on nitrogen by R 8 .
  • R represents granatanyl optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents granatanyl which is bound to L by carbon and optionally substituted by one or more groups as defined for R 8 . In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R 5 represents granatanyl which is bound to L by carbon and substituted on nitrogen by R 8 .
  • the groups R 6 and R 7 may be identical or different and represent hydrogen or for example methyl or ethyl.
  • the groups R 8 and R 9 may be identical or different and represent hydrogen; a C 1- ⁇ alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from Ci -3 alkyloxy, C 1-3 alkylthio, Ci -3 alkyl-S(O) 2 , C 1-3 alkylamino and di- (C 1-3 alkyl)amino; -C 1-4 alkyl-C 3-1 ocycloalkyl, for example -CH 2 -cyclopropyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkylthio, Ci -3 alkyl- S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; C 3- iocycloalkyl optionally substituted by one or more substituents selected from C ⁇ alkyl, for example methyl, ethyl or propyl, optional
  • R 9 represents methyl, ethyl or propyl.
  • n is 1 and L is an optionally substituted C 1-10 alkyl or C 3-12 cycloalkyl linker. In another embodiment, for the compound of formula (I), (II) or (Ha), n is 1 and L is an optionally substituted C 2-10 alkyl linker. In another embodiment, for the compound of formula (I), (II) or (Ha), n is 0 and m is 1.
  • R 2 to R 4 , R 6 and R 7 are as hereinbefore defined; and L represents a linker selected from among optionally substituted C 1-10 alkyl, optionally substituted C 2- ioalkenyl, optionally substituted C 6-14 aryl, optionally substituted -C 2- 4alkyl-C 6-14 aryl, optionally substituted -C 6- i 4 aryl-C 1-4 alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 1; m denotes 1 or 2; R 5 denotes a group which is bound to L via a nitrogen atom, selected from optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl,
  • R 2 to R 4 , R and R 7 are as hereinbefore defined; and L represents a linker selected from among optionally substituted C 2-10 alkyl, optionally substituted C 2-1 oalkenyl, optionally substituted C 6-14 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted -C 6 -i 4 aryl-C 1-4 alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 1; m denotes 1 or 2; R 5 denotes a group which is bound to L via a nitrogen atom, selected from optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl,
  • L represents a linker selected from optionally substituted d-ioalkyl, optionally substituted C 2- ] 0 alkenyl, optionally substituted C 6- i 4 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted -C 6-14 aryl-C 1-4 alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1 ; m denotes 1 or 2; R 5 denotes a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl and azacycloh
  • L represents a linker selected from optionally substituted C 2 , 10 alkyl, optionally substituted C 2-]0 alkenyl, optionally substituted C 6-14 aryl, optionally substituted -C 2-4 alkyl-C 6- i 4 aryl, optionally substituted -C 6-14 aryl-C 1-4 alkyl, optionally substituted C 3- i 2 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1 ; m denotes 1 or 2; R 5 denotes a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl and azacycloh
  • R 2 to R 4 , R 6 and R 7 are as hereinbefore defined;
  • L represents a linker selected from optionally substituted Cnoalkyl, optionally substituted C 2 -ioalkenyl, optionally substituted C6-i 4 aryl, optionally substituted -C 2-4 alkyl-C 6- i 4 aryl, optionally substituted -C 6-14 aryl-C 1- 4alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1 ; m denotes 1 or 2; R 5 denotes a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazin
  • R 2 , m, n and R 5 to R 8 are as hereinbefore defined; and R 3 represents an optionally substituted d-ioalkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl or optionally substituted C 6- i 4 aryl group or R 2 and R 3 together represent a saturated or unsaturated C 3-4 alkyl bridge optionally comprising 1 or 2 heteroatoms; R 4 represents hydrogen, OMe, OH, Me, Et, Pr, OEt, NHMe, NH 2 , F, Cl, Br, O-propargyl, O-butynyl, CN, SMe, NMe 2 , CONH 2 , ethynyl, propynyl, butynyl and allyl; and L denotes a linker selected from among optionally substituted phenyl
  • R 2 represents hydrogen or a methyl or ethyl group
  • R 3 represents isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl
  • p is 1 or 2
  • R 4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, fluorine or chlorine
  • m is 0
  • n is 1
  • R 5 denotes a group selected from piperidinyl, morpholinyl, pyrrolidinyl, sulfoxomorpholinyl, piperazinyl, thiomorpholinyl or tropenyl each optionally substituted by one or more groups as defined for R 8
  • R 8 is methyl, ethyl or propyl, or pharmacologically acceptable salts thereof.
  • R 2 represents a methyl or ethyl group
  • R 3 represents a cyclopentyl
  • p is 0, 1 or 2
  • each R 4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, fluorine or chlorine, or two adjacent R 4 are linked to form an OCH 2 O bridge
  • m is 0
  • n is 1
  • R 5 denotes a group selected from piperidinyl, morpholinyl, granatanyl, oxogranatanyl, pyrrolidinyl, sulfoxomorpholinyl, piperazinyl, thiomorpholinyl and tropenyl each optionally substituted by one or more groups as defined for R 8
  • R 8 is methyl, ethyl or propyl, or pharmacologically acceptable salts thereof.
  • R 2 represents an ethyl group
  • R 3 represents a cyclopentyl
  • p is 0, 1 or 2
  • each R 4 represents methoxy, methyl, fluorine or chlorine, or two adjacent R 4 are linked to form an OCH 2 O bridge
  • m is 0 or 1
  • L represents a linker selected from optionally substituted Cj.ioalkyl or optionally substituted C 3-12 cycloalkyl
  • n is 1
  • R 5 denotes a group selected from NR 8 R 9 , piperidinyl, granatanyl and pyrrolidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 and R 9 are each independently methyl, ethyl or propyl, or pharmacologically acceptable salts thereof.
  • R 2 represents an ethyl group
  • R 3 represents a cyclopentyl
  • p is 0, 1 or 2
  • each R 4 represents methoxy, methyl, fluorine or chlorine, or two adjacent R 4 are linked to form an OCH 2 O bridge
  • m is 0 or 1
  • L is cyclohexyl
  • n is 1
  • R 5 denotes a group selected from NR 8 R 9 , piperidinyl, granatanyl and pyrrolidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 and R 9 are each independently methyl, ethyl or propyl, or pharmacologically acceptable salts thereof.
  • R 2 represents a Ci_ 3 alkyl group
  • R 3 represents an optionally substituted C 1-10 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl
  • L represents a linker selected from optionally substituted Ci_ioalkyl or optionally substituted C 3 _i 2 cycloalkyl
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR 8 R 9 and piperidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent C 1-6 alkyl
  • R 4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine
  • R 4b is hydrogen
  • R 2 represents a C 1-B aIlCyI group
  • R 3 represents an optionally substituted CMoalkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl
  • L represents a linker selected from optionally substituted C 1-10 alkyl or optionally substituted C 3- i 2 cycloalkyl
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR S R 9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent C 1-6 alkyl
  • R 4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine
  • R 4b or R 4c is hydrogen
  • R 2 is C 1-3 alkyl group
  • R 3 represents an optionally substituted Q.ioalkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl
  • L represents a linker selected from optionally substituted Cj.joalkyl or optionally substituted C 3- i 2 cycloalkyl
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR 8 R and granatanyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent C 1-6 alkyl
  • R 4a represents methoxy, methyl, ethoxy, chlorine or fluorine
  • R 4b is hydrogen
  • R represents an ethyl group
  • R represents a cyclopentyl
  • L represents a cyclohexyl linker
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR R and piperidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent methyl or ethyl groups
  • R 4a represents hydrogen, methoxy, chlorine or fluorine
  • R 4b is hydrogen
  • R 4c is fluorine
  • R 4a is selected from methoxy, chlorine or fluorine, or when R 4c is hydrogen, R 4a and R 4b together form a OCH 2 O bridge, or pharmacologically acceptable salts thereof.
  • R 2 represents an ethyl group
  • R 3 represents a cyclopentyl
  • L represents a cyclohexyl linker
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR R 9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent methyl or ethyl groups
  • R 4a represents hydrogen, methoxy, chlorine or fluorine
  • R 4a is selected from methoxy, chlorine or fluorine, or when R 4c is hydrogen, R 4a and R 4b together form a OCH 2 O bridge, or pharmacologically acceptable salts thereof.
  • R 2 represents an ethyl group
  • R 3 represents a cyclopentyl
  • L represents a cyclohexyl linker
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR 8 R 9 and granatanyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent methyl or ethyl groups
  • R 4a represents hydrogen, methoxy, chlorine or fluorine
  • R 4b is hydrogen
  • R 4c is fluorine
  • R 4a is selected from methoxy, chlorine or fluorine, or when R 4 ° is hydrogen, R 4a and R 4b together form a OCH 2 O bridge, or pharmacologically acceptable salts thereof.
  • R represents an ethyl group
  • R represents a cyclopentyl
  • n denotes 0
  • m denotes 1 or 2
  • R 5 denotes a pyrrolidinyl optionally substituted by one or more groups as defined for R
  • R represent a methyl or ethyl group
  • R 4a represents hydrogen, methoxy, chlorine or fluorine
  • R 4c is fluorine
  • R 4a is selected from methoxy, chlorine or fluorine, or when R 4c is hydrogen, R 4a and R 4b together form a OCH 2 O bridge, or pharmacologically acceptable salts thereof.
  • R 2 represents an ethyl group
  • R 3 represents a cyclopentyl
  • n denotes 0
  • m denotes 1 or 2
  • R 5 denotes a granatanyl optionally substituted by one or more groups as defined for R
  • R represents a methyl or ethyl group
  • R 4a represents hydrogen, methoxy, chlorine or fluorine
  • R 4c is fluorine
  • R 4a is selected from methoxy, chlorine or fluorine, or when R 4c is hydrogen, R 4a and R 4b together form a OCH 2 O bridge, or pharmacologically acceptable salts thereof.
  • a particular compound of the invention is the compound of Examples 1 or the pharmacologically acceptable salts thereof.
  • particular compounds of the invention are compounds selected from any of the Examples or the pharmacologically acceptable salts thereof.
  • particular compounds of the invention are compounds selected from any of Examples 1, 136, 179, 180, 181, 182, 183, 184, 185, 186,
  • particular compounds of the invention are compounds selected from any of Examples 1, 179, 180, 181, 182, 183, 189, 190, 192, 193, 197, 198, 199, 201, 204, 209, 211, 212 and 213, or the pharmacologically acceptable salts thereof.
  • the compounds according to the first, second, third, fourth and fifth aspects of the invention may be present in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers and also in the form of the free bases or the corresponding salts with pharmacologically acceptable acids, such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulfonic acid.
  • pharmacologically acceptable acids such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulfonic acid.
  • the compounds of formula (I), (II) or (Ha) above may be converted to a pharmaceutically acceptable salt or solvate thereof, for example, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate salt, or a metal salt such as a calcium, magnesium, sodium or potassium salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate salt
  • a metal salt such as a calcium, magnesium, sodium or potassium salt.
  • Certain compounds of formula (I), (II) or (Ha) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I), (II) or (Ha) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention.
  • the invention also relates to a process for preparing a compound of general formula (H) 5
  • R 4 is as hereinbefore defined; and R 10 denotes OH, NH-L m -R 5 n , OMe, OEt, and, when R 10 denotes OH, OMe or OEt, optionally after previous hydrolysis of the ester group -COR 10 , reacting with an amine of general formula (VI):
  • R 5 , L and m are as hereinbefore defined to give a compound of formula (II).
  • R 10 is a substituent selected from among OH, NH-LR 5 , -O-methyl and -O-ethyl.
  • leaving group includes leaving groups such as for example -O-methyl, -SCN, fluoride, chloride, bromide, iodide, methanesulfonyl, trifluoromethanesulfonyl or j ⁇ -toluenesulfonyl.
  • the leaving group A is chloride.
  • reaction of a compound of formula (III) with a compound of formula (IV) may be carried out in the presence of an acid, for example a Bronsted acid such as p-toluene sulfonic acid or hydrochloric acid, or in the presence of a suitable palladium catalyst, for example palladium acetate, with an appropriate ligand, for example 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, and a base, for example caesium carbonate, Alternatively, there is provided a process for preparing a compound of general formula (II),
  • R 10 is a substituent selected from among OH, NH-LR 5 , -O-methyl and -O-ethyl.
  • leaving group includes leaving groups such as for example -O-methyl, -SCN, fluoride, chloride, bromide, iodide, methanesulfonyl, trifluoromethanesulfonyl or j9-toluenesulfonyl.
  • the leaving group A is chloride.
  • a compound of formula (I) may be prepared by reacting a compound of general formula (III), (III) wherein R 2 and R 3 are as hereinbefore defined and A is a leaving group, with an optionally substituted compound of general formula (IVa):
  • Methylating reagents are described in Compendium of Organic Synthesis, vol 1, page 202 and include the use methyl iodide in the presence of a base, for example sodium hydride.
  • a base for example sodium hydride.
  • Compounds of Formula (VIII) may be obtained by the reduction and cyclisation of a compound of formula (IX)
  • R 2 to R 4 , and A are as hereinbefore defined.
  • Conditions for the reduction and coupling of a compound of formula (IX) include reduction and coupling with Fe powder and acetic acid;
  • compounds of Formula (VIII) may be obtained by the cyclisation of a compound of formula (X)
  • R 0 is a C 1-2 alkyl group
  • R 2 to R 4 , and A are as hereinbefore defined.
  • the protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene and P.G.M. Wuts, Wiley Interscience (1999).
  • the invention further relates to compounds of formula (I), (II) or (Ha) for use as pharmaceutical compositions.
  • compounds of formula (I), (II) or (Ha) are of use as pharmaceutical compositions with an antiproliferative activity.
  • the invention also relates to the use of a compound of formula (I), (II) or (Ha) for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
  • PIk inhibitors should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • PIk inhibitors should be useful in the treatment of other disorders associated with uncontrolled cellular proliferation.
  • One aspect of the current invention therefore relates to the use of one or more of the compounds of formula (I), (II) or (Ha) in the treatment of disorders characterised by excessive or anomalous cell proliferation.
  • diseases include for example: viral infections such as HIV and Kaposi's sarcoma; inflammatory and autoimmune diseases such as colitis, rheumatoid arthritis, Alzheimer's disease, glomerulonephritis and wound healing; bacterial, fungal and parasitic infections such as malaria and emphysema; dermatological diseases such as psoriasis; bone diseases; cardiovascular diseases such as restenosis and cardiomyopathy.
  • the compounds in the present invention may be used for the prevention, short- or long-term treatment of the above- mentioned diseases, also in combination with other active substances used for the same indications.
  • the invention also relates to a method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective amount of a compound of formula (I) 5 (II) or (Ha).
  • the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), (II) or (Ha), or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
  • the compounds of formula (I) and (II) have activity as pharmaceuticals, in particular as modulators or inhibitors of PIk activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:
  • carcinoma including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin;
  • lymphoid lineage including acute lymphocytic leukaemia, B cell lymphoma and Burketts lymphoma;
  • hematopoietic tumours of myeloid lineage including acute and chronic myelogenous leukaemias and promyelocytic leukaemia;
  • tumours of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma; and (5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
  • the compounds of formula (I) and (II) are useful in the treatment of tumours of the lung, breast and prostate.
  • the present invention provides a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the invention still further provides a method of modulating polo-like kinase (PIk) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • PIk polo-like kinase
  • solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (II) or (Ha) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99%w (per cent by weight), more preferably from 0.05 to
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate and anti oxidants such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents such as
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p- hydroxybenzoate, anti oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p- hydroxybenzoate, anti oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil in water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the size of the dose for therapeutic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used.
  • a dose in the range, for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
  • anti cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* -reductase such as finasteride; (iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6- chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperaz
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy;
  • GDEPT gene directed enzyme pro drug therapy
  • immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using ami idiotypic antibodies; and (x) other inhibitors of cell cycle such as Eg5, Chkl or PARP inhibitors.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor
  • approaches to decrease T cell anergy approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using ami idiotypic antibodies
  • other inhibitors of cell cycle such as Eg5, Chkl or PARP inhibitors.
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz or 500MHz, in CDCl 3 , DMSOd 6 or DMSO-d ⁇ + d 4 -AcOH unless otherwise indicated;
  • MS Mass spectra
  • HPLC component comprised generally either an Agilent 1100, Waters Alliance HT (2790 & 2795) equipment or an HPIlOO pump and Diode Array with CTC autosampler and was run on a Phenomenex Gemini Cl 8 5mm, 50 x 2 mm column (or similar) eluting with either acidic eluent (for example, using a gradient between 0 - 95% water / acetonitrile with 5% of a 1% formic acid in 50:50 wate ⁇ acetonitrile (v/v) mixture; or using an equivalent solvent system with methanol instead of acetonitrile), or basic eluent (for example, using a gradient between 0 - 95% water / acetonitrile with 5% of a 0.1% 880 Ammonia in acetonitrile mixture); and the MS component comprised generally a Waters ZQ mass spect
  • Example 15 10-cyclopentyl-3-[(3,4-dimethylphenyl)amino]-9-ehtyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
  • Example 18 3-[(3-chloro-5-fluoro-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
  • Example 21 10-cyclopentyl-9-ethyl-7-methyl-3-[ [3-(trifluoromethyl)phenyl] amino]-2,4,7,9, 10- pentazabicyclo [4.4.0] deca- 1 ,3 ,5-trien-8-one
  • Example 36 N-[4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino] -2-methyl-phenyl] acetamide
  • Example 39 N-[4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino] -5-methoxy-2-methyl-phenyl] benzamide
  • Example 42 3-[(3-chloro-2-methyl-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
  • Example 51 3-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3 ⁇ yl)amino] benzamide
  • Example 59 10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(1,3-oxazol-5-yl)phenyl]amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
  • Example 61 10-cycIopentyl-9-ethyl-7-methyl-3-[(4-pyrazol-1-ylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
  • Example 71 10-cyclopentyl-9-ethyl-7-methyl-3-[(3-phenylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
  • Example 75 10-cyclopentyl-9-ethyl-7-methyl-3-[(3-methylphenyl)amino]-2,4,7,9,10- pentazabicycIo[4.4.0]deca-l,3,5-trien-8-one
  • Example 90 5-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-1,3,5- trien-3-yl)amino]-2-methyl-benzonitrile
  • Example 108 3-[(4-benzylphenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
  • Example 177 10-cyclopentyl-9-ethyl-3-(1H-indazol-7-ylamino)-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-2,4,11-trien-8-one
  • reaction mixture was diluted with water (2 mL) and methanol (5 mL) and solution submitted to ion exchange chromatography, using an SCX-2 column (5 g).
  • the column was eluted through with methanol (40 ml) before the crude product was eluted from the column
  • Example 181 4- [(5-cy clopentyM-ethyl ⁇ -methyl-S-oxo ⁇ S ⁇ P-pentazabicycIo [4.4.0] deca-6,8,10- trien-8-yl)amino]-N-(l-methyl-4-piperidyl)benzamide

Abstract

Il est proposé un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Il est également proposé un procédé pour la fabrication du composé de formule (I) et l'utilisation du composé de formule (I) comme médicament et dans le traitement du cancer.
PCT/GB2007/003719 2006-10-03 2007-10-02 Composés WO2008040951A1 (fr)

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WO2011018518A1 (fr) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Préparation régiosélective de dérivés de 2-amino-5trifluorométhylpyrimidine
CN103570699A (zh) * 2013-09-29 2014-02-12 北京万全德众医药生物技术有限公司 一种制备普卡必利的方法
US8785464B2 (en) 2008-11-24 2014-07-22 Boehringer Ingelheim International Gmbh Pyrimidine derivatives that inhibit FAK/PTK2
US8846689B2 (en) 2008-11-24 2014-09-30 Boehringer Ingelheim International Gmbh Substituted pyrimidines for the treatment of diseases such as cancer
US9351974B2 (en) 2011-11-10 2016-05-31 OSI Pharmaceuticals, LLC Substituted pteridinones for the treatment of cancer
JP2019510801A (ja) * 2016-04-07 2019-04-18 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッドＤａｎａ−Ｆａｒｂｅｒ Ｃａｎｃｅｒ Ｉｎｓｔｉｔｕｔｅ， Ｉｎｃ． ピリミド−ジアゼピノンキナーゼ骨格化合物およびｐｉ３ｋ媒介性障害の治療方法
WO2021174165A1 (fr) * 2020-02-28 2021-09-02 Remix Therapeutics Inc. Amides hétérocycliques et leur utilisation pour moduler l'épissage
WO2023034812A1 (fr) * 2021-08-30 2023-03-09 Remix Therapeutics Inc. Composés et procédés de modulation de l'épissage

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8785464B2 (en) 2008-11-24 2014-07-22 Boehringer Ingelheim International Gmbh Pyrimidine derivatives that inhibit FAK/PTK2
US8846689B2 (en) 2008-11-24 2014-09-30 Boehringer Ingelheim International Gmbh Substituted pyrimidines for the treatment of diseases such as cancer
US9676762B2 (en) 2008-11-24 2017-06-13 Boehringer Ingelheim International Gmbh Pyrimidine compounds containing seven-membered fused ring systems
WO2011018518A1 (fr) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Préparation régiosélective de dérivés de 2-amino-5trifluorométhylpyrimidine
US9351974B2 (en) 2011-11-10 2016-05-31 OSI Pharmaceuticals, LLC Substituted pteridinones for the treatment of cancer
CN103570699A (zh) * 2013-09-29 2014-02-12 北京万全德众医药生物技术有限公司 一种制备普卡必利的方法
JP2019510801A (ja) * 2016-04-07 2019-04-18 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッドＤａｎａ−Ｆａｒｂｅｒ Ｃａｎｃｅｒ Ｉｎｓｔｉｔｕｔｅ， Ｉｎｃ． ピリミド−ジアゼピノンキナーゼ骨格化合物およびｐｉ３ｋ媒介性障害の治療方法
WO2021174165A1 (fr) * 2020-02-28 2021-09-02 Remix Therapeutics Inc. Amides hétérocycliques et leur utilisation pour moduler l'épissage
CN115515679A (zh) * 2020-02-28 2022-12-23 雷密克斯医疗公司 杂环酰胺及其用于调节剪接的用途
WO2023034812A1 (fr) * 2021-08-30 2023-03-09 Remix Therapeutics Inc. Composés et procédés de modulation de l'épissage

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